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+{"_id": "4983", "title": "", "text": "Microstructural development of human newborn cerebral white matter assessed in vivo by diffusiontensor magnetic resonance imaging.Alterations of the architecture of cerebral white matter in thedeveloping human brain can affect cortical development and result in functional disabilities. A line scandiffusion-weighted magnetic resonance imaging (MRI) sequence with diffusion tensor analysis wasapplied to measure the apparent diffusion coefficient, to calculate relative anisotropy, and to delineatethree-dimensional fiber architecture in cerebral white matter in preterm (n = 17) and full-term infants (n= 7). To assess effects of prematurity on cerebral white matter development, early gestation preterminfants (n = 10) were studied a second time at term. In the central white matter the mean apparentdiffusion coefficient at 28 wk was high, 1.8 microm2/ms, and decreased toward term to 1.2 microm2/ms.In the posterior limb of the internal capsule, the mean apparent diffusion coefficients at both times weresimilar (1.2 versus 1.1 microm2/ms). Relative anisotropy was higher the closer birth was to term withgreater absolute values in the internal capsule than in the central white matter. Preterm infants at termshowed higher mean diffusion coefficients in the central white matter (1.4 +/- 0.24 versus 1.15 +/- 0.09microm2/ms, p = 0.016) and lower relative anisotropy in both areas compared with full-term infants(white matter, 10.9 +/- 0.6 versus 22.9 +/- 3.0%, p = 0.001; internal capsule, 24.0 +/- 4.44 versus33.1 +/- 0.6% p = 0.006). Nonmyelinated fibers in the corpus callosum were visible by diffusion tensorMRI as early as 28 wk; full-term and preterm infants at term showed marked differences in white matterfiber organization. The data indicate that quantitative assessment of water diffusion by diffusion tensorMRI provides insight into microstructural development in cerebral white matter in living infants.", "metadata": {}}
+{"_id": "5836", "title": "", "text": "Induction of myelodysplasia by myeloid-derived suppressor cells.Myelodysplastic syndromes (MDS) areage-dependent stem cell malignancies that share biological features of activated adaptive immuneresponse and ineffective hematopoiesis. Here we report that myeloid-derived suppressor cells (MDSC),which are classically linked to immunosuppression, inflammation, and cancer, were markedly expanded inthe bone marrow of MDS patients and played a pathogenetic role in the development of ineffectivehematopoiesis. These clonally distinct MDSC overproduce hematopoietic suppressive cytokines andfunction as potent apoptotic effectors targeting autologous hematopoietic progenitors. Using multipletransfected cell models, we found that MDSC expansion is driven by the interaction of theproinflammatory molecule S100A9 with CD33. These 2 proteins formed a functional ligand/receptor pairthat recruited components to CD33’s immunoreceptor tyrosine-based inhibition motif (ITIM), inducingsecretion of the suppressive cytokines IL-10 and TGF-β by immature myeloid cells. S100A9 transgenicmice displayed bone marrow accumulation of MDSC accompanied by development of progressivemultilineage cytopenias and cytological dysplasia. Importantly, early forced maturation of MDSC by eitherall-trans-retinoic acid treatment or active immunoreceptor tyrosine-based activation motif–bearing(ITAM-bearing) adapter protein (DAP12) interruption of CD33 signaling rescued the hematologicphenotype. These findings indicate that primary bone marrow expansion of MDSC driven by theS100A9/CD33 pathway perturbs hematopoiesis and contributes to the development of MDS.", "metadata": {}}
+{"_id": "7912", "title": "", "text": "BC1 RNA, the transcript from a master gene for ID element amplification, is able to prime its own reversetranscription.ID elements are short interspersed elements (SINEs) found in high copy number in manyrodent genomes. BC1 RNA, an ID-related transcript, is derived from the single copy BC1 RNA gene. TheBC1 RNA gene has been shown to be a master gene for ID element amplification in rodent genomes. IDelements are dispersed through a process termed retroposition. The retroposition process involves anumber of potential regulatory steps. These regulatory steps may include transcription in the appropriatetissue, transcript stability, priming of the RNA transcript for reverse transcription and integration. Thisstudy focuses on priming of the RNA transcript for reverse transcription. BC1 RNA gene transcripts areshown to be able to prime their own reverse transcription in an efficient intramolecular and site-specificfashion. This self-priming ability is a consequence of the secondary structure of the 3'-unique region. Theobservation that a gene actively amplified throughout rodent evolution makes a RNA capable of efficientself-primed reverse transcription strongly suggests that self-priming is at least one feature establishingthe BC1 RNA gene as a master gene for amplification of ID elements.", "metadata": {}}
+{"_id": "18670", "title": "", "text": "The DNA Methylome of Human Peripheral Blood Mononuclear CellsDNA methylation plays an importantrole in biological processes in human health and disease. Recent technological advances allow unbiasedwhole-genome DNA methylation (methylome) analysis to be carried out on human cells. Usingwhole-genome bisulfite sequencing at 24.7-fold coverage (12.3-fold per strand), we report acomprehensive (92.62%) methylome and analysis of the unique sequences in human peripheral bloodmononuclear cells (PBMC) from the same Asian individual whose genome was deciphered in the YHproject. PBMC constitute an important source for clinical blood tests world-wide. We found that 68.4% ofCpG sites and <0.2% of non-CpG sites were methylated, demonstrating that non-CpG cytosinemethylation is minor in human PBMC. Analysis of the PBMC methylome revealed a rich epigenomiclandscape for 20 distinct genomic features, including regulatory, protein-coding, non-coding, RNA-coding,and repeat sequences. Integration of our methylome data with the YH genome sequence enabled a firstcomprehensive assessment of allele-specific methylation (ASM) between the two haploid methylomes ofany individual and allowed the identification of 599 haploid differentially methylated regions (hDMRs)covering 287 genes. Of these, 76 genes had hDMRs within 2 kb of their transcriptional start sites of which>80% displayed allele-specific expression (ASE). These data demonstrate that ASM is a recurrentphenomenon and is highly correlated with ASE in human PBMCs. Together with recently reported similarstudies, our study provides a comprehensive resource for future epigenomic research and confirms newsequencing technology as a paradigm for large-scale epigenomics studies.", "metadata": {}}
+{"_id": "19238", "title": "", "text": "The human myelin basic protein gene is included within a 179-kilobase transcription unit: expression inthe immune and central nervous systems.Two human Golli (for gene expressed in the oligodendrocytelineage)-MBP (for myelin basic protein) cDNAs have been isolated from a human oligodendroglioma cellline. Analysis of these cDNAs has enabled us to determine the entire structure of the human Golli-MBPgene. The Golli-MBP gene, which encompasses the MBP transcription unit, is approximately 179 kb inlength and consists of 10 exons, seven of which constitute the MBP gene. The human Golli-MBP genecontains two transcription start sites, each of which gives rise to a family of alternatively splicedtranscripts. At least two Golli-MBP transcripts, containing the first three exons of the gene and one ormore MBP exons, are produced from the first transcription start site. The second family of transcriptscontains only MBP exons and produces the well-known MBPs. In humans, RNA blot analysis revealed thatGolli-MBP transcripts were expressed in fetal thymus, spleen, and human B-cell and macrophage celllines, as well as in fetal spinal cord. These findings clearly link the expression of exons encoding theautoimmunogen/encephalitogen MBP in the central nervous system to cells and tissues of the immunesystem through normal expression of the Golli-MBP gene. They also establish that this genetic locus,which includes the MBP gene, is conserved among species, providing further evidence that the MBPtranscription unit is an integral part of the Golli transcription unit and suggest that this structuralarrangement is important for the genetic function and/or regulation of these genes.", "metadata": {}}
+{"_id": "33370", "title": "", "text": "Targeting A20 Decreases Glioma Stem Cell Survival and Tumor GrowthGlioblastomas are deadly cancersthat display a functional cellular hierarchy maintained by self-renewing glioblastoma stem cells (GSCs).GSCs are regulated by molecular pathways distinct from the bulk tumor that may be useful therapeutictargets. We determined that A20 (TNFAIP3), a regulator of cell survival and the NF-kappaB pathway, isoverexpressed in GSCs relative to non-stem glioblastoma cells at both the mRNA and protein levels. Todetermine the functional significance of A20 in GSCs, we targeted A20 expression with lentiviral-mediateddelivery of short hairpin RNA (shRNA). Inhibiting A20 expression decreased GSC growth and survivalthrough mechanisms associated with decreased cell-cycle progression and decreased phosphorylation ofp65/RelA. Elevated levels of A20 in GSCs contributed to apoptotic resistance: GSCs were less susceptibleto TNFalpha-induced cell death than matched non-stem glioma cells, but A20 knockdown sensitized GSCsto TNFalpha-mediated apoptosis. The decreased survival of GSCs upon A20 knockdown contributed to thereduced ability of these cells to self-renew in primary and secondary neurosphere formation assays. Thetumorigenic potential of GSCs was decreased with A20 targeting, resulting in increased survival of micebearing human glioma xenografts. In silico analysis of a glioma patient genomic database indicates thatA20 overexpression and amplification is inversely correlated with survival. Together these data indicatethat A20 contributes to glioma maintenance through effects on the glioma stem cell subpopulation.Although inactivating mutations in A20 in lymphoma suggest A20 can act as a tumor suppressor, similarpoint mutations have not been identified through glioma genomic sequencing: in fact, our data suggestA20 may function as a tumor enhancer in glioma through promotion of GSC survival. A20 anticancertherapies should therefore be viewed with caution as effects will likely differ depending on the tumortype.", "metadata": {}}
+{"_id": "36474", "title": "", "text": "Efficient targeting of expressed and silent genes in human ESCs and iPSCs using zinc-fingernucleasesRealizing the full potential of human embryonic stem cells (hESCs) and induced pluripotentstem cells (hiPSCs) requires efficient methods for genetic modification. However, techniques to generatecell type–specific lineage reporters, as well as reliable tools to disrupt, repair or overexpress genes bygene targeting, are inefficient at best and thus are not routinely used. Here we report the highly efficienttargeting of three genes in human pluripotent cells using zinc-finger nuclease (ZFN)–mediated genomeediting. First, using ZFNs specific for the OCT4 (POU5F1) locus, we generated OCT4-eGFP reporter cells tomonitor the pluripotent state of hESCs. Second, we inserted a transgene into the AAVS1 locus togenerate a robust drug-inducible overexpression system in hESCs. Finally, we targeted the PITX3 gene,demonstrating that ZFNs can be used to generate reporter cells by targeting non-expressed genes inhESCs and hiPSCs.", "metadata": {}}
+{"_id": "54440", "title": "", "text": "Empirical Bayesian models for analysing molecular serotyping microarraysBACKGROUND Microarraysoffer great potential as a platform for molecular diagnostics, testing clinical samples for the presence ofnumerous biomarkers in highly multiplexed assays. In this study applied to infectious diseases, data froma microarray designed for molecular serotyping of Streptococcus pneumoniae was used, identifying thepresence of any one of 91 known pneumococcal serotypes from DNA extracts. This microarrayincorporated oligonucleotide probes for all known capsular polysaccharide synthesis genes and required astatistical analysis of the microarray intensity data to determine which serotype, or combination ofserotypes, were present within a sample based on the combination of genes detected. RESULTS Wepropose an empirical Bayesian model for calculating the probabilities of combinations of serotypes fromthe microarray data. The model takes into consideration the dependencies between serotypes, induced bygenes they have in common, and by homologous genes which, although not identical, are similar to eachother in sequence. For serotypes which are very similar in capsular gene composition, extra probes areincluded on the microarray, providing additional information which is integrated into the Bayesian model.For each serotype combination with high probability, a second model, a Bayesian random effects model isapplied to determine the relative abundance of each serotype. CONCLUSIONS To assess the accuracy ofthe proposed analysis we applied our methods to experimental data from samples containing individualserotypes and samples containing combinations of serotypes with known levels of abundance. All but twoof the known serotypes of S. pneumoniae that were tested as individual samples could be uniquelydetermined by the Bayesian model. The model also enabled the presence of combinations of serotypeswithin samples to be determined. Serotypes with very low abundance within a combination of serotypescan be detected (down to 2% abundance in this study). As well as detecting the presence of serotypecombinations, an approximate measure of the percentage abundance of the serotypes within thecombination can be obtained.", "metadata": {}}
+{"_id": "70115", "title": "", "text": "Bayesian measures of model complexity and fitSummary. We consider the problem of comparing complexhierarchical models in which the number of parameters is not clearly defined. Using an informationtheoretic argument we derive a measure pD for the effective number of parameters in a model as thedifference between the posterior mean of the deviance and the deviance at the posterior means of theparameters of interest. In general pD approximately corresponds to the trace of the product of Fisher'sinformation and the posterior covariance, which in normal models is the trace of the ‘hat’ matrixprojecting observations onto fitted values. Its properties in exponential families are explored. Theposterior mean deviance is suggested as a Bayesian measure of fit or adequacy, and the contributions ofindividual observations to the fit and complexity can give rise to a diagnostic plot of deviance residualsagainst leverages. Adding pD to the posterior mean deviance gives a deviance information criterion forcomparing models, which is related to other information criteria and has an approximate decisiontheoretic justification. The procedure is illustrated in some examples, and comparisons are drawn withalternative Bayesian and classical proposals. Throughout it is emphasized that the quantities required aretrivial to compute in a Markov chain Monte Carlo analysis.", "metadata": {}}
+{"_id": "70490", "title": "", "text": "Simplifying likelihood ratiosLikelihood ratios are one of the best measures of diagnostic accuracy,although they are seldom used, because interpreting them requires a calculator to convert back and forthbetween “probability” and “odds” of disease. This article describes a simpler method of interpretinglikelihood ratios, one that avoids calculators, nomograms, and conversions to “odds” of disease. Severalexamples illustrate how the clinician can use this method to refine diagnostic decisions at the bedside.", "metadata": {}}
+{"_id": "72159", "title": "", "text": "induction of early IFN-inducible genes in the absence of typeOn recognition of influenza virus (Flu) byTLR7, plasmacytoid dendritic cells (pDCs) produce type I IFN in significant amounts. Synthetic TLR7ligands induce the maturation of pDCs, as evidenced by the expression of costimulatory molecules andthe production of proinflammatory cytokines; however, they induce only low-level production ofIFN-alpha. To dissect the TLR7 signaling in pDCs and how these different profiles are induced, we studiedthe effects of 2 TLR7 ligands (Flu and CL097) on the activation of blood-isolated pDCs and the humanGEN2.2 pDC cell line. Type I IFN production by pDCs correlates with differential interferon regulatoryfactor 7 (IRF7) translocation into the nucleus induced by the 2 TLR7 ligands. Surprisingly, with bothactivators we nevertheless observed the rapid expression of the IFN-inducible genes mxa, cxcl10, andtrail within 4 hours of stimulation. This expression, controlled by STAT1 phosphorylation, wasindependent of type I IFN. STAT1 activation was found to be strictly dependent on the PI3K-p38MAPKpathway, showing a new signaling pathway leading to rapid expression of IFN-inducible genes after TLR7triggering. Thus, pDCs, through this unusual TLR7 signaling, have the capacity to promptly respond toviral infection during the early phases of the innate immune response.", "metadata": {}}
+{"_id": "79447", "title": "", "text": "Arteriolar function in visceral adipose tissue is impaired in human obesity.OBJECTIVE The purpose of thisstudy was to characterize the relationship between adipose tissue phenotype and depot-specificmicrovascular function in fat. METHODS AND RESULTS In 30 obese subjects (age 42±11 years, bodymass index 46±11 kg/m(2)) undergoing bariatric surgery, we intraoperatively collected visceral andsubcutaneous adipose tissue and characterized depot-specific adipose phenotypes. We assessedvasomotor function of the adipose microvasculature using videomicroscopy of small arterioles (75-250μm) isolated from different fat compartments. Endothelium-dependent, acetylcholine-mediatedvasodilation was severely impaired in visceral arterioles, compared to the subcutaneous depot (P<0.001by ANOVA). Nonendothelium dependent responses to papaverine and nitroprusside were similar.Endothelial nitric oxide synthase inhibition with N(ω)-nitro-l-arginine methyl ester reduced subcutaneousvasodilation but had no effect on severely blunted visceral arteriolar responses. Visceral fat exhibitedgreater expression of proinflammatory, oxidative stress-related, hypoxia-induced, and proangiogenicgenes; increased activated macrophage populations; and had a higher capacity for cytokine productionex vivo. CONCLUSIONS Our findings provide clinical evidence that the visceral microenvironment may beintrinsically toxic to arterial health providing a potential mechanism by which visceral adiposity burden islinked to atherosclerotic vascular disease. Our findings also support the evolving concept that bothadipose tissue quality and quantity may play significant roles in shaping cardiovascular phenotypes inhuman obesity.", "metadata": {}}
+{"_id": "87758", "title": "", "text": "Common Carotid Intima Media Thickness and Ankle-Brachial Pressure Index Correlate with Local but NotGlobal Atheroma Burden: A Cross Sectional Study Using Whole Body Magnetic ResonanceAngiographyBACKGROUND Common carotid intima media thickness (CIMT) and ankle brachial pressureindex (ABPI) are used as surrogate marker of atherosclerosis, and have been shown to correlate witharterial stiffness, however their correlation with global atherosclerotic burden has not been previouslyassessed. We compare CIMT and ABPI with atheroma burden as measured by whole body magneticresonance angiography (WB-MRA). METHODS 50 patients with symptomatic peripheral arterial diseasewere recruited. CIMT was measured using ultrasound while rest and exercise ABPI were performed.WB-MRA was performed in a 1.5T MRI scanner using 4 volume acquisitions with a divided dose ofintravenous gadolinium gadoterate meglumine (Dotarem, Guerbet, FR). The WB-MRA data was dividedinto 31 anatomical arterial segments with each scored according to degree of luminal narrowing: 0 =normal, 1 = <50%, 2 = 50-70%, 3 = 70-99%, 4 = vessel occlusion. The segment scores were summedand from this a standardized atheroma score was calculated. RESULTS The atherosclerotic burden washigh with a standardised atheroma score of 39.5±11. Common CIMT showed a positive correlation withthe whole body atheroma score (β 0.32, p = 0.045), however this was due to its strong correlation withthe neck and thoracic segments (β 0.42 p = 0.01) with no correlation with the rest of the body. ABPIcorrelated with the whole body atheroma score (β -0.39, p = 0.012), which was due to a strongcorrelation with the ilio-femoral vessels with no correlation with the thoracic or neck vessels. On multiplelinear regression, no correlation between CIMT and global atheroma burden was present (β 0.13 p =0.45), while the correlation between ABPI and atheroma burden persisted (β -0.45 p = 0.005).CONCLUSION ABPI but not CIMT correlates with global atheroma burden as measured by whole bodycontrast enhanced magnetic resonance angiography in a population with symptomatic peripheral arterialdisease. However this is primarily due to a strong correlation with ilio-femoral atheroma burden.", "metadata": {}}
+{"_id": "92308", "title": "", "text": "Loss of immune escape mutations during persistent HCV infection in pregnancy enhances replication ofvertically transmitted virusesGlobally, about 1% of pregnant women are persistently infected with thehepatitis C virus (HCV). Mother-to-child transmission of HCV occurs in 3-5% of pregnancies and accountsfor most new childhood infections. HCV-specific CD8(+) cytotoxic T lymphocytes (CTLs) are vital in theclearance of acute HCV infections, but in the 60-80% of infections that persist, these cells becomefunctionally exhausted or select for mutant viruses that escape T cell recognition. Increased HCVreplication during pregnancy suggests that maternofetal immune tolerance mechanisms may furtherimpair HCV-specific CTLs, limiting their selective pressure on persistent viruses. To assess this possibility,we characterized circulating viral quasispecies during and after consecutive pregnancies in two women.This revealed a loss of some escape mutations in HLA class I epitopes during pregnancy that wasassociated with emergence of more fit viruses. CTL selective pressure was reimposed after childbirth, atwhich point escape mutations in these epitopes again predominated in the quasispecies and viral loaddropped sharply. Importantly, the viruses transmitted perinatally were those with enhanced fitness dueto reversion of escape mutations. Our findings indicate that the immunoregulatory changes of pregnancyreduce CTL selective pressure on HCV class I epitopes, thereby facilitating vertical transmission of viruseswith optimized replicative fitness.", "metadata": {}}
+{"_id": "92499", "title": "", "text": "The journey of developing hematopoietic stem cells.Hematopoietic stem cells (HSCs) develop duringembryogenesis in a complex process that involves multiple anatomical sites. Once HSC precursors havebeen specified from mesoderm, they have to mature into functional HSCs and undergo self-renewingdivisions to generate a pool of HSCs. During this process, developing HSCs migrate through variousembryonic niches, which provide signals for their establishment and the conservation of their self-renewalability. These processes have to be recapitulated to generate HSCs from embryonic stem cells.Elucidating the interactions between developing HSCs and their niches should facilitate the generationand expansion of HSCs in vitro to exploit their clinical potential.", "metadata": {}}
+{"_id": "97884", "title": "", "text": "The sacroiliac joint in the spondyloarthropathies.The term spondyloarthropathy (SpA) describes anddefines a group of related inflammatory joint disease that share characteristic clinical features and aunique association with the major histocompatibility complex class I molecule HLA-B27. Five subgroupscan be differentiated: ankylosing spondylitis, reactive arthritis, psoriatic arthritis, arthritis associated withinflammatory bowel disease, and undifferentiated SpA. The sacroiliac joints are centrally involved in theSpA, most clearly and pathognomonic in ankylosing spondylitis, in which most patients are affected earlyin the disease. Overcoming some of the diagnostic difficulties of early sacroiliitis, dynamic magneticresonance imaging was shown to visualize both acute and chronic changes in the sacroiliac joints. Theinflammation in the sacroiliac joints in patients with SpA was recently examined in more detail; usingimmunohistology and in situ hybridrization, T cells, macrophages, and various cytokines were found ininfiltrates. Biopsy specimens were obtained under guided computed tomography, and in the same study,intra-articular corticosteroid treatment was successfully undertaken. Further investigation of such biopsyspecimens showed the absence of DNA of reactive arthritis-associated bacteria. The pathogenesis of theSpA and the reason for the tropism for the sacroiliac joints is still obscure. The nature of the relation ofthe genetic background of SpA to initially triggering bacterial infections remains to be established. Inchronic disease, autoimmune mechanisms might be more important.", "metadata": {}}
+{"_id": "102662", "title": "", "text": "A rapid method for extraction of cotton (Gossypium spp.) genomic DNA suitable for RFLP or PCRanalysisExtraction of high-quality genomic DNA fromGossypium (cotton) species is difficult due to highlevels of polysaccharide, oxidizable quinones, and other interfering substances. We describe a procedurethat consistently permits isolation of cotton genomic DNA of satisfactory size and quality for RFLP andPCR analysis, as well as for most routine cloning applications. Several antioxidants, phenol-bindingreagents, and phenol oxidase inhibitors are used throughout the procedure, and most polysaccharides areeliminated early in the procedure by isolation of nuclei.", "metadata": {}}
+{"_id": "103007", "title": "", "text": "Cross sectional stature and weight reference curves for the UK, 1990.The current reference curves ofstature and weight for the UK were first published in 1966 and have been used ever since despiteincreasing concern that they may not adequately describe the growth of present day British children.Using current data from seven sources new reference curves have been estimated from birth to 20 yearsfor children in 1990. The great majority of the data are nationally representative. The analysis usedCole's LMS method and has produced efficient estimates of the conventional centiles and gives a good fitto the data. These curves differ from the currently used curves at key ages for both stature and weight.In view of the concerns expressed about the current curves and the differences between them and thenew curves, it is proposed that the curves presented here should be adopted as the new UK referencecurves.", "metadata": {}}
+{"_id": "104130", "title": "", "text": "The suture provides a niche for mesenchymal stem cells of craniofacial bonesBone tissue undergoesconstant turnover supported by stem cells. Recent studies showed that perivascular mesenchymal stemcells (MSCs) contribute to the turnover of long bones. Craniofacial bones are flat bones derived from adifferent embryonic origin than the long bones. The identity and regulating niche for craniofacial-boneMSCs remain unknown. Here, we identify Gli1+ cells within the suture mesenchyme as the main MSCpopulation for craniofacial bones. They are not associated with vasculature, give rise to all craniofacialbones in the adult and are activated during injury repair. Gli1+ cells are typical MSCs in vitro. Ablation ofGli1+ cells leads to craniosynostosis and arrest of skull growth, indicating that these cells are anindispensable stem cell population. Twist1(+/-) mice with craniosynostosis show reduced Gli1+ MSCs insutures, suggesting that craniosynostosis may result from diminished suture stem cells. Our studyindicates that craniofacial sutures provide a unique niche for MSCs for craniofacial bone homeostasis andrepair.", "metadata": {}}
+{"_id": "106301", "title": "", "text": "Cardiac neural crest cells contribute to the dormant multipotent stem cell in the mammalian heartArodentcardiac side population cell fraction formed clonal spheroids in serum-free medium, which expressednestin, Musashi-1, and multi-drug resistance transporter gene 1, markers of undifferentiated neuralprecursor cells. These markers were lost following differentiation, and were replaced by the expression ofneuron-, glial-, smooth muscle cell–, or cardiomyocyte-specific proteins. Cardiosphere-derived cellstransplanted into chick embryos migrated to the truncus arteriosus and cardiac outflow tract andcontributed to dorsal root ganglia, spinal nerves, and aortic smooth muscle cells. Lineage studies usingdouble transgenic mice encoding protein 0–Cre/Floxed-EGFP revealed undifferentiated and differentiatedneural crest-derived cells in the fetal myocardium. Undifferentiated cells expressed GATA-binding protein4 and nestin, but not actinin, whereas the differentiated cells were identified as cardiomyocytes. Theseresults suggest that cardiac neural crest-derived cells migrate into the heart, remain there as dormantmultipotent stem cells—and under the right conditions—differentiate into cardiomyocytes and typicalneural crest-derived cells, including neurons, glia, and smooth muscle.", "metadata": {}}
+{"_id": "116792", "title": "", "text": "The mammalian target of rapamycin signaling pathway mediates epileptogenesis in a model of temporallobe epilepsy.Understanding molecular mechanisms mediating epileptogenesis is critical for developingmore effective therapies for epilepsy. We recently found that the mammalian target of rapamycin (mTOR)signaling pathway is involved in epileptogenesis, and mTOR inhibitors prevent epilepsy in a mouse modelof tuberous sclerosis complex. Here, we investigated the potential role of mTOR in a rat model oftemporal lobe epilepsy initiated by status epilepticus. Acute kainate-induced seizures resulted in biphasicactivation of the mTOR pathway, as evident by an increase in phospho-S6 (P-S6) expression. An initialrise in P-S6 expression started approximately 1 h after seizure onset, peaked at 3-6 h, and returned tobaseline by 24 h in both hippocampus and neocortex, reflecting widespread stimulation of mTORsignaling by acute seizure activity. After resolution of status epilepticus, a second increase in P-S6 wasobserved in hippocampus only, which started at 3 d, peaked 5-10 d, and persisted for several weeks afterkainate injection, correlating with the development of chronic epileptogenesis within hippocampus. ThemTOR inhibitor rapamycin, administered before kainate, blocked both the acute and chronic phases ofseizure-induced mTOR activation and decreased kainate-induced neuronal cell death, neurogenesis,mossy fiber sprouting, and the development of spontaneous epilepsy. Late rapamycin treatment, aftertermination of status epilepticus, blocked the chronic phase of mTOR activation and reduced mossy fibersprouting and epilepsy but not neurogenesis or neuronal death. These findings indicate that mTORsignaling mediates mechanisms of epileptogenesis in the kainate rat model and that mTOR inhibitorshave potential antiepileptogenic effects in this model.", "metadata": {}}
+{"_id": "118568", "title": "", "text": "Acute administration of recombinant Angiopoietin-1 ameliorates multiple-organ dysfunction syndromeand improves survival in murine sepsis.INTRODUCTION Endothelial activation leading to vascular barrierbreakdown plays an essential role in the pathophysiology of multiple-organ dysfunction syndrome(MODS) in sepsis. Increasing evidence suggests that the function of the vessel-protective factorAngiopoietin-1 (Ang-1), a ligand of the endothelial-specific Tie2 receptor, is inhibited by its antagonistAngiopoietin-2 (Ang-2) during sepsis. In order to reverse the effects of the sepsis-induced suppression ofAng-1 and elevation of Ang-2 we aimed to investigate whether an intravenous injection of recombinanthuman (rh) Ang-1 protects against MODS in murine sepsis. METHODS Polymicrobiological abdominalsepsis was induced by cecal ligation and puncture (CLP). Mice were treated with either 1 μg ofintravenous rhAng-1 or control buffer immediately after CLP induction and every 8h thereafter.Sham-operated animals served as time-matched controls. RESULTS Compared to buffer-treated controls,rhAng-1 treated septic mice showed significant improvements in several hematologic and biochemicalindicators of MODS. Moreover, rhAng-1 stabilized endothelial barrier function, as evidenced by inhibitionof protein leakage from lung capillaries into the alveolar compartment. Histological analysis revealed thatrhAng-1 treatment attenuated leukocyte infiltration in lungs and kidneys of septic mice, probably due toreduced endothelial adhesion molecule expression in rhAng-1 treated mice. Finally, the protective effectsof rhAng-1 treatment were reflected by an improved survival time in a lethal CLP model. CONCLUSIONSIn a clinically relevant murine sepsis model, intravenous rhAng-1 treatment alone is sufficient tosignificantly improve a variety of sepsis-associated organ dysfunctions and survival time, most likely bypreserving endothelial barrier function. Further studies are needed to pave the road for clinical applicationof this therapy concept.", "metadata": {}}
+{"_id": "120626", "title": "", "text": "Mechanisms linking obesity to insulin resistance and type 2 diabetesObesity is associated with anincreased risk of developing insulin resistance and type 2 diabetes. In obese individuals, adipose tissuereleases increased amounts of non-esterified fatty acids, glycerol, hormones, pro-inflammatory cytokinesand other factors that are involved in the development of insulin resistance. When insulin resistance isaccompanied by dysfunction of pancreatic islet β-cells — the cells that release insulin — failure to controlblood glucose levels results. Abnormalities in β-cell function are therefore critical in defining the risk anddevelopment of type 2 diabetes. This knowledge is fostering exploration of the molecular and geneticbasis of the disease and new approaches to its treatment and prevention.", "metadata": {}}
+{"_id": "123859", "title": "", "text": "Tracking the fate of glomerular epithelial cells in vivo using serial multiphoton imaging in novel mousemodels with fluorescent lineage tagsPodocytes are critical in the maintenance of a healthy glomerularfilter; however, they have been difficult to study in the intact kidney because of technical limitations.Here we report the development of serial multiphoton microscopy (MPM) of the same glomeruli overseveral days to visualize the motility of podocytes and parietal epithelial cells (PECs) in vivo. Inpodocin-GFP mice, podocytes formed sporadic multicellular clusters after unilateral ureteral ligation andmigrated into the parietal Bowman's capsule. The tracking of single cells in podocin-confetti micefeaturing cell-specific expression of CFP, GFP, YFP or RFP revealed the simultaneous migration of multiplepodocytes. In phosphoenolpyruvate carboxykinase (PEPCK)-GFP mice, serial MPM found PEC-to-podocytemigration and nanotubule connections. Our data support a highly dynamic rather than a static nature ofthe glomerular environment and cellular composition. Future application of this new approach shouldadvance our understanding of the mechanisms of glomerular injury and regeneration.", "metadata": {}}
+{"_id": "140874", "title": "", "text": "CTCF binding at the H19 imprinting control region mediates maternally inherited higher-order chromatinconformation to restrict enhancer access to Igf2.It is thought that the H19 imprinting control region (ICR)directs the silencing of the maternally inherited Igf2 allele through a CTCF-dependent chromatininsulator. The ICR has been shown to interact physically with a silencer region in Igf2, differentiallymethylated region (DMR)1, but the role of CTCF in this chromatin loop and whether it restricts thephysical access of distal enhancers to Igf2 is not known. We performed systematic chromosomeconformation capture analyses in the Igf2/H19 region over >160 kb, identifying sequences that interactphysically with the distal enhancers and the ICR. We found that, on the paternal chromosome, enhancersinteract with the Igf2 promoters but that, on the maternal allele, this is prevented by CTCF binding withinthe H19 ICR. CTCF binding in the maternal ICR regulates its interaction with matrix attachment region(MAR)3 and DMR1 at Igf2, thus forming a tight loop around the maternal Igf2 locus, which maycontribute to its silencing. Mutation of CTCF binding sites in the H19 ICR leads to loss of CTCF binding andde novo methylation of a CTCF target site within Igf2 DMR1, showing that CTCF can coordinate regionalepigenetic marks. This systematic chromosome conformation capture analysis of an imprinting clusterreveals that CTCF has a critical role in the epigenetic regulation of higher-order chromatin structure andgene silencing over considerable distances in the genome.", "metadata": {}}
+{"_id": "143251", "title": "", "text": "De novo assembly of a PML nuclear subcompartment occurs through multiple pathways and inducestelomere elongation.Telomerase-negative tumor cells use an alternative lengthening of telomeres (ALT)pathway that involves DNA recombination and repair to maintain their proliferative potential. Thecytological hallmark of this process is the accumulation of promyelocytic leukemia (PML) nuclear proteinat telomeric DNA to form ALT-associated PML bodies (APBs). Here, the de novo formation of a telomericPML nuclear subcompartment was investigated by recruiting APB protein components. We show thatfunctionally distinct proteins were able to initiate the formation of bona fide APBs with high efficiency in aself-organizing and self-propagating manner. These included: (1) PML and Sp100 as the constitutingcomponents of PML nuclear bodies, (2) telomere repeat binding factors 1 and 2 (TRF1 and TRF2,respectively), (3) the DNA repair protein NBS1 and (4) the SUMO E3 ligase MMS21, as well as theisolated SUMO1 domain, through an interacting domain of another protein factor. By contrast, the repairfactors Rad9, Rad17 and Rad51 were less efficient in APB nucleation but were recruited to preassembledAPBs. The artificially created APBs induced telomeric extension through a DNA repair mechanism, asinferred from their colocalization with sites of non-replicative DNA synthesis and histone H2A.Xphosphorylation, and an increase of the telomere repeat length. These activities were absent afterrecruitment of the APB factors to a pericentric locus and establish APBs as functional intermediates of theALT pathway.", "metadata": {}}
+{"_id": "152245", "title": "", "text": "Effects of an opal termination codon preceding the nsP4 gene sequence in the O'Nyong-Nyong virusgenome on Anopheles gambiae infectivity.The genomic RNA of an alphavirus encodes four differentnonstructural proteins, nsP1, nsP2, nsP3, and nsP4. The polyprotein P123 is produced when translationterminates at an opal termination codon between nsP3 and nsP4. The polyprotein P1234 is producedwhen translational readthrough occurs or when the opal termination codon has been replaced by a sensecodon in the alphavirus genome. Evolutionary pressures appear to have maintained genomic sequencesencoding both a stop codon (opal) and an open reading frame (arginine) as a general feature of theO'nyong-nyong virus (ONNV) genome, indicating that both are required at some point. Alternatereplication of ONNVs in both vertebrate and invertebrate hosts may determine predominance of aparticular codon at this locus in the viral quasispecies. However, no systematic study has previouslytested this hypothesis in whole animals. We report here the results of the first study to investigate in anatural mosquito host the functional significance of the opal stop codon in an alphavirus genome. Weused a full-length cDNA clone of ONNV to construct a series of mutants in which the arginine betweennsP3 and nsP4 was replaced with an opal, ochre, or amber stop codon. The presence of an opal stopcodon upstream of nsP4 nearly doubled (75.5%) the infectivity of ONNV over that of virus possessing acodon for the amino acid arginine at the corresponding position (39.8%). Although the frequency withwhich the opal virus disseminated from the mosquito midgut did not differ significantly from that of thearginine virus on days 8 and 10, dissemination did began earlier in mosquitoes infected with the opalvirus. Although a clear fitness advantage is provided to ONNV by the presence of an opal codon betweennsP3 and nsP4 in Anopheles gambiae, sequence analysis of ONNV RNA extracted from mosquito bodiesand heads indicated codon usage at this position corresponded with that of the virus administered in theblood meal. These results suggest that while selection of ONNV variants is occurring, de novo mutation atthe position between nsP3 and nsP4 does not readily occur in the mosquito. Taken together, these resultssuggest that the primary fitness advantage provided to ONNV by the presence of an opal codon betweennsP3 and nsP4 is related to mosquito infectivity.", "metadata": {}}
+{"_id": "153744", "title": "", "text": "Down-regulation of a host microRNA by a Herpesvirus saimiri noncoding RNA.T cells transformed byHerpesvirus saimiri express seven viral U-rich noncoding RNAs of unknown function called HSURs. Wenoted that conserved sequences in HSURs 1 and 2 constitute potential binding sites for three host-cellmicroRNAs (miRNAs). Coimmunoprecipitation experiments confirmed that HSURs 1 and 2 interact withthe predicted miRNAs in virally transformed T cells. The abundance of one of these miRNAs, miR-27, isdramatically lowered in transformed cells, with consequent effects on the expression of miR-27 targetgenes. Transient knockdown and ectopic expression of HSUR 1 demonstrate that it directs degradation ofmature miR-27 in a sequence-specific and binding-dependent manner. This viral strategy illustrates useof a ncRNA to manipulate host-cell gene expression via the miRNA pathway.", "metadata": {}}
+{"_id": "159469", "title": "", "text": "HTRF: A Technology Tailored for Drug Discovery –A Review of Theoretical Aspects and RecentApplicationsHTRF (Homogeneous Time Resolved Fluorescence) is the most frequently used generic assaytechnology to measure analytes in a homogenous format, which is the ideal platform used for drug targetstudies in high-throughput screening (HTS). This technology combines fluorescence resonance energytransfer technology (FRET) with time-resolved measurement (TR). In TR-FRET assays, a signal isgenerated through fluorescent resonance energy transfer between a donor and an acceptor moleculewhen in close proximity to each other. Buffer and media interference is dramatically reduced bydual-wavelength detection, and the final signal is proportional to the extent of product formation. TheHTRF assay is usually sensitive and robust that can be miniaturized into the 384 and 1536-well plateformats. This assay technology has been applied to many antibody-based assays including GPCRsignaling (cAMP and IP-One), kinases, cytokines and biomarkers, bioprocess (antibody and proteinproduction), as well as the assays for protein-protein, proteinpeptide, and protein-DNA/RNA interactions.Since its introduction to the drug-screening world over ten years ago, researchers have used HTRF toexpedite the study of GPCRs, kinases, new biomarkers, protein-protein interactions, and other targets ofinterest. HTRF has also been utilized as an alternative method for bioprocess monitoring. Thefirst-generation HTRF technology, which uses Europium cryptate as a fluorescence donor to monitorreactions between biomolecules, was extended in 2008 through the introduction of a second-generationdonor, Terbium cryptate (Tb), enhancing screening performance. Terbium cryptate possesses differentphotophysical properties compared to Europium, including increased quantum yield and a higher molarextinction coefficient. In addition to being compatible with the same acceptor fluorophors used withEuropium, it can serve as a donor fluorophore to green-emitting fluors because it has multiple emissionpeaks including one at 490 nm. Moreover, all Terbium HTRF assays can be read on the sameHTRF-compatible instruments as Europium HTRF assays. Overall, HTRF is a highly sensitive, robusttechnology for the detection of molecular interactions in vitro and is widely used for primary andsecondary screening phases of drug development. This review addresses the general principles of HTRFand its current applications in drug discovery.", "metadata": {}}
+{"_id": "164189", "title": "", "text": "Chk1 inhibits replication factory activation but allows dormant origin firing in existing factoriesReplicationorigins are licensed by loading MCM2-7 hexamers before entry into S phase. However, only \u000010% oflicensed origins are normally used in S phase, with the others remaining dormant. When fork progressionis inhibited, dormant origins initiate nearby to ensure that all of the DNA is eventually replicated. Inapparent contrast, replicative stress activates ataxia telangiectasia and rad-3-related (ATR) and Chk1checkpoint kinases that inhibit origin firing. In this study, we show that at low levels of replication stress,ATR/Chk1 predominantly suppresses origin initiation by inhibiting the activation of new replicationfactories, thereby reducing the number of active factories. At the same time, inhibition of replication forkprogression allows dormant origins to initiate within existing replication factories. The inhibition of newfactory activation by ATR/Chk1 therefore redirects replication toward active factories where forks areinhibited and away from regions that have yet to start replication. This minimizes the deleteriousconsequences of fork stalling and prevents similar problems from arising in unreplicated regions of thegenome.", "metadata": {}}
+{"_id": "164985", "title": "", "text": "Fra-1 protooncogene regulates IL-6 expression in macrophages and promotes the generation of M2dmacrophagesThe tumor microenvironment (TME) plays a prominent role in the growth of tumor cells. Asthe major inflammatory component of the TME, M2d macrophages are educated by the TME such thatthey adopt an immunosuppressive role that promotes tumor metastasis and progression. Fra-1 formsactivator protein-1 heterodimers with Jun partners and drives gene transcription. Fra-1 is thought todrastically induce tumorigenesis and progression. However, the functional role of Fra-1 in the generationof M2d macrophages is poorly understood to date. Here, we demonstrate that 4T1 mammary carcinomacells, when co-cultured with RAW264.7 macrophage cells, skew the RAW264.7 macrophage celldifferentiation into M2d macrophages. The 4T1 cells stimulate de novo overexpression of Fra-1 inRAW264.7 cells, and then Fra-1 binds to the interleukin 6 (IL-6) promoter to increase the production ofthe cytokine IL-6 in RAW264.7 cells. IL-6 acts in an autocrine fashion to skew RAW264.7 macrophage celldifferentiation into M2d macrophages. These findings open new insights into how to reverse M2dmacrophage-induced immune tolerance to improve the efficacy of immunotherapeutic approaches.", "metadata": {}}
+{"_id": "169264", "title": "", "text": "Analysis of SiO2 nanoparticles binding proteins in rat blood and brain homogenateA multitude ofnanoparticles, such as titanium oxide (TiO2), zinc oxide, aluminum oxide, gold oxide, silver oxide, ironoxide, and silica oxide, are found in many chemical, cosmetic, pharmaceutical, and electronic products.Recently, SiO2 nanoparticles were shown to have an inert toxicity profile and no association with anirreversible toxicological change in animal models. Hence, exposure to SiO2 nanoparticles is on theincrease. SiO2 nanoparticles are routinely used in numerous materials, from strengthening filler forconcrete and other construction composites, to nontoxic platforms for biomedical application, such asdrug delivery and theragnostics. On the other hand, recent in vitro experiments indicated that SiO2nanoparticles were cytotoxic. Therefore, we investigated these nanoparticles to identify potentially toxicpathways by analyzing the adsorbed protein corona on the surface of SiO2 nanoparticles in the blood andbrain of the rat. Four types of SiO2 nanoparticles were chosen for investigation, and the protein corona ofeach type was analyzed using liquid chromatography-tandem mass spectrometry technology. In total,115 and 48 plasma proteins from the rat were identified as being bound to negatively charged 20 nm and100 nm SiO2 nanoparticles, respectively, and 50 and 36 proteins were found for 20 nm and 100 nmarginine-coated SiO2 nanoparticles, respectively. Higher numbers of proteins were adsorbed onto the 20nm sized SiO2 nanoparticles than onto the 100 nm sized nanoparticles regardless of charge. Whenproteins were compared between the two charges, higher numbers of proteins were found forarginine-coated positively charged SiO2 nanoparticles than for the negatively charged nanoparticles. Theproteins identified as bound in the corona from SiO2 nanoparticles were further analyzed with ClueGO, aCytoscape plugin used in protein ontology and for identifying biological interaction pathways. Proteinsbound on the surface of nanoparticles may affect functional and conformational properties anddistributions in complicated biological processes.", "metadata": {}}
+{"_id": "175735", "title": "", "text": "Inferring nucleosome positions with their histone mark annotation from ChIP dataMOTIVATION Thenucleosome is the basic repeating unit of chromatin. It contains two copies each of the four core histonesH2A, H2B, H3 and H4 and about 147 bp of DNA. The residues of the histone proteins are subject tonumerous post-translational modifications, such as methylation or acetylation. Chromatinimmunoprecipitiation followed by sequencing (ChIP-seq) is a technique that provides genome-wideoccupancy data of these modified histone proteins, and it requires appropriate computational methods.RESULTS We present NucHunter, an algorithm that uses the data from ChIP-seq experiments directedagainst many histone modifications to infer positioned nucleosomes. NucHunter annotates each of thesenucleosomes with the intensities of the histone modifications. We demonstrate that these annotations canbe used to infer nucleosomal states with distinct correlations to underlying genomic features andchromatin-related processes, such as transcriptional start sites, enhancers, elongation by RNApolymerase II and chromatin-mediated repression. Thus, NucHunter is a versatile tool that can be used topredict positioned nucleosomes from a panel of histone modification ChIP-seq experiments and inferdistinct histone modification patterns associated to different chromatin states. AVAILABILITY Thesoftware is available at http://epigen.molgen.mpg.de/nuchunter/.", "metadata": {}}
+{"_id": "188911", "title": "", "text": "Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented withgranulocyte/macrophage colony-stimulating factorAntigen-presenting, major histocompatibility complex(MHC) class II-rich dendritic cells are known to arise from bone marrow. However, marrow lacks maturedendritic cells, and substantial numbers of proliferating less-mature cells have yet to be identified. Themethodology for inducing dendritic cell growth that was recently described for mouse blood now has beenmodified to MHC class II-negative precursors in marrow. A key step is to remove the majority ofnonadherent, newly formed granulocytes by gentle washes during the first 2-4 d of culture. This leavesbehind proliferating clusters that are loosely attached to a more firmly adherent \"stroma. \" At days 4-6the clusters can be dislodged, isolated by 1-g sedimentation, and upon reculture, large numbers ofdendritic cells are released. The latter are readily identified on the basis of their distinct cell shape,ultrastructure, and repertoire of antigens, as detected with a panel of monoclonal antibodies. Thedendritic cells express high levels of MHC class II products and act as powerful accessory cells forinitiating the mixed leukocyte reaction. Neither the clusters nor mature dendritic cells are generated ifmacrophage colony-stimulating factor rather than granulocyte/macrophage colony-stimulating factor(GM-CSF) is applied. Therefore, GM-CSF generates all three lineages of myeloid cells (granulocytes,macrophages, and dendritic cells). Since > 5 x 10(6) dendritic cells develop in 1 wk from precursorswithin the large hind limb bones of a single animal, marrow progenitors can act as a major source ofdendritic cells. This feature should prove useful for future molecular and clinical studies of this otherwisetrace cell type.", "metadata": {}}
+{"_id": "195352", "title": "", "text": "Insulin action and resistance in obesity and type 2 diabetesNutritional excess is a major forerunner oftype 2 diabetes. It enhances the secretion of insulin, but attenuates insulin's metabolic actions in theliver, skeletal muscle and adipose tissue. However, conflicting evidence indicates a lack of knowledge ofthe timing of these events during the development of obesity and diabetes, pointing to a key gap in ourunderstanding of metabolic disease. This Perspective reviews alternate viewpoints and recent results onthe temporal and mechanistic connections between hyperinsulinemia, obesity and insulin resistance.Although much attention has addressed early steps in the insulin signaling cascade, insulin resistance inobesity seems to be largely elicited downstream of these steps. New findings also connect insulinresistance to extensive metabolic cross-talk between the liver, adipose tissue, pancreas and skeletalmuscle. These and other advances over the past 5 years offer exciting opportunities and dauntingchallenges for the development of new therapeutic strategies for the treatment of type 2 diabetes.", "metadata": {}}
+{"_id": "202259", "title": "", "text": "Effect of lowering blood pressure on cardiovascular events and mortality in patients on dialysis: asystematic review and meta-analysis of randomised controlled trialsBACKGROUND Patients undergoingdialysis have a substantially increased risk of cardiovascular mortality and morbidity. Although severaltrials have shown the cardiovascular benefits of lowering blood pressure in the general population, thereis uncertainty about the efficacy and tolerability of reducing blood pressure in patients on dialysis. We dida systematic review and meta-analysis to assess the effect of blood pressure lowering in patients ondialysis. METHODS We systematically searched Medline, Embase, and the Cochrane Library database fortrials reported between 1950 and November, 2008, without language restriction. We extracted astandardised dataset from randomised controlled trials of blood pressure lowering in patients on dialysisthat reported cardiovascular outcomes. Meta-analysis was done with a random effects model. FINDINGSWe identified eight relevant trials, which provided data for 1679 patients and 495 cardiovascular events.Weighted mean systolic blood pressure was 4.5 mm Hg lower and diastolic blood pressure 2.3 mm Hglower in actively treated patients than in controls. Blood pressure lowering treatment was associated withlower risks of cardiovascular events (RR 0.71, 95% CI 0.55-0.92; p=0.009), all-cause mortality (RR 0.80,0.66-0.96; p=0.014), and cardiovascular mortality (RR 0.71, 0.50-0.99; p=0.044) than controlregimens. The effects seem to be consistent across a range of patient groups included in the studies.INTERPRETATION Treatment with agents that lower blood pressure should routinely be considered forindividuals undergoing dialysis to reduce the very high cardiovascular morbidity and mortality rate in thispopulation.", "metadata": {}}
+{"_id": "207972", "title": "", "text": "Interaction of an adenovirus E3 14.7-kilodalton protein with a novel tumor necrosis factor alpha-induciblecellular protein containing leucine zipper domains.Early region 3 (E3) of group C human adenoviruses(Ad) encodes several inhibitors of tumor necrosis factor alpha (TNF-alpha) cytolysis, including an E314.7-kDa protein (E3-14.7K) and a heterodimer containing two polypeptides of 10.4 and 14.5 kDa. Tounderstand the mechanism by which the viral proteins inhibit TNF-alpha functions, the E3-14.7K proteinwas used to screen a HeLa cell cDNA library to search for interacting proteins in the yeast two-hybridsystem. A novel protein containing multiple leucine zipper domains without any significant homology withany known protein was identified and has been named FIP-2 (for 14.7K-interacting protein). FIP-2interacted with E3-14.7K both in vitro and in vivo. It colocalized with Ad E3-14.7K in the cytoplasm,especially near the nuclear membrane, and caused redistribution of the viral protein. FIP-2 by itself doesnot cause cell death; however, it can reverse the protective effect of E3-14.7K on cell killing induced byoverexpression of the intracellular domain of the 55-kDa TNF receptor or by RIP, a death protein involvedin the TNF-alpha and Fas apoptosis pathways. Deletion analysis indicates that the reversal effect of FIP-2depends on its interaction with E3-14.7K. Three major mRNA forms of FIP-2 have been detected inmultiple human tissues, and expression of the transcripts was induced by TNF-alpha treatment in atime-dependent manner in two different cell lines. FIP-2 has consensus sequences for several potentialposttranslational modifications. These data suggest that FIP-2 is one of the cellular targets for AdE3-14.7K and that its mechanism of affecting cell death involves the TNF receptor, RIP, or a downstreammolecule affected by either of these two molecules.", "metadata": {}}
+{"_id": "213017", "title": "", "text": "PML induces compaction, TRF2 depletion and DNA damage signaling at telomeres and promotes theiralternative lengthening.The alternative lengthening of telomeres (ALT) mechanism allows cancer cells toescape senescence and apoptosis in the absence of active telomerase. A characteristic feature of thispathway is the assembly of ALT-associated promyelocytic leukemia (PML) nuclear bodies (APBs) attelomeres. Here, we dissected the role of APBs in a human ALT cell line by performing an RNAinterference screen using an automated 3D fluorescence microscopy platform and advanced 3D imageanalysis. We identified 29 proteins that affected APB formation, which included proteins involved intelomere and chromatin organization, protein sumoylation and DNA repair. By integrating and extendingthese findings, we found that APB formation induced clustering of telomere repeats, telomere compactionand concomitant depletion of the shelterin protein TRF2 (also known as TERF2). These APB-dependentchanges correlated with the induction of a DNA damage response at telomeres in APBs as evident by astrong enrichment of the phosphorylated form of the ataxia telangiectasia mutated (ATM) kinase.Accordingly, we propose that APBs promote telomere maintenance by inducing a DNA damage responsein ALT-positive tumor cells through changing the telomeric chromatin state to trigger ATMphosphorylation.", "metadata": {}}
+{"_id": "219475", "title": "", "text": "Gr-1+CD11b+ myeloid cells tip the balance of immune protection to tumor promotion in thepremetastatic lung.The mechanisms by which a primary tumor affects a selected distant organ beforetumor cell arrival remain to be elucidated. This report shows that Gr-1+CD11b+ cells are significantlyincreased in lungs of mice bearing mammary adenocarcinomas before tumor cell arrival. In thepremetastatic lungs, these immature myeloid cells significantly decrease IFN-gamma production andincrease proinflammatory cytokines. In addition, they produce large quantities of matrixmetalloproteinase 9 (MMP9) and promote vascular remodeling. Deletion of MMP9 normalizes aberrantvasculature in the premetastatic lung and diminishes lung metastasis. The production and activity ofMMP9 is selectively restricted to lungs and organs with a large number of Gr-1+CD11b+ cells. Our workreveals a novel protumor mechanism for Gr-1+CD11b+ cells that changes the premetastatic lung into aninflammatory and proliferative environment, diminishes immune protection, and promotes metastasisthrough aberrant vasculature formation. Thus, inhibition of Gr-1+CD11b+ cells could normalize thepremetastatic lung environment, improve host immunosurveillance, and inhibit tumor metastasis.", "metadata": {}}
+{"_id": "226488", "title": "", "text": "Activin/Nodal signalling in stem cells.Activin/Nodal growth factors control a broad range of biologicalprocesses, including early cell fate decisions, organogenesis and adult tissue homeostasis. Here, weprovide an overview of the mechanisms by which the Activin/Nodal signalling pathway governs stem cellfunction in these different stages of development. We describe recent findings that associateActivin/Nodal signalling to pathological conditions, focusing on cancer stem cells in tumorigenesis and itspotential as a target for therapies. Moreover, we will discuss future directions and questions thatcurrently remain unanswered on the role of Activin/Nodal signalling in stem cell self-renewal,differentiation and proliferation.", "metadata": {}}
+{"_id": "236204", "title": "", "text": "Distinct RNA-dependent RNA polymerases are required for RNAi triggered by double-stranded RNA versustruncated transgenes in Paramecium tetraureliaIn many eukaryotes, RNA-dependent RNA polymerases(RdRPs) play key roles in the RNAi pathway. They have been implicated in the recognition and processingof aberrant transcripts triggering the process, and in amplification of the silencing response. We havetested the functions of RdRP genes from the ciliate Paramecium tetraurelia in experimentally induced andendogenous mechanisms of gene silencing. In this organism, RNAi can be triggered either by high-copy,truncated transgenes or by directly feeding cells with double-stranded RNA (dsRNA). Surprisingly,dsRNA-induced silencing depends on the putatively functional RDR1 and RDR2 genes, which are requiredfor the accumulation of both primary siRNAs and a distinct class of small RNAs suggestive of secondarysiRNAs. In contrast, a third gene with a highly divergent catalytic domain, RDR3, is required for siRNAaccumulation when RNAi is triggered by truncated transgenes. Our data further implicate RDR3 in theaccumulation of previously described endogenous siRNAs and in the regulation of the surface antigengene family. While only one of these genes is normally expressed in any clonal cell line, the knockdown ofRDR3 leads to co-expression of multiple antigens. These results provide evidence for a functionalspecialization of Paramecium RdRP genes in distinct RNAi pathways operating during vegetative growth.", "metadata": {}}
+{"_id": "238409", "title": "", "text": "Mechanisms of Renal Cell Apoptosis Induced by Cyclosporine A: A Systematic Review of in vitroStudiesBackground:Chronic cyclosporine A (CsA) nephrotoxicity (CCN) is a major cause of chronic renaldysfunction and has no effective clinical interventions yet. Objective: To reveal the mechanisms of renalcell apoptosis in CCN, we analyzed all in vitro studies of such mechanisms. Methods: We collected all invitro studies about the mechanisms of renal cell apoptosis induced by CsA in Medline (1966 to July 2010),Embase (1980 to July 2010) and ISI (1986 to July 2010), evaluated their quality according to in vitrostandards and extracted data following the PICOS principles and synthesized the data. Results: First,CsAcould upregulate Fas and Fas-L expression, increase FADD and apoptosis enzymes (caspase-2, -3, -4, -7,-8, -9 and -10) and downregulate the Bcl-2 and Bcl-xL. Second, CsA could induce oxidative stress anddamage the antioxidant defense system. Third, CsA could increase the expression of HERP, GRP78 andCHOP. Fourth, CsA could induce renal cell apoptosis and increase their iNOS and p53 expression incultured cells. Conclusions: At least four pathways are involved in renal cell apoptosis induced by CsA indifferent cell species. Caspases might be their final common pathway in vitro. They might all providepotential points for interventions, but these need to be confirmed in vivo.", "metadata": {}}
+{"_id": "243694", "title": "", "text": "Blood stem cells emerge from aortic endothelium by a novel type of cell transitionThe ontogeny ofhaematopoietic stem cells (HSCs) during embryonic development is still highly debated, especially theirpossible lineage relationship to vascular endothelial cells. The first anatomical site from which cells withlong-term HSC potential have been isolated is the aorta-gonad-mesonephros (AGM), more specifically thevicinity of the dorsal aortic floor. But although some authors have presented evidence that HSCs mayarise directly from the aortic floor into the dorsal aortic lumen, others support the notion that HSCs firstemerge within the underlying mesenchyme. Here we show by non-invasive, high-resolution imaging oflive zebrafish embryos, that HSCs emerge directly from the aortic floor, through a stereotyped processthat does not involve cell division but a strong bending then egress of single endothelial cells from theaortic ventral wall into the sub-aortic space, and their concomitant transformation into haematopoieticcells. The process is polarized not only in the dorso-ventral but also in the rostro-caudal versusmedio-lateral direction, and depends on Runx1 expression: in Runx1-deficient embryos, the exit eventsare initially similar, but much rarer, and abort into violent death of the exiting cell. These resultsdemonstrate that the aortic floor is haemogenic and that HSCs emerge from it into the sub-aortic space,not by asymmetric cell division but through a new type of cell behaviour, which we call an endothelialhaematopoietic transition.", "metadata": {}}
+{"_id": "253672", "title": "", "text": "Probable person to person transmission of novel avian influenza A (H7N9) virus in Eastern China, 2013:epidemiological investigationOBJECTIVE To determine whether the novel avian influenza H7N9 virus cantransmit from person to person and its efficiency. DESIGN Epidemiological investigations conducted aftera family cluster of two patients with avian H7N9 in March 2013. SETTING Wuxi, Eastern China.PARTICIPANTS Two patients, their close contacts, and relevant environments. Samples from the patientsand environments were collected and tested by real time reverse transcriptase-polymerase chain reaction(rRT-PCR), viral culture, and haemagglutination inhibition assay. Any contacts who became ill hadsamples tested for avian H7N9 by rRT-PCR. Paired serum samples were obtained from contacts forserological testing by haemagglutination inhibition assays. MAIN OUTCOMES MEASURES Clinical data,history of exposure before the onset of illnesses, and results of laboratory testing of pathogens andfurther analysis of sequences and phylogenetic tree to isolated strains. RESULTS The index patientbecame ill five to six days after his last exposure to poultry. The second patient, his daughter aged 32,who provided unprotected bedside care in the hospital, had no known exposure to poultry. She developedsymptoms six days after her last contact with her father. Two strains were isolated successfully from thetwo patients. Genome sequence and analyses of phylogenetic trees showed that both viruses were almostgenetically identical. Forty three close contacts of both patients were identified. One had mild illness buthad negative results for avian H7N9 by rRT-PCR. All 43 close contacts tested negative forhaemagglutination inhibition antibodies specific for avian H7N9. CONCLUSIONS The infection of thedaughter probably resulted from contact with her father (the index patient) during unprotected exposure,suggesting that in this cluster the virus was able to transmit from person to person. The transmissibilitywas limited and non-sustainable.", "metadata": {}}
+{"_id": "263364", "title": "", "text": "Genetic Variation in the Interleukin-28B Gene Is Associated with Spontaneous Clearance and Progressionof Hepatitis C Virus in Moroccan PatientsBACKGROUND Genetic variation in the IL28B gene has beenstrongly associated with treatment outcomes, spontaneous clearance and progression of the hepatitis Cvirus infection (HCV). The aim of the present study was to investigate the role of polymorphisms at thislocus with progression and outcome of HCV infection in a Moroccan population. METHODS We analyzed acohort of 438 individuals among them 232 patients with persistent HCV infection, of whom 115 patientshad mild chronic hepatitis and 117 had advanced liver disease (cirrhosis and hepatocellular carcinoma),68 individuals who had naturally cleared HCV and 138 healthy subjects. The IL28B SNPs rs12979860 andrs8099917 were genotyped using a TaqMan 5' allelic discrimination assay. RESULTS The protectivers12979860-C and rs8099917-T alleles were more common in subjects with spontaneous clearance(77.9% vs 55.2%; p = 0.00001 and 95.6% vs 83.2%; p = 0.0025, respectively). Individuals withclearance were 4.69 (95% CI, 1.99-11.07) times more likely to have the C/C genotype for rs12979860polymorphism (p = 0.0017) and 3.55 (95% CI, 0.19-66.89) times more likely to have the T/T genotypeat rs8099917. Patients with advanced liver disease carried the rs12979860-T/T genotype more frequentlythan patients with mild chronic hepatitis C (OR = 1.89; 95% CI, 0.99-3.61; p = 0.0532) and this risk waseven more pronounced when we compared them with healthy controls (OR = 4.27; 95% CI, 2.08-8.76; p= 0.0005). The rs8099917-G allele was also associated with advanced liver disease (OR = 2.34; 95% CI,1.40-3.93; p = 0.0100). CONCLUSIONS In the Moroccan population, polymorphisms near the IL28B geneplay a role both in spontaneous clearance and progression of HCV infection.", "metadata": {}}
+{"_id": "266641", "title": "", "text": "CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T regcellsRegulatory T (T reg) cells are critical regulators of immune tolerance. Most T reg cells are definedbased on expression of CD4, CD25, and the transcription factor, FoxP3. However, these markers haveproven problematic for uniquely defining this specialized T cell subset in humans. We found that the IL-7receptor (CD127) is down-regulated on a subset of CD4+ T cells in peripheral blood. We demonstratethat the majority of these cells are FoxP3+, including those that express low levels or no CD25. Acombination of CD4, CD25, and CD127 resulted in a highly purified population of T reg cells accountingfor significantly more cells that previously identified based on other cell surface markers. These cells werehighly suppressive in functional suppressor assays. In fact, cells separated based solely on CD4 andCD127 expression were anergic and, although representing at least three times the number of cells(including both CD25+CD4+ and CD25−CD4+ T cell subsets), were as suppressive as the “classic”CD4+CD25hi T reg cell subset. Finally, we show that CD127 can be used to quantitate T reg cell subsetsin individuals with type 1 diabetes supporting the use of CD127 as a biomarker for human T reg cells.", "metadata": {}}
+{"_id": "275294", "title": "", "text": "Environmental factors that influence the cutaneous production of vitamin DAll vertebrates, includinghumans, obtain most of their daily vitamin D requirement from casual exposure to sunlight. Duringexposure to sunlight, the solar ultraviolet B photons (290-315 nm) penetrate into the skin where theycause the photolysis of 7-dehydrocholesterol to precholecalciferol. Once formed, precholecalciferolundergoes a thermally induced rearrangement of its double bonds to form cholecalciferol. An increase inskin pigmentation, aging, and the topical application of a sunscreen diminishes the cutaneous productionof cholecalciferol. Latitude, season, and time of day as well as ozone pollution in the atmosphereinfluence the number of solar ultraviolet B photons that reach the earth's surface, and thereby, alter thecutaneous production of cholecalciferol. In Boston, exposure to sunlight during the months of Novemberthrough February will not produce any significant amounts of cholecalciferol in the skin. Becausewindowpane glass absorbs ultraviolet B radiation, exposure of sunlight through glass windows will notresult in any production of cholecalciferol. It is now recognized that vitamin D insufficiency and vitamin Ddeficiency are common in elderly people, especially in those who are infirm and not exposed to sunlightor who live at latitudes that do not provide them with sunlight-mediated cholecalciferol during the wintermonths. Vitamin D insufficiency and deficiency exacerbate osteoporosis, cause osteomalacia, andincrease the risk of skeletal fractures. Vitamin D insufficiency and deficiency can be prevented byencouraging responsible exposure to sunlight and/or consumption of a multivitamin tablet that contains10 micrograms (400 IU) vitamin D.", "metadata": {}}
+{"_id": "279052", "title": "", "text": "Genomic imprinting in development, growth, behavior and stem cells.Genes that are subject to genomicimprinting in mammals are preferentially expressed from a single parental allele. This imprintedexpression of a small number of genes is crucial for normal development, as these genes often directlyregulate fetal growth. Recent work has also demonstrated intricate roles for imprinted genes in the brain,with important consequences on behavior and neuronal function. Finally, new studies have revealed theimportance of proper expression of specific imprinted genes in induced pluripotent stem cells and in adultstem cells. As we review here, these findings highlight the complex nature and developmental importanceof imprinted genes.", "metadata": {}}
+{"_id": "285794", "title": "", "text": "Quantitative Detection of Hepatitis C Virus RNA by Light Cycler PCR and Comparison with Two DifferentPCR AssaysThe new Light Cycler technology was adapted to the detection of hepatitis C virus (HCV) RNAin clinical samples. Sera from 81 patients were tested by Light Cycler PCR, AMPLICOR HCV Monitor assay,and in-house PCR. Our data demonstrate that Light Cycler is a fast and reliable method for the detectionand quantitation of HCV RNA.", "metadata": {}}
+{"_id": "293661", "title": "", "text": "Targeting arginine metabolism pathway to treat arginine-dependent cancers.The significant disparities inmetabolism between tumor and normal cells have inspired the development of metabolism-basedanti-tumor therapeutics. Arginine is a semi-essential amino acid because normal cells can not onlysynthesize arginine de novo but also take up extracellular arginine. Several types of tumors haveabnormalities in arginine metabolism enzymes and completely rely on extracellular arginine to supportnecessary biological processes. This property is referred to as arginine auxotrophy. Taking advantage ofcharacteristic arginine auxotrophy in tumors, arginine deprivation, which is generally induced by the useof arginine deiminase (ADI) and arginase I, has been investigated as a novel strategy for cancer therapy.Arginine deprivation demonstrated promising efficacy against arginine-auxotrophic tumors. By integratingperspectives from both clinical oncologists and laboratory scientists, this article reviews the importantaspects of arginine deprivation as a promising anticancer therapy.", "metadata": {}}
+{"_id": "301838", "title": "", "text": "Rank Signaling Links the Development of Invariant γδ T Cell Progenitors and Aire+ MedullaryEpitheliumThe thymic medulla provides a specialized microenvironment for the negative selection of Tcells, with the presence of autoimmune regulator (Aire)-expressing medullary thymic epithelial cells(mTECs) during the embryonic-neonatal period being both necessary and sufficient to establishlong-lasting tolerance. Here we showed that emergence of the first cohorts of Aire(+) mTECs at this keydevelopmental stage, prior to αβ T cell repertoire selection, was jointly directed by Rankl(+) lymphoidtissue inducer cells and invariant Vγ5(+) dendritic epidermal T cell (DETC) progenitors that are the firstthymocytes to express the products of gene rearrangement. In turn, generation of Aire(+) mTECs thenfostered Skint-1-dependent, but Aire-independent, DETC progenitor maturation and the emergence of aninvariant DETC repertoire. Hence, our data attributed a functional importance to the temporaldevelopment of Vγ5(+) γδ T cells during thymus medulla formation for αβ T cell tolerance induction anddemonstrated a Rank-mediated reciprocal link between DETC and Aire(+) mTEC maturation.", "metadata": {}}
+{"_id": "301866", "title": "", "text": "Long-term immune deficiency after allogeneic stem cell transplantation: B-cell deficiency is associatedwith late infections.Immune reconstitution was analyzed in 140 consecutive patients who were 2-yeardisease-free and who underwent myeloablative allogeneic transplantation. A CD4 and CD8 defect wasobserved involving naive, terminally differentiated, memory and competent cells and above limits valuesfor activated subsets. Natural killer cells normalize at six months while we observed expansion ofCD19(+)/CD5(+) B cells after three months and a persisting defect of memory B cells. Chronicgraft-versus-host disease did not influence significantly those parameters for CD8 subsets while the naïveand competent CD4 subsets were strongly affected. But the most profound impact of chronicgraft-versus-host disease was on B-cell subsets, especially on the memory B population. The cumulativeincidence of late severe infections was low (14% at four years). Using Cox's models, only low B-cellcounts at 12 (P=0.02) and 24 (P=0.001) months were associated with the hazard of developing lateinfection, in particular if patients did not develop chronic graft-versus-host disease.", "metadata": {}}
+{"_id": "306006", "title": "", "text": "The stimulatory potency of T cell antigens is influenced by the formation of the immunological synapse.Tcell activation is predicated on the interaction between the T cell receptor and peptide-majorhistocompatibility (pMHC) ligands. The factors that determine the stimulatory potency of a pMHCmolecule remain unclear. We describe results showing that a peptide exhibiting many hallmarks of aweak agonist stimulates T cells to proliferate more than the wild-type agonist ligand. An in silico approachsuggested that the inability to form the central supramolecular activation cluster (cSMAC) could underliethe increased proliferation. This conclusion was supported by experiments that showed that enhancingcSMAC formation reduced stimulatory capacity of the weak peptide. Our studies highlight the fact that acomplex interplay of factors determines the quality of a T cell antigen.", "metadata": {}}
+{"_id": "306311", "title": "", "text": "Control of glutamate clearance and synaptic efficacy by glial coverage of neurons.Analysis of excitatorysynaptic transmission in the rat hypothalamic supraoptic nucleus revealed that glutamate clearance and,as a consequence, glutamate concentration and diffusion in the extracellular space, is associated with thedegree of astrocytic coverage of its neurons. Reduction in glutamate clearance, whether inducedpharmacologically or associated with a relative decrease of glial coverage in the vicinity of synapses,affected transmitter release through modulation of presynaptic metabotropic glutamate receptors.Astrocytic wrapping of neurons, therefore, contributes to the regulation of synaptic efficacy in the centralnervous system.", "metadata": {}}
+{"_id": "308862", "title": "", "text": "Duration of androgen suppression in the treatment of prostate cancer.BACKGROUND The combination ofradiotherapy plus long-term medical suppression of androgens (> or = 2 years) improves overall survivalin patients with locally advanced prostate cancer. We compared the use of radiotherapy plus short-termandrogen suppression with the use of radiotherapy plus long-term androgen suppression in the treatmentof locally advanced prostate cancer. METHODS We randomly assigned patients with locally advancedprostate cancer who had received external-beam radiotherapy plus 6 months of androgen suppression totwo groups, one to receive no further treatment (short-term suppression) and the other to receive 2.5years of further treatment with a luteinizing hormone-releasing hormone agonist (long-termsuppression). An outcome of noninferiority of short-term androgen suppression as compared withlong-term suppression required a hazard ratio of more than 1.35 for overall survival, with a one-sidedalpha level of 0.05. An interim analysis showed futility, and the results are presented with an adjustedone-sided alpha level of 0.0429. RESULTS A total of 1113 men were registered, of whom 970 wererandomly assigned, 483 to short-term suppression and 487 to long-term suppression. After a medianfollow-up of 6.4 years, 132 patients in the short-term group and 98 in the long-term group had died; thenumber of deaths due to prostate cancer was 47 in the short-term group and 29 in the long-term group.The 5-year overall mortality for short-term and long-term suppression was 19.0% and 15.2%,respectively; the observed hazard ratio was 1.42 (upper 95.71% confidence limit, 1.79; P=0.65 fornoninferiority). Adverse events in both groups included fatigue, diminished sexual function, and hotflushes. CONCLUSIONS The combination of radiotherapy plus 6 months of androgen suppression providesinferior survival as compared with radiotherapy plus 3 years of androgen suppression in the treatment oflocally advanced prostate cancer. (ClinicalTrials.gov number, NCT00003026.)", "metadata": {}}
+{"_id": "313394", "title": "", "text": "A Functional Neuroimaging Study of Sound Localization: Visual Cortex Activity Predicts Performance inEarly-Blind IndividualsBlind individuals often demonstrate enhanced nonvisual perceptual abilities.However, the neural substrate that underlies this improved performance remains to be fully understood.An earlier behavioral study demonstrated that some early-blind people localize sounds more accuratelythan sighted controls using monaural cues. In order to investigate the neural basis of these behavioraldifferences in humans, we carried out functional imaging studies using positron emission tomography anda speaker array that permitted pseudo-free-field presentations within the scanner. During binaural soundlocalization, a sighted control group showed decreased cerebral blood flow in the occipital lobe, which wasnot seen in early-blind individuals. During monaural sound localization (one ear plugged), the subgroup ofearly-blind subjects who were behaviorally superior at sound localization displayed two activation foci inthe occipital cortex. This effect was not seen in blind persons who did not have superior monaural soundlocalization abilities, nor in sighted individuals. The degree of activation of one of these foci was stronglycorrelated with sound localization accuracy across the entire group of blind subjects. The results showthat those blind persons who perform better than sighted persons recruit occipital areas to carry outauditory localization under monaural conditions. We therefore conclude that computations carried out inthe occipital cortex specifically underlie the enhanced capacity to use monaural cues. Our findings shedlight not only on intermodal compensatory mechanisms, but also on individual differences in thesemechanisms and on inhibitory patterns that differ between sighted individuals and those deprived ofvision early in life.", "metadata": {}}
+{"_id": "313403", "title": "", "text": "High-Infiltration of Tumor-Associated Macrophages Predicts Unfavorable Clinical Outcome forNode-Negative Breast CancerThe tumor microenvironment is composed of tumor cells, fibroblasts,endothelial cells and infiltrating immune cells, which may inhibit or promote tumor growth andprogression. The objectives of this retrospective study were to characterize the density oftumor-associated macrophages (TAMs) in breast cancer, and to correlate the density of TAMs withclinicopathological parameters. Paraffin-embedded specimens and clinicopathological data, including upto 5 years follow-up information, were obtained from 172 breast cancer patients. Immunohistochemicalstaining for CD68 (marker for macrophages) was performed and evaluated in a blinded fashion. We foundthat TAMs were significantly frequent in high histopathological grade breast cancer patients. Breastcancer patients with a high density of TAMs had significantly lower rates of disease-free survival and5-year overall survival than patients with low density of TAMs. Furthermore, high-infiltration of TAMsindicated worse survival rate for patients with node-negative breast cancer. In conclusion, the number ofTAMs in the tumor stroma is an independent predictor of survival time for breast cancer patients.High-infiltration of TAMs is a significant unfavorable prognostic factor for patients with invasive breastcancer and, as such, is a potentially useful prognostic marker for breast cancer.", "metadata": {}}
+{"_id": "317204", "title": "", "text": "Murine Dishevelled 3 Functions in Redundant Pathways with Dishevelled 1 and 2 in Normal CardiacOutflow Tract, Cochlea, and Neural Tube DevelopmentDishevelled (Dvl) proteins are important signalingcomponents of both the canonical beta-catenin/Wnt pathway, which controls cell proliferation andpatterning, and the planar cell polarity (PCP) pathway, which coordinates cell polarity within a sheet ofcells and also directs convergent extension cell (CE) movements that produce narrowing and elongationof the tissue. Three mammalian Dvl genes have been identified and the developmental roles of Dvl1 andDvl2 were previously determined. Here, we identify the functions of Dvl3 in development and provideevidence of functional redundancy among the three murine Dvls. Dvl3(-/-) mice died perinatally withcardiac outflow tract abnormalities, including double outlet right ventricle and persistent truncusarteriosis. These mutants also displayed a misorientated stereocilia in the organ of Corti, a phenotypethat was enhanced with the additional loss of a single allele of the PCP component Vangl2/Ltap(LtapLp/+). Although neurulation appeared normal in both Dvl3(-/-) and LtapLp/+ mutants,Dvl3(+/-);LtapLp/+ combined mutants displayed incomplete neural tube closure. Importantly, we showthat many of the roles of Dvl3 are also shared by Dvl1 and Dvl2. More severe phenotypes were observedin Dvl3 mutants with the deficiency of another Dvl, and increasing Dvl dosage genetically with Dvltransgenes demonstrated the ability of Dvls to compensate for each other to enable normal development.Interestingly, global canonical Wnt signaling appeared largely unaffected in the double Dvl mutants,suggesting that low Dvl levels are sufficient for functional canonical Wnt signals. In summary, wedemonstrate that Dvl3 is required for cardiac outflow tract development and describe its importance inthe PCP pathway during neurulation and cochlea development. Finally, we establish severaldevelopmental processes in which the three Dvls are functionally redundant.", "metadata": {}}
+{"_id": "323030", "title": "", "text": "Dynamics of adherens junctions in epithelial establishment, maintenance, and remodelingThe epithelialcadherin (E-cadherin)-catenin complex binds to cytoskeletal components and regulatory and signalingmolecules to form a mature adherens junction (AJ). This dynamic structure physically connectsneighboring epithelial cells, couples intercellular adhesive contacts to the cytoskeleton, and helps defineeach cell's apical-basal axis. Together these activities coordinate the form, polarity, and function of allcells in an epithelium. Several molecules regulate AJ formation and integrity, including Rho familyGTPases and Par polarity proteins. However, only recently, with the development of live-cell imaging, hasthe extent to which E-cadherin is actively turned over at junctions begun to be appreciated. This turnovercontributes to junction formation and to the maintenance of epithelial integrity during tissue homeostasisand remodeling.", "metadata": {}}
+{"_id": "323335", "title": "", "text": "Long-term outcome of patients with asystole induced by head-up tilt test.AIMS To analyse the long-termoutcome of the largest reported cohort of patients presenting asystole during head-up tilt test. METHODSAND RESULTS Since 1990, 1322 patients with syncope of unknown origin have undergone tilt-tabletesting. Of those, 330 patients (24 X 9%) presented an abnormal response (syncope or pre-syncope).Furthermore, 58 of those patients (17 X 5%) suffered a period of asystole (> or = 3000 ms) during thetest. Asystole (median (interquartile range)) lasted 10 (4, 19 X 2) s (range 3-90). Two different protocols(angles) of tilting (Westminster (60 degrees) n=1124; isoproterenol (80 degrees) n=198)) influenced thetime to the syncopal episode (13 (6 X 5, 20 X 5) vs 2 (1, 6 X 5) min, P=0,0005) but not the duration ofthe asystole. During this period, therapy for asystole featured three different stages: first patients weretreated with pacemakers; later drug therapy (metoprolol and/or etilefrine) was recommended; lastly(from 1995), no specific treatment was given. In a cohort age- and gender-matched study, those patientswithout were compared to those with asystole in a 2:1 basis. During 40 X 7 months of follow-up (17 X 7,66 X 8), 12 patients (20 X 6%) with asystole had syncopal recurrences. Furthermore, 34 patients (28 X8%) without asystole presented syncopal episodes during a follow-up of 51 X 6 months (29 X 3, 73 X 1)(P=ns). The Kaplan-Meier analysis in patients with and without asystole showed a mean time free ofrecurrence of 92 X 6 +/- 6 months vs 82 X 6 +/- 4 X 7 months (P=ns). The previous number of syncopeshad a significant relationship with recurrences (P=0 X 002), but not therapy. There were no cardiacrelated deaths. CONCLUSIONS (1) Asystole during head-up tilt test does not imply a malignant outcomeand syncope recurrence is low; (2) pacemaker or drug therapy do not significantly influence outcomewhich correlates to the previous number of syncopal episodes but not to gender, age, asystoleoccurrence, asystole duration and timing to asystole during head-up tilt test; (3) tilting protocol (angle)might influence time to and incidence of asystole during head-up tilt test.", "metadata": {}}
+{"_id": "327319", "title": "", "text": "ZINC 15 – Ligand Discovery for EveryoneMany questions about the biological activity and availability ofsmall molecules remain inaccessible to investigators who could most benefit from their answers. Tonarrow the gap between chemoinformatics and biology, we have developed a suite of ligand annotation,purchasability, target, and biology association tools, incorporated into ZINC and meant for investigatorswho are not computer specialists. The new version contains over 120 million purchasable \"drug-like\"compounds--effectively all organic molecules that are for sale--a quarter of which are available forimmediate delivery. ZINC connects purchasable compounds to high-value ones such as metabolites,drugs, natural products, and annotated compounds from the literature. Compounds may be accessed bythe genes for which they are annotated as well as the major and minor target classes to which thosegenes belong. It offers new analysis tools that are easy for nonspecialists yet with few limitations forexperts. ZINC retains its original 3D roots--all molecules are available in biologically relevant,ready-to-dock formats. ZINC is freely available at http://zinc15.docking.org.", "metadata": {}}
+{"_id": "335029", "title": "", "text": "Condensin-mediated remodeling of the mitotic chromatin landscape in fission yeastThe eukaryoticgenome consists of DNA molecules far longer than the cells that contain them. They reach their greatestcompaction during chromosome condensation in mitosis. This process is aided by condensin, a structuralmaintenance of chromosomes (SMC) family member. The spatial organization of mitotic chromosomesand how condensin shapes chromatin architecture are not yet fully understood. Here we use chromosomeconformation capture (Hi-C) to study mitotic chromosome condensation in the fission yeastSchizosaccharomyces pombe. This showed that the interphase landscape characterized by smallchromatin domains is replaced by fewer but larger domains in mitosis. Condensin achieves this by settingup longer-range, intrachromosomal DNA interactions, which compact and individualize chromosomes. Atthe same time, local chromatin contacts are constrained by condensin, with profound implications forlocal chromatin function during mitosis. Our results highlight condensin as a major determinant thatchanges the chromatin landscape as cells prepare their genomes for cell division.", "metadata": {}}
+{"_id": "341324", "title": "", "text": "Efficacy of the 6-month thrice-weekly regimen in the treatment of new sputum smear-positive pulmonarytuberculosis under clinical trial conditions.BACKGROUND Under the Revised National Tuberculosis ControlProgramme of India, patients with new smear-positive pulmonary tuberculosis are treated with athrice-weekly regimen of antitubercular drugs (2H(3)R(3)Z(3)E(3)/4H(3)R(3) [H isoniazid, R rifampicin, Zpyrazinamide and E ethambutol]) for 6 months. We conducted a retrospective analysis of the efficacyandtolerability of this regimen under clinical trial conditions in HIV-negative patients with newlydiagnosed smear-positive pulmonary tuberculosis. METHODS We retrospectively analysed the data onpatients assigned to the control regimen (2H (3)R(3)Z(3)E(3)/4H(3)R(3)) in two clinical trials during2001-06 at the National Institute for Research in Tuberculosis, Chennai, India. RESULTS Of the 268patients treated with this regimen, data for efficacy analysis were available for 249. At the end oftreatment, of 249 patients, 238 (96%) had a favourable status. Treatment failure occurred in theremaining 11: 7 in whom the organisms were initially drug-susceptible and 4 with initial drug resistance.Of the 238 patients who had a favourable status at the end of treatment, 14 (6%) had recurrence oftuberculosis during the following 24 months. In the intention-to-treat analysis, 245 (94%) of 262 patientshad a favourable status at the end of treatment. Of the 28 patients with initial drug resistance, 24 (86%)had a favourable outcome. Only 4 of these 24 patients were found to have recurrence of tuberculosis in 2years of follow-up. Among the 221 patients initially infected with drug-susceptible organisms, drugresistance did not develop in any of the 7 patients in whom the treatment failed or the 10 who hadrecurrence of tuberculosis. Further, 5 of the 7 patients in whom the treatment failed continued to excretedrug-susceptible bacilli at 6 months. Adverse drug reactions were observed in 38 (14%) of the 262patients. Only 3 (1.1%) needed a modification in the treatment. CONCLUSION This thrice-weekly6-month regimen of antitubercular drugs, when administered under full supervision, is associated with ahigh rate of favourable treatment outcomes in HIV-negative patients with newly diagnosed sputumsmearpositive pulmonary tuberculosis. There are few adverse drug reactions in these patients.", "metadata": {}}
+{"_id": "343052", "title": "", "text": "Curcumin attenuates inflammatory response in IL-1beta-induced human synovial fibroblasts andcollagen-induced arthritis in mouse model.Curcumin, a major component of turmeric, has been shown toexhibit anti-oxidant and anti-inflammatory activities. The present study was performed to determinewhether curcumin is efficacious against both collagen-induced arthritis (CIA) in mice andIL-1beta-induced activation in fibroblast-like synoviocytes (FLSs). DBA/1 mice were immunized withbovine type II collagen (CII) and treated with curcumin every other day for 2weeks after the initialimmunization. For arthritis, we evaluated the incidence of disease and used an arthritis index based onpaw thickness. In vitro proliferation of CII- or concanavalin A-induced splenic T cells was examined usingIFN-gamma production. Pro-inflammatory cytokines TNF-alpha and IL-1beta were examined in the mouseankle joint and serum IgG1 and IgG2a isotypes were analyzed. The expression levels of prostaglandinE(2) (PGE(2)), cyclooxygenase-2 (COX-2), and matrix metalloproteinases (MMPs) in human FLSs werealso determined. The results showed that compared with untreated CIA mice, curcumin-treated micedownregulated clinical arthritis score, the proliferation of splenic T cells, expression levels of TNF-alphaand IL-1beta in the ankle joint, and expression levels of IgG2a in serum. Additionally, by altering nuclearfactor (NF)-kappaB transcription activity in FLSs, curcumin inhibited PGE(2) production, COX-2expression, and MMP secretion. These results suggest that curcumin can effectively suppressinflammatory response by inhibiting pro-inflammatory mediators and regulating humoral and cellularimmune responses.", "metadata": {}}
+{"_id": "344240", "title": "", "text": "Loss of IGF-IEa or IGF-IEb impairs myogenic differentiation.Actions of protein products resulting fromalternative splicing of the Igf1 gene have received increasing attention in recent years. However, thesignificance and functional relevance of these observations remain poorly defined. To address functions ofIGF-I splice variants, we examined the impact of loss of IGF-IEa and IGF-IEb on the proliferation anddifferentiation of cultured mouse myoblasts. RNA interference-mediated reductions in total IGF-I, IGF-IEaalone, or IGF-IEb alone had no effect on cell viability in growth medium. However, cells deficient in totalIGF-I or IGF-IEa alone proliferated significantly slower than control cells or cells deficient in IGF-IEb inserum-free media. Simultaneous loss of both or specific loss of either splice variant significantly inhibitedmyosin heavy chain (MyHC) immunoreactivity by 70-80% (P < 0.01) under differentiation conditions (48h in 2% horse serum) as determined by Western immunoblotting. This loss in protein was associated withreduced MyHC isoform mRNAs, because reductions in total IGF-I or IGF-IEa mRNA significantly reducedMyHC mRNAs by approximately 50-75% (P < 0.05). Loss of IGF-IEb also reduced MyHC isoform mRNAsignificantly, with the exception of Myh7, but to a lesser degree (\u000020-40%, P < 0.05). Provision ofmature IGF-I, but not synthetic E peptides, restored Myh3 expression to control levels in cells deficient inIGF-IEa or IGF-IEb. Collectively, these data suggest that IGF-I splice variants may regulate myoblastdifferentiation through the actions of mature IGF-I and not the E peptides.", "metadata": {}}
+{"_id": "350542", "title": "", "text": "Antimicrobial peptide pleurocidin synergizes with antibiotics through hydroxyl radical formation andmembrane damage, and exerts antibiofilm activity.BACKGROUND Pleurocidin, a 25-mer antimicrobialpeptide (AMP), is known to exert bactericidal activity. However, the synergistic activity and mechanism(s)of pleurocidin in combination with conventional antibiotics, and the antibiofilm effect of the peptide arepoorly understood. METHODS The interaction between pleurocidin and antibiotics was evaluated usingcheckerboard assay. To study the mechanism(s) involved in their synergism, we detected hydroxylradical formation using 3'-(p-hydroxyphenyl) fluorescein, measured the NAD(+)/NADH ratio by NAD(+)cycling assay, observed change in bacterial viability with the hydroxyl radical scavenger thiourea, andinvestigated cytoplasmic membrane damage using propidium iodide. Also, the antibiofilm effect ofpleurocidin was examined with the tissue culture plate method. RESULTS All combinations of pleurocidinand antibiotics showed synergistic interaction against bacterial strains (fractional inhibitory concentrationindex (FICI)≤0.5) except for Enterococcus faecium treated with a combination of the peptide andampicillin (FICI=0.75). We identified that pleurocidin alone and in combinations with antibiotics inducedformation of hydroxyl radicals. The oxidative stress was caused by a transient NADH depletion and theaddition of thiourea prevented bacterial death, especially in the case of the combined treatment ofpleurocidin and ampicillin showing synergisms. The combination of pleurocidin and erythromycinincreased permeability of bacterial cytoplasmic membrane. Additionally, pleurocidin exhibited a potentinhibitory effect on preformed biofilm of bacterial organisms. In conclusion, pleurocidin synergized withantibiotics through hydroxyl radical formation and membrane-active mechanism, and exerted antibiofilmactivity. GENERAL SIGNIFICANCE The synergistic effect between pleurocidin and antibiotics suggests theAMP is a potential therapeutic agent and adjuvant for antimicrobial chemotherapy.", "metadata": {}}
+{"_id": "356218", "title": "", "text": "Outcome of pregnancy in women with moderate or severe renal insufficiency.BACKGROUND Pregnantwomen with mild preexisting renal disease have relatively few complications of pregnancy, but the risksof maternal and obstetrical complications in women with moderate or severe renal insufficiency remainuncertain. METHODS We determined the frequency and types of maternal and obstetrical complicationsand the outcomes of pregnancy in 67 women with primary renal disease (82 pregnancies). All the womenhad initial serum creatinine concentrations of at least 1.4 mg per deciliter (124 mumol per liter) andgestations that continued beyond the first trimester. RESULTS The mean (+/- SD) serum creatinineconcentration increased from 1.9 +/- 0.8 mg per deciliter (168 +/- 71 mumol per liter) in earlypregnancy to 2.5 +/- 1.3 mg per deciliter (221 +/- 115 mumol per liter) in the third trimester. Thefrequency of hypertension rose from 28 percent at base line to 48 percent in the third trimester, and thatof high-grade proteinuria (urinary protein excretion, > 3000 mg per liter) from 23 percent to 41 percent.For the 70 pregnancies (57 women) for which data were available during pregnancy and immediatelypost partum, pregnancy-related loss of maternal renal function occurred in 43 percent. Eight of thesepregnancies (10 percent of the total) were associated with rapid acceleration of maternal renalinsufficiency. Obstetrical complications included a high rate of preterm delivery (59 percent) and growthretardation (37 percent). The infant survival rate was 93 percent. CONCLUSIONS Among pregnantwomen with moderate or severe renal insufficiency, the rates of complications due to worsening renalfunction, hypertension, and obstetrical complications are increased, but fetal survival is high.", "metadata": {}}
+{"_id": "364522", "title": "", "text": "High-mobility group box-1 protein induces osteogenic phenotype changes in aortic valve interstitialcells.OBJECTIVES Calcific aortic valve (AV) disease is known to be an inflammation-related process.High-mobility group box-1 (HMGB1) protein and Toll-like receptor 4 (TLR4) have been reported toparticipate in several inflammatory diseases. The purpose of the present study was to determine whetherthe HMGB1-TLR4 axis is involved in calcific AV disease, and to evaluate the effect of HMGB1, and itspotential mechanisms, on the pro-osteogenic phenotype change of valvular interstitial cells (VICs).METHODS Expression of HMGB1 and TLR4 in human calcific AVs was evaluated usingimmunohistochemical staining and immunoblotting. Cultured VICs were used as an in vitro model. TheVICs were stimulated with HMGB1 for analysis, with versus without TLR4 small interfering ribonucleic acid(siRNA), c-Jun N-terminal kinase mitogen-activated protein kinase (JNK MAPK), and nuclear factorkappa-B (NF-κB) inhibitors. RESULTS Enhanced accumulation of HMGB1 and TLR4 was observed incalcific valves. Moreover, we found that HMGB1 induced high levels of pro-inflammatory cytokineproduction and promoted the osteoblastic differentiation and calcification of VICs. In addition, HMGB1induced phosphorylation of JNK MAPK and NF-κB. However, these effects were markedly suppressed bysiRNA silencing of TLR4. In addition, blockade of JNK MAPK and NF-κB phosphorylation prohibitedHMGB1-induced production of pro-osteogenic factors, and mineralization of VICs. CONCLUSIONS TheHMGB1 protein may promote osteoblastic differentiation and calcification of VICs, through theTLR4-JNK-NF-κB signaling pathway.", "metadata": {}}
+{"_id": "365896", "title": "", "text": "RiboSys, a high-resolution, quantitative approach to measure the in vivo kinetics of pre-mRNA splicingand 3'-end processing in Saccharomyces cerevisiae.We describe methods for obtaining a quantitativedescription of RNA processing at high resolution in budding yeast. As a model gene expression system,we constructed tetON (for induction studies) and tetOFF (for repression, derepression, and RNAdegradation studies) yeast strains with a series of reporter genes integrated in the genome under thecontrol of a tetO7 promoter. Reverse transcription and quantitative real-time-PCR (RT-qPCR) methodswere adapted to allow the determination of mRNA abundance as the average number of copies per cell ina population. Fluorescence in situ hybridization (FISH) measurements of transcript numbers in individualcells validated the RT-qPCR approach for the average copy-number determination despite the broaddistribution of transcript levels within a population of cells. In addition, RT-qPCR was used to distinguishthe products of the different steps in splicing of the reporter transcripts, and methods were developed tomap and quantify 3'-end cleavage and polyadenylation. This system permits pre-mRNA production,splicing, 3'-end maturation and degradation to be quantitatively monitored with unprecedented kineticdetail, suitable for mathematical modeling. Using this approach, we demonstrate that reporter transcriptsare spliced prior to their 3'-end cleavage and polyadenylation, that is, cotranscriptionally.", "metadata": {}}
+{"_id": "368506", "title": "", "text": "Generation of mice with a conditional allele for the p75(NTR) neurotrophin receptor gene.The p75(NTR)neurotrophin receptor has been implicated in multiple biological and pathological processes. Whilesignificant advances have recently been made in understanding the physiologic role of p75(NTR) , manydetails and aspects remain to be determined. This is in part because the two existing knockout mousemodels (Exons 3 or 4 deleted, respectively), both display features that defy definitive conclusions. Herewe describe the generation of mice that carry a conditional p75(NTR) (p75(NTR-FX) ) allele made byflanking Exons 4-6, which encode the transmembrane and all cytoplasmic domains, by loxP sites. Tovalidate this novel conditional allele, both neural crest-specific p75(NTR) /Wnt1-Cre mutants andconventional p75(NTR) null mutants were generated. Both mutants displayed abnormal hind limbreflexes, implying that loss of p75(NTR) in neural crest-derived cells causes a peripheral neuropathysimilar to that seen in conventional p75(NTR) mutants. This novel conditional p75(NTR) allele will offernew opportunities to investigate the role of p75(NTR) in specific tissues and cells.", "metadata": {}}
+{"_id": "371289", "title": "", "text": "A Triple-Stain Flow Cytometric Method to Assess Plasma- and Acrosome-Membrane Integrity ofCryopreserved Bovine Sperm Immediately after Thawing in Presence of Egg-Yolk Particles1AbstractSimultaneously evaluating postthaw viability and acrosome integrity of spermatozoa by flow cytometrywould provide a valuable testing tool in both research and routine work. In the present study, a newtriple-stain combination was developed for the simultaneous evaluation of viability and acrosome integrityof bovine sperm processed in egg yolk-based extender by flow cytometer. SYBR-14 and propidium iodide(PI) enabled the discrimination of sperm cells from egg yolk and debris particles, which was instrumentalfor the flow cytometric analyses of frozen-thawed bovine sperm, because it implied that washing steps toremove egg yolk were no longer required. In addition, phycoerythrin-conjugated peanut agglutinin(PE-PNA) was used to discriminate acrosome-damaged/reacted sperm cells from acrosome-intact cells.Repeatability was calculated using two processed ejaculates of 10 bulls. Three straws per batch wereanalyzed in duplicate measurements. Method-agreement analysis between the SYBR-14/PE-PNA/PI andfluorescein isothiocyanate (FITC)-conjugated PNA was performed, with FITC-PNA/PI staining beingcarried out on 14 frozen-thawed semen samples immediately after thawing and after a 3-h incubation at37°C. The British Standards Institution repeatability index of the SYBR-14/PE-PNA/PI combination was2.6%. On average, the FITC-PNA/PI method showed a 6.3% overestimation of the live andacrosome-intact sperm cell subpopulation. In conclusion, the new triple-stain combination is highlyrepeatable and easy to use in routine application, and it provides a more precise estimate for the rate ofsperm cells with intact head membrane and acrosome compared to the generally used and validatedFITC-PNA/PI staining.", "metadata": {}}
+{"_id": "374902", "title": "", "text": "Universal voluntary HIV testing with immediate antiretroviral therapy as a strategy for elimination of HIVtransmission: a mathematical model.BACKGROUND Roughly 3 million people worldwide were receivingantiretroviral therapy (ART) at the end of 2007, but an estimated 6.7 million were still in need oftreatment and a further 2.7 million became infected with HIV in 2007. Prevention efforts might reduceHIV incidence but are unlikely to eliminate this disease. We investigated a theoretical strategy ofuniversal voluntary HIV testing and immediate treatment with ART, and examined the conditions underwhich the HIV epidemic could be driven towards elimination. METHODS We used mathematical models toexplore the effect on the case reproduction number (stochastic model) and long-term dynamics of theHIV epidemic (deterministic transmission model) of testing all people in our test-case community (aged15 years and older) for HIV every year and starting people on ART immediately after they are diagnosedHIV positive. We used data from South Africa as the test case for a generalised epidemic, and assumedthat all HIV transmission was heterosexual. FINDINGS The studied strategy could greatly accelerate thetransition from the present endemic phase, in which most adults living with HIV are not receiving ART, toan elimination phase, in which most are on ART, within 5 years. It could reduce HIV incidence andmortality to less than one case per 1000 people per year by 2016, or within 10 years of fullimplementation of the strategy, and reduce the prevalence of HIV to less than 1% within 50 years. Weestimate that in 2032, the yearly cost of the present strategy and the theoretical strategy would both beUS$1.7 billion; however, after this time, the cost of the present strategy would continue to increasewhereas that of the theoretical strategy would decrease. INTERPRETATION Universal voluntary HIVtesting and immediate ART, combined with present prevention approaches, could have a major effect onsevere generalised HIV/AIDS epidemics. This approach merits further mathematical modelling, research,and broad consultation.", "metadata": {}}
+{"_id": "380526", "title": "", "text": "Common variants in DGKK are strongly associated with risk of hypospadiasHypospadias is a commoncongenital malformation of the male external genitalia. We performed a genome-wide association studyusing pooled DNA from 436 individuals with hypospadias (cases) and 494 controls of European descentand selected the highest ranked SNPs for individual genotyping in the discovery sample, an additionalDutch sample of 133 cases and their parents, and a Swedish series of 266 cases and 402 controls.Individual genotyping of two SNPs (rs1934179 and rs7063116) in DGKK, encoding diacylglycerol kinaseκ, produced compelling evidence for association with hypospadias in the discovery sample (allele-specificodds ratio (OR) = 2.5, P = 2.5 × 10−11 and OR = 2.3, P = 2.9 × 10−9, respectively) and in the Dutch(OR = 3.9, P = 2.4 × 10−5 and OR = 3.8, P = 3.4 × 10−5) and Swedish (OR = 2.5, P = 2.6 × 10−8 andOR = 2.2, P = 2.7 × 10−6) replication samples. Expression studies showed expression of DGKK inpreputial tissue of cases and controls, which was lower in carriers of the risk allele of rs1934179 (P =0.047). We propose DGKK as a major risk gene for hypospadias.", "metadata": {}}
+{"_id": "381602", "title": "", "text": "Neutrophils Suppress Intraluminal NK Cell-Mediated Tumor Cell Clearance and Enhance Extravasation ofDisseminated Carcinoma Cells.UNLABELLED Immune cells promote the initial metastatic dissemination ofcarcinoma cells from primary tumors. In contrast to their well-studied functions in the initial stages ofmetastasis, the specific roles of immunocytes in facilitating progression through the critical later steps ofthe invasion-metastasis cascade remain poorly understood. Here, we define novel functions of neutrophilsin promoting intraluminal survival and extravasation at sites of metastatic dissemination. We show thatCD11b(+)/Ly6G(+) neutrophils enhance metastasis formation via two distinct mechanisms. First,neutrophils inhibit natural killer cell function, which leads to a significant increase in the intraluminalsurvival time of tumor cells. Thereafter, neutrophils operate to facilitate extravasation of tumor cellsthrough the secretion of IL1β and matrix metalloproteinases. These results identify neutrophils as keyregulators of intraluminal survival and extravasation through their cross-talk with host cells anddisseminating carcinoma cells. SIGNIFICANCE This study provides important insights into the systemiccontributions of neutrophils to cancer metastasis by identifying how neutrophils facilitate intermediatesteps of the invasion-metastasis cascade. We demonstrate that neutrophils suppress natural killer cellactivity and increase extravasation of tumor cells. Cancer Discov; 6(6); 630-49. ©2016 AACR.This articleis highlighted in the In This Issue feature, p. 561.", "metadata": {}}
+{"_id": "393001", "title": "", "text": "High Km soluble 5'-nucleotidase from human placenta. Properties and allosteric regulation by IMP andATP.A human placental soluble \"high Km\" 5'-nucleotidase has been separated from \"low Km\"5'-nucleotidase and nonspecific phosphatase by AMP-Sepharose affinity chromatography. The enzymewas purified 8000-fold to a specific activity of 25.6 mumol/min/mg. The subunit molecular mass is 53kDa, and the native molecular mass is 210 kDa, suggesting a tetrameric structure. Soluble high Km5'-nucleotidase is most active with IMP and GMP and their deoxy derivatives. IMP is hydrolyzed 15 timesfaster than AMP. The enzyme has a virtually absolute requirement for magnesium ions and is regulatedby them. Purine nucleoside 5'-triphosphates strongly activate the enzyme with the potency order dATPgreater than ATP greater than GTP. 2,3-Diphosphoglycerate activates the enzyme as potently as ATP.Three millimolar ATP decreased the Km for IMP from 0.33 to 0.09 mM and increased the Vmax 12-fold.ATP activation was modified by the IMP concentration. At 20 microM IMP the ATP-dependent activationcurve was sigmoidal, while at 2 mM IMP it was hyperbolic. The A0.5 values for ATP were 2.26 and 0.70mM, and the relative maximal velocities were 32.9 and 126.0 nmol/min, respectively. Inorganicphosphate shifts the hyperbolic substrate velocity relationship for IMP to a sigmoidal one. Withphysiological concentrations of cofactors (3 mM ATP, 1-4 mM Pi, 150 mM KCl) at pH 7.4, the enzyme is25-35 times more active toward 100 microM IMP than 100 microM AMP. These data show that: (a)soluble human placental high Km 5'-nucleotidase coexists in human placenta with the low Km enzyme;(b) under physiological conditions the enzyme favors the hydrolysis of IMP and is critically regulated byIMP, ATP, and Pi levels; and (c) kinetic properties of ATP and IMP are each modified by the othercompound suggesting complex interaction of the associated binding sites.", "metadata": {}}
+{"_id": "406733", "title": "", "text": "Histones are incorporated in trans during reassembly of the yeast PHO5 promoter.In yeast, remodeling ofPHO5 promoter chromatin upon activation is accompanied by transient hyperacetylation and subsequenteviction of histones from the promoter in trans. In the course of rerepression, nucleosomes have to bereassembled on the promoter. We have analyzed where the histones for reassembly of the inactivepromoter chromatin come from. The use of a strain with two differently tagged and differently regulatedversions of histone H3 allowed us to discriminate between histones originating from the chromatinfraction and histones arising from the soluble histone pool. In this way, we show that the incorporatedhistones originate from a source in trans. Promoter closure occurs very rapidly, and the histonechaperones Asf1 and Hir1 as well as the SWI/SNF nucleosome remodeling complex appear to beimportant for rapid reassembly of nucleosomes at the PHO5 promoter.", "metadata": {}}
+{"_id": "409280", "title": "", "text": "National study of physician awareness and adherence to cardiovascular disease preventionguidelines.BACKGROUND Few data have evaluated physician adherence to cardiovascular disease (CVD)prevention guidelines according to physician specialty or patient characteristics, particularly gender.METHODS AND RESULTS An online study of 500 randomly selected physicians (300 primary carephysicians, 100 obstetricians/gynecologists, and 100 cardiologists) used a standardized questionnaire toassess awareness of, adoption of, and barriers to national CVD prevention guidelines by specialty. Anexperimental case study design tested physician accuracy and determinants of CVD risk level assignmentand application of guidelines among high-, intermediate-, or low-risk patients. Intermediate-risk women,as assessed by the Framingham risk score, were significantly more likely to be assigned to a lower-riskcategory by primary care physicians than men with identical risk profiles (P<0.0001), and trends weresimilar for obstetricians/gynecologists and cardiologists. Assignment of risk level significantly predictedrecommendations for lifestyle and preventive pharmacotherapy. After adjustment for risk assignment,the impact of patient gender on preventive care was not significant except for less aspirin (P<0.01) andmore weight management recommended (P<0.04) for intermediate-risk women. Physicians did not ratethemselves as very effective in their ability to help patients prevent CVD. Fewer than 1 in 5 physiciansknew that more women than men die each year from CVD. CONCLUSIONS Perception of risk was theprimary factor associated with CVD preventive recommendations. Gender disparities in recommendationsfor preventive therapy were explained largely by the lower perceived risk despite similar calculated riskfor women versus men. Educational interventions for physicians are needed to improve the quality of CVDpreventive care and lower morbidity and mortality from CVD for men and women.", "metadata": {}}
+{"_id": "410286", "title": "", "text": "TECHNICAL ADVANCE Floral dip: a simplified method for Agrobacterium-mediatedThe Agrobacteriumvacuum infiltration method has made it possible to transform Arabidopsis thaliana without plant tissueculture or regeneration. In the present study, this method was evaluated and a substantially modifiedtransformation method was developed. The labor-intensive vacuum infiltration process was eliminated infavor of simple dipping of developing floral tissues into a solution containing Agrobacterium tumefaciens,5% sucrose and 500 microliters per litre of surfactant Silwet L-77. Sucrose and surfactant were critical tothe success of the floral dip method. Plants inoculated when numerous immature floral buds and fewsiliques were present produced transformed progeny at the highest rate. Plant tissue culture media, thehormone benzylamino purine and pH adjustment were unnecessary, and Agrobacterium could be appliedto plants at a range of cell densities. Repeated application of Agrobacterium improved transformationrates and overall yield of transformants approximately twofold. Covering plants for 1 day to retainhumidity after inoculation also raised transformation rates twofold. Multiple ecotypes were transformableby this method. The modified method should facilitate high-throughput transformation of Arabidopsis forefforts such as T-DNA gene tagging, positional cloning, or attempts at targeted gene replacement.", "metadata": {}}
+{"_id": "418246", "title": "", "text": "Pathway connectivity and signaling coordination in the yeast stress-activated signaling networkStressedcells coordinate a multi-faceted response spanning many levels of physiology. Yet knowledge of thecomplete stress-activated regulatory network as well as design principles for signal integration remainsincomplete. We developed an experimental and computational approach to integrate available proteininteraction data with gene fitness contributions, mutant transcriptome profiles, and phospho-proteomechanges in cells responding to salt stress, to infer the salt-responsive signaling network in yeast. Theinferred subnetwork presented many novel predictions by implicating new regulators, uncoveringunrecognized crosstalk between known pathways, and pointing to previously unknown 'hubs' of signalintegration. We exploited these predictions to show that Cdc14 phosphatase is a central hub in thenetwork and that modification of RNA polymerase II coordinates induction of stress-defense genes withreduction of growth-related transcripts. We find that the orthologous human network is enriched forcancer-causing genes, underscoring the importance of the subnetwork's predictions in understandingstress biology.", "metadata": {}}
+{"_id": "427082", "title": "", "text": "Premigratory and migratory neural crest cells are multipotent in vivo.The neural crest (NC) is anembryonic stem/progenitor cell population that generates a diverse array of cell lineages, includingperipheral neurons, myelinating Schwann cells, and melanocytes, among others. However, there is along-standing controversy as to whether this broad developmental perspective reflects in vivomultipotency of individual NC cells or whether the NC is comprised of a heterogeneous mixture oflineage-restricted progenitors. Here, we resolve this controversy by performing in vivo fate mapping ofsingle trunk NC cells both at premigratory and migratory stages using the R26R-Confetti mouse model.By combining quantitative clonal analyses with definitive markers of differentiation, we demonstrate thatthe vast majority of individual NC cells are multipotent, with only few clones contributing to singlederivatives. Intriguingly, multipotency is maintained in migratory NC cells. Thus, our findings providedefinitive evidence for the in vivo multipotency of both premigratory and migrating NC cells in the mouse.", "metadata": {}}
+{"_id": "427865", "title": "", "text": "Implementing the ESHRE 'poor responder' criteria in research studies: methodological implications.TheBologna criteria for defining poor ovarian response (POR) during IVF provide a useful template for newresearch in this field of assisted conception. However, designing studies around the European Society forHuman Reproduction and Embryology POR criteria can be methodologically challenging, as the newdefinition includes various POR subpopulations with diverse baseline characteristics and unknown clinicalprognosis. When designing RCTs, potential result bias may be introduced if women from eachsubpopulation are not evenly allocated between intervention groups. In the case of small ormoderate-size RCTs, a single-sequence randomization method may not ensure balanced allocationbetween groups. Stratified randomization methods provide an alternative methodological approach.Depending on the chosen methodology, patient characteristics and outcomes within each interventiongroup may be better reported according to relevant subpopulations.", "metadata": {}}
+{"_id": "432261", "title": "", "text": "Generation of gene-edited rats by delivery of CRISPR/Cas9 protein and donor DNA into intact zygotesusing electroporationThe generation of gene-edited animals using the CRISPRs/Cas9 system is based onmicroinjection into zygotes which is inefficient, time consuming and demands high technical skills. Wereport the optimization of an electroporation method for intact rat zygotes using sgRNAs and Cas9 proteinin combination or not with ssODNs (~100 nt). This resulted in high frequency of knockouts, between 15and 50% of analyzed animals. Importantly, using ssODNs as donor template resulted in precise knock-inmutations in 25-100% of analyzed animals, comparable to microinjection. Electroporation of long ssDNAor dsDNA donors successfully used in microinjection in the past did not allow generation ofgenome-edited animals despite dsDNA visualization within zygotes. Thus, simultaneous electroporation ofa large number of intact rat zygotes is a rapid, simple, and efficient method for the generation of avariety of genome-edited rats.", "metadata": {}}
+{"_id": "435529", "title": "", "text": "Uridylation of miRNAs by HEN1 SUPPRESSOR1 in ArabidopsisHEN1-mediated 2'-O-methylation has beenshown to be a key mechanism to protect plant microRNAs (miRNAs) and small interfering RNAs (siRNAs)as well as animal piwi-interacting RNAs (piRNAs) from degradation and 3' terminal uridylation [1-8].However, enzymes uridylating unmethylated miRNAs, siRNAs, or piRNAs in hen1 are unknown. In thisstudy, a genetic screen identified a second-site mutation hen1 suppressor1-2 (heso1-2) that partiallysuppresses the morphological phenotypes of the hypomorphic hen1-2 allele and the null hen1-1 allele inArabidopsis. HESO1 encodes a terminal nucleotidyl transferase that prefers to add untemplated uridine tothe 3' end of RNA, which is completely abolished by 2'-O-methylation. heso1-2 affects the profile ofu-tailed miRNAs and siRNAs and increases the abundance of truncated and/or normal sized ones in hen1,which often results in increased total amount of miRNAs and siRNAs in hen1. In contrast, overexpressingHESO1 in hen1-2 causes more severe morphological defects and less accumulation of miRNAs. Theseresults demonstrate that HESO1 is an enzyme uridylating unmethylated miRNAs and siRNAs in hen1.These observations also suggest that uridylation may destabilize unmethylated miRNAs through anunknown mechanism and compete with 3'-to-5' exoribonuclease activities in hen1. This study shall haveimplications on piRNA uridylation in hen1 in animals.", "metadata": {}}
+{"_id": "437924", "title": "", "text": "Pre-Exposure Prophylaxis to Prevent HIV Infection: Current Status, Future Opportunities andChallengesAs the global incidence of HIV exceeds 2 million new infections annually, effectiveinterventions to decrease HIV transmission are needed. Randomized, placebo-controlled studies havedemonstrated that daily oral antiretroviral pre-exposure prophylaxis (PrEP) with a fixed-dose combinationtablet containing tenofovir disoproxil fumarate and emtricitabine can significantly reduce HIV incidenceamong diverse at-risk populations. In these studies, the efficacy of PrEP was correlated with levels ofadherence. Official guidelines recommend provision of PrEP to people at greatest risk of HIV acquisition,and demonstration projects suggest that high levels of uptake and adherence are possible outside ofcontrolled studies. However, several potential barriers to implementing PrEP remain. These challengesinclude low awareness and utilization of PrEP by at-risk individuals, uncertainty about adherence in‘real-world’ settings, the majority of healthcare providers being untrained in PrEP provision, limited dataabout potential adverse effects from long-term use of tenofovir–emtricitabine, high costs of PrEPmedications, and stigma associated with PrEP use and the behaviors that would warrant PrEP. Innovativepharmacologic chemoprophylactic approaches could provide solutions to some of these challenges.Less-than-daily oral dosing regimens and long-acting injectable medications could reduce pill burdensand facilitate adherence, and local delivery of PrEP medications to genital compartments via gels, ringsand films may limit systemic drug exposure and potential toxicities. As the portfolio of chemoprophylacticagents and delivery systems expands to meet the diverse sexual health needs and product preferences ofindividuals who may benefit from PrEP, it is hoped that antiretroviral chemoprophylaxis could become anacceptable, feasible, and highly effective addition to existing HIV prevention strategies.", "metadata": {}}
+{"_id": "439670", "title": "", "text": "Prepregnancy BMI and the risk of gestational diabetes: a systematic review of the literature withmeta-analysis.The objective of this study is to assess and quantify the risk for gestational diabetesmellitus (GDM) according to prepregnancy maternal body mass index (BMI). The design is a systematicreview of observational studies published in the last 30 years. Four electronic databases were searchedfor publications (1977-2007). BMI was elected as the only measure of obesity, and all diagnostic criteriafor GDM were accepted. Studies with selective screening for GDM were excluded. There were no languagerestrictions. The methodological quality of primary studies was assessed. Some 1745 citations werescreened, and 70 studies (two unpublished) involving 671 945 women were included (59 cohorts and 11case-controls). Most studies were of high or medium quality. Compared with women with a normal BMI,the unadjusted pooled odds ratio (OR) of an underweight woman developing GDM was 0.75 (95%confidence interval [CI] 0.69 to 0.82). The OR for overweight, moderately obese and morbidly obesewomen were 1.97 (95% CI 1.77 to 2.19), 3.01 (95% CI 2.34 to 3.87) and 5.55 (95% CI 4.27 to 7.21)respectively. For every 1 kg m(-2) increase in BMI, the prevalence of GDM increased by 0.92% (95% CI0.73 to 1.10). The risk of GDM is positively associated with prepregnancy BMI. This information isimportant when counselling women planning a pregnancy.", "metadata": {}}
+{"_id": "456304", "title": "", "text": "Multiple risk behaviour: increasing socio-economic gap over time?BACKGROUND Unhealthy behavioursoften occur in combination. In this study the relationship between education and lifestyle, defined as acluster of risk behaviours, has been analysed with the purpose to assess socio-economic changes inmultiple risk behaviour over time. METHODS Cross-sectional data from the Belgian Health InterviewSurveys 1997, 2001 and 2004 were analysed. This study is restricted to persons aged ≥ 15 years withinformation on those health behaviours and education (n = 7431, n = 8142 and n = 7459, respectively).A lifestyle index was created based on the sum of the four unhealthy behaviours: smokers vs.non-smokers, risky versus non-risky alcohol use, sedentaryness vs. physically active and poor vs. healthydiet. The lifestyle index was dichotomized as low (0-2) vs. high (3-4). For the assessment ofsocio-economic inequalities in multiple risk behaviour, summary measures as Odds Ratio (OR) andRelative Index of Inequality (RII) were calculated using logistic regression, stratified by sex. RESULTS Ofthe adult population, 7.5% combined three to four unhealthy behaviours. Lower educated men are themost at risk. Besides, the OR among men significantly increased from 1.6 in 2001 to 3.4 in 2004 (P =0.029). The increase of the OR among women was less pronounced. The RII, on the other hand, did notshow any gradient, neither for men nor for women. CONCLUSION Multiple risk behaviour is morecommon among lower educated people. An increasing polarization in socio-economic inequalities isassessed from 2001 to 2004 among men. Therefore, health promotion programmes should focus on thelower socio-economic classes and target risk behaviours simultaneously.", "metadata": {}}
+{"_id": "457630", "title": "", "text": "Variations and Trends in Health Burden of Visual Impairment Due to Cataract: A Global Analysis.PurposeTo evaluate the global trends in health burden of people visually impaired from cataract in terms ofdisability-adjusted life years (DALY) and its correlations with national levels of socioeconomicdevelopment. Methods Global, regional, and national DALY numbers, crude rate, and age-standardizedrate of cataract vision loss by age and sex were obtained from the database of the Global Burden ofDisease Study 2015. The human development index, per capita gross domestic product, and othercountry-level data were derived from international open databases. Regression analysis was used toassess the correlations between age-standardized DALY rate and socioeconomic variables. Results Theglobal DALY numbers of cataract vision loss increased by 89.42%, from 2048.18 (95%CI [confidenceinterval]: 1457.60-2761.80) thousands in 1990 to 3879.74 (95% CI: 2766.07-5232.43) thousands in2015 (P < 0.001). Females had higher DALY number 315.83 (95%CI: 237.17-394.4) and crude rate38.29 (95%CI: 35.35-41.23) after adjusting for age and country (all P < 0.001). The age-standardizedDALY rate was higher in countries with low human development index (HDI), with 91.03 (95%CI:73.04-108.75) for low HDI, 81.67 (95%CI: 53.24-108.82) for medium HDI, 55.89 (95%CI: 36.87-69.63)for high HDI, and 17.10 (95%CI: 13.91-26.84) for very high HDI countries (P < 0.01), respectively. Thenational age-standardized DALY rates in 2015 were negatively associated with both HDI (R2 = 0.489, P <0.001) and per capita gross domestic product (R2 = 0.331, P < 0.001). Stepwise multiple regressionshowed that HDI was significantly correlated with national age-standardized DALY rates in 2015 afteradjusting for other confounding factors (P < 0.001). Conclusions The global health burden of vision lossdue to cataract increased between 1990 and 2015 despite considerable efforts from the World HealthOrganization and VISION 2020 initiatives.", "metadata": {}}
+{"_id": "461550", "title": "", "text": "Multiplex genome engineering using CRISPR/Cas systems.Functional elucidation of causal geneticvariants and elements requires precise genome editing technologies. The type II prokaryotic CRISPR(clustered regularly interspaced short palindromic repeats)/Cas adaptive immune system has been shownto facilitate RNA-guided site-specific DNA cleavage. We engineered two different type II CRISPR/Cassystems and demonstrate that Cas9 nucleases can be directed by short RNAs to induce precise cleavageat endogenous genomic loci in human and mouse cells. Cas9 can also be converted into a nicking enzymeto facilitate homology-directed repair with minimal mutagenic activity. Lastly, multiple guide sequencescan be encoded into a single CRISPR array to enable simultaneous editing of several sites within themammalian genome, demonstrating easy programmability and wide applicability of the RNA-guidednuclease technology.", "metadata": {}}
+{"_id": "463309", "title": "", "text": "Transformation of intact yeast cells treated with alkali cations.Intact yeast cells treated with alkali cationstook up plasmid DNA. Li+, Cs+, Rb+, K+, and Na+ were effective in inducing competence. Conditions forthe transformation of Saccharomyces cerevisiae D13-1A with plasmid YRp7 were studied in detail withCsCl. The optimum incubation time was 1 h, and the optimum cell concentration was 5 x 10(7) cells perml. The optimum concentration of Cs+ was 1.0 M. Transformation efficiency increased with increasingconcentrations of plasmid DNA. Polyethylene glycol was absolutely required. Heat pulse and variouspolyamines or basic proteins stimulated the uptake of plasmid DNA. Besides circular DNA, linear plasmidDNA was also taken up by Cs+-treated yeast cells, although the uptake efficiency was considerablyreduced. The transformation efficiency with Cs+ or Li+ was comparable with that of conventionalprotoplast methods for a plasmid containing ars1, although not for plasmids containing a 2 microns originreplication.", "metadata": {}}
+{"_id": "463533", "title": "", "text": "Health-Related Quality of Life as Measured with EQ-5D among Populations with and without SpecificChronic Conditions: A Population-Based Survey in Shaanxi Province, ChinaINTRODUCTION The aim ofthis study was to examine health-related quality of life (HRQoL) as measured by EQ-5D and to investigatethe influence of chronic conditions and other risk factors on HRQoL based on a distributed sample locatedin Shaanxi Province, China. METHODS A multi-stage stratified cluster sampling method was performed toselect subjects. EQ-5D was employed to measure the HRQoL. The likelihood that individuals with selectedchronic diseases would report any problem in the EQ-5D dimensions was calculated and tested relative tothat of each of the two reference groups. Multivariable linear regression models were used to investigatefactors associated with EQ VAS. RESULTS The most frequently reported problems involvedpain/discomfort (8.8%) and anxiety/depression (7.6%). Nearly half of the respondents who reportedproblems in any of the five dimensions were chronic patients. Higher EQ VAS scores were associated withthe male gender, higher level of education, employment, younger age, an urban area of residence,access to free medical service and higher levels of physical activity. Except for anemia, all the selectedchronic diseases were indicative of a negative EQ VAS score. The three leading risk factors werecerebrovascular disease, cancer and mental disease. Increases in age, number of chronic conditions andfrequency of physical activity were found to have a gradient effect. CONCLUSION The results of thepresent work add to the volume of knowledge regarding population health status in this area, apart fromthe known health status using mortality and morbidity data. Medical, policy, social and individualattention should be given to the management of chronic diseases and improvement of HRQoL.Longitudinal studies must be performed to monitor changes in HRQoL and to permit evaluation of theoutcomes of chronic disease intervention programs.", "metadata": {}}
+{"_id": "464511", "title": "", "text": "Memory and Modularity in Cell-Fate Decision MakingGenetically identical cells sharing an environment candisplay markedly different phenotypes. It is often unclear how much of this variation derives fromchance, external signals, or attempts by individual cells to exert autonomous phenotypic programs. Byobserving thousands of cells for hundreds of consecutive generations under constant conditions, wedissect the stochastic decision between a solitary, motile state and a chained, sessile state in Bacillussubtilis. We show that the motile state is 'memoryless', exhibiting no autonomous control over the timespent in the state. In contrast, the time spent as connected chains of cells is tightly controlled, enforcingcoordination among related cells in the multicellular state. We show that the three-protein regulatorycircuit governing the decision is modular, as initiation and maintenance of chaining are geneticallyseparable functions. As stimulation of the same initiating pathway triggers biofilm formation, we arguethat autonomous timing allows a trial commitment to multicellularity that external signals could extend.", "metadata": {}}
+{"_id": "469066", "title": "", "text": "Lpd depletion reveals that SRF specifies radial versus tangential migration of pyramidal neuronsDuringcorticogenesis, pyramidal neurons (\u000080% of cortical neurons) arise from the ventricular zone, passthrough a multipolar stage to become bipolar and attach to radial glia, and then migrate to their properposition within the cortex. As pyramidal neurons migrate radially, they remain attached to their glialsubstrate as they pass through the subventricular and intermediate zones, regions rich in tangentiallymigrating interneurons and axon fibre tracts. We examined the role of lamellipodin (Lpd), a homologue ofa key regulator of neuronal migration and polarization in Caenorhabditis elegans, in corticogenesis. Lpddepletion caused bipolar pyramidal neurons to adopt a tangential, rather than radial-glial, migrationmode without affecting cell fate. Mechanistically, Lpd depletion reduced the activity of SRF, atranscription factor regulated by changes in the ratio of polymerized to unpolymerized actin. Therefore,Lpd depletion exposes a role for SRF in directing pyramidal neurons to select a radial migration pathwayalong glia rather than a tangential migration mode.", "metadata": {}}
+{"_id": "470625", "title": "", "text": "Identification of p18 INK4c as a tumor suppressor gene in glioblastoma multiforme.Genomic alterationsleading to aberrant activation of cyclin/cyclin-dependent kinase (cdk) complexes drive the pathogenesisof many common human tumor types. In the case of glioblastoma multiforme (GBM), these alterationsare most commonly due to homozygous deletion of p16(INK4a) and less commonly due to genomicamplifications of individual genes encoding cyclins or cdks. Here, we describe deletion of the p18(INK4c)cdk inhibitor as a novel genetic alteration driving the pathogenesis of GBM. Deletions of p18(INK4c) oftenoccurred in tumors also harboring homozygous deletions of p16(INK4a). Expression of p18(INK4c) wascompletely absent in 43% of GBM primary tumors studied by immunohistochemistry. Lentiviralreconstitution of p18(INK4c) expression at physiologic levels in p18(INK4c)-deficient but notp18(INK4c)-proficient GBM cells led to senescence-like G(1) cell cycle arrest. These studies identifyp18(INK4c) as a GBM tumor suppressor gene, revealing an additional mechanism leading to aberrantactivation of cyclin/cdk complexes in this terrible malignancy.", "metadata": {}}
+{"_id": "471735", "title": "", "text": "Two-stage control of an oxidative stress regulon: the Escherichia coli SoxR protein triggersredox-inducible expression of the soxS regulatory gene.Escherichia coli responds to the redox stressimposed by superoxide-generating agents such as paraquat by activating the synthesis of as many as 80polypeptides. Expression of a key group of these inducible proteins is controlled at the transcriptionallevel by the soxRS locus (the soxRS regulon). A two-stage control system was hypothesized for soxRS, inwhich an intracellular redox signal would trigger the SoxR protein as a transcriptional activator of thesoxS gene and the resulting increased levels of SoxS protein would activate transcription of the varioussoxRS regulon genes (B. Demple and C.F. Amábile Cuevas, Cell 67:837-839, 1990). We have constructedoperon fusions of the E. coli lac genes to the soxS promoter to monitor soxS transcription. Expressionfrom the soxS promoter is strongly inducible by paraquat in a manner strictly dependent on a functionalsoxR gene. Several other superoxide-generating agents also trigger soxR(+)-dependent soxS expression,and the inductions by paraquat and phenazine methosulfate were dependent on the presence of oxygen.Numerous other oxidative stress agents (H2O2, gamma rays, heat shock, etc.) failed to induce soxS,while aerobic growth of superoxide dismutase-deficient bacteria triggered soxR-dependent soxSexpression. These results indicate a specific redox signal for soxS induction. A direct role for SoxR proteinin the activation of the soxS gene is indicated by band-shift and DNase I footprinting experiments thatdemonstrate specific binding of the SoxR protein in cell extracts to the soxS promoter. The mode of SoxRbinding to DNA appears to be similar to that of its homolog MerR in that the SoxR footprint spans the -10to -35 region of the soxS promoter.", "metadata": {}}
+{"_id": "471921", "title": "", "text": "Air pollution and cardiovascular disease: a statement for healthcare professionals from the Expert Panelon Population and Prevention Science of the American Heart Association.Air pollution is a heterogeneous,complex mixture of gases, liquids, and particulate matter. Epidemiological studies have demonstrated aconsistent increased risk for cardiovascular events in relation to both short- and long-term exposure topresent-day concentrations of ambient particulate matter. Several plausible mechanistic pathways havebeen described, including enhanced coagulation/thrombosis, a propensity for arrhythmias, acute arterialvasoconstriction, systemic inflammatory responses, and the chronic promotion of atherosclerosis. Thepurpose of this statement is to provide healthcare professionals and regulatory agencies with acomprehensive review of the literature on air pollution and cardiovascular disease. In addition, theimplications of these findings in relation to public health and regulatory policies are addressed. Practicalrecommendations for healthcare providers and their patients are outlined. In the final section,suggestions for future research are made to address a number of remaining scientific questions.", "metadata": {}}
+{"_id": "474325", "title": "", "text": "Non-invasive ventilation in chronic obstructive pulmonary disease patients: helmet versus facial maskThehelmet is a new interface with the potential of increasing the success rate of non-invasive ventilation byimproving tolerance. To perform a physiological comparison between the helmet and the conventionalfacial mask in delivering non-invasive ventilation in hypercapnic patients with chronic obstructivepulmonary disease. Prospective, controlled, randomized study with cross-over design. In 10 patients weevaluated gas exchange, inspiratory effort, patient–ventilator synchrony and patient tolerance after 30min of non-invasive ventilation delivered either by helmet or facial mask; both trials were preceded byperiods of spontaneous unassisted breathing. Arterial blood gases, inspiratory effort, duration ofdiaphragm contraction and ventilator assistance, effort-to-support delays (at the beginning and at theend of inspiration), number of ineffective efforts, and patient comfort. Non-invasive ventilation improvedgas exchange (p< 0.05) and inspiratory effort (p< 0.01) with both interfaces. The helmet, however, wasless efficient than the mask in reducing inspiratory effort (p< 0.05) and worsened the patient–ventilatorsynchrony, as indicated by the longer delays to trigger on (p< 0.05) and cycle off (p< 0.05) themechanical assistance and by the number of ineffective efforts (p< 0.005). Patient comfort was nodifferent with the two interfaces. Helmet and facial mask were equally tolerated and both were effectivein ameliorating gas exchange and decreasing inspiratory effort. The helmet, however, was less efficient indecreasing inspiratory effort and worsened the patient–ventilator interaction.", "metadata": {}}
+{"_id": "485020", "title": "", "text": "Case Management and Client Access to Health and Social Services in Outpatient Substance AbuseTreatmentA primary goal of case management is to coordinate services across treatment settings and tointegrate substance abuse services with other types of services offered in the community, includinghousing, mental health, medical, and social services. However, case management is a global constructthat consists of several key dimensions, which include extent of case management coverage, the degreeof management of the referral process, and the location of case management activity (on-site, off-site, orboth). This study examines the relationship between specific dimensions of case management and theutilization of health and ancillary social services in outpatient substance abuse treatment. In general,results suggest that more active case management during the referral process and providing casemanagement both on-site and off-site are most consistent with our predictions of greater use of healthand ancillary social services by substance abuse clients. However, these effects are specific to generalhealth care and mental health services. Case management appears to have little effect on use of socialservices or aftercare plans.", "metadata": {}}
+{"_id": "493346", "title": "", "text": "Evidence that the Ipl1-Sli15 (Aurora Kinase-INCENP) Complex Promotes Chromosome Bi-orientation byAltering Kinetochore-Spindle Pole ConnectionsHow sister kinetochores attach to microtubules fromopposite spindle poles during mitosis (bi-orientation) remains poorly understood. In yeast, the ortholog ofthe Aurora B-INCENP protein kinase complex (Ipl1-Sli15) may have a role in this crucial process, becauseit is necessary to prevent attachment of sister kinetochores to microtubules from the same spindle pole.We investigated IPL1 function in cells that cannot replicate their chromosomes but nevertheless duplicatetheir spindle pole bodies (SPBs). Kinetochores detach from old SPBs and reattach to old and new SPBswith equal frequency in IPL1+ cells, but remain attached to old SPBs in ipl1 mutants. This raises thepossibility that Ipl1-Sli15 facilitates bi-orientation by promoting turnover of kinetochore-SPB connectionsuntil traction of sister kinetochores toward opposite spindle poles creates tension in the surroundingchromatin.", "metadata": {}}
+{"_id": "496873", "title": "", "text": "CRITICAL REVIEW Cutaneous Vasculitis Update: Diagnostic Criteria,Vasculitis, inflammation of the vesselwall, can result in mural destruction with hemorrhage, aneurysm formation, and infarction, orintimal-medial hyperplasia and subsequent stenosis leading to tissue ischemia. The skin, in part due to itslarge vascular bed, exposure to cold temperatures, and frequent presence of stasis, is involved in manydistinct as well as un-named vasculitic syndromes that vary from localized and self-limited to generalizedand life-threatening with multi-organ disease. To exclude mimics of vasculitis, diagnosis of cutaneousvasculitis requires biopsy confirmation where its acute signs (fibrinoid necrosis), chronic signs(endarteritis obliterans), or past signs (acellular scar of healed arteritis) must be recognized and presenceof extravascular findings such as patterned fibrosis or collagenolytic granulomas noted. Althoughvasculitis can be classified by etiology, many cases have no identifiable cause, and a single etiologicagent can elicit several distinct clinicopathologic expressions of vasculitis. Therefore, the classification ofcutaneous vasculitis is best approached morphologically by determining vessel size and principalinflammatory response. These histologic patterns roughly correlate with pathogenic mechanisms that,when coupled with direct immunofluorescent examination, anti-neutrophil cytoplasmic antibody (ANCA)status, and findings from work-up for systemic disease, allow for specific diagnosis, and ultimately, moreeffective therapy. Herein, we review cutaneous vasculitis focusing on diagnostic criteria, classification,epidemiology, etiology, pathogenesis, and evaluation of the cutaneous vasculitis patient.", "metadata": {}}
+{"_id": "502591", "title": "", "text": "E2F-dependent histone acetylation and recruitment of the Tip60 acetyltransferase complex to chromatinin late G1.E2F proteins can either activate or repress transcription. Following mitogenic stimulation,repressive E2F4-p130-histone deacetylase complexes dissociate from, while activating species (E2F1, -2,and -3) associate with, target promoters. Histones H3 and H4 simultaneously become hyperacetylated,but it remains unclear whether this is a prerequisite or a consequence of E2F binding. Here, we show thatactivating E2F species are required for hyperacetylation of target chromatin in human cells.Overexpression of a dominant-negative (DN) E2F1 mutant in serum-stimulated T98G cells blocked all E2Fbinding, H4 acetylation, and, albeit partially, H3 acetylation. Target gene activation and S-phase entrywere also blocked by DN E2F1. Conversely, ectopic activation of E2F1 rapidly induced H3 and H4acetylation, demonstrating a direct role for E2F in these events. E2F1 was previously shown to bind thehistone acetyltransferases (HATs) p300/CBP and PCAF/GCN5. In our hands, ectopically expressed E2F1also bound the unrelated HAT Tip60 and induced recruitment of five subunits of the Tip60 complex(Tip60, TRRAP, p400, Tip48, and Tip49) to target promoters in vivo. Moreover, E2F-dependentrecruitment of Tip60 to chromatin occurred in late G(1) following serum stimulation. We speculate thatthe activities of multiple HAT complexes account for E2F-dependent acetylation, transcription, andS-phase entry.", "metadata": {}}
+{"_id": "502797", "title": "", "text": "Chemical approaches to stem cell biology and therapeutics.Small molecules that modulate stem cell fateand function offer significant opportunities that will allow the full realization of the therapeutic potential ofstem cells. Rational design and screening for small molecules have identified useful compounds to probefundamental mechanisms of stem cell self-renewal, differentiation, and reprogramming and havefacilitated the development of cell-based therapies and therapeutic drugs targeting endogenous stem andprogenitor cells for repair and regeneration. Here, we will discuss recent scientific and therapeuticprogress, as well as new perspectives and future challenges for using chemical approaches in stem cellbiology and regenerative medicine.", "metadata": {}}
+{"_id": "503050", "title": "", "text": "Genome-wide maps of chromatin state in pluripotent and lineage-committed cellsWe report theapplication of single-molecule-based sequencing technology for high-throughput profiling of histonemodifications in mammalian cells. By obtaining over four billion bases of sequence from chromatinimmunoprecipitated DNA, we generated genome-wide chromatin-state maps of mouse embryonic stemcells, neural progenitor cells and embryonic fibroblasts. We find that lysine 4 and lysine 27 trimethylationeffectively discriminates genes that are expressed, poised for expression, or stably repressed, andtherefore reflect cell state and lineage potential. Lysine 36 trimethylation marks primary coding andnon-coding transcripts, facilitating gene annotation. Trimethylation of lysine 9 and lysine 20 is detected atsatellite, telomeric and active long-terminal repeats, and can spread into proximal unique sequences.Lysine 4 and lysine 9 trimethylation marks imprinting control regions. Finally, we show that chromatinstate can be read in an allele-specific manner by using single nucleotide polymorphisms. This studyprovides a framework for the application of comprehensive chromatin profiling towards characterizationof diverse mammalian cell populations.", "metadata": {}}
+{"_id": "515489", "title": "", "text": "Oncofetal long noncoding RNA PVT1 promotes proliferation and stem cell-like property of hepatocellularcarcinoma cells by stabilizing NOP2.UNLABELLED Many protein-coding oncofetal genes are highlyexpressed in murine and human fetal liver and silenced in adult liver. The protein products of thesehepatic oncofetal genes have been used as clinical markers for the recurrence of hepatocellular carcinoma(HCC) and as therapeutic targets for HCC. Herein we examined the expression profiles of long noncodingRNAs (lncRNAs) found in fetal and adult liver in mice. Many fetal hepatic lncRNAs were identified; one ofthese, lncRNA-mPvt1, is an oncofetal RNA that was found to promote cell proliferation, cell cycling, andthe expression of stem cell-like properties of murine cells. Interestingly, we found that humanlncRNA-hPVT1 was up-regulated in HCC tissues and that patients with higher lncRNA-hPVT1 expressionhad a poor clinical prognosis. The protumorigenic effects of lncRNA-hPVT1 on cell proliferation, cellcycling, and stem cell-like properties of HCC cells were confirmed both in vitro and in vivo bygain-of-function and loss-of-function experiments. Moreover, mRNA expression profile data showed thatlncRNA-hPVT1 up-regulated a series of cell cycle genes in SMMC-7721 cells. By RNA pulldown and massspectrum experiments, we identified NOP2 as an RNA-binding protein that binds to lncRNA-hPVT1. Weconfirmed that lncRNA-hPVT1 up-regulated NOP2 by enhancing the stability of NOP2 proteins and thatlncRNA-hPVT1 function depends on the presence of NOP2. CONCLUSION Our study demonstrates that theexpression of many lncRNAs is up-regulated in early liver development and that the fetal liver can beused to search for new diagnostic markers for HCC. LncRNA-hPVT1 promotes cell proliferation, cellcycling, and the acquisition of stem cell-like properties in HCC cells by stabilizing NOP2 protein.Regulation of the lncRNA-hPVT1/NOP2 pathway may have beneficial effects on the treatment of HCC.", "metadata": {}}
+{"_id": "516867", "title": "", "text": "Candida albicans, a distinctive fungal model for cellular aging studyThe unicellular eukaryotic organismsrepresent the popular model systems to understand aging in eukaryotes. Candida albicans, a polymorphicfungus, appears to be another distinctive unicellular aging model in addition to the budding yeastSaccharomyces cerevisiae and fission yeast Schizosaccharomyces pombe. The two types of Candida cells,yeast (blastospore) form and hyphal (filamentous) form, have similar replicative lifespan. Taking theadvantage of morphologic changes, we are able to obtain cells of different ages. Old Candida cells tend toaccumulate glycogen and oxidatively damaged proteins. Deletion of the SIR2 gene causes a decrease oflifespan, while insertion of an extra copy of SIR2 extends lifespan, indicating that like in S. cerevisiae,Sir2 regulates cellular aging in C. albicans. Interestingly, Sir2 deletion does not result in the accumulationof extra-chromosomal rDNA molecules, but influences the retention of oxidized proteins in mother cells,suggesting that the extra-chromosomal rDNA molecules may not be associated with cellular aging in C.albicans. This novel aging model, which allows efficient large-scale isolation of old cells, may facilitatebiochemical characterizations and genomics/proteomics studies of cellular aging, and help to verify theaging pathways observed in other organisms including S. cerevisiae.", "metadata": {}}
+{"_id": "519974", "title": "", "text": "ANKTM1, a TRP-like Channel Expressed in Nociceptive Neurons, Is Activated by ColdTemperaturesMammals detect temperature with specialized neurons in the peripheral nervous system.Four TRPV-class channels have been implicated in sensing heat, and one TRPM-class channel in sensingcold. The combined range of temperatures that activate these channels covers a majority of the relevantphysiological spectrum sensed by most mammals, with a significant gap in the noxious cold range. Here,we describe the characterization of ANKTM1, a cold-activated channel with a lower activation temperaturecompared to the cold and menthol receptor, TRPM8. ANKTM1 is a distant family member of TRP channelswith very little amino acid similarity to TRPM8. It is found in a subset of nociceptive sensory neuronswhere it is coexpressed with TRPV1/VR1 (the capsaicin/heat receptor) but not TRPM8. Consistent with theexpression of ANKTM1, we identify noxious cold-sensitive sensory neurons that also respond to capsaicinbut not to menthol.", "metadata": {}}
+{"_id": "520579", "title": "", "text": "Plasma vitamin D metabolites and risk of colorectal cancer in women.OBJECTIVE Experimental evidencesuggests that 1,25-dihydroxyvitamin D and its precursor, 25-hydroxyvitamin D [25(OH)D], may aid inthe prevention of colorectal cancer. We therefore examined risk in relation to plasma concentrations ofthese vitamin D metabolites. METHODS In a nested case-control study among women in the Nurses'Health Study, we identified 193 colorectal cancer cases, ages 46 to 78 years, diagnosed up to 11 yearsafter blood collection. Two controls were matched per case on year of birth and month of blood draw.Odds ratios (OR) for risk of colorectal cancer were calculated using conditional logistic regressionadjusted for body mass index, physical activity, smoking, family history, use of hormone replacementtherapy, aspirin use, and dietary intakes. RESULTS We found a significant inverse linear associationbetween plasma 25(OH)D and risk of colorectal cancer (P = 0.02). Among women in the highest quintile,the OR (95% confidence interval) was 0.53 (0.27-1.04). This inverse association remained strong whenlimited to women > or =60 years at blood collection (P = 0.006) but was not apparent among theyounger women (P = 0.70). Benefit from higher 25(OH)D concentrations was observed for cancers at thedistal colon and rectum (P = 0.02) but was not evident for those at the proximal colon (P = 0.81). Incontrast to 25(OH)D, we did not observe an association between 1,25-dihydroxyvitamin D and colorectalcancer, although risk was elevated among the women in the highest quintile if they were also in the lowerhalf of the 25(OH)D distribution (OR, 2.52; 95% confidence interval, 1.04-6.11). CONCLUSION Fromthese results and supporting evidence from previous studies, we conclude that higher plasma levels of25(OH)D are associated with a lower risk of colorectal cancer in older women, particularly for cancers atthe distal colon and rectum.", "metadata": {}}
+{"_id": "544971", "title": "", "text": "DNA Deamination Mediates Innate Immunity to Retroviral InfectionCEM15/APOBEC3G is a cellular proteinrequired for resistance to infection by virion infectivity factor (Vif)-deficient human immunodeficiencyvirus (HIV). Here, using a murine leukemia virus (MLV)-based system, we provide evidence thatCEM15/APOBEC3G is a DNA deaminase that is incorporated into virions during viral production andsubsequently triggers massive deamination of deoxycytidine to deoxyuridine within the retroviral minus(first)-strand cDNA, thus providing a probable trigger for viral destruction. Furthermore, HIV Vif canprotect MLV from this CEM15/APOBEC3G-dependent restriction. These findings imply that targeted DNAdeamination is a major strategy of innate immunity to retroviruses and likely also contributes to thesequence variation observed in many viruses (including HIV).", "metadata": {}}
+{"_id": "581832", "title": "", "text": "Global, regional, and national disability-adjusted life-years (DALYs) for 315 diseases and injuries andhealthy life expectancy (HALE), 1990–2015: a systematic analysis for the Global Burden of Disease Study2015BACKGROUND Healthy life expectancy (HALE) and disability-adjusted life-years (DALYs) providesummary measures of health across geographies and time that can inform assessments ofepidemiological patterns and health system performance, help to prioritise investments in research anddevelopment, and monitor progress toward the Sustainable Development Goals (SDGs). We aimed toprovide updated HALE and DALYs for geographies worldwide and evaluate how disease burden changeswith development. METHODS We used results from the Global Burden of Diseases, Injuries, and RiskFactors Study 2015 (GBD 2015) for all-cause mortality, cause-specific mortality, and non-fatal diseaseburden to derive HALE and DALYs by sex for 195 countries and territories from 1990 to 2015. Wecalculated DALYs by summing years of life lost (YLLs) and years of life lived with disability (YLDs) for eachgeography, age group, sex, and year. We estimated HALE using the Sullivan method, which draws fromage-specific death rates and YLDs per capita. We then assessed how observed levels of DALYs and HALEdiffered from expected trends calculated with the Socio-demographic Index (SDI), a composite indicatorconstructed from measures of income per capita, average years of schooling, and total fertility rate.FINDINGS Total global DALYs remained largely unchanged from 1990 to 2015, with decreases incommunicable, neonatal, maternal, and nutritional (Group 1) disease DALYs offset by increased DALYsdue to non-communicable diseases (NCDs). Much of this epidemiological transition was caused bychanges in population growth and ageing, but it was accelerated by widespread improvements in SDI thatalso correlated strongly with the increasing importance of NCDs. Both total DALYs and age-standardisedDALY rates due to most Group 1 causes significantly decreased by 2015, and although total burdenclimbed for the majority of NCDs, age-standardised DALY rates due to NCDs declined. Nonetheless,age-standardised DALY rates due to several high-burden NCDs (including osteoarthritis, drug usedisorders, depression, diabetes, congenital birth defects, and skin, oral, and sense organ diseases) eitherincreased or remained unchanged, leading to increases in their relative ranking in many geographies.From 2005 to 2015, HALE at birth increased by an average of 2·9 years (95% uncertainty interval2·9-3·0) for men and 3·5 years (3·4-3·7) for women, while HALE at age 65 years improved by 0·85 years(0·78-0·92) and 1·2 years (1·1-1·3), respectively. Rising SDI was associated with consistently higherHALE and a somewhat smaller proportion of life spent with functional health loss; however, rising SDIwas related to increases in total disability. Many countries and territories in central America and easternsub-Saharan Africa had increasingly lower rates of disease burden than expected given their SDI. At thesame time, a subset of geographies recorded a growing gap between observed and expected levels ofDALYs, a trend driven mainly by rising burden due to war, interpersonal violence, and various NCDs.INTERPRETATION Health is improving globally, but this means more populations are spending more timewith functional health loss, an absolute expansion of morbidity. The proportion of life spent in ill healthdecreases somewhat with increasing SDI, a relative compression of morbidity, which supports continuedefforts to elevate personal income, improve education, and limit fertility. Our analysis of DALYs and HALEand their relationship to SDI represents a robust framework on which to benchmark geography-specifichealth performance and SDG progress. Country-specific drivers of disease burden, particularly for causeswith higher-than-expected DALYs, should inform financial and research investments, prevention efforts,health policies, and health system improvement initiatives for all countries along the developmentcontinuum. FUNDING Bill & Melinda Gates Foundation.", "metadata": {}}
+{"_id": "583260", "title": "", "text": "Adverse drug events: database construction and in silico prediction.Adverse drug events (ADEs) are theharms associated with uses of given medications at normal dosages, which are crucial for a drug to beapproved in clinical use or continue to stay on the market. Many ADEs are not identified in trials until thedrug is approved for clinical use, which results in adverse morbidity and mortality. To date, millions ofADEs have been reported around the world. Methods to avoid or reduce ADEs are an important issue fordrug discovery and development. Here, we reported a comprehensive database of adverse drug events(namely MetaADEDB), which included more than 520,000 drug-ADE associations among 3059 uniquecompounds (including 1330 drugs) and 13,200 ADE items by data integration and text mining. Allcompounds and ADEs were annotated with the most commonly used concepts defined in Medical SubjectHeadings (MeSH). Meanwhile, a computational method, namely the phenotypic network inference model(PNIM), was developed for prediction of potential ADEs based on the database. The area under thereceive operating characteristic curve (AUC) is more than 0.9 by 10-fold cross validation, while the AUCvalue was 0.912 for an external validation set extracted from the US-FDA Adverse Events ReportingSystem, which indicated that the prediction capability of the method was reliable. MetaADEDB isaccessible free of charge at http://www.lmmd.org/online_services/metaadedb/. The database and themethod provide us a useful tool to search for known side effects or predict potential side effects for agiven drug or compound.", "metadata": {}}
+{"_id": "596817", "title": "", "text": "Genetic Tests for Ecological and Allopatric Speciation in Anoles on an Island ArchipelagoFrom Darwin'sstudy of the Galapagos and Wallace's study of Indonesia, islands have played an important role inevolutionary investigations, and radiations within archipelagos are readily interpreted as supporting theconventional view of allopatric speciation. Even during the ongoing paradigm shift towards other modesof speciation, island radiations, such as the Lesser Antillean anoles, are thought to exemplify this process.Geological and molecular phylogenetic evidence show that, in this archipelago, Martinique anoles provideseveral examples of secondary contact of island species. Four precursor island species, with up to 8 mybpdivergence, met when their islands coalesced to form the current island of Martinique. Moreover, adjacentanole populations also show marked adaptation to distinct habitat zonation, allowing both allopatric andecological speciation to be tested in this system. We take advantage of this opportunity of replicatedisland coalescence and independent ecological adaptation to carry out an extensive population geneticstudy of hypervariable neutral nuclear markers to show that even after these very substantial periods ofspatial isolation these putative allospecies show less reproductive isolation than conspecific populations inadjacent habitats in all three cases of subsequent island coalescence. The degree of genetic interchangeshows that while there is always a significant genetic signature of past allopatry, and this may be quitestrong if the selection regime allows, there is no case of complete allopatric speciation, in spite of thestrong primae facie case for it. Importantly there is greater genetic isolation across the xeric/rainforestecotone than is associated with any secondary contact. This rejects the development of reproductiveisolation in allopatric divergence, but supports the potential for ecological speciation, even though fullspeciation has not been achieved in this case. It also explains the paucity of anole species in the LesserAntilles compared to the Greater Antilles.", "metadata": {}}
+{"_id": "597790", "title": "", "text": "Deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes inmiceAlthough mast cell functions have classically been related to allergic responses, recent studiesindicate that these cells contribute to other common diseases such as multiple sclerosis, rheumatoidarthritis, atherosclerosis, aortic aneurysm and cancer. This study presents evidence that mast cells alsocontribute to diet-induced obesity and diabetes. For example, white adipose tissue (WAT) from obesehumans and mice contain more mast cells than WAT from their lean counterparts. Furthermore, in thecontext of mice on a Western diet, genetically induced deficiency of mast cells, or their pharmacologicalstabilization, reduces body weight gain and levels of inflammatory cytokines, chemokines and proteasesin serum and WAT, in concert with improved glucose homeostasis and energy expenditure. Mechanisticstudies reveal that mast cells contribute to WAT and muscle angiogenesis and associated cell apoptosisand cathepsin activity. Adoptive transfer experiments of cytokine-deficient mast cells show that thesecells, by producing interleukin-6 (IL-6) and interferon-gamma (IFN-gamma), contribute to mouse adiposetissue cysteine protease cathepsin expression, apoptosis and angiogenesis, thereby promotingdiet-induced obesity and glucose intolerance. Our results showing reduced obesity and diabetes in micetreated with clinically available mast cell-stabilizing agents suggest the potential of developing newtherapies for these common human metabolic disorders.", "metadata": {}}
+{"_id": "599582", "title": "", "text": "Familial aphasic episodes: another variant of partial epilepsy with simple inheritance?We report on afamily having partial epilepsy with simple inheritance. The affected members commonly have aphasicepisodes with secondary generalization; onset occurred either in adolescence or adulthood. Patients'response to medication has varied greatly. No neurological defects or decline in intelligence were found.The case represents another variety of rare familial partial epilepsy with neocortical epilepsy features.", "metadata": {}}
+{"_id": "600437", "title": "", "text": "Endosome-ER Contacts Control Actin Nucleation and Retromer Function through VAP-DependentRegulation of PI4PVAP (VAPA and VAPB) is an evolutionarily conserved endoplasmic reticulum(ER)-anchored protein that helps generate tethers between the ER and other membranes through whichlipids are exchanged across adjacent bilayers. Here, we report that by regulating PI4P levels onendosomes, VAP affects WASH-dependent actin nucleation on these organelles and the function of theretromer, a protein coat responsible for endosome-to-Golgi traffic. VAP is recruited to retromer buddingsites on endosomes via an interaction with the retromer SNX2 subunit. Cells lacking VAP accumulate highlevels of PI4P, actin comets, and trans-Golgi proteins on endosomes. Such defects are mimicked bydownregulation of OSBP, a VAP interactor and PI4P transporter that participates in VAP-dependentER-endosomes tethers. These results reveal a role of PI4P in retromer-/WASH-dependent budding fromendosomes. Collectively, our data show how the ER can control budding dynamics and association withthe cytoskeleton of another membrane by direct contacts leading to bilayer lipid modifications.", "metadata": {}}
+{"_id": "600808", "title": "", "text": "Anaphase-Promoting Complex/Cyclosome–Dependent Proteolysis of Human Cyclin a Starts at theBeginning of Mitosis and Is Not Subject to the Spindle Assembly CheckpointCyclin A is a stable protein inS and G2 phases, but is destabilized when cells enter mitosis and is almost completely degraded beforethe metaphase to anaphase transition. Microinjection of antibodies against subunits of theanaphase-promoting complex/cyclosome (APC/C) or against human Cdc20 (fizzy) arrested cells atmetaphase and stabilized both cyclins A and B1. Cyclin A was efficiently polyubiquitylated by Cdc20 orCdh1-activated APC/C in vitro, but in contrast to cyclin B1, the proteolysis of cyclin A was not delayed bythe spindle assembly checkpoint. The degradation of cyclin B1 was accelerated by inhibition of the spindleassembly checkpoint. These data suggest that the APC/C is activated as cells enter mitosis andimmediately targets cyclin A for degradation, whereas the spindle assembly checkpoint delays thedegradation of cyclin B1 until the metaphase to anaphase transition. The “destruction box” (D-box) ofcyclin A is 10–20 residues longer than that of cyclin B. Overexpression of wild-type cyclin A delayed themetaphase to anaphase transition, whereas expression of cyclin A mutants lacking a D-box arrested cellsin anaphase.", "metadata": {}}
+{"_id": "601033", "title": "", "text": "Human T Cell Leukemia Virus Reactivation with Progression of Adult T-CellLeukemia-LymphomaBACKGROUND Human T-cell leukemia virus-associated adult T-cellleukemia-lymphoma (ATLL) has a very poor prognosis, despite trials of a variety of different treatmentregimens. Virus expression has been reported to be limited or absent when ATLL is diagnosed, and thishas suggested that secondary genetic or epigenetic changes are important in disease pathogenesis.METHODS AND FINDINGS We prospectively investigated combination chemotherapy followed byantiretroviral therapy for this disorder. Nineteen patients were prospectively enrolled between 2002 and2006 at five medical centers in a phase II clinical trial of infusional chemotherapy with etoposide,doxorubicin, and vincristine, daily prednisone, and bolus cyclophosphamide (EPOCH) given for two to sixcycles until maximal clinical response, and followed by antiviral therapy with daily zidovudine,lamivudine, and alpha interferon-2a for up to one year. Seven patients were on study for less than onemonth due to progressive disease or chemotherapy toxicity. Eleven patients achieved an objectiveresponse with median duration of response of thirteen months, and two complete remissions. Duringchemotherapy induction, viral RNA expression increased (median 190-fold), and virus replicationoccurred, coincident with development of disease progression. CONCLUSIONS EPOCH chemotherapyfollowed by antiretroviral therapy is an active therapeutic regimen for adult T-cell leukemia-lymphoma,but viral reactivation during induction chemotherapy may contribute to treatment failure. Alternativetherapies are sorely needed in this disease that simultaneously prevent virus expression, and arecytocidal for malignant cells.", "metadata": {}}
+{"_id": "602760", "title": "", "text": "Montelukast and fluticasone compared with salmeterol and fluticasone in protecting against asthmaexacerbation in adults: one year, double blind, randomised, comparative trial.OBJECTIVES To assess theeffect of montelukast versus salmeterol added to inhaled fluticasone propionate on asthma exacerbationin patients whose symptoms are inadequately controlled with fluticasone alone. Design and setting A 52week, two period, double blind, multicentre trial during which patients whose symptoms remaineduncontrolled by inhaled corticosteroids were randomised to add montelukast or salmeterol.PARTICIPANTS Patients (15-72 years; n = 1490) had a clinical history of chronic asthma for > or = 1year, a baseline forced expiratory volume in one second (FEV1) value 50-90% predicted, and a betaagonist improvement of > or = 12% in FEV1. MAIN OUTCOME MEASURES The primary end point was thepercentage of patients with at least one asthma exacerbation. RESULTS 20.1% of the patients in thegroup receiving montelukast and fluticasone had an asthma exacerbation compared with 19.1% in thegroup receiving salmeterol and fluticasone; the difference was 1% (95% confidence interval -3.1% to5.0%). With a risk ratio (montelukast-fluticasone/salmeterol-fluticasone) of 1.05 (0.86 to 1.29),treatment with montelukast and fluticasone was shown to be non-inferior to treatment with salmeteroland fluticasone. Salmeterol and fluticasone significantly increased FEV1 before a beta agonist was usedand morning peak expiratory flow compared with montelukast and fluticasone (P < or = 0.001), whereasFEV1 after a beta agonist was used and improvements in asthma specific quality of life and nocturnalawakenings were similar between the groups. Montelukast and fluticasone significantly (P = 0.011)reduced peripheral blood eosinophil counts compared with salmeterol and fluticasone. Both treatmentswere generally well tolerated. CONCLUSION The addition of montelukast in patients whose symptomsremain uncontrolled by inhaled fluticasone could provide equivalent clinical control to salmeterol.", "metadata": {}}
+{"_id": "612002", "title": "", "text": "Control of assembly and function of glutamate receptors by the amino-terminal domain.The extracellularamino-terminal domains (ATDs) of the ionotropic glutamate receptor subunits form a semiautonomouscomponent of all glutamate receptors that resides distal to the membrane and controls a surprisinglydiverse set of receptor functions. These functions include subunit assembly, receptor trafficking, channelgating, agonist potency, and allosteric modulation. The many divergent features of the differentionotropic glutamate receptor classes and different subunits within a class may stem from differentialregulation by the amino-terminal domains. The emerging knowledge of the structure and function of theamino-terminal domains reviewed here may enable targeting of this region for the therapeuticmodulation of glutamatergic signaling. Toward this end, NMDA receptor antagonists that interact with theGluN2B ATD show promise in animal models of ischemia, neuropathic pain, and Parkinson's disease.", "metadata": {}}
+{"_id": "615047", "title": "", "text": "Fission yeast and other yeasts as emergent models to unravel cellular aging in eukaryotes.In the pastyears, simple organisms such as yeasts and worms have contributed a great deal to aging research.Studies pioneered in Saccharomyces cerevisiae were useful to elucidate a significant number of molecularmechanisms underlying cellular aging and to discover novel longevity genes. Importantly, these genesproved many times to be conserved in multicellular eukaryotes. Consequently, such discovery approachesare being extended to other yeast models, such as Schizosaccharomyces pombe, Candida albicans,Kluyveromyces lactis, and Cryptococcus neoformans. In fission yeast, researchers have found linksbetween asymmetrical cell division and nutrient signaling pathways with aging. In this review, we discussthe state of knowledge on the mechanisms controlling both replicative and chronological aging in Spombe and the other emergent yeast models.", "metadata": {}}
+{"_id": "623486", "title": "", "text": "Centrifugal elutriation as a method for isolation of large numbers of functionally intact human peripheralblood monocytes.Centrifugal elutriation was used further to isolate human peripheral blood monocytes(HPBM) from mononuclear-enriched cells harvested as a secondary component following plateletconcentration collection samples. HPBM were recovered in either one or two populations consisting ofeither total HPBM or small (SM) and large monocytes (LM). The elutriation was carried out at 3,500 +/- 5rpm for the separation of lymphocytes and HPBM in Ca++- and Mg++-free PBS without EDTA. Anaverage of 5.05 +/- 1.50 X 10(8) HPBM were recovered in the total HPBM with a purity of 95% +/- 3%.The SM and LM were obtained by splitting the total HPBM into two equal populations with an HPBM purityof 92% +/- 3% and 93% +/- 3, respectively, by nonspecific esterase staining. The elutriation media wereshown to have no effect on viability by trypan blue exclusion. All three HPBM populations were shown tobe histochemically (lack of reactivity to leu-1 and leu-7) and functionally (depletion of NK cell activity)purified from the lymphocyte population. The HPBM populations were enriched in HLA-Dr, OKM-1, OKM-5,MY-8, and leu M-3 monoclonal antibody marker staining. There were no differences in percent positivecells between SM and LM populations for any of the monocyte-specific monoclonal antibodies. All threemonocyte populations mediated antibody-dependent cell-mediated cytotoxicity to human red blood cells,with LM mediating more lysis (27.0% +/- 5%) than SM (7% +/- 3%).(ABSTRACT TRUNCATED AT 250WORDS)", "metadata": {}}
+{"_id": "641459", "title": "", "text": "Asthma in United States Olympic athletes who participated in the 1996 Summer Games.BACKGROUNDAsthma prevalence appears to be increasing in the general population. We sought to determine whetherasthma prevalence has also increased in highly competitive athletes. OBJECTIVE Our aim was todetermine how many United States Olympic athletes who were chosen to participate in the 1996 SummerOlympic Games had a past history of asthma or symptoms that suggested asthma or took asthmamedications. METHODS We analyzed responses to questions that asked about allergic and respiratorydiseases on the United States Olympic Committee (USOC) Medical History Questionnaire that wascompleted by all athletes who were chosen to represent the US at the 1996 Summer Olympic Games inAtlanta. RESULTS Of the 699 athletes who completed the questionnaire, 107 (15.3%) had a previousdiagnosis of asthma, and 97 (13.9%) recorded use of an asthma medication at some time in the past.One hundred seventeen (16.7%) reported use of an asthma medication, a diagnosis of asthma, or both(which was our basis for the diagnosis of asthma). Seventy-three (10. 4%) of the athletes were currentlytaking an asthma medication at the time that they were processed in Atlanta or noted that they tookasthma medications on a permanent or semipermanent basis and were considered to have activeasthma. Athletes who participated in cycling and mountain biking had the highest prevalence of havingbeen told that they had asthma or had taken an asthma medication in the past (50%). Frequency ofactive asthma varied from 45% of cyclists and emountain bikers to none of the divers and weight lifters.Only about 11% of the athletes who participated in the 1984 Summer Olympic Games were reported tohave had exercise-induced asthma on the basis of other criteria that may have been less restrictive. Onthe basis of these less restrictive criteria, more than 20% of the athletes who participated in the 1996Olympic Games might have been considered to have had asthma. CONCLUSIONS Asthma appeared tohave been more prevalent in athletes who participated in the 1996 Summer Games than in the generalpopulation or in those who participated in the 1984 Summer Games. This study also suggests thatasthma may influence the sport that an athlete chooses.", "metadata": {}}
+{"_id": "641786", "title": "", "text": "Relapse specific mutations in NT5C2 in childhood acute lymphoblastic leukemiaRelapsed childhood acutelymphoblastic leukemia (ALL) carries a poor prognosis, despite intensive retreatment, owing to intrinsicdrug resistance. The biological pathways that mediate resistance are unknown. Here, we report thetranscriptome profiles of matched diagnosis and relapse bone marrow specimens from ten individualswith pediatric B-lymphoblastic leukemia using RNA sequencing. Transcriptome sequencing identified 20newly acquired, novel nonsynonymous mutations not present at initial diagnosis, with 2 individualsharboring relapse-specific mutations in the same gene, NT5C2, encoding a 5'-nucleotidase. Full-exonsequencing of NT5C2 was completed in 61 further relapse specimens, identifying additional mutations in5 cases. Enzymatic analysis of mutant proteins showed that base substitutions conferred increasedenzymatic activity and resistance to treatment with nucleoside analog therapies. Clinically, all individualswho harbored NT5C2 mutations relapsed early, within 36 months of initial diagnosis (P = 0.03). Theseresults suggest that mutations in NT5C2 are associated with the outgrowth of drug-resistant clones inALL.", "metadata": {}}
+{"_id": "643765", "title": "", "text": "Relationship between Sloan-Kettering virus expression and mouse follicular developmentSloan-Ketteringvirus gene product (Ski) is an unique nuclear pro-oncoprotein and belongs to the ski/sno proto-oncogenefamily. Ski plays multiple roles in a variety of cell types, it can induce both oncogenic transformation andterminal muscle differentiation when expressed at high levels. Ski/SnoN are important transcriptionregulators of the transforming growth factor-β (TGF-β) superfamily and function mainly throughheterodimers. Since TGF-β superfamily are key regulators of follicle development and it has beenpreviously shown that SnoN is also vital to follicle development, this research was conducted to clarify therelationship between Ski expression and mouse follicular development, in ovaries of neonatal andgonadotropin-induced immature mice by immunohistochemical and real-time PCR techniques. Inpostnatal mice, positive staining for Ski was highly detected in oocyte nuclei at postnatal day 1. Withfollicular development, the localization moved gradually from oocyte nuclei to perinuclear space and thetotal levels decreased. During the estrous cycle, Ski expression was apparent at proestrus and estrus,faint at metestrus, highest at diestrus. After injection of gonadotropin, Ski was found in perinuclear spaceand weak in oocyte nuclei. Following the initiation of luteinization, the expression of Ski was found incorpus luteum. Real-time PCR results also showed that Ski mRNA expression was opposite toovulation-related genes during the cumulus expansion, with the development of the follicles, itsexpression level decreased. Ski is expressed in a specific manner during follicle development, ovulationand luteinization. So Ski might play essential roles in these processes especially during early folliculardevelopment.", "metadata": {}}
+{"_id": "649951", "title": "", "text": "Involvement of CB1 cannabinoid receptors in emotional behaviourRationale: Endogenous and exogenouscannabinoids acting through the CB1 cannabinoid receptors are implicated in the control of a variety ofbehavioural and neuroendocrine functions, including emotional responses, and learning and memoryprocesses. Recently, knockout mice deficient in the CB1 cannabinoid receptor have been generated, andthese animals result in an excellent tool to evaluate the neurophysiology of the endogenous cannabinoidsystem. Objectives: To establish the role of the CB1 cannabinoid receptor in several emotional-relatedbehavioural responses, including aggressiveness, anxiety, depression and learning models, using CB1knockout mice. Methods: We evaluated the spontaneous responses of CB1 knockout mice and wild-typecontrols under different behavioural paradigms, including the light/dark box, the chronic unpredictablemild stress, the resident–intruder test and the active avoidance paradigm. Results: Our findings showedthat CB1 knockout mice presented an increase in the aggressive response measured in theresident–intruder test and an anxiogenic-like response in the light/dark box. Furthermore, a highersensitivity to exhibit depressive-like responses in the chronic unpredictable mild stress procedure wasobserved in CB1 knockout mice, suggesting an increased susceptibility to develop an anhedonic state inthese animals. Finally, CB1 knockout mice showed a significant increase in the conditioned responsesproduced in the active avoidance model, suggesting an improvement of learning and memory processes.Conclusions: Taken together these findings demonstrate that endogenous cannabinoids through theactivation of CB1 receptors are implicated in the control of emotional behaviour and participate in thephysiological processes of learning and memory.", "metadata": {}}
+{"_id": "654735", "title": "", "text": "Exosomal levels of miRNA-21 from cerebrospinal fluids associated with poor prognosis and tumorrecurrence of glioma patientsGlioma is a most common type of primary brain tumors. Extracellularvesicles, in the form of exosomes, are known to mediate cell-cell communication by transportingcell-derived proteins and nucleic acids, including various microRNAs (miRNAs). Here we examined thecerebrospinal fluid (CSF) from patients with recurrent glioma for the levels of cancer-related miRNAs, andevaluated the values for prognosis by comparing the measures of CSF-, serum-, and exosome-containedmiR-21 levels. Samples from seventy glioma patients following surgery were compared with those frombrain trauma patients as a non-tumor control group. Exosomal miR-21 levels in the CSF of gliomapatients were found significantly higher than in the controls; whereas no difference was detected inserum-derived exosomal miR-21 expression. The CSF-derived exosomal miR-21 levels correlated withtumor spinal/ventricle metastasis and the recurrence with anatomical site preference. From additional198 glioma tissue samples, we verified that miR-21 levels associated with tumor grade of diagnosis andnegatively correlated with the median values of patient overall survival time. We further used a lentiviralinhibitor to suppress miR-21 expression in U251 cells. The results showed that the levels of miR-21 targetgenes of PTEN, RECK and PDCD4 were up-regulated at protein levels. Therefore, we concluded that theexosomal miR-21 levels could be demonstrated as a promising indicator for glioma diagnosis andprognosis, particularly with values to predict tumor recurrence or metastasis.", "metadata": {}}
+{"_id": "663464", "title": "", "text": "Age\u0000associated microRNA expression in human peripheral blood is associated with all\u0000cause mortalityand age\u0000related traitsRecent studies provide evidence of correlations of DNA methylation and expressionof protein-coding genes with human aging. The relations of microRNA expression with age andage-related clinical outcomes have not been characterized thoroughly. We explored associations of agewith whole-blood microRNA expression in 5221 adults and identified 127 microRNAs that weredifferentially expressed by age at P < 3.3 × 10-4 (Bonferroni-corrected). Most microRNAs wereunderexpressed in older individuals. Integrative analysis of microRNA and mRNA expression revealedchanges in age-associated mRNA expression possibly driven by age-associated microRNAs in pathwaysthat involve RNA processing, translation, and immune function. We fitted a linear model to predict'microRNA age' that incorporated expression levels of 80 microRNAs. MicroRNA age correlated modestlywith predicted age from DNA methylation (r = 0.3) and mRNA expression (r = 0.2), suggesting thatmicroRNA age may complement mRNA and epigenetic age prediction models. We used the differencebetween microRNA age and chronological age as a biomarker of accelerated aging (Δage) and found thatΔage was associated with all-cause mortality (hazards ratio 1.1 per year difference, P = 4.2 × 10-5adjusted for sex and chronological age). Additionally, Δage was associated with coronary heart disease,hypertension, blood pressure, and glucose levels. In conclusion, we constructed a microRNA ageprediction model based on whole-blood microRNA expression profiling. Age-associated microRNAs andtheir targets have potential utility to detect accelerated aging and to predict risks for age-relateddiseases.", "metadata": {}}
+{"_id": "665817", "title": "", "text": "Histone deacetylases (HDACs) in frontotemporal lobar degeneration.AIMS Frontotemporal lobardegeneration (FTLD) is clinically and pathologically heterogeneous. Although associated with variations inMAPT, GRN and C9ORF72, the pathogenesis of these, and of other nongenetic, forms of FTLD, remainsunknown. Epigenetic factors such as histone regulation by histone deacetylases (HDAC) may play a rolein the dysregulation of transcriptional activity, thought to underpin the neurodegenerative process.METHODS The distribution and intensity of HDACs 4, 5 and 6 was assessed semi-quantitatively inimmunostained sections of temporal cortex with hippocampus, and cerebellum, from 33 pathologicallyconfirmed cases of FTLD and 27 controls. RESULTS We found a significantly greater intensity ofcytoplasmic immunostaining for HDAC4 and HDAC6 in granule cells of the dentate gyrus in cases of FTLDoverall compared with controls, and specifically in cases of FTLD tau-Picks compared with FTLD tau-MAPTand controls. No differences were noted between FTLD-TDP subtypes, or between the different geneticand nongenetic forms of FTLD. No changes were seen in HDAC5 in any FTLD or control cases.CONCLUSIONS Dysregulation of HDAC4 and/or HDAC6 could play a role in the pathogenesis of FTLD-tauassociated with Pick bodies, although their lack of immunostaining implies that such changes do notcontribute directly to the formation of Pick bodies.", "metadata": {}}
+{"_id": "667451", "title": "", "text": "Evolution and Impact of Subclonal Mutations in Chronic Lymphocytic LeukemiaClonal evolution is a keyfeature of cancer progression and relapse. We studied intratumoral heterogeneity in 149 chroniclymphocytic leukemia (CLL) cases by integrating whole-exome sequence and copy number to measurethe fraction of cancer cells harboring each somatic mutation. We identified driver mutations aspredominantly clonal (e.g., MYD88, trisomy 12, and del(13q)) or subclonal (e.g., SF3B1 and TP53),corresponding to earlier and later events in CLL evolution. We sampled leukemia cells from 18 patients attwo time points. Ten of twelve CLL cases treated with chemotherapy (but only one of six withouttreatment) underwent clonal evolution, predominantly involving subclones with driver mutations (e.g.,SF3B1 and TP53) that expanded over time. Furthermore, presence of a subclonal driver mutation was anindependent risk factor for rapid disease progression. Our study thus uncovers patterns of clonalevolution in CLL, providing insights into its stepwise transformation, and links the presence of subcloneswith adverse clinical outcomes.", "metadata": {}}
+{"_id": "680949", "title": "", "text": "The transcriptional program of sporulation in budding yeastDiploid cells of budding yeast produce haploidcells through the developmental program of sporulation, which consists of meiosis and sporemorphogenesis. DNA microarrays containing nearly every yeast gene were used to assay changes in geneexpression during sporulation. At least seven distinct temporal patterns of induction were observed. Thetranscription factor Ndt80 appeared to be important for induction of a large group of genes at the end ofmeiotic prophase. Consensus sequences known or proposed to be responsible for temporal regulationcould be identified solely from analysis of sequences of coordinately expressed genes. The temporalexpression pattern provided clues to potential functions of hundreds of previously uncharacterized genes,some of which have vertebrate homologs that may function during gametogenesis.", "metadata": {}}
+{"_id": "695938", "title": "", "text": "Grass plants bind, retain, uptake, and transport infectious prions.Prions are the protein-based infectiousagents responsible for prion diseases. Environmental prion contamination has been implicated in diseasetransmission. Here, we analyzed the binding and retention of infectious prion protein (PrP(Sc)) to plants.Small quantities of PrP(Sc) contained in diluted brain homogenate or in excretory materials (urine andfeces) can bind to wheat grass roots and leaves. Wild-type hamsters were efficiently infected by ingestionof prion-contaminated plants. The prion-plant interaction occurs with prions from diverse origins,including chronic wasting disease. Furthermore, leaves contaminated by spraying with a prion-containingpreparation retained PrP(Sc) for several weeks in the living plant. Finally, plants can uptake prions fromcontaminated soil and transport them to aerial parts of the plant (stem and leaves). These findingsdemonstrate that plants can efficiently bind infectious prions and act as carriers of infectivity, suggestinga possible role of environmental prion contamination in the horizontal transmission of the disease.", "metadata": {}}
+{"_id": "696006", "title": "", "text": "Innate lymphoid cells mediate influenza-induced airway hyper-reactivity independently of adaptiveimmunityPatients with asthma, a major public health problem, are at high risk for serious disease frominfluenza virus infection, but the pathogenic mechanisms by which influenza A causes airway disease andasthma are not fully known. We show here in a mouse model that influenza infection acutely inducedairway hyper-reactivity (AHR), a cardinal feature of asthma, independently of T helper type 2 (TH2) cellsand adaptive immunity. Instead, influenza infection induced AHR through a previously unknown pathwaythat required the interleukin 13 (IL-13)–IL-33 axis and cells of the non-T cell, non-B cell innate lymphoidtype called 'natural helper cells'. Infection with influenza A virus, which activates the NLRP3inflammasome, resulted in much more production of IL-33 by alveolar macrophages, which in turnactivated natural helper cells producing substantial IL-13.", "metadata": {}}
+{"_id": "704526", "title": "", "text": "The behaviour change wheel: A new method for characterising and designing behaviour changeinterventionsBACKGROUND Improving the design and implementation of evidence-based practicedepends on successful behaviour change interventions. This requires an appropriate method forcharacterising interventions and linking them to an analysis of the targeted behaviour. There exists aplethora of frameworks of behaviour change interventions, but it is not clear how well they serve thispurpose. This paper evaluates these frameworks, and develops and evaluates a new framework aimed atovercoming their limitations. METHODS A systematic search of electronic databases and consultation withbehaviour change experts were used to identify frameworks of behaviour change interventions. Thesewere evaluated according to three criteria: comprehensiveness, coherence, and a clear link to anoverarching model of behaviour. A new framework was developed to meet these criteria. The reliabilitywith which it could be applied was examined in two domains of behaviour change: tobacco control andobesity. RESULTS Nineteen frameworks were identified covering nine intervention functions and sevenpolicy categories that could enable those interventions. None of the frameworks reviewed covered the fullrange of intervention functions or policies, and only a minority met the criteria of coherence or linkage toa model of behaviour. At the centre of a proposed new framework is a 'behaviour system' involving threeessential conditions: capability, opportunity, and motivation (what we term the 'COM-B system'). Thisforms the hub of a 'behaviour change wheel' (BCW) around which are positioned the nine interventionfunctions aimed at addressing deficits in one or more of these conditions; around this are placed sevencategories of policy that could enable those interventions to occur. The BCW was used reliably tocharacterise interventions within the English Department of Health's 2010 tobacco control strategy andthe National Institute of Health and Clinical Excellence's guidance on reducing obesity. CONCLUSIONSInterventions and policies to change behaviour can be usefully characterised by means of a BCWcomprising: a 'behaviour system' at the hub, encircled by intervention functions and then by policycategories. Research is needed to establish how far the BCW can lead to more efficient design of effectiveinterventions.", "metadata": {}}
+{"_id": "708425", "title": "", "text": "Intermittent prophylaxis with oral truvada protects macaques from rectal SHIV infection.HIV continues tospread globally, mainly through sexual contact. Despite advances in treatment and care, preventingtransmission with vaccines or microbicides has proven difficult. A promising strategy to avoidtransmission is prophylactic treatment with antiretroviral drugs before exposure to HIV. Clinical trialsevaluating the efficacy of daily treatment with the reverse transcriptase inhibitors tenofovir disoproxilfumarate (TDF) or Truvada (TDF plus emtricitabine) are under way. We hypothesized that intermittentprophylactic treatment with long-acting antiviral drugs would be as effective as daily dosing in blockingthe earliest stages of viral replication and preventing mucosal transmission. We tested this hypothesis byintermittently giving prophylactic Truvada to macaque monkeys and then exposing them rectally tosimian-human immunodeficiency virus (SHIV) once a week for 14 weeks. A simple regimen with an oraldose of Truvada given 1, 3, or 7 days before exposure followed by a second dose 2 hours after exposurewas as protective as daily drug administration, possibly because of the long intracellular persistence ofthe drugs. In addition, a two-dose regimen initiated 2 hours before or after virus exposure was effective,and full protection was obtained by doubling the Truvada concentration in both doses. We saw noprotection if the first dose was delayed until 24 hours after exposure, underscoring the importance ofblocking initial replication in the mucosa. Our results show that intermittent prophylactic treatment withan antiviral drug can be highly effective in preventing SHIV infection, with a wide window of protection.They strengthen the possibility of developing feasible, cost-effective strategies to prevent HIVtransmission in humans.", "metadata": {}}
+{"_id": "711256", "title": "", "text": "RNA is favourable for analysing EGFR mutations in malignant pleural effusion of lung cancer.Malignantpleural effusion (MPE) is a useful specimen allowing for the evaluation of EGFR status in nonsmall celllung cancer (NSCLC). However, direct sequencing of genomic DNA from MPE samples was found not to besensitive for EGFR mutation detection. To test whether EGFR analysis from RNA is less prone tointerference from nontumour cells that have no or lower EGFR expression, we compared three methods(sequencing from cell-derived RNA versus sequencing and mass-spectrometric analysis from genomicDNA), in parallel, for EGFR mutation detection from MPE samples in 150 lung adenocarcinoma patientsreceiving first-line tyrosine kinase inhibitors (TKIs). Among these MPE samples, EGFR mutations weremuch more frequently identified by sequencing using RNA than by sequencing and mass-spectrometricanalysis from genomic DNA (for all mutations, 67.3 versus 44.7 and 46.7%; for L858R or exon 19deletions, 61.3 versus 41.3 and 46.7%, respectively). The better mutation detection yield of sequencingfrom RNA was coupled with the superior prediction of clinical efficacy of first-line TKIs. In patients withacquired resistance, EGFR sequencing from RNA provided satisfactory detection of T790M (54.2%). Theseresults demonstrated that EGFR sequencing using RNA as template greatly improves sensitivity for EGFRmutation detection from samples of MPE, highlighting RNA as the favourable source for analysing EGFRmutations from heterogeneous MPE specimens in NSCLC.", "metadata": {}}
+{"_id": "712078", "title": "", "text": "Pharmacological correction of a defect in PPARγ signaling ameliorates disease severity in Cftr-deficientmiceCystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator(encoded by Cftr) that impair its role as an apical chloride channel that supports bicarbonate transport.Individuals with cystic fibrosis show retained, thickened mucus that plugs airways and obstructs luminalorgans as well as numerous other abnormalities that include inflammation of affected organs, alterationsin lipid metabolism and insulin resistance. Here we show that colonic epithelial cells and whole lung tissuefrom Cftr-deficient mice show a defect in peroxisome proliferator-activated receptor-gamma(PPAR-gamma, encoded by Pparg) function that contributes to a pathological program of geneexpression. Lipidomic analysis of colonic epithelial cells suggests that this defect results in part fromreduced amounts of the endogenous PPAR-gamma ligand 15-keto-prostaglandin E(2) (15-keto-PGE(2)).Treatment of Cftr-deficient mice with the synthetic PPAR-gamma ligand rosiglitazone partially normalizesthe altered gene expression pattern associated with Cftr deficiency and reduces disease severity.Rosiglitazone has no effect on chloride secretion in the colon, but it increases expression of the genesencoding carbonic anhydrases 4 and 2 (Car4 and Car2), increases bicarbonate secretion and reducesmucus retention. These studies reveal a reversible defect in PPAR-gamma signaling in Cftr-deficient cellsthat can be pharmacologically corrected to ameliorate the severity of the cystic fibrosis phenotype inmice.", "metadata": {}}
+{"_id": "712320", "title": "", "text": "Visualization of volatile substances in different organelles with an atmospheric-pressure massmicroscope.We have developed a mass microscope (mass spectrometry imager with spatial resolutionhigher than the naked eye) equipped with an atmospheric pressure ion-source chamber for laserdesorption/ionization (AP-LDI) and a quadrupole ion trap time-of-flight (QIT-TOF) analyzer. The opticalmicroscope combined with the mass spectrometer permitted us to precisely determine the relevant tissueregion prior to performing imaging mass spectrometry (IMS). An ultraviolet laser tightly focused with atriplet lens was used to achieve high spatial resolution. An atmospheric pressure ion-source chamberenables us to analyze fresh samples with minimal loss of intrinsic water or volatile compounds.Mass-microscopic AP-LDI imaging of freshly cut ginger rhizome sections revealed that 6-gingerol ([M +K](+)at m/z 333.15, positive mode; [M - H](-) at m/z 293.17, negative mode) and the monoterpene ([M+ K](+) at m/z 191.09), which are the compounds related to pungency and flavor, respectively, werelocalized in oil drop-containing organelles. AP-LDI-tandem MS/MS analyses were applied to compareauthentic signals from freshly cut ginger directly with the standard reagent. Thus, ouratmosphere-imaging mass spectrometer enabled us to monitor a quality of plants at the organelle level.", "metadata": {}}
+{"_id": "718601", "title": "", "text": "Coding of Sweet, Bitter, and Umami Tastes Different Receptor Cells Sharing Similar SignalingPathwaysMammals can taste a wide repertoire of chemosensory stimuli. Two unrelated families ofreceptors (T1Rs and T2Rs) mediate responses to sweet, amino acids, and bitter compounds. Here, wedemonstrate that knockouts of TRPM5, a taste TRP ion channel, or PLCbeta2, a phospholipase Cselectively expressed in taste tissue, abolish sweet, amino acid, and bitter taste reception, but do notimpact sour or salty tastes. Therefore, despite relying on different receptors, sweet, amino acid, andbitter transduction converge on common signaling molecules. Using PLCbeta2 taste-blind animals, wethen examined a fundamental question in taste perception: how taste modalities are encoded at thecellular level. Mice engineered to rescue PLCbeta2 function exclusively in bitter-receptor expressing cellsrespond normally to bitter tastants but do not taste sweet or amino acid stimuli. Thus, bitter is encodedindependently of sweet and amino acids, and taste receptor cells are not broadly tuned across thesemodalities.", "metadata": {}}
+{"_id": "719812", "title": "", "text": "Green synthesis of silver nanoparticles and characterization of their inhibitory effects on AGEs formationusing biophysical techniquesAdvanced glycation end-products (AGEs) resulting from non-enzymaticglycation are one of the major factors implicated in secondary complications of diabetes. Scientists arefocusing on discovering new compounds that may be used as potential AGEs inhibitors without affectingthe normal structure and function of biomolecules. A number of natural and synthetic compounds havebeen proposed as AGE inhibitors. In this study, we investigated the inhibitory effects of AgNPs (silvernanoparticles) in AGEs formation. AgNPs (~30.5 nm) synthesized from Aloe Vera leaf extract werecharacterized using UV-Vis spectroscopy, energy-dispersive X-ray spectroscopy (EDX), highresolution-transmission electron microscopy, X-ray diffraction and dynamic light scattering (DLS)techniques. The inhibitory effects of AgNPs on AGEs formation were evaluated by investigating the degreeof reactivity of free amino groups (lysine and arginine residues), protein-bound carbonyl andcarboxymethyl lysine (CML) content, and the effects on protein structure using various physicochemicaltechniques. The results showed that AgNPs significantly inhibit AGEs formation in a concentrationdependent manner and that AgNPs have a positive effect on protein structure. These findings stronglysuggest that AgNPs may play a therapeutic role in diabetes-related complications.", "metadata": {}}
+{"_id": "735130", "title": "", "text": "Myosin Light Chain–activating Phosphorylation Sites Are Required for Oogenesis in DrosophilaTheDrosophila spaghetti squash ( sqh ) gene encodes the regulatory myosin light chain (RMLC) of nonmusclemyosin II. Biochemical analysis of vertebrate nonmuscle and smooth muscle myosin II has establishedthat phosphorylation of certain amino acids of the RMLC greatly increases the actin-dependent myosinATPase and motor activity of myosin in vitro. We have assessed the in vivo importance of these sites,which in Drosophila correspond to serine-21 and threonine-20, by creating a series of transgenes inwhich these specific amino acids were altered. The phenotypes of the transgenes were examined in anotherwise null mutant background during oocyte development in Drosophila females. Germ linecystoblasts entirely lacking a functional sqh gene show severe defects in proliferation and cytokinesis.The ring canals, cytoplasmic bridges linking the oocyte to the nurse cells in the egg chamber, areabnormal, suggesting a role of myosin II in their establishment or maintenance. In addition, numerousaggregates of myosin heavy chain accumulate in the sqh null cells. Mutant sqh transgene sqh -A20, A21in which both serine-21 and threonine-20 have been replaced by alanines behaves in most respectsidentically to the null allele in this system, with the exception that no heavy chain aggregates are found.In contrast, expression of sqh -A21, in which only the primary phosphorylation target serine-21 site isaltered, partially restores functionality to germ line myosin II, allowing cystoblast division and oocytedevelopment, albeit with some cytokinesis failure, defects in the rapid cytoplasmic transport from nursecells to cytoplasm characteristic of late stage oogenesis, and some damaged ring canals. Substituting aglutamate for the serine-21 (mutant sqh -E21) allows oogenesis to be completed with minimal defects,producing eggs that can develop normally to produce fertile adults. Flies expressing sqh -A20, in whichonly the secondary phosphorylation site is absent, appear to be entirely wild type. Taken together, thisgenetic evidence argues that phosphorylation at serine-21 is critical to RMLC function in activating myosinII in vivo, but that the function can be partially provided by phosphorylation at threonine-20.", "metadata": {}}
+{"_id": "739734", "title": "", "text": "Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years.Two thousandthree hundred and thirty two nonselected brains from 1- to 100-year-old individuals were examined usingimmunocytochemistry (AT8) and Gallyas silver staining for abnormal tau; immunocytochemistry (4G8)and Campbell-Switzer staining were used for the detection ofβ-amyloid. A total of 342 cases was negativein the Gallyas stain but when restaged for AT8 only 10 were immunonegative. Fifty-eight cases hadsubcortical tau predominantly in the locus coeruleus, but there was no abnormal cortical tau (subcorticalStages a-c). Cortical involvement (abnormal tau in neurites) was identified first in the transentorhinalregion (Stage 1a, 38 cases). Transentorhinal pyramidal cells displayed pretangle material (Stage 1b, 236cases). Pretangles gradually became argyrophilic neurofibrillary tangles (NFTs) that progressed in parallelwith NFT Stages I to VI. Pretangles restricted to subcortical sites were seen chiefly at younger ages. Ofthe total cases, 1,031 (44.2%) had β-amyloid plaques. The first plaques occurred in the neocortex afterthe onset of tauopathy in the brainstem. Plaques generally developed in the 40s in 4% of all cases,culminating in their tenth decade (75%). β-amyloid plaques and NFTs were significantly correlated (p <0.0001). These data suggest that tauopathy associated with sporadic Alzheimer disease may begin earlierthan previously thought and possibly in the lower brainstem rather than in the transentorhinal region.", "metadata": {}}
+{"_id": "750781", "title": "", "text": "Coronary bypass graft patency in patients with diabetes in the Bypass Angioplasty RevascularizationInvestigation (BARI).BACKGROUND Few studies have compared long-term status of bypass graftsbetween patients with and without diabetes, and uncertainty exists as to whether diabetes independentlypredicts poor clinical outcome after CABG. METHODS AND RESULTS Among 1526 patients in BARI whounderwent CABG as initial revascularization, 99 of 292 (34%) with treated diabetes mellitus (TDM) (thoseon insulin or oral hypoglycemic agents) and 469 of 1234 (38%) without TDM had follow-up angiography.Angiograms with the longest interval from initial surgery and before any percutaneous graft intervention(mean 3.9 years) were reviewed. An average of 3.0 grafts were placed at initial CABG for patients withTDM (n=297; internal mammary artery [IMA], 33%) and 2.9 grafts for patients without TDM (n=1347;IMA, 34%). Patients with TDM were more likely than those without to have small (<1.5 mm) grafteddistal vessels (29% versus 22%) and vessels of poor quality (9% versus 6%). On follow-up angiography,89% of IMA grafts were free of stenoses > or =50% among patients with TDM versus 85% amongpatients without TDM (P=0.23). For vein grafts, the corresponding percentages were 71% versus 75%(P=0.40). After statistical adjustment, TDM was unrelated to having a graft stenosis > or =50%(adjusted odds ratio, 0.87; 95% CI, 0.58 to 1.32). CONCLUSIONS Despite diabetic patients' havingsmaller distal vessels and vessels judged to be of poorer quality, diabetes does not appear to adverselyaffect patency of IMA or vein grafts over an average of 4-year follow-up. Previously observed differencesin survival between CABG-treated patients with and without diabetes may be largely a result ofdifferential risk of mortality from noncardiac causes.", "metadata": {}}
+{"_id": "751192", "title": "", "text": "A novel ATAC-seq approach reveals lineage-specific reinforcement of the open chromatin landscape viacooperation between BAF and p63BACKGROUND Open chromatin regions are correlated with activeregulatory elements in development and are dysregulated in diseases. The BAF (SWI/SNF) complex isessential for development, and has been demonstrated to remodel reconstituted chromatin in vitro and tocontrol the accessibility of a few individual regions in vivo. However, it remains unclear where and howBAF controls the open chromatin landscape to regulate developmental processes, such as humanepidermal differentiation. RESULTS Using a novel \"on-plate\" ATAC-sequencing approach for profiling openchromatin landscapes with a low number of adherent cells, we demonstrate that the BAF complex isessential for maintaining 11.6 % of open chromatin regions in epidermal differentiation. TheseBAF-dependent open chromatin regions are highly cell-type-specific and are strongly enriched for bindingsites for p63, a master epidermal transcription factor. The DNA sequences of p63 binding sitesintrinsically favor nucleosome formation and are inaccessible in other cell types without p63 to preventectopic activation. In epidermal cells, BAF and p63 mutually recruit each other to maintain 14,853 openchromatin regions. We further demonstrate that BAF and p63 cooperatively position nucleosomes awayfrom p63 binding sites and recruit transcriptional machinery to control tissue differentiation.CONCLUSIONS BAF displays high specificity in controlling the open chromatin landscape during epidermaldifferentiation by cooperating with the master transcription factor p63 to maintain lineage-specific openchromatin regions.", "metadata": {}}
+{"_id": "752423", "title": "", "text": "Aging, habitual exercise, and dynamic arterial compliance.BACKGROUND A reduction in compliance of thelarge-sized cardiothoracic (central) arteries is an independent risk factor for the development ofcardiovascular disease with advancing age. METHODS AND RESULTS We determined the role of habitualexercise on the age-related decrease in central arterial compliance by using both cross-sectional andinterventional approaches. First, we studied 151 healthy men aged 18 to 77 years: 54 were sedentary,45 were recreationally active, and 53 were endurance exercise-trained. Central arterial compliance(simultaneous B-mode ultrasound and arterial applanation tonometry on the common carotid artery) waslower (P:<0.05) in middle-aged and older men than in young men in all 3 groups. There were nosignificant differences between sedentary and recreationally active men at any age. However, arterialcompliance in the endurance-trained middle-aged and older men was 20% to 35% higher than in the 2less active groups (P:<0.01). As such, age-related differences in central arterial compliance were smallerin the endurance-trained men than in the sedentary and recreationally active men. Second, we studied20 middle-aged and older (53+/-2 years) sedentary healthy men before and after a 3-month aerobicexercise intervention (primarily walking). Regular exercise increased central arterial compliance(P:<0.01) to levels similar to those of the middle-aged and older endurance-trained men. These effectswere independent of changes in body mass, adiposity, arterial blood pressure, or maximal oxygenconsumption. CONCLUSIONS Regular aerobic-endurance exercise attenuates age-related reductions incentral arterial compliance and restores levels in previously sedentary healthy middle-aged and oldermen. This may be one mechanism by which habitual exercise lowers the risk of cardiovascular disease inthis population.", "metadata": {}}
+{"_id": "756887", "title": "", "text": "A comparison of cancer screening practices in cancer survivors and in the general population: the Koreannational health and nutrition examination survey (KNHANES) 2001–2007This study aimed to describecancer screening rates for second primary cancer among cancer survivors in Korea, and to compare theserates with those of two control groups: individuals without a history of cancer but with other chronicdiseases, and individuals without a history of cancer and without other chronic diseases. The study is across-sectional analysis of 15,556 adults ≥30 years old who participated in the 2001, 2005, and 2007Korean National Health and Nutrition Examination Surveys (KNHANES). The prevalence of breast,cervical, gastric, and colorectal cancer screening examinations according to national guidelines wasassessed and compared to two control groups. Screening rates among cancer survivors were 48.5, 54.7,34.7, and 28.6% for breast, cervical, gastric, and colorectal cancer screening, respectively. Cancersurvivors showed higher screening rates for all four cancer sites compared with both control groups, butbreast cancer screening was only statistically significant after adjusting gender, age, marital status,education, income, working status, health insurance, smoking and drinking status, and self-reportedhealth status. Cancer survivors were more likely than individuals without a cancer history to obtainscreening examinations according to recommended guidelines. Still, screening rates even amongsurvivors were suboptimal, emphasizing the need for a more systematic approach to second primarycancer screening and prevention.", "metadata": {}}
+{"_id": "778436", "title": "", "text": "Negative effect of the transcriptional activator GAL4The yeast transcriptional activator GAL4 binds specificsites on DNA to activate transcription of adjacent genes1–5. The distinct activating regions of GAL4 arerich in acidic residues and it has been suggested that these regions interact with another proteincomponent of the transcriptional machinery (such as the TATA-binding protein or RNA polymerase II)while the DNA-binding region serves to position the activating region near the gene6,7,8. Here we showthat various GAL4 derivatives, when expressed at high levels in yeast, inhibit transcription of certaingenes lacking GAL4 binding sites, that more efficient activators inhibit more strongly and that inhibitiondoes not depend on the DNA-binding domain. We suggest that this inhibition, which we call squelching,reflects titration of a transcription factor by the activating region of GAL4.", "metadata": {}}
+{"_id": "790598", "title": "", "text": "The Bayh–Dole Act and university research and developmentThis paper examines the relationshipbetween university research and development (R&D) activities and the Bayh-Dole Act. This act made itmuch easier for universities to obtain patents from research funded by the federal government and mayhave provided universities with an incentive to alter their R&D activities. The Act may provide anincentive to reduce basic research (which does not generate licensing fees) and increase applied research(which does generate patents and licensing fees). In addition, industry might be more willing to funduniversity R&D projects since the results would now be easier to patent. This paper differs from theexisting literature which uses patent data (a measure of research output) by using research anddevelopment data (a measure of inventive input) to examine the effect of the Act.", "metadata": {}}
+{"_id": "791050", "title": "", "text": "The relation between past exposure to fine particulate air pollution and prevalent anxiety: observationalcohort studyOBJECTIVE To determine whether higher past exposure to particulate air pollution isassociated with prevalent high symptoms of anxiety. DESIGN Observational cohort study. SETTINGNurses' Health Study. PARTICIPANTS 71,271 women enrolled in the Nurses' Health Study residingthroughout the contiguous United States who had valid estimates on exposure to particulate matter for atleast one exposure period of interest and data on anxiety symptoms. MAIN OUTCOME MEASURESMeaningfully high symptoms of anxiety, defined as a score of 6 points or greater on the phobic anxietysubscale of the Crown-Crisp index, administered in 2004. RESULTS The 71,271 eligible women were agedbetween 57 and 85 years (mean 70 years) at the time of assessment of anxiety symptoms, with aprevalence of high anxiety symptoms of 15%. Exposure to particulate matter was characterized usingestimated average exposure to particulate matter <2.5 μm in diameter (PM2.5) and 2.5 to 10 μm indiameter (PM2.5-10) in the one month, three months, six months, one year, and 15 years prior toassessment of anxiety symptoms, and residential distance to the nearest major road two years prior toassessment. Significantly increased odds of high anxiety symptoms were observed with higher exposureto PM2.5 for multiple averaging periods (for example, odds ratio per 10 µg/m(3) increase in prior onemonth average PM2.5: 1.12, 95% confidence interval 1.06 to 1.19; in prior 12 month average PM2.5:1.15, 1.06 to 1.26). Models including multiple exposure windows suggested short term averaging periodswere more relevant than long term averaging periods. There was no association between anxiety andexposure to PM2.5-10. Residential proximity to major roads was not related to anxiety symptoms in adose dependent manner. CONCLUSIONS Exposure to fine particulate matter (PM2.5) was associated withhigh symptoms of anxiety, with more recent exposures potentially more relevant than more distantexposures. Research evaluating whether reductions in exposure to ambient PM2.5 would reduce thepopulation level burden of clinically relevant symptoms of anxiety is warranted.", "metadata": {}}
+{"_id": "797114", "title": "", "text": "A mitochondrially targeted compound delays aging in yeast through a mechanism linking mitochondrialmembrane lipid metabolism to mitochondrial redox biology\u0000A recent study revealed a mechanism ofdelaying aging in yeast by a natural compound which specifically impacts mitochondrial redox processes.In this mechanism, exogenously added lithocholic bile acid enters yeast cells, accumulates mainly in theinner mitochondrial membrane, and elicits an age-related remodeling of phospholipid synthesis andmovement within both mitochondrial membranes. Such remodeling of mitochondrial phospholipiddynamics progresses with the chronological age of a yeast cell and ultimately causes significant changesin mitochondrial membrane lipidome. These changes in the composition of membrane phospholipids altermitochondrial abundance and morphology, thereby triggering changes in the age-related chronology ofsuch longevity-defining redox processes as mitochondrial respiration, the maintenance of mitochondrialmembrane potential, the preservation of cellular homeostasis of mitochondrially produced reactiveoxygen species, and the coupling of electron transport to ATP synthesis.", "metadata": {}}
+{"_id": "798152", "title": "", "text": "Isolation from African Sykes' monkeys (Cercopithecus mitis) of a lentivirus related to human and simianimmunodeficiency viruses.Analysis of serum samples from 100 wild-caught or colony-born Sykes'monkeys (Cercopithecus mitis) in Kenya revealed that 59 animals had antibodies cross-reactive to humanimmunodeficiency virus type 2 (HIV-2) and to simian immunodeficiency viruses (SIVs). A lentivirus,designated SIVsyk, was isolated from five of six seropositive asymptomatic Sykes' monkeys, but in fourcases isolation was possible only after depletion of CD8+ lymphocytes and cocultivation of theCD4(+)-enriched cell population with peripheral blood mononuclear cells from seronegative Sykes'monkeys. SIVsyk resembled other SIVs and HIVs morphologically, had an Mg2(+)-dependent reversetranscriptase enzyme, and replicated in and was cytopathic for CEMx174 and Sup-T1 cells. SIVsykdifferred substantially from other SIVs, however, in that it failed to replicate in normal human,mangabey, and macaque peripheral blood mononuclear cells and serum from seropositive Sykes'monkeys immunoprecipitated env antigens from HIV-1 as well as from HIV-2, SIVsmm, and SIVagm.These data demonstrate a high prevalence of natural infection in Sykes' monkeys in Kenya with alentivirus that appears to be unique with respect to its host range and antigenic cross-reactivity.", "metadata": {}}
+{"_id": "799586", "title": "", "text": "Role of the Single-Stranded DNA–Binding Protein SsbB in Pneumococcal Transformation: Maintenance ofa Reservoir for Genetic PlasticityBacteria encode a single-stranded DNA (ssDNA) binding protein (SSB)crucial for genome maintenance. In Bacillus subtilis and Streptococcus pneumoniae, an alternative SSB,SsbB, is expressed uniquely during competence for genetic transformation, but its precise role has beendisappointingly obscure. Here, we report our investigations involving comparison of a null mutant(ssbB(-)) and a C-ter truncation (ssbBΔ7) of SsbB of S. pneumoniae, the latter constructed becauseSSBs' acidic tail has emerged as a key site for interactions with partner proteins. We provide evidencethat SsbB directly protects internalized ssDNA. We show that SsbB is highly abundant, potentiallyallowing the binding of ~1.15 Mb ssDNA (half a genome equivalent); that it participates in the processingof ssDNA into recombinants; and that, at high DNA concentration, it is of crucial importance forchromosomal transformation whilst antagonizing plasmid transformation. While the latter observationexplains a long-standing observation that plasmid transformation is very inefficient in S. pneumoniae(compared to chromosomal transformation), the former supports our previous suggestion that SsbBcreates a reservoir of ssDNA, allowing successive recombination cycles. SsbBΔ7 fulfils the reservoirfunction, suggesting that SsbB C-ter is not necessary for processing protein(s) to access stored ssDNA.We propose that the evolutionary raison d'être of SsbB and its abundance is maintenance of thisreservoir, which contributes to the genetic plasticity of S. pneumoniae by increasing the likelihood ofmultiple transformation events in the same cell.", "metadata": {}}
+{"_id": "803312", "title": "", "text": "Cerebral organoids model human brain development and microcephalyThe complexity of the human brainhas made it difficult to study many brain disorders in model organisms, highlighting the need for an invitro model of human brain development. Here we have developed a human pluripotent stem cell-derivedthree-dimensional organoid culture system, termed cerebral organoids, that develop various discrete,although interdependent, brain regions. These include a cerebral cortex containing progenitor populationsthat organize and produce mature cortical neuron subtypes. Furthermore, cerebral organoids are shownto recapitulate features of human cortical development, namely characteristic progenitor zoneorganization with abundant outer radial glial stem cells. Finally, we use RNA interference andpatient-specific induced pluripotent stem cells to model microcephaly, a disorder that has been difficult torecapitulate in mice. We demonstrate premature neuronal differentiation in patient organoids, a defectthat could help to explain the disease phenotype. Together, these data show that three-dimensionalorganoids can recapitulate development and disease even in this most complex human tissue.", "metadata": {}}
+{"_id": "810480", "title": "", "text": "Localization of a gene for partial epilepsy to chromosome 10qThere is strong evidence for a geneticcontribution to epilepsy, but it is commonly assumed that this genetic contribution is limited to‘generalized’ epilepsies, and that most forms of ‘partial’ epilepsy are nongenetic. In a linkage analysis of asingle family containing 11 affected individuals, we obtained strong evidence for localization of a gene forpartial epilepsy. This susceptibility gene maps to chromosome 10q, with a maximum two–point lod scorefor D10S192 of 3.99 at θ=0.0. All affected individuals share a single haplotype for seven tightly linkedcontiguous markers; the maximum lod score for this haplotype is 4.83 at θ=0.0. Key recombinants placethe susceptibility locus within a 10 centimorgan interval.", "metadata": {}}
+{"_id": "825728", "title": "", "text": "Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer Prrx1.Theepithelial-mesenchymal transition (EMT) is required in the embryo for the formation of tissues for whichcells originate far from their final destination. Carcinoma cells hijack this program for tumordissemination. The relevance of the EMT in cancer is still debated because it is unclear how thesemigratory cells colonize distant tissues to form macrometastases. We show that the homeobox factorPrrx1 is an EMT inducer conferring migratory and invasive properties. The loss of Prrx1 is required forcancer cells to metastasize in vivo, which revert to the epithelial phenotype concomitant with theacquisition of stem cell properties. Thus, unlike the classical EMT transcription factors, Prrx1 uncouplesEMT and stemness, and is a biomarker associated with patient survival and lack of metastasis.", "metadata": {}}
+{"_id": "829646", "title": "", "text": "A cohort study of the risk of cervical intraepithelial neoplasia grade 2 or 3 in relation to papillomavirusinfection.BACKGROUND Human papillomavirus (HPV) has been associated with cervical intraepithelialneoplasia, but the temporal relation between the infection and the neoplasia remains unclear, as does therelative importance of the specific type of HPV, other sexually transmitted diseases, and other riskfactors. METHODS We studied prospectively a cohort of 241 women who presented for evaluation ofsexually transmitted disease and had negative cervical cytologic tests. The women were followed everyfour months with cytologic and colposcopic examinations of the uterine cervix and tests for HPV DNA andother sexually transmitted diseases. RESULTS Cervical intraepithelial neoplasia grade 2 or 3 wasconfirmed by biopsy in 28 women. On the basis of survival analysis, the cumulative incidence of cervicalintraepithelial neoplasia at two years was 28 percent among women with a positive test for HPV and 3percent among those without detectable HPV DNA: The risk was highest among those with HPV type 16or 18 infection (adjusted relative risk as compared with that in women without HPV infection, 11; 95percent confidence interval, 4.6 to 26; attributable risk, 52 percent). All 24 cases of cervicalintraepithelial neoplasia grade 2 or 3 among HPV-positive women were detected within 24 months afterthe first positive test for HPV. After adjustment for the presence of HPV infection, the development ofcervical intraepithelial neoplasia was also associated with younger age at first intercourse, the presenceof serum antibodies to Chlamydia trachomatis, the presence of serum antibodies to cytomegalovirus, andcervical infection with Neisseria gonorrhoeae. CONCLUSIONS Cervical intraepithelial neoplasia is acommon and apparently early manifestation of cervical infection by HPV, particularly types 16 and 18.", "metadata": {}}
+{"_id": "831167", "title": "", "text": "Investigating survival prognosis of glioblastoma using evolutional properties of gene networksIn recentyears, there has been widespread interest and a large number of publications on the application of graphtheory techniques into constructing and analyzing biologically-informed gene networks from cancer cellline data sets. Current research efforts have predominantly looked at an overall static, topological,representation of the network, and have not investigated the application of graph theoretical techniquesto evolutionary investigations of cancer. A number of these studies have used graph theory metrics, suchas degree, betweenness, and closeness centrality, to identify important hub genes in these networks.However, these have not fully investigated the importance of genes across the different stages of thedisease. Previous human glioblastoma publications have identified four subtypes of glioblastoma inadults, based on signature genes. In one such publication, Verhaak et al. found that the subtypescorrespond to a narrow median survival range, from 11.3 months for the most aggressive subtype, to13.1 months for the least aggressive one. In this work, we present an evolutionary graph theory study ofglioblastoma based on survival data categorization, confirming genes associated with different survivaltimes identified using established graph theory metrics. The work is extending the application of graphtheory approaches to evolutionary studies of cancer cell line data.", "metadata": {}}
+{"_id": "834336", "title": "", "text": "Compound heterozygous ZMPSTE24 mutations reduce prelamin A processing and result in a severeprogeroid phenotype.Hutchinson–Gilford progeria syndrome (HGPS; OMIM 176670) is an extremely rarebut devastating disorder that mimics premature aging.1–3 Affected children appear normal at birth buttypically develop failure to thrive in the first two years. Other features include alopecia, micrognathia,loss of subcutaneous fat with prominent veins, abnormal dentition, sclerodermatous skin changes, andosteolysis of the clavicles and distal phalanges. The mean age of death is at age 13 years, mostcommonly due to atherosclerosis. HGPS is mainly sporadic in occurrence, but a genetic cause has nowbeen implicated following the identification of de novo heterozygous mutations in the LMNA gene in themajority of HGPS patients.4,5 A single family showing autosomal recessive inheritance of homozygousLMNA mutations has also been reported.6  LMNA encodes lamins A and C, components of the nuclearlamina, a meshwork underlying the nuclear envelope that serves as a structural support and is alsothought to contribute to chromatin organisation and the regulation of gene expression.7,8 Interestingly,mutations in LMNA have recently been associated with at least eight inherited disorders, known aslaminopathies, with differential dystrophic effects on a variety of tissues including muscle, neurones, skin,bone, and adipose tissue (reviewed in Mounkes et al 9). However, the realisation that these disordersshare common genetic defects has led to clinical re-evaluation, with emerging evidence of significantphenotypic overlap.10 Hence the laminopathies might reasonably be considered as a spectrum of relateddiseases. HGPS has phenotypic similarities to several other laminopathies, in particular the atypicalWerner’s syndrome11 and mandibuloacral dysplasia (MAD; OMIM 248370 and 608612).12 Thesediseases are associated with lipodystrophy,3,13 which is the most prominent feature of anotherlaminopathy, familial partial lipodystrophy of the Dunnigan variety (OMIM 151660).14 MAD has beenfurther classified as two …", "metadata": {}}
+{"_id": "841371", "title": "", "text": "Reliability of patient responses in pay for performance schemes: analysis of national General PractitionerPatient Survey data in EnglandOBJECTIVE To assess the robustness of patient responses to a newnational survey of patient experience as a basis for providing financial incentives to doctors. DESIGNAnalysis of the representativeness of the respondents to the GP Patient Survey compared with those whowere sampled (5.5 million patients registered with 8273 general practices in England in January 2009)and with the general population. Analysis of non-response bias looked at the relation between practiceresponse rates and scores on the survey. Analysis of the reliability of the survey estimated the proportionof the variance of practice scores attributable to true differences between practices. RESULTS The overallresponse rate was 38.2% (2.2 million responses), which is comparable to that in surveys using similarmethodology in the UK. Men, young adults, and people living in deprived areas were under-representedamong respondents. However, for questions related to pay for performance, there was no systematicassociation between response rates and questionnaire scores. Two questions which triggered paymentsto general practitioners were reliable measures of practice performance, with average practice-levelreliability coefficients of 93.2% and 95.0%. Less than 3% and 0.5% of practices had fewer than thenumber of responses required to achieve conventional reliability levels of 90% and 70%. A change to thepayment formula in 2009 resulted in an increase in the average impact of random variation in patientscores on payments to general practitioners compared with payments made in 2007 and 2008.CONCLUSIONS There is little evidence to support the concern of some general practitioners that lowresponse rates and selective non-response bias have led to systematic unfairness in payments attachedto questionnaire scores. The study raises issues relating to the validity and reliability of payments basedon patient surveys and provides lessons for the UK and for other countries considering the use of patientexperience as part of pay for performance schemes.", "metadata": {}}
+{"_id": "849771", "title": "", "text": "Impact of low alcohol verbal descriptors on perceived strength: An experimental studyOBJECTIVES Lowalcohol labels are a set of labels that carry descriptors such as 'low' or 'lighter' to denote alcohol contentin beverages. There is growing interest from policymakers and producers in lower strength alcoholproducts. However, there is a lack of evidence on how the general population perceives verbal descriptorsof strength. The present research examines consumers' perceptions of strength (% ABV) and appeal ofalcohol products using low or high alcohol verbal descriptors. DESIGN A within-subjects experimentalstudy in which participants rated the strength and appeal of 18 terms denoting low (nine terms), high(eight terms) and regular (one term) strengths for either (1) wine or (2) beer according to drinkingpreference. METHODS Thousand six hundred adults (796 wine and 804 beer drinkers) sampled from anationally representative UK panel. RESULTS Low, Lower, Light, Lighter, and Reduced formed a clusterand were rated as denoting lower strength products than Regular, but higher strength than the clusterwith intensifiers consisting of Extra Low, Super Low, Extra Light, and Super Light. Similar clustering inperceived strength was observed amongst the high verbal descriptors. Regular was the most appealingstrength descriptor, with the low and high verbal descriptors using intensifiers rated least appealing.CONCLUSIONS The perceived strength and appeal of alcohol products diminished the more the verbaldescriptors implied a deviation from Regular. The implications of these findings are discussed in terms ofpolicy implications for lower strength alcohol labelling and associated public health outcomes. Statementof contribution What is already known about this subject? Current UK and EU legislation limits the numberof low strength verbal descriptors and the associated alcohol by volume (ABV) to 1.2% ABV and lower.There is growing interest from policymakers and producers to extend the range of lower strength alcoholproducts above the current cap of 1.2% ABV set out in national legislation. There is a lack of evidence onhow the general population perceives verbal descriptors of alcohol product strength (both low and high).What does this study add? Verbal descriptors of lower strength wine and beer form two clusters andeffectively communicate reduced alcohol content. Low, Lower, Light, Lighter, and Reduced wereconsidered lower in strength than Regular (average % ABV). Descriptors using intensifiers (Extra Low,Super Low, Extra Light, and Super Light) were considered lowest in strength. Similar clustering inperceived strength was observed amongst the high verbal descriptors. The appeal of alcohol productsreduced the more the verbal descriptors implied a deviation from Regular.", "metadata": {}}
+{"_id": "854417", "title": "", "text": "Transgenic Interleukin 10 Prevents Induction of Experimental Autoimmune EncephalomyelitisTheeffectiveness of interleukin 10 (IL-10) in the treatment of autoimmune-mediated central nervous systeminflammation is controversial. Studies of the model system, experimental autoimmune encephalomyelitis(EAE), using various routes, regimens, and delivery methods of IL-10 suggest that these variables mayaffect its immunoregulatory function. To study the influence of these factors on IL-10 regulation of EAEpathogenesis, we have analyzed transgenic mice expressing human IL-10 (hIL-10) transgene under thecontrol of a class II major histocompatibility complex (MHC) promoter. The hIL-10 transgenic mice arehighly resistant to EAE induced by active immunization, and this resistance appears to be mediated bysuppression of autoreactive T cell function. Myelin-reactive T helper 1 cells are induced butnonpathogenic in the IL-10 transgenic mice. Antibody depletion confirmed that EAE resistance isdependent on the presence of the transgenic IL-10. Mice expressing the hIL-10 transgene but not theendogenous murine IL-10 gene demonstrated that transgenic IL-10 from MHC class II–expressing cells issufficient to block induction of EAE. This study demonstrates that IL-10 can prevent EAE completely ifpresent at appropriate levels and times during disease induction.", "metadata": {}}
+{"_id": "857189", "title": "", "text": "Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutationsThe proteincytotoxic T lymphocyte antigen-4 (CTLA-4) is an essential negative regulator of immune responses, andits loss causes fatal autoimmunity in mice. We studied a large family in which five individuals presentedwith a complex, autosomal dominant immune dysregulation syndrome characterized byhypogammaglobulinemia, recurrent infections and multiple autoimmune clinical features. We identified aheterozygous nonsense mutation in exon 1 of CTLA4. Screening of 71 unrelated patients with comparableclinical phenotypes identified five additional families (nine individuals) with previously undescribed splicesite and missense mutations in CTLA4. Clinical penetrance was incomplete (eight adults of a total of 19genetically proven CTLA4 mutation carriers were considered unaffected). However, CTLA-4 proteinexpression was decreased in regulatory T cells (Treg cells) in both patients and carriers with CTLA4mutations. Whereas Treg cells were generally present at elevated numbers in these individuals, theirsuppressive function, CTLA-4 ligand binding and transendocytosis of CD80 were impaired. Mutations inCTLA4 were also associated with decreased circulating B cell numbers. Taken together, mutations inCTLA4 resulting in CTLA-4 haploinsufficiency or impaired ligand binding result in disrupted T and B cellhomeostasis and a complex immune dysregulation syndrome.", "metadata": {}}
+{"_id": "864491", "title": "", "text": "Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity inhuman tumor xenografts.PD 0332991 is a highly specific inhibitor of cyclin-dependent kinase 4 (Cdk4)(IC50, 0.011 micromol/L) and Cdk6 (IC50, 0.016 micromol/L), having no activity against a panel of 36additional protein kinases. It is a potent antiproliferative agent against retinoblastoma (Rb)-positivetumor cells in vitro, inducing an exclusive G1 arrest, with a concomitant reduction ofphospho-Ser780/Ser795 on the Rb protein. Oral administration of PD 0332991 to mice bearing theColo-205 human colon carcinoma produces marked tumor regression. Therapeutic doses of PD 0332991cause elimination of phospho-Rb and the proliferative marker Ki-67 in tumor tissue and down-regulationof genes under the transcriptional control of E2F. The results indicate that inhibition of Cdk4/6 alone issufficient to cause tumor regression and a net reduction in tumor burden in some tumors.", "metadata": {}}
+{"_id": "878526", "title": "", "text": "Neutrophils support lung colonization of metastasis-initiating breast cancer cellsDespite progress in thedevelopment of drugs that efficiently target cancer cells, treatments for metastatic tumours are oftenineffective. The now well-established dependency of cancer cells on their microenvironment suggests thattargeting the non-cancer-cell component of the tumour might form a basis for the development of noveltherapeutic approaches. However, the as-yet poorly characterized contribution of host responses duringtumour growth and metastatic progression represents a limitation to exploiting this approach. Here weidentify neutrophils as the main component and driver of metastatic establishment within the(pre-)metastatic lung microenvironment in mouse breast cancer models. Neutrophils have a fundamentalrole in inflammatory responses and their contribution to tumorigenesis is still controversial. Using variousstrategies to block neutrophil recruitment to the pre-metastatic site, we demonstrate that neutrophilsspecifically support metastatic initiation. Importantly, we find that neutrophil-derived leukotrienes aid thecolonization of distant tissues by selectively expanding the sub-pool of cancer cells that retain hightumorigenic potential. Genetic or pharmacological inhibition of the leukotriene-generating enzymearachidonate 5-lipoxygenase (Alox5) abrogates neutrophil pro-metastatic activity and consequentlyreduces metastasis. Our results reveal the efficacy of using targeted therapy against a specific tumourmicroenvironment component and indicate that neutrophil Alox5 inhibition may limit metastaticprogression.", "metadata": {}}
+{"_id": "881332", "title": "", "text": "Effect of Previous Miscarriage on Depressive Symptoms During Subsequent Pregnancy and Postpartum inthe First Baby StudyOur objective was to test the hypothesis that nulliparous women with a history ofmiscarriage have an increased risk of depression during late pregnancy, and at 1, 6, and 12 monthspostpartum compared to women without a history of miscarriage. We conducted secondary analysis of alongitudinal cohort study, the First Baby Study, and compared 448 pregnant women with a history ofmiscarriage to 2,343 pregnant women without a history of miscarriage on risk of probable depression(score >12 on the Edinburgh Postnatal Depression Scale). Logistic regression models were used toestimate odds ratios at each time point and generalized estimating equations were used to obtainestimates in longitudinal analysis. Women with a history of miscarriage were not more likely than womanwithout a history of miscarriage to score in the probable depression range during the third trimester or at6 or 12 months postpartum but were more likely at 1 month postpartum, after adjustment forsociodemographic factors (OR 1.66, 95 % CI 1.03–2.69). Women with a history of miscarriage may bemore vulnerable to depression during the first month postpartum than women without prior miscarriage,but this effect does not appear to persist beyond this time period. We support the promotion ofawareness surrounding this issue and recommend that research is planned to identify risk factors thatmay position a woman with a history of miscarriage to be at higher risk for depression.", "metadata": {}}
+{"_id": "883747", "title": "", "text": "IL-1β, IL-4 and IL-12 control the fate of group 2 innate lymphoid cells in human airway inflammation inthe lungsGroup 2 innate lymphoid cells (ILC2s) secrete type 2 cytokines, which protect against parasitesbut can also contribute to a variety of inflammatory airway diseases. We report here that interleukin 1β(IL-1β) directly activated human ILC2s and that IL-12 induced the conversion of these activated ILC2sinto interferon-γ (IFN-γ)-producing ILC1s, which was reversed by IL-4. The plasticity of ILCs wasmanifested in diseased tissues of patients with severe chronic obstructive pulmonary disease (COPD) orchronic rhinosinusitis with nasal polyps (CRSwNP), which displayed IL-12 or IL-4 signatures and theaccumulation of ILC1s or ILC2s, respectively. Eosinophils were a major cellular source of IL-4, whichrevealed cross-talk between IL-5-producing ILC2s and IL-4-producing eosinophils. We propose that IL-12and IL-4 govern ILC2 functional identity and that their imbalance results in the perpetuation of type 1 ortype 2 inflammation.", "metadata": {}}
+{"_id": "885056", "title": "", "text": "SummarySteroid receptor RNA activator (SRA), the only known RNA coactivator, augmentstransactivation by nuclear receptors (NRs). We identified SLIRP (SRA stem-loop interacting RNA bindingprotein) binding to a functional substructure of SRA, STR7. SLIRP is expressed in normal and tumortissues, contains an RNA recognition motif (RRM), represses NR transactivation in a SRA- andRRM-dependent manner, augments the effect of Tamoxifen, and modulates association of SRC-1 withSRA. SHARP, a RRM-containing corepressor, also binds STR7, augmenting repression with SLIRP. SLIRPcolocalizes with SKIP (Chr14q24.3), another NR coregulator, and reduces SKIP-potentiated NR signaling.SLIRP is recruited to endogenous promoters (pS2 and metallothionein), the latter in a SRA-dependentmanner, while NCoR promoter recruitment is dependent on SLIRP. The majority of the endogenous SLIRPresides in the mitochondria. Our data demonstrate that SLIRP modulates NR transactivation, suggest itmay regulate mitochondrial function, and provide mechanistic insight into interactions between SRA,SLIRP, SRC-1, and NCoR.", "metadata": {}}
+{"_id": "888896", "title": "", "text": "Naringenin inhibits allergen-induced airway inflammation and airway responsiveness and inhibitsNF-kappaB activity in a murine model of asthma.Naringenin, a flavonoid, has antiinflammatory andimmunomodulatory properties. We investigated whether naringenin could attenuate allergen-inducedairway inflammation and its possible mechanism in a murine model of asthma. Mice were sensitized andchallenged with ovalbumin. Some mice were administered with naringenin before ovalbumin challenge.We evaluated the development of airway inflammation and airway reactivity. Interleukin (IL)4, IL13,chemokine (C-C motif) ligand (CCL)5, and CCL11 in bronchoalveolar lavage fluid and serum total IgEwere detected by ELISA. IkappaBalpha degradation and inducible nitric oxide synthase (iNOS) in lungswere measured by Western blot. We also tested NF-kappaB binding activity by electrophoretic mobilityshift assay. The mRNA levels of iNOS, CCL5, and CCL11 were detected by real-time PCR. Naringeninattenuated ovalbumin-induced airway inflammation and airway reactivity in experimental mice. Thenaringenin-treated mice had lower levels of IL4 and IL13 in the bronchoalveolar lavage fluid and lowerserum total IgE. Furthermore, naringenin inhibited pulmonary IkappaBalpha degradation and NF-kappaBDNA-binding activity. The levels of CCL5, CCL11, and iNOS were also significantly reduced. The resultsindicated that naringenin may play protective roles in the asthma process. The inhibition of NF-kappaBand the decreased expression of its target genes may account for this phenomenon.", "metadata": {}}
+{"_id": "919007", "title": "", "text": "The evolution of Fox genes and their role in development and diseaseThe forkhead box (Fox) family oftranscription factors, which originated in unicellular eukaryotes, has expanded over time through multipleduplication events, and sometimes through gene loss, to over 40 members in mammals. Fox genes haveevolved to acquire a specialized function in many key biological processes. Mutations in Fox genes have aprofound effect on human disease, causing phenotypes as varied as cancer, glaucoma and languagedisorders. We summarize the salient features of the evolution of the Fox gene family and highlight thediverse contribution of various Fox subfamilies to developmental processes, from organogenesis tospeech acquisition.", "metadata": {}}
+{"_id": "927561", "title": "", "text": "Emergent structures and dynamics of cell colonies by contact inhibition of locomotionCells in tissues canorganize into a broad spectrum of structures according to their function. Drastic changes of organization,such as epithelial-mesenchymal transitions or the formation of spheroidal aggregates, are oftenassociated either to tissue morphogenesis or to cancer progression. Here, we study the organization ofcell colonies by means of simulations of self-propelled particles with generic cell-like interactions. Theinterplay between cell softness, cell-cell adhesion, and contact inhibition of locomotion (CIL) yieldsstructures and collective dynamics observed in several existing tissue phenotypes. These include regulardistributions of cells, dynamic cell clusters, gel-like networks, collectively migrating monolayers, and 3Daggregates. We give analytical predictions for transitions between noncohesive, cohesive, and 3D cellarrangements. We explicitly show how CIL yields an effective repulsion that promotes cell dispersal,thereby hindering the formation of cohesive tissues. Yet, in continuous monolayers, CIL leads to collectivecell motion, ensures tensile intercellular stresses, and opposes cell extrusion. Thus, our work highlightsthe prominent role of CIL in determining the emergent structures and dynamics of cell colonies.", "metadata": {}}
+{"_id": "928281", "title": "", "text": "Failure of cell cleavage induces senescence in tetraploid primary cellsTetraploidy can arise from variousmitotic or cleavage defects in mammalian cells, and inheritance of multiple centrosomes inducesaneuploidy when tetraploid cells continue to cycle. Arrest of the tetraploid cell cycle is thereforepotentially a critical cellular control. We report here that primary rat embryo fibroblasts (REF52) andhuman foreskin fibroblasts become senescent in tetraploid G1 after drug- or small interfering RNA(siRNA)-induced failure of cell cleavage. In contrast, T-antigen-transformed REF52 and p53+/+ HCT116tumor cells rapidly become aneuploid by continuing to cycle after cleavage failure. Tetraploid primarycells quickly become quiescent, as determined by loss of the Ki-67 proliferation marker and of thefluorescent ubiquitination-based cell cycle indicator/late cell cycle marker geminin. Arrest is not due toDNA damage, as the γ-H2AX DNA damage marker remains at control levels after tetraploidy induction.Arrested tetraploid cells finally become senescent, as determined by SA-β-galactosidase activity.Tetraploid arrest is dependent on p16INK4a expression, as siRNA suppression of p16INK4a bypassestetraploid arrest, permitting primary cells to become aneuploid. We conclude that tetraploid primary cellscan become senescent without DNA damage and that induction of senescence is critical to tetraploidyarrest.", "metadata": {}}
+{"_id": "935034", "title": "", "text": "Cell death: the significance of apoptosis.Publisher Summary The classification of cell death can be basedon morphological or biochemical criteria or on the circumstances of its occurrence. Currently, irreversiblestructural alteration provides the only unequivocal evidence of death; biochemical indicators of cell deaththat are universally applicable have to be precisely defined and studies of cell function or of reproductivecapacity do not necessarily differentiate between death and dormant states from which recovery may bepossible. It has also proved feasible to categorize most if not all dying cells into one or the other of twodiscrete and distinctive patterns of morphological change, which have, generally, been found to occurunder disparate but individually characteristic circumstances. One of these patterns is the swellingproceeding to rupture of plasma and organelle membranes and dissolution of organizedstructure—termed “coagulative necrosis. ” It results from injury by agents, such as toxins and ischemia,affects cells in groups rather than singly, and evokes exudative inflammation when it develops in vivo.The other morphological pattern is characterized by condensation of the cell with maintenance oforganelle integrity and the formation of surface protuberances that separate as membrane-boundedglobules; in tissues, these are phagocytosed and digested by resident cells, there being no associatedinflammation.", "metadata": {}}
+{"_id": "935538", "title": "", "text": "The mitochondrial RNA-binding protein GRSF1 localizes to RNA granules and is required forposttranscriptional mitochondrial gene expression.RNA-binding proteins are at the heart ofposttranscriptional gene regulation, coordinating the processing, storage, and handling of cellular RNAs.We show here that GRSF1, previously implicated in the binding and selective translation of influenzamRNAs, is targeted to mitochondria where it forms granules that colocalize with foci of newly synthesizedmtRNA next to mitochondrial nucleoids. GRSF1 preferentially binds RNAs transcribed from threecontiguous genes on the light strand of mtDNA, the ND6 mRNA, and the long noncoding RNAs for cytband ND5, each of which contains multiple consensus binding sequences. RNAi-mediated knockdown ofGRSF1 leads to alterations in mitochondrial RNA stability, abnormal loading of mRNAs and lncRNAs on themitochondrial ribosome, and impaired ribosome assembly. This results in a specific protein synthesisdefect and a failure to assemble normal amounts of the oxidative phosphorylation complexes. These dataimplicate GRSF1 as a key regulator of posttranscriptional mitochondrial gene expression.", "metadata": {}}
+{"_id": "946756", "title": "", "text": "Identification and purification of a 62,000-dalton protein that binds specifically to the polypyrimidine tractof introns.A protein of molecular size 62,000 daltons (p62) was detected in HeLa cell nuclear extracts byUV cross-linking to mRNA precursors. p62 binds specifically to the polypyrimidine tract of the 3' splice siteregion of introns. p62 purified to homogeneity binds the polypyrimidine tract of pre-mRNAs. This bindingdoes not require the AG dinucleotide at the 3' splice site. Alterations in the polypyrimidine tract thatreduce the binding of p62 yield a corresponding reduction in the efficiency of formation of a U2snRNP/pre-mRNA complex and splicing. The p62 protein is retained in the spliceosome, where it remainsbound to the pre-mRNA. This polypyrimidine tract binding protein (pPTB) is proposed to be a criticalcomponent in recognition of the 3' splice site during splicing.", "metadata": {}}
+{"_id": "947631", "title": "", "text": "Capsule endoscopy in acute upper gastrointestinal hemorrhage: a prospective cohortstudy.BACKGROUND AND STUDY AIMS Capsule endoscopy may play a role in the evaluation of patientspresenting with acute upper gastrointestinal hemorrhage in the emergency department. PATIENTS ANDMETHODS We evaluated adults with acute upper gastrointestinal hemorrhage presenting to theemergency departments of two academic centers. Patients ingested a wireless video capsule, which wasfollowed immediately by a nasogastric tube aspiration and later by esophagogastroduodenoscopy (EGD).We compared capsule endoscopy with nasogastric tube aspiration for determination of the presence ofblood, and with EGD for discrimination of the source of bleeding, identification of peptic/inflammatorylesions, safety, and patient satisfaction. RESULTS The study enrolled 49 patients (32 men, 17 women;mean age 58.3 ± 19 years), but three patients did not complete the capsule endoscopy and five wereintolerant of the nasogastric tube. Blood was detected in the upper gastrointestinal tract significantlymore often by capsule endoscopy (15 /18 [83.3 %]) than by nasogastric tube aspiration (6 /18 [33.3 %];P = 0.035). There was no significant difference in the identification of peptic/inflammatory lesionsbetween capsule endoscopy (27 /40 [67.5 %]) and EGD (35 /40 [87.5 %]; P = 0.10, OR 0.39 95 %CI0.11 - 1.15). Capsule endoscopy reached the duodenum in 45 /46 patients (98 %). One patient (2.2 %)had self-limited shortness of breath and one (2.2 %) had coughing on capsule ingestion. CONCLUSIONSIn an emergency department setting, capsule endoscopy appears feasible and safe in people presentingwith acute upper gastrointestinal hemorrhage. Capsule endoscopy identifies gross blood in the uppergastrointestinal tract, including the duodenum, significantly more often than nasogastric tube aspirationand identifies inflammatory lesions, as well as EGD. Capsule endoscopy may facilitate patient triage andearlier endoscopy, but should not be considered a substitute for EGD.", "metadata": {}}
+{"_id": "949309", "title": "", "text": "Electroporation of Cas9 protein/sgRNA into early pronuclear zygotes generates non-mosaic mutants inthe mouse.The CRISPR/Cas9 system is a powerful tool for elucidating the roles of genes in a wide varietyof organisms including mice. To obtain genetically modified embryos or mice by this method, Cas9 mRNAand sgRNA are usually introduced into zygotes by microinjection or electroporation. However, mostmutants generated with this method are genetically mosaic, composed of several types of cells carryingdifferent mutations, which complicates phenotype analysis in founder embryos or mice. To simplify theanalysis and to elucidate the roles of genes involved in developmental processes, a method for producingnon-mosaic mutants is needed. Here, we established a method for generating non-mosaic mouse mutantembryos. We introduced Cas9 protein and sgRNA into in vitro fertilized (IVF) zygotes by electroporation,which enabled the genome editing to occur before the first replication of the mouse genome. As a result,all of the cells in the mutant carried the same set of mutations. This method solves the problem ofmosaicism/allele complexity in founder mutant embryos or mice generated by the CRIPSR/Cas9 system.", "metadata": {}}
+{"_id": "950306", "title": "", "text": "Molecular Basis for Target RNA Recognition and Cleavage by Human RISCThe RNA-Induced SilencingComplex (RISC) is a ribonucleoprotein particle composed of a single-stranded short interfering RNA(siRNA) and an endonucleolytically active Argonaute protein, capable of cleaving mRNAs complementaryto the siRNA. The mechanism by which RISC cleaves a target RNA is well understood, however it remainsenigmatic how RISC finds its target RNA. Here, we show, both in vitro and in vivo, that the accessibility ofthe target site correlates directly with the efficiency of cleavage, demonstrating that RISC is unable tounfold structured RNA. In the course of target recognition, RISC transiently contacts single-stranded RNAnonspecifically and promotes siRNA-target RNA annealing. Furthermore, the 5' part of the siRNA withinRISC creates a thermodynamic threshold that determines the stable association of RISC and the targetRNA. We therefore provide mechanistic insights by revealing features of RISC and target RNAs that arecrucial to achieve efficiency and specificity in RNA interference.", "metadata": {}}
+{"_id": "952111", "title": "", "text": "Cancer associated fibroblasts (CAFs) in tumor microenvironment.Cancer associated fibroblasts (CAFs) isone of the most crucial components of the tumor microenvironment which promotes the growth andinvasion of cancer cells by various mechanisms. CAFs demonstrate a high degree of heterogeneity due totheir various origins; however, many distinct morphological features and physiological functions of CAFshave been identified. It is becoming clear that the crosstalk between the cancer cells and the CAFs playsa key role in the progression of cancer, and understanding this mutual relationship would eventuallyenable us to treat cancer patients by targeting CAFs. In this review, we will discuss the latest findings onthe role of CAFs in tumorigenesis and metastasis as well as potential therapeutic implication of CAFs.", "metadata": {}}
+{"_id": "970012", "title": "", "text": "Cold Exposure Promotes Atherosclerotic Plaque Growth and Instability via UCP1-DependentLipolysisMolecular mechanisms underlying the cold-associated high cardiovascular risk remain unknown.Here, we show that the cold-triggered food-intake-independent lipolysis significantly increased plasmalevels of small low-density lipoprotein (LDL) remnants, leading to accelerated development ofatherosclerotic lesions in mice. In two genetic mouse knockout models (apolipoprotein E(-/-) [ApoE(-/-)]and LDL receptor(-/-) [Ldlr(-/-)] mice), persistent cold exposure stimulated atherosclerotic plaque growthby increasing lipid deposition. Furthermore, marked increase of inflammatory cells and plaque-associatedmicrovessels were detected in the cold-acclimated ApoE(-/-) and Ldlr(-/-) mice, leading to plaqueinstability. Deletion of uncoupling protein 1 (UCP1), a key mitochondrial protein involved inthermogenesis in brown adipose tissue (BAT), in the ApoE(-/-) strain completely protected mice from thecold-induced atherosclerotic lesions. Cold acclimation markedly reduced plasma levels of adiponectin, andsystemic delivery of adiponectin protected ApoE(-/-) mice from plaque development. These findingsprovide mechanistic insights on low-temperature-associated cardiovascular risks.", "metadata": {}}
+{"_id": "980008", "title": "", "text": "Mild overexpression of MeCP2 causes a progressive neurological disorder in mice.Mutations in theX-linked methyl-CpG-binding protein 2 (MECP2), encoding a transcriptional repressor, cause Rettsyndrome and a variety of related neurodevelopmental disorders. The vast majority of mutationsassociated with human disease are loss-of-function mutations, but precisely what aspect of MeCP2function is responsible for these phenotypes remains unknown. We overexpressed wild-type humanprotein in transgenic mice using a large genomic clone containing the entire human MECP2 locus.Detailed neurobehavioral and electrophysiological studies in transgenic line MeCP2(Tg1), which expressesMeCP2 at approximately 2-fold wild-type levels, demonstrated onset of phenotypes around 10 weeks ofage. Surprisingly, these mice displayed enhanced motor and contextual learning and enhanced synapticplasticity in the hippocampus. After 20 weeks of age, however, these mice developed seizures, becamehypoactive and approximately 30% of them died by 1 year of age. These data demonstrate that MeCP2levels must be tightly regulated in vivo, and that even mild overexpression of this protein is detrimental.Furthermore, these results support the possibility that duplications or gain-of-function mutations inMECP2 might underlie some cases of X-linked delayed-onset neurobehavioral disorders.", "metadata": {}}
+{"_id": "980196", "title": "", "text": "Alcohol Sales and Risk of Serious AssaultBACKGROUND Alcohol is a contributing cause of unintentionalinjuries, such as motor vehicle crashes. Prior research on the association between alcohol use and violentinjury was limited to survey-based data, and the inclusion of cases from a single trauma centre, withoutadequate controls. Beyond these limitations was the inability of prior researchers to comprehensivelycapture most alcohol sales. In Ontario, most alcohol is sold through retail outlets run by the provincialgovernment, and hospitals are financed under a provincial health care system. We assessed the risk ofbeing hospitalized due to assault in association with retail alcohol sales across Ontario. METHODS ANDFINDINGS We performed a population-based case-crossover analysis of all persons aged 13 years andolder hospitalized for assault in Ontario from 1 April 2002 to 1 December 2004. On the day prior to eachassault case's hospitalization, the volume of alcohol sold at the store in closest proximity to the victim'shome was compared to the volume of alcohol sold at the same store 7 d earlier. Conditional logisticregression analysis was used to determine the associated relative risk (RR) of assault per 1,000 l higherdaily sales of alcohol. Of the 3,212 persons admitted to hospital for assault, nearly 25% were betweenthe ages of 13 and 20 y, and 83% were male. A total of 1,150 assaults (36%) involved the use of a sharpor blunt weapon, and 1,532 (48%) arose during an unarmed brawl or fight. For every 1,000 l more ofalcohol sold per store per day, the relative risk of being hospitalized for assault was 1.13 (95%confidence interval [CI] 1.02-1.26). The risk was accentuated for males (1.18, 95% CI 1.05-1.33), youthaged 13 to 20 y (1.21, 95% CI 0.99-1.46), and those in urban areas (1.19, 95% CI 1.06-1.35).CONCLUSIONS The risk of being a victim of serious assault increases with alcohol sales, especially amongyoung urban men. Akin to reducing the risk of driving while impaired, consideration should be given tonovel methods of preventing alcohol-related violence.", "metadata": {}}
+{"_id": "982650", "title": "", "text": "miR-375 inhibits autophagy and reduces viability of hepatocellular carcinoma cells under hypoxicconditions.BACKGROUND & AIMS Tumor cells survive hypoxic conditions by inducing autophagy. Weinvestigated the roles of microRNAs (miRNAs) in regulating autophagy of hepatocellular carcinoma (HCC)cells under hypoxic conditions. METHODS We used gain- and loss-of-function methods to evaluate theeffect of miRNAs on autophagy in human HCC cell lines (Huh7 and Hep3B) under hypoxic conditions.Autophagy was quantified by immunoblot, immunofluoresence, and transmission electron microscopyanalyses, and after incubation of cells with bafilomycin A1. We used a luciferase reporter assay to confirmassociations between miRNAs and their targets. We analyzed growth of HCC xenograft tumors in nudemice. RESULTS miR-375 was down-regulated in HCC cells and tissues; it inhibited autophagy underhypoxic conditions by suppressing the conversion of LC3I to LC3II and thereby autophagic flux. Theability of miR-375 to inhibit autophagy was independent of its ability to regulate3'-phosphoinositide-dependent protein kinase-1-AKT-mammalian target of rapamycin signaling, butinstead involved suppression of ATG7, an autophagy-associated gene. miR-375 bound directly to apredicted site in the 3' untranslated region of ATG7. Up-regulating miR-375 or down-regulating ATG7inhibited mitochondrial autophagy of HCC cells, reduced the elimination of damaged mitochondria underhypoxia, increased release of mitochondrial apoptotic proteins, and reduced viability of HCC cells. Inmice, xenograft tumors that expressed miR-375 had fewer autophagic cells, larger areas of necrosis, andgrew more slowly than tumors from HCC cells that expressed lower levels of miR-375. CONCLUSIONSmiR-375 inhibits autophagy by reducing expression of ATG7 and impairs viability of HCC cells underhypoxic conditions in culture and in mice. miRNAs that inhibit autophagy of cancer cells might bedeveloped as therapeutics.", "metadata": {}}
+{"_id": "984825", "title": "", "text": "Pseudouridine profiling reveals regulated mRNA pseudouridylation in yeast and humancellsPost-transcriptional modification of RNA nucleosides occurs in all living organisms. Pseudouridine, themost abundant modified nucleoside in non-coding RNAs, enhances the function of transfer RNA andribosomal RNA by stabilizing the RNA structure. Messenger RNAs were not known to containpseudouridine, but artificial pseudouridylation dramatically affects mRNA function--it changes the geneticcode by facilitating non-canonical base pairing in the ribosome decoding centre. However, withoutevidence of naturally occurring mRNA pseudouridylation, its physiological relevance was unclear. Here wepresent a comprehensive analysis of pseudouridylation in Saccharomyces cerevisiae and human RNAsusing Pseudo-seq, a genome-wide, single-nucleotide-resolution method for pseudouridine identification.Pseudo-seq accurately identifies known modification sites as well as many novel sites in non-codingRNAs, and reveals hundreds of pseudouridylated sites in mRNAs. Genetic analysis allowed us to assignmost of the new modification sites to one of seven conserved pseudouridine synthases, Pus1-4, 6, 7 and9. Notably, the majority of pseudouridines in mRNA are regulated in response to environmental signals,such as nutrient deprivation in yeast and serum starvation in human cells. These results suggest amechanism for the rapid and regulated rewiring of the genetic code through inducible mRNAmodifications. Our findings reveal unanticipated roles for pseudouridylation and provide a resource foridentifying the targets of pseudouridine synthases implicated in human disease.", "metadata": {}}
+{"_id": "991137", "title": "", "text": "The descent of memory T-cell subsetsThe immune system has evolved by continuously increasing itscomplexity to provide the host with an advantage over infectious agents. The development ofimmunological memory engenders long-lasting protection and lengthens the lifespan of the host. Thegeneration of subsets of memory T cells with distinct homing and functional properties increases ourdefensive capabilities. However, the developmental relationship of memory T-cell subsets is a matter ofdebate. In this Opinion article, in light of recent developments, we suggest that it is probable that twodistinct lineages comprise the memory CD8+ T-cell population generated in response to infection.", "metadata": {}}
+{"_id": "991139", "title": "", "text": "Differential distribution of IL28B.rs12979860 single-nucleotide polymorphism among Egyptian healthcareworkers with and without a hepatitis C virus-specific cellular immune responseThe CC genotype of theinterleukin (IL)-28B.rs12979860 gene has been associated with spontaneous hepatitis C virus (HCV)clearance and treatment response. The distribution and correlation of an IL28B.rs12979860single-nucleotide polymorphism (SNP) with HCV-specific cell-mediated immune (CMI) responses amongEgyptian healthcare workers (HCWs) is not known. We determined this relationship in 402 HCWs whoserve a patient cohort with ~85 % HCV prevalence. We enrolled 402 HCWs in four groups: group 1 (n =258), seronegative aviremic subjects; group 2 (n = 25), seronegative viremic subjects; group 3 (n = 41),subjects with spontaneously resolved HCV infection; and group 4 (n = 78), chronic HCV patients. Allsubjects were tested for an HCV-specific CMI response using an ex-vivo interferon-gamma (IFNγ)ELISpot assay with nine HCV genotype-4a overlapping 15-mer peptide pools corresponding to all of theHCV proteins. All subjects were tested for IL28B.rs12979860 SNP by real-time PCR. An HCV-specific CMIwas demonstrated in ~27 % of the seronegative aviremic HCWs (group 1), suggesting clearance ofinfection after low-level exposure to HCV. The frequency of IL28B.rs12979860 C allele homozygosity inthe four groups was 49 %, 48 %, 49 %, and 23 %, while that of the T allele was 14 %, 16 %, 12 and 19%, respectively, suggesting differential distributions among subjects with different HCV status. Asreported, IL28B.rs12979860 predicted the outcome of HCV infection (p < 0.05), but we did not find anyrelationship between the IL28B genotypes and the outcome of HCV-specific CMI responses in the fourgroups (p > 0.05). The data show differential IL28B.rs12979860 genotype distribution among EgyptianHCWs with different HCV status and could not predict the outcome of HCV-specific CMI responses.", "metadata": {}}
+{"_id": "994800", "title": "", "text": "TCR ligand density and affinity determine peripheral induction of Foxp3 in vivoT cell receptor (TCR)ligation is required for the extrathymic differentiation of forkhead box p3(+) (Foxp3(+)) regulatory Tcells. Several lines of evidence indicate that weak TCR stimulation favors induction of Foxp3 in theperiphery; however, it remains to be determined how TCR ligand potency influences this process. Wecharacterized the density and affinity of TCR ligand favorable for Foxp3 induction and found that a lowdose of a strong agonist resulted in maximal induction of Foxp3 in vivo. Initial Foxp3 induction by weakagonist peptide could be enhanced by disruption of TCR-peptide major histocompatibility complex (pMHC)interactions or alteration of peptide dose. However, time course experiments revealed that Foxp3-positivecells induced by weak agonist stimulation are deleted, along with their Foxp3-negative counterparts,whereas Foxp3-positive cells induced by low doses of the strong agonist persist. Our results suggest that,together, pMHC ligand potency, density, and duration of TCR interactions define a cumulative quantity ofTCR stimulation that determines initial peripheral Foxp3 induction. However, in the persistence of inducedFoxp3(+) T cells, TCR ligand potency and density are noninterchangeable factors that influence the routeto peripheral tolerance.", "metadata": {}}
+{"_id": "997143", "title": "", "text": "Electromagnetic interference from radio frequency identification inducing potentially hazardous incidentsin critical care medical equipment.CONTEXT Health care applications of autoidentification technologies,such as radio frequency identification (RFID), have been proposed to improve patient safety and also thetracking and tracing of medical equipment. However, electromagnetic interference (EMI) by RFID onmedical devices has never been reported. OBJECTIVE To assess and classify incidents of EMI by RFID oncritical care equipment. DESIGN AND SETTING Without a patient being connected, EMI by 2 RFIDsystems (active 125 kHz and passive 868 MHz) was assessed under controlled conditions during May2006, in the proximity of 41 medical devices (in 17 categories, 22 different manufacturers) at theAcademic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands. Assessment took placeaccording to an international test protocol. Incidents of EMI were classified according to a critical careadverse events scale as hazardous, significant, or light. RESULTS In 123 EMI tests (3 per medicaldevice), RFID induced 34 EMI incidents: 22 were classified as hazardous, 2 as significant, and 10 as light.The passive 868-MHz RFID signal induced a higher number of incidents (26 incidents in 41 EMI tests;63%) compared with the active 125-kHz RFID signal (8 incidents in 41 EMI tests; 20%); difference 44%(95% confidence interval, 27%-53%; P < .001). The passive 868-MHz RFID signal induced EMI in 26medical devices, including 8 that were also affected by the active 125-kHz RFID signal (26 in 41 devices;63%). The median distance between the RFID reader and the medical device in all EMI incidents was 30cm (range, 0.1-600 cm). CONCLUSIONS In a controlled nonclinical setting, RFID induced potentiallyhazardous incidents in medical devices. Implementation of RFID in the critical care environment shouldrequire on-site EMI tests and updates of international standards.", "metadata": {}}
+{"_id": "1006165", "title": "", "text": "Potent RNAi by short RNA triggers.RNA interference (RNAi) is a gene-silencing mechanism by which aribonucleoprotein complex, the RNA-induced silencing complex (RISC) and a double-stranded (ds)short-interfering RNA (siRNA), targets a complementary mRNA for site-specific cleavage and subsequentdegradation. While longer dsRNA are endogenously processed into 21- to 24-nucleotide (nt) siRNAs ormiRNAs to induce gene silencing, RNAi studies in human cells typically use synthetic 19- to 20-nt siRNAduplexes with 2-nt overhangs at the 3'-end of both strands. Here, we report that systematic synthesisand analysis of siRNAs with deletions at the passenger and/or guide strand revealed a short RNAi trigger,16-nt siRNA, which induces potent RNAi in human cells. Our results indicate that the minimal requirementfor dsRNA to trigger RNAi is an approximately 42 A A-form helix with approximately 1.5 helical turns. The16-nt siRNA more effectively knocked down mRNA and protein levels than 19-nt siRNA when targetingthe endogenous CDK9 gene, suggesting that 16-nt siRNA is a more potent RNAi trigger. In vitro kineticanalysis of RNA-induced silencing complex (RISC) programmed in HeLa cells indicates that 16-nt siRNAhas a higher RISC-loading capacity than 19-nt siRNA. These results suggest that RISC assembly andactivation during RNAi does not necessarily require a 19-nt duplex siRNA and that 16-nt duplexes can bedesigned as more potent triggers to induce RNAi.", "metadata": {}}
+{"_id": "1022115", "title": "", "text": "IL-23–responsive innate lymphoid cells are increased in inflammatory bowel diseaseResults ofexperimental and genetic studies have highlighted the role of the IL-23/IL-17 axis in the pathogenesis ofinflammatory bowel disease (IBD). IL-23-driven inflammation has been primarily linked to Th17 cells;however, we have recently identified a novel population of innate lymphoid cells (ILCs) in mice thatproduces IL-17, IL-22, and IFN-γ in response to IL-23 and mediates innate colitis. The relevance of ILCpopulations in human health and disease is currently poorly understood. In this study, we have analyzedthe role of IL-23-responsive ILCs in the human intestine in control and IBD patients. Our results showincreased expression of the Th17-associated cytokine genes IL17A and IL17F among intestinal CD3\u0000cells in IBD. IL17A and IL17F expression is restricted to CD56\u0000 ILCs, whereas IL-23 induces IL22 andIL26 in the CD56\u0000 ILC compartment. Furthermore, we observed a significant and selective increase inCD127\u0000CD56\u0000 ILCs in the inflamed intestine in Crohn's disease (CD) patients but not in ulcerative colitispatients. These results indicate that IL-23-responsive ILCs are present in the human intestine and thatintestinal inflammation in CD is associated with the selective accumulation of a phenotypically distinct ILCpopulation characterized by inflammatory cytokine expression. ILCs may contribute to intestinalinflammation through cytokine production, lymphocyte recruitment, and organization of the inflammatorytissue and may represent a novel tissue-specific target for subtypes of IBD.", "metadata": {}}
+{"_id": "1031534", "title": "", "text": "Scaling of Dorsal-Ventral Patterning by Embryo Size-Dependent Degradation of Spemann’s OrganizerSignalsSpemann's organizer plays a key role in dorsal-ventral (DV) patterning in the amphibian embryoby secreting diffusible proteins such as Chordin, an antagonist to ventralizing bone morphogeneticproteins (BMPs). The DV patterning is so robust that an amphibian embryo with its ventral half surgicallyremoved can develop into a smaller but proportionally patterned larva. Here, we show that this robustpatterning depends on facilitated Chordin degradation and requires the expression of theChordin-proteinase inhibitor Sizzled on the opposite side. Sizzled, which is stable and diffuses widelyalong the DV axis, stabilizes Chordin and expands its distribution in the ventral direction. This expandedChordin distribution, in turn, limits BMP-dependent Sizzled production, forming an axis-wide feedbackloop for shaping Chordin's activity. Using bisection assays, we demonstrate that Chordin degradation isdynamically controlled by embryo-size-coupled Sizzled accumulation. We propose a scaling model thatenables the DV pattern to adjust proportionally to embryonic axis size.", "metadata": {}}
+{"_id": "1032372", "title": "", "text": "Augmenting Antitumor Immune Responses with Epigenetic Modifying AgentsEpigenetic silencing ofimmune-related genes is a striking feature of the cancer genome that occurs in the process oftumorigenesis. This phenomena impacts antigen processing and antigen presentation by tumor cells andfacilitates evasion of immunosurveillance. Further modulation of the tumor microenvironment by alteredexpression of immunosuppressive cytokines impairs antigen-presenting cells and cytolytic T-cell function.The potential reversal of immunosuppression by epigenetic modulation is therefore a promising andversatile therapeutic approach to reinstate endogenous immune recognition and tumor lysis. Pre-clinicalstudies have identified multiple elements of the immune system that can be modulated by epigeneticmechanisms and result in improved antigen presentation, effector T-cell function, and breakdown ofsuppressor mechanisms. Recent clinical studies are utilizing epigenetic therapies prior to, or incombination with, immune therapies to improve clinical outcomes.", "metadata": {}}
+{"_id": "1044552", "title": "", "text": "Activation of proteinase-activated receptor 2 in human osteoarthritic cartilage upregulates catabolic andproinflammatory pathways capable of inducing cartilage degradation: a basic sciencestudyProteinase-activated receptors (PARs) belong to a family of G protein-coupled receptors. PARs areactivated by a serine-dependent cleavage generating a tethered activating ligand. PAR-2 was shown to beinvolved in inflammatory pathways. We investigated the in situ levels and modulation of PAR-2 in humannormal and osteoarthritis (OA) cartilage/chondrocytes. Furthermore, we evaluated the role of PAR-2 onthe synthesis of the major catabolic factors in OA cartilage, including metalloproteinase (MMP)-1 andMMP-13 and the inflammatory mediator cyclooxygenase 2 (COX-2), as well as the PAR-2-activatedsignalling pathways in OA chondrocytes. PAR-2 expression was determined using real-time reversetranscription-polymerase chain reaction and protein levels by immunohistochemistry in normal and OAcartilage. Protein modulation was investigated in OA cartilage explants treated with a specificPAR-2-activating peptide (PAR-2-AP), SLIGKV-NH2 (1 to 400 μM), interleukin 1 beta (IL-1β) (100pg/mL), tumor necrosis factor-alpha (TNF-α) (5 ng/mL), transforming growth factor-beta-1 (TGF-β1) (10ng/mL), or the signalling pathway inhibitors of p38 (SB202190), MEK1/2 (mitogen-activated proteinkinase kinase) (PD98059), and nuclear factor-kappa B (NF-κB) (SN50), and PAR-2 levels weredetermined by immunohistochemistry. Signalling pathways were analyzed on OA chondrocytes byWestern blot using specific phospho-antibodies against extracellular signal-regulated kinase 1/2 (Erk1/2),p38, JNK (c-jun N-terminal kinase), and NF-κB in the presence or absence of the PAR-2-AP and/or IL-1β.PAR-2-induced MMP and COX-2 levels in cartilage were determined by immunohistochemistry. PAR-2 isproduced by human chondrocytes and is significantly upregulated in OA compared with normalchondrocytes (p < 0.04 and p < 0.03, respectively). The receptor levels were significantly upregulated byIL-1β (p < 0.006) and TNF-α (p < 0.002) as well as by the PAR-2-AP at 10, 100, and 400 μM (p < 0.02)and were downregulated by the inhibition of p38. After 48 hours of incubation, PAR-2 activationsignificantly induced MMP-1 and COX-2 starting at 10 μM (both p < 0.005) and MMP-13 at 100 μM (p <0.02) as well as the phosphorylation of Erk1/2 and p38 within 5 minutes of incubation (p < 0.03). Thoughnot statistically significant, IL-1β produced an additional effect on the activation of Erk1/2 and p38. Thisstudy documents, for the first time, functional consequences of PAR-2 activation in human OA cartilage,identifies p38 as the major signalling pathway regulating its synthesis, and demonstrates that specificPAR-2 activation induces Erk1/2 and p38 in OA chondrocytes. These results suggest PAR-2 as a potentialnew therapeutic target for the treatment of OA.", "metadata": {}}
+{"_id": "1049501", "title": "", "text": "Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute tolupus-like diseaseNeutrophil extracellular traps (NETs) are implicated in autoimmunity, but how they aregenerated and their roles in sterile inflammation remain unclear. Ribonucleoprotein immune complexes(RNP ICs), inducers of NETosis, require mitochondrial reactive oxygen species (ROS) for maximal NETstimulation. After RNP IC stimulation of neutrophils, mitochondria become hypopolarized and translocateto the cell surface. Extracellular release of oxidized mitochondrial DNA is proinflammatory in vitro, andwhen this DNA is injected into mice, it stimulates type I interferon (IFN) signaling through a pathwaydependent on the DNA sensor STING. Mitochondrial ROS are also necessary for spontaneous NETosis oflow-density granulocytes from individuals with systemic lupus erythematosus. This was also observed inindividuals with chronic granulomatous disease, who lack NADPH oxidase activity but still developautoimmunity and type I IFN signatures. Mitochondrial ROS inhibition in vivo reduces disease severityand type I IFN responses in a mouse model of lupus. Together, these findings highlight a role formitochondria in the generation not only of NETs but also of pro-inflammatory oxidized mitochondrial DNAin autoimmune diseases.", "metadata": {}}
+{"_id": "1065627", "title": "", "text": "Microenvironment rigidity modulates responses to the HER2 receptor tyrosine kinase inhibitor lapatinibvia YAP and TAZ transcription factors.Stiffness is a biophysical property of the extracellular matrix thatmodulates cellular functions, including proliferation, invasion, and differentiation, and it also may affecttherapeutic responses. Therapeutic durability in cancer treatments remains a problem for bothchemotherapies and pathway-targeted drugs, but the reasons for this are not well understood. Tumorprogression is accompanied by changes in the biophysical properties of the tissue, and we asked whethermatrix rigidity modulated the sensitive versus resistant states in HER2-amplified breast cancer cellresponses to the HER2-targeted kinase inhibitor lapatinib. The antiproliferative effect of lapatinib wasinversely proportional to the elastic modulus of the adhesive substrata. Down-regulation of themechanosensitive transcription coactivators YAP and TAZ, either by siRNA or with the small-moleculeYAP/TEAD inhibitor verteporfin, eliminated modulus-dependent lapatinib resistance. Reduction of YAP invivo in mice also slowed the growth of implanted HER2-amplified tumors, showing a trend of increasingsensitivity to lapatinib as YAP decreased. Thus we address the role of stiffness in resistance to andefficacy of a HER2 pathway-targeted therapeutic via the mechanotransduction arm of the Hippo pathway.", "metadata": {}}
+{"_id": "1067605", "title": "", "text": "Effective population size and patterns of molecular evolution and variationThe effective size of apopulation, Ne, determines the rate of change in the composition of a population caused by genetic drift,which is the random sampling of genetic variants in a finite population. Ne is crucial in determining thelevel of variability in a population, and the effectiveness of selection relative to drift. This article reviewsthe properties of Ne in a variety of different situations of biological interest, and the factors that influenceit. In particular, the action of selection means that Ne varies across the genome, and advances ingenomic techniques are giving new insights into how selection shapes Ne.", "metadata": {}}
+{"_id": "1068106", "title": "", "text": "Is emotional dysregulation part of the psychopathology of ADHD in adults?Attention-deficit hyperactivitydisorder is a common condition in adulthood. The disorder is characterized by symptoms of inattention,hyperactivity, and impulsivity. Alongside these symptoms, it is discussed whether symptoms of emotionaldysregulation could add additional and better description of the psychopathology of ADHD. Neither thecurrent ICD-10 and DSM-IV nor the upcoming DSM-5 includes symptoms of emotional dysregulation as acore aspect of ADHD. Several authors (e.g., Wender 1995) describe adult ADHD in a more differentiatedway and propose concepts of the disorder that consider the subjective experiences of the adult patient byintroducing the symptomatology of emotional symptoms. Empirical studies attest this dimensionsufficient reliability and validity. Symptoms of emotional dysregulation are definable and seem to bedistinct factors of the psychopathology of adult ADHD. Pharmacological and psychotherapeuticinterventions help to alleviate this type of symptoms. This review attests a decisive role to the emotionalsymptoms in the ADHD symptomatology, which should be taken in serious consideration by futureresearch.", "metadata": {}}
+{"_id": "1070920", "title": "", "text": "A neural basis for melanocortin-4 receptor regulated appetitePro-opiomelanocortin (POMC)- andagouti-related peptide (AgRP)-expressing neurons of the arcuate nucleus of the hypothalamus (ARC) areoppositely regulated by caloric depletion and coordinately stimulate and inhibit homeostatic satiety,respectively. This bimodality is principally underscored by the antagonistic actions of these ligands atdownstream melanocortin-4 receptors (MC4R) in the paraventricular nucleus of the hypothalamus (PVH).Although this population is critical to energy balance, the underlying neural circuitry remains unknown.Using mice expressing Cre recombinase in MC4R neurons, we demonstrate bidirectional control of feedingfollowing real-time activation and inhibition of PVH(MC4R) neurons and further identify these cells as afunctional exponent of ARC(AgRP) neuron-driven hunger. Moreover, we reveal this function to bemediated by a PVH(MC4R)\u0000lateral parabrachial nucleus (LPBN) pathway. Activation of this circuitencodes positive valence, but only in calorically depleted mice. Thus, the satiating and appetitive natureof PVH(MC4R)\u0000LPBN neurons supports the principles of drive reduction and highlights this circuit as apromising target for antiobesity drug development.", "metadata": {}}
+{"_id": "1071991", "title": "", "text": "Lymph node T cell responses predict the efficacy of live attenuated SIV vaccinesLive attenuated simianimmunodeficiency virus (SIV) vaccines (LAVs) remain the most efficacious of all vaccines in nonhumanprimate models of HIV and AIDS, yet the basis of their robust protection remains poorly understood. Herewe show that the degree of LAV-mediated protection against intravenous wild-type SIVmac239 challengestrongly correlates with the magnitude and function of SIV-specific, effector-differentiated T cells in thelymph node but not with the responses of such T cells in the blood or with other cellular, humoral andinnate immune parameters. We found that maintenance of protective T cell responses is associated withpersistent LAV replication in the lymph node, which occurs almost exclusively in follicular helper T cells.Thus, effective LAVs maintain lymphoid tissue-based, effector-differentiated, SIV-specific T cells thatintercept and suppress early wild-type SIV amplification and, if present in sufficient frequencies, cancompletely control and perhaps clear infection, an observation that provides a rationale for thedevelopment of safe, persistent vectors that can elicit and maintain such responses.", "metadata": {}}
+{"_id": "1084062", "title": "", "text": "Activation of Serotonin 2C Receptors in Dopamine Neurons Inhibits Binge-like Eating inMiceBACKGROUND Neural networks that regulate binge eating remain to be identified, and effectivetreatments for binge eating are limited. METHODS We combined neuroanatomic, pharmacologic,electrophysiological, Cre-lox, and chemogenetic approaches to investigate the functions of5-hydroxytryptamine (5-HT) 2C receptor (5-HT2CR) expressed by dopamine (DA) neurons in theregulation of binge-like eating behavior in mice. RESULTS We showed that 5-HT stimulates DA neuralactivity through a 5-HT2CR-mediated mechanism, and activation of this midbrain 5-HT\u0000DA neural circuiteffectively inhibits binge-like eating behavior in mice. Notably, 5-HT medications, including fluoxetine,d-fenfluramine, and lorcaserin (a selective 5-HT2CR agonist), act on 5-HT2CRs expressed by DA neuronsto inhibit binge-like eating in mice. CONCLUSIONS We identified the 5-HT2CR population in DA neuronsas one potential target for antibinge therapies, and provided preclinical evidence that 5-HT2CR agonistscould be used to treat binge eating.", "metadata": {}}
+{"_id": "1084345", "title": "", "text": "Restoration of chaperone-mediated autophagy in aging liver improves cellular maintenance and hepaticfunctionChaperone-mediated autophagy (CMA), a selective mechanism for degradation of cytosolicproteins in lysosomes, contributes to the removal of altered proteins as part of the cellular quality-controlsystems. We have previously found that CMA activity declines in aged organisms and have proposed thatthis failure in cellular clearance could contribute to the accumulation of altered proteins, the abnormalcellular homeostasis and, eventually, the functional loss characteristic of aged organisms. To determinewhether these negative features of aging can be prevented by maintaining efficient autophagic activityuntil late in life, in this work we have corrected the CMA defect in aged rodents. We have generated adouble transgenic mouse model in which the amount of the lysosomal receptor for CMA, previously shownto decrease in abundance with age, can be modulated. We have analyzed in this model the consequencesof preventing the age-dependent decrease in receptor abundance in aged rodents at the cellular andorgan levels. We show here that CMA activity is maintained until advanced ages if the decrease in thereceptor abundance is prevented and that preservation of autophagic activity is associated with lowerintracellular accumulation of damaged proteins, better ability to handle protein damage and improvedorgan function.", "metadata": {}}
+{"_id": "1102268", "title": "", "text": "The Incidence and Repetition of Hospital-Treated Deliberate Self Harm: Findings from the World's FirstNational RegistryBACKGROUND Suicide is a significant public health issue with almost one million peopledying by suicide each year worldwide. Deliberate self harm (DSH) is the single most important risk factorfor suicide yet few countries have reliable data on DSH. We developed a national DSH registry in theRepublic of Ireland to establish the incidence of hospital-treated DSH at national level and the spectrumand pattern of presentations with DSH and repetition. METHODS AND FINDINGS Between 2003 and2009, the Irish National Registry of Deliberate Self Harm collected data on DSH presentations to all 40hospital emergency departments in the country. Data were collected by trained data registration officersusing standard methods of case ascertainment and definition. The Registry recorded 75,119 DSHpresentations involving 48,206 individuals. The total incidence rate fell from 209 (95% CI: 205-213) per100,000 in 2003 to 184 (95% CI: 180-189) per 100,000 in 2006 and increased again to 209 (95% CI:204-213) per 100,000 in 2009. The most notable annual changes were successive 10% increases in themale rate in 2008 and 2009. There was significant variation by age with peak rates in women in the15-19 year age group (620 (95% CI: 605-636) per 100,000), and in men in the 20-24 age group (427(95% CI: 416-439) per 100,000). Repetition rates varied significantly by age, method of self harm andnumber of previous episodes. CONCLUSIONS Population-based data on hospital-treated DSH representan important index of the burden of mental illness and suicide risk in the community. The increased DSHrate in Irish men in 2008 and 2009 coincided with the advent of the economic recession in Ireland. Thefindings underline the need for developing effective interventions to reduce DSH repetition rates as a keypriority for health systems.", "metadata": {}}
+{"_id": "1103795", "title": "", "text": "A Common Mechanism of Cellular Death Induced by Bactericidal AntibioticsAntibiotic mode-of-actionclassification is based upon drug-target interaction and whether the resultant inhibition of cellularfunction is lethal to bacteria. Here we show that the three major classes of bactericidal antibiotics,regardless of drug-target interaction, stimulate the production of highly deleterious hydroxyl radicals inGram-negative and Gram-positive bacteria, which ultimately contribute to cell death. We also show, incontrast, that bacteriostatic drugs do not produce hydroxyl radicals. We demonstrate that the mechanismof hydroxyl radical formation induced by bactericidal antibiotics is the end product of an oxidative damagecellular death pathway involving the tricarboxylic acid cycle, a transient depletion of NADH,destabilization of iron-sulfur clusters, and stimulation of the Fenton reaction. Our results suggest that allthree major classes of bactericidal drugs can be potentiated by targeting bacterial systems thatremediate hydroxyl radical damage, including proteins involved in triggering the DNA damage response,e.g., RecA.", "metadata": {}}
+{"_id": "1122198", "title": "", "text": "Increased atherosclerosis in mice reconstituted with apolipoprotein E nullmacrophages.Macrophage-derived foam cells express apolipoprotein E (apoE) abundantly inatherosclerotic lesions. To examine the physiologic role of apoE secretion by the macrophage inatherogenesis, bone marrow transplantation was used to reconstitute C57BL/6 mice with macrophagesthat were either null or wild type for the apoE gene. After 13 weeks on an atherogenic diet, C57BL/6 micereconstituted with apoE null marrow developed 10-fold more atherosclerosis than controls in the absenceof significant differences in serum cholesterol levels or lipoprotein profiles. ApoE expression was absent inthe macrophage-derived foam cells of C57BL/6 mice reconstituted with apoE null marrow. Thus, lack ofapoE expression by the macrophage promotes foam cell formation. These data support a protective rolefor apoE expression by the macrophage in early atherogenesis.", "metadata": {}}
+{"_id": "1122279", "title": "", "text": "Endothelium-mediated relaxation of porcine collateral-dependent arterioles is improved by exercisetraining.BACKGROUND Endothelium-dependent modulation of coronary tone is impaired in thecollateral-dependent coronary microcirculation. We used a porcine model of chronic coronary occlusionand collateral development to evaluate the hypothesis that exercise training enhancesendothelium-mediated relaxation and increases endothelial nitric oxide synthase (ecNOS) mRNA levels ofcollateral-dependent microvasculature. METHODS AND RESULTS Adult female miniature swine weresubjected to chronic, progressive ameroid occlusion of the proximal left circumflex coronary artery (LCx);after 2 months, animals were randomly exposed to 16-week exercise-training (EX group; treadmillrunning) or sedentary (SED group; cage confinement) protocols. After completion of EX or SEDprograms, coronary arterioles ( approximately 100 microm in diameter) were isolated fromcollateral-dependent LCx (distal to occlusion) and nonoccluded left anterior descending coronary artery(LAD) regions of each heart. Arterioles were studied by in vitro videomicroscopy or frozen for ecNOSmRNA analysis (RT-PCR techniques). Relaxation to the endothelium-dependent vasodilator bradykininwas decreased (P<0.05) in arterioles isolated from collateral-dependent LCx versus nonoccluded LADregions of SED animals. Bradykinin-mediated relaxation, however, was not different in LCx versus LADarterioles isolated from EX animals. Nitroprusside-induced relaxation was unaffected by either chronicocclusion or exercise. Importantly, ecNOS mRNA expression was significantly decreased in arteriolesisolated from LCx versus LAD regions of SED animals. After training, ecNOS mRNA expression was notdifferent between LAD and LCx arterioles. CONCLUSIONS These data indicate that exercise trainingenhances bradykinin-mediated relaxation of collateral-dependent LCx arterioles isolated after chroniccoronary occlusion, most likely because of effects on ecNOS mRNA expression and increased productionof NO.", "metadata": {}}
+{"_id": "1127562", "title": "", "text": "Loss of the RhoGAP SRGP-1 promotes the clearance of dead and injured cells in CaenorhabditiselegansMulticellular animals rapidly clear dying cells from their bodies. Many of the pathways thatmediate this cell removal are conserved through evolution. Here, we identify srgp-1 as a negativeregulator of cell clearance in both Caenorhabditis elegans and mammalian cells. Loss of srgp-1 functionresults in improved engulfment of apoptotic cells, whereas srgp-1 overexpression inhibits apoptotic cellcorpse removal. We show that SRGP-1 functions in engulfing cells and functions as a GTPase activatingprotein (GAP) for CED-10 (Rac1). Interestingly, loss of srgp-1 function promotes not only the clearance ofalready dead cells, but also the removal of cells that have been brought to the verge of death throughsublethal apoptotic, necrotic or cytotoxic insults. In contrast, impaired engulfment allows damaged cellsto escape clearance, which results in increased long-term survival. We propose that C. elegans uses theengulfment machinery as part of a primitive, but evolutionarily conserved, survey mechanism thatidentifies and removes unfit cells within a tissue.", "metadata": {}}
+{"_id": "1145473", "title": "", "text": "Abnormalities in the myeloid progenitor compartment in Down syndrome fetal liver precede acquisition ofGATA1 mutations.Down syndrome (DS) children have a high frequency of acute megakaryoblasticleukemia (AMKL) in early childhood. At least 2 in utero genetic events are required, although notsufficient, for DS-AMKL: trisomy 21 (T21) and N-terminal-truncating GATA1 mutations. To investigate therole of T21 in DS-AMKL, we compared second trimester hemopoiesis in DS without GATA1 mutations togestation-matched normal controls. In all DS fetal livers (FLs), but not marrows,megakaryocyte-erythroid progenitor frequency was increased (55.9% +/- 4% vs 17.1% +/- 3%,CD34(+)CD38(+) cells; P < .001) with common myeloid progenitors (19.6% +/- 2% vs 44.0% +/- 7%)and granulocyte-monocyte (GM) progenitors (15.8% +/- 4% vs 34.5% +/- 9%) commensuratelyreduced. Clonogenicity of DS-FL versus normal FL CD34(+) cells was markedly increased (78% +/- 7%vs 15% +/- 3%) affecting megakaryocyte-erythroid ( approximately 7-fold higher) and GM andcolony-forming unit-granulocyte, erythrocyte macrophage, megakaryocyte (CFU-GEMM) progenitors.Replating efficiency of CFU-GEMM was also markedly increased. These data indicate that T21 itselfprofoundly disturbs FL hemopoiesis and they provide a testable hypothesis to explain the increasedsusceptibility to GATA1 mutations in DS-AMKL and DS-associated transient myeloproliferative disorder.", "metadata": {}}
+{"_id": "1148122", "title": "", "text": "Regulatory and metabolic rewiring during laboratory evolution of ethanol tolerance in E.coliUnderstanding the genetic basis of adaptation is a central problem in biology. However, revealing theunderlying molecular mechanisms has been challenging as changes in fitness may result fromperturbations to many pathways, any of which may contribute relatively little. We have developed acombined experimental/computational framework to address this problem and used it to understand thegenetic basis of ethanol tolerance in Escherichia coli. We used fitness profiling to measure theconsequences of single-locus perturbations in the context of ethanol exposure. A module-levelcomputational analysis was then used to reveal the organization of the contributing loci into cellularprocesses and regulatory pathways (e.g. osmoregulation and cell-wall biogenesis) whose modificationssignificantly affect ethanol tolerance. Strikingly, we discovered that a dominant component of adaptationinvolves metabolic rewiring that boosts intracellular ethanol degradation and assimilation. Throughphenotypic and metabolomic analysis of laboratory-evolved ethanol-tolerant strains, we investigatednaturally accessible pathways of ethanol tolerance. Remarkably, these laboratory-evolved strains, by andlarge, follow the same adaptive paths as inferred from our coarse-grained search of the fitness landscape.", "metadata": {}}
+{"_id": "1153655", "title": "", "text": "Familial risk of lymphoproliferative tumors in families of patients with chronic lymphocytic leukemia:results from the Swedish Family-Cancer Database.The importance of genetic factors in etiology of chroniclymphocytic leukemia (CLL) is suggested by family and population studies. However, the spectrum ofmalignancies sharing common genetic factors with CLL and the effects of sex and age on familial risk areunknown. We used the Swedish Family-Cancer Database to test for increased familial risks of CLL andother lymphoproliferative tumors. Cancer diagnoses from 1958 to 1998 were assessed in 14 336first-degree relatives of 5918 CLL cases and in 28 876 first-degree relatives of 11 778 controls. Cancerrisks in relatives of cases were compared with those in relatives of controls using marginal survivalmodels. Relatives of cases were at significantly increased risk for CLL (relative risk [RR] = 7.52; 95%confidence interval [CI], 3.63-15.56), for non-Hodgkin lymphoma (RR = 1.45; 95% CI, 0.98-2.16), andfor Hodgkin lymphoma (RR = 2.35; 95% CI, 1.08-5.08). CLL risks were similar in parents, siblings, andoffspring of cases, in male and female relatives, and were not affected by the case's age at diagnosis.Anticipation was not significant when analyzed using life table methods. We conclude that the familialcomponent of CLL is shared with other lymphoproliferative malignances, suggesting common geneticpathways. However, because clinically diagnosed CLL is uncommon, absolute excess risk to relatives issmall.", "metadata": {}}
+{"_id": "1156322", "title": "", "text": "Collagen/Polypropylene composite mesh biocompatibility in abdominal wall reconstruction.BACKGROUNDIntraperitoneal placement of polypropylene mesh leads to extensive visceral adhesions and iscontraindicated. Different coatings are used to improve polypropylene mesh properties. Collagen is aprotein with unique biocompatibility and cell ingrowth enhancement potential. A novel acetic acidextracted collagen coating was developed to allow placement of polypropylene mesh in direct contactwith viscera. The authors' aim was to evaluate the long-term influence of acetic acid extracted collagencoating on surgical aspects and biomechanical properties of polypropylene mesh implanted in directcontact with viscera, including complications, adhesions with viscera, strength of incorporation, andmicroscopic inflammatory reaction. METHODS Forty adult Wistar rats were divided into two groups:experimental (polypropylene mesh/acetic acid extracted collagen coating) and control (polypropylenemesh only). Astandardized procedure of mesh implantation was performed. Animals were killed 3 monthsafter surgery and analyzed for complications, mesh area covered by adhesions, type of adhesions,strength of incorporation, and intensity of inflammatory response. RESULTS The mean adhesion area waslower for polypropylene mesh/acetic acid extracted collagen coating (14.5 percent versus 69.9 percent, p< 0.001). Adhesion severity was decreased in the experimental group: grades 0 and 1 were morefrequent (p < 0.04 and p < 0.002, respectively) and grade 3 was less frequent (p < 0.0001). Anassociation between adhesion area and severity was found (p < 0.0001). Complications, strength ofincorporation, and intensity of inflammatory response to the mesh were similar. CONCLUSIONS Visceraladhesions to polypropylene mesh are significantly reduced because of acetic acid extracted collagencoating. The collagen coating does not increase complications or induce alterations of polypropylenemesh incorporation.", "metadata": {}}
+{"_id": "1171121", "title": "", "text": "Microvessel Density and Status of p53 Protein as Potential Prognostic Factors for Adjuvant AnthracyclineChemotherapy in Retrospective Analysis of Early Breast Cancer Patients GroupA considerable subgroup ofpatients with early breast cancer does not address benefits of anthracycline based chemotherapy. Theaim of this retrospective study was to investigate the effect of microvessel density (MVD) and status ofp53 protein on 5-year disease free survival (DFS) in the group of breast cancer patients treated withanthracyclines in adjuvant setting. Correlations between MVD, p53 status and other clinicopathologicalparameters were also assessed. MVD and p53 status were analyzed immunohistochemically in the groupof 172 women with breast cancer in clinical stage T1-2, N1-N2, M0. There were 123 tumors (71.5 %)with lower MVD (≤ 214.8 microvesells/mm(2)) and 49 (28.5 %) with higher MVD (>214.8microvesells/mm(2)). The proportion of higher MVD tumors significantly increased in N2 (P = 0.000) andin estrogen (P = 0.046) or progesterone receptors (P = 0.029) negative tumors. p53 positivity wasindicated in 50 cancers (29.1 %) and was significantly associated with higher grade (P = 0.000), steroidreceptors negativity (P = 0.000), cytokeratin5/6 positivity (P = 0.026), topoisomerase IIα overexpression(P = 0.005) and higher proliferation rate (P = 0.001). In univariate analysis, higher MVD (P = 0.016) andp53 negativity (P = 0.023) were significantly related with longer DFS (median follow-up 36 months). Inmultivariate Cox regression analysis MVD was independently associated with DFS. These data suggestthat higher MVD is favourable prognostic factors for early advanced breast cancer patients after adjuvantanthracycline based chemotherapy.", "metadata": {}}
+{"_id": "1173667", "title": "", "text": "Ranking of elimination feasibility between malaria-endemic countriesExperience gained from the GlobalMalaria Eradication Program (1955-72) identified a set of shared technical and operational factors thatenabled some countries to successfully eliminate malaria. Spatial data for these factors were assembledfor all malaria-endemic countries and combined to provide an objective, relative ranking of countries bytechnical, operational, and combined elimination feasibility. The analysis was done separately forPlasmodium falciparum and Plasmodium vivax, and the limitations of the approach were discussed. Therelative rankings suggested that malaria elimination would be most feasible in countries in the Americasand Asia, and least feasible in countries in central and west Africa. The results differed when feasibilitywas measured by technical or operational factors, highlighting the different types of challenge faced byeach country. The results are not intended to be prescriptive, predictive, or to provide absoluteassessments of feasibility, but they do show that spatial information is available to facilitateevidence-based assessments of the relative feasibility of malaria elimination by country that can berapidly updated.", "metadata": {}}
+{"_id": "1180972", "title": "", "text": "Genetics of obesity in adult adoptees and their biological siblings.An adoption study of genetic effects onobesity in adulthood was carried out in which adoptees separated from their natural parents very early inlife were compared with their biological full and half siblings reared by their natural parents. The adopteesrepresented four groups who by sampling from a larger population were categorised as either thin,medium weight, overweight, or obese. Weight and height were obtained for 115 full siblings of 57adoptees and for 850 half siblings of 341 adoptees. In full siblings body mass index (kg/m2) significantlyincreased with weight of the adoptees. Body mass index of the half siblings showed a steady but weakerincrease across the four weight groups of adoptees. There were no significant interactions with sex of theadoptees, sex of the siblings, or (for the half siblings) sex of the common parent. In contrast with thefindings in half siblings and (previously) the natural parents there was a striking, significant increase inbody mass index between full siblings of overweight and obese adoptees. The degree of fatness in adultsliving in the same environment appears to be influenced by genetic factors independent of sex, whichmay include polygenic as well as major gene effects on obesity.", "metadata": {}}
+{"_id": "1191830", "title": "", "text": "2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European LeagueAgainst Rheumatism collaborative initiative.OBJECTIVE The 1987 American College of Rheumatology(ACR; formerly the American Rheumatism Association) classification criteria for rheumatoid arthritis (RA)have been criticised for their lack of sensitivity in early disease. This work was undertaken to develop newclassification criteria for RA. METHODS A joint working group from the ACR and the European LeagueAgainst Rheumatism developed, in three phases, a new approach to classifying RA. The work focused onidentifying, among patients newly presenting with undifferentiated inflammatory synovitis, factors thatbest discriminated between those who were and those who were not at high risk for persistent and/orerosive disease--this being the appropriate current paradigm underlying the disease construct 'RA'.RESULTS In the new criteria set, classification as 'definite RA' is based on the confirmed presence ofsynovitis in at least one joint, absence of an alternative diagnosis better explaining the synovitis, andachievement of a total score of 6 or greater (of a possible 10) from the individual scores in four domains:number and site of involved joints (range 0-5), serological abnormality (range 0-3), elevated acute-phaseresponse (range 0-1) and symptom duration (two levels; range 0-1). CONCLUSION This newclassification system redefines the current paradigm of RA by focusing on features at earlier stages ofdisease that are associated with persistent and/or erosive disease, rather than defining the disease by itslate-stage features. This will refocus attention on the important need for earlier diagnosis and institutionof effective disease-suppressing therapy to prevent or minimise the occurrence of the undesirablesequelae that currently comprise the paradigm underlying the disease construct 'RA'.", "metadata": {}}
+{"_id": "1192458", "title": "", "text": "A role for fibroblasts in mediating the effects of tobacco-induced epithelial cell growth andinvasion.Cigarette smoke and smokeless tobacco extracts contain multiple carcinogenic compounds, butlittle is known about the mechanisms by which tumors develop and progress upon chronic exposure tocarcinogens such as those present in tobacco products. Here, we examine the effects of smokelesstobacco extracts on human oral fibroblasts. We show that smokeless tobacco extracts elevated the levelsof intracellular reactive oxygen, oxidative DNA damage, and DNA double-strand breaks in adose-dependent manner. Extended exposure to extracts induced fibroblasts to undergo a senescence-likegrowth arrest, with striking accompanying changes in the secretory phenotype. Using cocultures ofsmokeless tobacco extracts-exposed fibroblasts and immortalized but nontumorigenic keratinocytes, wefurther show that factors secreted by extracts-modified fibroblasts increase the proliferation andinvasiveness of partially transformed epithelial cells, but not their normal counterparts. In addition,smokeless tobacco extracts-exposed fibroblasts caused partially transformed keratinocytes to lose theexpression of E-cadherin and ZO-1, as well as involucrin, changes that are indicative of compromisedepithelial function and commonly associated with malignant progression. Together, our results suggestthat fibroblasts may contribute to tumorigenesis indirectly by increasing epithelial cell aggressiveness.Thus, tobacco may not only initiate mutagenic changes in epithelial cells but also promote the growth andinvasion of mutant cells by creating a procarcinogenic stromal environment.", "metadata": {}}
+{"_id": "1196631", "title": "", "text": "ImmTAC-redirected tumour cell killing induces and potentiates antigen cross-presentation by dendriticcellsAntigen cross-presentation by dendritic cells (DCs) is thought to play a critical role in driving apolyclonal and durable T cell response against cancer. It follows, therefore, that the capacity of emergingimmunotherapeutic agents to orchestrate tumour eradication may depend on their ability to induceantigen cross-presentation. ImmTACs [immune-mobilising monoclonal TCRs (T cell receptors) againstcancer] are a new class of soluble bi-specific anti-cancer agents that combine pico-molar affinityTCR-based antigen recognition with T cell activation via a CD3-specific antibody fragment. ImmTACsspecifically recognise human leucocyte antigen (HLA)-restricted tumour-associated antigens, presentedby cancer cells, leading to T cell redirection and a potent anti-tumour response. Using an ImmTACspecific for a HLA-A*02-restricted peptide derived from the melanoma antigen gp100 (termedIMCgp100), we here observe that ImmTAC-driven melanoma-cell death leads to cross-presentation ofmelanoma antigens by DCs. These, in turn, can activate both melanoma-specific T cells and polyclonal Tcells redirected by IMCgp100. Moreover, activation of melanoma-specific T cells by cross-presenting DCsis enhanced in the presence of IMCgp100; a feature that serves to increase the prospect of breakingtolerance in the tumour microenvironment. The mechanism of DC cross-presentation occurs via‘cross-dressing’ which involves the rapid and direct capture by DCs of membrane fragments from dyingtumour cells. DC cross-presentation of gp100-peptide-HLA complexes was visualised and quantified usinga fluorescently labelled soluble TCR. These data demonstrate how ImmTACs engage with the innate andadaptive components of the immune system enhancing the prospect of mediating an effective anddurable anti-tumour response in patients.", "metadata": {}}
+{"_id": "1203035", "title": "", "text": "Basal keratinocyte tetrasomy in low-grade squamous intra-epithelial lesions of the cervix is restricted tohigh and intermediate risk HPV infection but is not type-specificHuman papillomavirus (HPV) infectionappears to be an early event in cervical carcinogenesis with additional abnormalities being required forbiological transformation. We have analysed 179 low-grade cervical squamous intra-epithelial lesions(SILs) and 15 normal cervices for the presence of HPV using both in situ hybridization and polymerasechain reaction (PCR). PCR was performed with GP5+/GP6+ primers followed by hybridization usingprobes for low (HPV 6, 11, 40, 42, 43, 44), intermediate (HPV 31, 33, 35, 39, 51, 52, 58, 59, 66 and 68)and high-risk HPVs (HPV 16, 18, 45 and 56). Interphase cytogenetic analysis using pericentromericprobes for chromosomes 1, 3, 4, 6, 10, 11, 17, 18 and X was also performed to identify numericalchromosomal abnormalities. Tetrasomy of all nine chromosomes was identified within basalkeratinocytes, was restricted to epithelia infected with high risk (17 of 46) or intermediate risk (23 of 83)HPVs but was not HPV type-specific. Tetrasomy was not identified in any of the epithelia infected with lowrisk HPVs (n = 62). These numbers include multiple infection. These findings indicate that the induction oftetrasomy is a property restricted to high and intermediate-risk HPV types but that it is not type-specific.The factors governing which lesions will develop this abnormality are as yet unclear. © 2000 CancerResearch Campaign", "metadata": {}}
+{"_id": "1215116", "title": "", "text": "“Rapid-Impact Interventions”: How a Policy of Integrated Control for Africa's Neglected Tropical DiseasesCould Benefit the PoorOver the past two decades there have been significant achievements in the controlof a handful of important human tropical infections [1]. These achievements include the substantivereductions in the prevalence and incidence of the so-called neglected diseases such as lymphaticfilariasis, onchocerciasis, guinea worm, leprosy, and trachoma (Box 1) [2]. Each of these neglecteddiseases is a poverty-promoting and often stigmatizing condition occurring primarily in rural areas oflow-income countries (Box 2) [3]. They are ancient afflictions, described in the Bible and other ancienttexts, which have burdened humanity for millennia [3]. But now, as a result of aggressive regionalvertical interventions, there is a possibility that some neglected tropical infections could be eventuallycontrolled to the point of elimination in some areas of endemicity [2–8]. In the case of guinea worminfection, disease eradication might also soon be possible [9]. Box 2. Common Features of the NeglectedTropical Diseases          Ancient afflictions that have burdened humanity forcenturies      Poverty-promoting conditions      Associated with stigma      Rural areas of low-incomecountries and fragile states      No commercial markets for products that target thesediseases      Interventions, when applied, have a history of success", "metadata": {}}
+{"_id": "1220287", "title": "", "text": "FTY720 (fingolimod) is a neuroprotective and disease-modifying agent in cellular and mouse models ofHuntington disease.Huntington disease (HD) is a genetic neurodegenerative disorder for which there iscurrently no cure and no way to stop or even slow the brain changes it causes. In the present study, weaimed to investigate whether FTY720, the first approved oral therapy for multiple sclerosis, may beeffective in HD models and eventually constitute an alternative therapeutic approach for the treatment ofthe disease. Here, we utilized preclinical target validation paradigms and examined the in vivo efficacy ofchronic administration of FTY720 in R6/2 HD mouse model. Our findings indicate that FTY720 improvedmotor function, prolonged survival and reduced brain atrophy in R6/2 mice. The beneficial effect ofFTY720 administration was associated with a significant strengthening of neuronal activity andconnectivity and, with reduction of mutant huntingtin aggregates, and it was also paralleled by increasedphosphorylation of mutant huntingtin at serine 13/16 residues that are predicted to attenuate proteintoxicity.", "metadata": {}}
+{"_id": "1225513", "title": "", "text": "Specificity Residues Determine Binding Affinity for Two-Component Signal TransductionSystemsUNLABELLED Two-component systems (TCS) comprise histidine kinases and their cognateresponse regulators and allow bacteria to sense and respond to a wide variety of signals. Histidinekinases (HKs) phosphorylate and dephosphorylate their cognate response regulators (RRs) in response tostimuli. In general, these reactions appear to be highly specific and require an appropriate associationbetween the HK and RR proteins. The Myxococcus xanthus genome encodes one of the largest repertoiresof signaling proteins in bacteria (685 open reading frames [ORFs]), including at least 127 HKs and atleast 143 RRs. Of these, 27 are bona fide NtrC-family response regulators, 21 of which are encodedadjacent to their predicted cognate kinases. Using system-wide profiling methods, we determined thatthe HK-NtrC RR pairs display a kinetic preference during both phosphotransfer and phosphatasefunctions, thereby defining cognate signaling systems in M. xanthus. Isothermal titration calorimetrymeasurements indicated that cognate HK-RR pairs interact with dissociation constants (Kd) ofapproximately 1 µM, while noncognate pairs had no measurable binding. Lastly, a chimera generatedbetween the histidine kinase, CrdS, and HK1190 revealed that residues conferring phosphotransfer andphosphatase specificity dictate binding affinity, thereby establishing discrete protein-protein interactionswhich prevent cross talk. The data indicate that binding affinity is a critical parameter governingsystem-wide signaling fidelity for bacterial signal transduction proteins. IMPORTANCE Using in vitrophosphotransfer and phosphatase profiling assays and isothermal titration calorimetry, we have taken asystem-wide approach to demonstrate specificity for a family of two-component signaling proteins inMyxococcus xanthus. Our results demonstrate that previously identified specificity residues dictatebinding affinity and that phosphatase specificity follows phosphotransfer specificity for cognate HK-RRpairs. The data indicate that preferential binding affinity is the basis for signaling fidelity in bacterialtwo-component systems.", "metadata": {}}
+{"_id": "1226452", "title": "", "text": "hnRNP A1 associates with telomere ends and stimulates telomerase activity.Telomerase is aribonucleoprotein enzyme complex that reverse-transcribes an integral RNA template to add short DNArepeats to the 3'-ends of telomeres. G-quadruplex structure in a DNA substrate can block its extension bytelomerase. We have found that hnRNP A1--which was previously implicated in telomere lengthregulation--binds to both single-stranded and structured human telomeric repeats, and in the latter case,it disrupts their higher-order structure. Using an in vitro telomerase assay, we observed that depletion ofhnRNP A/B proteins from 293 human embryonic kidney cell extracts dramatically reduced telomeraseactivity, which was fully recovered upon addition of purified recombinant hnRNP A1. This finding suggeststhat hnRNP A1 functions as an auxiliary, if not essential, factor of telomerase holoenzyme. We furthershow, using chromatin immunoprecipitation, that hnRNP A1 associates with human telomeres in vivo. Wepropose that hnRNP A1 stimulates telomere elongation through unwinding of a G-quadruplex or G-Ghairpin structure formed at each translocation step.", "metadata": {}}
+{"_id": "1227277", "title": "", "text": "Rapamycin passes the torch: a new generation of mTOR inhibitorsMammalian target of rapamycin(mTOR) is an atypical protein kinase that controls growth and metabolism in response to nutrients,growth factors and cellular energy levels, and it is frequently dysregulated in cancer and metabolicdisorders. Rapamycin is an allosteric inhibitor of mTOR, and was approved as an immuno-suppressant in1999. In recent years, interest has focused on its potential as an anticancer drug. However, theperformance of rapamycin and its analogues (rapalogues) has been undistinguished despite isolatedsuccesses in subsets of cancer, suggesting that the full therapeutic potential of targeting mTOR has yet tobe exploited. A new generation of ATP-competitive inhibitors that directly target the mTOR catalytic sitedisplay potent and comprehensive mTOR inhibition and are in early clinical trials.", "metadata": {}}
+{"_id": "1234098", "title": "", "text": "Dynamic capsule restructuring by the main pneumococcal autolysin LytA in response to theepitheliumBacterial pathogens produce complex carbohydrate capsules to protect against bactericidalimmune molecules. Paradoxically, the pneumococcal capsule sensitizes the bacterium to antimicrobialpeptides found on epithelial surfaces. Here we show that upon interaction with antimicrobial peptides,encapsulated pneumococci survive by removing capsule from the cell surface within minutes in a processdependent on the suicidal amidase autolysin LytA. In contrast to classical bacterial autolysis, duringcapsule shedding, LytA promotes bacterial survival and is dispersed circumferentially around the cell.However, both autolysis and capsule shedding depend on the cell wall hydrolytic activity of LytA. Capsuleshedding drastically increases invasion of epithelial cells and is the main pathway by which pneumococcireduce surface bound capsule during early acute lung infection of mice. The previously unrecognized roleof LytA in removing capsule to combat antimicrobial peptides may explain why nearly all clinical isolatesof pneumococci conserve this enzyme despite the lethal selective pressure of antibiotics.", "metadata": {}}
+{"_id": "1241113", "title": "", "text": "The mammalian Scribble polarity protein regulates epithelial cell adhesion and migration throughE-cadherinScribble (Scrib) is a conserved polarity protein required in Drosophila melanogaster forsynaptic function, neuroblast differentiation, and epithelial polarization. It is also a tumor suppressor. Inrodents, Scrib has been implicated in receptor recycling and planar polarity but not in apical/basalpolarity. We now show that knockdown of Scrib disrupts adhesion between Madin–Darby canine kidneyepithelial cells. As a consequence, the cells acquire a mesenchymal appearance, migrate more rapidly,and lose directionality. Although tight junction assembly is delayed, confluent monolayers remainpolarized. These effects are independent of Rac activation or Scrib binding to βPIX. Rather, Scribdepletion disrupts E-cadherin–mediated cell–cell adhesion. The changes in morphology and migration arephenocopied by E-cadherin knockdown. Adhesion is partially rescued by expression of anE-cadherin–α-catenin fusion protein but not by E-cadherin–green fluorescent protein. These resultssuggest that Scrib stabilizes the coupling between E-cadherin and the catenins and are consistent withthe idea that mammalian Scrib could behave as a tumor suppressor by regulating epithelial cell adhesionand migration.", "metadata": {}}
+{"_id": "1243475", "title": "", "text": "Histone acetylation and DNA demethylation of T cells result in an anaplastic large cell lymphoma-likephenotype.A characteristic feature of anaplastic large cell lymphoma is the significant repression of theT-cell expression program despite its T-cell origin. The reasons for this down-regulation of T-cellphenotype are still unknown. To elucidate whether epigenetic mechanisms are responsible for the loss ofthe T-cell phenotype, we treated anaplastic large cell lymphoma and T-cell lymphoma/leukemia cell lines(n=4, each) with epigenetic modifiers to evoke DNA demethylation and histone acetylation. Global geneexpression data from treated and untreated cell lines were generated and selected, and differentiallyexpressed genes were evaluated by real-time reverse transcriptase polymerase chain reaction andwestern blot analysis. Additionally, histone H3 lysine 27 trimethylation was analyzed by chromatinimmunoprecipitation. Combined DNA demethylation and histone acetylation of anaplastic large celllymphoma cells was not able to reconstitute their T-cell phenotype. Instead, the same treatment inducedin T cells: (i) an up-regulation of anaplastic large cell lymphoma-characteristic genes (e.g. ID2, LGALS1,c-JUN), and (ii) an almost complete extinction of their T-cell phenotype including CD3, LCK and ZAP70. Inaddition, suppressive trimethylation of histone H3 lysine 27 of important T-cell transcription factor genes(GATA3, LEF1, TCF1) was present in anaplastic large cell lymphoma cells, which is in line with theirabsence in primary tumor specimens as demonstrated by immunohistochemistry. Our data suggest thatepigenetically activated suppressors (e.g. ID2) contribute to the down-regulation of the T-cell expressionprogram in anaplastic large cell lymphoma, which is maintained by trimethylation of histone H3 lysine 27.", "metadata": {}}
+{"_id": "1256116", "title": "", "text": "YEASTRACT: providing a programmatic access to curated transcriptional regulatory associations inSaccharomyces cerevisiae through a web services interfaceThe YEAst Search for TranscriptionalRegulators And Consensus Tracking (YEASTRACT) information system (http://www.yeastract.com) wasdeveloped to support the analysis of transcription regulatory associations in Saccharomyces cerevisiae.Last updated in June 2010, this database contains over 48,200 regulatory associations betweentranscription factors (TFs) and target genes, including 298 specific DNA-binding sites for 110characterized TFs. All regulatory associations stored in the database were revisited and detailedinformation on the experimental evidences that sustain those associations was added and classified asdirect or indirect evidences. The inclusion of this new data, gathered in response to the requests ofYEASTRACT users, allows the user to restrict its queries to subsets of the data based on the existence ornot of experimental evidences for the direct action of the TFs in the promoter region of their target genes.Another new feature of this release is the availability of all data through a machine readable web-serviceinterface. Users are no longer restricted to the set of available queries made available through theexisting web interface, and can use the web service interface to query, retrieve and exploit theYEASTRACT data using their own implementation of additional functionalities. The YEASTRACTinformation system is further complemented with several computational tools that facilitate the use of thecurated data when answering a number of important biological questions. Since its first release in 2006,YEASTRACT has been extensively used by hundreds of researchers from all over the world. We expectthat by making the new data and services available, the system will continue to be instrumental for yeastbiologists and systems biology researchers.", "metadata": {}}
+{"_id": "1259280", "title": "", "text": "Mechanisms that Specify Promoter Nucleosome Location and IdentityThe chromatin architecture ofeukaryotic gene promoters is generally characterized by a nucleosome-free region (NFR) flanked by atleast one H2A.Z variant nucleosome. Computational predictions of nucleosome positions based onthermodynamic properties of DNA-histone interactions have met with limited success. Here we show thatthe action of the essential RSC remodeling complex in S. cerevisiae helps explain the discrepancybetween theory and experiment. In RSC-depleted cells, NFRs shrink such that the average positions offlanking nucleosomes move toward predicted sites. Nucleosome positioning at distinct subsets ofpromoters additionally requires the essential Myb family proteins Abf1 and Reb1, whose binding sites areenriched in NFRs. In contrast, H2A.Z deposition is dispensable for nucleosome positioning. By regulatingH2A.Z deposition using a steroid-inducible protein splicing strategy, we show that NFR establishment isnecessary for H2A.Z deposition. These studies suggest an ordered pathway for the assembly of promoterchromatin architecture.", "metadata": {}}
+{"_id": "1259359", "title": "", "text": "HIV seropositivity and tuberculosis in a large general hospital in Malawi.The incidence of the acquiredimmunodeficiency syndrome (AIDS) in Malawi is one of the highest in Central Africa. Since tuberculosis isan important initial manifestations of the disease, consecutive patients admitted to the tuberculosis (TB)wards of Zomba General Hospital, Malawi, were asked for permission to undergo a humanimmunodeficiency virus (HIV)-antibodies test. In addition, two other studies were done: from September1986 all medical in-patients, clinically suspected for immune deficiency and from April 1988 all blooddonors were tested for HIV seropositivity. Seventy-five percent of the TB patients volunteered; 32 out of125 (26%) were seropositive. In the high-risk age groups (20-40 years) this percentage rose to 32.Among the medical in-patients suspected of immune deficiency the seropositivity rose sharply from April1987 to October 1988. Among the blood donors tested, 20% were seropositive.", "metadata": {}}
+{"_id": "1263446", "title": "", "text": "Determinants of neonatal mortality in IndonesiaBACKGROUND Neonatal mortality accounts for almost 40per cent of under-five child mortality, globally. An understanding of the factors related to neonatalmortality is important to guide the development of focused and evidence-based health interventions toprevent neonatal deaths. This study aimed to identify the determinants of neonatal mortality inIndonesia, for a nationally representative sample of births from 1997 to 2002. METHODS The data sourcefor the analysis was the 2002-2003 Indonesia Demographic and Health Survey from which survivalinformation of 15,952 singleton live-born infants born between 1997 and 2002 was examined. Multilevellogistic regression using a hierarchical approach was performed to analyze the factors associated withneonatal deaths, using community, socio-economic status and proximate determinants. RESULTS At thecommunity level, the odds of neonatal death was significantly higher for infants from East Java (OR =5.01, p = 0.00), and for North, Central and Southeast Sulawesi and Gorontalo combined (OR = 3.17, p =0.03) compared to the lowest neonatal mortality regions of Bali, South Sulawesi and Jambi provinces. Aprogressive reduction in the odds was found as the percentage of deliveries assisted by trained deliveryattendants in the cluster increased. The odds of neonatal death were higher for infants born to bothmother and father who were employed (OR = 1.84, p = 0.00) and for infants born to father who wereunemployed (OR = 2.99, p = 0.02). The odds were also higher for higher rank infants with a short birthinterval (OR = 2.82, p = 0.00), male infants (OR = 1.49, p = 0.01), smaller than average-sized infants(OR = 2.80, p = 0.00), and infant's whose mother had a history of delivery complications (OR = 1.81, p= 0.00). Infants receiving any postnatal care were significantly protected from neonatal death (OR =0.63, p = 0.03). CONCLUSION Public health interventions directed at reducing neonatal death shouldaddress community, household and individual level factors which significantly influence neonatal mortalityin Indonesia. Low birth weight and short birth interval infants as well as perinatal health services factors,such as the availability of skilled birth attendance and postnatal care utilization should be taken intoaccount when planning the interventions to reduce neonatal mortality in Indonesia.", "metadata": {}}
+{"_id": "1265945", "title": "", "text": "High density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory boweldiseases and heterozygous advantage in ulcerative colitisGenome-wide association studies of the relatedchronic inflammatory bowel diseases (IBD) known as Crohn's disease and ulcerative colitis have shownstrong evidence of association to the major histocompatibility complex (MHC). This region encodes alarge number of immunological candidates, including the antigen-presenting classical human leukocyteantigen (HLA) molecules. Studies in IBD have indicated that multiple independent associations exist atHLA and non-HLA genes, but they have lacked the statistical power to define the architecture ofassociation and causal alleles. To address this, we performed high-density SNP typing of the MHC in>32,000 individuals with IBD, implicating multiple HLA alleles, with a primary role for HLA-DRB1*01:03in both Crohn's disease and ulcerative colitis. Noteworthy differences were observed between thesediseases, including a predominant role for class II HLA variants and heterozygous advantage observed inulcerative colitis, suggesting an important role of the adaptive immune response in the colonicenvironment in the pathogenesis of IBD.", "metadata": {}}
+{"_id": "1275505", "title": "", "text": "High-Threshold Mechanosensitive Ion Channels Blocked by a Novel Conopeptide Mediate Pressure-EvokedPainLittle is known about the molecular basis of somatosensory mechanotransduction in mammals. Wescreened a library of peptide toxins for effects on mechanically activated currents in cultured dorsal rootganglion neurons. One conopeptide analogue, termed NMB-1 for noxious mechanosensation blocker 1,selectively inhibits (IC50 1 µM) sustained mechanically activated currents in a subset of sensory neurons.Biotinylated NMB-1 retains activity and binds selectively to peripherin-positive nociceptive sensoryneurons. The selectivity of NMB-1 was confirmed by the fact that it has no inhibitory effects onvoltage-gated sodium and calcium channels, or ligand-gated channels such as acid-sensing ion channelsor TRPA1 channels. Conversely, the tarantula toxin, GsMTx-4, which inhibits stretch-activated ionchannels, had no effects on mechanically activated currents in sensory neurons. In behavioral assays,NMB-1 inhibits responses only to high intensity, painful mechanical stimulation and has no effects on lowintensity mechanical stimulation or thermosensation. Unexpectedly, NMB-1 was found to also be aninhibitor of rapid FM1-43 loading (a measure of mechanotransduction) in cochlear hair cells. These datademonstrate that pharmacologically distinct channels respond to distinct types of mechanical stimuli andsuggest that mechanically activated sustained currents underlie noxious mechanosensation. NMB-1 thusprovides a novel diagnostic tool for the molecular definition of channels involved in hearing andpressure-evoked pain.", "metadata": {}}
+{"_id": "1281769", "title": "", "text": "Hyperactive Neuroendocrine Secretion Causes Size, Feeding, and Metabolic Defects of C. elegansBardet-Biedl Syndrome MutantsBardet-Biedl syndrome, BBS, is a rare autosomal recessive disorder withclinical presentations including polydactyly, retinopathy, hyperphagia, obesity, short stature, cognitiveimpairment, and developmental delays. Disruptions of BBS proteins in a variety of organisms impair ciliaformation and function and the multi-organ defects of BBS have been attributed to deficiencies in variouscilia-associated signaling pathways. In C. elegans, bbs genes are expressed exclusively in the sixtyciliated sensory neurons of these animals and bbs mutants exhibit sensory defects as well as body size,feeding, and metabolic abnormalities. Here we show that in contrast to many other cilia-defectivemutants, C. elegans bbs mutants exhibit increased release of dense-core vesicles and organism-widephenotypes associated with enhanced activities of insulin, neuropeptide, and biogenic amine signalingpathways. We show that the altered body size, feeding, and metabolic abnormalities of bbs mutants canbe corrected to wild-type levels by abrogating the enhanced secretion of dense-core vesicles withoutconcomitant correction of ciliary defects. These findings expand the role of BBS proteins to the regulationof dense-core-vesicle exocytosis and suggest that some features of Bardet-Biedl Syndrome may becaused by excessive neuroendocrine secretion.", "metadata": {}}
+{"_id": "1283401", "title": "", "text": "Fiji: an open-source platform for biological-image analysisFiji is a distribution of the popular open-sourcesoftware ImageJ focused on biological-image analysis. Fiji uses modern software engineering practices tocombine powerful software libraries with a broad range of scripting languages to enable rapid prototypingof image-processing algorithms. Fiji facilitates the transformation of new algorithms into ImageJ pluginsthat can be shared with end users through an integrated update system. We propose Fiji as a platform forproductive collaboration between computer science and biology research communities.", "metadata": {}}
+{"_id": "1285713", "title": "", "text": "Pharmacologic characterization of a potent inhibitor of class I phosphatidylinositide 3-kinases.Extensiveevidence implicates activation of the lipid phosphatidylinositide 3-kinase (PI3K) pathway in the genesisand progression of various human cancers. PI3K inhibitors thus have considerable potential as molecularcancer therapeutics. Here, we detail the pharmacologic properties of a prototype of a new series ofinhibitors of class I PI3K. PI103 is a potent inhibitor with low IC50 values against recombinant PI3Kisoforms p110alpha (2 nmol/L), p110beta (3 nmol/L), p110delta (3 nmol/L), and p110gamma (15nmol/L). PI103 also inhibited TORC1 by 83.9% at 0.5 micromol/L and exhibited an IC50 of 14 nmol/Lagainst DNA-PK. A high degree of selectivity for the PI3K family was shown by the lack of activity ofPI103 in a panel of 70 protein kinases. PI103 potently inhibited proliferation and invasion of a widevariety of human cancer cells in vitro and showed biomarker modulation consistent with inhibition of PI3Ksignaling. PI103 was extensively metabolized, but distributed rapidly to tissues and tumors. This resultedin tumor growth delay in eight different human cancer xenograft models with various PI3K pathwayabnormalities. Decreased phosphorylation of AKT was observed in U87MG gliomas, consistent with druglevels achieved. We also showed inhibition of invasion in orthotopic breast and ovarian cancer xenograftmodels and obtained evidence that PI103 has antiangiogenic potential. Despite its rapid in vivometabolism, PI103 is a valuable tool compound for exploring the biological function of class I PI3K andimportantly represents a lead for further optimization of this novel class of targeted molecular cancertherapeutic.", "metadata": {}}
+{"_id": "1286352", "title": "", "text": "Optimized CRISPR/Cas tools for efficient germline and somatic genome engineering in Drosophila.Thetype II clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas)system has emerged recently as a powerful method to manipulate the genomes of various organisms.Here, we report a toolbox for high-efficiency genome engineering of Drosophila melanogaster consistingof transgenic Cas9 lines and versatile guide RNA (gRNA) expression plasmids. Systematic evaluationreveals Cas9 lines with ubiquitous or germ-line-restricted patterns of activity. We also demonstratedifferential activity of the same gRNA expressed from different U6 snRNA promoters, with the previouslyuntested U6:3 promoter giving the most potent effect. An appropriate combination of Cas9 and gRNAallows targeting of essential and nonessential genes with transmission rates ranging from 25-100%. Wealso demonstrate that our optimized CRISPR/Cas tools can be used for offset nicking-based mutagenesis.Furthermore, in combination with oligonucleotide or long double-stranded donor templates, our reagentsallow precise genome editing by homology-directed repair with rates that make selection markersunnecessary. Last, we demonstrate a novel application of CRISPR/Cas-mediated technology in revealingloss-of-function phenotypes in somatic cells following efficient biallelic targeting by Cas9 expressed in aubiquitous or tissue-restricted manner. Our CRISPR/Cas tools will facilitate the rapid evaluation of mutantphenotypes of specific genes and the precise modification of the genome with single-nucleotide precision.Our results also pave the way for high-throughput genetic screening with CRISPR/Cas.", "metadata": {}}
+{"_id": "1287809", "title": "", "text": "Cost-effectiveness of 10-Year Risk Thresholds for Initiation of Statin Therapy for Primary Prevention ofCardiovascular Disease.IMPORTANCE The American College of Cardiology and the American HeartAssociation (ACC/AHA) cholesterol treatment guidelines have wide-scale implications for treating adultswithout history of atherosclerotic cardiovascular disease (ASCVD) with statins. OBJECTIVE To estimatethe cost-effectiveness of various 10-year ASCVD risk thresholds that could be used in the ACC/AHAcholesterol treatment guidelines. DESIGN, SETTING, AND PARTICIPANTS Microsimulation model,including lifetime time horizon, US societal perspective, 3% discount rate for costs, and health outcomes.In the model, hypothetical individuals from a representative US population aged 40 to 75 years receivedstatin treatment, experienced ASCVD events, and died from ASCVD-related or non-ASCVD-related causesbased on ASCVD natural history and statin treatment parameters. Data sources for model parametersincluded National Health and Nutrition Examination Surveys, large clinical trials and meta-analyses forstatin benefits and treatment, and other published sources. MAIN OUTCOMES AND MEASURES EstimatedASCVD events prevented and incremental costs per quality-adjusted life-year (QALY) gained. RESULTS Inthe base-case scenario, the current ASCVD threshold of 7.5% or higher, which was estimated to beassociated with 48% of adults treated with statins, had an incremental cost-effectiveness ratio (ICER) of$37,000/QALY compared with a 10% or higher threshold. More lenient ASCVD thresholds of 4.0% orhigher (61% of adults treated) and 3.0% or higher (67% of adults treated) had ICERs of $81,000/QALYand $140,000/QALY, respectively. Shifting from a 7.5% or higher ASCVD risk threshold to a 3.0% orhigher ASCVD risk threshold was estimated to be associated with an additional 161,560 cardiovasculardisease events averted. Cost-effectiveness results were sensitive to changes in the disutility associatedwith taking a pill daily, statin price, and the risk of statin-induced diabetes. In probabilistic sensitivityanalysis, there was a higher than 93% chance that the optimal ASCVD threshold was 5.0% or lower usinga cost-effectiveness threshold of $100,000/QALY. CONCLUSIONS AND RELEVANCE In thismicrosimulation model of US adults aged 45 to 75 years [corrected], the current 10-year ASCVD riskthreshold (≥7.5% risk threshold) used in the ACC/AHA cholesterol treatment guidelines has anacceptable cost-effectiveness profile (ICER, $37,000/QALY), but more lenient ASCVD thresholds would beoptimal using cost-effectiveness thresholds of $100,000/QALY (≥4.0% risk threshold) or $150,000/QALY(≥3.0% risk threshold). The optimal ASCVD threshold was sensitive to patient preferences for taking apill daily, changes to statin price, and the risk of statin-induced diabetes.", "metadata": {}}
+{"_id": "1292369", "title": "", "text": "Biochemical Properties of Highly Neuroinvasive Prion StrainsInfectious prions propagate from peripheralentry sites into the central nervous system (CNS), where they cause progressive neurodegeneration thatultimately leads to death. Yet the pathogenesis of prion disease can vary dramatically depending on thestrain, or conformational variant of the aberrantly folded and aggregated protein, PrP(Sc). Although mostprion strains invade the CNS, some prion strains cannot gain entry and do not cause clinical signs ofdisease. The conformational basis for this remarkable variation in the pathogenesis among strains isunclear. Using mouse-adapted prion strains, here we show that highly neuroinvasive prion strainsprimarily form diffuse aggregates in brain and are noncongophilic, conformationally unstable indenaturing conditions, and lead to rapidly lethal disease. These neuroinvasive strains efficiently generatePrP(Sc) over short incubation periods. In contrast, the weakly neuroinvasive prion strains form largefibrillary plaques and are stable, congophilic, and inefficiently generate PrP(Sc) over long incubationperiods. Overall, these results indicate that the most neuroinvasive prion strains are also the least stable,and support the concept that the efficient replication and unstable nature of the most rapidly convertingprions may be a feature linked to their efficient spread into the CNS.", "metadata": {}}
+{"_id": "1320137", "title": "", "text": "The twin-arginine translocation (Tat) protein export pathwayThe twin-arginine translocation (Tat) proteinexport system is present in the cytoplasmic membranes of most bacteria and archaea and has the highlyunusual property of transporting fully folded proteins. The system must therefore provide atransmembrane pathway that is large enough to allow the passage of structured macromolecularsubstrates of different sizes but that maintains the impermeability of the membrane to ions. In theGram-negative bacterium Escherichia coli, this complex task can be achieved by using only three smallmembrane proteins: TatA, TatB and TatC. In this Review, we summarize recent advances in ourunderstanding of how this remarkable machine operates.", "metadata": {}}
+{"_id": "1322614", "title": "", "text": "New developments in the ATSAS program package for small-angle scattering data analysisNewdevelopments in the program package ATSAS (version 2.4) for the processing and analysis of isotropicsmall-angle X-ray and neutron scattering data are described. They include (i) multiplatform datamanipulation and display tools, (ii) programs for automated data processing and calculation of overallparameters, (iii) improved usage of high- and low-resolution models from other structural methods, (iv)new algorithms to build three-dimensional models from weakly interacting oligomeric systems andcomplexes, and (v) enhanced tools to analyse data from mixtures and flexible systems. The new ATSASrelease includes installers for current major platforms (Windows, Linux and Mac OSX) and providesimproved indexed user documentation. The web-related developments, including a user discussion forumand a widened online access to run ATSAS programs, are also presented.", "metadata": {}}
+{"_id": "1332250", "title": "", "text": "The First Myriapod Genome Sequence Reveals Conservative Arthropod Gene Content and GenomeOrganisation in the Centipede Strigamia maritimaMyriapods (e.g., centipedes and millipedes) display asimple homonomous body plan relative to other arthropods. All members of the class are terrestrial, butthey attained terrestriality independently of insects. Myriapoda is the only arthropod class notrepresented by a sequenced genome. We present an analysis of the genome of the centipede Strigamiamaritima. It retains a compact genome that has undergone less gene loss and shuffling than previouslysequenced arthropods, and many orthologues of genes conserved from the bilaterian ancestor that havebeen lost in insects. Our analysis locates many genes in conserved macro-synteny contexts, and manysmall-scale examples of gene clustering. We describe several examples where S. maritima showsdifferent solutions from insects to similar problems. The insect olfactory receptor gene family is absentfrom S. maritima, and olfaction in air is likely effected by expansion of other receptor gene families. Forsome genes S. maritima has evolved paralogues to generate coding sequence diversity, where insectsuse alternate splicing. This is most striking for the Dscam gene, which in Drosophila generates more than100,000 alternate splice forms, but in S. maritima is encoded by over 100 paralogues. We see anintriguing linkage between the absence of any known photosensory proteins in a blind organism and theadditional absence of canonical circadian clock genes. The phylogenetic position of myriapods allows us toidentify where in arthropod phylogeny several particular molecular mechanisms and traits emerged. Forexample, we conclude that juvenile hormone signalling evolved with the emergence of the exoskeleton inthe arthropods and that RR-1 containing cuticle proteins evolved in the lineage leading to Mandibulata.We also identify when various gene expansions and losses occurred. The genome of S. maritima offers usa unique glimpse into the ancestral arthropod genome, while also displaying many adaptations to itsspecific life history.", "metadata": {}}
+{"_id": "1333643", "title": "", "text": "Genetic and Functional Diversification of Small RNA Pathways in PlantsMulticellular eukaryotes producesmall RNA molecules (approximately 21–24 nucleotides) of two general types, microRNA (miRNA) andshort interfering RNA (siRNA). They collectively function as sequence-specific guides to silence or regulategenes, transposons, and viruses and to modify chromatin and genome structure. Formation or activity ofsmall RNAs requires factors belonging to gene families that encode DICER (or DICER-LIKE [DCL]) andARGONAUTE proteins and, in the case of some siRNAs, RNA-dependent RNA polymerase (RDR) proteins.Unlike many animals, plants encode multiple DCL and RDR proteins. Using a series of insertion mutantsof Arabidopsis thaliana, unique functions for three DCL proteins in miRNA (DCL1), endogenous siRNA(DCL3), and viral siRNA (DCL2) biogenesis were identified. One RDR protein (RDR2) was required for allendogenous siRNAs analyzed. The loss of endogenous siRNA in dcl3 and rdr2 mutants was associatedwith loss of heterochromatic marks and increased transcript accumulation at some loci. Defects insiRNA-generation activity in response to turnip crinkle virus in dcl2 mutant plants correlated withincreased virus susceptibility. We conclude that proliferation and diversification of DCL and RDR genesduring evolution of plants contributed to specialization of small RNA-directed pathways for development,chromatin structure, and defense.", "metadata": {}}
+{"_id": "1336292", "title": "", "text": "Immunosuppressant FTY720 inhibits thymocyte emigration.One major role of the thymus is to providethe peripheral immune system with mature T cells, but the mechanisms involving the cellular export arenot fully understood. In this study, we examined the ability of a novel immunosuppressive reagent,FTY720, to inhibit T cell export from the thymus. Daily administration of FTY720 at a dose of 1 mg / kgresulted in a marked decrease in the number of peripheral blood T lymphocytes. In the thymus,long-term daily administration of FTY720 caused a three- to fourfold increase in the proportion of maturemedullary thymocytes (CD4(+)CD8(-) and CD4(-)CD8(+)) as well as a slight decrease in thedouble-positive cell (CD4(+)CD8(+)) ratio. Phenotypic analysis (TCRalpha beta, H-2K(d), CD44, CD69and CD24) revealed that these increased subsets represent possible peripheral recent thymic emigrants.High level expression of L-selectin by these subsets further suggests that they were prevented fromleaving the thymus. By intrathymic labeling with fluorescein isothiocyanate, only one fourth of labeledcells could be detected in the lymph nodes and in the spleen of FTY720-treated mice compared tosaline-treated control mice. Taken together, these results suggest that the immunosuppressive action ofFTY720, at least in part, could be due to its inhibitory effect on T cell emigration from the thymus to theperiphery.", "metadata": {}}
+{"_id": "1338283", "title": "", "text": "Validating a conceptual model for an inter-professional approach to shared decision making: a mixedmethods studyRATIONALE, AIMS AND OBJECTIVES Following increased interest in havinginter-professional (IP) health care teams engage patients in decision making, we developed a conceptualmodel for an IP approach to shared decision making (SDM) in primary care. We assessed the validity ofthe model with stakeholders in Canada. METHODS In 15 individual interviews and 7 group interviews with79 stakeholders, we asked them to: (1) propose changes to the IP-SDM model; (2) identify barriers andfacilitators to the model's implementation in clinical practice; and (3) assess the model using a theoryappraisal questionnaire. We performed a thematic analysis of the transcripts and a descriptive analysis ofthe questionnaires. RESULTS Stakeholders suggested placing the patient at its centre; extending theconcept of family to include significant others; clarifying outcomes; highlighting the concept of time;merging the micro, meso and macro levels in one figure; and recognizing the influence of theenvironment and emotions. The most common barriers identified were time constraints, insufficientresources and an imbalance of power among health professionals. The most common facilitators wereeducation and training in inter-professionalism and SDM, motivation to achieve an IP approach to SDM,and mutual knowledge and understanding of disciplinary roles. Most stakeholders considered that theconcepts and relationships between the concepts were clear and rated the model as logical, testable,having clear schematic representation, and being relevant to inter-professional collaboration, SDM andprimary care. CONCLUSIONS Stakeholders validated the new IP-SDM model for primary care settings andproposed few modifications. Future research should assess if the model helps implement SDM in IPclinical practice.", "metadata": {}}
+{"_id": "1344498", "title": "", "text": "Glutaminolysis activates Rag-mTORC1 signaling.Amino acids control cell growth via activation of thehighly conserved kinase TORC1. Glutamine is a particularly important amino acid in cell growth controland metabolism. However, the role of glutamine in TORC1 activation remains poorly defined. Glutamineis metabolized through glutaminolysis to produce α-ketoglutarate. We demonstrate that glutamine incombination with leucine activates mammalian TORC1 (mTORC1) by enhancing glutaminolysis andα-ketoglutarate production. Inhibition of glutaminolysis prevented GTP loading of RagB and lysosomaltranslocation and subsequent activation of mTORC1. Constitutively active Rag heterodimer activatedmTORC1 in the absence of glutaminolysis. Conversely, enhanced glutaminolysis or a cell-permeableα-ketoglutarate analog stimulated lysosomal translocation and activation of mTORC1. Finally, cell growthand autophagy, two processes controlled by mTORC1, were regulated by glutaminolysis. Thus, mTORC1senses and is activated by glutamine and leucine via glutaminolysis and α-ketoglutarate productionupstream of Rag. This may provide an explanation for glutamine addiction in cancer cells.", "metadata": {}}
+{"_id": "1346695", "title": "", "text": "microRNA-31/factor-inhibiting hypoxia-inducible factor 1 nexus regulates keratinocytedifferentiation.Notch plays a critical role in the transition from proliferation to differentiation in theepidermis and corneal epithelium. Furthermore, aberrant Notch signaling is a feature of diseases likepsoriasis, eczema, nonmelanoma skin cancer, and melanoma where differentiation and proliferation areimpaired. Whereas much is known about the downstream events following Notch signaling, factorsresponsible for negatively regulating Notch receptor signaling after ligand activation are incompletelyunderstood. Notch can undergo hydroxylation by factor-inhibiting hypoxia-inducible factor 1 (FIH-1);however, the biological significance of this phenomenon is unclear. Here we show that FIH-1 expression isup-regulated in diseased epidermis and corneal epithelium. Elevating FIH-1 levels in primary humanepidermal keratinocytes (HEKs) and human corneal epithelial keratinocytes (HCEKs) impairsdifferentiation in submerged cultures and in a \"three-dimensional\" organotypic raft model of humanepidermis, in part, via a coordinate decrease in Notch signaling. Knockdown of FIH-1 enhanceskeratinocyte differentiation. Loss of FIH-1 in vivo increased Notch activity in the limbal epithelium,resulting in a more differentiated phenotype. microRNA-31 (miR-31) is an endogenous negative regulatorof FIH-1 expression that results in keratinocyte differentiation, mediated by Notch activation. Ectopicallyexpressing miR-31 in an undifferentiated corneal epithelial cell line promotes differentiation andrecapitulates a corneal epithelium in a three-dimensional raft culture model. Our results define apreviously unknown mechanism for keratinocyte fate decisions where Notch signaling potential is, in part,controlled through a miR-31/FIH-1 nexus.", "metadata": {}}
+{"_id": "1349033", "title": "", "text": "Advantages of larval control for African malaria vectors: Low mobility and behavioural responsiveness ofimmature mosquito stages allow high effective coverageBased on sensitivity analysis of theMacDonald-Ross model, it has long been argued that the best way to reduce malaria transmission is totarget adult female mosquitoes with insecticides that can reduce the longevity and human-feedingfrequency of vectors. However, these analyses have ignored a fundamental biological difference betweenmosquito adults and the immature stages that precede them: adults are highly mobile flying insects thatcan readily detect and avoid many intervention measures whereas mosquito eggs, larvae and pupae areconfined within relatively small aquatic habitats and cannot readily escape control measures. Wehypothesize that the control of adult but not immature mosquitoes is compromised by their ability toavoid interventions such as excito-repellant insecticides. We apply a simple model of interventionavoidance by mosquitoes and demonstrate that this can substantially reduce effective coverage, in termsof the proportion of the vector population that is covered, and overall impact on malaria transmission. Wereview historical evidence that larval control of African malaria vectors can be effective and conclude thatthe only limitations to the effective coverage of larval control are practical rather than fundamental.Larval control strategies against the vectors of malaria in sub-Saharan Africa could be highly effective,complementary to adult control interventions, and should be prioritized for further development,evaluation and implementation as an integral part of Rolling Back Malaria.", "metadata": {}}
+{"_id": "1354567", "title": "", "text": "The Arabidopsis Chromatin-Modifying Nuclear siRNA Pathway Involves a Nucleolar RNA ProcessingCenterIn Arabidopsis thaliana, small interfering RNAs (siRNAs) direct cytosine methylation at endogenousDNA repeats in a pathway involving two forms of nuclear RNA polymerase IV (Pol IVa and Pol IVb),RNA-DEPENDENT RNA POLYMERASE 2 (RDR2), DICER-LIKE 3 (DCL3), ARGONAUTE4 (AGO4), thechromatin remodeler DRD1, and the de novo cytosine methyltransferase DRM2. We show that RDR2,DCL3, AGO4, and NRPD1b (the largest subunit of Pol IVb) colocalize with siRNAs within the nucleolus. Bycontrast, Pol IVa and DRD1 are external to the nucleolus and colocalize with endogenous repeat loci.Mutation-induced loss of pathway proteins causes downstream proteins to mislocalize, revealing theirorder of action. Pol IVa acts first, and its localization is RNA dependent, suggesting an RNA template. Wehypothesize that maintenance of the heterochromatic state involves locus-specific Pol IVa transcriptionfollowed by siRNA production and assembly of AGO4- and NRPD1b-containing silencing complexes withinnucleolar processing centers.", "metadata": {}}
+{"_id": "1358909", "title": "", "text": "Peripheral arterial disease in the elderly: The Rotterdam Study.To assess the age- and sex-specificprevalence of peripheral arterial disease (PAD) and intermittent claudication (IC) in an elderly population,we performed a population-based study in 7715 subjects (40% men, 60% women) aged 55 years andover. The presence of PAD and IC was determined by measuring the ankle-arm systolic blood pressureindex (AAI) and by means of the World Health Organization/Rose questionnaire, respectively. PAD wasconsidered present when the AAI was <0.90 in either leg. The prevalence of PAD was 19.1% (95%confidence interval, 18.1% to 20.0%): 16.9% in men and 20.5% in women. Symptoms of IC werereported by 1.6% (95% confidence interval, 1.3% to 1.9%) of the study population (2.2% in men, 1.2%in women). Of those with PAD, 6.3% reported symptoms of IC (8.7% in men, 4.9% in women), whereasin 68.9% of those with IC an AAI below 0.90 was found. Subjects with an AAI <0.90 were more likely tobe smokers, to have hypertension, and to have symptomatic or asymptomatic cardiovascular diseasecompared with subjects with an AAI of 0.90 or higher. The authors conclude that the prevalence of PAD inthe elderly is high whereas the prevalence of IC is rather low, although both prevalences clearly increasewith advancing age. The vast majority of PAD patients reports no symptoms of IC.", "metadata": {}}
+{"_id": "1360607", "title": "", "text": "Antioxidants attenuate the plasma cytokine response to exercise in humans.Exercise increases plasmaTNF-alpha, IL-1beta, and IL-6, yet the stimuli and sources of TNF-alpha and IL-1beta remain largelyunknown. We tested the role of oxidative stress and the potential contribution of monocytes in thiscytokine (especially IL-1beta) response in previously untrained individuals. Six healthy nonathletesperformed two 45-min bicycle exercise sessions at 70% of Vo(2 max) before and after a combination ofantioxidants (vitamins E, A, and C for 60 days; allopurinol for 15 days; and N-acetylcysteine for 3 days).Blood was drawn at baseline, end-exercise, and 30 and 120 min postexercise. Plasma cytokines weredetermined by ELISA and monocyte intracellular cytokine level by flow cytometry. Before antioxidants,TNF-alpha increased by 60%, IL-1beta by threefold, and IL-6 by sixfold secondary to exercise (P < 0.05).After antioxidants, plasma IL-1beta became undetectable, the TNF-alpha response to exercise wasabolished, and the IL-6 response was significantly blunted (P < 0.05). Exercise did not increase thepercentage of monocytes producing the cytokines or their mean fluorescence intensity. We conclude thatin untrained humans oxidative stress is a major stimulus for exercise-induced cytokine production andthat monocytes play no role in this process.", "metadata": {}}
+{"_id": "1365188", "title": "", "text": "Relation between colonic proglucagon expression and metabolic response to oligofructose in high fatdiet-fed mice.Several data suggest that fermentable dietary fiber could play a role in the control ofobesity and associated metabolic disorders. The aim of this study was to investigate the putative role ofshort chain fructo-oligosaccharide (OFS) - a non-digestible oligosaccharide - in mice fed a standard dietand in mice fed two distinct high fat diets inducing metabolic disorders associated to obesity. Weconfirmed, in mice, several effects previously shown in rats fed a standard diet enriched with OFS,namely an increase in total and empty caecum weight, a significant decrease in epididymal fat mass, andan increase in colonic and portal plasma glucagon-like peptide-1 (GLP-1), a phenomenon positivelycorrelated with a higher colonic proglucagon mRNA level. Curiously, 4-week treatment with OFS added atthe same dose induced different effects when added in the two different high fat diets. OFS decreasedenergy intake, body weight gain, glycemia, and epididymal fat mass only when added together with thehigh fat-carbohydrate free diet, in which OFS promoted colonic proglucagon expression and insulinsecretion. Our results support an association between the increase in proglucagon expression in theproximal colon and OFS effects on glycemia, fat mass development, and/or body weight gain. Inconclusion, dietary oligosaccharides would constitute an interesting class of dietary fibers promoting, incertain conditions, endogenous GLP-1 production, with beneficial physiological consequences. Thisremains to be proven in human studies.", "metadata": {}}
+{"_id": "1371440", "title": "", "text": "Aurora B phosphorylates spatially distinct targets to differentially regulate the kinetochore-microtubuleinterface.Accurate chromosome segregation requires carefully regulated interactions betweenkinetochores and microtubules, but how plasticity is achieved to correct diverse attachment defectsremains unclear. Here we demonstrate that Aurora B kinase phosphorylates three spatially distincttargets within the conserved outer kinetochore KNL1/Mis12 complex/Ndc80 complex (KMN) network, thekey player in kinetochore-microtubule attachments. The combinatorial phosphorylation of the KMNnetwork generates graded levels of microtubule-binding activity, with full phosphorylation severelycompromising microtubule binding. Altering the phosphorylation state of each protein causescorresponding chromosome segregation defects. Importantly, the spatial distribution of these targetsalong the kinetochore axis leads to their differential phosphorylation in response to changes in tensionand attachment state. In total, rather than generating exclusively binary changes in microtubule binding,our results suggest a mechanism for the tension-dependent fine-tuning of kinetochore-microtubuleinteractions.", "metadata": {}}
+{"_id": "1373287", "title": "", "text": "Prognostic importance of 6-mercaptopurine dose intensity in acute lymphoblasticleukemia.6-Mercaptopurine (6MP) and methotrexate are the backbone of continuation therapy forchildhood acute lymphoblastic leukemia (ALL). In studies of oral 6MP and methotrexate, indices ofchronic systemic exposure to active metabolites of these agents, namely, red blood cell (RBC)concentrations of methotrexate polyglutamates (MTXPGs) and thioguanine nucleotides (TGNs) havepositively correlated with event-free survival (EFS). Our objective was to evaluate whether MTXPGs,TGNs, and the dose intensity of administered methotrexate and 6MP were prognostic in the setting of atreatment protocol in which all treatment was coordinated through a single center, and the weekly dosesof methotrexate were given parenterally. On protocol Total XII, 182 children achieved remission andreceived weekly methotrexate 40 mg/m2 parenterally and daily oral 6MP, interrupted every 6 weeksduring the first year by pulse chemotherapy. A total of 709 TGN, 418 MTX-PG, and 267 thiopurinemethyltransferase (TPMT) measurements, along with complete dose intensity information (dose receiveddivided by protocol dose per week) for 19,046 weeks of 6MP and methotrexate, were analyzed. Inunivariate analyses, only higher dose intensity of 6MP and of weekly methotrexate were significantpredictors of overall EFS (P =.006 and. 039, respectively). The occurrence of neutropenia was associatedwith worse outcome (P =.040). In a multivariate analysis, only higher dose intensity of 6MP (P =.020)was a significant predictor of EFS, with lower TPMT activity (P =.096) tending to associate with betteroutcome. 6MP dose intensity was also associated (P =.007) with EFS among patients with homozygouswild-type TPMT phenotype. Lower 6MP dose intensity was primarily due to missed weeks of therapy andnot to reductions in daily dose. We conclude that increased dose-intensity of oral 6MP is an importantdeterminant of EFS in ALL, particularly among those children with a homozygous wild-type TPMTphenotype. However, increasing intensity of therapy such that neutropenia precludes chemotherapyadministration may be counterproductive.", "metadata": {}}
+{"_id": "1379127", "title": "", "text": "Orai1 and STIM1 are critical for breast tumor cell migration and metastasis.Tumor metastasis is theprimary cause of death of cancer patients. Understanding the molecular mechanisms underlying tumormetastasis will provide potential drug targets. We report here that Orai1 and STIM1, both of which areinvolved in store-operated calcium entry, are essential for breast tumor cell migration in vitro and tumormetastasis in mice. Reduction of Orai1 or STIM1 by RNA interference in highly metastatic human breastcancer cells or treatment with a pharmacological inhibitor of store-operated calcium channels decreasedtumor metastasis in animal models. Our data demonstrate a role for Orai1 and STIM1 in tumormetastasis and suggest store-operated calcium entry channels as potential cancer therapeutic targets.", "metadata": {}}
+{"_id": "1381673", "title": "", "text": "Mouse Spermatogenic Stem Cells Continually Interconvert between Equipotent Singly Isolated andSyncytial StatesThe identity and behavior of mouse spermatogenic stem cells have been a long-standingfocus of interest. In the prevailing \"As model,\" stem cell function is restricted to singly isolated (As)spermatogonia. By examining single-cell dynamics of GFRα1+ stem cells in vivo, we evaluate analternative hypothesis that, through fragmentation, syncytial spermatogonia also contribute to stem cellfunction in homeostasis. We use live imaging and pulse labeling to quantitatively determine the fates ofindividual GFRα1+ cells and find that, during steady-state spermatogenesis, the entire GFRα1+population comprises a single stem cell pool, in which cells continually interconvert between As andsyncytial states. A minimal biophysical model, relying only on the rates of incomplete cell division andsyncytial fragmentation, precisely predicts the stochastic fates of GFRα1+ cells during steady state andpostinsult regeneration. Thus, our results define an alternative and dynamic model for spermatogenicstem cell function in the mouse testis.", "metadata": {}}
+{"_id": "1383826", "title": "", "text": "Pseudoknots: RNA Structures with Diverse FunctionsRNA molecules fulfill a diverse set of biologicalfunctions within cells, from the transfer of genetic information from DNA to protein, to enzymaticcatalysis. Reflecting this range of roles, simple linear strings of RNA—made up of uracil, guanine,cytosine, and adenine—form a variety of complex three-dimensional structures. Just as proteins formdistinct structural motifs such as zinc fingers and beta barrels, certain structures are also commonlyadopted by RNA molecules. Among the most prevalent RNA structures is a motif known as thepseudoknot. First recognized in the turnip yellow mosaic virus [1], a pseudoknot is an RNA structure thatis minimally composed of two helical segments connected by single-stranded regions or loops (Figure 1).Although several distinct folding topologies of pseudoknots exist, the best characterized is the H type. Inthe H-type fold, the bases in the loop of a hairpin form intramolecular pairs with bases outside of thestem (Figure 1A and and1B).1B). This causes the formation of a second stem and loop, resulting in apseudoknot with two stems and two loops (Figure 1C). The two stems are able to stack on top of eachother to form a quasi-continuous helix with one continuous and one discontinuous strand. Thesingle-stranded loop regions often interact with the adjacent stems (loop 1–stem 2 or loop 2–stem 1) toform hydrogen bonds and to participate in the overall structure of the molecule. Hence, this relativelysimple fold can yield very complex and stable RNA structures. Due to variation of the lengths of the loopsand stems, as well as the types of interactions between them, pseudoknots represent a structurallydiverse group. It is fitting that they play a variety of diverse roles in biology. These roles include formingthe catalytic core of various ribozymes [2,3], self-splicing introns [4], and telomerase [5]. Additionally,pseudoknots play critical roles in altering gene expression by inducing ribosomal frameshifting in manyviruses [6–9].", "metadata": {}}
+{"_id": "1386103", "title": "", "text": "An essential role for interferon gamma in resistance to Mycobacterium tuberculosis infectionTuberculosis,a major health problem in developing countries, has reemerged in recent years in many industrializedcountries. The increased susceptibility of immunocompromised individuals to tuberculosis, and manyexperimental studies indicate that T cell-mediated immunity plays an important role in resistance. Thelymphokine interferon gamma (IFN-gamma) is thought to be a principal mediator of macrophageactivation and resistance to intracellular pathogens. Mice have been developed which fail to produceIFN-gamma (gko), because of a targeted disruption of the gene for IFN-gamma. Upon infection withMycobacterium tuberculosis, although they develop granulomas, gko mice fail to produce reactivenitrogen intermediates and are unable to restrict the growth of the bacilli. In contrast to control mice, gkomice exhibit heightened tissue necrosis and succumb to a rapid and fatal course of tuberculosis that couldbe delayed, but not prevented, by treatment with exogenous recombinant IFN-gamma.", "metadata": {}}
+{"_id": "1387104", "title": "", "text": "Malignancies, prothrombotic mutations, and the risk of venous thrombosis.CONTEXT Venous thrombosisis a common complication in patients with cancer, leading to additional morbidity and compromisingquality of life. OBJECTIVE To identify individuals with cancer with an increased thrombotic risk, evaluatingdifferent tumor sites, the presence of distant metastases, and carrier status of prothrombotic mutations.DESIGN, SETTING, AND PATIENTS A large population-based, case-control (Multiple Environmental andGenetic Assessment [MEGA] of risk factors for venous thrombosis) study of 3220 consecutive patientsaged 18 to 70 years, with a first deep venous thrombosis of the leg or pulmonary embolism, betweenMarch 1, 1999, and May 31, 2002, at 6 anticoagulation clinics in the Netherlands, and separate 2131control participants (partners of the patients) reported via a questionnaire on acquired risk factors forvenous thrombosis. Three months after discontinuation of the anticoagulant therapy, all patients andcontrols were interviewed, a blood sample was taken, and DNA was isolated to ascertain the factor VLeiden and prothrombin 20210A mutations. MAIN OUTCOME MEASURE Risk of venous thrombosis.RESULTS The overall risk of venous thrombosis was increased 7-fold in patients with a malignancy (oddsratio [OR], 6.7; 95% confidence interval [CI], 5.2-8.6) vs persons without malignancy. Patients withhematological malignancies had the highest risk of venous thrombosis, adjusted for age and sex(adjusted OR, 28.0; 95% CI, 4.0-199.7), followed by lung cancer and gastrointestinal cancer. The risk ofvenous thrombosis was highest in the first few months after the diagnosis of malignancy (adjusted OR,53.5; 95% CI, 8.6-334.3). Patients with cancer with distant metastases had a higher risk vs patientswithout distant metastases (adjusted OR, 19.8; 95% CI, 2.6-149.1). Carriers of the factor V Leidenmutation who also had cancer had a 12-fold increased risk vs individuals without cancer and factor VLeiden (adjusted OR, 12.1; 95% CI, 1.6-88.1). Similar results were indirectly calculated for theprothrombin 20210A mutation in patients with cancer. CONCLUSIONS Patients with cancer have a highlyincreased risk of venous thrombosis especially in the first few months after diagnosis and in the presenceof distant metastases. Carriers of the factor V Leiden and prothrombin 20210A mutations appear to havean even higher risk.", "metadata": {}}
+{"_id": "1387654", "title": "", "text": "The Hippo signaling pathway restricts the oncogenic potential of an intestinal regenerationprogram.Although a developmental role for Hippo signaling in organ size control is well appreciated, howthis pathway functions in tissue regeneration is largely unknown. Here we address this issue using adextran sodium sulfate (DSS)-induced colonic regeneration model. We find that regenerating cryptsexpress elevated Yes-associated protein (YAP) levels. Inactivation of YAP causes no obvious intestinaldefects under normal homeostasis, but severely impairs DSS-induced intestinal regeneration. Conversely,hyperactivation of YAP results in widespread early-onset polyp formation following DSS treatment. Thus,the YAP oncoprotein must be exquisitely controlled in tissue regeneration to allow compensatoryproliferation and prevent the intrinsic oncogenic potential of a tissue regeneration program.", "metadata": {}}
+{"_id": "1388704", "title": "", "text": "The essence of SNPs.Single nucleotide polymorphisms (SNPs) are an abundant form of genome variation,distinguished from rare variations by a requirement for the least abundant allele to have a frequency of1% or more. A wide range of genetics disciplines stand to benefit greatly from the study and use of SNPs.The recent surge of interest in SNPs stems from, and continues to depend upon, the merging andcoincident maturation of several research areas, i.e. (i) large-scale genome analysis and relatedtechnologies, (ii) bio-informatics and computing, (iii) genetic analysis of simple and complex diseasestates, and (iv) global human population genetics. These fields will now be propelled forward, often intouncharted territories, by ongoing discovery efforts that promise to yield hundreds of thousands of humanSNPs in the next few years. Major questions are now being asked, experimentally, theoretically andethically, about the most effective ways to unlock the full potential of the upcoming SNP revolution.", "metadata": {}}
+{"_id": "1389264", "title": "", "text": "Combination inhibition of PI3K and mTORC1 yields durable remissions in orthotopic patient-derivedxenografts of HER2-positive breast cancer brain metastasesBrain metastases represent the greatestclinical challenge in treating HER2-positive breast cancer. We report the development of orthotopicpatient-derived xenografts (PDXs) of HER2-expressing breast cancer brain metastases (BCBM), and theiruse for the identification of targeted combination therapies. Combined inhibition of PI3K and mTORresulted in durable tumor regressions in three of five PDXs, and therapeutic response was correlated witha reduction in the phosphorylation of 4EBP1, an mTORC1 effector. The two nonresponding PDXs showedhypermutated genomes with enrichment of mutations in DNA-repair genes, which suggests anassociation of genomic instability with therapeutic resistance. These findings suggest that abiomarker-driven clinical trial of PI3K inhibitor in combination with an mTOR inhibitor should beconducted for patients with HER2-positive BCBM.", "metadata": {}}
+{"_id": "1391126", "title": "", "text": "Activation of Frontal Neocortical Areas by Vocal Production in MarmosetsPrimates often rely on vocalcommunication to mediate social interactions. Although much is known about the acoustic structure ofprimate vocalizations and the social context in which they are usually uttered, our knowledge about theneocortical control of audio-vocal interactions in primates is still incipient, being mostly derived fromlesion studies in squirrel monkeys and macaques. To map the neocortical areas related to vocal control ina New World primate species, the common marmoset, we employed a method previously used withsuccess in other vertebrate species: Analysis of the expression of the immediate early gene Egr-1 infreely behaving animals. The neocortical distribution of Egr-1 immunoreactive cells in three marmosetsthat were exposed to the playback of conspecific vocalizations and vocalized spontaneously (H/V group)was compared to data from three other marmosets that also heard the playback but did not vocalize (H/ngroup). The anterior cingulate cortex, the dorsomedial prefrontal cortex and the ventrolateral prefrontalcortex presented a higher number of Egr-1 immunoreactive cells in the H/V group than in H/n animals.Our results provide direct evidence that the ventrolateral prefrontal cortex, the region that comprisesBroca's area in humans and has been associated with auditory processing of species-specific vocalizationsand orofacial control in macaques, is engaged during vocal output in marmosets. Altogether, our resultssupport the notion that the network of neocortical areas related to vocal communication in marmosets isquite similar to that of Old world primates. The vocal production role played by these areas and theirimportance for the evolution of speech in primates are discussed.", "metadata": {}}
+{"_id": "1398021", "title": "", "text": "Familial hiatal hernia in a large five generation family confirming true autosomal dominantinheritance.BACKGROUND Familial hiatal hernia has only rarely been documented. AIMS To describe thepattern of inheritance of familial hiatal hernia within an affected family. SUBJECTS Thirty eight membersof a family pedigree across five generations. METHODS All family members were interviewed andinvestigated by barium meal for evidence of a hiatal hernia. RESULTS Twenty three of 38 family membershad radiological evidence of a hiatal hernia. No individual with a hiatal hernia was born to unaffectedparents. In one case direct male to male transmission was shown. CONCLUSIONS Familial inheritance ofhiatal hernia does occur. Evidence of direct male to male transmission points to an autosomal dominantmode of inheritance.", "metadata": {}}
+{"_id": "1410197", "title": "", "text": "An Excitatory Loop with Astrocytes Contributes to Drive Neurons to Seizure ThresholdSeizures in focalepilepsies are sustained by a highly synchronous neuronal discharge that arises at restricted brain sitesand subsequently spreads to large portions of the brain. Despite intense experimental research in thisfield, the earlier cellular events that initiate and sustain a focal seizure are still not well defined. Theiridentification is central to understand the pathophysiology of focal epilepsies and to develop newpharmacological therapies for drug-resistant forms of epilepsy. The prominent involvement of astrocytesin ictogenesis was recently proposed. We test here whether a cooperation between astrocytes andneurons is a prerequisite to support ictal (seizure-like) and interictal epileptiform events. Simultaneouspatch-clamp recording and Ca2+ imaging techniques were performed in a new in vitro model of focalseizures induced by local applications of N-methyl-D-aspartic acid (NMDA) in rat entorhinal cortex slices.We found that a Ca2+ elevation in astrocytes correlates with both the initial development and themaintenance of a focal, seizure-like discharge. A delayed astrocyte activation during ictal discharges wasalso observed in other models (including the whole in vitro isolated guinea pig brain) in which the site ofgeneration of seizure activity cannot be precisely monitored. In contrast, interictal discharges were notassociated with Ca2+ changes in astrocytes. Selective inhibition or stimulation of astrocyte Ca2+signalling blocked or enhanced, respectively, ictal discharges, but did not affect interictal dischargegeneration. Our data reveal that neurons engage astrocytes in a recurrent excitatory loop (possiblyinvolving gliotransmission) that promotes seizure ignition and sustains the ictal discharge. Thisneuron-astrocyte interaction may represent a novel target to develop effective therapeutic strategies tocontrol seizures.", "metadata": {}}
+{"_id": "1412089", "title": "", "text": "Diminished performance on neuropsychological testing in late life depression is correlated withmicrostructural white matter abnormalities.BACKGROUND Traditional T2 weighted MR imaging results arenon-specific for the extent of underlying white matter structural abnormalities present in late lifedepression (LLD). Diffusion tensor imaging provides a unique opportunity to investigate the extent andnature of structural injury, but has been limited by examining only a subset of regions of interest (ROI)and by confounds common to the study of an elderly population, including comorbid vascular pathology.Furthermore, comprehensive correlation of diffusion tensor imaging (DTI) measurements, including axialand radial diffusivity measurements, has not been demonstrated in the late life depression population.METHODS 51 depressed and 16 non-depressed, age- and cerebrovascular risk factor-matched elderlysubjects underwent traditional anatomic T1 and T2 weight imaging, as well as DTI. The DTI data wereskeletonized using tract based spatial statistics (TBSS), and both regional and global analyses wereperformed. RESULTS Widespread structural abnormalities within white matter were detected in the LLDgroup, accounting for age, gender and education and matched for cerebrovascular risk factors and globalT2 white matter hyperintensities (T2WMH). Regional differences were most prominent in uncinate andcingulate white matter and were generally characterized by an increase in radial diffusivity. Age-relatedchanges particularly in the cingulate bundle were more advanced in individuals with LLD relative tocontrols. Regression analysis demonstrated significant correlations of regional fractional anisotropy andradial diffusivity with five different neuropsychological factor scores. TBSS analysis demonstrated agreater extent of white matter abnormalities in LLD not responsive to treatment, as compared tocontrols. CONCLUSIONS White matter integrity is compromised in late life depression, largely manifestedby increased radial diffusivity in specific regions, suggesting underlying myelin injury. A possiblemechanism for underlying myelin injury is chronic white matter ischemia related to intrinsiccerebrovascular disease. In some regions such as the cingulate bundle, the white matter injury related tolate life depression appears to be independent of and compounded by age-related changes. Thecorrelations with neuropsychological testing indicate the essential effects of white matter injury onfunctional status. Lastly, response to treatment may depend on the extent of white matter injury,suggesting a need for intact functional networks.", "metadata": {}}
+{"_id": "1428830", "title": "", "text": "The atypical antipsychotic olanzapine causes weight gain by targeting serotonin receptor 2C.Atypicalantipsychotics such as olanzapine often induce excessive weight gain and type 2 diabetes. However, themechanisms underlying these drug-induced metabolic perturbations remain poorly understood. Here, weused an experimental model that reproduces olanzapine-induced hyperphagia and obesity in femaleC57BL/6 mice. We found that olanzapine treatment acutely increased food intake, impaired glucosetolerance, and altered physical activity and energy expenditure in mice. Furthermore, olanzapine-inducedhyperphagia and weight gain were blunted in mice lacking the serotonin 2C receptor (HTR2C). Finally, weshowed that treatment with the HTR2C-specific agonist lorcaserin suppressed olanzapine-inducedhyperphagia and weight gain. Lorcaserin treatment also improved glucose tolerance in olanzapine-fedmice. Collectively, our studies suggest that olanzapine exerts some of its untoward metabolic effects viaantagonism of HTR2C.", "metadata": {}}
+{"_id": "1428840", "title": "", "text": "Case-control study of endogenous steroid hormones and endometrial cancer.BACKGROUND It has beensuggested that identified risk factors for endometrial cancer operate through a single etiologic pathway,i.e., exposure to relatively high levels of unopposed estrogen (estrogen in the absence of progestins).Only a few studies, however, have addressed this issue directly. PURPOSE We assessed the risk ofdeveloping endometrial cancer among both premenopausal and postmenopausal women in relation to thecirculating levels of steroid hormones and sex hormone-binding globulin (SHBG). The independent effectof hormones was assessed after adjustment for other known risk factors. METHODS The data used in theanalysis are from a case-control study conducted in five geographic regions in the United States. Incidentcases were newly diagnosed during the period from June 1, 1987, through May 15, 1990. The casepatients, aged 20-74 years, were matched to control subjects by age, race, and geographic region. Thecommunity control subjects were obtained by random-digit-dialing procedures (for subjects 20-64 yearsold) and from files of the Health Care Financing Administration (for subjects > or = 65 years old).Additional control subjects who were having a hysterectomy performed for benign conditions wereobtained from the participating centers. Women reporting use of exogenous estrogens or oralcontraceptives within 6 months of interview were excluded, resulting in 68 case patients and 107 controlsubjects among premenopausal women and 208 case patients and 209 control subjects amongpostmenopausal women. The hormone analyses were performed on blood samples obtained from casepatients or from hysterectomy control subjects before surgery. The odds ratios (ORs) and 95%confidence intervals (CIs) were estimated by use of an unconditional logistic regression analysis after wecontrolled for matching variables and potential confounders. All P values were two-sided. RESULTS Highcirculating levels of androstenedione were associated with 3.6-fold and 2.8-fold increased risks amongpremenopausal and postmenopausal women, respectively, after adjustment for other factors (P for trend= .01 and < .001, respectively). Risks related to other hormone fractions varied by menopausal status.Among postmenopausal women, a reduced risk was associated with high SHBG levels and persisted afteradjustment was made for obesity and other factors (OR = 0.51; 95% CI = 0.27-0.95). High estronelevels were associated with increased risk (OR = 3.8; 95% CI = 2.2-6.6), although adjustment for otherrisk factors (particularly body mass index) diminished the effect (OR = 2.2; 95% CI = 1.2-4.4).Albumin-bound estradiol (E2), a marker of the bioavailable fraction, also remained an important riskfactor after adjustment was made for other factors (OR = 2.0; 95% CI = 1.0-3.9). In contrast, highconcentrations of total, free, and albumin-bound E2 were unrelated to increased risk in premenopausalwomen. In both premenopausal and postmenopausal groups, risks associated with obesity and fatdistribution were not affected by adjustment for hormones. CONCLUSION High endogenous levels ofunopposed estrogen are related to increased risk of endometrial cancer, but their independence fromother risk factors is inconsistent with being a common underlying biologic pathway through which all riskfactors for endometrial cancer operate. IMPLICATIONS Further research should focus on alternativeendocrinologic mechanisms for risk associated with obesity and body fat distribution and for the biologicrelevance of the increased risk associated with androstenedione in both premenopausal andpostmenopausal disease.", "metadata": {}}
+{"_id": "1447990", "title": "", "text": "FOXO4 is necessary for neural differentiation of human embryonic stem cells.Proteostasis is critical formaintaining cell function and proteome stability may play an important role in human embryonic stemcell (hESC) immortality. Notably, hESC populations exhibit a high assembly of active proteasomes, a keynode of the proteostasis network. FOXO4, an insulin/IGF-1 responsive transcription factor, regulatesproteasome activity in hESCs. We find that loss of FOXO4 reduces the potential of hESCs to differentiateinto neural lineages. Therefore, FOXO4 crosses evolutionary boundaries and links hESC function toinvertebrate longevity modulation.", "metadata": {}}
+{"_id": "1449692", "title": "", "text": "Gestational protein restriction affects trophoblast differentiation.Whether and how gestational proteinrestriction (PR) affects placental development and function remain unknown. To test the hypothesis thatPR can affect trophoblast differentiation in mid-and late pregnancy, rats were fed a 20% or an isocaloric6% protein diet from Day 1 to 14 or 18 of pregnancy and effects of PR on trophoblast differentiation weredetermined by changes in expressions of marker gene(s) for trophoblast lineages. At Day 18 ofpregnancy, PR increased expressions of Esrrb, Id1 andId2 (trophoblast stem cell markers), decreasedexpressions of Ascl2 (spongiotrophblast cell marker) and Prl2c1 (trophoblast giant cell marker), but didnot alter expressions of Gjb3 and Pcdh12(glycogen cell markers) in the junctional zone (JZ). In thelabyrinth zone (LZ), PR did not change expressions of Prl2b1 (trophoblast giant cell marker), Gcm1 andSyna (syncytiotrophoblast cell markers), but decrease expression of Ctsq (sinusoidal trophoblast giantcell marker). These results indicate that PR impairs the differentiation of trophoblast stem cell intospongiotrophoblast and trophoblast giant cells in JZ, and formation of sinusoidal trophoblast giant cells inLZ.", "metadata": {}}
+{"_id": "1454773", "title": "", "text": "In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology innon-human primates.The programmed death-1 (PD-1) receptor serves as an immunologic checkpoint,limiting bystander tissue damage and preventing the development of autoimmunity during inflammatoryresponses. PD-1 is expressed by activated T cells and downmodulates T-cell effector functions uponbinding to its ligands, PD-L1 and PD-L2, on antigen-presenting cells. In patients with cancer, theexpression of PD-1 on tumor-infiltrating lymphocytes and its interaction with the ligands on tumor andimmune cells in the tumor microenvironment undermine antitumor immunity and support its rationale forPD-1 blockade in cancer immunotherapy. This report details the development and characterization ofnivolumab, a fully human IgG4 (S228P) anti-PD-1 receptor-blocking monoclonal antibody. Nivolumabbinds to PD-1 with high affinity and specificity, and effectively inhibits the interaction between PD-1 andits ligands. In vitro assays demonstrated the ability of nivolumab to potently enhance T-cell responsesand cytokine production in the mixed lymphocyte reaction and superantigen or cytomegalovirusstimulation assays. No in vitro antibody-dependent cell-mediated or complement-dependent cytotoxicitywas observed with the use of nivolumab and activated T cells as targets. Nivolumab treatment did notinduce adverse immune-related events when given to cynomolgus macaques at high concentrations,independent of circulating anti-nivolumab antibodies where observed. These data provide acomprehensive preclinical characterization of nivolumab, for which antitumor activity and safety havebeen demonstrated in human clinical trials in various solid tumors.", "metadata": {}}
+{"_id": "1456068", "title": "", "text": "Combined Impact of Lifestyle-Related Factors on Total and Cause-Specific Mortality among ChineseWomen: Prospective Cohort StudyBACKGROUND Although cigarette smoking, excessive alcohol drinking,obesity, and several other well-studied unhealthy lifestyle-related factors each have been linked to therisk of multiple chronic diseases and premature death, little is known about the combined impact onmortality outcomes, in particular among Chinese and other non-Western populations. The objective ofthis study was to quantify the overall impact of lifestyle-related factors beyond that of active cigarettesmoking and alcohol consumption on all-cause and cause-specific mortality in Chinese women. METHODSAND FINDINGS We used data from the Shanghai Women's Health Study, an ongoing population-basedprospective cohort study in China. Participants included 71,243 women aged 40 to 70 years enrolledduring 1996-2000 who never smoked or drank alcohol regularly. A healthy lifestyle score was created onthe basis of five lifestyle-related factors shown to be independently associated with mortality outcomes(normal weight, lower waist-hip ratio, daily exercise, never exposed to spouse's smoking, higher dailyfruit and vegetable intake). The score ranged from zero (least healthy) to five (most healthy) points.During an average follow-up of 9 years, 2,860 deaths occurred, including 775 from cardiovasculardisease (CVD) and 1,351 from cancer. Adjusted hazard ratios for mortality decreased progressively withan increasing number of healthy lifestyle factors. Compared to women with a score of zero, hazard ratios(95% confidence intervals) for women with four to five factors were 0.57 (0.44-0.74) for total mortality,0.29 (0.16-0.54) for CVD mortality, and 0.76 (0.54-1.06) for cancer mortality. The inverse associationbetween the healthy lifestyle score and mortality was seen consistently regardless of chronic diseasestatus at baseline. The population attributable risks for not having 4-5 healthy lifestyle factors were 33%for total deaths, 59% for CVD deaths, and 19% for cancer deaths. CONCLUSIONS In this first study, toour knowledge, to quantify the combined impact of lifestyle-related factors on mortality outcomes inChinese women, a healthier lifestyle pattern-including being of normal weight, lower central adiposity,participation in physical activity, nonexposure to spousal smoking, and higher fruit and vegetableintake-was associated with reductions in total and cause-specific mortality among lifetime nonsmokingand nondrinking women, supporting the importance of overall lifestyle modification in disease prevention.Please see later in the article for the Editors' Summary.", "metadata": {}}
+{"_id": "1469751", "title": "", "text": "Aptamer-functionalized lipid nanoparticles targeting osteoblasts as a novel RNA interference–based boneanabolic strategyCurrently, major concerns about the safety and efficacy of RNA interference(RNAi)-based bone anabolic strategies still exist because of the lack of direct osteoblast-specific deliverysystems for osteogenic siRNAs. Here we screened the aptamer CH6 by cell-SELEX, specifically targetingboth rat and human osteoblasts, and then we developed CH6 aptamer–functionalized lipid nanoparticles(LNPs) encapsulating osteogenic pleckstrin homology domain-containing family O member 1 (Plekho1)siRNA (CH6-LNPs-siRNA). Our results showed that CH6 facilitated in vitro osteoblast-selective uptake ofPlekho1 siRNA, mainly via macropinocytosis, and boosted in vivo osteoblast-specific Plekho1 genesilencing, which promoted bone formation, improved bone microarchitecture, increased bone mass andenhanced mechanical properties in both osteopenic and healthy rodents. These results indicate thatosteoblast-specific aptamer-functionalized LNPs could act as a new RNAi-based bone anabolic strategy,advancing the targeted delivery selectivity of osteogenic siRNAs from the tissue level to the cellular level.", "metadata": {}}
+{"_id": "1471041", "title": "", "text": "High abundance of plasma cells secreting transglutaminase 2–specific IgA autoantibodies with limitedsomatic hypermutation in celiac disease intestinal lesionsCeliac disease is an immune-mediated disorderin which mucosal autoantibodies to the enzyme transglutaminase 2 (TG2) are generated in response tothe exogenous antigen gluten in individuals who express human leukocyte antigen HLA-DQ2 or HLA-DQ8(ref. 3). We assessed in a comprehensive and nonbiased manner the IgA anti-TG2 response byexpression cloning of the antibody repertoire of ex vivo–isolated intestinal antibody-secreting cells(ASCs). We found that TG2-specific plasma cells are markedly expanded within the duodenal mucosa inindividuals with active celiac disease. TG2-specific antibodies were of high affinity yet showed littleadaptation by somatic mutations. Unlike infection-induced peripheral blood plasmablasts, theTG2-specific ASCs had not recently proliferated and were not short-lived ex vivo. Altogether, theseobservations demonstrate that there is a germline repertoire with high affinity for TG2 that may favormassive generation of autoreactive B cells. TG2-specific antibodies did not block enzymatic activity andserved as substrates for TG2-mediated crosslinking when expressed as IgD or IgM but not as IgA1 orIgG1. This could result in preferential recruitment of plasma cells from naive IgD- and IgM-expressing Bcells, thus possibly explaining why the antibody response to TG2 bears signs of a primary immuneresponse despite the disease chronicity.", "metadata": {}}
+{"_id": "1472815", "title": "", "text": "Alterations of white matter integrity in adults with major depressive disorder: a magnetic resonanceimaging study.OBJECTIVE The purpose of our study was to investigate alterations of white matterintegrity in adults with major depressive disorder (MDD) using magnetic resonance imaging (MRI).METHODS We performed diffusion tensor imaging with a 3T MRI scanner on 45 patients with majordepression and 45 healthy controls matched for age, sex and education. Using a voxel-based analysis, wemeasured the fractional anisotropy (FA), and we investigated the differences between the patient andcontrol groups. We examined the correlations between the microstructure abnormalities of white matterand symptom severity, age of illness onset and cumulative illness duration, respectively. RESULTS Wefound a significant decrease in FA in the left hemisphere, including the anterior limb of the internalcapsule and the inferior parietal portion of the superior longitudinal fasciculus, in patients with MDDcompared with healthy controls. Diffusion tensor imaging measures in the left anterior limb of the internalcapsule were negatively related to the severity of depressive symptoms, even after we controlled for ageand sex. CONCLUSION Our findings provide new evidence of microstructural changes of white matter innon-late-onset adult depression. Our results complement those observed in late-life depression andsupport the hypothesis that the disruption of cortical- subcortical circuit integrity may be involved in theetiology of major depressive disorder.", "metadata": {}}
+{"_id": "1495563", "title": "", "text": "[Clinical study on the therapeutic effect of acupuncture in the treatment of post-strokedepression].OBJECTIVE To observe the therapeutic effect of \"Xingnao Kaiqiao Zhenfa\" (AcupunctureTechnique for Restoring Consciousness) in the treatment of post-stroke depression. METHODS A total of256 stroke patients were divided into acupuncture group (n = 180, male 138, female 42) and medicationgroup (n = 76, male 57 and female 19) according to their visiting sequence to our hospital. Acupointsused were Neiguan (PC 6), Renzhong (GV 26), Baihui (GV 20), Yintang (EX-HN 3) and Sanyinjiao (SP6,the affected side) and the needles were retained for 20 min every time. Patients of medication groupwere asked to take Amitriptyline (50 mg/d at first, 200 mg/d). Acupuncture treatment was conductedtwice daily, and after one month's treatment the therapeutic effect was evaluated. Self-Rating DepressionScale (SDS) and Hamilton Rating Scale for Depression (HRSD) were used to assess the patient's state ofdepression. RESULTS After the treatment, of the 180 and 76 cases in acupuncture and medicationgroups, 31 (17.2%) and 13 (17.1%) were cured, 73 (40.6%) and 18 (23.7%) had a markedimprovement in their depression state, 27 (15.0%) and 12 (15.8%) had an improvement, 49 (27.2%)and 33 (43.4%) failed, with the effective rates being 72.8% and 56.6% respectively. The markedlyeffective rate and the total effective rate of acupuncture group were significantly higher than those ofmedication group (P < 0.05). After the treatment, the total scores of SDS and HRSD and the severityindex of two groups decreased pronouncedly in comparison with those of their individual pre-treatment;and the therapeutic effects of acupuncture group were significantly better than those of medication groupin reducing SDS, HRSD and severity index (P < 0 .05). In addition, the decreased values of depression,pessimistic mood and irritability of acupuncture group were all bigger than those of medication group (P< 0.05). No significant difference was found between two groups in the decreased value of insomnia (P >0.05). CONCLUSION \"Acupuncture Technique for Restoring Consciousness\" can effectively improvedepression patients' symptoms and the therapeutic effect of acupuncture is markedly superior to that ofmedication for post-stroke patients.", "metadata": {}}
+{"_id": "1499964", "title": "", "text": "30 Years of NF-κB: A Blossoming of Relevance to Human PathobiologyNF-κB was discovered 30 years agoas a rapidly inducible transcription factor. Since that time, it has been found to have a broad role in geneinduction in diverse cellular responses, particularly throughout the immune system. Here, we summarizeelaborate regulatory pathways involving this transcription factor and use recent discoveries in humangenetic diseases to place specific proteins within their relevant medical and biological contexts.", "metadata": {}}
+{"_id": "1507222", "title": "", "text": "Increased gene expression of brown fat uncoupling protein (UCP)1 and skeletal muscle UCP2 and UCP3 inMAC16-induced cancer cachexia.Weight loss in cancer cachexia is attributable to decreased food intakeand/or enhanced energy expenditure. We investigated the roles of the uncoupling proteins (UCPs) UCPI,-2, and -3 in a murine model of cachexia, the MAC16 adenocarcinoma. Weight fell to 24% below that ofnon-tumor-bearing controls (P < 0.01) 18 days after MAC16 inoculation, with significant reductions infat-pad mass (-67%; P < 0.01) and muscle mass (-20%; P < 0.01). Food intake was 26-60% lower (P <0.01) than in controls on days 17-18. Non-tumor-bearing mice, pair-fed to match MAC16-inducedhypophagia, showed less weight loss (10% below controls, P < 0.01; 16% above MAC-16, P < 0.01) andsmaller decreases in fat-pad mass (21% below controls, P < 0.01). Core temperature in MAC16 mice wassignificantly lower (-2.4 degrees C, P < 0.01) than in controls, and pair-feeding had no effect. MAC16mice showed significantly higher UCP1 mRNA levels in brown adipose tissue (BAT) than in controls(+63%, P < 0.01), and pair-feeding had no effect. UCP2 and -3 expression in BAT did not differsignificantly between groups. By contrast, UCP2 mRNA levels in skeletal muscle were comparablyincreased in both MAC16 and pair-fed groups (respectively, 183 and 163% above controls; both, P <0.05), with no significant difference between these two groups. Similarly, UCP3 mRNA was significantlyhigher than controls in both MAC16 (+163%, P < 0.05) and pair-fed (+253%, P < 0.01) groups, with nosignificant difference between the two experimental groups. Overexpression of UCP1 in BAT inMAC16-bearing mice may be an adaptive response to hypothermia, which is apparently induced by tumorproducts; increased thermogenesis in BAT could increase total energy expenditure and, thus, contributeto tissue wasting. Increased UCP2 and -3 expression in muscle are both attributable to reduced foodintake and may be involved in lipid utilization during lipolysis in MAC16-induced cachexia.", "metadata": {}}
+{"_id": "1522336", "title": "", "text": "In vitro Anti-Tumor Effects of Statins on Head and Neck Squamous Cell Carcinoma: A SystematicReviewBACKGROUND Statins are commonly used against arteriosclerotic disease, but recentretrospective analyses have suggested that statins also prevent cancer. The aim of this systematic reviewis to verify the vitro anti-tumor effects of statins on head and neck squamous cell carcinoma. METHODSStudies were gathered by searching Cochrane, MEDLINE, EMBASE, LILACS, and PubMed, up until May 9,2015, with no time or language restrictions. Only in vitro studies that discuss the effect of statins on headand neck carcinoma were selected. RESULTS Of 153 identified papers, 14 studies met the inclusioncriteria. These studies demonstrated that statins had a significant effect on head and neck squamous cellcarcinoma cell lines and influenced cell viability, cell cycle, cell death, and protein expression levelsinvolved in pathways of carcinogenesis, which corroborates with the potential in vitro anti-tumor effects.It provides highlights about the biological mechanisms of statins used alone or associated with traditionaltherapy for cancer. CONCLUSIONS Though there are few studies on the topic, currently availableevidence suggests that statins shows that preclinical experiments supports the potentiality of statin as anadjuvant agent in chemotherapy and/or radiotherapy approaches routinely used in the management ofHNSCC and should undergo further clinical assessment.", "metadata": {}}
+{"_id": "1522647", "title": "", "text": "Circulating Mitochondrial DNA in Patients in the ICU as a Marker of Mortality: Derivation andValidationBACKGROUND Mitochondrial DNA (mtDNA) is a critical activator of inflammation and the innateimmune system. However, mtDNA level has not been tested for its role as a biomarker in the intensivecare unit (ICU). We hypothesized that circulating cell-free mtDNA levels would be associated withmortality and improve risk prediction in ICU patients. METHODS AND FINDINGS Analyses of mtDNA levelswere performed on blood samples obtained from two prospective observational cohort studies of ICUpatients (the Brigham and Women's Hospital Registry of Critical Illness [BWH RoCI, n = 200] andMolecular Epidemiology of Acute Respiratory Distress Syndrome [ME ARDS, n = 243]). mtDNA levels inplasma were assessed by measuring the copy number of the NADH dehydrogenase 1 gene usingquantitative real-time PCR. Medical ICU patients with an elevated mtDNA level (≥3,200 copies/µl plasma)had increased odds of dying within 28 d of ICU admission in both the BWH RoCI (odds ratio [OR] 7.5,95% CI 3.6-15.8, p = 1×10(-7)) and ME ARDS (OR 8.4, 95% CI 2.9-24.2, p = 9×10(-5)) cohorts, whileno evidence for association was noted in non-medical ICU patients. The addition of an elevated mtDNAlevel improved the net reclassification index (NRI) of 28-d mortality among medical ICU patients whenadded to clinical models in both the BWH RoCI (NRI 79%, standard error 14%, p<1×10(-4)) and MEARDS (NRI 55%, standard error 20%, p = 0.007) cohorts. In the BWH RoCI cohort, those with anelevated mtDNA level had an increased risk of death, even in analyses limited to patients with sepsis oracute respiratory distress syndrome. Study limitations include the lack of data elucidating the concisepathological roles of mtDNA in the patients, and the limited numbers of measurements for some ofbiomarkers. CONCLUSIONS Increased mtDNA levels are associated with ICU mortality, and inclusion ofmtDNA level improves risk prediction in medical ICU patients. Our data suggest that mtDNA could serveas a viable plasma biomarker in medical ICU patients.", "metadata": {}}
+{"_id": "1538080", "title": "", "text": "Fructosamine Is a Useful Indicator of Hyperglycaemia and Glucose Control in Clinical and EpidemiologicalStudies – Cross-Sectional and Longitudinal Experience from the AMORIS CohortCONTEXT Fructosamine isa glycemic biomarker which may be useful for indication and control of diabetes respectively. OBJECTIVEThe objective of the study was to evaluate fructosamine as an indicator of hyperglycaemia and glucosecontrol in subjects with diabetes. DESIGN, SETTING & PATIENTS From the AMORIS cohort, subjects withserum glucose, fructosamine and HbA1c from the same examination were studied cross-sectionally andlongitudinally (n = 10,987; 5,590 overnight-fasting). The guidelines of the American Diabetes Associationwere followed for classification of prediabetes and diabetes. Separate analyses were performed inpatients with a newly detected or a known diagnosis of type 1 or type 2 diabetes respectively. RESULTSAll three biomarkers were strongly correlated. With regard to the association between fructosamine andHbA1c Pearson linear correlation coefficients in the range of 0.67-0.75 were observed in fasting andnon-fasting subjects with type 1 or type 2 diabetes. Analyses of glucose control in fasting patients withtype 2 diabetes having all three biomarkers measured at three separate occasions within on average 290days of the index examination showed similar trends over time for glucose, fructosamine and HbA1c.Discrimination of subjects with and without diabetes across the range of fructosamine levels was good(area under curve (AUC) 0.91-0.95) and a fructosamine level of 2.5 mmol/L classified subjects todiabetes with a sensitivity of 61% and a specificity of 97%. CONCLUSIONS Fructosamine is closelyassociated with HbA1c and glucose respectively and may be a useful biomarker of hyperglycaemia andglucose control in clinical and epidemiological studies.", "metadata": {}}
+{"_id": "1539159", "title": "", "text": "Lifeact: a versatile marker to visualize F-actinLive imaging of the actin cytoskeleton is crucial for thestudy of many fundamental biological processes, but current approaches to visualize actin have severallimitations. Here we describe Lifeact, a 17-amino-acid peptide, which stained filamentous actin (F-actin)structures in eukaryotic cells and tissues. Lifeact did not interfere with actin dynamics in vitro and in vivoand in its chemically modified peptide form allowed visualization of actin dynamics in nontransfectablecells.", "metadata": {}}
+{"_id": "1542437", "title": "", "text": "Robustness of Random Forest-based gene selection methodsGene selection is an important part ofmicroarray data analysis because it provides information that can lead to a better mechanisticunderstanding of an investigated phenomenon. At the same time, gene selection is very difficult becauseof the noisy nature of microarray data. As a consequence, gene selection is often performed with machinelearning methods. The Random Forest method is particularly well suited for this purpose. In this work,four state-of-the-art Random Forest-based feature selection methods were compared in a gene selectioncontext. The analysis focused on the stability of selection because, although it is necessary fordetermining the significance of results, it is often ignored in similar studies. The comparison ofpost-selection accuracy in the validation of Random Forest classifiers revealed that all investigatedmethods were equivalent in this context. However, the methods substantially differed with respect to thenumber of selected genes and the stability of selection. Of the analysed methods, the Boruta algorithmpredicted the most genes as potentially important. The post-selection classifier error rate, which is afrequently used measure, was found to be a potentially deceptive measure of gene selection quality.When the number of consistently selected genes was considered, the Boruta algorithm was clearly thebest. Although it was also the most computationally intensive method, the Boruta algorithm'scomputational demands could be reduced to levels comparable to those of other algorithms by replacingthe Random Forest importance with a comparable measure from Random Ferns (a similar but simplifiedclassifier). Despite their design assumptions, the minimal optimal selection methods, were found to selecta high fraction of false positives.", "metadata": {}}
+{"_id": "1544804", "title": "", "text": "Improved variant discovery through local re-alignment of short-read next-generation sequencing datausing SRMAA primary component of next-generation sequencing analysis is to align short reads to areference genome, with each read aligned independently. However, reads that observe the samenon-reference DNA sequence are highly correlated and can be used to better model the true variation inthe target genome. A novel short-read micro realigner, SRMA, that leverages this correlation to betterresolve a consensus of the underlying DNA sequence of the targeted genome is described here.", "metadata": {}}
+{"_id": "1546650", "title": "", "text": "Functional elements within the dynein microtubule-binding domainDynein interacts with microtubulesthrough an ATP-sensitive linkage mapped to a structurally complex region of the heavy chain followingthe fourth P-loop motif. Virtually nothing is known regarding how binding affinity is achieved andmodulated during ATP hydrolysis. We have performed a detailed dissection of the microtubule contactsite, using fragment expression, alanine substitution, and peptide competition. Our work identifies threeclusters of amino acids important for the physical contact with microtubules; two of these fall within aregion sharing sequence homology with MAP1B, the third in a region just downstream. Amino acidsubstitutions within any one of these regions can eliminate or weaken microtubule binding (KK3379, 80,E3385, K3387, K3397, KK3410,11, W3414, RKK3418-20, F3426, R3464, S3466, and K3467), suggestingthat their activities are highly coordinated. A peptide that actively displaces MAP1B from microtubulesperturbs dynein binding, supporting previous evidence for similar sites of interaction. We have alsoidentified four amino acids whose substitutions affect release of the motor from the microtubule (E3413,R3444, E3460, and C3469). These suggest that nucleotide-sensitive affinity may be locally controlled atthe site of contact. Our work is the first detailed description of dynein-tubulin interactions and provides aframework for understanding how affinity is achieved and modulated.", "metadata": {}}
+{"_id": "1550937", "title": "", "text": "The Transcription Factors Egr2 and Egr3 Are Essential for the Control of Inflammation andAntigen-Induced Proliferation of B and T CellsLymphocytes provide optimal responses against pathogenswith minimal inflammatory pathology. However, the intrinsic mechanisms regulating these responses areunknown. Here, we report that deletion of both transcription factors Egr2 and Egr3 in lymphocytesresulted in a lethal autoimmune syndrome with excessive serum proinflammatory cytokines but alsoimpaired antigen receptor-induced proliferation of B and T cells. Egr2- and Egr3-defective B and T cellshad hyperactive signal transducer and activator of transcription-1 (STAT1) and STAT3 while antigenreceptor-induced activation of transcription factor AP-1 was severely impaired. We discovered that Egr2and/or Egr3 directly induced expression of suppressor of cytokine signaling-1 (SOCS1) and SOCS3,inhibitors of STAT1 and STAT3, and also blocked the function of Batf, an AP-1 inhibitor, in B and T cells.Thus, Egr2 and Egr3 regulate B and T cell function in adaptive immune responses and homeostasis bypromoting antigen receptor signaling and controlling inflammation.", "metadata": {}}
+{"_id": "1554348", "title": "", "text": "Effect of hyperosmolality on alkaline phosphatase and stress-response protein 27 of MCF-7 breast cancercellsMCF-7, a continuous cell line derived from a human breast carcinoma, exhibits very low alkalinephosphatase (ALP) activity. The enzyme is heat-stable and is inhibited by L-phenylalanine andL-phenylalanylgly-cylglycine, but not by L-homoarginine, 1-bromotetramisole, or levamisole. These dataindicate that MCF-7 produces term-placental ALP, the oncodevelopmental enzyme form inappropriatelyexpressed by a variety of human tumors. In contrast to human cancer cells that produce this enzymemonophenotypically, ALP activity of MCF-7 cells is not significantly increased by glucocorticoids or sodiumbutyrate. By comparison, exposure to hyperosmolality causes a striking increase in enzyme activity.Cycloheximide blocks this effect. The results obtained with cell-free assays were confirmed bycytochemical and immunocytochemical assays on whole cells. Because some of the agents tested in theenzyme modulation experiments affect cell proliferation, their possible effect on two stress-responseproteins (srp 27 and srp 72) was also examined; specific immunocytochemical assays were used. Thesetests revealed that neither protein is affected by glucocorticoids; that sodium butyrate has no effect onsrp 27, but alters the intracellular distribution of srp 72; and that hyperosmolality, while not significantlyaffecting srp 72, causes an increase in srp 27.", "metadata": {}}
+{"_id": "1568684", "title": "", "text": "The Bile Acid Chenodeoxycholic Acid Increases Human Brown Adipose Tissue Activity.The interest inbrown adipose tissue (BAT) as a target to combat metabolic disease has recently been renewed with thediscovery of functional BAT in humans. In rodents, BAT can be activated by bile acids, which activate type2 iodothyronine deiodinase (D2) in BAT via the G-coupled protein receptor TGR5, resulting in increasedoxygen consumption and energy expenditure. Here we examined the effects of oral supplementation ofthe bile acid chenodeoxycholic acid (CDCA) on human BAT activity. Treatment of 12 healthy femalesubjects with CDCA for 2 days resulted in increased BAT activity. Whole-body energy expenditure wasalso increased upon CDCA treatment. In vitro treatment of primary human brown adipocytes derived withCDCA or specific TGR5 agonists increased mitochondrial uncoupling and D2 expression, an effect that wasabsent in human primary white adipocytes. These findings identify bile acids as a target to activate BAT inhumans.", "metadata": {}}
+{"_id": "1569031", "title": "", "text": "RNase H and Postreplication Repair Protect Cells from Ribonucleotides Incorporated in DNAThe chemicalidentity and integrity of the genome is challenged by the incorporation of ribonucleoside triphosphates(rNTPs) in place of deoxyribonucleoside triphosphates (dNTPs) during replication. Misincorporation islimited by the selectivity of DNA replicases. We show that accumulation of ribonucleosidemonophosphates (rNMPs) in the genome causes replication stress and has toxic consequences,particularly in the absence of RNase H1 and RNase H2, which remove rNMPs. We demonstrate thatpostreplication repair (PRR) pathways-MMS2-dependent template switch and Pol ζ-dependent bypass-arecrucial for tolerating the presence of rNMPs in the chromosomes; indeed, we show that Pol ζ efficientlyreplicates over 1-4 rNMPs. Moreover, cells lacking RNase H accumulate mono- and polyubiquitylatedPCNA and have a constitutively activated PRR. Our findings describe a crucial function for RNase H1,RNase H2, template switch, and translesion DNA synthesis in overcoming rNTPs misincorporated duringDNA replication, and may be relevant for the pathogenesis of Aicardi-Goutières syndrome.", "metadata": {}}
+{"_id": "1574014", "title": "", "text": "Selective elimination of high constitutive activity or chemokine binding in the human herpesvirus 8encoded seven transmembrane oncogene ORF74.Open reading frame 74 (ORF74) encoded by humanherpesvirus 8 is a highly constitutively active seven transmembrane (7TM) receptor stimulated byangiogenic chemokines, e.g. growth-related oncogene-alpha, and inhibited by angiostatic chemokinese.g. interferon-gamma-inducible protein. Transgenic mice expressing ORF74 under control of the CD2promoter develop highly vascularized Kaposi's sarcoma-like tumors. Through targeted mutagenesis wehere create three distinct phenotypes of ORF74: a receptor with normal, high constitutive signalingthrough the phospholipase C pathway but deprived of binding and action of chemokines obtained throughdeletion of 22 amino acids from the N-terminal extension; an ORF74 with high constitutive activity butwith selective elimination of stimulatory regulation by angiogenic chemokines obtained throughsubstitution of basic residues at the extracellular ends of TM-V or TM-VI; and an ORF74 lackingconstitutive activity but with preserved ability to be stimulated by agonist chemokines obtained throughintroduction of an Asp residue on the hydrophobic, presumed membrane-exposed face of TM-II. It isconcluded that careful molecular dissection can selectively eliminate either agonist or inverse agonistmodulation as well as high constitutive activity of the virally encoded oncogene ORF74 and that thesemutant forms presumably can be used in transgenic animals to identify the molecular mechanism of itstransforming activity.", "metadata": {}}
+{"_id": "1576955", "title": "", "text": "An insulin-like signaling pathway affects both longevity and reproduction in Caenorhabditiselegans.Mutations in daf-2 and age-1 cause a dramatic increase in longevity as well as developmentalarrest at the dauer diapause stage in Caenorhabditis elegans. daf-2 and age-1 encode components of aninsulin-like signaling pathway. Both daf-2 and age-1 act at a similar point in the genetic epistasispathway for dauer arrest and longevity and regulate the activity of the daf-16 gene. Mutations in daf-16cause a dauer-defective phenotype and are epistatic to the diapause arrest and life span extensionphenotypes of daf-2 and age-1 mutants. Here we show that mutations in this pathway also affect fertilityand embryonic development. Weak daf-2 alleles, and maternally rescued age-1 alleles that cause lifespan extension but do not arrest at the dauer stage, also reduce fertility and viability. We find thatage-1(hx546) has reduced both maternal and zygotic age-1 activity. daf-16 mutations suppress all of thedaf-2 and age-1 phenotypes, including dauer arrest, life span extension, reduced fertility, and viabilitydefects. These data show that insulin signaling, mediated by DAF-2 through the AGE-1phosphatidylinositol-3-OH kinase, regulates reproduction and embryonic development, as well as dauerdiapause and life span, and that DAF-16 transduces these signals. The regulation of fertility, life span,and metabolism by an insulin-like signaling pathway is similar to the endocrine regulation of metabolismand fertility by mammalian insulin signaling.", "metadata": {}}
+{"_id": "1583041", "title": "", "text": "Estimating prion concentration in fluids and tissues by quantitative PMCAPrions, the proteinaceousinfectious agent responsible for prion diseases, can be detected with high sensitivity by protein misfoldingcyclic amplification (PMCA) technology. Here we describe a quantitative PMCA procedure to calculate theconcentration of very low levels of prions in biological samples. Using this procedure, we determined thequantities of misfolded prion protein (PrPSc) in brain, spleen, blood and urine of scrapie-affectedhamsters.", "metadata": {}}
+{"_id": "1583134", "title": "", "text": "Positional cloning of the APECED geneAutoimmune polyglandular syndrome type I (APS 1, also calledAPECED) is an autosomal-recessive disorder that maps to human chromosome 21q22.3 between markersD21S49 and D21S171 by linkage studies. We have isolated a novel gene from this region, AIRE(autoimmune regulator), which encodes a protein containing motifs suggestive of a transcription factorincluding two zinc-finger (PHD-finger) motifs, a proline-rich region and three LXXLL motifs. Twomutations, a C\u0000T substitution that changes the Arg 257 (CGA) to a stop codon (TGA) and an A\u0000Gsubstitution that changes the Lys 83 (AAG) to a Glu codon (GAG), were found in this novel gene in Swissand Finnish APECED patients. The Arg257stop (R257X) is the predominant mutation in Finnish APECEDpatients, accounting for 10/12 alleles studied. These results indicate that this gene is responsible for thepathogenesis of APECED. The identification of the gene defective in APECED should facilitate the geneticdiagnosis and potential treatment of the disease and further enhance our general understanding of themechanisms underlying autoimmune diseases.", "metadata": {}}
+{"_id": "1590744", "title": "", "text": "AMP-Activated Protein Kinase: An Ubiquitous Signaling Pathway With Key Roles in the CardiovascularSystemThe AMP-activated protein kinase (AMPK) is a key regulator of cellular and whole-body energyhomeostasis, which acts to restore energy homoeostasis whenever cellular energy charge is depleted.Over the last 2 decades, it has become apparent that AMPK regulates several other cellular functions andhas specific roles in cardiovascular tissues, acting to regulate cardiac metabolism and contractile function,as well as promoting anticontractile, anti-inflammatory, and antiatherogenic actions in blood vessels. Inthis review, we discuss the role of AMPK in the cardiovascular system, including the molecular basis ofmutations in AMPK that alter cardiac physiology and the proposed mechanisms by which AMPK regulatesvascular function under physiological and pathophysiological conditions.", "metadata": {}}
+{"_id": "1595617", "title": "", "text": "Differentiation of trophoblast stem cells into giant cells is triggered by p57/Kip2 inhibition of CDK1activity.Genome endoreduplication during mammalian development is a rare event for which themechanism is unknown. It first appears when fibroblast growth factor 4 (FGF4) deprivation inducesdifferentiation of trophoblast stem (TS) cells into the nonproliferating trophoblast giant (TG) cells requiredfor embryo implantation. Here we show that RO3306 inhibition of cyclin-dependent protein kinase 1(CDK1), the enzyme required to enter mitosis, induced differentiation of TS cells into TG cells. Incontrast, RO3306 induced abortive endoreduplication and apoptosis in embryonic stem cells, revealingthat inactivation of CDK1 triggers endoreduplication only in cells programmed to differentiate intopolyploid cells. Similarly, FGF4 deprivation resulted in CDK1 inhibition by overexpressing twoCDK-specific inhibitors, p57/KIP2 and p21/CIP1. TS cell mutants revealed that p57 was required totrigger endoreduplication by inhibiting CDK1, while p21 suppressed expression of the checkpoint proteinkinase CHK1, thereby preventing induction of apoptosis. Furthermore, Cdk2(-/-) TS cells revealed thatCDK2 is required for endoreduplication when CDK1 is inhibited. Expression of p57 in TG cells wasrestricted to G-phase nuclei to allow CDK activation of S phase. Thus, endoreduplication in TS cells istriggered by p57 inhibition of CDK1 with concomitant suppression of the DNA damage response by p21.", "metadata": {}}
+{"_id": "1605196", "title": "", "text": "Atg5-independent autophagy regulates mitochondrial clearance and is essential for iPSCreprogrammingSuccessful generation of induced pluripotent stem cells entails a major metabolic switchfrom mitochondrial oxidative phosphorylation to glycolysis during the reprogramming process. Themechanism of this metabolic reprogramming, however, remains elusive. Here, our results suggest that anAtg5-independent autophagic process mediates mitochondrial clearance, a characteristic event involvedin the metabolic switch. We found that blocking such autophagy, but not canonical autophagy, inhibitsmitochondrial clearance, in turn, preventing iPSC induction. Furthermore, AMPK seems to be upstream ofthis autophagic pathway and can be targeted by small molecules to modulate mitochondrial clearanceduring metabolic reprogramming. Our work not only reveals that the Atg5-independent autophagy iscrucial for establishing pluripotency, but it also suggests that iPSC generation and tumorigenesis share asimilar metabolic switch.", "metadata": {}}
+{"_id": "1605392", "title": "", "text": "A mutation in Orai1 causes immune deficiency by abrogating CRAC channel functionAntigen stimulation ofimmune cells triggers Ca2+ entry through Ca2+ release-activated Ca2+ (CRAC) channels, promoting theimmune response to pathogens by activating the transcription factor NFAT. We have previously shownthat cells from patients with one form of hereditary severe combined immune deficiency (SCID)syndrome are defective in store-operated Ca2+ entry and CRAC channel function. Here we identify thegenetic defect in these patients, using a combination of two unbiased genome-wide approaches: amodified linkage analysis with single-nucleotide polymorphism arrays, and a Drosophila RNA interferencescreen designed to identify regulators of store-operated Ca2+ entry and NFAT nuclear import. Bothapproaches converged on a novel protein that we call Orai1, which contains four putative transmembranesegments. The SCID patients are homozygous for a single missense mutation in ORAI1, and expressionof wild-type Orai1 in SCID T cells restores store-operated Ca2+ influx and the CRAC current (ICRAC). Wepropose that Orai1 is an essential component or regulator of the CRAC channel complex.", "metadata": {}}
+{"_id": "1606628", "title": "", "text": "Estimates of global prevalence of childhood underweight in 1990 and 2015.CONTEXT One key target ofthe United Nations Millennium Development goals is to reduce the prevalence of underweight amongchildren younger than 5 years by half between 1990 and 2015. OBJECTIVE To estimate trends inchildhood underweight by geographic regions of the world. DESIGN, SETTING, AND PARTICIPANTS Timeseries study of prevalence of underweight, defined as weight 2 SDs below the mean weight for age of theNational Center for Health Statistics and World Health Organization (WHO) reference population. Nationalprevalence rates derived from the WHO Global Database on Child Growth and Malnutrition, which includesdata on approximately 31 million children younger than 5 years who participated in 419 nationalnutritional surveys in 139 countries from 1965 through 2002. MAIN OUTCOME MEASURES Linearmixed-effects modeling was used to estimate prevalence rates and numbers of underweight children byregion in 1990 and 2015 and to calculate the changes (ie, increase or decrease) to these values between1990 and 2015. RESULTS Worldwide, underweight prevalence was projected to decline from 26.5% in1990 to 17.6% in 2015, a change of -34% (95% confidence interval [CI], -43% to -23%). In developedcountries, the prevalence was estimated to decrease from 1.6% to 0.9%, a change of -41% (95% CI,-92% to 343%). In developing regions, the prevalence was forecasted to decline from 30.2% to 19.3%, achange of -36% (95% CI, -45% to -26%). In Africa, the prevalence of underweight was forecasted toincrease from 24.0% to 26.8%, a change of 12% (95% CI, 8%-16%). In Asia, the prevalence wasestimated to decrease from 35.1% to 18.5%, a change of -47% (95% CI, -58% to -34%). Worldwide,the number of underweight children was projected to decline from 163.8 million in 1990 to 113.4 millionin 2015, a change of -31% (95% CI, -40% to -20%). Numbers are projected to decrease in allsubregions except the subregions of sub-Saharan, Eastern, Middle, and Western Africa, which areexpected to experience substantial increases in the number of underweight children. CONCLUSIONS Anoverall improvement in the global situation is anticipated; however, neither the world as a whole, nor thedeveloping regions, are expected to achieve the Millennium Development goals. This is largely due to thedeteriorating situation in Africa where all subregions, except Northern Africa, are expected to fail to meetthe goal.", "metadata": {}}
+{"_id": "1616661", "title": "", "text": "Canonical Wnt signaling regulates organ-specific assembly and differentiation of CNS vasculature.Everyorgan depends on blood vessels for oxygen and nutrients, but the vasculature associated with individualorgans can be structurally and molecularly diverse. The central nervous system (CNS) vasculatureconsists of a tightly sealed endothelium that forms the blood-brain barrier, whereas blood vessels ofother organs are more porous. Wnt7a and Wnt7b encode two Wnt ligands produced by theneuroepithelium of the developing CNS coincident with vascular invasion. Using genetic mouse models,we found that these ligands directly target the vascular endothelium and that the CNS uses the canonicalWnt signaling pathway to promote formation and CNS-specific differentiation of the organ's vasculature.", "metadata": {}}
+{"_id": "1617327", "title": "", "text": "Bone progenitor dysfunction induces myelodysplasia and secondary leukemiaMesenchymal cellscontribute to the 'stroma' of most normal and malignant tissues, with specific mesenchymal cellsparticipating in the regulatory niches of stem cells. By examining how mesenchymal osteolineage cellsmodulate haematopoiesis, here we show that deletion of Dicer1 specifically in mouse osteoprogenitors,but not in mature osteoblasts, disrupts the integrity of haematopoiesis. Myelodysplasia resulted andacute myelogenous leukaemia emerged that had acquired several genetic abnormalities while havingintact Dicer1. Examining gene expression altered in osteoprogenitors as a result of Dicer1 deletionshowed reduced expression of Sbds, the gene mutated in Schwachman-Bodian-Diamond syndrome-ahuman bone marrow failure and leukaemia pre-disposition condition. Deletion of Sbds in mouseosteoprogenitors induced bone marrow dysfunction with myelodysplasia. Therefore, perturbation ofspecific mesenchymal subsets of stromal cells can disorder differentiation, proliferation and apoptosis ofheterologous cells, and disrupt tissue homeostasis. Furthermore, primary stromal dysfunction can resultin secondary neoplastic disease, supporting the concept of niche-induced oncogenesis.", "metadata": {}}
+{"_id": "1624106", "title": "", "text": "Generating diploid embryos from Xenopus tropicalis.A spectacular advantage of Xenopus tropicalis is theease with which diploid embryos can be generated year round. By the simple administration of humanchorionic gonadotropin, an investigator can generate many hundreds of synchronized embryos by in vitrofertilization or thousands of embryos from a mating pair. The ability to induce ovulations when desiredfacilitates many different experiments such as experimental embryology, molecular manipulation of geneproducts, and genetics.", "metadata": {}}
+{"_id": "1630949", "title": "", "text": "Oct4-Induced Pluripotency in Adult Neural Stem CellsThe four transcription factors Oct4, Sox2, Klf4, andc-Myc can induce pluripotency in mouse and human fibroblasts. We previously described directreprogramming of adult mouse neural stem cells (NSCs) by Oct4 and either Klf4 or c-Myc. NSCsendogenously express Sox2, c-Myc, and Klf4 as well as several intermediate reprogramming markers.Here we report that exogenous expression of the germline-specific transcription factor Oct4 is sufficientto generate pluripotent stem cells from adult mouse NSCs. These one-factor induced pluripotent stemcells (1F iPS) are similar to embryonic stem cells in vitro and in vivo. Not only can these cells can beefficiently differentiated into NSCs, cardiomyocytes, and germ cells in vitro, but they are also capable ofteratoma formation and germline transmission in vivo. Our results demonstrate that Oct4 is required andsufficient to directly reprogram NSCs to pluripotency.", "metadata": {}}
+{"_id": "1631583", "title": "", "text": "Getting started with yeast.Publisher Summary The yeast Saccharomyces cerevisiae is now recognized asa model system representing a simple eukaryote whose genome can be easily manipulated. Yeast hasonly a slightly greater genetic complexity than bacteria and shares many of the technical advantages thatpermitted rapid progress in the molecular genetics of prokaryotes and their viruses. Some of theproperties that make yeast particularly suitable for biological studies include rapid growth, dispersedcells, the ease of replica plating and mutant isolation, a well-defined genetic system, and most important,a highly versatile DNA transformation system. Being nonpathogenic, yeast can be handled with littleprecautions. Large quantities of normal baker's yeast are commercially available and can provide a cheapsource for biochemical studies. The development of DNA transformation has made yeast particularlyaccessible to gene cloning and genetic engineering techniques. Structural genes corresponding tovirtually any genetic trait can be identified by complementation from plasmid libraries. Plasmids can beintroduced into yeast cells either as replicating molecules or by integration into the genome. In contrastto most other organisms, integrative recombination of transforming DNA in yeast proceeds exclusively viahomologous recombination. Cloned yeast sequences, accompanied by foreign sequences on plasmids, cantherefore be directed at will to specific locations in the genome.", "metadata": {}}
+{"_id": "1635872", "title": "", "text": "PCNA functions as a molecular platform to trigger Cdt1 destruction and preventre-replicationUbiquitin-mediated proteolysis of the replication licensing factor Cdt1 (Cdc10-dependenttranscript 1) in S phase is a key mechanism that limits DNA replication to a single round per cell cycle inmetazoans. In Xenopus egg extracts, Cdt1 is destroyed on chromatin during DNA replication. Here, wereport that replication-dependent proteolysis of Cdt1 requires its interaction with proliferating cell nuclearantigen (PCNA), a homotrimeric processivity factor for DNA polymerases. Cdt1 binds to PCNA through aconsensus PCNA-interaction motif that is conserved in Cdt1 of all metazoans, and removal of PCNA fromegg extracts inhibits replication-dependent Cdt1 destruction. Mutation of the PCNA-interaction motifyields a stabilized Cdt1 protein that induces re-replication. DDB1, a component of the Cul4 E3 ubiquitinligase that mediates human Cdt1 proteolysis in response to DNA damage, is also required forreplication-dependent Cdt1 destruction. Cdt1 and DDB1 interact in extracts, and DDB1 chromatin loadingis dependent on the binding of Cdt1 to PCNA, which indicates that PCNA docking activates the pre-formedCdt1–Cul4DDB1 ligase complex. Thus, PCNA functions as a platform for Cdt1 destruction, ensuringefficient and temporally restricted inactivation of a key cell-cycle regulator.", "metadata": {}}
+{"_id": "1641873", "title": "", "text": "Meiosis in Drosophila: seeing is believing.Recently many exciting advances have been achieved in ourunderstanding of Drosophila meiosis due to combined cytological and genetic approaches. Newtechniques have permitted the characterization of chromosome position and spindle formation in femalemeiosis I. The proteins encoded by the nod and ncd genes, two genes known to be needed for the properpartitioning of chromosomes lacking exchange events, have been identified and found to be kinesin-likemotors. The effects of mutations in these genes on the spindle and chromosomes, together with thelocalization of the proteins, have yielded a model for the mechanism of female meiosis I. In male meiosisI, the chromosomal regions responsible for homolog pairing have been resolved to the level of specificDNA sequences. This provides a foundation for elucidating the molecular basis of meiotic pairing. Thecytological techniques available in Drosophila also have permitted inroads into the regulation ofsister-chromatid segregation. The products of two genes (mei-S332 and ord) essential forsister-chromatid cohesion have been identified recently. Additional advances in understanding Drosophilameiosis are the delineation of a functional centromere by using minichromosome derivatives and theidentification of several regulatory genes for the meiotic cell cycle.", "metadata": {}}
+{"_id": "1642727", "title": "", "text": "Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease: a randomizedtrial.CONTEXT Many observational studies have shown that physical activity reduces the risk of cognitivedecline; however, evidence from randomized trials is lacking. OBJECTIVE To determine whether physicalactivity reduces the rate of cognitive decline among older adults at risk. DESIGN AND SETTINGRandomized controlled trial of a 24-week physical activity intervention conducted between 2004 and2007 in metropolitan Perth, Western Australia. Assessors of cognitive function were blinded to groupmembership. PARTICIPANTS We recruited volunteers who reported memory problems but did not meetcriteria for dementia. Three hundred eleven individuals aged 50 years or older were screened foreligibility, 89 were not eligible, and 52 refused to participate. A total of 170 participants were randomizedand 138 participants completed the 18-month assessment. INTERVENTION Participants were randomlyallocated to an education and usual care group or to a 24-week home-based program of physical activity.MAIN OUTCOME MEASURE Change in Alzheimer Disease Assessment Scale-Cognitive Subscale(ADAS-Cog) scores (possible range, 0-70) over 18 months. RESULTS In an intent-to-treat analysis,participants in the intervention group improved 0.26 points (95% confidence interval, -0.89 to 0.54) andthose in the usual care group deteriorated 1.04 points (95% confidence interval, 0.32 to 1.82) on theADAS-Cog at the end of the intervention. The absolute difference of the outcome measure between theintervention and control groups was -1.3 points (95% confidence interval,-2.38 to -0.22) at the end ofthe intervention. At 18 months, participants in the intervention group improved 0.73 points (95%confidence interval, -1.27 to 0.03) on the ADAS-Cog, and those in the usual care group improved 0.04points (95% confidence interval, -0.46 to 0.88). Word list delayed recall and Clinical Dementia Ratingsum of boxes improved modestly as well, whereas word list total immediate recall, digit symbol coding,verbal fluency, Beck depression score, and Medical Outcomes 36-Item Short-Form physical and mentalcomponent summaries did not change significantly. CONCLUSIONS In this study of adults with subjectivememory impairment, a 6-month program of physical activity provided a modest improvement in cognitionover an 18-month follow-up period. TRIAL REGISTRATION anzctr.org.au Identifier:ACTRN12605000136606.", "metadata": {}}
+{"_id": "1649738", "title": "", "text": "Variants at 6q21 implicate PRDM1 in the etiology of therapy-induced second malignancies after Hodgkin'slymphomaSurvivors of pediatric Hodgkin's lymphoma are at risk for radiation therapy–induced secondmalignant neoplasms (SMNs). We identified two variants at chromosome 6q21 associated with SMNs insurvivors of Hodgkin's lymphoma treated with radiation therapy as children but not as adults. Thevariants comprise a risk locus associated with decreased basal expression of PRDM1 (encoding PR domaincontaining 1, with ZNF domain) and impaired induction of the PRDM1 protein after radiation exposure.These data suggest a new gene-exposure interaction that may implicate PRDM1 in the etiology ofradiation therapy-induced SMNs.", "metadata": {}}
+{"_id": "1667063", "title": "", "text": "Long non-coding RNA profiling of human lymphoid progenitor cells reveals transcriptional divergence of Bcell and T cell lineagesTo elucidate the transcriptional 'landscape' that regulates human lymphoidcommitment during postnatal life, we used RNA sequencing to assemble the long non-codingtranscriptome across human bone marrow and thymic progenitor cells spanning the earliest stages of Blymphoid and T lymphoid specification. Over 3,000 genes encoding previously unknown long non-codingRNAs (lncRNAs) were revealed through the analysis of these rare populations. Lymphoid commitmentwas characterized by lncRNA expression patterns that were highly stage specific and were more lineagespecific than those of protein-coding genes. Protein-coding genes co-expressed with neighboring lncRNAgenes showed enrichment for ontologies related to lymphoid differentiation. The exquisite cell-typespecificity of global lncRNA expression patterns independently revealed new developmental relationshipsamong the earliest progenitor cells in the human bone marrow and thymus.", "metadata": {}}
+{"_id": "1669173", "title": "", "text": "The VTI family of SNARE proteins is necessary for plant viability and mediates different protein transportpathways.The Arabidopsis genome contains a family of v-SNAREs: VTI11, VTI12, and VTI13. Only VTI11and VTI12 are expressed at appreciable levels. Although these two proteins are 60% identical, theycomplement different transport pathways when expressed in the yeast vti1 mutant. VTI11 was identifiedrecently as the mutated gene in the shoot gravitropic mutant zig. Here, we show that the vti11 zigmutant has defects in vascular patterning and auxin transport. An Arabidopsis T-DNA insertion mutant,vti12, had a normal phenotype under nutrient-rich growth conditions. However, under nutrient-poorconditions, vti12 showed an accelerated senescence phenotype, suggesting that VTI12 may play a role inthe plant autophagy pathway. VTI11 and VTI12 also were able to substitute for each other in theirrespective SNARE complexes, and a double-mutant cross between zig and vti12 was embryo lethal.These results suggest that some VTI1 protein was necessary for plant viability and that the two proteinswere partially functionally redundant.", "metadata": {}}
+{"_id": "1676568", "title": "", "text": "CLASPs link focal adhesion-associated microtubule capture to localized exocytosis and adhesion siteturnoverTurnover of integrin-based focal adhesions (FAs) with the extracellular matrix (ECM) is essentialfor coordinated cell movement. In collectively migrating human keratinocytes, FAs assemble near theleading edge, grow and mature as a result of contractile forces and disassemble underneath theadvancing cell body. We report that clustering of microtubule-associated CLASP1 and CLASP2 proteinsaround FAs temporally correlates with FA turnover. CLASPs and LL5β (also known as PHLDB2), whichrecruits CLASPs to FAs, facilitate FA disassembly. CLASPs are further required for FA-associated ECMdegradation, and matrix metalloprotease inhibition slows FA disassembly similarly to CLASP or PHLDB2(LL5β) depletion. Finally, CLASP-mediated microtubule tethering at FAs establishes an FA-directedtransport pathway for delivery, docking and localized fusion of exocytic vesicles near FAs. We proposethat CLASPs couple microtubule organization, vesicle transport and cell interactions with the ECM,establishing a local secretion pathway that facilitates FA turnover by severing cell-matrix connections.", "metadata": {}}
+{"_id": "1684489", "title": "", "text": "CHD4 Is a RanGTP-Dependent MAP that Stabilizes Microtubules and Regulates Bipolar SpindleFormationBACKGROUND Production of the GTP-bound form of the Ran GTPase (RanGTP) aroundchromosomes induces spindle assembly by activating nuclear localization signal (NLS)-containingproteins. Several NLS proteins have been identified as spindle assembly factors, but the complexity of theprocess led us to search for additional proteins with distinct roles in spindle assembly. RESULTS Weidentify a chromatin-remodeling ATPase, CHD4, as a RanGTP-dependent microtubule (MT)-associatedprotein (MAP). MT binding occurs via the region containing an NLS and chromatin-binding domains. InXenopus egg extracts and cultured cells, CHD4 largely dissociates from mitotic chromosomes andpartially localizes to the spindle. Immunodepletion of CHD4 from egg extracts significantly reduces thequantity of MTs produced around chromatin and prevents spindle assembly. CHD4 RNAi in both HeLa andDrosophila S2 cells induces defects in spindle assembly and chromosome alignment in early mitosis,leading to chromosome missegregation. Further analysis in egg extracts and in HeLa cells reveals thatCHD4 is a RanGTP-dependent MT stabilizer. Moreover, the CHD4-containing NuRD complex promotesorganization of MTs into bipolar spindles in egg extracts. Importantly, this function of CHD4 isindependent of chromatin remodeling. CONCLUSIONS Our results uncover a new role for CHD4 as a MAPrequired for MT stabilization and involved in generating spindle bipolarity.", "metadata": {}}
+{"_id": "1686881", "title": "", "text": "Myocardial muscarinic receptor upregulation and normal response to isoproterenol in denervated heartsby familial amyloid polyneuropathy.BACKGROUND Patients with familial amyloid polyneuropathy, a rarehereditary form of amyloidosis, have progressive autonomic neuropathy. The disease usually does notinduce heart failure but is associated with sudden death, conduction disturbances, and an increased riskof complications during anesthesia. Although cardiac sympathetic denervation has been clearlydemonstrated, the postsynaptic status of the cardiac autonomic nervous system remains unelucidated.METHODS AND RESULTS Twenty-one patients were studied (age, 39+/-11 years; normal coronaryarteries; left ventricular ejection fraction 68+/-9%). To evaluate the density and affinity constants ofmyocardial muscarinic receptors, PET with (11)C-MQNB (methylquinuclidinyl benzilate), a specifichydrophilic antagonist, was used. Cardiac beta-receptor functional efficiency was studied by the heartrate (HR) response to intravenous infusion of isoproterenol (5 minutes after 2 mg of atropine, 5, 10, and15 ng/kg per minute during 5 minutes per step). The mean muscarinic receptor density was higher inpatients than in control subjects (B'(max), 35.5+/-8.9 versus 26.1+/-6.7 pmol/mL, P=0.003), withoutchange in receptor affinity. The increase in HR after injection of atropine as well as of MQNB was lower inpatients compared with control subjects despite a similar basal HR (DeltaHR after atropine, 11+/-21%versus 62+/-17%; P<0.001), consistent with parasympathetic denervation. Incremental infusion ofisoproterenol induced a similar increase in HR in patients and control subjects. CONCLUSIONS Cardiacautonomic denervation in familial amyloid polyneuropathy results in an upregulation of myocardialmuscarinic receptors but without change in cardiac beta-receptor responsiveness to catecholamines.", "metadata": {}}
+{"_id": "1686997", "title": "", "text": "6-phosphogluconate dehydrogenase links oxidative PPP, lipogenesis and tumor growth by inhibitingLKB1-AMPK signalingThe oxidative pentose phosphate pathway (PPP) contributes to tumour growth, butthe precise contribution of 6-phosphogluconate dehydrogenase (6PGD), the third enzyme in thispathway, to tumorigenesis remains unclear. We found that suppression of 6PGD decreased lipogenesisand RNA biosynthesis and elevated ROS levels in cancer cells, attenuating cell proliferation and tumourgrowth. 6PGD-mediated production of ribulose-5-phosphate (Ru-5-P) inhibits AMPK activation bydisrupting the active LKB1 complex, thereby activating acetyl-CoA carboxylase 1 and lipogenesis. Ru-5-Pand NADPH are thought to be precursors in RNA biosynthesis and lipogenesis, respectively; thus, ourfindings provide an additional link between the oxidative PPP and lipogenesis through Ru-5-P-dependentinhibition of LKB1-AMPK signalling. Moreover, we identified and developed 6PGD inhibitors, physcion andits derivative S3, that effectively inhibited 6PGD, cancer cell proliferation and tumour growth in nude micexenografts without obvious toxicity, suggesting that 6PGD could be an anticancer target.", "metadata": {}}
+{"_id": "1695604", "title": "", "text": "Plant Nuclear RNA Polymerase IV Mediates siRNA and DNA Methylation-Dependent HeterochromatinFormationAll eukaryotes have three nuclear DNA-dependent RNA polymerases, namely, Pol I, II, and III.Interestingly, plants have catalytic subunits for a fourth nuclear polymerase, Pol IV. Genetic andbiochemical evidence indicates that Pol IV does not functionally overlap with Pol I, II, or III and isnonessential for viability. However, disruption of the Pol IV catalytic subunit genes NRPD1 or NRPD2inhibits heterochromatin association into chromocenters, coincident with losses in cytosine methylation atpericentromeric 5S gene clusters and AtSN1 retroelements. Loss of CG, CNG, and CNN methylation in PolIV mutants implicates a partnership between Pol IV and the methyltransferase responsible forRNA-directed de novo methylation. Consistent with this hypothesis, 5S gene and AtSN1 siRNAs areessentially eliminated in Pol IV mutants. The data suggest that Pol IV helps produce siRNAs that target denovo cytosine methylation events required for facultative heterochromatin formation and higher-orderheterochromatin associations.", "metadata": {}}
+{"_id": "1701063", "title": "", "text": "Sema3A regulates bone-mass accrual through sensory innervationsSemaphorin 3A (Sema3A) is adiffusible axonal chemorepellent that has an important role in axon guidance. Previous studies havedemonstrated that Sema3a−/− mice have multiple developmental defects due to abnormal neuronalinnervations. Here we show in mice that Sema3A is abundantly expressed in bone, and cell-based assaysshowed that Sema3A affected osteoblast differentiation in a cell-autonomous fashion. Accordingly,Sema3a−/− mice had a low bone mass due to decreased bone formation. However, osteoblast-specificSema3A-deficient mice (Sema3acol1−/− and Sema3aosx−/− mice) had normal bone mass, even thoughthe expression of Sema3A in bone was substantially decreased. In contrast, mice lacking Sema3A inneurons (Sema3asynapsin−/− and Sema3anestin−/− mice) had low bone mass, similar to Sema3a−/−mice, indicating that neuron-derived Sema3A is responsible for the observed bone abnormalitiesindependent of the local effect of Sema3A in bone. Indeed, the number of sensory innervations oftrabecular bone was significantly decreased in Sema3asynapsin−/− mice, whereas sympatheticinnervations of trabecular bone were unchanged. Moreover, ablating sensory nerves decreased bonemass in wild-type mice, whereas it did not reduce the low bone mass in Sema3anestin−/− mice further,supporting the essential role of the sensory nervous system in normal bone homeostasis. Finally,neuronal abnormalities in Sema3a−/− mice, such as olfactory development, were identified inSema3asynasin−/− mice, demonstrating that neuron-derived Sema3A contributes to the abnormalneural development seen in Sema3a−/− mice, and indicating that Sema3A produced in neuronsregulates neural development in an autocrine manner. This study demonstrates that Sema3A regulatesbone remodelling indirectly by modulating sensory nerve development, but not directly by acting onosteoblasts.", "metadata": {}}
+{"_id": "1709625", "title": "", "text": "Direct lineage reprogramming: strategies, mechanisms, and applications.The direct lineagereprogramming of one specialized cell type into another using defined factors has fundamentallyre-shaped traditional concepts regarding the epigenetic stability of differentiated cells. With the rapidincrease in cell types generated through direct conversion in recent years, this strategy has become apromising approach for producing functional cells. Here, we review recent advances in lineagereprogramming, including the identification of novel reprogramming factors, underlying molecularmechanisms, strategies for generating functionally mature cells, and assays for characterizing inducedcells. We also discuss progress toward the application of lineage reprogramming and the major futurechallenges for this strategy.", "metadata": {}}
+{"_id": "1710116", "title": "", "text": "Converging Intracranial Markers of Conscious AccessWe compared conscious and nonconsciousprocessing of briefly flashed words using a visual masking procedure while recording intracranialelectroencephalogram (iEEG) in ten patients. Nonconscious processing of masked words was observed inmultiple cortical areas, mostly within an early time window (<300 ms), accompanied by inducedgamma-band activity, but without coherent long-distance neural activity, suggesting a quickly dissipatingfeedforward wave. In contrast, conscious processing of unmasked words was characterized by theconvergence of four distinct neurophysiological markers: sustained voltage changes, particularly inprefrontal cortex, large increases in spectral power in the gamma band, increases in long-distance phasesynchrony in the beta range, and increases in long-range Granger causality. We argue that all of thosemeasures provide distinct windows into the same distributed state of conscious processing. These resultshave a direct impact on current theoretical discussions concerning the neural correlates of consciousaccess.", "metadata": {}}
+{"_id": "1711571", "title": "", "text": "Hyperglycemia is associated with increased bone mineral density and decreased trabecular bone score inelderly Japanese men: The Fujiwara-kyo osteoporosis risk in men (FORMEN) study.PURPOSE Patientswith type 2 diabetes mellitus (T2DM) have an increased fracture risk despite having higher areal bonemineral density (aBMD). This study aimed to clarify the association between glycemic and insulinresistance status and bone microarchitecture, and whether pentosidine and bone turnover markers playany roles in the association. METHODS A total of 2012 community-dwelling men aged ≥65yearscompleted baseline measurements of spine aBMD, fasting plasma glucose (FPG) and serum insulin,hemoglobin A1c (HbA1c), osteocalcin, type I procollagen N-terminal propeptide, type I collagenC-terminal crosslinking telopeptide, tartrate-resistant acid phosphatase isoenzyme 5b, pentosidine,height and weight and an interview regarding past disease history. Homeostasis modelassessment-insulin resistance (HOMA-IR) was also calculated. T2DM was defined as physician-diagnosedmiddle age or elderly-onset diabetes mellitus, or according to biochemical test results. To evaluate bonemicroarchitecture, trabecular bone score (TBS) was calculated at the same vertebrae as those used foraBMD measurement. RESULTS After excluding participants who had a disease history and/or were takingmedications affecting bone metabolism, 1683 men (age, 72.9±5.2years) were analyzed. Men with T2DMhad significantly higher aBMD compared to those without T2DM. There was no significant difference inTBS. However, FPG, HbA1c and HOMA-IR levels were significantly inversely correlated with TBS afteradjusting for age, BMI and aBMD. Multivariate linear regression analyses revealed that glycemic indices(FPG and HbA1c) were significantly associated with increased aBMD and decreased TBS, and thatHOMA-IR was associated only with TBS. These associations did not change after further adjusting forbone turnover makers and pentosidine levels. CONCLUSIONS Hyperglycemia and elevatedinsulin-resistance were associated with low TBS independently of bone turnover and pentosidine levels.", "metadata": {}}
+{"_id": "1727042", "title": "", "text": "Matrix Remodeling Promotes Pulmonary Hypertension through Feedback Mechanoactivation of theYAP/TAZ-miR-130/301 Circuit.Pulmonary hypertension (PH) is a deadly vascular disease with enigmaticmolecular origins. We found that vascular extracellular matrix (ECM) remodeling and stiffening are earlyand pervasive processes that promote PH. In multiple pulmonary vascular cell types, such ECM stiffeninginduced the microRNA-130/301 family via activation of the co-transcription factors YAP and TAZ.MicroRNA-130/301 controlled a PPAR?-APOE-LRP8 axis, promoting collagen deposition andLOX-dependent remodeling and further upregulating YAP/TAZ via a mechanoactive feedback loop. Inturn, ECM remodeling controlled pulmonary vascular cell crosstalk via such mechanotransduction,modulation of secreted vasoactive effectors, and regulation of associated microRNA pathways. In vivo,pharmacologic inhibition of microRNA-130/301, APOE, or LOX activity ameliorated ECM remodeling andPH. Thus, ECM remodeling, as controlled by the YAP/TAZ-miR-130/301 feedback circuit, is an early PHtrigger and offers combinatorial therapeutic targets for this devastating disease.", "metadata": {}}
+{"_id": "1727493", "title": "", "text": "Exosomal transfer of stroma-derived miR21 confers paclitaxel resistance in ovarian cancer cells throughtargeting APAF1Advanced ovarian cancer usually spreads to the visceral adipose tissue of the omentum.However, the omental stromal cell-derived molecular determinants that modulate ovarian cancer growthhave not been characterized. Here, using next-generation sequencing technology, we identifysignificantly higher levels of microRNA-21 (miR21) isomiRNAs in exosomes and tissue lysates isolatedfrom cancer-associated adipocytes (CAAs) and fibroblasts (CAFs) than in those from ovarian cancer cells.Functional studies reveal that miR21 is transferred from CAAs or CAFs to the cancer cells, where itsuppresses ovarian cancer apoptosis and confers chemoresistance by binding to its direct novel target,APAF1. These data suggest that the malignant phenotype of metastatic ovarian cancer cells can bealtered by miR21 delivered by exosomes derived from neighbouring stromal cells in the omental tumourmicroenvironment, and that inhibiting the transfer of stromal-derived miR21 is an alternative modality inthe treatment of metastatic and recurrent ovarian cancer.", "metadata": {}}
+{"_id": "1733337", "title": "", "text": "Age-related changes in kynurenic acid production in rat brain.Two separate in vitro assays were used toexamine the biosynthesis of the broad spectrum excitatory amino acid receptor antagonist kynurenic acid(KYNA) during the life span of the adult rat. Assessment of KYNA's anabolic enzyme kynurenineaminotransferase revealed steady increases between 3 and 24 months of age in all five brain regionsexamined. No changes were observed in the liver. The changes were particularly pronounced in thecortex and in the striatum where enzyme activity increased three-fold during the period studied. KYNAproduction from its bioprecursor L-kynurenine was also investigated in tissue slices and was found to besignificantly enhanced in the cortex and hippocampus of old animals. The effect of depolarizing agents orsodium replacement was virtually identical in tissues from young and old rats. These data, which are inexcellent agreement with reports on an age-dependent increase of KYNA concentration in brain tissue,suggest an enhanced KYNA tone in the aged brain. Together with the reported decline in cerebralexcitatory amino acid receptor densities with age, increased production of KYNA may play a role incognitive and memory dysfunction in old animals.", "metadata": {}}
+{"_id": "1744097", "title": "", "text": "The polycomb group protein Suz12 is required for embryonic stem cell differentiation.Polycomb group(PcG) proteins form multiprotein complexes, called Polycomb repressive complexes (PRCs). PRC2contains the PcG proteins EZH2, SUZ12, and EED and represses transcription through methylation oflysine (K) 27 of histone H3 (H3). Suz12 is essential for PRC2 activity and its inactivation results in earlylethality of mouse embryos. Here, we demonstrate that Suz12(-/-) mouse embryonic stem (ES) cells canbe established and expanded in tissue culture. The Suz12(-/-) ES cells are characterized by global loss ofH3K27 trimethylation (H3K27me3) and higher expression levels of differentiation-specific genes.Moreover, Suz12(-/-) ES cells are impaired in proper differentiation, resulting in a lack of repression of EScell markers as well as activation of differentiation-specific genes. Finally, we demonstrate that the PcGsare actively recruited to several genes during ES cell differentiation, which despite an increase inH3K27me3 levels is not always sufficient to prevent transcriptional activation. In summary, wedemonstrate that Suz12 is required for the establishment of specific expression programs required for EScell differentiation. Furthermore, we provide evidence that PcGs have different mechanisms to regulatetranscription during cellular differentiation.", "metadata": {}}
+{"_id": "1744752", "title": "", "text": "The 1.9 A structure of a proteasome-11S activator complex and implications for proteasome-PAN/PA700interactions.Proteasomes are cylindrical structures that function in multiple cellular processes bydegrading a wide variety of cytosolic and nuclear proteins. Substrate access and product release from theenclosed catalytic chamber occurs through axial pores that are opened by activator complexes. Here, wereport high-resolution structures of wild-type and mutant archaeal proteasomes bound to the activatorPA26. These structures support the proposal that an ordered open conformation is required forproteolysis and that its formation can be triggered by outward displacement of surrounding residues. Thestructures and associated biochemical assays reveal the mechanism of binding, which involves aninteraction between the PA26 C terminus and a conserved lysine. Surprisingly, biochemical observationsimplicate an equivalent interaction for the unrelated ATP-dependent activators PAN and PA700.", "metadata": {}}
+{"_id": "1748921", "title": "", "text": "Innate Immune and Chemically Triggered Oxidative Stress Modifies Translational FidelityTranslationalfidelity, essential for protein and cell function, requires accurate transfer RNA (tRNA) aminoacylation.Purified aminoacyl-tRNA synthetases exhibit a fidelity of one error per 10,000 to 100,000 couplings. Theaccuracy of tRNA aminoacylation in vivo is uncertain, however, and might be considerably lower. Here weshow that in mammalian cells, approximately 1% of methionine (Met) residues used in protein synthesisare aminoacylated to non-methionyl-tRNAs. Remarkably, Met-misacylation increases up to tenfold uponexposing cells to live or non-infectious viruses, toll-like receptor ligands or chemically induced oxidativestress. Met is misacylated to specific non-methionyl-tRNA families, and these Met-misacylated tRNAs areused in translation. Met-misacylation is blocked by an inhibitor of cellular oxidases, implicating reactiveoxygen species (ROS) as the misacylation trigger. Among six amino acids tested, tRNA misacylationoccurs exclusively with Met. As Met residues are known to protect proteins against ROS-mediateddamage, we propose that Met-misacylation functions adaptively to increase Met incorporation intoproteins to protect cells against oxidative stress. In demonstrating an unexpected conditional aspect ofdecoding mRNA, our findings illustrate the importance of considering alternative iterations of the geneticcode.", "metadata": {}}
+{"_id": "1754001", "title": "", "text": "Yeast sirtuins and the regulation of aging.The sirtuins are a phylogenetically conserved family of NAD(+)-dependent protein deacetylases that consume one molecule of NAD(+) for every deacetylated lysine sidechain. Their requirement for NAD(+) potentially makes them prone to regulation by fluctuations inNAD(+) or biosynthesis intermediates, thus linking them to cellular metabolism. The Sir2 protein fromSaccharomyces cerevisiae is the founding sirtuin family member and has been well characterized as ahistone deacetylase that functions in transcriptional silencing of heterochromatin domains and as apro-longevity factor for replicative life span (RLS), defined as the number of times a mother cell divides(buds) before senescing. Deleting SIR2 shortens RLS, while increased gene dosage causes extension.Furthermore, Sir2 has been implicated in mediating the beneficial effects of caloric restriction (CR) on lifespan, not only in yeast, but also in higher eukaryotes. While this paradigm has had its share ofdisagreements and debate, it has also helped rapidly drive the aging research field forward. S. cerevisiaehas four additional sirtuins, Hst1, Hst2, Hst3, and Hst4. This review discusses the function of Sir2 and theHst homologs in replicative aging and chronological aging, and also addresses how the sirtuins areregulated in response to environmental stresses such as CR.", "metadata": {}}
+{"_id": "1759213", "title": "", "text": "The effect of combination treatment with aliskiren and blockers of the renin-angiotensin system onhyperkalaemia and acute kidney injury: systematic review and meta-analysisOBJECTIVE To examine thesafety of using aliskiren combined with agents used to block the renin-angiotensin system. DESIGNSystematic review and meta-analysis of randomised controlled trials. DATA SOURCES Medline, Embase,the Cochrane Library, and two trial registries, published up to 7 May 2011. STUDY SELECTION Publishedand unpublished randomised controlled trials that compared combined treatment using aliskiren andangiotensin converting enzyme inhibitors or angiotensin receptor blockers with monotherapy using theseagents for at least four weeks and that provided numerical data on the adverse event outcomes ofhyperkalaemia and acute kidney injury. A random effects model was used to calculate pooled risk ratiosand 95% confidence intervals for these outcomes. RESULTS 10 randomised controlled studies (4814participants) were included in the analysis. Combination therapy with aliskiren and angiotensin convertingenzyme inhibitors or angiotensin receptor blockers significantly increased the risk of hyperkalaemiacompared with monotherapy using angiotensin converting enzymes or angiotensin receptor blockers(relative risk 1.58, 95% confidence interval 1.24 to 2.02) or aliskiren alone (1.67, 1.01 to 2.79). The riskof acute kidney injury did not differ significantly between the combined therapy and monotherapy groups(1.14, 0.68 to 1.89). CONCLUSION Use of aliskerin in combination with angiotensin converting enzymeinhibitors or angiotensin receptor blockers is associated with an increased risk for hyperkalaemia. Thecombined use of these agents warrants careful monitoring of serum potassium levels.", "metadata": {}}
+{"_id": "1769799", "title": "", "text": "The ins and outs of DNA transfer in bacteria.Transformation and conjugation permit the passage of DNAthrough the bacterial membranes and represent dominant modes for the transfer of genetic informationbetween bacterial cells or between bacterial and eukaryotic cells. As such, they are responsible for thespread of fitness-enhancing traits, including antibiotic resistance. Both processes usually involve therecognition of double-stranded DNA, followed by the transfer of single strands. Elaborate molecularmachines are responsible for negotiating the passage of macromolecular DNA through the layers of thecell surface. All or nearly all the machine components involved in transformation and conjugation havebeen identified, and here we present models for their roles in DNA transport.", "metadata": {}}
+{"_id": "1771079", "title": "", "text": "Synaptic islands defined by the territory of a single astrocyte.In the mammalian brain, astrocytesmodulate neuronal function, in part, by synchronizing neuronal firing and coordinating synaptic networks.Little, however, is known about how this is accomplished from a structural standpoint. To investigate thestructural basis of astrocyte-mediated neuronal synchrony and synaptic coordination, thethree-dimensional relationships between cortical astrocytes and neurons was investigated. Using atransgenic and viral approach to label astrocytes with enhanced green fluorescent protein, we performeda three-dimensional reconstruction of astrocytes from tissue sections or live animals in vivo. We foundthat cortical astrocytes occupy nonoverlapping territories similar to those described in the hippocampus.Using immunofluorescence labeling of neuronal somata, a single astrocyte enwraps on average fourneuronal somata with an upper limit of eight. Single-neuron dye-fills allowed us to estimate that oneastrocyte contacts 300-600 neuronal dendrites. Together with the recent findings showing that glial Ca2+signaling is restricted to individual astrocytes in vivo, and that Ca2+ signaling leads to gliotransmission,we propose the concept of functional islands of synapses in which groups of synapses confined within theboundaries of an individual astrocyte are modulated by the gliotransmitter environment controlled by thatastrocyte. Our description offers a new structurally based conceptual framework to evaluate functionaldata involving interactions between neurons and astrocytes in the mammalian brain.", "metadata": {}}
+{"_id": "1780819", "title": "", "text": "Role of DNA Methylation and Epigenetic Silencing of HAND2 in Endometrial CancerDevelopmentBACKGROUND Endometrial cancer incidence is continuing to rise in the wake of the currentageing and obesity epidemics. Much of the risk for endometrial cancer development is influenced by theenvironment and lifestyle. Accumulating evidence suggests that the epigenome serves as the interfacebetween the genome and the environment and that hypermethylation of stem cell polycomb group targetgenes is an epigenetic hallmark of cancer. The objective of this study was to determine the functional roleof epigenetic factors in endometrial cancer development. METHODS AND FINDINGS Epigenome-widemethylation analysis of >27,000 CpG sites in endometrial cancer tissue samples (n = 64) and controlsamples (n = 23) revealed that HAND2 (a gene encoding a transcription factor expressed in theendometrial stroma) is one of the most commonly hypermethylated and silenced genes in endometrialcancer. A novel integrative epigenome-transcriptome-interactome analysis further revealed that HAND2is the hub of the most highly ranked differential methylation hotspot in endometrial cancer. Thesefindings were validated using candidate gene methylation analysis in multiple clinical sample sets oftissue samples from a total of 272 additional women. Increased HAND2 methylation was a feature ofpremalignant endometrial lesions and was seen to parallel a decrease in RNA and protein levels.Furthermore, women with high endometrial HAND2 methylation in their premalignant lesions were lesslikely to respond to progesterone treatment. HAND2 methylation analysis of endometrial secretionscollected using high vaginal swabs taken from women with postmenopausal bleeding specificallyidentified those patients with early stage endometrial cancer with both high sensitivity and high specificity(receiver operating characteristics area under the curve = 0.91 for stage 1A and 0.97 for higher thanstage 1A). Finally, mice harbouring a Hand2 knock-out specifically in their endometrium were shown todevelop precancerous endometrial lesions with increasing age, and these lesions also demonstrated alack of PTEN expression. CONCLUSIONS HAND2 methylation is a common and crucial molecular alterationin endometrial cancer that could potentially be employed as a biomarker for early detection ofendometrial cancer and as a predictor of treatment response. The true clinical utility of HAND2 DNAmethylation, however, requires further validation in prospective studies. Please see later in the article forthe Editors' Summary.", "metadata": {}}
+{"_id": "1781626", "title": "", "text": "Socioeconomic factors, material inequalities, and perceived control in self-rated health: cross-sectionaldata from seven post-communist countries.This study examined the association between perceivedcontrol and several socioeconomic variables and self-rated health in seven post-communist countries(Russia, Estonia, Lithuania, Latvia, Hungary, Poland, Czech Republic). Questionnaire interviews wereused to collect data on self-rated health in the last 12 months, education, marital status, perceivedcontrol based on nine questions, and material deprivation based on availability of food, clothing andheating. For each population, two ecological measures of material inequalities were available: aninequality score estimated from the survey data as the distance between the 90th and 10th percentiles ofmaterial deprivation, and Gini coefficient from published sources. Data on 5330 men and women aged20-60 were analysed. Prevalence of poor health (worse than average) varied between 8% in Czechs and19% in Hungarians. The age-sex-adjusted odds ratio for university vs primary education was 0.36(0.26-0.49); odds ratios per 1 standard deviation increase in perceived control and in materialdeprivation were 0.58 (95% CI 0.48-0.69) and 1.51 (1.40-1.63), respectively. The odds ratio for anincrease in inequality equivalent to the difference between the most and the least unequal populationswas 1.49 (0.88-2.52) using the material inequality score and 1.41 (0.91-2.20) using the Gini coefficient.No indication of an effect of either inequality measure was seen after adjustment for individuals'deprivation or perceived control. The results suggest that, as in western populations, education andmaterial deprivation are strongly related to self-rated health. Perceived control appeared statistically tomediate some of the effects of material deprivation. The non-significant effects of both ecologicalmeasures of inequality were eliminated by controlling for individuals' characteristics.", "metadata": {}}
+{"_id": "1782201", "title": "", "text": "Integrin αvβ3/c-src “Oncogenic Unit” Promotes Anchorage-independence and Tumor ProgressionIntegrinsregulate adhesion-dependent growth, survival and invasion of tumor cells. In particular, expression ofintegrin alpha(v)beta(3) is associated with progression of a variety of human tumors. Here we reveal apreviously undescribed adhesion-independent role for integrin alpha(v)beta(3) in pancreatic cancer andother carcinomas. Specifically, alpha(v)beta(3) expressed in carcinoma cells enhancedanchorage-independent tumor growth in vitro and increased lymph node metastases in vivo. Theseeffects required recruitment of c-Src to the beta(3) integrin cytoplasmic tail, leading to c-Src activation,Crk-associated substrate (CAS) phosphorylation and tumor cell survival that, unexpectedly, wasindependent of cell adhesion or focal adhesion kinase (FAK) activation. Pharmacological blockade of c-Srckinase activity or decreased expression of endogenous alpha(v)beta(3) integrin or c-Src not only inhibitedanchorage-independent growth but also suppressed metastasis in vivo, yet these manipulations did notaffect tumor cell migration or invasion. These data define an unexpected role for an integrin as amediator of anchorage independence, suggesting that an alpha(v)beta(3)-c-Src signaling module mayaccount for the aggressive behavior of integrin alpha(v)beta(3)-expressing tumors in humans.", "metadata": {}}
+{"_id": "1791637", "title": "", "text": "Genomewide Analysis of PRC1 and PRC2 Occupancy Identifies Two Classes of Bivalent DomainsInembryonic stem (ES) cells, bivalent chromatin domains with overlapping repressive (H3 lysine 27tri-methylation) and activating (H3 lysine 4 tri-methylation) histone modifications mark the promoters ofmore than 2,000 genes. To gain insight into the structure and function of bivalent domains, we mappedkey histone modifications and subunits of Polycomb-repressive complexes 1 and 2 (PRC1 and PRC2)genomewide in human and mouse ES cells by chromatin immunoprecipitation, followed by ultrahigh-throughput sequencing. We find that bivalent domains can be segregated into two classes -- the firstoccupied by both PRC2 and PRC1 (PRC1-positive) and the second specifically bound by PRC2(PRC2-only). PRC1-positive bivalent domains appear functionally distinct as they more efficiently retainlysine 27 tri-methylation upon differentiation, show stringent conservation of chromatin state, andassociate with an overwhelming number of developmental regulator gene promoters. We also usedcomputational genomics to search for sequence determinants of Polycomb binding. This analysis revealedthat the genomewide locations of PRC2 and PRC1 can be largely predicted from the locations, sizes, andunderlying motif contents of CpG islands. We propose that large CpG islands depleted of activating motifsconfer epigenetic memory by recruiting the full repertoire of Polycomb complexes in pluripotent cells.", "metadata": {}}
+{"_id": "1791714", "title": "", "text": "Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinomametastasis.Epithelial-mesenchymal transition (EMT) is implicated in converting stationary epithelial tumorcells into motile mesenchymal cells during metastasis. However, the involvement of EMT in metastasis isstill controversial, due to the lack of a mesenchymal phenotype in human carcinoma metastases. Using aspontaneous squamous cell carcinoma mouse model, we show that activation of the EMT-inducingtranscription factor Twist1 is sufficient to promote carcinoma cells to undergo EMT and disseminate intoblood circulation. Importantly, in distant sites, turning off Twist1 to allow reversion of EMT is essential fordisseminated tumor cells to proliferate and form metastases. Our study demonstrates in vivo therequirement of \"reversible EMT\" in tumor metastasis and may resolve the controversy on the importanceof EMT in carcinoma metastasis.", "metadata": {}}
+{"_id": "1797622", "title": "", "text": "Control of Apoptosis by Asymmetric Cell DivisionAsymmetric cell division and apoptosis (programmed celldeath) are two fundamental processes that are important for the development and function ofmulticellular organisms. We have found that the processes of asymmetric cell division and apoptosis canbe functionally linked. Specifically, we show that asymmetric cell division in the nematode Caenorhabditiselegans is mediated by a pathway involving three genes, dnj-11 MIDA1, ces-2 HLF, and ces-1 Snail, thatdirectly control the enzymatic machinery responsible for apoptosis. Interestingly, the MIDA1-like proteinGlsA of the alga Volvox carteri, as well as the Snail-related proteins Snail, Escargot, and Worniu ofDrosophila melanogaster, have previously been implicated in asymmetric cell division. Therefore, C.elegans dnj-11 MIDA1, ces-2 HLF, and ces-1 Snail may be components of a pathway involved inasymmetric cell division that is conserved throughout the plant and animal kingdoms. Furthermore,based on our results, we propose that this pathway directly controls the apoptotic fate in C. elegans, andpossibly other animals as well.", "metadata": {}}
+{"_id": "1800734", "title": "", "text": "CXCR2 mediates NADPH oxidase–independent neutrophil extracellular trap formation in cystic fibrosisairway inflammationUpon activation, neutrophils release DNA fibers decorated with antimicrobial proteins,forming neutrophil extracellular traps (NETs). Although NETs are bactericidal and contribute to innatehost defense, excessive NET formation has been linked to the pathogenesis of autoinflammatorydiseases. However, the mechanisms regulating NET formation, particularly during chronic inflammation,are poorly understood. Here we show that the G protein–coupled receptor (GPCR) CXCR2 mediates NETformation. Downstream analyses showed that CXCR2-mediated NET formation was independent ofNADPH oxidase and involved Src family kinases. We show the pathophysiological relevance of thismechanism in cystic fibrosis lung disease, characterized by chronic neutrophilic inflammation. We foundabundant NETs in airway fluids of individuals with cystic fibrosis and mouse cystic fibrosis lung disease,and NET amounts correlated with impaired obstructive lung function. Pulmonary blockade of CXCR2 byintra-airway delivery of small-molecule antagonists inhibited NET formation and improved lung function invivo without affecting neutrophil recruitment, proteolytic activity or antibacterial host defense. Thesestudies establish CXCR2 as a receptor mediating NADPH oxidase–independent NET formation and provideevidence that this GPCR pathway is operative and druggable in cystic fibrosis lung disease.", "metadata": {}}
+{"_id": "1805641", "title": "", "text": "Modelling the Impact of Artemisinin Combination Therapy and Long-Acting Treatments on MalariaTransmission IntensityBACKGROUND Artemisinin derivatives used in recently introduced combinationtherapies (ACTs) for Plasmodium falciparum malaria significantly lower patient infectiousness and havethe potential to reduce population-level transmission of the parasite. With the increased interest inmalaria elimination, understanding the impact on transmission of ACT and other antimalarial drugs withdifferent pharmacodynamics becomes a key issue. This study estimates the reduction in transmissionthat may be achieved by introducing different types of treatment for symptomatic P. falciparum malariain endemic areas. METHODS AND FINDINGS We developed a mathematical model to predict the potentialimpact on transmission outcomes of introducing ACT as first-line treatment for uncomplicated malaria insix areas of varying transmission intensity in Tanzania. We also estimated the impact that could beachieved by antimalarials with different efficacy, prophylactic time, and gametocytocidal effects. Rates oftreatment, asymptomatic infection, and symptomatic infection in the six study areas were estimatedusing the model together with data from a cross-sectional survey of 5,667 individuals conducted prior topolicy change from sulfadoxine-pyrimethamine to ACT. The effects of ACT and other drug types ongametocytaemia and infectiousness to mosquitoes were independently estimated from clinical trial data.Predicted percentage reductions in prevalence of infection and incidence of clinical episodes achieved byACT were highest in the areas with low initial transmission. A 53% reduction in prevalence of infectionwas seen if 100% of current treatment was switched to ACT in the area where baseline slide-prevalenceof parasitaemia was lowest (3.7%), compared to an 11% reduction in the highest-transmission setting(baseline slide prevalence = 57.1%). Estimated percentage reductions in incidence of clinical episodeswere similar. The absolute size of the public health impact, however, was greater in thehighest-transmission area, with 54 clinical episodes per 100 persons per year averted compared to fiveper 100 persons per year in the lowest-transmission area. High coverage was important. Reducingpresumptive treatment through improved diagnosis substantially reduced the number of treatmentcourses required per clinical episode averted in the lower-transmission settings although there was someloss of overall impact on transmission. An efficacious antimalarial regimen with no specificgametocytocidal properties but a long prophylactic time was estimated to be more effective at reducingtransmission than a short-acting ACT in the highest-transmission setting. CONCLUSIONS Our resultssuggest that ACTs have the potential for transmission reductions approaching those achieved byinsecticide-treated nets in lower-transmission settings. ACT partner drugs and nonartemisinin regimenswith longer prophylactic times could result in a larger impact in higher-transmission settings, althoughtheir long term benefit must be evaluated in relation to the risk of development of parasite resistance.", "metadata": {}}
+{"_id": "1818578", "title": "", "text": "Systems metabolic engineering of Escherichia coli for L-threonine productionAmino-acid producers havetraditionally been developed by repeated random mutagenesis owing to the difficulty in rationallyengineering the complex and highly regulated metabolic network. Here, we report the development of thegenetically defined L-threonine overproducing Escherichia coli strain by systems metabolic engineering.Feedback inhibitions of aspartokinase I and III (encoded by thrA and lysC, respectively) andtranscriptional attenuation regulations (located in thrL) were removed. Pathways for Thr degradationwere removed by deleting tdh and mutating ilvA. The metA and lysA genes were deleted to make moreprecursors available for Thr biosynthesis. Further target genes to be engineered were identified bytranscriptome profiling combined with in silico flux response analysis, and their expression levels weremanipulated accordingly. The final engineered E. coli strain was able to produce Thr with a high yield of0.393 g per gram of glucose, and 82.4 g/l Thr by fed-batch culture. The systems metabolic engineeringstrategy reported here may be broadly employed for developing genetically defined organisms for theefficient production of various bioproducts.", "metadata": {}}
+{"_id": "1831916", "title": "", "text": "Association Between ADHD and Obesity: A Systematic Review and Meta-Analysis.OBJECTIVE Impulsivityand inattention related to attention deficit hyperactivity disorder (ADHD) may increase food intake and,consequently, weight gain. However, findings on the association between obesity/overweight and ADHDare mixed. The authors conducted a meta-analysis to estimate this association. METHOD A broad rangeof databases was searched through Aug. 31, 2014. Unpublished studies were also obtained. Study qualitywas rated with the Newcastle-Ottawa Scale. Random-effects models were used. RESULTS Forty-twostudies that included a total of 728,136 individuals (48,161 ADHD subjects; 679,975 comparisonsubjects) were retained. A significant association between obesity and ADHD was found for both children(odds ratio=1.20, 95% CI=1.05-1.37) and adults (odds ratio=1.55, 95% CI=1.32-1.81). The pooledprevalence of obesity was increased by about 70% in adults with ADHD (28.2%, 95% CI=22.8-34.4)compared with those without ADHD (16.4%, 95% CI=13.4-19.9), and by about 40% in children withADHD (10.3%, 95% CI=7.9-13.3) compared with those without ADHD (7.4%, 95% CI=5.4-10.1). Thesignificant association between ADHD and obesity remained when limited to studies 1) reporting oddsratios adjusted for possible confounding factors; 2) diagnosing ADHD by direct interview; and 3) usingdirectly measured height and weight. Gender, study setting, study country, and study quality did notmoderate the association between obesity and ADHD. ADHD was also significantly associated withoverweight. Individuals medicated for ADHD were not at higher risk of obesity. CONCLUSIONS This studyprovides meta-analytic evidence for a significant association between ADHD and obesity/overweight.Further research should address possible underlying mechanisms and the long-term effects of ADHDtreatments on weight in individuals with both ADHD and obesity.", "metadata": {}}
+{"_id": "1834762", "title": "", "text": "Amyloid-DNA Composites of Bacterial Biofilms Stimulate Autoimmunity.Research on the humanmicrobiome has established that commensal and pathogenic bacteria can influence obesity, cancer, andautoimmunity through mechanisms mostly unknown. We found that a component of bacterial biofilms,the amyloid protein curli, irreversibly formed fibers with bacterial DNA during biofilm formation. Thisinteraction accelerated amyloid polymerization and created potent immunogenic complexes that activatedimmune cells, including dendritic cells, to produce cytokines such as type I interferons, which arepathogenic in systemic lupus erythematosus (SLE). When given systemically, curli-DNA compositestriggered immune activation and production of autoantibodies in lupus-prone and wild-type mice. We alsofound that the infection of lupus-prone mice with curli-producing bacteria triggered higher autoantibodytiters compared to curli-deficient bacteria. These data provide a mechanism by which the microbiome andbiofilm-producing enteric infections may contribute to the progression of SLE and point to a potentialmolecular target for treatment of autoimmunity.", "metadata": {}}
+{"_id": "1836154", "title": "", "text": "Comprehensive genomic characterization defines human glioblastoma genes and core pathwaysHumancancer cells typically harbour multiple chromosomal aberrations, nucleotide substitutions and epigeneticmodifications that drive malignant transformation. The Cancer Genome Atlas ( TCGA) pilot project aimsto assess the value of large- scale multi- dimensional analysis of these molecular characteristics in humancancer and to provide the data rapidly to the research community. Here we report the interim integrativeanalysis of DNA copy number, gene expression and DNA methylation aberrations in 206 glioblastomas -the most common type of primary adult brain cancer - and nucleotide sequence aberrations in 91 of the206 glioblastomas. This analysis provides new insights into the roles of ERBB2, NF1 and TP53, uncoversfrequent mutations of the phosphatidylinositol- 3- OH kinase regulatory subunit gene PIK3R1, andprovides a network view of the pathways altered in the development of glioblastoma. Furthermore,integration of mutation, DNA methylation and clinical treatment data reveals a link between MGMTpromoter methylation and a hypermutator phenotype consequent to mismatch repair deficiency intreated glioblastomas, an observation with potential clinical implications. Together, these findingsestablish the feasibility and power of TCGA, demonstrating that it can rapidly expand knowledge of themolecular basis of cancer.", "metadata": {}}
+{"_id": "1840993", "title": "", "text": "LY2405319, an Engineered FGF21 Variant, Improves the Metabolic Status of Diabetic MonkeysFibroblastgrowth factor 21 (FGF21) is a novel metabolic regulator that represents a promising target for thetreatment of several metabolic diseases. Administration of recombinant wild type FGF21 to diabeticanimals leads to a dramatic improvement in glycaemia and ameliorates other systemic measures ofmetabolic health. Here we report the pharmacologic outcomes observed in non-human primates uponadministration of a recently described FGF21 analogue, LY2405319 (LY). Diabetic rhesus monkeys weretreated subcutaneously with LY once daily for a period of seven weeks. The doses of LY used were 3, 9and 50 mg/kg each delivered in an escalating fashion with washout measurements taken at 2, 4, 6 and 8weeks following the final LY dose. LY therapy led to a dramatic and rapid lowering of several importantmetabolic parameters including glucose, body weight, insulin, cholesterol and triglyceride levels at alldoses tested. In addition, we observed favorable changes in circulating profiles of adipokines, withincreased adiponectin and reduced leptin indicative of direct FGF21 action on adipose tissue. Importantly,and for the first time we show that FGF21 based therapy has metabolic efficacy in an animal with latestage diabetes. While the glycemic efficacy of LY in this animal was partially attenuated its lipid loweringeffect was fully preserved suggesting that FGF21 may be a viable treatment option even in patients withadvanced disease progression. These findings support continued exploration of the FGF21 pathway forthe treatment of metabolic disease.", "metadata": {}}
+{"_id": "1848452", "title": "", "text": "Epigenetic Control of Stem Cell Potential during Homeostasis, Aging, and Disease.Stem cell decline is animportant cellular driver of aging-associated pathophysiology in multiple tissues. Epigenetic regulation iscentral to establishing and maintaining stem cell function, and emerging evidence indicates thatepigenetic dysregulation contributes to the altered potential of stem cells during aging. Unlike terminallydifferentiated cells, the impact of epigenetic dysregulation in stem cells is propagated beyond self;alterations can be heritably transmitted to differentiated progeny, in addition to being perpetuated andamplified within the stem cell pool through self-renewal divisions. This Review focuses on recent studiesexamining epigenetic regulation of tissue-specific stem cells in homeostasis, aging, and aging-relateddisease.", "metadata": {}}
+{"_id": "1852826", "title": "", "text": "Host–Parasite Interactions and the Evolution of Gene ExpressionInteractions between hosts and parasitesprovide an ongoing source of selection that promotes the evolution of a variety of features in theinteracting species. Here, we use a genetically explicit mathematical model to explore how patterns ofgene expression evolve at genetic loci responsible for host resistance and parasite infection. Our resultsreveal the striking yet intuitive conclusion that gene expression should evolve along very differenttrajectories in the two interacting species. Specifically, host resistance loci should frequently evolve toco-express alleles, whereas parasite infection loci should evolve to express only a single allele. This resultarises because hosts that co-express resistance alleles are able to recognize and clear a greater diversityof parasite genotypes. By the same token, parasites that co-express antigen or elicitor alleles are morelikely to be recognized and cleared by the host, and this favours the expression of only a single allele. Ourmodel provides testable predictions that can help interpret accumulating data on expression levels forgenes relevant to host−parasite interactions.", "metadata": {}}
+{"_id": "1855679", "title": "", "text": "A crucial role for interleukin (IL)-1 in the induction of IL-17–producing T cells that mediate autoimmuneencephalomyelitisIt was recently demonstrated that interleukin (IL)-23–driven IL-17–producing (ThIL-17)T cells mediate inflammatory pathology in certain autoimmune diseases. We show that the induction ofantigen-specific ThIL-17 cells, but not T helper (Th)1 or Th2 cells, by immunization with antigens andadjuvants is abrogated in IL-1 receptor type I–deficient (IL-1RI−/−) mice. Furthermore, the incidence ofexperimental autoimmune encephalomyelitis (EAE) was significantly lower in IL-1RI−/− compared withwild-type mice, and this correlated with a failure to induce autoantigen-specific ThIL-17 cells, whereasinduction of Th1 and Th2 responses was not substantially different. However, EAE was induced inIL-1RI−/�� mice by adoptive transfer of autoantigen-specific cells from wild-type mice with EAE. IL-23alone did not induce IL-17 production by T cells from IL-1RI−/− mice, and IL-23–induced IL-17production was substantially enhanced by IL-1α or IL-1β, even in the absence of T cell receptorstimulation. We demonstrate essential roles for phosphatidylinositol 3-kinase, nuclear factor κB, andnovel protein kinase C isoforms in IL-1– and IL-23–mediated IL-17 production. Tumor necrosis factor αalso synergized with IL-23 to enhance IL-17 production, and this was IL-1 dependent. Our findingsdemonstrate that IL-1 functions upstream of IL-17 to promote pathogenic ThIL-17 cells in EAE.", "metadata": {}}
+{"_id": "1866911", "title": "", "text": "Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1mutation carriersBasal-like breast cancers arising in women carrying mutations in the BRCA1 gene,encoding the tumor suppressor protein BRCA1, are thought to develop from the mammary stem cell. Toexplore early cellular changes that occur in BRCA1 mutation carriers, we have prospectively isolateddistinct epithelial subpopulations from normal mammary tissue and preneoplastic specimens fromindividuals heterozygous for a BRCA1 mutation. We describe three epithelial subsets including basalstem/progenitor, luminal progenitor and mature luminal cells. Unexpectedly, we found that breast tissuefrom BRCA1 mutation carriers harbors an expanded luminal progenitor population that showsfactor-independent growth in vitro. Moreover, gene expression profiling revealed that breast tissueheterozygous for a BRCA1 mutation and basal breast tumors were more similar to normal luminalprogenitor cells than any other subset, including the stem cell–enriched population. The c-KIT tyrosinekinase receptor (encoded by KIT) emerged as a key marker of luminal progenitor cells and was morehighly expressed in BRCA1-associated preneoplastic tissue and tumors. Our findings suggest that anaberrant luminal progenitor population is a target for transformation in BRCA1-associated basal tumors .", "metadata": {}}
+{"_id": "1871230", "title": "", "text": "Getting to the site of inflammation: the leukocyte adhesion cascade updatedNeutrophil recruitment,lymphocyte recirculation and monocyte trafficking all require adhesion and transmigration throughblood-vessel walls. The traditional three steps of rolling, activation and firm adhesion have recently beenaugmented and refined. Slow rolling, adhesion strengthening, intraluminal crawling and paracellular andtranscellular migration are now recognized as separate, additional steps. In neutrophils, a secondactivation pathway has been discovered that does not require signalling through G-protein-coupledreceptors and the signalling steps leading to integrin activation are beginning to emerge. This Reviewfocuses on new aspects of one of the central paradigms of inflammation and immunity — the leukocyteadhesion cascade.", "metadata": {}}
+{"_id": "1871499", "title": "", "text": "Genome-wide loss of 5-hmC is a novel epigenetic feature of Huntington'sdisease.5-Hydroxymethylcytosine (5-hmC) may represent a new epigenetic modification of cytosine.While the dynamics of 5-hmC during neurodevelopment have recently been reported, little is knownabout its genomic distribution and function(s) in neurodegenerative diseases such as Huntington'sdisease (HD). We here observed a marked reduction of the 5-hmC signal in YAC128 (yeast artificialchromosome transgene with 128 CAG repeats) HD mouse brain tissues when compared withage-matched wild-type (WT) mice, suggesting a deficiency of 5-hmC reconstruction in HD brains duringpostnatal development. Genome-wide distribution analysis of 5-hmC further confirmed the diminishmentof the 5-hmC signal in striatum and cortex in YAC128 HD mice. General genomic features of 5-hmC arehighly conserved, not being affected by either disease or brain regions. Intriguingly, we have identifieddisease-specific (YAC128 versus WT) differentially hydroxymethylated regions (DhMRs), and found thatacquisition of DhmRs in gene body is a positive epigenetic regulator for gene expression. Ingenuitypathway analysis (IPA) of genotype-specific DhMR-annotated genes revealed that alternation of a numberof canonical pathways involving neuronal development/differentiation (Wnt/β-catenin/Sox pathway,axonal guidance signaling pathway) and neuronal function/survival (glutamate receptor/calcium/CREB,GABA receptor signaling, dopamine-DARPP32 feedback pathway, etc.) could be important for the onset ofHD. Our results indicate that loss of the 5-hmC marker is a novel epigenetic feature in HD, and that thisaberrant epigenetic regulation may impair the neurogenesis, neuronal function and survival in HD brain.Our study also opens a new avenue for HD treatment; re-establishing the native 5-hmC landscape mayhave the potential to slow/halt the progression of HD.", "metadata": {}}
+{"_id": "1886551", "title": "", "text": "Planning for Postdisaster ResiliencyThe focus of this article is planning for resiliency in the aftermath of acatastrophe. First, the authors offer their conception of planning for resiliency as a goal for recoveringcommunities, and the benefits of planning in efforts to create more resilient places. Next, they discussmajor issues associated with planning for postdisaster recovery, including barriers posed by federal andstate governments to planning for resiliency, the promise and risks of compact urban form models forguiding rebuilding, and the failure to involve citizens in planning for disasters. Finally, they discusslessons from prior research that address these issues and policy recommendations that foster predisasterrecovery planning for resilient communities.", "metadata": {}}
+{"_id": "1887056", "title": "", "text": "Increased stress-induced inflammatory responses in male patients with major depression and increasedearly life stress.OBJECTIVE The authors sought to determine innate immune system activation followingpsychosocial stress in patients with major depression and increased early life stress. METHOD Plasmainterleukin (IL)-6, lymphocyte subsets, and DNA binding of nuclear factor (NF)-kB in peripheral bloodmononuclear cells were compared in medically healthy male subjects with current major depression andincreased early life stress (N=14) versus nondepressed male comparison subjects (N=14) before andafter completion of the Trier Social Stress Test. RESULTS Trier Social Stress Test-induced increases inIL-6 and NF-kappaB DNA-binding were greater in major depression patients with increased early lifestress and independently correlated with depression severity, but not early life stress. Natural killer (NK)cell percentages also increased following stress. However, there were no differences between groups andno correlation between NK cell percentage and stress-induced NF-kappaB DNA-binding or IL-6.CONCLUSIONS Male major depression patients with increased early life stress exhibit enhancedinflammatory responsiveness to psychosocial stress, providing preliminary indication of a link betweenmajor depression, early life stress and adverse health outcomes in diseases associated with inflammation.", "metadata": {}}
+{"_id": "1889358", "title": "", "text": "KIF3A/B: a heterodimeric kinesin superfamily protein that works as a microtubule plus end-directedmotor for membrane organelle transportWe cloned a new member of the murine brain kinesinsuperfamily, KIF3B, and found that its amino acid sequence is highly homologous but not identical toKIF3A, which we previously cloned and named KIF3 (47% identical). KIF3B is localized in various organtissues and developing neurons of mice and accumulates with anterogradely moving membranousorganelles after ligation of nerve axons. Immunoprecipitation assay of the brain revealed that KIF3Bforms a complex with KIF3A and three other high molecular weight (approximately 100 kD)-associatedpolypeptides, called the kinesin superfamily-associated protein 3 (KAP3). In vitro reconstruction usingbaculovirus expression systems showed that KIF3A and KIF3B directly bind with each other in theabsence of KAP3. The recombinant KIF3A/B complex (approximately 50-nm rod with two globular headsand a single globular tail) demonstrated plus end-directed microtubule sliding activity in vitro. Inaddition, we showed that KIF3B itself has motor activity in vitro, by making a complex of wild-type KIF3Band a chimeric motor protein (KIF3B head and KIF3A rod tail). Subcellular fractionation of mouse brainhomogenates showed a considerable amount of the native KIF3 complex to be associated with membranefractions other than synaptic vesicles. Immunoprecipitation by anti-KIF3B antibody-conjugated beads andits electron microscopic study also revealed that KIF3 is associated with membranous organelles.Moreover, we found that the composition of KAP3 is different in the brain and testis. Our findings suggestthat KIF3B forms a heterodimer with KIF3A and functions as a new microtubule-based anterogradetranslocator for membranous organelles, and that KAP3 may determine functional diversity of the KIF3complex in various kinds of cells in vivo.", "metadata": {}}
+{"_id": "1897324", "title": "", "text": "A genetic screen identifies an LKB1–MARK signalling axis controlling the Hippo–YAP pathwayTheHippo–YAP pathway is an emerging signalling cascade involved in the regulation of stem cell activity andorgan size. To identify components of this pathway, we performed an RNAi-based kinome screen inhuman cells. Our screen identified several kinases not previously associated with Hippo signalling thatcontrol multiple cellular processes. One of the hits, LKB1, is a common tumour suppressor whosemechanism of action is only partially understood. We demonstrate that LKB1 acts through its substratesof the microtubule affinity-regulating kinase family to regulate the localization of the polarity determinantScribble and the activity of the core Hippo kinases. Our data also indicate that YAP is functionallyimportant for the tumour suppressive effects of LKB1. Our results identify a signalling axis that links YAPactivation with LKB1 mutations, and have implications for the treatment of LKB1-mutant humanmalignancies. In addition, our findings provide insight into upstream signals of the Hippo–YAP signallingcascade.", "metadata": {}}
+{"_id": "1900152", "title": "", "text": "Beyond melanoma: inhibiting the PD-1/PD-L1 pathway in solid tumors.Immune checkpoint inhibitorshave been identified as breakthrough treatment in melanoma given its dramatic response to PD-1/PD-L1blockade. This is likely to extend to many other cancers as hundreds of clinical trials are being conductedor proposed using this exciting modality of therapy in a variety of malignancies. While immune checkpointinhibitors have been extensively studied in melanoma and more recently in lung cancer, little is knownregarding immune checkpoint blockade in other cancers. This review will focus on the tumor immunemicroenvironment, the expression of PD-1/PD-L1 and the effect of immune modulation using PD-1 orPD-L1 inhibitors in patients with head and neck, prostate, urothelial, renal, breast, gastrointestinal andlung cancers.", "metadata": {}}
+{"_id": "1904291", "title": "", "text": "Partitioning the symptoms of hypoglycaemia using multi-sample confirmatory factor analysisTheallocation of hypoglycaemic symptoms to autonomie or neuroglycopenic groups tends to occur on an apriori basis. In view of the practical need for clear symptom markers of hypoglycaemia more scientificapproaches must be pursued. Substantial evidence is presented from two large scale studies weperformed which support a three factor model of hypoglycaemic symptomatology, based on the statisticalassociations discovered among symptoms reported by diabetic patients. Study 1 involved 295insulin-treated outpatients and found that 11 key hypoglycaemic symptoms segregated into three clearfactors: autonomie (sweating, palpitation, shaking and hunger) neuroglycopenic (confusion, drowsiness,odd behaviour, speech difficulty and incoordination), and malaise (nausea and headache). The threefactors were validated on a separate group of 303 insulin-treated diabetic out-patients. Confirmatoryfactor analyses showed that the three factor model was the optimal model for explaining symptomcovariance in each group. A multi-sample confirmatory factor analysis tested the rigorous assumptionsthat the relative loadings of symptoms on factors across groups were equal, and that the residualvariance for each symptom was identical across groups. These assumptions were successful, indicatingthat the three factor model was replicated in detail across these two large samples. It is suggested thatthe results indicate valid groupings of symptoms that may be used in future research and in clinicalpractice.", "metadata": {}}
+{"_id": "1905095", "title": "", "text": "Extracellular vesicles from human cardiac progenitor cells inhibit cardiomyocyte apoptosis and improvecardiac function after myocardial infarction.AIMS Recent evidence suggests that cardiac progenitor cells(CPCs) may improve cardiac function after injury. The underlying mechanisms are indirect, but theirmediators remain unidentified. Exosomes and other secreted membrane vesicles, hereafter collectivelyreferred to as extracellular vesicles (EVs), act as paracrine signalling mediators. Here, we report that EVssecreted by human CPCs are crucial cardioprotective agents. METHODS AND RESULTS CPCs were derivedfrom atrial appendage explants from patients who underwent heart valve surgery. CPC-conditionedmedium (CM) inhibited apoptosis in mouse HL-1 cardiomyocytic cells, while enhancing tube formation inhuman umbilical vein endothelial cells. These effects were abrogated by depleting CM of EVs. They werereproduced by EVs secreted by CPCs, but not by those secreted by human dermal fibroblasts.Transmission electron microscopy and nanoparticle tracking analysis showed most EVs to be 30-90 nm indiameter, the size of exosomes, although smaller and larger vesicles were also present. MicroRNAs mosthighly enriched in EVs secreted by CPCs compared with fibroblasts included miR-210, miR-132, andmiR-146a-3p. miR-210 down-regulated its known targets, ephrin A3 and PTP1b, inhibiting apoptosis incardiomyocytic cells. miR-132 down-regulated its target, RasGAP-p120, enhancing tube formation inendothelial cells. Infarcted hearts injected with EVs from CPCs, but not from fibroblasts, exhibited lesscardiomyocyte apoptosis, enhanced angiogenesis, and improved LV ejection fraction (0.8 ± 6.8 vs. -21.3± 4.5%; P < 0.05) compared with those injected with control medium. CONCLUSION EVs are the activecomponent of the paracrine secretion by human CPCs. As a cell-free approach, EVs could circumventmany of the limitations of cell transplantation.", "metadata": {}}
+{"_id": "1907601", "title": "", "text": "Increased Adipocyte O2 Consumption Triggers HIF-1α, Causing Inflammation and Insulin Resistance inObesityAdipose tissue hypoxia and inflammation have been causally implicated in obesity-induced insulinresistance. Here, we report that, early in the course of high-fat diet (HFD) feeding and obesity, adipocyterespiration becomes uncoupled, leading to increased oxygen consumption and a state of relativeadipocyte hypoxia. These events are sufficient to trigger HIF-1α induction, setting off the chronic adiposetissue inflammatory response characteristic of obesity. At the molecular level, these events involvesaturated fatty acid stimulation of the adenine nucleotide translocase 2 (ANT2), an inner mitochondrialmembrane protein, which leads to the uncoupled respiratory state. Genetic or pharmacologic inhibition ofeither ANT2 or HIF-1α can prevent or reverse these pathophysiologic events, restoring a state of insulinsensitivity and glucose tolerance. These results reveal the sequential series of events in obesity-inducedinflammation and insulin resistance.", "metadata": {}}
+{"_id": "1910120", "title": "", "text": "Lpcat3-dependent production of arachidonoyl phospholipids is a key determinant of triglyceridesecretionThe role of specific phospholipids (PLs) in lipid transport has been difficult to assess due to aninability to selectively manipulate membrane composition in vivo. Here we show that the phospholipidremodeling enzyme lysophosphatidylcholine acyltransferase 3 (Lpcat3) is a critical determinant oftriglyceride (TG) secretion due to its unique ability to catalyze the incorporation of arachidonate intomembranes. Mice lacking Lpcat3 in the intestine fail to thrive during weaning and exhibit enterocyte lipidaccumulation and reduced plasma TGs. Mice lacking Lpcat3 in the liver show reduced plasma TGs,hepatosteatosis, and secrete lipid-poor very low-density lipoprotein (VLDL) lacking arachidonoyl PLs.Mechanistic studies indicate that Lpcat3 activity impacts membrane lipid mobility in living cells,suggesting a biophysical basis for the requirement of arachidonoyl PLs in lipidating lipoprotein particles.These data identify Lpcat3 as a key factor in lipoprotein production and illustrate how manipulation ofmembrane composition can be used as a regulatory mechanism to control metabolic pathways.", "metadata": {}}
+{"_id": "1914588", "title": "", "text": "Characterization of a single-stranded DNA-binding protein from Pseudomonas aeruginosaPAO1.Single-stranded DNA-binding protein (SSB) plays an important role in DNA metabolism, such as inDNA replication, repair, and recombination, and is essential for cell survival. We characterized thesingle-stranded DNA (ssDNA)-binding properties of Pseudomonas aeruginosa PAO1 SSB (PaSSB) by usingfluorescence quenching measurements and electrophoretic mobility shift analysis (EMSA). Analysis ofpurified PaSSB by gel filtration chromatography revealed a stable tetramer in solution. In fluorescencetitrations, PaSSB bound 22-32 nucleotides (nt) per tetramer depending on salt concentration. UsingEMSA, we characterized the stoichiometry of PaSSB complexed with a series of ssDNA homopolymers,and the size of the binding site was determined to be 29 ± 1 nt. Furthermore, EMSA results indicated thatthe dissociation constants of PaSSB for the first tetramer were less than those for the second tetramer.On the basis of these biophysical analyses, the ssDNA binding mode of PaSSB is expected to benoncooperative.", "metadata": {}}
+{"_id": "1917068", "title": "", "text": "Primary cilia and coordination of receptor tyrosine kinase (RTK) signalling.Primary cilia aremicrotubule-based sensory organelles that coordinate signalling pathways in cell-cycle control, migration,differentiation and other cellular processes critical during development and for tissue homeostasis.Accordingly, defects in assembly or function of primary cilia lead to a plethora of developmental disordersand pathological conditions now known as ciliopathies. In this review, we summarize the current status ofthe role of primary cilia in coordinating receptor tyrosine kinase (RTK) signalling pathways. Further, wepresent potential mechanisms of signalling crosstalk and networking in the primary cilium and discusshow defects in ciliary RTK signalling are linked to human diseases and disorders.", "metadata": {}}
+{"_id": "1921218", "title": "", "text": "Detecting and targeting tumor relapse by its resistance to innate effectors at early recurrenceTumorrecurrence represents a major clinical challenge. Our data show that emergent recurrent tumors acquirea phenotype radically different from that of their originating primary tumors. This phenotype allows themto evade a host-derived innate immune response elicited by the progression from minimal residualdisease (MRD) to actively growing recurrence. Screening for this innate response predicted accurately inwhich mice recurrence would occur. Premature induction of recurrence resensitized MRD to the primarytherapy, suggesting a possible paradigm shift for clinical treatment of dormant disease in which thecurrent expectant approach is replaced with active attempts to uncover MRD before evolution of theescape phenotype is complete. By combining screening with second-line treatments targeting innateinsensitivity, up to 100% of mice that would have otherwise relapsed were cured. These data may opennew avenues for early detection and appropriately timed, highly targeted treatment of tumor recurrenceirrespective of tumor type or frontline treatment.", "metadata": {}}
+{"_id": "1922901", "title": "", "text": "Forces in Tissue Morphogenesis and PatterningDuring development, mechanical forces cause changes insize, shape, number, position, and gene expression of cells. They are therefore integral to anymorphogenetic processes. Force generation by actin-myosin networks and force transmission throughadhesive complexes are two self-organizing phenomena driving tissue morphogenesis. Coordination andintegration of forces by long-range force transmission and mechanosensing of cells within tissues producelarge-scale tissue shape changes. Extrinsic mechanical forces also control tissue patterning by modulatingcell fate specification and differentiation. Thus, the interplay between tissue mechanics and biochemicalsignaling orchestrates tissue morphogenesis and patterning in development.", "metadata": {}}
+{"_id": "1933281", "title": "", "text": "CD169+ MACROPHAGES PRESENT LIPID ANTIGENS TO MEDIATE EARLY ACTIVATION OF INVARIANT NKTCELLS IN LYMPH NODESInvariant natural killer T cells (iNKT cells) are involved in the host defenseagainst microbial infection. Although it is known that iNKT cells recognize glycolipids presented by CD1d,how and where they encounter antigen in vivo remains unclear. Here we used multiphoton microscopy tovisualize the dynamics and activation of iNKT cells in lymph nodes. After antigen administration, iNKTcells became confined in a CD1d-dependent manner in close proximity to subcapsular sinus CD169(+)macrophages. These macrophages retained, internalized and presented lipid antigen and were requiredfor iNKT cell activation, cytokine production and population expansion. Thus, CD169(+) macrophages canact as true antigen-presenting cells controlling early iNKT cell activation and favoring the fast initiation ofimmune responses.", "metadata": {}}
+{"_id": "1941721", "title": "", "text": "Oxygen Metabolism Causes Chromosome Breaks and Is Associated with the Neuronal Apoptosis Observedin DNA Double-Strand Break Repair MutantsCells deficient in a major DNA double-strand break repairpathway (nonhomologous DNA end joining [NHEJ]) have increased spontaneous chromosome breaks;however, the source of these chromosome breaks has remained undefined. Here, we show that theobserved spontaneous chromosome breaks are partially suppressed by reducing the cellular oxygentension. Conversely, elevating the level of reactive oxygen species by overexpressing the antioxidantenzyme superoxide dismutase 1 (SOD1), in a transgenic mouse, increases chromosome breakage. Theeffect of SOD1 can also be modulated by cellular oxygen tension. The elevated chromosome breakagecorrelates histologically with a significant increase in the amount of neuronal cell death in Ku86(-/-) SOD1transgenic embryos over that seen in Ku86(-/-) embryos. Therefore, oxygen metabolism is a majorsource of the genomic instability observed in NHEJ-deficient cells and, presumably, in all cells.", "metadata": {}}
+{"_id": "1944452", "title": "", "text": "Insertional mutagenesis in gene therapy and stem cell biology.PURPOSE OF REVIEW Recent preclinicaland clinical studies revealed that the semirandom insertion of transgenes into chromosomal DNA ofhematopoietic cells may induce clonal competition, which potentially may even trigger leukemia orsarcoma. Insertional mutagenesis caused by gene vectors has thus led to major uncertainty among thosedeveloping advanced hematopoietic cell therapies. This review summarizes novel studies of underlyingmechanisms; these studies have demonstrated the possibility of improved gene vector biosafety andgenerated new insights into stem cell biology. RECENT FINDINGS The characteristic insertion pattern ofvarious retroviral gene vector systems may be explained by properties of the viral integrase andassociated cellular cofactors. Cell culture assays and animal models, including disease-specific andcancer-prone mouse models, are emerging that reveal the contributions of vector features and systemicfactors to induction of clonal imbalance. Databases summarizing vector insertion sites in dominanthematopoietic clones are evolving as new tools to identify genes that regulate clonal homeostasis.SUMMARY Mechanistic studies of insertional mutagenesis by random gene vector insertion will lead toimproved tools for advanced hematopoietic cell therapy. Simultaneously, fascinating insights into genenetworks that regulate cell fitness will be generated, with important consequences for the fields ofhematology, oncology and regenerative medicine.", "metadata": {}}
+{"_id": "1946610", "title": "", "text": "Markets, voucher subsidies and free nets combine to achieve high bed net coverage in ruralTanzaniaBACKGROUND Tanzania has a well-developed network of commercial ITN retailers. In 2004, thegovernment introduced a voucher subsidy for pregnant women and, in mid 2005, helped distribute freenets to under-fives in small number of districts, including Rufiji on the southern coast, during a childhealth campaign. Contributions of these multiple insecticide-treated net delivery strategies existing at thesame time and place to coverage in a poor rural community were assessed. METHODS Cross-sectionalhousehold survey in 6,331 members of randomly selected 1,752 households of 31 rural villages ofDemographic Surveillance System in Rufiji district, Southern Tanzania was conducted in 2006. Aquestionnaire was administered to every consenting respondent about net use, treatment status anddelivery mechanism. FINDINGS Net use was 62.7% overall, 87.2% amongst infants (0 to 1 year), 81.8%amongst young children (>1 to 5 years), 54.5% amongst older children (6 to 15 years) and 59.6%amongst adults (>15 years). 30.2% of all nets had been treated six months prior to interview. Thebiggest source of nets used by infants was purchase from the private sector with a voucher subsidy(41.8%). Half of nets used by young children (50.0%) and over a third of those used by older children(37.2%) were obtained free of charge through the vaccination campaign. The largest source of netsamongst the population overall was commercial purchase (45.1% use) and was the primary means forprotecting adults (60.2% use). All delivery mechanisms, especially sale of nets at full market price,under-served the poorest but no difference in equity was observed between voucher-subsidized andfreely distributed nets. CONCLUSION All three delivery strategies enabled a poor rural community toachieve net coverage high enough to yield both personal and community level protection for the entirepopulation. Each of them reached their relevant target group and free nets only temporarily suppressedthe net market, illustrating that in this setting that these are complementary rather than mutuallyexclusive approaches.", "metadata": {}}
+{"_id": "1958440", "title": "", "text": "Human chorionic gonadotropin levels in maternal blood in late pregnancy: relation to birthweight, sex andcondition of the infant at birth.A total of 527 blood samples was obtained from an unselected populationof women between 36 and 40 weeks gestation. Serum human chorionic gonadotropin (hCG) levels weremeasured using a specific radioimmunoassay for the beta 1-subunit of hCG. Serum hCG levels werehigher in primigravidae and in women carrying female fetuses. They were also related to the birthweightof the child and to the occurrence of fetal distress.", "metadata": {}}
+{"_id": "1964163", "title": "", "text": "Brain-Specific Phosphorylation of MeCP2 Regulates Activity-Dependent Bdnf Transcription, DendriticGrowth, and Spine MaturationMutations or duplications in MECP2 cause Rett and Rett-like syndromes,neurodevelopmental disorders characterized by mental retardation, motor dysfunction, and autisticbehaviors. MeCP2 is expressed in many mammalian tissues and functions as a global repressor oftranscription; however, the molecular mechanisms by which MeCP2 dysfunction leads to theneural-specific phenotypes of RTT remain poorly understood. Here, we show that neuronal activity andsubsequent calcium influx trigger the de novo phosphorylation of MeCP2 at serine 421 (S421) by aCaMKII-dependent mechanism. MeCP2 S421 phosphorylation is induced selectively in the brain inresponse to physiological stimuli. Significantly, we find that S421 phosphorylation controls the ability ofMeCP2 to regulate dendritic patterning, spine morphogenesis, and the activity-dependent induction ofBdnf transcription. These findings suggest that, by triggering MeCP2 phosphorylation, neuronal activityregulates a program of gene expression that mediates nervous system maturation and that disruption ofthis process in individuals with mutations in MeCP2 may underlie the neural-specific pathology of RTT.", "metadata": {}}
+{"_id": "1967017", "title": "", "text": "A Candidate Gene Approach Identifies the TRAF1/C5 Region as a Risk Factor for RheumatoidArthritisCorrection for:    Kurreeman FAS, Padyukov L, Marques RB, Schrodi SJ, Seddighzadeh M, et al.(2007) A Candidate Gene Approach Identifies the TRAF1/C5 Region as a Risk Factor for RheumatoidArthritis. PLoS Med 4(9): e278. doi:10.1371/journal.pmed.0040278    In Table 1, the allele ratio incolumn eight (Allele Ratiosb: Cases, Controls) refers to allele A: allele B and not allele1:allele2 asdescribed in footnote b, with Allele A being the Susceptibility Allele as denoted in column seven. Thefootnote should read:    bNumber of alleles were compared in cases versus controls: allele A: allele Bcases, allele A: allele B controls. Allele A refers to the susceptibility alleles as given in column seven.", "metadata": {}}
+{"_id": "1967410", "title": "", "text": "Potential use of γ-secretase modulators in the treatment of Alzheimer disease.Although significantprogress has occurred in the past 20 years regarding our understanding of Alzheimer diseasepathogenesis, we have yet to identify disease-modifying therapeutics capable of substantially altering theclinical course of this prevalent neurodegenerative disease. In this short review, we discuss 2 approachesthat are currently being tested clinically (γ-secretase inhibition and γ-secretase modulation) andemphasize the significant differences between these 2 therapeutic approaches. We also discuss certaingenetic- and biomarker-based translational and clinical trial paradigms that may assist in developing auseful therapeutic agent.", "metadata": {}}
+{"_id": "1970884", "title": "", "text": "Rational design of a flavivirus vaccine by abolishing viral RNA 2'-O methylation.Viruses that replicate inthe cytoplasm cannot access the host nuclear capping machinery. These viruses have evolved viralmethyltransferase(s) to methylate N-7 and 2'-O cap of their RNA; alternatively, they \"snatch\" host mRNAcap to form the 5' end of viral RNA. The function of 2'-O methylation of viral RNA cap is to mimic cellularmRNA and to evade host innate immune restriction. A cytoplasmic virus defective in 2'-O methylation isreplicative, but its viral RNA lacks 2'-O methylation and is recognized and eliminated by the host immuneresponse. Such a mutant virus could be rationally designed as a live attenuated vaccine. Here, we useJapanese encephalitis virus (JEV), an important mosquito-borne flavivirus, to prove this novel vaccineconcept. We show that JEV methyltransferase is responsible for both N-7 and 2'-O cap methylations aswell as evasion of host innate immune response. Recombinant virus completely defective in 2'-Omethylation was stable in cell culture after being passaged for >30 days. The mutant virus wasattenuated in mice, elicited robust humoral and cellular immune responses, and retained the engineeredmutation in vivo. A single dose of immunization induced full protection against lethal challenge with JEVstrains in mice. Mechanistically, the attenuation phenotype was attributed to the enhanced sensitivity ofthe mutant virus to the antiviral effects of interferon and IFIT proteins. Collectively, the resultsdemonstrate the feasibility of using 2'-O methylation-defective virus as a vaccine approach; this vaccineapproach should be applicable to other flaviviruses and nonflaviviruses that encode their own viral 2'-Omethyltransferases.", "metadata": {}}
+{"_id": "1974176", "title": "", "text": "Fruit consumption and risk of type 2 diabetes: results from three prospective longitudinal cohortstudiesOBJECTIVE To determine whether individual fruits are differentially associated with risk of type 2diabetes. DESIGN Prospective longitudinal cohort study. SETTING Health professionals in the UnitedStates. PARTICIPANTS 66,105 women from the Nurses' Health Study (1984-2008), 85,104 women fromthe Nurses' Health Study II (1991-2009), and 36,173 men from the Health Professionals Follow-up Study(1986-2008) who were free of major chronic diseases at baseline in these studies. MAIN OUTCOMEMEASURE Incident cases of type 2 diabetes, identified through self report and confirmed bysupplementary questionnaires. RESULTS During 3,464,641 person years of follow-up, 12,198 participantsdeveloped type 2 diabetes. After adjustment for personal, lifestyle, and dietary risk factors of diabetes,the pooled hazard ratio of type 2 diabetes for every three servings/week of total whole fruit consumptionwas 0.98 (95% confidence interval 0.97 [corrected] to 0.99). With mutual adjustment of individual fruits,the pooled hazard ratios of type 2 diabetes for every three servings/week were 0.74 (0.66 to 0.83) forblueberries, 0.88 (0.83 to 0.93) for grapes and raisins, 0.89 (0.79 to 1.01) for prunes, 0.93 (0.90 to0.96) for apples and pears, 0.95 (0.91 to 0.98) for bananas, 0.95 (0.91 to 0.99) for grapefruit, 0.97(0.92 to 1.02) for peaches, plums, and apricots, 0.99 (0.95 to 1.03) for oranges, 1.03 (0.96 to 1.10) forstrawberries, and 1.10 (1.02 to 1.18) for cantaloupe. The pooled hazard ratio for the same increment infruit juice consumption was 1.08 (1.05 to 1.11). The associations with risk of type 2 diabetes differedsignificantly among individual fruits (P<0.001 in all cohorts). CONCLUSION Our findings suggest thepresence of heterogeneity in the associations between individual fruit consumption and risk of type 2diabetes. Greater consumption of specific whole fruits, particularly blueberries, grapes, and apples, issignificantly associated with a lower risk of type 2 diabetes, whereas greater consumption of fruit juice isassociated with a higher risk.", "metadata": {}}
+{"_id": "1976183", "title": "", "text": "OncomiR-196 promotes an invasive phenotype in oral cancer through the NME4-JNK-TIMP1-MMPsignaling pathwayBACKGROUND MicroRNA-196 (miR-196), which is highly up-regulated in oral cancercells, has been reported to be aberrantly expressed in several cancers; however, the significance ofmiR-196 in oral cancer has not yet been addressed. METHODS Cellular functions in response to miR-196modulation were examined, including cell growth, migration, invasion and radio/chemosensitivity.Algorithm-based studies were used to identify the regulatory target of miR-196. The miR-196 target geneand downstream molecular mechanisms were confirmed by RT-qPCR, western blot, luciferase reporterand confocal microscopy analyses. miR-196 expression was determined in paired cancer and adjacentnormal tissues from oral cancer patients. RESULTS Both miR-196a and miR-196b were highlyover-expressed in the cancer tissue and correlated with lymph node metastasis (P = 0.001 and P =0.006, respectively). Functionally, miR-196 actively promoted cell migration and invasion withoutaffecting cell growth. Mechanistically, miR-196 performed it's their function by inhibiting NME4 expressionand further activating p-JNK, suppressing TIMP1, and augmenting MMP1/9. CONCLUSION miR-196contributes to oral cancer by promoting cell migration and invasion. Clinically, miR-196a/b wassignificantly over-expressed in the cancer tissues and correlated with lymph node metastasis. Thus, ourfindings provide new knowledge of the underlying mechanism of cancer metastasis. miR-196 may serveas a promising marker for better oral cancer management.", "metadata": {}}
+{"_id": "1982286", "title": "", "text": "Reverse engineering of TLX oncogenic transcriptional networks identifies RUNX1 as tumor suppressor inT-ALLThe TLX1 and TLX3 transcription factor oncogenes have a key role in the pathogenesis of T cellacute lymphoblastic leukemia (T-ALL). Here we used reverse engineering of global transcriptionalnetworks to decipher the oncogenic regulatory circuit controlled by TLX1 and TLX3. This systems biologyanalysis defined T cell leukemia homeobox 1 (TLX1) and TLX3 as master regulators of an oncogenictranscriptional circuit governing T-ALL. Notably, a network structure analysis of this hierarchical networkidentified RUNX1 as a key mediator of the T-ALL induced by TLX1 and TLX3 and predicted atumor-suppressor role for RUNX1 in T cell transformation. Consistent with these results, we identifiedrecurrent somatic loss-of-function mutations in RUNX1 in human T-ALL. Overall, these results place TLX1and TLX3 at the top of an oncogenic transcriptional network controlling leukemia development, show thepower of network analyses to identify key elements in the regulatory circuits governing human cancerand identify RUNX1 as a tumor-suppressor gene in T-ALL.", "metadata": {}}
+{"_id": "1986482", "title": "", "text": "The Impact of the New WHO Antiretroviral Treatment Guidelines on HIV Epidemic Dynamics and Cost inSouth AfricaBACKGROUND Since November 2009, WHO recommends that adults infected with HIV shouldinitiate antiretroviral therapy (ART) at CD4+ cell counts of ≤350 cells/µl rather than ≤200 cells/µl. SouthAfrica decided to adopt this strategy for pregnant and TB co-infected patients only. We estimated theimpact of fully adopting the new WHO guidelines on HIV epidemic dynamics and associated costs.METHODS AND FINDING We used an established model of the transmission and control of HIV inspecified sexual networks and healthcare settings. We quantified the model to represent Hlabisasubdistrict, KwaZulu-Natal, South Africa. We predicted the HIV epidemic dynamics, number on ART andprogram costs under the new guidelines relative to treating patients at ≤200 cells/µl for the next 30years. During the first five years, the new WHO treatment guidelines require about 7% extra annualinvestments, whereas 28% more patients receive treatment. Furthermore, there will be a more profoundimpact on HIV incidence, leading to relatively less annual costs after seven years. The resultingcumulative net costs reach a break-even point after on average 16 years. CONCLUSIONS Our studystrengthens the WHO recommendation of starting ART at ≤350 cells/µl for all HIV-infected patients. Apartfrom the benefits associated with many life-years saved, a modest frontloading appears to lead to netsavings within a limited time-horizon. This finding is robust to alternative assumptions and foreseeablechanges in ART prices and effectiveness. Therefore, South Africa should aim at rapidly expanding itshealthcare infrastructure to fully embrace the new WHO guidelines.", "metadata": {}}
+{"_id": "1991105", "title": "", "text": "ER-associated mitochondrial division links the distribution of mitochondria and mitochondrial DNA inyeastMitochondrial division is important for mitochondrial distribution and function. Recent data havedemonstrated that ER-mitochondria contacts mark mitochondrial division sites, but the molecular basisand functions of these contacts are not understood. Here we show that in yeast, the ER-mitochondriatethering complex, ERMES, and the highly conserved Miro GTPase, Gem1, are spatially and functionallylinked to ER-associated mitochondrial division. Gem1 acts as a negative regulator of ER-mitochondriacontacts, an activity required for the spatial resolution and distribution of newly generated mitochondrialtips following division. Previous data have demonstrated that ERMES localizes with a subset of activelyreplicating mitochondrial nucleoids. We show that mitochondrial division is spatially linked to nucleoidsand that a majority of these nucleoids segregate prior to division, resulting in their distribution into newlygenerated tips in the mitochondrial network. Thus, we postulate that ER-associated division serves to linkthe distribution of mitochondria and mitochondrial nucleoids in cells.DOI:http://dx.doi.org/10.7554/eLife.00422.001.", "metadata": {}}
+{"_id": "1996292", "title": "", "text": "BMI-1 Autoantibody as a New Potential Biomarker for Cervical CarcinomaBMI-1 is overexpressed in avariety of cancers, which can elicit an immune response leading to the induction of autoantibodies.However, BMI-1 autoantibody as a biomarker has seldom been studied with the exception ofnasopharyngeal carcinoma. Whether BMI-1 autoantibodies can be used as a biomarker for cervicalcarcinoma is unclear. In this study,BMI-1 proteins were isolated by screening of a T7 phage cDNA libraryfrom mixed cervical carcinoma tissues. We analyzed BMI-1 autoantibody levels in serum samples from 67patients with cervical carcinoma and 65 controls using ELISA and immunoblot. BMI-1 mRNA or proteinlevels were over-expressed in cervical carcinoma cell lines. Immunoblot results exhibited increased BMI-1autoantibody levels in patient sera compared to normal sera. Additionally, the results for antibody affinityassay showed that there was no difference between cervical polyps and normal sera of BMI-1autoantibody levels, but it was significantly greater in patient sera than that in normal controls (patient0.827±0.043 and normal 0.445±0.023; P<0.001). What's more, the levels of BMI-1 autoantibodyincreased significantly at stage I (0.672±0.019) compared to normal sera (P<0.001), and levels of BMI-1autoantibodies were increased gradually during the tumor progression (stage I 0.672±0.019; stage II0.775 ±0.019; stage III 0.890 ±0.027; stage IV 1.043±0.041), which were significantly correlated withdisease progression of cervical cancer (P<0.001). Statistical analyses using logistic regression andreceiver operating characteristics (ROC) curves indicated that the BMI-1 autoantibody level can be usedas a biomarker for cervical carcinoma (sensitivity 0.78 and specificity 0.76; AUC = 0.922). In conclusion,measuring BMI-1 autoantibody levels of patients with cervical cancer could have clinical prognostic valueas well as a non-tissue specific biomarker for neoplasms expressing BMI-1.", "metadata": {}}
+{"_id": "2000038", "title": "", "text": "MicroRNAs can generate thresholds in target gene expressionMicroRNAs (miRNAs) are short, highlyconserved noncoding RNA molecules that repress gene expression in a sequence-dependent manner. Weperformed single-cell measurements using quantitative fluorescence microscopy and flow cytometry tomonitor a target gene's protein expression in the presence and absence of regulation by miRNA. We findthat although the average level of repression is modest, in agreement with previous population-basedmeasurements, the repression among individual cells varies dramatically. In particular, we show thatregulation by miRNAs establishes a threshold level of target mRNA below which protein production ishighly repressed. Near this threshold, protein expression responds sensitively to target mRNA input,consistent with a mathematical model of molecular titration. These results show that miRNAs can act bothas a switch and as a fine-tuner of gene expression.", "metadata": {}}
+{"_id": "2014909", "title": "", "text": "Oncogenic mTOR signaling recruits myeloid-derived suppressor cells to promote tumorinitiationMyeloid-derived suppressor cells (MDSCs) play critical roles in primary and metastatic cancerprogression. MDSC regulation is widely variable even among patients harbouring the same type ofmalignancy, and the mechanisms governing such heterogeneity are largely unknown. Here, integratinghuman tumour genomics and syngeneic mammary tumour models, we demonstrate that mTOR signallingin cancer cells dictates a mammary tumour's ability to stimulate MDSC accumulation through regulatingG-CSF. Inhibiting this pathway or its activators (for example, FGFR) impairs tumour progression, which ispartially rescued by restoring MDSCs or G-CSF. Tumour-initiating cells (TICs) exhibit elevated G-CSF.MDSCs reciprocally increase TIC frequency through activating Notch in tumour cells, forming afeedforward loop. Analyses of primary breast cancers and patient-derived xenografts corroborate thesemechanisms in patients. These findings establish a non-canonical oncogenic role of mTOR signalling inrecruiting pro-tumorigenic MDSCs and show how defined cancer subsets may evolve to promote anddepend on a distinct immune microenvironment.", "metadata": {}}
+{"_id": "2015126", "title": "", "text": "Management of women who have a genetic predisposition for breast cancer.The management of womenwho have a genetic predisposition for breast cancer requires careful planning. Women who have BRCA 1and BRCA 2 mutations are at increased risk for breast cancer and for other cancers as well, particularlyovarian cancer. Screening, prophlyactic surgery, and chemoprevention are commonly utilized strategiesin the management of these patients, and women may choose more than one of these strategies. Norandomized prospective trials have assessed the impact of these strategies specifically in mutationcarriers. All patients should be informed that screening, prophylactic surgery, and chemoprevention havethe potential for harm as well as benefit.", "metadata": {}}
+{"_id": "2015929", "title": "", "text": "Astrocytes from Familial and Sporadic ALS Patients are Toxic to Motor NeuronsAmyotrophic lateralsclerosis (ALS) is a fatal motor neuron disease, with astrocytes implicated as contributing substantially tomotor neuron death in familial (F)ALS. However, the proposed role of astrocytes in the pathology of ALSderives in part from rodent models of FALS based upon dominant mutations within the superoxidedismutase 1 (SOD1) gene, which account for <2% of all ALS cases. Their role in sporadic (S)ALS, whichaffects >90% of ALS patients, remains to be established. Using astrocytes generated from postmortemtissue from both FALS and SALS patients, we show that astrocytes derived from both patient groups aresimilarly toxic to motor neurons. We also demonstrate that SOD1 is a viable target for SALS, as itsknockdown significantly attenuates astrocyte-mediated toxicity toward motor neurons. Our data highlightastrocytes as a non-cell autonomous component in SALS and provide an in vitro model system toinvestigate common disease mechanisms and evaluate potential therapies for SALS and FALS.", "metadata": {}}
+{"_id": "2028532", "title": "", "text": "High-intensity functional exercise program and protein-enriched energy supplement for older personsdependent in activities of daily living: a randomised controlled trial.The aims of this randomisedcontrolled trial were to determine if a high-intensity functional exercise program improves balance, gaitability, and lower-limb strength in older persons dependent in activities of daily living and if an intake ofprotein-enriched energy supplement immediately after the exercises increases the effects of the training.One hundred and ninety-one older persons dependent in activities of daily living, living in residential carefacilities, and with a Mini-Mental State Examination (MMSE) score of ? 10 participated. They wererandomised to a high-intensity functional exercise program or a control activity, which included 29sessions over 3 months, as well as to protein-enriched energy supplement or placebo. Berg BalanceScale, self-paced and maximum gait speed, and one-repetition maximum in lower-limb strength werefollowed-up at three and six months and analysed by 2 x 2 factorial ANCOVA, using the intention-to-treatprinciple. At three months, the exercise group had improved significantly in self-paced gait speedcompared with the control group (mean difference 0.04 m/s, p = 0.02). At six months, there weresignificant improvements favouring the exercise group for Berg Balance Scale (1.9 points, p = 0.05),self-paced gait speed (0.05 m/s, p = 0.009), and lower-limb strength (10.8 kg, p = 0.03). No interactioneffects were seen between the exercise and nutrition interventions. In conclusion, a high-intensityfunctional exercise program has positive long-term effects in balance, gait ability, and lower-limbstrength for older persons dependent in activities of daily living. An intake of protein-enriched energysupplement immediately after the exercises does not appear to increase the effects of the training.", "metadata": {}}
+{"_id": "2030623", "title": "", "text": "Inhibition of fatty acid oxidation modulates immunosuppressive functions of myeloid-derived suppressorcells and enhances cancer therapiesMyeloid-derived suppressor cells (MDSC) promote tumor growth byinhibiting T-cell immunity and promoting malignant cell proliferation and migration. The therapeuticpotential of blocking MDSC in tumors has been limited by their heterogeneity, plasticity, and resistance tovarious chemotherapy agents. Recent studies have highlighted the role of energy metabolic pathways inthe differentiation and function of immune cells; however, the metabolic characteristics regulating MDSCremain unclear. We aimed to determine the energy metabolic pathway(s) used by MDSC, establish itsimpact on their immunosuppressive function, and test whether its inhibition blocks MDSC and enhancesantitumor therapies. Using several murine tumor models, we found that tumor-infiltrating MDSC(T-MDSC) increased fatty acid uptake and activated fatty acid oxidation (FAO). This was accompanied byan increased mitochondrial mass, upregulation of key FAO enzymes, and increased oxygen consumptionrate. Pharmacologic inhibition of FAO blocked immune inhibitory pathways and functions in T-MDSC anddecreased their production of inhibitory cytokines. FAO inhibition alone significantly delayed tumorgrowth in a T-cell-dependent manner and enhanced the antitumor effect of adoptive T-cell therapy.Furthermore, FAO inhibition combined with low-dose chemotherapy completely inhibited T-MDSCimmunosuppressive effects and induced a significant antitumor effect. Interestingly, a similar increase infatty acid uptake and expression of FAO-related enzymes was found in human MDSC in peripheral bloodand tumors. These results support the possibility of testing FAO inhibition as a novel approach to blockMDSC and enhance various cancer therapies.", "metadata": {}}
+{"_id": "2032877", "title": "", "text": "Predicting mortality of patients hospitalized for acutely exacerbated chronic obstructive pulmonarydisease.PURPOSE To identify factors affecting the short-term prognosis of patients with acutelyexacerbated chronic obstructive pulmonary disease (COPD). PATIENTS AND METHODS The 590 patientshaving COPD as primary disease who were hospitalized in the pneumology unit of a university hospitalfrom 1981 to 1990 were studied. A standardized protocol for the treatment of acutely exacerbated COPDwas adopted for all the patients. The patient records were retrospectively analyzed by two observers, and23 clinical and laboratory variables defining the patient status on admission were collected. Age andarterial gas data were also taken into account, and the outcome mortality was recorded. Interobserverreproducibility was tested by computing the kappa coefficient and Spearman's rho for dichotomous andcontinuous variables, respectively. The relationship of clinical and laboratory factors to the outcome wasassessed first by univariate analysis and then by a logistic regression analysis assessing the independentpredictive role of variables previously shown to be univariately correlated with mortality. RESULTS Themortality rate was 14.4%. The logistic regression analysis identified four independent predictors of death:age (odds ratio [OR] 1.07; 95% confidence interval [CI] 1.04 to 1.11), alveolar-arterial oxygen gradientgreater than 41 mm Hg (OR 2.33; 95% CI 1.39 to 3.90), ventricular arrhythmias (OR 1.91; 95% CI 1.10to 3.31), and atrial fibrillation (OR 2.27; 95% CI 1.14 to 4.51). CONCLUSIONS Patients with acutelyexacerbated COPD having a high risk of death can be identified at the time of admission. Variablesreflecting heart dysfunction are important determinants of this risk. Among pulmonary function data, onlyalveolar-arterial oxygen gradient contributes to the predictive model.", "metadata": {}}
+{"_id": "2033917", "title": "", "text": "Clathrin is required for the function of the mitotic spindleClathrin has an established function in thegeneration of vesicles that transfer membrane and proteins around the cell. The formation ofclathrin-coated vesicles occurs continuously in non-dividing cells, but is shut down during mitosis, whenclathrin concentrates at the spindle apparatus. Here, we show that clathrin stabilizes fibres of the mitoticspindle to aid congression of chromosomes. Clathrin bound to the spindle directly by the amino-terminaldomain of clathrin heavy chain. Depletion of clathrin heavy chain using RNA interference prolongedmitosis; kinetochore fibres were destabilized, leading to defective congression of chromosomes to themetaphase plate and persistent activation of the spindle checkpoint. Normal mitosis was rescued byclathrin triskelia but not the N-terminal domain of clathrin heavy chain, indicating that stabilization ofkinetochore fibres was dependent on the unique structure of clathrin. The importance of clathrin fornormal mitosis may be relevant to understanding human cancers that involve gene fusions of clathrinheavy chain.", "metadata": {}}
+{"_id": "2039912", "title": "", "text": "The origin and neuronal function of in vivo nonsynaptic glutamate.Basal extracellular glutamate sampledin vivo is present in micromolar concentrations in the extracellular space outside the synaptic cleft, andneither the origin nor the function of this glutamate is known. This report reveals that blockade ofglutamate release from the cystine-glutamate antiporter produced a significant decrease (60%) inextrasynaptic glutamate levels in the rat striatum, whereas blockade of voltage-dependent Na+ andCa2+ channels produced relatively minimal changes (0-30%). This indicates that the primary origin of invivo extrasynaptic glutamate in the striatum arises from nonvesicular glutamate release by thecystine-glutamate antiporter. By measuring [35S]cystine uptake, it was shown that similar to vesicularrelease, the activity of the cystine-glutamate antiporter is negatively regulated by group II metabotropicglutamate receptors (mGluR2/3) via a cAMP-dependent protein kinase mechanism. Extracellularglutamate derived from the antiporter was shown to regulate extracellular levels of glutamate anddopamine. Infusion of the mGluR2/3 antagonist (RS)-1-amino-5-phosphonoindan-1-carboxylic acid(APICA) increased extracellular glutamate levels, and previous blockade of the antiporter prevented theAPICA-induced rise in extracellular glutamate. This suggests that glutamate released from the antiporteris a source of endogenous tone on mGluR2/3. Blockade of the antiporter also produced an increase inextracellular dopamine that was reversed by infusing the mGluR2/3 agonist(2R,4R)-4-aminopyrrolidine-2,4-dicarboxlylate, indicating that antiporter-derived glutamate canmodulate dopamine transmission via mGluR2/3 heteroreceptors. These results suggest that nonvesicularrelease from the cystine-glutamate antiporter is the primary source of in vivo extracellular glutamate andthat this glutamate can modulate both glutamate and dopamine transmission.", "metadata": {}}
+{"_id": "2042250", "title": "", "text": "Disease-associated functions of IL-33: the new kid in the IL-1 familyInterleukin-33 (IL-33), a newlydescribed member of the IL-1 family, is expressed by many cell types following pro-inflammatorystimulation and is thought to be released on cell lysis. The IL-33 receptor, consisting of ST2 and IL-1receptor accessory protein, is also widely expressed, particularly by T helper 2 (TH2) cells and mast cells.IL-33 is host-protective against helminth infection and reduces atherosclerosis by promoting TH2-typeimmune responses. However, IL-33 can also promote the pathogenesis of asthma by expanding TH2 cellsand mediate joint inflammation, atopic dermatitis and anaphylaxis by mast cell activation. Thus IL-33could be a new target for therapeutic intervention across a range of diseases.", "metadata": {}}
+{"_id": "2048139", "title": "", "text": "Interferon alpha therapy for hepatitis C: treatment completion and response rates among patients withsubstance use disordersBackgroundIndividuals with substance use disorders (SUDs) are at increased riskfor hepatitis C viral infection (HCV), and few studies have explored their treatment responses empirically.The objective of this study was to assess interferon alpha therapy (IFN) completion and response ratesamong patients with HCV who had a history of comorbid SUDs. More data is needed to inform treatmentstrategies and guidelines for these patients. Using a medical record database, information wasretrospectively collected on 307,437 veterans seen in the Veterans Integrated Service Network 20 (VISN20) of the Veterans Healthcare Administration (VHA) between 1998 and 2003. For patients treated withany type of IFN (including regular or pegylated IFN) or combination therapy (IFN and ribavirin) who had aknown HCV genotype, IFN completion and response rates were compared among patients with a historyof SUD (SUD+ Group) and patients without a history of SUD (SUD- Group).ResultsOdds ratio analysesrevealed that compared with the SUD- Group, the SUD+ Group was equally likely to complete IFNtherapy if they had genotypes 2 and 3 (73.1% vs. 68.0%), and if they had genotypes 1 and 4 (39.5% vs.39.9%). Within the sample of all patients who began IFN therapy, the SUD- and SUD+ groups weresimilarly likely to achieve an end of treatment response (genotypes 2 and 3, 52.8% vs. 54.3%;genotypes 1 and 4, 24.5% vs. 24.8%) and a sustained viral response (genotypes 2 and 3, 42.6% vs.41.1%; genotypes 1 and 4: 16.0% vs. 22.3%).ConclusionIndividuals with and without a history of SUDresponded to antiviral therapy for HCV at similar rates. Collectively, these findings suggest that patientswho have co-morbid SUD and HCV diagnoses can successfully complete a course of antiviral therapy.", "metadata": {}}
+{"_id": "2052720", "title": "", "text": "Association between infection with Helicobacter pylori and risk of gastric cancer: evidence from aprospective investigation.OBJECTIVE To investigate the association between gastric cancer and priorinfection with Helicobacter pylori. DESIGN Case-control comparison of prevalence of IgG antibodies to Hpylori in blood samples collected prospectively, before diagnosis of gastric cancer in the cases. Presenceof H pylori antibody (greater than 10 micrograms IgG/ml) determined by enzyme linked immunosorbentassay (ELISA). SUBJECTS 29 men with a subsequent diagnosis of gastric cancer and 116 aged matchedcontrols selected from over 22,000 middle aged men participating in two ongoing cohort studies (theBritish United Provident Association study and the Caerphilly collaborative heart disease study), who hadprovided blood samples during 1975-1982. RESULTS 20 of the 29 cases (69%) and 54 of the 116controls (47%) were positive for H pylori specific antibody. The median specific IgG concentration wassignificantly higher in the cases than controls (90 micrograms/ml v 3.6 micrograms/ml, p less than 0.01).The estimated odds ratio for the risk of gastric cancer in those with a history of infection with H pylori was2.77 (95% confidence interval 1.04 to 7.97, 2p = 0.039). CONCLUSIONS H pylori infection may be animportant cause of gastric cancer; between 35% and 55% of all cases may be associated with such aninfection.", "metadata": {}}
+{"_id": "2053540", "title": "", "text": "Oncostatin M and leukemia inhibitory factor do not use the same functional receptor in mice.Oncostatin M(OSM) and leukemia inhibitory factor (LIF) are members of the interleukin-6 (IL-6) subfamily of cytokinesthat use a common signal transducer gp130. Human OSM (hOSM) and LIF share a functional high-affinityreceptor that is composed of gp130 and LIF receptor beta subunit (LIFRbeta). A second high-affinityreceptor for hOSM was recently found to be formed by gp130 and the hOSM receptor beta subunit.However, the nature of murine OSM (mOSM) and its receptors has remained unknown. Using the recentlycloned mOSM cDNA, we produced recombinant mOSM and studied its biological activity and receptorstructure. Murine hematopoietic cell lines M1 and DA1.a, an embryonic stem cell line CCE, and Ba/F3transfectants expressing gp130 and LIFRbeta responded to murine LIF (mLIF) and hOSM equally well,while these cells responded to mOSM only at a 30-fold to 100-fold higher concentration than those ofmLIF and hOSM. In contrast, NIH3T3 cells responded to mOSM, but not to mLIF and hOSM. Scatchardplot analyses showed that mOSM bound to gp130 with low-affinity (kd = 2.8 to 4.2 nmol/L) and that thebinding affinity did not increase in the presence of LIFRbeta. However, mOSM bound to NIH3T3 cells withhigh-affinity (kd = 660 pmol/L), whereas mLIF did not bind to NIH3T3 cells at all. These results indicatethat unlike hOSM, mOSM and mLIF do not share the same functional receptor, and mOSM delivers signalsonly through its specific receptor complex. Further studies in mice will define the physiological roles ofOSM.", "metadata": {}}
+{"_id": "2056197", "title": "", "text": "Multifunctional in vivo vascular imaging using near-infrared II fluorescenceIn vivo real-timeepifluorescence imaging of mouse hind limb vasculatures in the second near-infrared region (NIR-II) isperformed using single-walled carbon nanotubes as fluorophores. Both high spatial (\u000030 μm) andtemporal (<200 ms per frame) resolution for small-vessel imaging are achieved at 1–3 mm deep in thehind limb owing to the beneficial NIR-II optical window that affords deep anatomical penetration and lowscattering. This spatial resolution is unattainable by traditional NIR imaging (NIR-I) or microscopiccomputed tomography, and the temporal resolution far exceeds scanning microscopic imagingtechniques. Arterial and venous vessels are unambiguously differentiated using a dynamiccontrast-enhanced NIR-II imaging technique on the basis of their distinct hemodynamics. Further, thedeep tissue penetration and high spatial and temporal resolution of NIR-II imaging allow for precisequantifications of blood velocity in both normal and ischemic femoral arteries, which are beyond thecapabilities of ultrasonography at lower blood velocities.", "metadata": {}}
+{"_id": "2058909", "title": "", "text": "Colorectal cancer survival in socioeconomic groups in England: variation is mainly in the short term afterdiagnosis.UNLABELLED The objective of this study was to examine differences in cancer survival betweensocioeconomic groups in England, with particular attention to survival in the short term of follow-up.PATIENTS AND METHODS Individuals diagnosed with colorectal cancer between 1996 and 2004 inEngland were identified from cancer registry records. Five-year cumulative relative survival and excessdeath rates were computed. RESULTS For colon cancer there was a very high excess death rate in thefirst month of follow-up, and the excess death rate was highest in the socioeconomically deprived groups.In subsequent periods, excess mortality rates were much lower and there was less socioeconomicvariation. The pattern of variation in excess death rates was generally similar in rectal cancer but thesocioeconomic difference in death rates persisted several years longer. If the excess death rates in theentire colorectal cancer patient population were the same as those observed in the most affluentsocioeconomic quintile, the annual reduction would be 360 deaths in colon cancer and 336 deaths inrectal cancer patients. These deaths occurred almost entirely in the first month and the first year afterdiagnosis. CONCLUSION Recent developments in the national cancer control agenda have included anincreasing emphasis on outcome measures, with short-term cancer survival an operational measure ofvariation and progress in cancer control. In providing clues to the nature of the survival differencesbetween socioeconomic groups, the results presented here give strong support for this strategy.", "metadata": {}}
+{"_id": "2060137", "title": "", "text": "Cardiac myocyte remodeling mediated by N-cadherin-dependent mechanosensing.Cell-to-cell adhesionsare crucial in maintaining the structural and functional integrity of cardiac cells. Little is known about themechanosensitivity and mechanotransduction of cell-to-cell interactions. Most studies of cardiacmechanotransduction and myofibrillogenesis have focused on cell-extracellular matrix (ECM)-specificinteractions. This study assesses the direct role of intercellular adhesion, specifically that ofN-cadherin-mediated mechanotransduction, on the morphology and internal organization of neonatalventricular cardiac myocytes. The results show that cadherin-mediated cell attachments are capable ofeliciting a cytoskeletal network response similar to that of integrin-mediated force response andtransmission, affecting myofibrillar organization, myocyte shape, and cortical stiffness. Traction forcesmediated by N-cadherin were shown to be comparable to those sustained by ECM. The directionalchanges in predicted traction forces as a function of imposed loads (gel stiffness) provide the addedevidence that N-cadherin is a mechanoresponsive adhesion receptor. Strikingly, the mechanicalsensitivity response (gain) in terms of the measured cell-spread area as a function of imposed load(adhesive substrate rigidity) was consistently higher for N-cadherin-coated surfaces compared with ECMprotein-coated surfaces. In addition, the cytoskeletal architecture of myocytes on an N-cadherin adhesivemicroenvironment was characteristically different from that on an ECM environment, suggesting that thetwo mechanotransductive cell adhesion systems may play both independent and complementary roles inmyocyte cytoskeletal spatial organization. These results indicate that cell-to-cell-mediated forceperception and transmission are involved in the organization and development of cardiac structure andfunction.", "metadata": {}}
+{"_id": "2061878", "title": "", "text": "NEAT1: A novel cancer\u0000related long non\u0000coding RNAAberrant overexpression of the long non-codingRNA NEAT1 (nuclear paraspeckle assembly transcript 1) has been documented in different types of solidtumours, such as lung cancer, oesophageal cancer, colorectal cancer and hepatocellular carcinoma, inwhich its high levels are associated with poor prognosis. In contrast, NEAT1 is downregulated in acutepromyelocytic leukaemia where it promotes leucocyte differentiation. In this review, we provide anoverview of current evidence concerning the oncogenic role and potential clinical utilities of NEAT1.Further investigations are warranted to elucidate the upstream and downstream mechanisms of NEAT1overexpression.", "metadata": {}}
+{"_id": "2062382", "title": "", "text": "The Function and Therapeutic Potential of Long Non-coding RNAs in Cardiovascular Development andDiseaseThe popularization of genome-wide analyses and RNA sequencing led to the discovery that a largepart of the human genome, while effectively transcribed, does not encode proteins. Long non-codingRNAs have emerged as critical regulators of gene expression in both normal and disease states. Studiesof long non-coding RNAs expressed in the heart, in combination with gene association studies, revealedthat these molecules are regulated during cardiovascular development and disease. Some longnon-coding RNAs have been functionally implicated in cardiac pathophysiology and constitute potentialtherapeutic targets. Here, we review the current knowledge of the function of long non-coding RNAs inthe cardiovascular system, with an emphasis on cardiovascular development and biology, focusing onhypertension, coronary artery disease, myocardial infarction, ischemia, and heart failure. We discusspotential therapeutic implications and the challenges of long non-coding RNA research, with directions forfuture research and translational focus.", "metadata": {}}
+{"_id": "2078658", "title": "", "text": "Oct4 links multiple epigenetic pathways to the pluripotency networkOct4 is a well-known transcriptionfactor that plays fundamental roles in stem cell self-renewal, pluripotency, and somatic cellreprogramming. However, limited information is available on Oct4-associated protein complexes and theirintrinsic protein-protein interactions that dictate Oct4's critical regulatory activities. Here we employed animproved affinity purification approach combined with mass spectrometry to purify Oct4 proteincomplexes in mouse embryonic stem cells (mESCs), and discovered many novel Oct4 partners importantfor self-renewal and pluripotency of mESCs. Notably, we found that Oct4 is associated with multiplechromatin-modifying complexes with documented as well as newly proved functional significance in stemcell maintenance and somatic cell reprogramming. Our study establishes a solid biochemical basis forgenetic and epigenetic regulation of stem cell pluripotency and provides a framework for exploringalternative factor-based reprogramming strategies.", "metadata": {}}
+{"_id": "2086909", "title": "", "text": "Tet1 is dispensable for maintaining pluripotency and its loss is compatible with embryonic and postnataldevelopment.The Tet family of enzymes (Tet1/2/3) converts 5-methylcytosine (5mC) to5-hydroxymethylcytosine (5hmC). Mouse embryonic stem cells (mESCs) highly express Tet1 and have anelevated level of 5hmC. Tet1 has been implicated in ESC maintenance and lineage specification in vitrobut its precise function in development is not well defined. To establish the role of Tet1 in pluripotencyand development, we have generated Tet1 mutant mESCs and mice. Tet1(-/-) ESCs have reduced levelsof 5hmC and subtle changes in global gene expression, and are pluripotent and support development oflive-born mice in tetraploid complementation assay, but display skewed differentiation towardtrophectoderm in vitro. Tet1 mutant mice are viable, fertile, and grossly normal, though some mutantmice have a slightly smaller body size at birth. Our data suggest that Tet1 loss leading to a partialreduction in 5hmC levels does not affect pluripotency in ESCs and is compatible with embryonic andpostnatal development.", "metadata": {}}
+{"_id": "2095573", "title": "", "text": "LDL-cholesterol concentrations: a genome-wide association studyBACKGROUND LDL cholesterol has acausal role in the development of cardiovascular disease. Improved understanding of the biologicalmechanisms that underlie the metabolism and regulation of LDL cholesterol might help to identify noveltherapeutic targets. We therefore did a genome-wide association study of LDL-cholesterol concentrations.METHODS We used genome-wide association data from up to 11,685 participants with measures ofcirculating LDL-cholesterol concentrations across five studies, including data for 293 461 autosomal singlenucleotide polymorphisms (SNPs) with a minor allele frequency of 5% or more that passed our qualitycontrol criteria. We also used data from a second genome-wide array in up to 4337 participants fromthree of these five studies, with data for 290,140 SNPs. We did replication studies in two independentpopulations consisting of up to 4979 participants. Statistical approaches, including meta-analysis andlinkage disequilibrium plots, were used to refine association signals; we analysed pooled data from allseven populations to determine the effect of each SNP on variations in circulating LDL-cholesterolconcentrations. FINDINGS In our initial scan, we found two SNPs (rs599839 [p=1.7x10(-15)] andrs4970834 [p=3.0x10(-11)]) that showed genome-wide statistical association with LDL cholesterol atchromosomal locus 1p13.3. The second genome screen found a third statistically associated SNP at thesame locus (rs646776 [p=4.3x10(-9)]). Meta-analysis of data from all studies showed an association ofSNPs rs599839 (combined p=1.2x10(-33)) and rs646776 (p=4.8x10(-20)) with LDL-cholesterolconcentrations. SNPs rs599839 and rs646776 both explained around 1% of the variation in circulatingLDL-cholesterol concentrations and were associated with about 15% of an SD change in LDL cholesterolper allele, assuming an SD of 1 mmol/L.   INTERPRETATION We found evidence for a novel locus for LDLcholesterol on chromosome 1p13.3. These results potentially provide insight into the biologicalmechanisms that underlie the regulation of LDL cholesterol and might help in the discovery of noveltherapeutic targets for cardiovascular disease.", "metadata": {}}
+{"_id": "2097256", "title": "", "text": "Population Density, Water Supply, and the Risk of Dengue Fever in Vietnam: Cohort Study and SpatialAnalysisBACKGROUND Aedes aegypti, the major vector of dengue viruses, often breeds in water storagecontainers used by households without tap water supply, and occurs in high numbers even in denseurban areas. We analysed the interaction between human population density and lack of tap water as acause of dengue fever outbreaks with the aim of identifying geographic areas at highest risk. METHODSAND FINDINGS We conducted an individual-level cohort study in a population of 75,000 geo-referencedhouseholds in Vietnam over the course of two epidemics, on the basis of dengue hospital admissions (n =3,013). We applied space-time scan statistics and mathematical models to confirm the findings. Weidentified a surprisingly narrow range of critical human population densities between around 3,000 to7,000 people/km² prone to dengue outbreaks. In the study area, this population density was typical ofvillages and some peri-urban areas. Scan statistics showed that areas with a high population density oradequate water supply did not experience severe outbreaks. The risk of dengue was higher in rural thanin urban areas, largely explained by lack of piped water supply, and in human population densities moreoften falling within the critical range. Mathematical modeling suggests that simple assumptions regardingarea-level vector/host ratios may explain the occurrence of outbreaks. CONCLUSIONS Rural areas maycontribute at least as much to the dissemination of dengue fever as cities. Improving water supply andvector control in areas with a human population density critical for dengue transmission could increasethe efficiency of control efforts. Please see later in the article for the Editors' Summary.", "metadata": {}}
+{"_id": "2099400", "title": "", "text": "Helicobacter pylori induces AGS cell motility and elongation via independent signalingpathways.Helicobacter pylori induces motogenic and cytoskeletal responses in gastric epithelial cells. Wedemonstrate that these responses can be induced via independent signaling pathways that often occur inparallel. The cag pathogenicity island appears to be nonessential for induction of motility, whereas theelongation phenotype depends on translocation and phosphorylation of CagA.", "metadata": {}}
+{"_id": "2107238", "title": "", "text": "The Sequence Alignment/Map format and SAMtoolsSUMMARY The Sequence Alignment/Map (SAM)format is a generic alignment format for storing read alignments against reference sequences, supportingshort and long reads (up to 128 Mbp) produced by different sequencing platforms. It is flexible in style,compact in size, efficient in random access and is the format in which alignments from the 1000 GenomesProject are released. SAMtools implements various utilities for post-processing alignments in the SAMformat, such as indexing, variant caller and alignment viewer, and thus provides universal tools forprocessing read alignments. AVAILABILITY http://samtools.sourceforge.net.", "metadata": {}}
+{"_id": "2119889", "title": "", "text": "Characterization of two classes of small molecule inhibitors of Arp2/3 complexPolymerization of actinfilaments directed by the actin-related protein (Arp)2/3 complex supports many types of cellularmovements. However, questions remain regarding the relative contributions of Arp2/3 complex versusother mechanisms of actin filament nucleation to processes such as path finding by neuronal growthcones; this is because of the lack of simple methods to inhibit Arp2/3 complex reversibly in living cells.Here we describe two classes of small molecules that bind to different sites on the Arp2/3 complex andinhibit its ability to nucleate actin filaments. CK-0944636 binds between Arp2 and Arp3, where it appearsto block movement of Arp2 and Arp3 into their active conformation. CK-0993548 inserts into thehydrophobic core of Arp3 and alters its conformation. Both classes of compounds inhibit formation ofactin filament comet tails by Listeria and podosomes by monocytes. Two inhibitors with differentmechanisms of action provide a powerful approach for studying the Arp2/3 complex in living cells.", "metadata": {}}
+{"_id": "2121272", "title": "", "text": "Stresses at the cell-to-substrate interface during locomotion of fibroblastsRecent technologicalimprovements in the elastic substrate method make it possible to produce spatially resolvedmeasurements of the tractions exerted by single motile cells. In this study we have applied thesedevelopments to produce maps of the tractions exerted by 3T3 fibroblasts during steady locomotion. Theresulting images have a spatial resolution of approximately 5 micrometers and a maximum intensity ofapproximately 10(2) kdyn/cm2 (10(4) pN/micrometers2). We find that the propulsive thrust for fibroblastlocomotion, approximately 0.2 dyn, is imparted to the substratum within 15 micrometers of the leadingedge. These observations demonstrate that the lamellipodium of the fibroblast is able to generate intensetraction stress. The cell body and posterior seem to be mechanically passive structures pulled forwardentirely by this action.", "metadata": {}}
+{"_id": "2130391", "title": "", "text": "Cancer-associated adipocytes exhibit an activated phenotype and contribute to breast cancerinvasion.Early local tumor invasion in breast cancer results in a likely encounter between cancer cells andmature adipocytes, but the role of these fat cells in tumor progression remains unclear. We show thatmurine and human tumor cells cocultivated with mature adipocytes exhibit increased invasive capacitiesin vitro and in vivo, using an original two-dimensional coculture system. Likewise, adipocytes cultivatedwith cancer cells also exhibit an altered phenotype in terms of delipidation and decreased adipocytemarkers associated with the occurrence of an activated state characterized by overexpression ofproteases, including matrix metalloproteinase-11, and proinflammatory cytokines [interleukin (IL)-6,IL-1β]. In the case of IL-6, we show that it plays a key role in the acquired proinvasive effect by tumorcells. Equally important, we confirm the presence of these modified adipocytes in human breast tumorsby immunohistochemistry and quantitative PCR. Interestingly, the tumors of larger size and/or withlymph nodes involvement exhibit the higher levels of IL-6 in tumor surrounding adipocytes. Collectively,all our data provide in vitro and in vivo evidence that (i) invasive cancer cells dramatically impactsurrounding adipocytes; (ii) peritumoral adipocytes exhibit a modified phenotype and specific biologicalfeatures sufficient to be named cancer-associated adipocytes (CAA); and (iii) CAAs modify the cancer cellcharacteristics/phenotype leading to a more aggressive behavior. Our results strongly support theinnovative concept that adipocytes participate in a highly complex vicious cycle orchestrated by cancercells to promote tumor progression that might be amplified in obese patients.", "metadata": {}}
+{"_id": "2138767", "title": "", "text": "Prevalence of cardiovascular disease risk factor in the Chinese population: the 2007-2008 China NationalDiabetes and Metabolic Disorders Study.AIMS Cardiovascular disease (CVD) is now the most prevalentand debilitating disease affecting the Chinese population. The goal of the present manuscript was toanalyse cardiovascular risk factors and the prevalence of non-fatal CVDs from data gathered from the2007-2008 China National Diabetes and Metabolic Disorders Study. METHODS AND RESULTS A nationallyrepresentative sample of 46 239 adults, 20 years of age or older, was randomly recruited using amultistage stratified design method. Lifestyle factors, diagnosis of CVD, stroke, diabetes, and familyhistory of each subject were collected, and an oral glucose tolerance test or a standard meal test wasperformed. Various non-fatal CVDs were reported by the subjects. SUDAAN software was used to performall weighted statistical analyses, with P < 0.05 considered statistically significant. The prevalence ofcoronary heart disease, stroke, and CVDs was 0.74, 1.07, and 1.78% in males; and 0.51, 0.60, and1.10% in females, respectively. The presence of CVDs increased with age in both males and females. Theprevalence of being overweight or obese, hypertension, dyslipidaemia, or hyperglycaemia was 36.67,30.09, 67.43, and 26.69% in males; and 29.77, 24.79, 63.98, and 23.62% in females, respectively. Inthe total sample of 46 239 patients, the prevalence of one subject having 1, 2, 3, or ≥4 of the 5 definedrisk factors (i.e. smoking, overweight or obese, hypertension, dyslipidaemia, or hyperglycaemia) was31.17, 27.38, 17.76, and 10.19%, respectively. Following adjustment for gender and age, the odds ratioof CVDs for those who had 1, 2, 3, or ≥4 risk factors was 2.36, 4.24, 4.88, and 7.22, respectively, whencompared with patients with no risk factors. CONCLUSION Morbidity attributed to the five definedcardiovascular risk factors was high in the Chinese population, with multiple risk factors present in thesame individual. Therefore, reasonable prevention strategies should be designed to attenuate the rapidrise in cardiovascular morbidity.", "metadata": {}}
+{"_id": "2138843", "title": "", "text": "Microvascular and Macrovascular Complications of DiabetesDiabetes is a group of chronic diseasescharacterized by hyperglycemia. Modern medical care uses a vast array of lifestyle and pharmaceuticalinterventions aimed at preventing and controlling hyperglycemia. In addition to ensuring the adequatedelivery of glucose to the tissues of the body, treatment of diabetes attempts to decrease the likelihoodthat the tissues of the body are harmed by hyperglycemia. The importance of protecting the body fromhyperglycemia cannot be overstated; the direct and indirect effects on the human vascular tree are themajor source of morbidity and mortality in both type 1 and type 2 diabetes. Generally, the injuriouseffects of hyperglycemia are separated into macrovascular complications (coronary artery disease,peripheral arterial disease, and stroke) and microvascular complications (diabetic nephropathy,neuropathy, and retinopathy). It is important for physicians to understand the relationship betweendiabetes and vascular disease because the prevalence of diabetes continues to increase in the UnitedStates, and the clinical armamentarium for primary and secondary prevention of these complications isalso expanding. ### Diabetic retinopathy  Diabetic retinopathy may be the most common microvascularcomplication of diabetes. It is responsible for \u0000 10,000 new cases of blindness every year in the UnitedStates alone.1 The risk of developing diabetic retinopathy or other microvascular complications ofdiabetes depends on both the duration and the severity of hyperglycemia. Development of diabeticretinopathy in patients with type 2 diabetes was found to be related to both severity of hyperglycemiaand presence of hypertension in the U.K. Prospective Diabetes Study (UKPDS), and most patients withtype 1 diabetes develop evidence of retinopathy within 20 years of diagnosis.2,3 Retinopathy may beginto develop as early as 7 years before the diagnosis of diabetes in patients with type 2 diabetes.1 Thereare several proposed pathological mechanisms by which diabetes may lead …", "metadata": {}}
+{"_id": "2139357", "title": "", "text": "Involvement of S-nitrosylation of actin in inhibition of neurotransmitter release by nitricoxideBACKGROUND The role of the diffusible messenger nitric oxide (NO) in the regulation of paintransmission is still a debate of matter, pro-nociceptive and/or anti-nociceptive. S-Nitrosylation, thereversible post-translational modification of selective cysteine residues in proteins, has emerged as animportant mechanism by which NO acts as a signaling molecule. The occurrence of S-nitrosylation in thespinal cord and its targets that may modulate pain transmission remain unclarified. The \"biotin-switch\"method and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry were employedfor identifying S-nitrosylated proteins. RESULTS Here we show that actin was a major proteinS-nitrosylated in the spinal cord by the NO donor, S-nitroso-N-acetyl-DL-penicillamine (SNAP).Interestingly, actin was S-nitrosylated, more in the S2 fraction than in the P2 fraction of the spinalhomogenate. Treatment of PC12 cells with SNAP caused rapid S-nitrosylation of actin and inhibiteddopamine release from the cells. Just like cytochalasin B, which depolymerizes actin, SNAP decreased theamount of filamentous actin cytoskeleton just beneath the membrane. The inhibition of dopamine releasewas not attenuated by inhibitors of soluble guanylyl cyclase and cGMP-dependent protein kinase.CONCLUSION The present study demonstrates that actin is a major S-nitrosylated protein in the spinalcord and suggests that NO directly regulates neurotransmitter release by S-nitrosylation in addition tothe well-known phosphorylation by cGMP-dependent protein kinase.", "metadata": {}}
+{"_id": "2140497", "title": "", "text": "Independent Association of Lobular Involution and Mammographic Breast Density With Breast CancerRiskBACKGROUND Lobular involution, or age-related atrophy of breast lobules, is inversely associatedwith breast cancer risk, and mammographic breast density (MBD) is positively associated with breastcancer risk. METHODS To evaluate whether lobular involution and MBD are independently associated withbreast cancer risk in women with benign breast disease, we performed a nested cohort study amongwomen (n = 2666) with benign breast disease diagnosed at Mayo Clinic between January 1, 1985, andDecember 31, 1991 and a mammogram available within 6 months of the diagnosis. Women werefollowed up for an average of 13.3 years to document any breast cancer incidence. Lobular involution wascategorized as none, partial, or complete; parenchymal pattern was classified using the Wolfeclassification as N1 (nondense), P1, P2 (ductal prominence occupying <25%, or >25% of the breast,respectively), or DY (extremely dense). Hazard ratios (HRs) and 95% confidence intervals (CIs) to assessassociations of lobular involution and MBD with breast cancer risk were estimated using adjusted Coxproportional hazards model. All tests of statistical significance were two-sided. RESULTS After adjustmentfor MBD, having no or partial lobular involution was associated with a higher risk of breast cancer thanhaving complete involution (none: HR of breast cancer incidence = 2.62, 95% CI = 1.39 to 4.94; partial:HR of breast cancer incidence = 1.61, 95% CI = 1.03 to 2.53; P(trend) = .002). Similarly, afteradjustment for involution, having dense breasts was associated with higher risk of breast cancer thanhaving nondense breasts (for DY: HR of breast cancer incidence = 1.67, 95% CI = 1.03 to 2.73; for P2:HR of breast cancer incidence = 1.96, 95% CI = 1.20 to 3.21; for P1: HR of breast cancer incidence =1.23, 95% CI = 0.67 to 2.26; P(trend) = .02). Having a combination of no involution and dense breastswas associated with higher risk of breast cancer than having complete involution and nondense breasts(HR of breast cancer incidence = 4.08, 95% CI = 1.72 to 9.68; P = .006). CONCLUSION Lobularinvolution and MBD are independently associated with breast cancer incidence; combined, they areassociated with an even greater risk for breast cancer.", "metadata": {}}
+{"_id": "2140513", "title": "", "text": "Pleiotropy as a mechanism to stabilize cooperationMost genes affect many traits. This phenomenon,known as pleiotropy, is a major constraint on evolution because adaptive change in one trait may beprevented because it would compromise other traits affected by the same genes. Here we show thatpleiotropy can have an unexpected effect and benefit one of the most enigmatic ofadaptations—cooperation. A spectacular act of cooperation occurs in the social amoeba Dictyosteliumdiscoideum, in which some cells die to form a stalk that holds the other cells aloft as reproductive spores.We have identified a gene, dimA, in D. discoideum that has two contrasting effects. It is required toreceive the signalling molecule DIF-1 that causes differentiation into prestalk cells. Ignoring DIF-1 andnot becoming prestalk should allow cells to cheat by avoiding the stalk. However, we find that inaggregations containing the wild-type cells, lack of the dimA gene results in exclusion from spores. Thispleiotropic linkage of stalk and spore formation limits the potential for cheating in D. discoideum becausedefecting on prestalk cell production results in an even greater reduction in spores. We propose that theevolution of pleiotropic links between cheating and personal costs can stabilize cooperative adaptations.", "metadata": {}}
+{"_id": "2147704", "title": "", "text": "The homeobox gene goosecoid controls cell migration in Xenopus embryos.Goosecoid (gsc), a homeoboxgene expressed specifically in the dorsal blastopore lip of the Xenopus gastrula, is considered to play animportant role in Spemann's organizer phenomenon. Lineage tracing and time-lapse microscopy wereused to follow the fate of embryonic cells microinjected with gsc mRNA. Microinjected gsc has non-cellautonomous effects, recruiting neighboring uninjected cells into a twinned dorsal axis. Ectopic expressionof gsc mRNA in ventral blastomeres as well as overexpression of gsc in dorsal blastomeres leads to cellmovement toward the anterior of the embryo. The results suggest a function for gsc in the control ofgastrulation movements in groups of cells, but not in dissociated cells, and demonstrate that a vertebratehomeobox gene can regulate region-specific cell migration.", "metadata": {}}
+{"_id": "2151983", "title": "", "text": "Epigenetic switch involved in activation of pioneer factor FOXA1-dependent enhancers.Transcriptionfactors (TFs) bind specifically to discrete regions of mammalian genomes called cis-regulatory elements.Among those are enhancers, which play key roles in regulation of gene expression during developmentand differentiation. Despite the recognized central regulatory role exerted by chromatin in control of TFfunctions, much remains to be learned regarding the chromatin structure of enhancers and how it isestablished. Here, we have analyzed on a genomic-scale enhancers that recruit FOXA1, a pioneertranscription factor that triggers transcriptional competency of these cis-regulatory sites. Importantly, wefound that FOXA1 binds to genomic regions showing local DNA hypomethylation and that itscell-type-specific recruitment to chromatin is linked to differential DNA methylation levels of its bindingsites. Using neural differentiation as a model, we showed that induction of FOXA1 expression and itssubsequent recruitment to enhancers is associated with DNA demethylation. Concomitantly, histone H3lysine 4 methylation is induced at these enhancers. These epigenetic changes may both stabilize FOXA1binding and allow for subsequent recruitment of transcriptional regulatory effectors. Interestingly, whencloned into reporter constructs, FOXA1-dependent enhancers were able to recapitulate their cell typespecificity. However, their activities were inhibited by DNA methylation. Hence, these enhancers areintrinsic cell-type-specific regulatory regions of which activities have to be potentiated by FOXA1 throughinduction of an epigenetic switch that includes notably DNA demethylation.", "metadata": {}}
+{"_id": "2158500", "title": "", "text": "Leptin treatment ameliorates anxiety in ob/ob obese mice.We investigated whether or not administeredleptin influences anxiety-like behavior in ob/ob mice. Repeated intraperitoneal administrations of leptinwere continued for 5 days. Anxiety was assessed in the standard elevated plus maze. Body weight wasmeasured daily. Repeated administrations of leptin significantly increased the percentage of the totalnumber of entries in the open arms and the number of total entries. The body weight was significantlyreduced by 13.2% after treatment. Leptin treatment ameliorated not only obesity but also anxiety inob/ob mice. Our results indicate that the treatment of obesity may lead to the solution of psychologicalproblems.", "metadata": {}}
+{"_id": "2158516", "title": "", "text": "Predicting new molecular targets for known drugsAlthough drugs are intended to be selective, at leastsome bind to several physiological targets, explaining side effects and efficacy. Because manydrug-target combinations exist, it would be useful to explore possible interactions computationally. Herewe compared 3,665 US Food and Drug Administration (FDA)-approved and investigational drugs againsthundreds of targets, defining each target by its ligands. Chemical similarities between drugs and ligandsets predicted thousands of unanticipated associations. Thirty were tested experimentally, including theantagonism of the beta(1) receptor by the transporter inhibitor Prozac, the inhibition of the5-hydroxytryptamine (5-HT) transporter by the ion channel drug Vadilex, and antagonism of thehistamine H(4) receptor by the enzyme inhibitor Rescriptor. Overall, 23 new drug-target associationswere confirmed, five of which were potent (<100 nM). The physiological relevance of one, the drugN,N-dimethyltryptamine (DMT) on serotonergic receptors, was confirmed in a knockout mouse. Thechemical similarity approach is systematic and comprehensive, and may suggest side-effects and newindications for many drugs.", "metadata": {}}
+{"_id": "2159648", "title": "", "text": "Bone loss and vascular calcification: A bi-directional interplay?Vascular calcification (VC) represents arecognized adverse predictor for cardiovascular morbidity and mortality. Previously considered passiveand degenerative, VC is now recognized as an active process that resembles bone formation, and sharesa number of histopathological features, mineral composition, and initiation mechanisms with bonedevelopment and metabolism. Oxidative stress and inflammation are key factors in both VC andosteoporosis (OP). Biochemical factors known to be primarily involved in the healthy bone metabolismalso regulate VC. These biomarkers include vitamin D, osteoprotegerin, osteopontin, matrix Gla protein,cathepsin K, fibroblast growth factor-23, and fetuin-A. A better understanding of this highly controlledregulatory network, with multiple, nested feedback loops and cross talk between organs, may help todecrease the growing prevalence of calcific vasculopathy as well as OP in the aging population, and toadvance in common preventive and therapeutic interventions targeted at both conditions.", "metadata": {}}
+{"_id": "2177022", "title": "", "text": "Immobilized chemokine fields and soluble chemokine gradients cooperatively shape migration patterns ofdendritic cells.Chemokines orchestrate immune cell trafficking by eliciting either directed or randommigration and by activating integrins in order to induce cell adhesion. Analyzing dendritic cell (DC)migration, we showed that these distinct cellular responses depended on the mode of chemokinepresentation within tissues. The surface-immobilized form of the chemokine CCL21, the heparansulfate-anchoring ligand of the CC-chemokine receptor 7 (CCR7), caused random movement of DCs thatwas confined to the chemokine-presenting surface because it triggered integrin-mediated adhesion. Upondirect contact with CCL21, DCs truncated the anchoring residues of CCL21, thereby releasing it from thesolid phase. Soluble CCL21 functionally resembles the second CCR7 ligand, CCL19, which lacks anchoringresidues and forms soluble gradients. Both soluble CCR7 ligands triggered chemotactic movement, butnot surface adhesion. Adhesive random migration and directional steering cooperate to produce dynamicbut spatially restricted locomotion patterns closely resembling the cellular dynamics observed insecondary lymphoid organs.", "metadata": {}}
+{"_id": "2192419", "title": "", "text": "Local proliferation dominates lesional macrophage accumulation in atherosclerosisDuring theinflammatory response that drives atherogenesis, macrophages accumulate progressively in theexpanding arterial wall. The observation that circulating monocytes give rise to lesional macrophages hasreinforced the concept that monocyte infiltration dictates macrophage buildup. Recent work hasindicated, however, that macrophage accumulation does not depend on monocyte recruitment in someinflammatory contexts. We therefore revisited the mechanism underlying macrophage accumulation inatherosclerosis. In murine atherosclerotic lesions, we found that macrophages turn over rapidly, after 4weeks. Replenishment of macrophages in these experimental atheromata depends predominantly on localmacrophage proliferation rather than monocyte influx. The microenvironment orchestrates macrophageproliferation through the involvement of scavenger receptor A (SR-A). Our study reveals macrophageproliferation as a key event in atherosclerosis and identifies macrophage self-renewal as a therapeutictarget for cardiovascular disease.", "metadata": {}}
+{"_id": "2194320", "title": "", "text": "Enzymatically active lysosomal proteases are associated with amyloid deposits in Alzheimer brain.Theformation of beta-amyloid in the brains of individuals with Alzheimer disease requires the proteolyticcleavage of a membrane-associated precursor protein. The proteases that may be involved in thisprocess have not yet been identified. Cathepsins are normally intracellular proteolytic enzymesassociated with lysosomes; however, when sections from Alzheimer brains were stained by antisera tocathepsin D and cathepsin B, high levels of immunoreactivity were also detected in senile plaques.Extracellular sites of cathepsin immunoreactivity were not seen in control brains from age-matchedindividuals without neurologic disease or from patients with Huntington disease or Parkinson disease. Insitu enzyme histochemistry of cathepsin D and cathepsin B on sections of neocortex using syntheticpeptides and protein substrates showed that senile plaques contained the highest levels of enzymaticallyactive cathepsin. At the ultrastructural level, cathepsin immunoreactivity in senile plaques was localizedprincipally to lysosomal dense bodies and lipofuscin granules, which were extracellular. Similar structureswere abundant in degenerating neurons of Alzheimer neocortex, and cathepsin-laden neuronal perikaryain various stages of disintegration could be seen within some senile plaques. The high levels ofenzymatically competent lysosomal proteases abnormally localized in senile plaques represent evidencefor candidate enzymes that may mediate the proteolytic formation of amyloid. We propose that amyloidprecursor protein within senile plaques is processed by lysosomal proteases principally derived fromdegenerating neurons. Escape of cathepsins from the stringently regulated intracellular milieu provides abasis for an abnormal sequence of proteolytic cleavages of accumulating amyloid precursor protein.", "metadata": {}}
+{"_id": "2205779", "title": "", "text": "Gastric juice miR-129 as a potential biomarker for screening gastric cancerMicroRNAs (miRNAs) playcrucial roles during the occurrence and development of gastric cancer. Conventional serological tests forscreening gastric cancer have limits on sensitivity and specificity. Several miRNAs in peripheral bloodhave been used as biomarkers of gastric cancer. However, most of these miRNAs are shared by severaltypes of cancer. Thanks to the tissue specificity of gastric juice, here we examined the feasibility of usinggastric juice miR-129-1/2, which are aberrantly expressed in gastric cancer, to screen gastric cancer.Total of 141 gastric juices samples from gastric cancer, gastric ulcer, atrophic gastritis, and minimalgastritis patients or subjects with normal mucosa were collected by gastroscopy. The gastric juicemiR-129-1/2 levels were detected by quantitative reverse transcription-polymerase chain reaction. Areceiver operating characteristic (ROC) curve was constructed for differentiating patients with gastriccancer from patients with benign gastric diseases. We showed that, compared with patients with benigngastric diseases, patients with gastric cancer had significantly lower levels of gastric juice miR-129-1-3pand miR-129-2-3p. The areas under ROC curve (AUC) were 0.639 and 0.651 for miR-129-1-3p andmiR-129-2-3p, respectively. Using the parallel combination test, the AUC was up to 0.656. In summary,our results suggest that gastric juice miR-129-1-3p and miR-129-2-3p are potential biomarkers for thescreening gastric cancer, and the detection of gastric juice miRNAs is a convenient non-invasion methodfor the diagnosis of gastric cancer.", "metadata": {}}
+{"_id": "2211868", "title": "", "text": "Epidemiological expansion, structural studies, and clinical challenges of new β-lactamases fromgram-negative bacteria.β-Lactamase evolution presents to the infectious disease community a majorchallenge in the treatment of infections caused by multidrug-resistant gram-negative bacteria. Becauseover 1,000 of these naturally occurring β-lactamases exist, attempts to correlate structure and functionhave become daunting. Although new enzymes in the extended-spectrum β-lactamase (ESBL) familiesare frequently identified, the older CTX-M-14 and CTX-M-15 enzymes have become the most prevalentESBLs in global surveillance. Carbapenemases with either serine-based or zinc-facilitated hydrolysismechanisms are posing some of the most critical problems. Most geographical regions now report KPCserine carbapenemases and the metallo-β-lactamases VIM, IMP, and NDM-1, even though NDM-1 wasonly recently identified. The rapid emergence of these newer enzymes, with multiple β-lactamasesappearing in a single organism, makes the design of new β-lactamase inactivators or β-lactamase-stableβ-lactams all the more difficult. Combination therapy will likely be required to counteract the continuingevolution of these insidious enzymes in multidrug-resistant pathogens.", "metadata": {}}
+{"_id": "2212067", "title": "", "text": "Robust synchronization of coupled circadian and cell cycle oscillators in single mammalian cellsCircadiancycles and cell cycles are two fundamental periodic processes with a period in the range of 1 day.Consequently, coupling between such cycles can lead to synchronization. Here, we estimated the mutualinteractions between the two oscillators by time-lapse imaging of single mammalian NIH3T3 fibroblastsduring several days. The analysis of thousands of circadian cycles in dividing cells clearly indicated thatboth oscillators tick in a 1:1 mode-locked state, with cell divisions occurring tightly 5 h before the peak incircadian Rev-Erbα-YFP reporter expression. In principle, such synchrony may be caused by eitherunidirectional or bidirectional coupling. While gating of cell division by the circadian cycle has been moststudied, our data combined with stochastic modeling unambiguously show that the reverse coupling ispredominant in NIH3T3 cells. Moreover, temperature, genetic, and pharmacological perturbations showedthat the two interacting cellular oscillators adopt a synchronized state that is highly robust over a widerange of parameters. These findings have implications for circadian function in proliferative tissues,including epidermis, immune cells, and cancer.", "metadata": {}}
+{"_id": "2225918", "title": "", "text": "Identification of a Brainstem Circuit Controlling FeedingHunger, driven by negative energy balance, elicitsthe search for and consumption of food. While this response is in part mediated by neurons in thehypothalamus, the role of specific cell types in other brain regions is less well defined. Here, we show thatneurons in the dorsal raphe nucleus, expressing vesicular transporters for GABA or glutamate (hereafter,DRNVgat and DRNVGLUT3 neurons), are reciprocally activated by changes in energy balance and thatmodulating their activity has opposite effects on feeding-DRNVgat neurons increase, whereasDRNVGLUT3 neurons suppress, food intake. Furthermore, modulation of these neurons in obese (ob/ob)mice suppresses food intake and body weight and normalizes locomotor activity. Finally, using molecularprofiling, we identify druggable targets in these neurons and show that local infusion of agonists forspecific receptors on these neurons has potent effects on feeding. These data establish the DRN as animportant node controlling energy balance. PAPERCLIP.", "metadata": {}}
+{"_id": "2236768", "title": "", "text": "Infection-induced NETosis is a dynamic process involving neutrophil multitasking in vivoNeutrophilextracellular traps (NETs) are released as neutrophils die in vitro in a process requiring hours, leaving atemporal gap that invasive microbes may exploit. Neutrophils capable of migration and phagocytosiswhile undergoing NETosis have not been documented. During Gram-positive skin infections, we directlyvisualized live polymorphonuclear cells (PMNs) in vivo rapidly releasing NETs, which prevented systemicbacterial dissemination. NETosis occurred during crawling, thereby casting large areas of NETs.NET-releasing PMNs developed diffuse decondensed nuclei, ultimately becoming devoid of DNA. Cells withabnormal nuclei showed unusual crawling behavior highlighted by erratic pseudopods andhyperpolarization consistent with the nucleus being a fulcrum for crawling. A requirement for bothToll-like receptor 2 and complement-mediated opsonization tightly regulated NET release. Additionally,live human PMNs injected into mouse skin developed decondensed nuclei and formed NETS in vivo, andintact anuclear neutrophils were abundant in Gram-positive human abscesses. Therefore early in infectionNETosis involves neutrophils that do not undergo lysis and retain the ability to multitask.", "metadata": {}}
+{"_id": "2242416", "title": "", "text": "Swim training suppresses tumor growth in mice.The present study was designed to determine the effectsof physical training on the development of cancer induced by the injection of Ehrlich tumor cells in mice.Male Swiss mice were subjected to a swim training protocol (5 days/wk for 6 wk, 1 h at 50% of maximalcapacity-trained groups) or remained sedentary in their cages (sedentary groups). The inoculation ofEhrlich tumor cells was performed at the end of the fourth week, and animals were killed after 6 wk oftraining. Heart and solid tumor weights were recorded, and tumor volumes were calculated. Portions ofthe tumors were used for the evaluation of macrophages and neutrophil accumulation or fixed in neutral10% buffered formalin for histological analysis. The tumor volume and weight were, respectively,approximately 270% and 280% greater in sedentary mice than in trained mice. Macrophage infiltration inthe tumor tissue was significantly lower in trained mice (0.65 +/- 0.16 vs. 1.78 +/- 0.43 macrophages x10(3) in the sedentary group). Moreover, neutrophil accumulation in tumors was slightly reduced afterexercise training, and the amount of tumor cells was reduced in trained mice. Exercise capacity wassubstantially increased in trained mice, as determined by a 440% increase in the exercise time at 50% ofmaximal capacity. In summary, swim training retarded the development of Ehrlich tumors in mice,accompanied by a reduction in macrophage infiltration and neutrophil accumulation. These findingsprovide conceptual support for clinical observations that controlled physical activities may be atherapeutically important approach to preventing cancer progression and may improve the outcome ofcancer treatment.", "metadata": {}}
+{"_id": "2248870", "title": "", "text": "Lung dendritic cells imprint T cell lung homing and promote lung immunity through the chemokinereceptor CCR4T cell trafficking into the lung is critical for lung immunity, but the mechanisms thatmediate T cell lung homing are not well understood. Here, we show that lung dendritic cells (DCs) imprintT cell lung homing, as lung DC-activated T cells traffic more efficiently into the lung in response to inhaledantigen and at homeostasis compared with T cells activated by DCs from other tissues. Consequently,lung DC-imprinted T cells protect against influenza more effectively than do gut and skin DC-imprinted Tcells. Lung DCs imprint the expression of CCR4 on T cells, and CCR4 contributes to T cell lung imprinting.Lung DC-activated, CCR4-deficient T cells fail to traffic into the lung as efficiently and to protect againstinfluenza as effectively as lung DC-activated, CCR4-sufficient T cells. Thus, lung DCs imprint T cell lunghoming and promote lung immunity in part through CCR4.", "metadata": {}}
+{"_id": "2251426", "title": "", "text": "microRNAs: A Safeguard against Turmoil?Emerging data suggest that microRNAs (miRNAs) areinstrumental in a variety of stress responses in addition to their more recognized role in development.Surprisingly, miRNAs, which normally suppress expression of target transcripts, may become activatorsof expression during stress. This might be partially explained by new interactions of miRNA/Argonautecomplexes with RNA-binding proteins that relocate from different subcellular compartments during stress.", "metadata": {}}
+{"_id": "2260571", "title": "", "text": "Vascular smooth muscle cell calcification is mediated by regulated exosome secretion.RATIONALE Matrixvesicles (MVs), secreted by vascular smooth muscle cells (VSMCs), form the first nidus for mineralizationand fetuin-A, a potent circulating inhibitor of calcification, is specifically loaded into MVs. However, theprocesses of fetuin-A intracellular trafficking and MV biogenesis are poorly understood. OBJECTIVE Theobjective of this study is to investigate the regulation, and role, of MV biogenesis in VSMC calcification.METHODS AND RESULTS Alexa488-labeled fetuin-A was internalized by human VSMCs, trafficked via theendosomal system, and exocytosed from multivesicular bodies via exosome release. VSMC-derivedexosomes were enriched with the tetraspanins CD9, CD63, and CD81, and their release was regulated bysphingomyelin phosphodiesterase 3. Comparative proteomics showed that VSMC-derived exosomes werecompositionally similar to exosomes from other cell sources but also shared components withosteoblast-derived MVs including calcium-binding and extracellular matrix proteins. Elevated extracellularcalcium was found to induce sphingomyelin phosphodiesterase 3 expression and the secretion ofcalcifying exosomes from VSMCs in vitro, and chemical inhibition of sphingomyelin phosphodiesterase 3prevented VSMC calcification. In vivo, multivesicular bodies containing exosomes were observed invessels from chronic kidney disease patients on dialysis, and CD63 was found to colocalize withcalcification. Importantly, factors such as tumor necrosis factor-α and platelet derived growth factor-BBwere also found to increase exosome production, leading to increased calcification of VSMCs in responseto calcifying conditions. CONCLUSIONS This study identifies MVs as exosomes and shows that factors thatcan increase exosome release can promote vascular calcification in response to environmental calciumstress. Modulation of the exosome release pathway may be as a novel therapeutic target for prevention.", "metadata": {}}
+{"_id": "2264455", "title": "", "text": "Vaccines against malariaThere is no licenced vaccine against any human parasitic disease andPlasmodium falciparum malaria, a major cause of infectious mortality, presents a great challenge tovaccine developers. This has led to the assessment of a wide variety of approaches to malaria vaccinedesign and development, assisted by the availability of a safe challenge model for small-scale efficacytesting of vaccine candidates. Malaria vaccine development has been at the forefront of assessing manynew vaccine technologies including novel adjuvants, vectored prime-boost regimes and the concept ofcommunity vaccination to block malaria transmission. Most current vaccine candidates target a singlestage of the parasite's life cycle and vaccines against the early pre-erythrocytic stages have shown mostsuccess. A protein in adjuvant vaccine, working through antibodies against sporozoites, and viral vectorvaccines targeting the intracellular liver-stage parasite with cellular immunity show partial efficacy inhumans, and the anti-sporozoite vaccine is currently in phase III trials. However, a more effectivemalaria vaccine suitable for widespread cost-effective deployment is likely to require a multi-componentvaccine targeting more than one life cycle stage. The most attractive near-term approach to develop sucha product is to combine existing partially effective pre-erythrocytic vaccine candidates.", "metadata": {}}
+{"_id": "2266471", "title": "", "text": "MicroRNA-21 is Induced by Rapamycin in a Model of Tuberous Sclerosis (TSC) andLymphangioleiomyomatosis (LAM)Lymphangioleiomyomatosis (LAM), a multisystem disease of women, ismanifest by the proliferation of smooth muscle-like cells in the lung resulting in cystic lung destruction.Women with LAM can also develop renal angiomyolipomas. LAM is caused by mutations in the tuberoussclerosis complex genes (TSC1 or TSC2), resulting in hyperactive mammalian Target of Rapamycin(mTOR) signaling. The mTOR inhibitor, Rapamycin, stabilizes lung function in LAM and decreases thevolume of renal angiomyolipomas, but lung function declines and angiomyolipomas regrow whentreatment is discontinued, suggesting that factors induced by mTORC1 inhibition may promote thesurvival of TSC2-deficient cells. Whether microRNA (miRNA, miR) signaling is involved in the response ofLAM to mTORC1 inhibition is unknown. We identified Rapamycin-dependent miRNA in LAM patientangiomyolipoma-derived cells using two separate screens. First, we assayed 132 miRNA of knownsignificance to tumor biology. Using a cut-off of >1.5-fold change, 48 microRNA wereRapamycin-induced, while 4 miRs were downregulated. In a second screen encompassing 946 miRNA, 18miRs were upregulated by Rapamycin, while eight were downregulated. Dysregulation of miRs 29b, 21,24, 221, 106a and 199a were common to both platforms and were classified as candidate \"RapamiRs. \"Validation by qRT-PCR confirmed that these microRNA were increased. miR-21, a pro-survival miR, wasthe most significantly increased by mTOR-inhibition (p<0.01). The regulation of miR-21 by Rapamycin iscell type independent. mTOR inhibition promotes the processing of the miR-21 transcript (pri-miR-21) toa premature form (pre-miR-21). In conclusion, our findings demonstrate that Rapamycin upregulatesmultiple miRs, including pro-survival miRs, in TSC2-deficient patient-derived cells. The induction of miRsmay contribute to the response of LAM and TSC patients to Rapamycin therapy.", "metadata": {}}
+{"_id": "2272614", "title": "", "text": "Reduced NF1 expression confers resistance to EGFR inhibition in lung cancer.Activating mutations in theEGF receptor (EGFR) are associated with clinical responsiveness to EGFR tyrosine kinase inhibitors (TKI),such as erlotinib and gefitinib. However, resistance eventually arises, often due to a second EGFRmutation, most commonly T790M. Through a genome-wide siRNA screen in a human lung cancer cell lineand analyses of murine mutant EGFR-driven lung adenocarcinomas, we found that erlotinib resistancewas associated with reduced expression of neurofibromin, the RAS GTPase-activating protein encoded bythe NF1 gene. Erlotinib failed to fully inhibit RAS-ERK signaling when neurofibromin levels were reduced.Treatment of neurofibromin-deficient lung cancers with a MAP-ERK kinase (MEK) inhibitor restoredsensitivity to erlotinib. Low levels of NF1 expression were associated with primary and acquired resistanceof lung adenocarcinomas to EGFR TKIs in patients. These findings identify a subgroup of patients withEGFR-mutant lung adenocarcinoma who might benefit from combination therapy with EGFR and MEKinhibitors.", "metadata": {}}
+{"_id": "2274272", "title": "", "text": "Human IRGM induces autophagy to eliminate intracellular mycobacteria.Immunity-related p47 guanosinetriphosphatases (IRG) play a role in defense against intracellular pathogens. We found that the murineIrgm1 (LRG-47) guanosine triphosphatase induced autophagy and generated large autolysosomalorganelles as a mechanism for the elimination of intracellular Mycobacterium tuberculosis. We alsoidentified a function for a human IRG protein in the control of intracellular pathogens and report that thehuman Irgm1 ortholog, IRGM, plays a role in autophagy and in the reduction of intracellular bacillaryload.", "metadata": {}}
+{"_id": "2276126", "title": "", "text": "Implementation of a Clinical Pharmacy Education Program in a Teaching Hospital: Resident OrientedDocumentation and InterventionThe aim of this study was to provide a clinical pharmacy educationprogram at Masih Daneshvari hospital, a University affiliated hospital, located in Tehran, Iran. For thispurpose, the most common pharmacist involved interventions and aspects of potential fields forpharmacy students and residents education was firstly identified. Clinical pharmacy interventions anddrug information forms were filled during the study period, from January 2006 till January 2007. Basedon the results of this study, a total number of 772 interventions were conducted during the study year.Drug information had the highest rate of 22.30% among all interventions, followed by dose adjustment,and therapeutic reduction or addition. The mean number of medications per patient was 8.62 ± 7.54. Inconclusion, it could be said that although in our country the challenge for the pharmacy as a profession isin its initial stages compared to the developed countries, the result of this study revealed a high demandfor this service among health care providers.", "metadata": {}}
+{"_id": "2291922", "title": "", "text": "The surgical anatomy of the conduction tissues.On the basis of our collective experience we havereviewed the disposition of the cardiac conduction tissues as they might be observed by the surgeon inboth normal and abnormal hearts. The sinus node lies subepicardially in the terminal sulcus; because ofits variable blood supply the entire superior cavoatrial junction is a potential danger area. There are nomorphologically discrete tracts extending through the atrial tissues between sinus and atrioventricularnodes. The atrioventricular node, the atrial extent of the atrioventricular conduction axis, is containedexclusively within the triangle of Koch. The axis penetrates through the central fibrous body and brancheson the muscular ventricular septum immediately beneath the interventricular component of themembranous septum. The landmarks to these structures are described as they might be seen throughthe right atrium, left atrium, and aorta. Consideration is then given to the surgical anatomy of theabnormal muscular atrioventricular connections that underscore the ventricular pre-excitationsyndromes. Finally, rules are developed whereby the disposition of the conduction tissues can bepredicted with accuracy in congenitally malformed hearts, in the settings of both normal and abnormalchamber connections. The most important variables in this respect are alignment between the atrial andventricular septal structures and the pattern of ventricular architecture present.", "metadata": {}}
+{"_id": "2295434", "title": "", "text": "Agreement between an online dietary assessment tool (myfood24) and an interviewer-administered 24-hdietary recall in British adolescents aged 11-18 years.myfood24 Is an online 24-h dietary assessment tooldeveloped for use among British adolescents and adults. Limited information is available regarding thevalidity of using new technology in assessing nutritional intake among adolescents. Thus, a relativevalidation of myfood24 against a face-to-face interviewer-administered 24-h multiple-pass recall (MPR)was conducted among seventy-five British adolescents aged 11-18 years. Participants were asked tocomplete myfood24 and an interviewer-administered MPR on the same day for 2 non-consecutive days atschool. Total energy intake (EI) and nutrients recorded by the two methods were compared usingintraclass correlation coefficients (ICC), Bland-Altman plots (using between and within-individualinformation) and weighted κ to assess the agreement. Energy, macronutrients and other reportednutrients from myfood24 demonstrated strong agreement with the interview MPR data, and ICC rangedfrom 0·46 for Na to 0·88 for EI. There was no significant bias between the two methods for EI,macronutrients and most reported nutrients. The mean difference between myfood24 and theinterviewer-administered MPR for EI was -230 kJ (-55 kcal) (95 % CI -490, 30 kJ (-117, 7 kcal); P=0·4)with limits of agreement ranging between 39 % (3336 kJ (-797 kcal)) lower and 34 % (2874 kJ (687kcal)) higher than the interviewer-administered MPR. There was good agreement in terms of classifyingadolescents into tertiles of EI (κ w =0·64). The agreement between day 1 and day 2 was as good formyfood24 as for the interviewer-administered MPR, reflecting the reliability of myfood24. myfood24 Hasthe potential to collect dietary data of comparable quality with that of an interviewer-administered MPR.", "metadata": {}}
+{"_id": "2296264", "title": "", "text": "Modulation of cancer chemotherapy by green tea.Biochemical modulation has played an important role inthe development of cancer chemotherapy. We have directed our attention to the intake of commonbeverages and investigated the effects of green tea and tea components on the antitumor activity ofdoxorubicin. We carried out the combined treatment of toxorubicin and green tea on Ehrlich ascitescarcinoma tumor-bearing mice. The oral administration of green tea enhanced 2.5-fold the inhibitoryeffects of doxorubicin on tumor growth. The Doxorubicin concentration in the tumor was increased by thecombination of green tea with doxorubicin. In contrast, the increase in doxorubicin concentration was notobserved in normal tissues after green tea combination. Furthermore, the enhancement of antitumoractivity of doxorubicin induced by green tea was observed in M5076 ovarian sarcoma, which has lowsensitivity to doxorubicin. These results suggest that drinking green tea can encourage cancerchemotherapy and may improve the quality of life of clinical patients.", "metadata": {}}
+{"_id": "2316374", "title": "", "text": "Histone deacetylase 5 interacts with Krüppel-like factor 2 and inhibits its transcriptional activity inendothelium.AIMS Vascular endothelial dysfunction and inflammation are hallmarks of atherosclerosis.Krüppel-like factor 2 (KLF2) is a key mediator of anti-inflammatory and anti-atherosclerotic properties ofthe endothelium. However, little is known of the molecular mechanisms for regulating KLF2transcriptional activation. METHODS AND RESULTS Here, we found that histone deacetylase 5 (HDAC5)associates with KLF2 and represses KLF2 transcriptional activation. HDAC5 resided with KLF2 in the nucleiof human umbilical cord vein endothelial cells (HUVECs). Steady laminar flow attenuated the associationof HDAC5 with KLF2 via stimulating HDAC5 phosphorylation-dependent nuclear export in HUVEC. We alsomapped the KLF2-HDAC5-interacting domains and found that the N-terminal region of HDAC5 interactswith the C-terminal domain of KLF2. Chromatin immunoprecipitation and luciferase reporter assaysshowed that HDAC5 through a direct association with KLF2 suppressed KLF2 transcriptional activation.HDAC5 overexpression inhibited KLF2-dependent endothelial nitric oxide synthesis (eNOS) promoteractivity in COS7 cell and gene expression in both HUVECs and bovine aortic endothelial cells (BAECs).Conversely, HDAC5 silencing enhanced KLF2 transcription and hence eNOS expression in HUVEC.Moreover, we observed that the level of eNOS protein in the thoracic aorta isolated from HDAC5 knockoutmice was higher, whereas expression of pro-inflammatory vascular cell adhesion molecule 1 was lower,compared with those of HDAC5 wild-type mice. CONCLUSIONS We reveal a novel role of HDAC5 inmodulating the KLF2 transcriptional activation and eNOS expression. These findings suggest that HDAC5,a binding partner and modulator of KLF2, could be a new therapeutic target to prevent vascularendothelial dysfunction associated with cardiovascular diseases.", "metadata": {}}
+{"_id": "2319305", "title": "", "text": "N348I in HIV-1 reverse transcriptase can counteract the nevirapine-mediated bias toward RNase Hcleavage during plus-strand initiation.Drug resistance-associated mutations in HIV-1 reversetranscriptase (RT) can affect the balance between polymerase and ribonuclease H (RNase H) activities ofthe enzyme. We have recently demonstrated that the N348I mutation in the connection domain causesselective dissociation from RNase H-competent complexes, whereas the functional integrity of thepolymerase-competent complex remains largely unaffected. N348I has been associated with resistance tothe non-nucleoside RT inhibitor (NNRTI), nevirapine; however, a possible mechanism that links changesin RNase H activity to changes in NNRTI susceptibility remains to be established. To address this problem,we consider recent findings suggesting that NNRTIs may affect the orientation of RT on its nucleic acidsubstrate and increase RNase H activity. Here we demonstrate that RNase H-mediated primer removal isindeed more efficient in the presence of NNRTIs; however, the N348I mutant enzyme is able tocounteract this effect. Efavirenz, a tight binding inhibitor, restricts the influence of the mutation. Thesefindings provide strong evidence to suggest that N348I can thwart the inhibitory effects of nevirapineduring initiation of (+)-strand DNA synthesis, which provides a novel mechanism for resistance. The dataare in agreement with clinical data, which demonstrate a stronger effect of N348I on susceptibility tonevirapine as compared with efavirenz.", "metadata": {}}
+{"_id": "2328272", "title": "", "text": "Cancer survivorship research: the challenge of recruiting adult long term cancer survivors from acooperative clinical trials groupINTRODUCTION With the growing number of adult cancer survivors, thereis increasing need for information that links potential late and long term effects with specific treatmentregimens. Few adult cancer patients are treated on clinical trials; however, patients previously enrolled inthese trials are an important source of information about treatment-related late effects. METHODSFocusing on colorectal cancer survivors, we used the database from five phase III randomized clinicaltrials from the National Surgical Adjuvant Breast & Bowel Project (NSABP) to recruit and enroll long termsurvivors in a study of late health outcomes and quality of life. We describe the challenges to recruitmentof patients more than 5 -20 years after treatment. RESULTS Sixty-five NSABP treatment sites wereinvited to enroll patients in the study. Sixty participated with the potential to recruit 2,408 patients. Wereceived registration forms on only 976 patients (41%) of whom 744 (76%) expressed interest inparticipating and 708 completed interviews (95% of those expressing interest; 29% of total potentialsample). There were multiple barriers to recruitment (difficulty locating patients, lack of institutionalcommitment, lack of patient interest). CONCLUSIONS Patients treated on clinical trials are an importantpotential source for examining the late effects of cancer treatments. Retrospective recruitment hassubstantial limitations. In the future, mechanisms should be established for prospective long-termfollow-up to identify and understand the frequency and type of late effects associated with cancertreatments. IMPLICATIONS FOR CANCER SURVIVORS As cancer patients are living longer, it will beimportant to learn from participants in clinical trials whether or not specific treatment regimens areassociated with any serious late effects.", "metadata": {}}
+{"_id": "2335873", "title": "", "text": "Arylsulfatase B Improves Locomotor Function after Mouse Spinal Cord InjuryBacterial chondroitinase ABC(ChaseABC) has been used to remove the inhibitory chondroitin sulfate chains from chondroitin sulfateproteoglycans to improve regeneration after rodent spinal cord injury. We hypothesized that themammalian enzyme arylsulfatase B (ARSB) would also enhance recovery after mouse spinal cord injury.Application of the mammalian enzyme would be an attractive alternative to ChaseABC because of itsmore robust chemical stability and reduced immunogenicity. A one-time injection of human ARSB intoinjured mouse spinal cord eliminated immunoreactivity for chondroitin sulfates within five days, and up to9 weeks after injury. After a moderate spinal cord injury, we observed improvements of locomotorrecovery assessed by the Basso Mouse Scale (BMS) in ARSB treated mice, compared to the buffer-treatedcontrol group, at 6 weeks after injection. After a severe spinal cord injury, mice injected with equivalentunits of ARSB or ChaseABC improved similarly and both groups achieved significantly more locomotorrecovery than the buffer-treated control mice. Serotonin and tyrosine hydroxylase immunoreactive axonswere more extensively present in mouse spinal cords treated with ARSB and ChaseABC, and theimmunoreactive axons penetrated further beyond the injury site in ARSB or ChaseABC treated mice thanin control mice. These results indicate that mammalian ARSB improves functional recovery after CNSinjury. The structural/molecular mechanisms underlying the observed functional improvement remain tobe elucidated.", "metadata": {}}
+{"_id": "2338488", "title": "", "text": "The World Health Organization Adult ADHD Self-Report Scale (ASRS): a short screening scale for use inthe general population.BACKGROUND A self-report screening scale of adult attention-deficit/hyperactivitydisorder (ADHD), the World Health Organization (WHO) Adult ADHD Self-Report Scale (ASRS) wasdeveloped in conjunction with revision of the WHO Composite International Diagnostic Interview (CIDI).The current report presents data on concordance of the ASRS and of a short-form ASRS screener withblind clinical diagnoses in a community sample. METHOD The ASRS includes 18 questions aboutfrequency of recent DSM-IV Criterion A symptoms of adult ADHD. The ASRS screener consists of six outof these 18 questions that were selected based on stepwise logistic regression to optimize concordancewith the clinical classification. ASRS responses were compared to blind clinical ratings of DSM-IV adultADHD in a sample of 154 respondents who previously participated in the US National Comorbidity SurveyReplication (NCS-R), oversampling those who reported childhood ADHD and adult persistence. RESULTSEach ASRS symptom measure was significantly related to the comparable clinical symptom rating, butvaried substantially in concordance (Cohen's kappa in the range 0.16-0.81). Optimal scoring to predictclinical syndrome classifications was to sum unweighted dichotomous responses across all 18 ASRSquestions. However, because of the wide variation in symptom-level concordance, the unweightedsix-question ASRS screener outperformed the unweighted 18-question ASRS in sensitivity (68.7% v.56.3%), specificity (99.5% v. 98.3%), total classification accuracy (97.9% v. 96.2%), and kappa (0.76 v.0.58). CONCLUSIONS Clinical calibration in larger samples might show that a weighted version of the18-question ASRS outperforms the six-question ASRS screener. Until that time, however, the unweightedscreener should be preferred to the full ASRS, both in community surveys and in clinical outreach andcase-finding initiatives.", "metadata": {}}
+{"_id": "2344892", "title": "", "text": "Human milk proresolving mediators stimulate resolution of acute inflammationHuman milk containsnutrients and bioactive products relevant to infant development and immunological protection. Here, weinvestigated the proresolving properties of milk using human milk lipid mediator isolates (HLMIs) anddetermined their impact on resolution programs in vivo and with human macrophages. HLMIs reducedthe maximum neutrophil numbers (14.6±1.2 × 106–11.0±1.0 × 106 cells per exudate) and shortenedthe resolution interval (Ri; 50% neutrophil reduction) by 54% compared with peritonitis. Using rigorousliquid-chromatography tandem-mass spectrometry (LC-MS-MS)-based lipid mediator (LM)metabololipidomics, we demonstrated that human milk possesses a proresolving LM-specializedproresolving mediator (LM-SPM) signature profile, containing SPMs (e.g. resolvins (Rv), protectins (PDs),maresins (MaRs), and lipoxins (LXs)) at bioactive levels (pico-nanomolar concentrations) that enhancedhuman macrophage efferocytosis and bacterial containment. SPMs identified in human milk includedD-series Rvs (e.g., RvD1, RvD2, RvD3, AT-RvD3, and RvD4), PD1, MaR1, E-series Rvs (e.g. RvE1, RvE2,and RvE3), and LXs (LXA4 and LXB4). Of the SPMs identified in human milk, RvD2 and MaR1 (50 ng permouse) individually shortened Ri by \u000075%. Milk from mastitis gave higher leukotriene B4 andprostanoids and lower SPM levels. Taken together, these findings provide evidence that human milk hasproresolving actions via comprehensive LM-SPM profiling, describing a potentially novel mechanism inmaternal–infant biochemical imprinting.", "metadata": {}}
+{"_id": "2352142", "title": "", "text": "Cerebral perfusion and stroke.Stroke is a heterogeneous syndrome caused by multiple diseasemechanisms, but all result in a disruption of cerebral blood flow with subsequent tissue damage. Thisreview covers the mechanisms responsible for regulation of the normal cerebral circulation, and how theyare disrupted in disease states. A central concept in treating patients with acute ischaemic stroke is theexistence of an ischaemic penumbra of potentially salvageable tissue, and the evidence for its existencein humans is reviewed.", "metadata": {}}
+{"_id": "2356950", "title": "", "text": "Epigenetic regulation of miR-184 by MBD1 governs neural stem cell proliferation anddifferentiation.Methyl-CpG binding protein 1 (MBD1) regulates gene expression via a DNAmethylation-mediated epigenetic mechanism. We have previously demonstrated that MBD1 deficiencyimpairs adult neural stem/progenitor cell (aNSC) differentiation and neurogenesis, but the underlyingmechanism was unclear. Here, we show that MBD1 regulates the expression of several microRNAs inaNSCs and, specifically, that miR-184 is directly repressed by MBD1. High levels of miR-184 promotedproliferation but inhibited differentiation of aNSCs, whereas inhibition of miR-184 rescued the phenotypesassociated with MBD1 deficiency. We further found that miR-184 regulates the expression of Numblike(Numbl), a known regulator of brain development, by binding to the 3'-UTR of Numbl mRNA and affectingits translation. Expression of exogenous Numbl could rescue the aNSC defects that result from eithermiR-184 overexpression or MBD1 deficiency. Therefore, MBD1, miR-184, and Numbl form a regulatorynetwork that helps control the balance between proliferation and differentiation of aNSCs.", "metadata": {}}
+{"_id": "2359152", "title": "", "text": "Landscape of genetic lesions in 944 patients with myelodysplastic syndromesHigh-throughput DNAsequencing significantly contributed to diagnosis and prognostication in patients with myelodysplasticsyndromes (MDS). We determined the biological and prognostic significance of genetic aberrations inMDS. In total, 944 patients with various MDS subtypes were screened for known/putativemutations/deletions in 104 genes using targeted deep sequencing and array-based genomichybridization. In total, 845/944 patients (89.5%) harbored at least one mutation (median, 3 per patient;range, 0-12). Forty-seven genes were significantly mutated with TET2, SF3B1, ASXL1, SRSF2, DNMT3A,and RUNX1 mutated in >10% of cases. Many mutations were associated with higher risk groups and/orblast elevation. Survival was investigated in 875 patients. By univariate analysis, 25/48 genes (resultingfrom 47 genes tested significantly plus PRPF8) affected survival (P<0.05). The status of 14 genescombined with conventional factors revealed a novel prognostic model ('Model-1') separating patientsinto four risk groups ('low', 'intermediate', 'high', 'very high risk') with 3-year survival of 95.2, 69.3, 32.8,and 5.3% (P<0.001). Subsequently, a 'gene-only model' ('Model-2') was constructed based on 14 genesalso yielding four significant risk groups (P<0.001). Both models were reproducible in the validationcohort (n=175 patients; P<0.001 each). Thus, large-scale genetic and molecular profiling of multipletarget genes is invaluable for subclassification and prognostication in MDS patients.", "metadata": {}}
+{"_id": "2360905", "title": "", "text": "Integrated molecular genetic profiling of pediatric high-grade gliomas reveals key differences with theadult disease.PURPOSE To define copy number alterations and gene expression signatures underlyingpediatric high-grade glioma (HGG). PATIENTS AND METHODS We conducted a high-resolution analysis ofgenomic imbalances in 78 de novo pediatric HGGs, including seven diffuse intrinsic pontine gliomas, and10 HGGs arising in children who received cranial irradiation for a previous cancer using single nucleotidepolymorphism microarray analysis. Gene expression was analyzed with gene expression microarrays for53 tumors. Results were compared with publicly available data from adult tumors. RESULTS Significantdifferences in copy number alterations distinguish childhood and adult glioblastoma. PDGFRA was thepredominant target of focal amplification in childhood HGG, including diffuse intrinsic pontine gliomas,and gene expression analyses supported an important role for deregulated PDGFRalpha signaling inpediatric HGG. No IDH1 hotspot mutations were found in pediatric tumors, highlighting moleculardifferences with adult secondary glioblastoma. Pediatric and adult glioblastomas were clearlydistinguished by frequent gain of chromosome 1q (30% v 9%, respectively) and lower frequency ofchromosome 7 gain (13% v 74%, respectively) and 10q loss (35% v 80%, respectively). PDGFRAamplification and 1q gain occurred at significantly higher frequency in irradiation-induced tumors,suggesting that these are initiating events in childhood gliomagenesis. A subset of pediatric HGGs showedminimal copy number changes. CONCLUSION Integrated molecular profiling showed substantialdifferences in the molecular features underlying pediatric and adult HGG, indicating that findings in adulttumors cannot be simply extrapolated to younger patients. PDGFRalpha may be a useful target forpediatric HGG, including diffuse pontine gliomas.", "metadata": {}}
+{"_id": "2374637", "title": "", "text": "Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expressionprofiles.Although genomewide RNA expression analysis has become a routine tool in biomedical research,extracting biological insight from such information remains a major challenge. Here, we describe apowerful analytical method called Gene Set Enrichment Analysis (GSEA) for interpreting gene expressiondata. The method derives its power by focusing on gene sets, that is, groups of genes that share commonbiological function, chromosomal location, or regulation. We demonstrate how GSEA yields insights intoseveral cancer-related data sets, including leukemia and lung cancer. Notably, where single-gene analysisfinds little similarity between two independent studies of patient survival in lung cancer, GSEA revealsmany biological pathways in common. The GSEA method is embodied in a freely available softwarepackage, together with an initial database of 1,325 biologically defined gene sets.", "metadata": {}}
+{"_id": "2380002", "title": "", "text": "The evolution of RNAs with multiple functions.Increasing numbers of transcripts have been reported totransmit both protein-coding and regulatory information. Apart from challenging our conception of thegene, this observation raises the question as to what extent this phenomenon occurs across the genomeand how and why such dual encoding of function has evolved in the eukaryotic genome. To address thisquestion, we consider the evolutionary path of genes in the earliest forms of life on Earth, where it isgenerally regarded that proteins evolved from a cellular machinery based entirely within RNA. This led tothe domination of protein-coding genes in the genomes of microorganisms, although it is likely that RNAnever lost its other capacities and functionalities, as evidenced by cis-acting riboswitches and UTRs. Onthe basis that the subsequent evolution of a more sophisticated regulatory architecture to provide higherlevels of epigenetic control and accurate spatiotemporal expression in developmentally complexorganisms is a complicated task, we hypothesize: (i) that mRNAs have been and remain subject tosecondary selection to provide trans-acting regulatory capability in parallel with protein-coding functions;(ii) that some and perhaps many protein-coding loci, possibly as a consequence of gene duplication, havelost protein-coding functions en route to acquiring more sophisticated trans-regulatory functions; (iii) thatmany transcripts have become subject to secondary processing to release different products; and (iv)that novel proteins have emerged within loci that previously evolved functionality as regulatory RNAs. Insupport of the idea that there is a dynamic flux between different types of informational RNAs in bothevolutionary and real time, we review recent observations that have arisen from transcriptomic surveysof complex eukaryotes and reconsider how these observations impact on the notion that apparentlydiscrete loci may express transcripts with more than one function. In conclusion, we posit that manyeukaryotic loci have evolved the capacity to transact a multitude of overlapping and potentiallyindependent functions as both regulatory and protein-coding RNAs.", "metadata": {}}
+{"_id": "2388819", "title": "", "text": "In Vitro–expanded Antigen-specific Regulatory T Cells Suppress Autoimmune DiabetesThe low number ofCD4+ CD25+ regulatory T cells (Tregs), their anergic phenotype, and diverse antigen specificity presentmajor challenges to harnessing this potent tolerogenic population to treat autoimmunity and transplantrejection. In this study, we describe a robust method to expand antigen-specific Tregs fromautoimmune-prone nonobese diabetic mice. Purified CD4+ CD25+ Tregs were expanded up to 200-fold inless than 2 wk in vitro using a combination of anti-CD3, anti-CD28, and interleukin 2. The expandedTregs express a classical cell surface phenotype and function both in vitro and in vivo to suppress effectorT cell functions. Most significantly, small numbers of antigen-specific Tregs can reverse diabetes afterdisease onset, suggesting a novel approach to cellular immunotherapy for autoimmunity.", "metadata": {}}
+{"_id": "2389574", "title": "", "text": "Stathmin overexpression identifies high-risk patients and lymph node metastasis in endometrialcancer.PURPOSE Overexpression of the oncogen Stathmin has been linked to aggressive endometrialcarcinoma and a potential for PI3Kinase inhibitors in this disease. We wanted to validate the prognosticvalue of Stathmin expression in a large prospective multicenter setting. As lymph node sampling is partof current surgical staging, we also aimed to test if Stathmin expression in endometrial curettagespecimens could predict lymph node metastasis. EXPERIMENTAL DESIGN A total of 1,076 endometrialcancer patients have been recruited from 10 centers to investigate the biological tumor marker Stathminin relation to clinicopathologic variables, including lymph node status and survival. Stathminimmunohistochemical staining was carried out in 477 hysterectomy and 818 curettage specimens.RESULTS Seventy-one percent of the patients (n = 763) were subjected to lymph node sampling, ofwhich 12% had metastatic nodes (n = 94). Overexpression of Stathmin was detected in 37% (302 of818) of the curettage and in 18% (84 of 477) of the hysterectomy specimens investigated. Stathminoverexpression in curettage and hysterectomy specimens were highly correlated and significantlyassociated with nonendometrioid histology, high grade, and aneuploidy. Stathmin analysis inpreoperative curettage samples significantly correlated with, and was an independent predictor of, lymphnode metastases. High Stathmin expression was associated with poor disease-specific survival (P ≤0.002) both in curettage and hysterectomy specimens. CONCLUSIONS Stathmin immunohistochemicalstaining identifies endometrial carcinomas with lymph node metastases and poor survival. The value, as apredictive marker for response to PI3Kinase inhibition and as a tool to stratify patients for lymph nodesampling in endometrial carcinomas, remains to be determined.", "metadata": {}}
+{"_id": "2391552", "title": "", "text": "Statin prophylaxis and inflammatory mediators following cardiopulmonary bypass: a systematicreviewINTRODUCTION Induction of an inflammatory response is thought to have a significant role in thecomplications that follow cardiopulmonary bypass (CPB). The statin drugs are increasingly beingrecognized as having potent anti-inflammatory effects and hence have potential to influence an importantmechanism of injury in CPB, although there is no current confirmation that this is indeed the case. Ourobjective was to systematically review if pre-operative prophylactic statin therapy, compared withplacebo or standard of care, can decrease the inflammatory response in people undergoing heart surgerywith CPB. METHODS We performed a systematic and comprehensive literature search for all randomizedcontrolled trials (RCTs) of open heart surgery with CPB in adults or children who received prophylacticstatin treatment prior to CPB, with reported outcomes which included markers of inflammation. Twoauthors independently identified eligible studies, extracted data, and assessed study quality usingstandardized instruments. Weighted mean difference (WMD) was the primary summary statistic with datapooled using a random effects model. Descriptive analysis was used when data could not be pooled.RESULTS Eight RCTs were included in the review, with the number of trials for each inflammatoryoutcome being even more limited. Pooled data demonstrated benefit with the use of statin to attenuatethe post-CPB increase in interleukins 6 and 8 (IL-6, IL-8), peak high sensitivity C-reactive protein(hsCRP), and tumor necrosis factor-alpha (TNF-alpha) post-CPB (WMD [95% confidence interval (CI)]-23.5 pg/ml [-36.6 to -10.5]; -23.4 pg/ml [-35.8 to -11.0]; -15.3 mg/L [CI -26.9 to -3.7]; -2.10 pg/ml[-3.83 to -0.37] respectively). Very limited RCT evidence suggests that prophylactic statin therapy mayalso decrease adhesion molecules following CPB including neutrophil CD11b and soluble P (sP)-selectin.CONCLUSIONS Although the RCT evidence may suggest a reduction in post-CPB inflammation by statintherapy, the evidence is not definitive due to significant limitations. Several of the trials were notmethodologically rigorous and statin intervention was highly variable in this small number of studies. Thissystematic review demonstrates that there is a significant gap that exists in the current literature inregards to the potential anti-inflammatory effect of statin therapy prior to CPB.", "metadata": {}}
+{"_id": "2402323", "title": "", "text": "Array-based Comparative Genomic Hybridization for Genome-Wide Screening of DNA Copy Number inBladder TumorsGenome-wide copy number profiles were characterized in 41 primary bladder tumorsusing array-based comparative genomic hybridization (array CGH). In addition to previously identifiedalterations in large chromosomal regions, alterations were identified in many small genomic regions,some with high-level amplifications or homozygous deletions. High-level amplifications were detected for192 genomic clones, most frequently at 6p22.3 (E2F3), 8p12 (FGFR1), 8q22.2 (CMYC), 11q13 (CCND1,EMS1, INT2), and 19q13.1 (CCNE). Homozygous deletions were detected in 51 genomic clones, with fourshowing deletions in more than one case: two clones mapping to 9p21.3 (CDKN2A/p16, in nine cases),one at 8p23.1 (three cases), and one at 11p13 (two cases). Significant correlations were observedbetween copy number gain of clones containing CCNE1 and gain of ERBB2, and between gain of CCND1and deletion of TP53. In addition, there was a significant complementary association between gain ofCCND1 and gain of E2F3. Although there was no significant relationship between copy number changesand tumor stage or grade, the linked behavior among genomic loci suggests that array CGH will beincreasingly important in understanding pathways critical to bladder tumor biology.", "metadata": {}}
+{"_id": "2405259", "title": "", "text": "Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6Epigeneticmodifiers have fundamental roles in defining unique cellular identity through the establishment andmaintenance of lineage-specific chromatin and methylation status. Several DNA modifications such as5-hydroxymethylcytosine (5hmC) are catalysed by the ten eleven translocation (Tet) methylcytosinedioxygenase family members, and the roles of Tet proteins in regulating chromatin architecture and genetranscription independently of DNA methylation have been gradually uncovered. However, the regulationof immunity and inflammation by Tet proteins independent of their role in modulating DNA methylationremains largely unknown. Here we show that Tet2 selectively mediates active repression of interleukin-6(IL-6) transcription during inflammation resolution in innate myeloid cells, including dendritic cells andmacrophages. Loss of Tet2 resulted in the upregulation of several inflammatory mediators, including IL-6,at late phase during the response to lipopolysaccharide challenge. Tet2-deficient mice were moresusceptible to endotoxin shock and dextran-sulfate-sodium-induced colitis, displaying a more severeinflammatory phenotype and increased IL-6 production compared to wild-type mice. IκBζ, anIL-6-specific transcription factor, mediated specific targeting of Tet2 to the Il6 promoter, furtherindicating opposite regulatory roles of IκBζ at initial and resolution phases of inflammation. For therepression mechanism, independent of DNA methylation and hydroxymethylation, Tet2 recruited Hdac2and repressed transcription of Il6 via histone deacetylation. We provide mechanistic evidence for thegene-specific transcription repression activity of Tet2 via histone deacetylation and for the prevention ofconstant transcription activation at the chromatin level for resolving inflammation.", "metadata": {}}
+{"_id": "2417551", "title": "", "text": "Control of immunity by the TNFR-related molecule OX40 (CD134).TNFR/TNF superfamily members cancontrol diverse aspects of immune function. Research over the past 10 years has shown that one of themost important and prominent interactions in this family is that between OX40 (CD134) and its partnerOX40L (CD252). These molecules strongly regulate conventional CD4 and CD8 T cells, and more recentdata are highlighting their ability to modulate NKT cell and NK cell function as well as to mediatecross-talk with professional antigen-presenting cells and diverse cell types such as mast cells, smoothmuscle cells, and endothelial cells. Additionally, OX40-OX40L interactions alter the differentiation andactivity of regulatory T cells. Blocking OX40L has produced strong therapeutic effects in multiple animalmodels of autoimmune and inflammatory disease, and, in line with a prospective clinical future, reagentsthat stimulate OX40 signaling are showing promise as adjuvants for vaccination as well as for treatmentof cancer.", "metadata": {}}
+{"_id": "2423940", "title": "", "text": "The Drosophila DHR96 nuclear receptor binds cholesterol and regulates cholesterolhomeostasis.Cholesterol homeostasis is required to maintain normal cellular function and avoid thedeleterious effects of hypercholesterolemia. Here we show that the Drosophila DHR96 nuclear receptorbinds cholesterol and is required for the coordinate transcriptional response of genes that are regulatedby cholesterol and involved in cholesterol uptake, trafficking, and storage. DHR96 mutants die whengrown on low levels of cholesterol and accumulate excess cholesterol when maintained on ahigh-cholesterol diet. The cholesterol accumulation phenotype can be attributed to misregulation ofnpc1b, an ortholog of the mammalian Niemann-Pick C1-like 1 gene NPC1L1, which is essential for dietarycholesterol uptake. These studies define DHR96 as a central regulator of cholesterol homeostasis.", "metadata": {}}
+{"_id": "2424794", "title": "", "text": "A neuroimaging investigation of the association between aerobic fitness, hippocampal volume, andmemory performance in preadolescent children.Because children are becoming overweight, unhealthy,and unfit, understanding the neurocognitive benefits of an active lifestyle in childhood has importantpublic health and educational implications. Animal research has indicated that aerobic exercise is relatedto increased cell proliferation and survival in the hippocampus as well as enhancedhippocampal-dependent learning and memory. Recent evidence extends this relationship to elderlyhumans by suggesting that high aerobic fitness levels in older adults are associated with increasedhippocampal volume and superior memory performance. The present study aimed to further extend thelink between fitness, hippocampal volume, and memory to a sample of preadolescent children. To thisend, magnetic resonance imaging was employed to investigate whether higher- and lower-fit 9- and10-year-old children showed differences in hippocampal volume and if the differences were related toperformance on an item and relational memory task. Relational but not item memory is primarilysupported by the hippocampus. Consistent with predictions, higher-fit children showed greater bilateralhippocampal volumes and superior relational memory task performance compared to lower-fit children.Hippocampal volume was also positively associated with performance on the relational but not the itemmemory task. Furthermore, bilateral hippocampal volume was found to mediate the relationship betweenfitness level (VO(2) max) and relational memory. No relationship between aerobic fitness, nucleusaccumbens volume, and memory was reported, which strengthens the hypothesized specific effect offitness on the hippocampus. The findings are the first to indicate that aerobic fitness may relate to thestructure and function of the preadolescent human brain.", "metadata": {}}
+{"_id": "2425364", "title": "", "text": "Association between maternal serum 25-hydroxyvitamin D level and pregnancy and neonatal outcomes:systematic review and meta-analysis of observational studies.OBJECTIVE To assess the effect of25-hydroxyvitamin D (25-OHD) levels on pregnancy outcomes and birth variables. DESIGN Systematicreview and meta-analysis. DATA SOURCES Medline (1966 to August 2012), PubMed (2008 to August2012), Embase (1980 to August 2012), CINAHL (1981 to August 2012), the Cochrane database ofsystematic reviews, and the Cochrane database of registered clinical trials. STUDY SELECTION Studiesreporting on the association between serum 25-OHD levels during pregnancy and the outcomes ofinterest (pre-eclampsia, gestational diabetes, bacterial vaginosis, caesarean section, small for gestationalage infants, birth weight, birth length, and head circumference). DATA EXTRACTION Two authorsindependently extracted data from original research articles, including key indicators of study quality. Wepooled the most adjusted odds ratios and weighted mean differences. Associations were tested insubgroups representing different patient characteristics and study quality. RESULTS 3357 studies wereidentified and reviewed for eligibility. 31 eligible studies were included in the final analysis. Insufficientserum levels of 25-OHD were associated with gestational diabetes (pooled odds ratio 1.49, 95%confidence interval 1.18 to 1.89), pre-eclampsia (1.79, 1.25 to 2.58), and small for gestational ageinfants (1.85, 1.52 to 2.26). Pregnant women with low serum 25-OHD levels had an increased risk ofbacterial vaginosis and low birthweight infants but not delivery by caesarean section. CONCLUSIONVitamin D insufficiency is associated with an increased risk of gestational diabetes, pre-eclampsia, andsmall for gestational age infants. Pregnant women with low 25-OHD levels had an increased risk ofbacterial vaginosis and lower birth weight infants, but not delivery by caesarean section.", "metadata": {}}
+{"_id": "2436602", "title": "", "text": "β-Adrenergic receptor antagonism prevents anxiety-like behavior and microglial reactivity induced byrepeated social defeat.Psychosocial stress is associated with altered immune function and development ofpsychological disorders including anxiety and depression. Here we show that repeated social defeat inmice increased c-Fos staining in brain regions associated with fear and threat appraisal and promotedanxiety-like behavior in a β-adrenergic receptor-dependent manner. Repeated social defeat alsosignificantly increased the number of CD11b(+)/CD45(high)/Ly6C(high) macrophages that trafficked tothe brain. In addition, several inflammatory markers were increased on the surface of microglia (CD14,CD86, and TLR4) and macrophages (CD14 and CD86) after social defeat. Repeated social defeat alsoincreased the presence of deramified microglia in the medial amygdala, prefrontal cortex, andhippocampus. Moreover, mRNA analysis of microglia indicated that repeated social defeat increased levelsof interleukin (IL)-1β and reduced levels of glucocorticoid responsive genes [glucocorticoid-inducedleucine zipper (GILZ) and FK506 binding protein-51 (FKBP51)]. The stress-dependent changes inmicroglia and macrophages were prevented by propranolol, a β-adrenergic receptor antagonist. Microgliaisolated from socially defeated mice and cultured ex vivo produced markedly higher levels of IL-6, tumornecrosis factor-α, and monocyte chemoattractant protein-1 after stimulation with lipopolysaccharidecompared with microglia from control mice. Last, repeated social defeat increased c-Fos activation in IL-1receptor type-1-deficient mice, but did not promote anxiety-like behavior or microglia activation in theabsence of functional IL-1 receptor type-1. These findings indicate that repeated social defeat-inducedanxiety-like behavior and enhanced reactivity of microglia was dependent on activation of β-adrenergicand IL-1 receptors.", "metadata": {}}
+{"_id": "2437807", "title": "", "text": "In vitro differentiation of transplantable neural precursors from human embryonic stem cellsTheremarkable developmental potential and replicative capacity of human embryonic stem (ES) cells promisean almost unlimited supply of specific cell types for transplantation therapies. Here we describe the invitro differentiation, enrichment, and transplantation of neural precursor cells from human ES cells. Uponaggregation to embryoid bodies, differentiating ES cells formed large numbers of neural tube–likestructures in the presence of fibroblast growth factor 2 (FGF-2). Neural precursors within theseformations were isolated by selective enzymatic digestion and further purified on the basis of differentialadhesion. Following withdrawal of FGF-2, they differentiated into neurons, astrocytes, andoligodendrocytes. After transplantation into the neonatal mouse brain, human ES cell–derived neuralprecursors were incorporated into a variety of brain regions, where they differentiated into both neuronsand astrocytes. No teratoma formation was observed in the transplant recipients. These results depicthuman ES cells as a source of transplantable neural precursors for possible nervous system repair.", "metadata": {}}
+{"_id": "2443495", "title": "", "text": "Characterization of prostaglandin E2 production by Candida albicans.Candida albicans produces lipidmetabolites that are functionally similar to host prostaglandins. These studies, using mass spectrometry,demonstrate that C. albicans produces authentic prostaglandin E(2) (PGE(2)) from arachidonic acid.Maximal PGE(2) production was achieved at 37 degrees C in stationary-phase culture supernatants and incell-free lysates generated from stationary-phase cells. Interestingly, PGE(2) production is inhibited byboth nonspecific cyclooxygenase and lipoxygenase inhibitors but not by inhibitors specific for thecyclooxygenase 2 isoenzyme. The C. albicans genome does not possess a cyclooxygenase homolog;however, several genes that may play a role in prostaglandin production from C. albicans wereinvestigated. It was found that a C. albicans fatty acid desaturase homolog (Ole2) and a multicopperoxidase homolog (Fet3) play roles in prostaglandin production, with ole2/ole2 and fet3/fet3 mutantstrains exhibiting reduced PGE(2) levels compared with parent strains. This work demonstrates that thesynthesis of PGE(2) in C. albicans proceeds via novel pathways.", "metadata": {}}
+{"_id": "2452989", "title": "", "text": "A global role for KLF1 in erythropoiesis revealed by ChIP-seq in primary erythroid cells.KLF1 regulates adiverse suite of genes to direct erythroid cell differentiation from bipotent progenitors. To determine thelocal cis-regulatory contexts and transcription factor networks in which KLF1 operates, we performedKLF1 ChIP-seq in the mouse. We found at least 945 sites in the genome of E14.5 fetal liver erythroid cellswhich are occupied by endogenous KLF1. Many of these recovered sites reside in erythroid genepromoters such as Hbb-b1, but the majority are distant to any known gene. Our data suggests KLF1directly regulates most aspects of terminal erythroid differentiation including production of alpha- andbeta-globin protein chains, heme biosynthesis, coordination of proliferation and anti-apoptotic pathways,and construction of the red cell membrane and cytoskeleton by functioning primarily as a transcriptionalactivator. Additionally, we suggest new mechanisms for KLF1 cooperation with other transcription factors,in particular the erythroid transcription factor GATA1, to maintain homeostasis in the erythroidcompartment.", "metadata": {}}
+{"_id": "2454002", "title": "", "text": "KOBAS 2.0: a web server for annotation and identification of enriched pathways anddiseasesHigh-throughput experimental technologies often identify dozens to hundreds of genes relatedto, or changed in, a biological or pathological process. From these genes one wants to identify biologicalpathways that may be involved and diseases that may be implicated. Here, we report a web server,KOBAS 2.0, which annotates an input set of genes with putative pathways and disease relationshipsbased on mapping to genes with known annotations. It allows for both ID mapping and cross-speciessequence similarity mapping. It then performs statistical tests to identify statistically significantlyenriched pathways and diseases. KOBAS 2.0 incorporates knowledge across 1327 species from 5 pathwaydatabases (KEGG PATHWAY, PID, BioCyc, Reactome and Panther) and 5 human disease databases(OMIM, KEGG DISEASE, FunDO, GAD and NHGRI GWAS Catalog). KOBAS 2.0 can be accessed athttp://kobas.cbi.pku.edu.cn.", "metadata": {}}
+{"_id": "2460304", "title": "", "text": "Translocation of sickle cell erythrocyte microRNAs into Plasmodium falciparum inhibits parasite translationand contributes to malaria resistance.Erythrocytes carrying a variant hemoglobin allele (HbS), whichcauses sickle cell disease and resists infection by the malaria parasite Plasmodium falciparum. Themolecular basis of this resistance, which has long been recognized as multifactorial, remains incompletelyunderstood. Here we show that the dysregulated microRNA (miRNA) composition, of either heterozygousHbAS or homozygous HbSS erythrocytes, contributes to resistance against P. falciparum. During theintraerythrocytic life cycle of P. falciparum, a subset of erythrocyte miRNAs translocate into the parasite.Two miRNAs, miR-451 and let-7i, were highly enriched in HbAS and HbSS erythrocytes, and thesemiRNAs, along with miR-223, negatively regulated parasite growth. Surprisingly, we found that miR-451and let-7i integrated into essential parasite messenger RNAs and, via impaired ribosomal loading,resulted in translational inhibition. Hence, sickle cell erythrocytes exhibit cell-intrinsic resistance tomalaria in part through an atypical miRNA activity, which may represent a unique host defense strategyagainst complex eukaryotic pathogens.", "metadata": {}}
+{"_id": "2462673", "title": "", "text": "CD28 and ITK signals regulate autoreactive T cell traffickingActivation of self-reactive T cells and theirtrafficking to target tissues leads to autoimmune organ destruction. Mice lacking the co-inhibitoryreceptor cytotoxic T lymphocyte antigen-4 (CTLA-4) develop fatal autoimmunity characterized bylymphocytic infiltration into nonlymphoid tissues. Here, we demonstrate that the CD28 co-stimulatorypathway regulates the trafficking of self-reactive Ctla4(-/-) T cells to tissues. Concurrent ablation of theCD28-activated Tec family kinase ITK does not block spontaneous T cell activation but instead causesself-reactive Ctla4(-/-) T cells to accumulate in secondary lymphoid organs. Despite excessivespontaneous T cell activation and proliferation in lymphoid organs, Itk(-/-); Ctla4(-/-) mice are otherwisehealthy, mount antiviral immune responses and exhibit a long lifespan. We propose that ITK specificallylicenses autoreactive T cells to enter tissues to mount destructive immune responses. Notably, ITKinhibitors mimic the null mutant phenotype and also prevent pancreatic islet infiltration by diabetogenic Tcells in mouse models of type 1 diabetes, highlighting their potential utility for the treatment of humanautoimmune disorders.", "metadata": {}}
+{"_id": "2466614", "title": "", "text": "Delayed and Accelerated Aging Share Common Longevity Assurance MechanismsMutant dwarf andcalorie-restricted mice benefit from healthy aging and unusually long lifespan. In contrast, mouse modelsfor DNA repair-deficient progeroid syndromes age and die prematurely. To identify mechanisms thatregulate mammalian longevity, we quantified the parallels between the genome-wide liver expressionprofiles of mice with those two extremes of lifespan. Contrary to expectation, we find significant,genome-wide expression associations between the progeroid and long-lived mice. Subsequent analysis ofsignificantly over-represented biological processes revealed suppression of the endocrine and energypathways with increased stress responses in both delayed and premature aging. To test the relevance ofthese processes in natural aging, we compared the transcriptomes of liver, lung, kidney, and spleen overthe entire murine adult lifespan and subsequently confirmed these findings on an independent agingcohort. The majority of genes showed similar expression changes in all four organs, indicating a systemictranscriptional response with aging. This systemic response included the same biological processes thatare triggered in progeroid and long-lived mice. However, on a genome-wide scale, transcriptomes ofnaturally aged mice showed a strong association to progeroid but not to long-lived mice. Thus, endocrineand metabolic changes are indicative of \"survival\" responses to genotoxic stress or starvation, whereasgenome-wide associations in gene expression with natural aging are indicative of biological age, whichmay thus delineate pro- and anti-aging effects of treatments aimed at health-span extension.", "metadata": {}}
+{"_id": "2474731", "title": "", "text": "Arginine depletion as a mechanism for the immune privilege of corneal allograftsThe cornea is an immuneprivileged tissue. Since arginase has been found to modulate T-cell function by depleting arginine, weinvestigated the expression of arginase in the cornea and its possible role in immune privilege using amurine transplant model. We found that both the endothelium and epithelium of murine corneas expressfunctional arginase I, capable of down-regulating T-cell proliferation in an in vitro culture system. Theadministration of the specific arginase inhibitor N-hydroxy-nor-L-Arg to recipient mice resulted in anaccelerated rejection of allogeneic C57BL/6 (B6) corneal grafts. In contrast, in vivo blockade of arginaseactivity had no effect in altering the course of rejection of primary skin grafts that express little, if any,arginase. In addition, the inhibition of arginase did not alter systemic T-cell proliferation. These datashow that arginase is functional in the cornea and contributes to the immune privilege of the eye, andthat modulation of arginase contributes to graft survival.", "metadata": {}}
+{"_id": "2475059", "title": "", "text": "Once-a-day Concerta methylphenidate versus three-times-daily methylphenidate in laboratory andnatural settings.OBJECTIVE Methylphenidate (MPH), the most commonly prescribed drug forattention-deficit/hyperactivity disorder (ADHD), has a short half-life, which necessitates multiple dailydoses. The need for multiple doses produces problems with medication administration during school andafter-school hours, and therefore with compliance. Previous long-acting stimulants and preparations haveshown effects equivalent to twice-daily dosing of MPH. This study tests the efficacy and duration ofaction, in natural and laboratory settings, of an extended-release MPH preparation designed to last 12hours and therefore be equivalent to 3-times-daily dosing. METHODS Sixty-eight children with ADHD, 6to 12 years old, participated in a within-subject, double-blind comparison of placebo, immediate-release(IR) MPH 3 times a day (tid), and Concerta, a once-daily MPH formulation. Three dosing levels ofmedication were used: 5 mg IR MPH tid/18 mg Concerta once a day (qd); 10 mg IR MPH tid/36 mgConcerta qd; and 15 mg IR MPH tid/54 mg Concerta qd. All children were currently medicated with MPHat enrollment, and each child's dose level was based on that child's MPH dosing before the study. Thedoses of Concerta were selected to be comparable to the daily doses of MPH that each child received. Toachieve the ascending rate of MPH delivery determined by initial investigations to provide the necessarycontinuous coverage, Concerta doses were 20% higher on a daily basis than a comparable tid regimen ofIR MPH. Children received each medication condition for 7 days. The investigation was conducted in thecontext of a background clinical behavioral intervention in both the natural environment and thelaboratory setting. Parents received behavioral parent training and teachers were taught to establish aschool-home daily report card (DRC). A DRC is a list of individual target behaviors that represent a child'smost salient areas of impairment. Teachers set daily goals for each child's impairment targets, andparents provided rewards at home for goal attainment. Each weekday, teachers completed the DRC, andit was used as a dependent measure of individualized medication response. Teachers and parents alsocompleted weekly standardized ratings of behavior and treatment effectiveness. To evaluate the timecourse of medication effects, children spent 12 hours in a laboratory setting on Saturdays and medicationeffects were measured using procedures and methods adapted from our summer treatment program.Measures of classroom behavior and academic productivity/accuracy were taken in a laboratoryclassroom setting during which children completed independent math and reading worksheets. Measuresof social behavior were taken in structured, small-group board game settings and unstructured recesssettings. Measures included behavior frequency counts, academic problems completed and accuracy,independent observations, teacher and counselor ratings, and individualized behavioral target goals.Reports of adverse events, sleep quality, and appetite were collected. RESULTS On virtually all measuresin all settings, both drug conditions were significantly different from placebo, and the 2 drugs were notdifferent from each other. In children's regular school settings, both medications improved behavior asmeasured by teacher ratings and individualized target behaviors (the DRC); these effects were seen intothe evening as measured by parent ratings. In the laboratory setting, effects of Concerta were equivalentto tid MPH and lasted at least through 12 hours after dosing. Concerta was significantly superior to tidMPH on 2 parent rating scores, and when asked, more parents preferred Concerta than preferred tid IRMPH or placebo. Side effects on children's sleep and appetite were similar for the 2 preparations. In thelab setting, both medications improved productivity and accuracy on arithmetic seatwork assignments,disruptive and on-task behavior, and classroom rule following. Both medications improved children's rulefollowing and negative behavior in small group board games, as well as in unstructured recess settings.Individual target behaviors also showed significant improvement with medication across domains in thelaboratory setting. Children's behavior across settings deteriorated across the laboratory day, and theprimary effect of medication was to prevent this deterioration as the day wore on. Results support theuse of background behavioral treatment in clinical trials of stimulant medication, and illustrate the utilityof a measure of individualized daily target goals (ie, the DRC) as an objective measure of medicationresponse in both the laboratory and natural school settings. CONCLUSION This investigation clearly", "metadata": {}}
+{"_id": "2479538", "title": "", "text": "Leaderless genes in bacteria: clue to the evolution of translation initiation mechanisms inprokaryotesBACKGROUND Shine-Dalgarno (SD) signal has long been viewed as the dominant translationinitiation signal in prokaryotes. Recently, leaderless genes, which lack 5'-untranslated regions (5'-UTR)on their mRNAs, have been shown abundant in archaea. However, current large-scale in silico analyseson initiation mechanisms in bacteria are mainly based on the SD-led initiation way, other than theleaderless one. The study of leaderless genes in bacteria remains open, which causes uncertainunderstanding of translation initiation mechanisms for prokaryotes. RESULTS Here, we study signals intranslation initiation regions of all genes over 953 bacterial and 72 archaeal genomes, then make aneffort to construct an evolutionary scenario in view of leaderless genes in bacteria. With an algorithmdesigned to identify multi-signal in upstream regions of genes for a genome, we classify all genes intoSD-led, TA-led and atypical genes according to the category of the most probable signal in their upstreamsequences. Particularly, occurrence of TA-like signals about 10 bp upstream to translation initiation site(TIS) in bacteria most probably means leaderless genes. CONCLUSIONS Our analysis reveals thatleaderless genes are totally widespread, although not dominant, in a variety of bacteria. Especially forActinobacteria and Deinococcus-Thermus, more than twenty percent of genes are leaderless. Analyzed inclosely related bacterial genomes, our results imply that the change of translation initiation mechanisms,which happens between the genes deriving from a common ancestor, is linearly dependent on thephylogenetic relationship. Analysis on the macroevolution of leaderless genes further shows that theproportion of leaderless genes in bacteria has a decreasing trend in evolution.", "metadata": {}}
+{"_id": "2481032", "title": "", "text": "Neuronal Sirt1 deficiency increases insulin sensitivity in both brain and peripheral tissues.Sirt1 is aNAD(+)-dependent class III deacetylase that functions as a cellular energy sensor. In addition to itswell-characterized effects in peripheral tissues, emerging evidence suggests that neuronal Sirt1 activityplays a role in the central regulation of energy balance and glucose metabolism. To assess this idea, wegenerated Sirt1 neuron-specific knockout (SINKO) mice. On both standard chow and HFD, SINKO micewere more insulin sensitive than Sirt1(f/f) mice. Thus, SINKO mice had lower fasting insulin levels,improved glucose tolerance and insulin tolerance, and enhanced systemic insulin sensitivity duringhyperinsulinemic euglycemic clamp studies. Hypothalamic insulin sensitivity of SINKO mice was alsoincreased over controls, as assessed by hypothalamic activation of PI3K, phosphorylation of Akt andFoxO1 following systemic insulin injection. Intracerebroventricular injection of insulin led to a greatersystemic effect to improve glucose tolerance and insulin sensitivity in SINKO mice compared withcontrols. In line with the in vivo results, insulin-induced AKT and FoxO1 phosphorylation were potentiatedby inhibition of Sirt1 in a cultured hypothalamic cell line. Mechanistically, this effect was traced to areduced effect of Sirt1 to directly deacetylate and repress IRS-1 function. The enhanced central insulinsignaling in SINKO mice was accompanied by increased insulin receptor signal transduction in liver,muscle, and adipose tissue. In summary, we conclude that neuronal Sirt1 negatively regulateshypothalamic insulin signaling, leading to systemic insulin resistance. Interventions that reduce neuronalSirt1 activity have the potential to improve systemic insulin action and limit weight gain on an obesigenicdiet.", "metadata": {}}
+{"_id": "2485101", "title": "", "text": "Candidate Causal Regulatory Effects by Integration of Expression QTLs with Complex Trait GeneticAssociationsThe recent success of genome-wide association studies (GWAS) is now followed by thechallenge to determine how the reported susceptibility variants mediate complex traits and diseases.Expression quantitative trait loci (eQTLs) have been implicated in disease associations through overlapsbetween eQTLs and GWAS signals. However, the abundance of eQTLs and the strong correlation structure(LD) in the genome make it likely that some of these overlaps are coincidental and not driven by thesame functional variants. In the present study, we propose an empirical methodology, which we callRegulatory Trait Concordance (RTC) that accounts for local LD structure and integrates eQTLs and GWASresults in order to reveal the subset of association signals that are due to cis eQTLs. We simulate genomicregions of various LD patterns with both a single or two causal variants and show that our scoreoutperforms SNP correlation metrics, be they statistical (r(2)) or historical (D'). Following the observationof a significant abundance of regulatory signals among currently published GWAS loci, we apply ourmethod with the goal to prioritize relevant genes for each of the respective complex traits. We detectseveral potential disease-causing regulatory effects, with a strong enrichment for immunity-relatedconditions, consistent with the nature of the cell line tested (LCLs). Furthermore, we present an extensionof the method in trans, where interrogating the whole genome for downstream effects of the diseasevariant can be informative regarding its unknown primary biological effect. We conclude that integratingcellular phenotype associations with organismal complex traits will facilitate the biological interpretationof the genetic effects on these traits.", "metadata": {}}
+{"_id": "2488880", "title": "", "text": "Gender-dependent differences in outcome after the treatment of infection in hospitalizedpatients.CONTEXT While it is established that management strategies and outcomes differ by gender formany diseases, its effect on infection has not been adequately studied. OBJECTIVE To investigate the roleof gender among hospitalized patients treated for infection. DESIGN Observational cohort studyconducted during a 26-month period from December 1996 through January 1999. SETTINGUniversity-affiliated hospital. PARTICIPANTS A total of 892 patients in the surgical units of the hospitalwith 1470 consecutive infectious episodes (782 in men and 688 in women). MAIN OUTCOME MEASURESMortality during hospitalization by gender for infection episodes overall and for specific infectious sites,including lung, peritoneum, bloodstream, catheter, urine, surgical site, and skin/soft tissue. RESULTSAmong all infections, there was no significant difference in mortality based on gender (men, 11.1% vswomen, 14.2%; P = .07). After logistic regression analysis, factors independently associated withmortality included higher APACHE (Acute Physiology and Chronic Health Evaluation) II score, older age,malignancy, blood transfusion, and diagnosis of infection more than 7 days after admission, but notgender (female odds ratio [OR] for death, 1.32; 95% confidence interval [CI], 0.90-1.94; P = .16).Mortality was higher in women for lung (men, 18% vs women, 34%; P = .002) and soft tissue (men, 2%vs women, 10%; P < or = .05) infection; for other infectious sites, mortality did not differ by gender.Factors associated with mortality due to pneumonia by logistic regression included higher APACHE IIscore, malignancy, diabetes mellitus, diagnosis of infection more than 7 days after admission, older age,transplantation, and female gender (OR for death, 2.25; 95% CI, 1.17-4.32; P = .02). CONCLUSIONSAlthough gender may not be predictive of mortality among all infections, women appear to be atincreased risk for death from hospital-acquired pneumonia, even after controlling for other comorbidities.", "metadata": {}}
+{"_id": "2492146", "title": "", "text": "Comparative Safety of Targeted Therapies for Metastatic Colorectal Cancer between Elderly and YoungerPatients: a Study Using the International Pharmacovigilance DatabaseMetastatic colorectal cancer(mCRC) is increasingly treated using targeted therapies. Post-marketing safety of these agents isunderstudied, especially in the elderly. This study aimed to compare, according to age, the adverse drugreactions (ADRs) of targeted therapies used for mCRC in real life. An extraction of VigiBase, whichcontains World Health Organization individual case safety reports (ICSRs), was performed. All ADRreports with aflibercept, bevacizumab, cetuximab, panitumumab, or regorafenib used in CRC wereconsidered. For all drugs, chi-square tests were used to compare frequencies of serious ADRs betweenpatients aged ≥75 and <75 years. For selected ADRs and each drug, the drug-ADR association comparedto other anticancer drugs was estimated through the proportional reporting ratio (PRR) in both agegroups. There were 21,565 ICSRs included, among which 74% were serious and 11% were fatal. Medianage was 64 years (Inter Quartile Range = 56–71) and 15% of patients were aged ≥75; 57% were male.Serious ICSRs accounted for 47,292 ADRs. Neutropenia was not more reported in elderly for all drugswhile diarrhea was more reported in elderly for panitumumab. Cardiac disorders were more reported inelderly patients, in particular heart failure, especially for bevacizumab, cetuximab, and regorafenib, aswere respiratory, thoracic, and mediastinal disorders. Most of PRR were not different between the twogroups, except encephalopathies, which were significantly associated with bevacizumab in the elderlyonly. ADRs related to targeted therapies used for mCRC treatment were different across age groups; yet,not systematically more reported or worse in elderly patients. Selected elderly patients could, therefore,be treated with these targeted therapies.", "metadata": {}}
+{"_id": "2494748", "title": "", "text": "CpG island methylation in premalignant stages of gastric carcinoma.There are limited reports onmethylation analysis of the premalignant lesions of gastric carcinoma thus far. This is despite the factthat gastric carcinoma is one of the tumors with a high frequency of CpG island hypermethylation. Todetermine the frequency and timing of hypermethylation during multistep gastric carcinogenesis,non-neoplastic gastric mucosa (n = 118), adenomas (n = 61), and carcinomas (n = 64) were analyzedfor their p16, human Mut L homologue 1 (hMLH1), death-associated protein (DAP)-kinase,thromobospondin-1 (THBS1), and tissue inhibitor of metalloproteinase 3 (TIMP-3) methylation statususing methylation-specific PCR. Three different classes of methylation behaviors were found in the fivetested genes. DAP-kinase was methylated at a similar frequency in all four stages, whereas hMLH1 andp16 were methylated in cancer samples (20.3% and 42.2%, respectively) more frequently than inintestinal metaplasia (6.3% and 2.1%, respectively) or adenomas (9.8% and 11.5%, respectively).However, hMLH1 and p16 were not methylated in chronic gastritis. THBS-1 and TIMP-3 were methylatedin all stages but showed a marked increase in hypermethylation frequency from chronic gastritis (10.1%and 14.5%, respectively) to intestinal metaplasia (34.7% and 36.7%, respectively; P < 0.05) and fromadenomas (28.3% and 26.7%, respectively) to carcinomas (48.4% and 57.4%, respectively: P < 0.05).The hMLH1, THBS1, and TIMP-3 hypermethylation frequencies were similar in both intestinal metaplasiaand adenomas, but the p16 hypermethylation frequency tended to be higher in adenomas (11.5%) thanin intestinal metaplasia (2.1%; P = 0.073). The average number of methylated genes was 0.6, 1.1, 1.1,and 2.0 per five genes per sample in chronic gastritis, intestinal metaplasia, adenomas, and carcinomas,respectively. This shows a marked increase in methylated genes from non-metaplastic mucosa tointestinal metaplasia (P = 0.001) as well as from premalignant lesions to carcinomas (P = 0.002). Theseresults suggest that CpG island hypermethylation occur early in multistep gastric carcinogenesis and tendto accumulate along the multistep carcinogenesis.", "metadata": {}}
+{"_id": "2496002", "title": "", "text": "Familial amyloidotic polyneuropathy: current and emerging treatment options for transthyretin-mediatedamyloidosisTransthyretin familial amyloid polyneuropathy (TTR-FAP) is a fatal clinical disordercharacterized by extracellular deposition of abnormal fibrils derived from misfolded, normally solubletransthyretin (TTR) molecules. The disease is most commonly caused by a point mutation within the TTRgene inherited in an autosomal dominant fashion. Over 100 of such mutations have been identified,leading to destabilization of the physiological TTR tetramer. As a result, many monomers originate with atendency for spontaneous conformational changes and self-aggregation. The main clinical feature ofTTR-FAP is progressive sensorimotor and autonomic neuropathy. In the beginning, this polyneuropathypredominantly involves small unmyelinated nerve fibers with the result of dissociated sensory lossdisproportionately affecting sensation of pain and temperature. Autonomic neuropathy typicallyaccompanies sensory deficits early in the disease course. The symptoms include orthostatic hypotension,constipation alternating with diarrhea, erectile dysfunction, anhydrosis, and urinary retention orincontinence. Later, involvement of motor fibers causes rapidly progressive weakness and gaitdisturbances. In addition to the peripheral nervous system, the heart and the gut are frequently affected.Onset of symptoms is bimodal, with one peak at age 33 years (early onset) and another distinct peak inthe sixth decade of life (late onset). The course of TTR-FAP is uniformly progressive and fatal. Deathoccurs an average of 10.8 years after the onset of symptoms in Portuguese patients, and 7.3 years inlate-onset Japanese patients. Common causes include cachexia, cardiac failure, arrhythmia, andsecondary infections. Liver transplantation is the standard therapy for patients who are in a clinicalcondition good enough to tolerate this intervention because it stops progression of neuropathy byremoving the main source of mutant TTR. Recently, orally administered tafamidis meglumine has beenapproved by European authorities for treatment of FAP. The substance has been shown to stabilize theTTR tetramer, thereby improving the outcome of patients with TTR-FAP. Various other strategies havebeen studied in vitro to prevent TTR amyloidosis, including gene therapy, immunization, dissolution ofTTR aggregates, and free radical scavengers, but none of them is ready for clinical use so far.", "metadata": {}}
+{"_id": "2506153", "title": "", "text": "Invariant natural killer T cells: bridging innate and adaptive immunityCells of the innate immune systeminteract with pathogens via conserved pattern-recognition receptors, whereas cells of the adaptiveimmune system recognize pathogens through diverse, antigen-specific receptors that are generated bysomatic DNA rearrangement. Invariant natural killer T (iNKT) cells are a subset of lymphocytes thatbridge the innate and adaptive immune systems. Although iNKT cells express T cell receptors that aregenerated by somatic DNA rearrangement, these receptors are semi-invariant and interact with a limitedset of lipid and glycolipid antigens, thus resembling the pattern-recognition receptors of the innateimmune system. Functionally, iNKT cells most closely resemble cells of the innate immune system, asthey rapidly elicit their effector functions following activation, and fail to develop immunological memory.iNKT cells can become activated in response to a variety of stimuli and participate in the regulation ofvarious immune responses. Activated iNKT cells produce several cytokines with the capacity to jump-startand modulate an adaptive immune response. A variety of glycolipid antigens that can differentially elicitdistinct effector functions in iNKT cells have been identified. These reagents have been employed to testthe hypothesis that iNKT cells can be harnessed for therapeutic purposes in human diseases. Here, wereview the innate-like properties and functions of iNKT cells and discuss their interactions with other celltypes of the immune system.", "metadata": {}}
+{"_id": "2522977", "title": "", "text": "Olmesartan-based therapies: an effective way to improve blood pressure control and cardiovascularprotection.The main purpose in hypertension treatment is the reduction of cardiovascular disease burden.Among different first-line antihypertensive drug classes, angiotensin-receptor blockers are characterizedby their both good effectiveness and tolerability. Furthermore, the interruption of the renin-angiotensincascade is related with several benefits in target organ protection and cardiovascular prevention. Amongdifferent angiotensin-receptor blockers, olmesartan has been examined in several trial of organprotection, showing improvements in several disease markers, such as microinflammation, regression ofboth plaque volume and vascular hypertrophy, as well as microalbuminuria prevention. Olmesartan hasbeen also widely examined in combination of either hydrochlorothiazide or amlodipine, as well as withboth drugs in a single-pill triple combination, showing improvements in antihypertensive efficacy withoutsignificant effects on tolerability. This treatment strategy based on a drug with such characteristics andthe availability of different types of combinations with other first-line drug classes may represent aneffective way for achieving blood pressure control in a majority of hypertensive patients and this couldalso be related with a better cardiovascular disease prevention.", "metadata": {}}
+{"_id": "2526777", "title": "", "text": "Manslaughter by Fake Artesunate in Asia—Will Africa Be Next?Falciparum malaria kills, and it particularlykills the rural poor. Artemisinin derivatives, such as artesunate, are a vital component of Plasmodiumfalciparum malaria treatment and control in the face of globally increasing antimalarial drug resistance.Since 1998 a worsening epidemic of sophisticated counterfeit “artesunate” tablets (containing noartesunate) has plagued mainland Southeast Asia (see Figure S1). In some countries, most of theavailable artesunate is fake [ 1–5]. Artemisinin derivatives are remarkably rapid in their antimalarialeffects, and they are very well tolerated. So where these medicines are available, they are sought after.But as they are relatively expensive, a demand is created for cheaper versions amongst the poorest andmost vulnerable people, upon whom the counterfeiters have preyed–with fatal results.", "metadata": {}}
+{"_id": "2533768", "title": "", "text": "Workshop: endothelial cell dysfunction leading to diabetic nephropathy : focus on nitric oxide.Clinicalmanifestations of diabetic nephropathy are an expression of diabetic microangiopathy. This reviewrevisits the previously proposed Steno hypothesis and advances our hypothesis that development ofendothelial cell dysfunction represents a common pathophysiological pathway of diabetic complications.Specifically, the ability of glucose to scavenge nitric oxide is proposed as the initiation phase ofendothelial dysfunction. Gradual accumulation of advanced glycated end products and induction ofplasminogen activator inhibitor-1, resulting in the decreased expression of endothelial nitric oxidesynthase and reduced generation of nitric oxide, are proposed to be pathophysiologically critical for themaintenance phase of endothelial dysfunction. The proposed conceptual shift toward the role ofendothelial dysfunction in diabetic complications may provide new strategies for their prevention.", "metadata": {}}
+{"_id": "2541699", "title": "", "text": "A nuclear Argonaute promotes multi-generational epigenetic inheritance and germlineimmortalityEpigenetic information is frequently erased near the start of each new generation. In somecases, however, epigenetic information can be transmitted from parent to progeny (multigenerationalepigenetic inheritance). A particularly notable example of this type of epigenetic inheritance isdouble-stranded RNA-mediated gene silencing in Caenorhabditis elegans. This RNA-mediated interference(RNAi) can be inherited for more than five generations. To understand this process, here we conduct agenetic screen for nematodes defective in transmitting RNAi silencing signals to future generations. Thisscreen identified the heritable RNAi defective 1 (hrde-1) gene. hrde-1 encodes an Argonaute protein thatassociates with small interfering RNAs in the germ cells of progeny of animals exposed todouble-stranded RNA. In the nuclei of these germ cells, HRDE-1 engages the nuclear RNAi defectivepathway to direct the trimethylation of histone H3 at Lys 9 (H3K9me3) at RNAi-targeted genomic loci andpromote RNAi inheritance. Under normal growth conditions, HRDE-1 associates with endogenouslyexpressed short interfering RNAs, which direct nuclear gene silencing in germ cells. In hrde-1- or nuclearRNAi-deficient animals, germline silencing is lost over generational time. Concurrently, these animalsexhibit steadily worsening defects in gamete formation and function that ultimately lead to sterility. Theseresults establish that the Argonaute protein HRDE-1 directs gene-silencing events in germ-cell nuclei thatdrive multigenerational RNAi inheritance and promote immortality of the germ-cell lineage. We proposethat C. elegans use the RNAi inheritance machinery to transmit epigenetic information, accrued by pastgenerations, into future generations to regulate important biological processes.", "metadata": {}}
+{"_id": "2543135", "title": "", "text": "Autophagic programmed cell death by selective catalase degradation.Autophagy plays a central role inregulating important cellular functions such as cell survival during starvation and control of infectiouspathogens. Recently, it has been shown that autophagy can induce cells to die; however, the mechanismof the autophagic cell death program is unclear. We now show that caspase inhibition leading to celldeath by means of autophagy involves reactive oxygen species (ROS) accumulation, membrane lipidoxidation, and loss of plasma membrane integrity. Inhibition of autophagy by chemical compounds orknocking down the expression of key autophagy proteins such as ATG7, ATG8, and receptor interactingprotein (RIP) blocks ROS accumulation and cell death. The cause of abnormal ROS accumulation is theselective autophagic degradation of the major enzymatic ROS scavenger, catalase. Caspase inhibitiondirectly induces catalase degradation and ROS accumulation, which can be blocked by autophagyinhibitors. These findings unveil a molecular mechanism for the role of autophagy in cell death andprovide insight into the complex relationship between ROS and nonapoptotic programmed cell death.", "metadata": {}}
+{"_id": "2547636", "title": "", "text": "Human epidermal stem cell function is regulated by circadian oscillations.Human skin copes with harmfulenvironmental factors that are circadian in nature, yet how circadian rhythms modulate the function ofhuman epidermal stem cells is mostly unknown. Here we show that in human epidermal stem cells andtheir differentiated counterparts, core clock genes peak in a successive and phased manner, establishingdistinct temporal intervals during the 24 hr day period. Each of these successive clock waves isassociated with a peak in the expression of subsets of transcripts that temporally segregate thepredisposition of epidermal stem cells to respond to cues that regulate their proliferation ordifferentiation, such as TGFβ and calcium. Accordingly, circadian arrhythmia profoundly affects stem cellfunction in culture and in vivo. We hypothesize that this intricate mechanism ensures homeostasis byproviding epidermal stem cells with environmentally relevant temporal functional cues during the courseof the day and that its perturbation may contribute to aging and carcinogenesis.", "metadata": {}}
+{"_id": "2559303", "title": "", "text": "Engraftment of engineered ES cell–derived cardiomyocytes but not BM cells restores contractile functionto the infarcted myocardiumCellular cardiomyoplasty is an attractive option for the treatment of severeheart failure. It is, however, still unclear and controversial which is the most promising cell source.Therefore, we investigated and examined the fate and functional impact of bone marrow (BM) cells andembryonic stem cell (ES cell)–derived cardiomyocytes after transplantation into the infarcted mouseheart. This proved particularly challenging for the ES cells, as their enrichment into cardiomyocytes andtheir long-term engraftment and tumorigenicity are still poorly understood. We generated transgenic EScells expressing puromycin resistance and enhanced green fluorescent protein cassettes under control ofa cardiac-specific promoter. Puromycin selection resulted in a highly purified (>99%) cardiomyocytepopulation, and the yield of cardiomyocytes increased 6–10-fold because of induction of proliferation onpurification. Long-term engraftment (4–5 months) was observed when co-transplanting selected EScell–derived cardiomyocytes and fibroblasts into the injured heart of syngeneic mice, and no teratomaformation was found (n = 60). Although transplantation of ES cell–derived cardiomyocytes improvedheart function, BM cells had no positive effects. Furthermore, no contribution of BM cells to cardiac,endothelial, or smooth muscle neogenesis was detected. Hence, our results demonstrate that ES-basedcell therapy is a promising approach for the treatment of impaired myocardial function and providesbetter results than BM-derived cells.", "metadata": {}}
+{"_id": "2565138", "title": "", "text": "Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancerOBJECTIVEPancreatic ductal adenocarcinoma (PDA) is characterised by stromal desmoplasia and vasculardysfunction, which critically impair drug delivery. This study examines the role of an abundantextracellular matrix component, the megadalton glycosaminoglycan hyaluronan (HA), as a noveltherapeutic target in PDA. METHODS Using a genetically engineered mouse model of PDA, the authorsenzymatically depleted HA by a clinically formulated PEGylated human recombinant PH20 hyaluronidase(PEGPH20) and examined tumour perfusion, vascular permeability and drug delivery. The preclinicalutility of PEGPH20 in combination with gemcitabine was assessed by short-term and survival studies.RESULTS PEGPH20 rapidly and sustainably depleted HA, inducing the re-expansion of PDA blood vesselsand increasing the intratumoral delivery of two chemotherapeutic agents, doxorubicin and gemcitabine.Moreover, PEGPH20 triggered fenestrations and interendothelial junctional gaps in PDA tumour endotheliaand promoted a tumour-specific increase in macromolecular permeability. Finally, combination therapywith PEGPH20 and gemcitabine led to inhibition of PDA tumour growth and prolonged survival overgemcitabine monotherapy, suggesting immediate clinical utility. CONCLUSIONS The authors demonstratethat HA impedes the intratumoral vasculature in PDA and propose that its enzymatic depletion beexplored as a means to improve drug delivery and response in patients with pancreatic cancer.", "metadata": {}}
+{"_id": "2566674", "title": "", "text": "Ribose 2′-O-methylation provides a molecular signature for the distinction of self and non-self mRNAdependent on the RNA sensor Mda5The 5′ cap structures of higher eukaryote mRNAs have ribose2′-O-methylation. Likewise, many viruses that replicate in the cytoplasm of eukaryotes have evolved2′-O-methyltransferases to autonomously modify their mRNAs. However, a defined biological role for2′-O-methylation of mRNA remains elusive. Here we show that 2′-O-methylation of viral mRNA wascritically involved in subverting the induction of type I interferon. We demonstrate that human and mousecoronavirus mutants lacking 2′-O-methyltransferase activity induced higher expression of type Iinterferon and were highly sensitive to type I interferon. Notably, the induction of type I interferon byviruses deficient in 2′-O-methyltransferase was dependent on the cytoplasmic RNA sensor Mda5. This linkbetween Mda5-mediated sensing of viral RNA and 2′-O-methylation of mRNA suggests that RNAmodifications such as 2′-O-methylation provide a molecular signature for the discrimination of self andnon-self mRNA.", "metadata": {}}
+{"_id": "2575938", "title": "", "text": "Relationship between activity levels, aerobic fitness, and body fat in 8- to 10-yr-old children.Therelationships between children's activity, aerobic fitness, and fatness are unclear. Indirect estimates ofactivity, e.g., heart rate (HR) and recall, may mask any associations. The purpose of this study was toassess these relationships by using the Tritrac-R3D, a pedometer, and heart rate. Thirty-four children,ages 8-10 yr, participated in the study. The Tritrac and pedometer were worn for up to 6 days. HR wasmeasured for 1 day. Activity measured by Tritrac or pedometer correlated positively to fitness in thewhole group (Tritrac, r = 0.66; pedometer, r = 0.59; P < 0.01) and in boys and girls separately (P <0.05) and correlated negatively to fatness in the whole group (r = -0.42, P < 0.05). In contrast, HR didnot correlate significantly to fitness, and HR of >139 beats/min correlated positively to fatness in girls (r= 0.64, P < 0.05). This suggests that HR is misleading as a measure of activity. This study supports apositive relationship between activity and fitness and suggests a negative relationship between fatnessand activity.", "metadata": {}}
+{"_id": "2576811", "title": "", "text": "Junctional actin assembly is mediated by Formin-like 2 downstream of Rac1Epithelial integrity is vitallyimportant, and its deregulation causes early stage cancer. De novo formation of an adherens junction(AJ) between single epithelial cells requires coordinated, spatial actin dynamics, but the mechanismssteering nascent actin polymerization for cell-cell adhesion initiation are not well understood. Here weinvestigated real-time actin assembly during daughter cell-cell adhesion formation in human breastepithelial cells in 3D environments. We identify formin-like 2 (FMNL2) as being specifically required foractin assembly and turnover at newly formed cell-cell contacts as well as for human epithelial lumenformation. FMNL2 associates with components of the AJ complex involving Rac1 activity and the FMNL2 Cterminus. Optogenetic control of Rac1 in living cells rapidly drove FMNL2 to epithelial cell-cell contactzones. Furthermore, Rac1-induced actin assembly and subsequent AJ formation critically depends onFMNL2. These data uncover FMNL2 as a driver for human epithelial AJ formation downstream of Rac1.", "metadata": {}}
+{"_id": "2582169", "title": "", "text": "Inhibition of HDM2 and activation of p53 by ribosomal protein L23.The importance of coordinating cellgrowth with proliferation has been recognized for a long time. The molecular basis of this relationship,however, is poorly understood. Here we show that the ribosomal protein L23 interacts with HDM2. Theinteraction involves the central acidic domain of HDM2 and an N-terminal domain of L23. L23 and L11,another HDM2-interacting ribosomal protein, can simultaneously yet distinctly interact with HDM2together to form a ternary complex. We show that, when overexpressed, L23 inhibits HDM2-induced p53polyubiquitination and degradation and causes a p53-dependent cell cycle arrest. On the other hand,knocking down L23 causes nucleolar stress and triggers translocation of B23 from the nucleolus to thenucleoplasm, leading to stabilization and activation of p53. Our data suggest that cells may maintain asteady-state level of L23 during normal growth; alternating the levels of L23 in response to changinggrowth conditions could impinge on the HDM2-p53 pathway by interrupting the integrity of the nucleolus.", "metadata": {}}
+{"_id": "2587396", "title": "", "text": "Association of Blood Monocyte and Platelet Markers with Carotid Artery Characteristics: TheAtherosclerosis Risk in Communities Carotid MRI StudyBackground: Atherosclerosis is characterized byinfiltration of inflammatory cells from circulating blood. Blood cell activation could play an important rolein plaque formation. Methods: We analyzed the relationship between blood cellular markers andquantitative measures of carotid wall components in 1,546 participants from the ARIC (AtherosclerosisRisk in Communities) Carotid MRI Study. Carotid imaging was performed using a gadoliniumcontrast-enhanced MRI and cellular phenotyping by flow cytometry. Results: Monocyte Toll-like receptor(TLR)-2 is associated with larger plaques, while CD14, myeloperoxidase, and TLR-4 associate withsmaller. Platelet CD40L is associated with smaller plaques and thinner caps, while P-selectin is associatedwith smaller core size. Conclusions: Blood cell activation is significantly associated with atheroscleroticchanges of the carotid wall.", "metadata": {}}
+{"_id": "2593298", "title": "", "text": "Vascular endothelial cadherin controls VEGFR-2 internalization and signaling from intracellularcompartmentsReceptor endocytosis is a fundamental step in controlling the magnitude, duration, andnature of cell signaling events. Confluent endothelial cells are contact inhibited in their growth andrespond poorly to the proliferative signals of vascular endothelial growth factor (VEGF). In a previousstudy, we found that the association of vascular endothelial cadherin (VEC) with VEGF receptor (VEGFR)type 2 contributes to density-dependent growth inhibition (Lampugnani, G.M., A. Zanetti, M. Corada, T.Takahashi, G. Balconi, F. Breviario, F. Orsenigo, A. Cattelino, R. Kemler, T.O. Daniel, and E. Dejana.2003. J. Cell Biol. 161:793–804). In the present study, we describe the mechanism through which VECreduces VEGFR-2 signaling. We found that VEGF induces the clathrin-dependent internalization ofVEGFR-2. When VEC is absent or not engaged at junctions, VEGFR-2 is internalized more rapidly andremains in endosomal compartments for a longer time. Internalization does not terminate its signaling;instead, the internalized receptor is phosphorylated, codistributes with active phospholipase C–γ, andactivates p44/42 mitogen-activated protein kinase phosphorylation and cell proliferation. Inhibition ofVEGFR-2 internalization reestablishes the contact inhibition of cell growth, whereas silencing thejunction-associated density-enhanced phosphatase-1/CD148 phosphatase restores VEGFR-2internalization and signaling. Thus, VEC limits cell proliferation by retaining VEGFR-2 at the membraneand preventing its internalization into signaling compartments.", "metadata": {}}
+{"_id": "2601135", "title": "", "text": "Diversification in the HIV-1 Envelope Hyper-variable Domains V2, V4, and V5 and Higher Probability ofTransmitted/Founder Envelope Glycosylation Favor the Development of Heterologous NeutralizationBreadthA recent study of plasma neutralization breadth in HIV-1 infected individuals at nine InternationalAIDS Vaccine Initiative (IAVI) sites reported that viral load, HLA-A*03 genotype, and subtype C infectionwere strongly associated with the development of neutralization breadth. Here, we refine the findings ofthat study by analyzing the impact of the transmitted/founder (T/F) envelope (Env), early Envdiversification, and autologous neutralization on the development of plasma neutralization breadth in 21participants identified during recent infection at two of those sites: Kigali, Rwanda (n = 9) and Lusaka,Zambia (n = 12). Single-genome analysis of full-length T/F Env sequences revealed that all 21 individualswere infected with a highly homogeneous population of viral variants, which were categorized as subtypeC (n = 12), A1 (n = 7), or recombinant AC (n = 2). An extensive amino acid sequence-based analysis ofvariable loop lengths and glycosylation patterns in the T/F Envs revealed that a lower ratio of NXS toNXT-encoded glycan motifs correlated with neutralization breadth. Further analysis comparing amino acidsequence changes, insertions/deletions, and glycan motif alterations between the T/F Env and autologousearly Env variants revealed that extensive diversification focused in the V2, V4, and V5 regions of gp120,accompanied by contemporaneous viral escape, significantly favored the development of breadth. Theseresults suggest that more efficient glycosylation of subtype A and C T/F Envs through fewer NXS-encodedglycan sites is more likely to elicit antibodies that can transition from autologous to heterologousneutralizing activity following exposure to gp120 diversification. This initiates an Env-antibodyco-evolution cycle that increases neutralization breadth, and is further augmented over time by additionalviral and host factors. These findings suggest that understanding how variation in the efficiency ofsite-specific glycosylation influences neutralizing antibody elicitation and targeting could advance thedesign of immunogens aimed at inducing antibodies that can transition from autologous to heterologousneutralizing activity.", "metadata": {}}
+{"_id": "2601324", "title": "", "text": "Glycolytic oligodendrocytes maintain myelin and long-term axonal integrityOligodendrocytes, themyelin-forming glial cells of the central nervous system, maintain long-term axonal integrity. However,the underlying support mechanisms are not understood. Here we identify a metabolic component ofaxon–glia interactions by generating conditional Cox10 (protoheme IX farnesyltransferase) mutant mice,in which oligodendrocytes and Schwann cells fail to assemble stable mitochondrial cytochrome c oxidase(COX, also known as mitochondrial complex IV). In the peripheral nervous system, Cox10 conditionalmutants exhibit severe neuropathy with dysmyelination, abnormal Remak bundles, muscle atrophy andparalysis. Notably, perturbing mitochondrial respiration did not cause glial cell death. In the adult centralnervous system, we found no signs of demyelination, axonal degeneration or secondary inflammation.Unlike cultured oligodendrocytes, which are sensitive to COX inhibitors, post-myelinationoligodendrocytes survive well in the absence of COX activity. More importantly, by in vivo magneticresonance spectroscopy, brain lactate concentrations in mutants were increased compared with controls,but were detectable only in mice exposed to volatile anaesthetics. This indicates that aerobic glycolysisproducts derived from oligodendrocytes are rapidly metabolized within white matter tracts. Becausemyelinated axons can use lactate when energy-deprived, our findings suggest a model in which axon–gliametabolic coupling serves a physiological function.", "metadata": {}}
+{"_id": "2603304", "title": "", "text": "Siglec-1 Is a Novel Dendritic Cell Receptor That Mediates HIV-1 Trans-Infection Through Recognition ofViral Membrane GangliosidesDendritic cells (DCs) are essential antigen-presenting cells for the inductionof immunity against pathogens. However, HIV-1 spread is strongly enhanced in clusters of DCs andCD4(+) T cells. Uninfected DCs capture HIV-1 and mediate viral transfer to bystander CD4(+) T cellsthrough a process termed trans-infection. Initial studies identified the C-type lectin DC-SIGN as the HIV-1binding factor on DCs, which interacts with the viral envelope glycoproteins. Upon DC maturation,however, DC-SIGN is down-regulated, while HIV-1 capture and trans-infection is strongly enhanced via aglycoprotein-independent capture pathway that recognizes sialyllactose-containing membranegangliosides. Here we show that the sialic acid-binding Ig-like lectin 1 (Siglec-1, CD169), which is highlyexpressed on mature DCs, specifically binds HIV-1 and vesicles carrying sialyllactose. Furthermore,Siglec-1 is essential for trans-infection by mature DCs. These findings identify Siglec-1 as a key factor forHIV-1 spread via infectious DC/T-cell synapses, highlighting a novel mechanism that mediates HIV-1dissemination in activated tissues.", "metadata": {}}
+{"_id": "2604063", "title": "", "text": "The composition of the gut microbiota throughout life, with an emphasis on early lifeThe intestinalmicrobiota has become a relevant aspect of human health. Microbial colonization runs in parallel withimmune system maturation and plays a role in intestinal physiology and regulation. Increasing evidenceon early microbial contact suggest that human intestinal microbiota is seeded before birth. Maternalmicrobiota forms the first microbial inoculum, and from birth, the microbial diversity increases andconverges toward an adult-like microbiota by the end of the first 3-5 years of life. Perinatal factors suchas mode of delivery, diet, genetics, and intestinal mucin glycosylation all contribute to influence microbialcolonization. Once established, the composition of the gut microbiota is relatively stable throughout adultlife, but can be altered as a result of bacterial infections, antibiotic treatment, lifestyle, surgical, and along-term change in diet. Shifts in this complex microbial system have been reported to increase the riskof disease. Therefore, an adequate establishment of microbiota and its maintenance throughout life wouldreduce the risk of disease in early and late life. This review discusses recent studies on the earlycolonization and factors influencing this process which impact on health.", "metadata": {}}
+{"_id": "2605032", "title": "", "text": "Intrauterine protein restriction combined with early postnatal overfeeding was not associated withadult-onset obesity but produced glucose intolerance by pancreatic dysfunctionWe investigated if whetherintrauterine protein restriction in combination with overfeeding during lactation would cause adult-onsetobesity and metabolic disorders. After birth, litters from dams fed with control (17% protein) and lowprotein (6% protein) diets were adjusted to a size of four (CO and LO groups, respectively) or eight (CCand LC groups, respectively) pups. All of the offspring were fed a diet containing 12% protein from thetime of weaning until they were 90 d old. Compared to the CC and LC groups, the CO and LO groups hadhigher relative and absolute food intakes, oxygen consumption and carbon dioxide production; lowerbrown adipose tissue weight and lipid content and greater weight gain and absolute and relative whiteadipose tissue weight and absolute lipid content. Compared with the CO and CC rats, the LC and LO ratsexhibited higher relative food intake, brown adipose tissue weight and lipid content, reduced oxygenconsumption, carbon dioxide production and spontaneous activity, increased relative retroperitonealadipose tissue weight and unaltered absolute white adipose tissue weight and lipid content. The fastingserum glucose was similar among the groups. The area under the glucose curve was higher in the LO andCO rats than in the LC and CC rats. The basal insulinemia and homeostasis model assessment of insulinresistance (HOMA-IR) were lower in the LO group than in the other groups. The total area under theinsulin curve for the LO rats was similar to the CC rats, and both were lower than the CO and LC rats. Kittwas higher in the LO, LC and CO groups than in the CC group. Thus, intrauterine protein restrictionfollowed by overfeeding during lactation did not induce obesity, but produced glucose intolerance byimpairing pancreatic function in adulthood.", "metadata": {}}
+{"_id": "2608447", "title": "", "text": "Somatic coding mutations in human induced pluripotent stem cellsDefined transcription factors caninduce epigenetic reprogramming of adult mammalian cells into induced pluripotent stem cells. AlthoughDNA factors are integrated during some reprogramming methods, it is unknown whether the genomeremains unchanged at the single nucleotide level. Here we show that 22 human induced pluripotent stem(hiPS) cell lines reprogrammed using five different methods each contained an average of fiveprotein-coding point mutations in the regions sampled (an estimated six protein-coding point mutationsper exome). The majority of these mutations were non-synonymous, nonsense or splice variants, andwere enriched in genes mutated or having causative effects in cancers. At least half of thesereprogramming-associated mutations pre-existed in fibroblast progenitors at low frequencies, whereasthe rest occurred during or after reprogramming. Thus, hiPS cells acquire genetic modifications inaddition to epigenetic modifications. Extensive genetic screening should become a standard procedure toensure hiPS cell safety before clinical use.", "metadata": {}}
+{"_id": "2613411", "title": "", "text": "Cell cycle, CDKs and cancer: a changing paradigmTumour-associated cell cycle defects are oftenmediated by alterations in cyclin-dependent kinase (CDK) activity. Misregulated CDKs induce unscheduledproliferation as well as genomic and chromosomal instability. According to current models, mammalianCDKs are essential for driving each cell cycle phase, so therapeutic strategies that block CDK activity areunlikely to selectively target tumour cells. However, recent genetic evidence has revealed that, whereasCDK1 is required for the cell cycle, interphase CDKs are only essential for proliferation of specialized cells.Emerging evidence suggests that tumour cells may also require specific interphase CDKs for proliferation.Thus, selective CDK inhibition may provide therapeutic benefit against certain human neoplasias.", "metadata": {}}
+{"_id": "2613775", "title": "", "text": "Sudden infant death syndrome.Despite declines in prevalence during the past two decades, sudden infantdeath syndrome (SIDS) continues to be the leading cause of death for infants aged between 1 month and1 year in developed countries. Behavioural risk factors identified in epidemiological studies include proneand side positions for infant sleep, smoke exposure, soft bedding and sleep surfaces, and overheating.Evidence also suggests that pacifier use at sleep time and room sharing without bed sharing areassociated with decreased risk of SIDS. Although the cause of SIDS is unknown, immaturecardiorespiratory autonomic control and failure of arousal responsiveness from sleep are importantfactors. Gene polymorphisms relating to serotonin transport and autonomic nervous system developmentmight make affected infants more vulnerable to SIDS. Campaigns for risk reduction have helped toreduce SIDS incidence by 50-90%. However, to reduce the incidence even further, greater strides mustbe made in reducing prenatal smoke exposure and implementing other recommended infant carepractices. Continued research is needed to identify the pathophysiological basis of SIDS.", "metadata": {}}
+{"_id": "2613813", "title": "", "text": "Regulation of heterochromatic silencing and histone H3 lysine-9 methylation by RNAi.Eukaryoticheterochromatin is characterized by a high density of repeats and transposons, as well as by modifiedhistones, and influences both gene expression and chromosome segregation. In the fission yeastSchizosaccharomyces pombe, we deleted the argonaute, dicer, and RNA-dependent RNA polymerasegene homologs, which encode part of the machinery responsible for RNA interference (RNAi). Deletionresults in the aberrant accumulation of complementary transcripts from centromeric heterochromaticrepeats. This is accompanied by transcriptional de-repression of transgenes integrated at the centromere,loss of histone H3 lysine-9 methylation, and impairment of centromere function. We propose thatdouble-stranded RNA arising from centromeric repeats targets formation and maintenance ofheterochromatin through RNAi.", "metadata": {}}
+{"_id": "2617858", "title": "", "text": "Conformational Changes during Pore Formation by the Perforin-Related Protein PleurotolysinMembraneattack complex/perforin-like (MACPF) proteins comprise the largest superfamily of pore-forming proteins,playing crucial roles in immunity and pathogenesis. Soluble monomers assemble into largetransmembrane pores via conformational transitions that remain to be structurally and mechanisticallycharacterised. Here we present an 11 Å resolution cryo-electron microscopy (cryo-EM) structure of thetwo-part, fungal toxin Pleurotolysin (Ply), together with crystal structures of both components (the lipidbinding PlyA protein and the pore-forming MACPF component PlyB). These data reveal a 13-fold pore 80Å in diameter and 100 Å in height, with each subunit comprised of a PlyB molecule atop a membranebound dimer of PlyA. The resolution of the EM map, together with biophysical and computationalexperiments, allowed confident assignment of subdomains in a MACPF pore assembly. The majorconformational changes in PlyB are a \u000070° opening of the bent and distorted central β-sheet of theMACPF domain, accompanied by extrusion and refolding of two α-helical regions into transmembraneβ-hairpins (TMH1 and TMH2). We determined the structures of three different disulphide bond-trappedprepore intermediates. Analysis of these data by molecular modelling and flexible fitting allows us togenerate a potential trajectory of β-sheet unbending. The results suggest that MACPF conformationalchange is triggered through disruption of the interface between a conserved helix-turn-helix motif andthe top of TMH2. Following their release we propose that the transmembrane regions assemble intoβ-hairpins via top down zippering of backbone hydrogen bonds to form the membrane-inserted β-barrel.The intermediate structures of the MACPF domain during refolding into the β-barrel pore establish astructural paradigm for the transition from soluble monomer to pore, which may be conserved across thewhole superfamily. The TMH2 region is critical for the release of both TMH clusters, suggesting why thisregion is targeted by endogenous inhibitors of MACPF function.", "metadata": {}}
+{"_id": "2619579", "title": "", "text": "The widespread regulation of microRNA biogenesis, function and decayMicroRNAs (miRNAs) are a largefamily of post-transcriptional regulators of gene expression that are \u000021 nucleotides in length andcontrol many developmental and cellular processes in eukaryotic organisms. Research during the pastdecade has identified major factors participating in miRNA biogenesis and has established basic principlesof miRNA function. More recently, it has become apparent that miRNA regulators themselves are subjectto sophisticated control. Many reports over the past few years have reported the regulation of miRNAmetabolism and function by a range of mechanisms involving numerous protein–protein and protein–RNAinteractions. Such regulation has an important role in the context-specific functions of miRNAs.", "metadata": {}}
+{"_id": "2638387", "title": "", "text": "The cytidine deaminase CEM15 induces hypermutation in newly synthesized HIV-1 DNAHigh mutationfrequency during reverse transcription has a principal role in the genetic variation of primate lentiviralpopulations. It is the main driving force for the generation of drug resistance and the escape fromimmune surveillance. G to A hypermutation is one of the characteristics of primate lentiviruses, as well asother retroviruses, during replication in vivo and in cell culture. The molecular mechanisms of thisprocess, however, remain to be clarified. Here, we demonstrate that CEM15 (also known asapolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3G; APOBEC3G), an endogenousinhibitor of human immunodeficiency virus type 1 (HIV-1) replication, is a cytidine deaminase and is ableto induce G to A hypermutation in newly synthesized viral DNA. This effect can be counteracted by theHIV-1 virion infectivity factor (Vif). It seems that this viral DNA mutator is a viral defence mechanism inhost cells that may induce either lethal hypermutation or instability of the incoming nascent viral reversetranscripts, which could account for the Vif-defective phenotype. Importantly, the accumulation ofCEM15-mediated non-lethal hypermutation in the replicating viral genome could potently contribute tothe genetic variation of primate lentiviral populations.", "metadata": {}}
+{"_id": "2647374", "title": "", "text": "Variants in the Toll-interacting protein gene are associated with susceptibility to sepsis in the Chinese HanpopulationINTRODUCTION Deregulated or excessive host immune responses contribute to thepathogenesis of sepsis. Toll-like receptor (TLR) signaling pathways and their negative regulators play apivotal role in the modulation of host immune responses and the development of sepsis. The objective ofthis study was to investigate the association of variants in the TLR signaling pathway genes and theirnegative regulator genes with susceptibility to sepsis in the Chinese Han population. METHODS Patientswith severe sepsis (n = 378) and healthy control subjects (n = 390) were enrolled. Five genes, namelyTLR2, TLR4, TLR9, MyD88 and TOLLIP, were investigated for their association with sepsis susceptibility bya tag single nucleotide polymorphism (SNP) strategy. Twelve tag SNPs were selected based on the dataof Chinese Han in Beijing from the HapMap project and genotyped by direct sequencing. The mRNAexpression levels of TOLLIP were determined using real-time quantitative Polymerase Chain Reaction(PCR) assays, and concentrations of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) weremeasured by enzyme-linked immunosorbent assay (ELISA). RESULTS Our results showed that the minorC-allele of rs5743867 in TOLLIP was significantly associated with the decreased risk of sepsis (Padj =0.00062, odds ratio (OR)adj = 0.71, 95% confidence interval (CI) 0.59 to 0.86) after adjustment forcovariates in multiple logistic regression analysis. A 3-SNP haplotype block harboring the associated SNPrs5743867 also displayed strong association with omnibus test P value of 0.00049. Haplotype GTCshowed a protective role against sepsis (Padj = 0.0012), while haplotype GCT showed an increased riskfor sepsis (Padj = 0.00092). After exposure to lipopolysaccharide (LPS), TOLLIP mRNA expression levelsin peripheral blood mononuclear cells (PBMCs) from homozygotes for the rs5743867C allele weresignificantly higher than in heterozygotes and homozygotes for the rs5743867T allele (P = 0.013 and P =0.01, respectively). Moreover, the concentrations of TNF-α and IL-6 in culture supernatants weresignificantly lower in the subjects of rs5743867CC genotype than in CT and TT genotype subjects (P =0.016 and P = 0.003 for TNF-α; P = 0.01 and P = 0.002 for IL-6, respectively). CONCLUSIONS Ourfindings indicated that the variants in TOLLIP were significantly associated with sepsis susceptibility in theChinese Han population.", "metadata": {}}
+{"_id": "2659805", "title": "", "text": "Children's estimates of food portion size: the development and evaluation of three portion sizeassessment tools for use with children.A number of methods have been developed to assist subjects inproviding an estimate of portion size but their application in improving portion size estimation by childrenhas not been investigated systematically. The aim was to develop portion size assessment tools for usewith children and to assess the accuracy of children's estimates of portion size using the tools. The toolswere food photographs, food models and an interactive portion size assessment system (IPSAS). Children(n 201), aged 4-16 years, were supplied with known quantities of food to eat, in school. Food leftoverswere weighed. Children estimated the amount of each food using each tool, 24 h after consuming thefood. The age-specific portion sizes represented were based on portion sizes consumed by children in anational survey. Significant differences were found between the accuracy of estimates using the threetools. Children of all ages performed well using the IPSAS and food photographs. The accuracy andprecision of estimates made using the food models were poor. For all tools, estimates of the amount offood served were more accurate than estimates of the amount consumed. Issues relating to reporting offoods left over which impact on estimates of the amounts of foods actually consumed require furtherstudy. The IPSAS has shown potential for assessment of dietary intake with children. Before practicalapplication in assessment of dietary intake of children the tool would need to be expanded to cover awider range of foods and to be validated in a 'real-life' situation.", "metadata": {}}
+{"_id": "2665425", "title": "", "text": "A 3D Map of the Yeast Kinetochore Reveals the Presence of Core and Accessory Centromere-SpecificHistoneThe budding yeast kinetochore is ~68 nm in length with a diameter slightly larger than a 25 nmmicrotubule. The kinetochores from the 16 chromosomes are organized in a stereotypic cluster encirclingcentral spindle microtubules. Quantitative analysis of the inner kinetochore cluster (Cse4, COMA) revealsstructural features not apparent in singly attached kinetochores. The cluster of Cse4-containingkinetochores is physically larger perpendicular to the spindle axis relative to the cluster of Ndc80molecules. If there was a single Cse4 (molecule or nucleosome) at the kinetochore attached to eachmicrotubule plus end, the cluster of Cse4 would appear geometrically identical to Ndc80. Thus, thestructure of the inner kinetochore at the surface of the chromosomes remains unsolved. We have usedpoint fluorescence microscopy and statistical probability maps to deduce the two-dimensional meanposition of representative components of the yeast kinetochore relative to the mitotic spindle inmetaphase. Comparison of the experimental images to three-dimensional architectures from convolutionof mathematical models reveals a pool of Cse4 radially displaced from Cse4 at the kinetochore andkinetochore microtubule plus ends. The pool of displaced Cse4 can be experimentally depleted in mRNAprocessing pat1Δ or xrn1Δ mutants. The peripheral Cse4 molecules do not template outer kinetochorecomponents. This study suggests an inner kinetochore plate at the centromere-microtubule interface inbudding yeast and yields information on the number of Ndc80 molecules at the microtubule attachmentsite.", "metadata": {}}
+{"_id": "2665675", "title": "", "text": "American Society of Clinical Oncology policy statement: the role of the oncologist in cancer preventionand risk assessment.Oncologists have a critical opportunity to utilize risk assessment and cancerprevention strategies to interrupt the initiation or progression of cancer in cancer survivors andindividuals at high risk of developing cancer. Expanding knowledge about the natural history andprognosis of cancers positions oncologists to advise patients regarding the risk of second malignanciesand treatment-related cancers. In addition, as recognized experts in the full spectrum of cancer care,oncologists are afforded opportunities for involvement in community-based cancer prevention activities.Although oncologists are currently providing many cancer prevention and risk assessment services totheir patients, economic barriers exist, including inadequate or lack of insurance, that may compromiseuniform patient access to these services. Additionally, insufficient reimbursement for existing anddeveloping interventions may discourage patient access to these services. The American Society ofClinical Oncology (ASCO), the medical society representing cancer specialists involved in patient care andclinical research, is committed to supporting oncologists in their wide-ranging involvement in cancerprevention. This statement on risk assessment and prevention counseling, although not intended to be acomprehensive overview of cancer prevention describes the current role of oncologists in risk assessmentand prevention; provides examples of risk assessment and prevention activities that should be offered byoncologists; identifies potential opportunities for coordination between oncologists and primary carephysicians in prevention education and coordination of care for cancer survivors; describes ASCO'sinvolvement in education and training of oncologists regarding prevention; and proposes improvement inthe payment environment to encourage patient access to these services.", "metadata": {}}
+{"_id": "2679511", "title": "", "text": "The BLM helicase contributes to telomere maintenance through processing of late-replicatingintermediate structuresWerner's syndrome (WS) and Bloom's syndrome (BS) are cancer predispositiondisorders caused by loss of function of the RecQ helicases WRN or BLM, respectively. BS and WS arecharacterized by replication defects, hyperrecombination events and chromosomal aberrations, which arehallmarks of cancer. Inefficient replication of the G-rich telomeric strand contributes to chromosomeaberrations in WS cells, demonstrating a link between WRN, telomeres and genomic stability. Herein, weprovide evidence that BLM also contributes to chromosome-end maintenance. Telomere defects (TDs) areobserved in BLM-deficient cells at an elevated frequency, which is similar to cells lacking a functionalWRN helicase. Loss of both helicases exacerbates TDs and chromosome aberrations, indicating that BLMand WRN function independently in telomere maintenance. BLM localization, particularly its recruitmentto telomeres, changes in response to replication dysfunction, such as in WRN-deficient cells or afteraphidicolin treatment. Exposure to replication challenge causes an increase in decatenateddeoxyribonucleic acid (DNA) structures and late-replicating intermediates (LRIs), which are visible asBLM-covered ultra-fine bridges (UFBs) in anaphase. A subset of UFBs originates from telomeric DNA andtheir frequency correlates with telomere replication defects. We propose that the BLM complexcontributes to telomere maintenance through its activity in resolving LRIs.", "metadata": {}}
+{"_id": "2682251", "title": "", "text": "Formation of a thymus from rat ES cells in xenogeneic nude mouse\u0000rat ES chimeras.Various conditionsfor differentiating embryonic stem (ES) cells or induced pluripotent stem (iPS) cells into specific kinds ofcell lines are under intensive investigation. However, the production of a functional organ with athree-dimensional structure from ES or iPS cells is difficult to achieve in vitro. In the present paper, wedescribe the establishment of a green fluorescent protein-expressing rat ES cell line and production ofmouse\u0000rat ES chimera by injecting rat ES cells into mouse blastocysts. The rat ES cells contributed tovarious organs in the chimera, including germ cells. When we injected ES cells into blastocysts of nu/numice lacking a thymus, the resultant chimeras produced thymus derived from rat ES cells in their bodies.The chimeric animals may provide a method for the derivation of various organs from ES or iPS cells.", "metadata": {}}
+{"_id": "2682997", "title": "", "text": "Wnt/beta-catenin signaling is required for CNS, but not non-CNS, angiogenesis.Despite the importance ofCNS blood vessels, the molecular mechanisms that regulate CNS angiogenesis and blood-brain barrier(BBB) formation are largely unknown. Here we analyze the role of Wnt/beta-catenin signaling inregulating the formation of CNS blood vessels. First, through the analysis of TOP-Gal Wnt reporter mice,we identify that canonical Wnt/beta-catenin signaling is specifically activated in CNS, but not non-CNS,blood vessels during development. This activation correlates with the expression of different Wnt ligandsby neural progenitor cells in distinct locations throughout the CNS, including Wnt7a and Wnt7b in ventralregions and Wnt1, Wnt3, Wnt3a, and Wnt4 in dorsal regions. Blockade of Wnt/beta-catenin signaling invivo specifically disrupts CNS, but not non-CNS, angiogenesis. These defects include reduction in vesselnumber, loss of capillary beds, and the formation of hemorrhagic vascular malformations that remainadherent to the meninges. Furthermore, we demonstrate that Wnt/beta-catenin signaling regulates theexpression of the BBB-specific glucose transporter glut-1. Taken together these experiments reveal anessential role for Wnt/beta-catenin signaling in driving CNS-specific angiogenesis and provide molecularevidence that angiogenesis and BBB formation are in part linked.", "metadata": {}}
+{"_id": "2686003", "title": "", "text": "Cyanidin-3-rutinoside, a natural polyphenol antioxidant, selectively kills leukemic cells by induction ofoxidative stress.Anthocyanins are a group of naturally occurring phenolic compounds widely available infruits and vegetables in human diets. They have broad biological activities including anti-mutagenesis andanticarcinogenesis, which are generally attributed to their antioxidant activities. We studied the effectsand the mechanisms of the most common type of anthocyanins, cyanidin-3-rutinoside, in severalleukemia and lymphoma cell lines. We found that cyanidin-3-rutinoside extracted and purified from theblack raspberry cultivar Jewel induced apoptosis in HL-60 cells in a dose- and time-dependent manner.Paradoxically, this compound induced the accumulation of peroxides, which are involved in the inductionof apoptosis in HL-60 cells. In addition, cyanidin-3-rutinoside treatment resulted in reactive oxygenspecies (ROS)-dependent activation of p38 MAPK and JNK, which contributed to cell death by activatingthe mitochondrial pathway mediated by Bim. Down-regulation of Bim or overexpression of Bcl-2 orBcl-x(L) considerably blocked apoptosis. Notably, cyanidin-3-rutinoside treatment did not lead toincreased ROS accumulation in normal human peripheral blood mononuclear cells and had no cytotoxiceffects on these cells. These results indicate that cyanidin-3-rutinoside has the potential to be used inleukemia therapy with the advantages of being widely available and selective against tumors.", "metadata": {}}
+{"_id": "2692522", "title": "", "text": "Gout-associated uric acid crystals activate the NALP3 inflammasomeDevelopment of the acute andchronic inflammatory responses known as gout and pseudogout are associated with the deposition ofmonosodium urate (MSU) or calcium pyrophosphate dihydrate (CPPD) crystals, respectively, in joints andperiarticular tissues. Although MSU crystals were first identified as the aetiological agent of gout in theeighteenth century and more recently as a ‘danger signal’ released from dying cells, little is known aboutthe molecular mechanisms underlying MSU- or CPPD-induced inflammation. Here we show that MSU andCPPD engage the caspase-1-activating NALP3 (also called cryopyrin) inflammasome, resulting in theproduction of active interleukin (IL)-1β and IL-18. Macrophages from mice deficient in variouscomponents of the inflammasome such as caspase-1, ASC and NALP3 are defective in crystal-inducedIL-1β activation. Moreover, an impaired neutrophil influx is found in an in vivo model of crystal-inducedperitonitis in inflammasome-deficient mice or mice deficient in the IL-1β receptor (IL-1R). These findingsprovide insight into the molecular processes underlying the inflammatory conditions of gout andpseudogout, and further support a pivotal role of the inflammasome in several autoinflammatorydiseases.", "metadata": {}}
+{"_id": "2701077", "title": "", "text": "Hematopoietic stem cell quiescence promotes error-prone DNA repair and mutagenesis.Most adult stemcells, including hematopoietic stem cells (HSCs), are maintained in a quiescent or resting state in vivo.Quiescence is widely considered to be an essential protective mechanism for stem cells that minimizesendogenous stress caused by cellular respiration and DNA replication. We demonstrate that HSCquiescence can also have detrimental effects. We found that HSCs have unique cell-intrinsic mechanismsensuring their survival in response to ionizing irradiation (IR), which include enhanced prosurvival geneexpression and strong activation of p53-mediated DNA damage response. We show that quiescent andproliferating HSCs are equally radioprotected but use different types of DNA repair mechanisms. Wedescribe how nonhomologous end joining (NHEJ)-mediated DNA repair in quiescent HSCs is associatedwith acquisition of genomic rearrangements, which can persist in vivo and contribute to hematopoieticabnormalities. Our results demonstrate that quiescence is a double-edged sword that renders HSCsintrinsically vulnerable to mutagenesis following DNA damage.", "metadata": {}}
+{"_id": "2714623", "title": "", "text": "Recruitment of Nck by CD3\u0000 Reveals a Ligand-Induced Conformational Change Essential for T CellReceptor Signaling and Synapse FormationHow membrane receptors initiate signal transduction uponligand binding is a matter of intense scrutiny. The T cell receptor complex (TCR-CD3) is composed of TCRalpha/beta ligand binding subunits bound to the CD3 subunits responsible for signal transduction.Although it has long been speculated that TCR-CD3 may undergo a conformational change, confirmationis still lacking. We present strong evidence that ligand engagement of TCR-CD3 induces a conformationalchange that exposes a proline-rich sequence in CD3 epsilon and results in recruitment of the adaptorprotein Nck. This occurs earlier than and independently of tyrosine kinase activation. Finally, byinterfering with Nck-CD3 epsilon association in vivo, we demonstrate that TCR-CD3 recruitment of Nck iscritical for maturation of the immune synapse and for T cell activation.", "metadata": {}}
+{"_id": "2721426", "title": "", "text": "Pseudo-Seq: Genome-Wide Detection of Pseudouridine Modifications in RNA.RNA molecules contain avariety of chemically diverse, posttranscriptionally modified bases. The most abundant modified basefound in cellular RNAs, pseudouridine (Ψ), has recently been mapped to hundreds of sites in mRNAs,many of which are dynamically regulated. Though the pseudouridine landscape has been determined inonly a few cell types and growth conditions, the enzymes responsible for mRNA pseudouridylation areuniversally conserved, suggesting many novel pseudouridylated sites remain to be discovered. Here, wepresent Pseudo-seq, a technique that allows the identification of sites of pseudouridylation genome-widewith single-nucleotide resolution. In this chapter, we provide a detailed description of Pseudo-seq. Weinclude protocols for RNA isolation from Saccharomyces cerevisiae, Pseudo-seq library preparation, anddata analysis, including descriptions of processing and mapping of sequencing reads, computationalidentification of sites of pseudouridylation, and assignment of sites to specific pseudouridine synthases.The approach presented here is readily adaptable to any cell or tissue type from which high-quality mRNAcan be isolated. Identification of novel pseudouridylation sites is an important first step in elucidating theregulation and functions of these modifications.", "metadata": {}}
+{"_id": "2722988", "title": "", "text": "The Mammalian EpigenomeChemical modifications to DNA and histone proteins form a complexregulatory network that modulates chromatin structure and genome function. The epigenome refers tothe complete description of these potentially heritable changes across the genome. The composition ofthe epigenome within a given cell is a function of genetic determinants, lineage, and environment. Withthe sequencing of the human genome completed, investigators now seek a comprehensive view of theepigenetic changes that determine how genetic information is made manifest across an incredibly variedbackground of developmental stages, tissue types, and disease states. Here we review current researchefforts, with an emphasis on large-scale studies, emerging technologies, and challenges ahead.", "metadata": {}}
+{"_id": "2727303", "title": "", "text": "Microtubule-associated histone deacetylase 6 supports the calcium store sensor STIM1 in mediatingmalignant cell behaviors.Stromal-interaction molecule 1 (STIM1) is an endoplasmic reticulum Ca(2+)storage sensor that promotes cell growth, migration, and angiogenesis in breast and cervical cancers.Here, we report that the microtubule-associated histone deacetylase 6 (HDAC6) differentially regulatesactivation of STIM1-mediated store-operated Ca(2+) entry (SOCE) between cervical cancer cells andnormal cervical epithelial cells. Confocal microscopy of living cells indicated that microtubule integrity wasnecessary for STIM1 trafficking to the plasma membrane and interaction with Orai1, an essential poresubunit of SOCE. Cancer cells overexpressed both STIM1 and Orai1 compared with normal cervicalepithelial cells. HDAC6 upregulation in cancer cells was accompanied by hypoacetylated α-tubulin.Tubastatin-A, a specific HDAC6 inhibitor, inhibited STIM1 translocation to plasma membrane and blockedSOCE activation in cancer cells but not normal epithelial cells. Genetic or pharmacologic inhibition ofHDAC6 blocked STIM1 membrane trafficking and downstream Ca(2+) influx, as evidenced by totalinternal reflection fluorescent images and intracellular Ca(2+) determination. In contrast, HDAC6inhibition did not affect interactions between STIM1 and the microtubule plus end-binding protein EB1.Analysis of surgical specimens confirmed that most cervical cancer tissues overexpressed STIM1 andOrai1, accompanied by hypoacetylated α-tubulin. Together, our results identify HDAC6 as a candidatetarget to disrupt STIM1-mediated SOCE as a general strategy to block malignant cell behavior.", "metadata": {}}
+{"_id": "2734421", "title": "", "text": "The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullarymicroenvironment and self-tolerance.Medullary thymic epithelial cells (mTECs) establish T cellself-tolerance through the expression of autoimmune regulator (Aire) and peripheral tissue-specificself-antigens. However, signals underlying mTEC development remain largely unclear. Here, wedemonstrate crucial regulation of mTEC development by receptor activator of NF-kappaB (RANK) andCD40 signals. Whereas only RANK signaling was essential for mTEC development during embryogenesis,in postnatal mice, cooperation between CD40 and RANK signals was required for mTEC development tosuccessfully establish the medullary microenvironment. Ligation of RANK or CD40 on fetal thymic stromain vitro induced mTEC development in a tumor necrosis factor-associated factor 6 (TRAF6)-, NF-kappaBinducing kinase (NIK)-, and IkappaB kinase beta (IKKbeta)-dependent manner. These results show thatdevelopmental-stage-dependent cooperation between RANK and CD40 promotes mTEC development,thereby establishing self-tolerance.", "metadata": {}}
+{"_id": "2739854", "title": "", "text": "Rare and common variants: twenty argumentsGenome-wide association studies have greatly improvedour understanding of the genetic basis of disease risk. The fact that they tend not to identify more than afraction of the specific causal loci has led to divergence of opinion over whether most of the variance ishidden as numerous rare variants of large effect or as common variants of very small effect. Here Ireview 20 arguments for and against each of these models of the genetic basis of complex traits andconclude that both classes of effect can be readily reconciled.", "metadata": {}}
+{"_id": "2754534", "title": "", "text": "DNA methylation status predicts cell type-specific enhancer activity.Cell-selective glucocorticoid receptor(GR) binding to distal regulatory elements is associated with cell type-specific regions of locally accessiblechromatin. These regions can either pre-exist in chromatin (pre-programmed) or be induced by thereceptor (de novo). Mechanisms that create and maintain these sites are not well understood. Weobserve a global enrichment of CpG density for pre-programmed elements, and implicate theirdemethylated state in the maintenance of open chromatin in a tissue-specific manner. In contrast, sitesthat are actively opened by GR (de novo) are characterized by low CpG density, and form a unique classof enhancers devoid of suppressive effect of agglomerated methyl-cytosines. Furthermore, treatmentwith glucocorticoids induces rapid changes in methylation levels at selected CpGs within de novo sites.Finally, we identify GR-binding elements with CpGs at critical positions, and show that methylation canaffect GR-DNA interactions in vitro. The findings present a unique link between tissue-specific chromatinaccessibility, DNA methylation and transcription factor binding and show that DNA methylation can be anintegral component of gene regulation by nuclear receptors.", "metadata": {}}
+{"_id": "2758012", "title": "", "text": "BLM helicase facilitates telomere replication during leading strand synthesis of telomeresBased on its invitro unwinding activity on G-quadruplex (G4) DNA, the Bloom syndrome-associated helicase BLM isproposed to participate in telomere replication by aiding fork progression through G-rich telomeric DNA.Single molecule analysis of replicated DNA (SMARD) was used to determine the contribution of BLMhelicase to telomere replication. In BLM-deficient cells, replication forks initiating from origins within thetelomere, which copy the G-rich strand by leading strand synthesis, moved slower through the telomerecompared with the adjacent subtelomere. Fork progression through the telomere was further slowed inthe presence of a G4 stabilizer. Using a G4-specific antibody, we found that deficiency of BLM, or anotherG4-unwinding helicase, the Werner syndrome-associated helicase WRN, resulted in increased G4structures in cells. Importantly, deficiency of either helicase led to greater increases in G4 DNA detectedin the telomere compared with G4 seen genome-wide. Collectively, our findings are consistent with BLMhelicase facilitating telomere replication by resolving G4 structures formed during copying of the G-richstrand by leading strand synthesis.", "metadata": {}}
+{"_id": "2762601", "title": "", "text": "Reflecting on 25 years with MYCJust over 25 years ago, MYC, the human homologue of a retroviraloncogene, was identified. Since that time, MYC research has been intense and the advances impressive.On reflection, it is astonishing how each incremental insight into MYC regulation and function has also hadan impact on numerous biological disciplines, including our understanding of molecular oncogenesis ingeneral. Here we chronicle the major advances in our understanding of MYC biology, and peer into thefuture of MYC research.", "metadata": {}}
+{"_id": "2774906", "title": "", "text": "Protective effects of exercise and phosphoinositide 3-kinase(p110alpha) signaling in dilated andhypertrophic cardiomyopathy.Physical activity protects against cardiovascular disease, and physiologicalcardiac hypertrophy associated with regular exercise is usually beneficial, in marked contrast topathological hypertrophy associated with disease. The p110alpha isoform of phosphoinositide 3-kinase(PI3K) plays a critical role in the induction of exercise-induced hypertrophy. Whether it or other genesactivated in the athlete's heart might have an impact on cardiac function and survival in a setting of heartfailure is unknown. To examine whether progressive exercise training and PI3K(p110alpha) activity affectsurvival and/or cardiac function in two models of heart disease, we subjected a transgenic mouse modelof dilated cardiomyopathy (DCM) to swim training, genetically crossed cardiac-specific transgenic micewith increased or decreased PI3K(p110alpha) activity to the DCM model, and subjected PI3K(p110alpha)transgenics to acute pressure overload (ascending aortic constriction). Life-span, cardiac function, andmolecular markers of pathological hypertrophy were examined. Exercise training and increased cardiacPI3K(p110alpha) activity prolonged survival in the DCM model by 15-20%. In contrast, reducedPI3K(p110alpha) activity drastically shortened lifespan by approximately 50%. IncreasedPI3K(p110alpha) activity had a favorable effect on cardiac function and fibrosis in the pressure-overloadmodel and attenuated pathological growth. PI3K(p110alpha) signaling negatively regulated Gprotein-coupled receptor stimulated extracellular responsive kinase and Akt (via PI3K, p110gamma)activation in isolated cardiomyocytes. These findings suggest that exercise and enhancedPI3K(p110alpha) activity delay or prevent progression of heart disease, and that supraphysiologic activitycan be beneficial. Identification of genes important for hypertrophy in the athlete's heart could offer newstrategies for treating heart failure.", "metadata": {}}
+{"_id": "2787558", "title": "", "text": "The effect of cigarette smoking, alcohol consumption and fruit and vegetable consumption on IVFoutcomes: a review and presentation of original dataBACKGROUND Lifestyle factors including cigarettesmoking, alcohol consumption and nutritional habits impact on health, wellness, and the risk of chronicdiseases. In the areas of in-vitro fertilization (IVF) and pregnancy, lifestyle factors influence oocyteproduction, fertilization rates, pregnancy and pregnancy loss, while chronic, low-grade oxidative stressmay underlie poor outcomes for some IVF cases. METHODS Here, we review the current literature andpresent some original, previously unpublished data, obtained from couples attending the PIVET MedicalCentre in Western Australia. RESULTS During the study, 80 % of females and 70 % of male partnerscompleted a 1-week diary documenting their smoking, alcohol and fruit and vegetable intake. Thesubsequent clinical outcomes of their IVF treatment such as quantity of oocytes collected, fertilizationrates, pregnancy and pregnancy loss were submitted to multiple regression analysis, in order toinvestigate the relationship between patients, treatment and the recorded lifestyle factors. Ofsignificance, it was found that male smoking caused an increased risk of pregnancy loss (p = 0.029),while female smoking caused an adverse effect on ovarian reserve. Both alcohol consumption (β = 0.074,p < 0.001) and fruit and vegetable consumption (β = 0.034, p < 0.001) had positive effects onfertilization. CONCLUSION Based on our results and the current literature, there is an important impact oflifestyle factors on IVF clinical outcomes. Currently, there are conflicting results regarding other lifestylefactors such as nutritional habits and alcohol consumption, but it is apparent that chronic oxidative stressinduced by lifestyle factors and poor nutritional habits associate with a lower rate of IVF success.", "metadata": {}}
+{"_id": "2810997", "title": "", "text": "Efficient Mitochondrial Genome Editing by CRISPR/Cas9The Clustered Regularly Interspaced ShortPalindromic Repeats (CRISPR)/Cas9 system has been widely used for nuclear DNA editing to generatemutations or correct specific disease alleles. Despite its flexible application, it has not been determined ifCRISPR/Cas9, originally identified as a bacterial defense system against virus, can be targeted tomitochondria for mtDNA editing. Here, we show that regular FLAG-Cas9 can localize to mitochondria toedit mitochondrial DNA with sgRNAs targeting specific loci of the mitochondrial genome. Expression ofFLAG-Cas9 together with gRNA targeting Cox1 and Cox3 leads to cleavage of the specific mtDNA loci. Inaddition, we observed disruption of mitochondrial protein homeostasis following mtDNA truncation orcleavage by CRISPR/Cas9. To overcome nonspecific distribution of FLAG-Cas9, we also created amitochondria-targeted Cas9 (mitoCas9). This new version of Cas9 localizes only to mitochondria;together with expression of gRNA targeting mtDNA, there is specific cleavage of mtDNA.MitoCas9-induced reduction of mtDNA and its transcription leads to mitochondrial membrane potentialdisruption and cell growth inhibition. This mitoCas9 could be applied to edit mtDNA together with gRNAexpression vectors without affecting genomic DNA. In this brief study, we demonstrate that mtDNAediting is possible using CRISPR/Cas9. Moreover, our development of mitoCas9 with specific localizationto the mitochondria should facilitate its application for mitochondrial genome editing.", "metadata": {}}
+{"_id": "2817000", "title": "", "text": "Histone Variant H2A.Z Marks the 5′ Ends of Both Active and Inactive Genes in EuchromatinIn S.cerevisiae, histone variant H2A.Z is deposited in euchromatin at the flanks of silent heterochromatin toprevent its ectopic spread. We show that H2A.Z nucleosomes are found at promoter regions of nearly allgenes in euchromatin. They generally occur as two positioned nucleosomes that flank a nucleosome-freeregion (NFR) that contains the transcription start site. Astonishingly, enrichment at 5' ends is observednot only at actively transcribed genes but also at inactive loci. Mutagenesis of a typical promoter revealeda 22 bp segment of DNA sufficient to program formation of a NFR flanked by two H2A.Z nucleosomes.This segment contains a binding site of the Myb-related protein Reb1 and an adjacent dT:dA tract.Efficient deposition of H2A.Z is further promoted by a specific pattern of histone H3 and H4 tailacetylation and the bromodomain protein Bdf1, a component of the Swr1 remodeling complex thatdeposits H2A.Z.", "metadata": {}}
+{"_id": "2820454", "title": "", "text": "Exercise and respiratory training improve exercise capacity and quality of life in patients with severechronic pulmonary hypertension.BACKGROUND Pulmonary hypertension (PH) is associated with restrictedphysical capacity, limited quality of life, and a poor prognosis because of right heart failure. The presentstudy is the first prospective randomized study to evaluate the effects of exercise and respiratory trainingin patients with severe symptomatic PH. METHODS AND RESULTS Thirty patients with PH (21 women;mean age, 50+/-13 years; mean pulmonary artery pressure, 50+/-15 mm Hg; mean World HealthOrganization [WHO] class, 2.9+/-0.5; pulmonary arterial hypertension, n=23; chronic thromboembolicPH, n=7) on stable disease-targeted medication were randomly assigned to a control (n=15) and aprimary training (n=15) group. Medication remained unchanged during the study period. Primary endpoints were the changes from baseline to week 15 in the distance walked in 6 minutes and in scores ofthe Short Form Health Survey quality-of-life questionnaire. Changes in WHO functional class, Borg scale,and parameters of echocardiography and gas exchange also were assessed. At week 15, patients in theprimary and secondary training groups had an improved 6-minute walking distance; the mean differencebetween the control and the primary training group was 111 m (95% confidence interval, 65 to 139 m;P<0.001). Exercise training was well tolerated and improved scores of quality of life, WHO functionalclass, peak oxygen consumption, oxygen consumption at the anaerobic threshold, and achievedworkload. Systolic pulmonary artery pressure values at rest did not change significantly after 15 weeks ofexercise and respiratory training (from 61+/-18 to 54+/-18 mm Hg) within the training group.CONCLUSIONS This study indicates that respiratory and physical training could be a promising adjunct tomedical treatment in severe PH. The effects add to the beneficial results of modern medical treatment.", "metadata": {}}
+{"_id": "2824347", "title": "", "text": "HIV-1 regulation of latency in the monocyte-macrophage lineage and in CD4+ T lymphocytes.Theintroduction in 1996 of the HAART raised hopes for the eradication of HIV-1. Unfortunately, the discoveryof latent HIV-1 reservoirs in CD4+ T cells and in the monocyte-macrophage lineage proved the optimismto be premature. The long-lived HIV-1 reservoirs constitute a major obstacle to the eradication of HIV-1.In this review, we focus on the establishment and maintenance of HIV-1 latency in the two major targetsfor HIV-1: the CD4+ T cells and the monocyte-macrophage lineage. Understanding the cell-typemolecular mechanisms of establishment, maintenance, and reactivation of HIV-1 latency in thesereservoirs is crucial for efficient therapeutic intervention. A complete viral eradication, the holy graal forclinicians, might be achieved by strategic interventions targeting latently and productively infected cells.We suggest that new approaches, such as the combination of different kinds of proviral activators, mayhelp to reduce dramatically the size of latent HIV-1 reservoirs in patients on HAART.", "metadata": {}}
+{"_id": "2825340", "title": "", "text": "Effects of Electro-Acupuncture Therapy on Post-Stroke Depression in Patients with Different Degrees ofMotor Function Impairments: a Pilot Study[Purpose] The present study examined whetherelectro-acupuncture therapy reduces post-stroke depression (PSD) and whether motor functionimpairments interact with the effects of the therapy. [Subjects] Twenty-eight PSD patients were assessedand assigned to either a good or poor motor function group depending on their motor grade. [Methods]The Beck Depression Inventory (BDI), Hamilton Depression Rating Scale (HDRS) and Manual Muscle Test(MMT) were administered at the screening and initial phases of the study, and at the 4th, 8th, 12th and16th week of the daily electro-acupuncture treatment. [Results] The electro-acupuncture treatmentreduced PSD (as assessed by BDI and HDRS) of the patients. In particular, the depression of the goodmotor function group was significantly more reduced than that of the poor motor function group. Thedegree of motor function impairment did not change throughout the study in either group. [Conclusion]The results of the present study demonstrate that electro-acupuncture therapy can improve PSD, andthat the treatment effect varies depending on the degree of motor function impairment.", "metadata": {}}
+{"_id": "2825380", "title": "", "text": "T cell receptor ligation induces the formation of dynamically regulated signaling assembliesTcell antigenreceptor (TCR) ligation initiates tyrosine kinase activation, signaling complex assembly, and immunesynapse formation. Here, we studied the kinetics and mechanics of signaling complex formation in liveJurkat leukemic T cells using signaling proteins fluorescently tagged with variants of enhanced GFP(EGFP). Within seconds of contacting coverslips coated with stimulatory antibodies, T cells developedsmall, dynamically regulated clusters which were enriched in the TCR, phosphotyrosine, ZAP-70, LAT,Grb2, Gads, and SLP-76, excluded the lipid raft marker enhanced yellow fluorescent protein–GPI, andwere competent to induce calcium elevations. LAT, Grb2, and Gads were transiently associated with theTCR. Although ZAP-70–containing clusters persisted for more than 20 min, photobleaching studiesrevealed that ZAP-70 continuously dissociated from and returned to these complexes. Strikingly, SLP-76translocated to a perinuclear structure after clustering with the TCR. Our results emphasize thedynamically changing composition of signaling complexes and indicate that these complexes can formwithin seconds of TCR engagement, in the absence of either lipid raft aggregation or the formation of acentral TCR-rich cluster.", "metadata": {}}
+{"_id": "2828460", "title": "", "text": "Developmental heterogeneity of cardiac fibroblasts does not predict pathological proliferation andactivation.RATIONALE Fibrosis is mediated partly by extracellular matrix-depositing fibroblasts in theheart. Although these mesenchymal cells are reported to have multiple embryonic origins, the functionalconsequence of this heterogeneity is unknown. OBJECTIVE We sought to validate a panel of surfacemarkers to prospectively identify cardiac fibroblasts. We elucidated the developmental origins of cardiacfibroblasts and characterized their corresponding phenotypes. We also determined proliferation rates ofeach developmental subset of fibroblasts after pressure overload injury. METHODS AND RESULTS Weshowed that Thy1(+)CD45(-)CD31(-)CD11b(-)Ter119(-) cells constitute the majority of cardiacfibroblasts. We characterized these cells using flow cytometry, epifluorescence and confocal microscopy,and transcriptional profiling (using reverse transcription polymerase chain reaction and RNA-seq). Weused lineage tracing, transplantation studies, and parabiosis to show that most adult cardiac fibroblastsderive from the epicardium, a minority arises from endothelial cells, and a small fraction fromPax3-expressing cells. We did not detect generation of cardiac fibroblasts by bone marrow or circulatingcells. Interestingly, proliferation rates of fibroblast subsets on injury were identical, and the relativeabundance of each lineage remained the same after injury. The anatomic distribution of fibroblastlineages also remained unchanged after pressure overload. Furthermore, RNA-seq analysis demonstratedthat Tie2-derived and Tbx18-derived fibroblasts within each operation group exhibit similar geneexpression profiles. CONCLUSIONS The cellular expansion of cardiac fibroblasts after transaorticconstriction surgery was not restricted to any single developmental subset. The parallel proliferation andactivation of a heterogeneous population of fibroblasts on pressure overload could suggest that commonsignaling mechanisms stimulate their pathological response.", "metadata": {}}
+{"_id": "2829179", "title": "", "text": "Pre-eclampsia: connecting angiogenic and metabolic pathways.Pre-eclampsia is a hypertensive disease ofpregnancy with a worldwide incidence of 5-8%. This review focuses on recent developments inpre-eclampsia research related to angiogenesis and metabolism. We first address the 'angiogenicimbalance' theory, which hypothesizes that pre-eclampsia results from an imbalance of factors thatpromote or antagonize angiogenesis, such as soluble fms-like tyrosine kinase (sFlt1), 2-methoxyestradiol(2-ME) and catechol-O-methyltransferase (COMT). Next, we analyze the association betweenpre-eclampsia and dysfunctional metabolism of both homocysteine and placental glycogen. We hope thatilluminating some of the various connections existing between angiogenesis and metabolism inpre-eclampsia will facilitate the update or reconsideration of old models of pathogenesis.", "metadata": {}}
+{"_id": "2831620", "title": "", "text": "Protein Lysine Acetylated/Deacetylated Enzymes and the Metabolism-Related DiseasesLysine acetylationis a reversible posttranslational modifcation, an epigenetic phenomenon, referred to as transfer of anacetyl group from acetyl CoA to lysine e- amino group of targeted protein, which is modulated byacetyltransferases (histone/ lysine (K) acetyltransferases, HATs/KATs) and deacetylases (histone/lysine(K) deacetylases, HDACs/KDACs). Lysine acetylation regulates various metabolic processes, such as fattyacid oxidation, Krebs cycle, oxidative phosphorylation, angiogenesis and so on. Thus disorders of lysineacetylation may be correlated with obesity, diabetes and cardiovascular disease, which are termed as themetabolic complication. With accumulating studies on proteomic acetylation, lysine acetylation alsoinvolves in cell immune status and degenerative diseases, for example, Alzheimer’s disease andHuntington’s disease. This review primarily summarizes the current studies of lysine acetylation inmetabolism modulation and in metabolism-related diseases, such as cardiovascular disease and fatmetabolism disorder.", "metadata": {}}
+{"_id": "2832403", "title": "", "text": "Differential Specificity of Endocrine FGF19 and FGF21 to FGFR1 and FGFR4 in Complex withKLBBACKGROUND Recent studies suggest that betaKlotho (KLB) and endocrine FGF19 and FGF21 redirectFGFR signaling to regulation of metabolic homeostasis and suppression of obesity and diabetes. However,the identity of the predominant metabolic tissue in which a major FGFR-KLB resides that criticallymediates the differential actions and metabolism effects of FGF19 and FGF21 remain unclear.METHODOLOGY/PRINCIPAL FINDINGS We determined the receptor and tissue specificity of FGF21 incomparison to FGF19 by using direct, sensitive and quantitative binding kinetics, and downstream signaltransduction and expression of early response gene upon administration of FGF19 and FGF21 in mice. Wefound that FGF21 binds FGFR1 with much higher affinity than FGFR4 in presence of KLB; while FGF19binds both FGFR1 and FGFR4 in presence of KLB with comparable affinity. The interaction of FGF21 withFGFR4-KLB is very weak even at high concentration and could be negligible at physiologicalconcentration. Both FGF19 and FGF21 but not FGF1 exhibit binding affinity to KLB. The binding of FGF1 isdependent on where FGFRs are present. Both FGF19 and FGF21 are unable to displace the FGF1 binding,and conversely FGF1 cannot displace FGF19 and FGF21 binding. These results indicate that KLB is anindispensable mediator for the binding of FGF19 and FGF21 to FGFRs that is not required for FGF1.Although FGF19 can predominantly activate the responses of the liver and to a less extent the adiposetissue, FGF21 can do so significantly only in the adipose tissue and adipocytes. Among several metabolicand endocrine tissues, the response of adipose tissue to FGF21 is predominant, and can be blunted bythe ablation of KLB or FGFR1. CONCLUSIONS Our results indicate that unlike FGF19, FGF21 is unable tobind FGFR4-KLB complex with affinity comparable to FGFR1-KLB, and therefore, at physiologicalconcentration less likely to directly and significantly target the liver where FGFR4-KLB predominantlyresides. However, both FGF21 and FGF19 have the potential to activate responses of primarily theadipose tissue where FGFR1-KLB resides.", "metadata": {}}
+{"_id": "2837758", "title": "", "text": "Therapeutic efficacy of a multi-epitope vaccine against Helicobacter pylori infection in BALB/c micemodel.Epitope vaccine is a promising option for therapeutic vaccination against Helicobacter pylori (H.pylori) infection. In this study, we constructed a multi-epitope vaccine with five epitopes and mucosaladjuvant E. coli heat-labile enterotoxin B subunit (LTB) named HUepi-LTB and evaluated its therapeuticeffect against H. pylori infection in BALB/c mice model. HUepi-LTB containing three Th epitopes fromUreB and two B cell epitopes from UreB and HpaA was constructed and expressed in E. coli. Oraltherapeutic immunization with HUepi-LTB significantly decreased H. pylori colonization compared withoral immunization with PBS, and the protection was correlated with antigen-specific CD4+ T cells and IgGand mucosal IgA antibody responses. This multi-epitope vaccine may be a promising vaccine candidatethat may help to control H. pylori infection.", "metadata": {}}
+{"_id": "2841164", "title": "", "text": "DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin fromapoptotic and necrotic cells.Increased levels of DNA fragments have frequently been found in the bloodplasma of cancer patients. Published data suggest that only a fraction of the DNA in blood plasma isderived from cancer cells. However, it is not known how much of the circulating DNA is from cancer orfrom noncancer cells. By quantitative methylation-specific PCR of the promoter region of the CDKN2Atumor suppressor gene, we were able to quantify the fraction of plasma DNA derived from tumor cells. Inthe plasma samples of 30 unselected cancer patients, we detected quantities of tumor DNA from only 3%to as much as 93% of total circulating DNA. We investigated possible origins of nontumor DNA in theplasma and demonstrate here a contribution of T-cell DNA in a few cases only. To investigate thepossibility that plasma DNA originates from apoptotic or necrotic cells, we performed studies withapoptotic (staurosporine) and necrotic (staurosporine plus oligomycin) cells in vitro and with mice afterinduction of apoptotic (anti-CD95) or necrotic (acetaminophen) liver injury. Increasing amounts of DNAwere found to be released in the supernatants of cells and in the blood plasma samples of treatedanimals. A clear discrimination of apoptotic and necrotic plasma DNA was possible by gel electrophoresis.The same characteristic patterns of DNA fragments could be identified in plasma derived from differentcancer patients. The data are consistent with the possibility that apoptotic and necrotic cells are a majorsource for plasma DNA in cancer patients.", "metadata": {}}
+{"_id": "2842550", "title": "", "text": "Pharmacodynamics and pharmacokinetics of eptifibatide in patients with acute coronary syndromes:prospective analysis from PURSUIT.BACKGROUND Platelet deposition and aggregation are central to thepathogenesis of ischemic complications of acute coronary syndromes (ACS). Pharmacodynamic effects ofthe platelet glycoprotein IIb/IIIa antagonist eptifibatide have been delineated in healthy subjects but notin patients with ACS. We assessed effects of eptifibatide on ex vivo platelet aggregation in patientsenrolled in the Platelet glycoprotein IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin(eptifibatide) Therapy (PURSUIT) trial of ACS. METHODS AND RESULTS Patients were randomly assignedto an intravenous bolus (180 microgram/kg) and 72-hour infusion of eptifibatide (2.0 microgram/kg perminute, n=48) or placebo (n=50). We assessed correlations of plasma eptifibatide levels with receptoroccupancy and inhibition of ex vivo platelet aggregation at 5 minutes and 1, 4, 24, 48, and 72 hoursduring treatment and 4 and 8 hours after termination of infusion. Blood was collected in buffered citrateand D-phenylalanyl-L-prolyl-L-arginine chloromethylketone anticoagulants. Although eptifibatideproduced profound, prolonged inhibition of platelet aggregation during therapy, aggregation appeared torecover partially by 4 hours after the bolus. The aggregation response was greater with thrombinreceptor agonist peptide versus ADP stimulation; inhibition of platelet aggregation was greater in bloodsamples anticoagulated with citrate versus D-phenylalanyl-L-prolyl-L-arginine chloromethylketone(PPACK). Plasma eptifibatide levels correlated significantly with receptor occupancy but not with inhibitionof platelet aggregation. CONCLUSIONS A bolus and infusion of eptifibatide inhibits platelet aggregationprofoundly in patients with ACS and is followed by brief, partial recovery. These results enhance ourunderstanding of the relation between pharmacodynamic and clinical effects of eptifibatide in suchpatients and may have important implications for its use in percutaneous interventions.", "metadata": {}}
+{"_id": "2844490", "title": "", "text": "Proinflammatory cytokines underlying the inflammation of Crohn's disease.PURPOSE OF REVIEW Toencapsulate our current understanding of the proinflammatory cytokines responsible for the inflammationunderlying Crohn's disease and the prospect of using this information to devise therapy for this conditionbased on inhibition of these cytokines. RECENT FINDINGS Current research is shedding new light on therole of both T helper cell (Th)1 and Th17 responses in the pathogenesis of Crohn's disease. Initial studiesconducted a decade ago highlighted the view that Crohn's disease inflammation is caused by aninterleukin-12-driven Th1 response, which resulted in the generation of interferon-gamma, which thenserved as the main inflammatory mediator. In recent years, however, this view has been largely eclipsedby studies, conducted mainly in murine models, showing that a Th17 response is the main cause ofCrohn's disease inflammation through the production of interleukin-17. Now, a somewhat more balancedview is emerging, which holds that interferon-gamma is still a major proinflammatory cytokine in Crohn'sdisease, although it may arise from both the Th1 and Th17-mediated responses at different phases of theinflammatory process. SUMMARY The new findings continue to support the idea thatanti-interleukin-12p40, an antibody that inhibits both the Th1 and Th17 response, is logically the mostpotent anticytokine for the treatment of Crohn's disease.", "metadata": {}}
+{"_id": "2844897", "title": "", "text": "STATISTICAL METHODS FOR ASSESSING AGREEMENT BETWEEN TWO METHODS OF CLINICALMEASUREMENTIn clinical measurement comparison of a new measurement technique with an establishedone is often needed to see whether they agree sufficiently for the new to replace the old. Suchinvestigations are often analysed inappropriately, notably by using correlation coefficients. The use ofcorrelation is misleading. An alternative approach, based on graphical techniques and simple calculations,is described, together with the relation between this analysis and the assessment of repeatability.", "metadata": {}}
+{"_id": "2851611", "title": "", "text": "The multidrug ABC transporter BmrC/BmrD of Bacillus subtilis is regulated via a ribosome-mediatedtranscriptional attenuation mechanismExpression of particular drug transporters in response to antibioticpressure is a critical element in the development of bacterial multidrug resistance, and represents aserious concern for human health. To obtain a better understanding of underlying regulatorymechanisms, we have dissected the transcriptional activation of the ATP-binding cassette (ABC)transporter BmrC/BmrD of the Gram-positive model bacterium Bacillus subtilis. By using promoter-GFPfusions and live cell array technology, we demonstrate a temporally controlled transcriptional activationof the bmrCD genes in response to antibiotics that target protein synthesis. Intriguingly, bmrCDexpression only occurs during the late-exponential and stationary growth stages, irrespective of thetiming of the antibiotic challenge. We show that this is due to tight transcriptional control by thetransition state regulator AbrB. Moreover, our results show that the bmrCD genes are co-transcribed withbmrB (yheJ), a small open reading frame immediately upstream of bmrC that harbors three alternativestem-loop structures. These stem-loops are apparently crucial for antibiotic-induced bmrCD transcription.Importantly, the antibiotic-induced bmrCD expression requires translation of bmrB, which implies thatBmrB serves as a regulatory leader peptide. Altogether, we demonstrate for the first time that aribosome-mediated transcriptional attenuation mechanism can control the expression of a multidrug ABCtransporter.", "metadata": {}}
+{"_id": "2853291", "title": "", "text": "The neural crest is a source of mesenchymal stem cells with specialized hematopoietic stem cell nichefunctionMesenchymal stem cells (MSCs) and osteolineage cells contribute to the hematopoietic stem cell(HSC) niche in the bone marrow of long bones. However, their developmental relationships remainunclear. In this study, we demonstrate that different MSC populations in the developing marrow of longbones have distinct functions. Proliferative mesoderm-derived nestin(-) MSCs participate in fetalskeletogenesis and lose MSC activity soon after birth. In contrast, quiescent neural crest-derivednestin(+) cells preserve MSC activity, but do not generate fetal chondrocytes. Instead, they differentiateinto HSC niche-forming MSCs, helping to establish the HSC niche by secreting Cxcl12. Perineuralmigration of these cells to the bone marrow requires the ErbB3 receptor. The neonatal Nestin-GFP(+)Pdgfrα(-) cell population also contains Schwann cell precursors, but does not comprise mature Schwanncells. Thus, in the developing bone marrow HSC niche-forming MSCs share a common origin withsympathetic peripheral neurons and glial cells, and ontogenically distinct MSCs have non-overlappingfunctions in endochondrogenesis and HSC niche formation.", "metadata": {}}
+{"_id": "2853685", "title": "", "text": "Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cellsInducedpluripotent stem cells (iPSCs) offer immense potential for regenerative medicine and studies of diseaseand development. Somatic cell reprogramming involves epigenomic reconfiguration, conferring iPSCswith characteristics similar to embryonic stem (ES) cells. However, it remains unknown how complete thereestablishment of ES-cell-like DNA methylation patterns is throughout the genome. Here we report thefirst whole-genome profiles of DNA methylation at single-base resolution in five human iPSC lines, alongwith methylomes of ES cells, somatic cells, and differentiated iPSCs and ES cells. iPSCs show significantreprogramming variability, including somatic memory and aberrant reprogramming of DNA methylation.iPSCs share megabase-scale differentially methylated regions proximal to centromeres and telomeresthat display incomplete reprogramming of non-CG methylation, and differences in CG methylation andhistone modifications. Lastly, differentiation of iPSCs into trophoblast cells revealed that errors inreprogramming CG methylation are transmitted at a high frequency, providing an iPSC reprogrammingsignature that is maintained after differentiation.", "metadata": {}}
+{"_id": "2867345", "title": "", "text": "Inheritance of coronary artery disease in men: an analysis of the role of the Y chromosomeBACKGROUNDA sexual dimorphism exists in the incidence and prevalence of coronary artery disease--men are morecommonly affected than are age-matched women. We explored the role of the Y chromosome in coronaryartery disease in the context of this sexual inequity. METHODS We genotyped 11 markers of themale-specific region of the Y chromosome in 3233 biologically unrelated British men from three cohorts:the British Heart Foundation Family Heart Study (BHF-FHS), West of Scotland Coronary Prevention Study(WOSCOPS), and Cardiogenics Study. On the basis of this information, each Y chromosome was trackedback into one of 13 ancient lineages defined as haplogroups. We then examined associations betweencommon Y chromosome haplogroups and the risk of coronary artery disease in cross-sectional BHF-FHSand prospective WOSCOPS. Finally, we undertook functional analysis of Y chromosome effects onmonocyte and macrophage transcriptome in British men from the Cardiogenics Study. FINDINGS Of ninehaplogroups identified, two (R1b1b2 and I) accounted for roughly 90% of the Y chromosome variantsamong British men. Carriers of haplogroup I had about a 50% higher age-adjusted risk of coronary arterydisease than did men with other Y chromosome lineages in BHF-FHS (odds ratio 1·75, 95% CI 1·20-2·54,p=0·004), WOSCOPS (1·45, 1·08-1·95, p=0·012), and joint analysis of both populations (1·56,1·24-1·97, p=0·0002). The association between haplogroup I and increased risk of coronary arterydisease was independent of traditional cardiovascular and socioeconomic risk factors. Analysis ofmacrophage transcriptome in the Cardiogenics Study revealed that 19 molecular pathways showingstrong differential expression between men with haplogroup I and other lineages of the Y chromosomewere interconnected by common genes related to inflammation and immunity, and that some of themhave a strong relevance to atherosclerosis. INTERPRETATION The human Y chromosome is associatedwith risk of coronary artery disease in men of European ancestry, possibly through interactions ofimmunity and inflammation. FUNDING British Heart Foundation; UK National Institute for HealthResearch; LEW Carty Charitable Fund; National Health and Medical Research Council of Australia;European Union 6th Framework Programme; Wellcome Trust.", "metadata": {}}
+{"_id": "2883827", "title": "", "text": "Cytoscape 2.8: new features for data integration and network visualizationUNLABELLED Cytoscape is apopular bioinformatics package for biological network visualization and data integration. Version 2.8introduces two powerful new features--Custom Node Graphics and Attribute Equations--which can beused jointly to greatly enhance Cytoscape's data integration and visualization capabilities. Custom NodeGraphics allow an image to be projected onto a node, including images generated dynamically or atremote locations. Attribute Equations provide Cytoscape with spreadsheet-like functionality in which thevalue of an attribute is computed dynamically as a function of other attributes and network properties.AVAILABILITY AND IMPLEMENTATION Cytoscape is a desktop Java application released under the LibraryGnu Public License (LGPL). Binary install bundles and source code for Cytoscape 2.8 are available fordownload from http://cytoscape.org.", "metadata": {}}
+{"_id": "2888272", "title": "", "text": "Detection of Histone Modifications at Specific Gene Loci in Single Cells in Histological SectionsChromatinimmunoprecipitation assays have contributed greatly to our understanding of the role of histonemodifications in gene regulation. However, they do not permit analysis with single-cell resolution, thusconfounding analyses of heterogeneous cell populations. Here we present a method that permitsvisualization of histone modifications of single genomic loci with single-cell resolution informaldehyde-fixed paraffin-embedded tissue sections based on combined use of in situ hybridization andproximity ligation assays. We show that dimethylation of lysine 4 of histone H3 (H3K4me2) at the MYH11locus is restricted to the smooth muscle cell (SMC) lineage in human and mouse tissue sections and thatthe mark persists even in phenotypically modulated SMC in atherosclerotic lesions that show nodetectable expression of SMC marker genes. This methodology has promise for broad applications in thestudy of epigenetic mechanisms in complex multicellular tissues in development and disease.", "metadata": {}}
+{"_id": "2890952", "title": "", "text": "Mechanistic characterization of the sulfur-relay system for eukaryotic 2-thiouridine biogenesis at tRNAwobble positionsThe wobble modification in tRNAs, 5-methoxycarbonylmethyl-2-thiouridine(mcm(5)s(2)U), is required for the proper decoding of NNR codons in eukaryotes. The 2-thio groupconfers conformational rigidity of mcm(5)s(2)U by largely fixing the C3'-endo ribose puckering, ensuringstable and accurate codon-anticodon pairing. We have identified five genes in Saccharomyces cerevisiae,YIL008w (URM1), YHR111w (UBA4), YOR251c (TUM1), YNL119w (NCS2) and YGL211w (NCS6), that arerequired for 2-thiolation of mcm(5)s(2)U. An in vitro sulfur transfer experiment revealed that Tum1pstimulated the cysteine desulfurase of Nfs1p, and accepted persulfide sulfurs from Nfs1p. URM1 is aubiquitin-related modifier, and UBA4 is an E1-like enzyme involved in protein urmylation. Thecarboxy-terminus of Urm1p was activated as an acyl-adenylate (-COAMP), then thiocarboxylated(-COSH) by Uba4p. The activated thiocarboxylate can be utilized in the subsequent reactions for2-thiouridine formation, mediated by Ncs2p/Ncs6p. We could successfully reconstitute the 2-thiouridineformation in vitro using recombinant proteins. This study revealed that 2-thiouridine formation shares apathway and chemical reactions with protein urmylation. The sulfur-flow of eukaryotic 2-thiouridineformation is distinct mechanism from the bacterial sulfur-relay system which is based on the persulfidechemistry.", "metadata": {}}
+{"_id": "2891825", "title": "", "text": "High prevalence of asthma in cross country skiers.OBJECTIVES To study the prevalence of asthma(asthma symptoms and bronchial hyperresponsiveness) in Swedish cross country skiers compared withnon-skiers and monitor changes in symptoms and bronchial hyperresponsiveness during the year.DESIGN Cross sectional study during the winter ski season and in the summer. SETTING Six ski clubs forélite skiers (total 47) in two different areas of Sweden. SUBJECTS 42 élite cross country skiers and 29non-skiing referents. MAIN OUTCOME MEASURES Bronchial responsiveness, asthma symptoms, and lungfunction. RESULTS Bronchial responsiveness was significantly greater and asthma symptoms moreprevalent in the skiers than in the referents. There was no difference in bronchial responsiveness withineither group between winter and summer. 15 of the 42 skiers used antiasthmatic drugs regularly and 23had a combination of asthma symptoms and hyperresponsive airways or physician diagnosed asthma, orboth. Altogether 33 skiers had symptoms of asthma or bronchial hyperresponsiveness. One of thereferents had symptoms of asthma and bronchial hyperresponsiveness, and none used antiasthmaticdrugs regularly. CONCLUSIONS Asthma, asthma-like symptoms, and bronchial hyperresponsiveness aremuch more common in cross country skiers than in the general population and non-skiers. Strenuousexercise at low temperatures entailing breathing large volumes of cold air is the most probableexplanation of persistent asthma in skiers.", "metadata": {}}
+{"_id": "2904102", "title": "", "text": "Characterization of biochemical properties of Bacillus subtilis RecQ helicase.RecQ family helicases functionas safeguards of the genome. Unlike Escherichia coli, the Gram-positive Bacillus subtilis bacteriumpossesses two RecQ-like homologues, RecQ[Bs] and RecS, which are required for the repair of DNAdouble-strand breaks. RecQ[Bs] also binds to the forked DNA to ensure a smooth progression of the cellcycle. Here we present the first biochemical analysis of recombinant RecQ[Bs]. RecQ[Bs] binds weakly tosingle-stranded DNA (ssDNA) and blunt-ended double-stranded DNA (dsDNA) but strongly to forkeddsDNA. The protein exhibits a DNA-stimulated ATPase activity and ATP- and Mg(2+)-dependent DNAhelicase activity with a 3' \u0000 5' polarity. Molecular modeling shows that RecQ[Bs] shares high sequenceand structure similarity with E. coli RecQ. Surprisingly, RecQ[Bs] resembles the truncated Saccharomycescerevisiae Sgs1 and human RecQ helicases more than RecQ[Ec] with regard to its enzymatic activities.Specifically, RecQ[Bs] unwinds forked dsDNA and DNA duplexes with a 3'-overhang but is inactive onblunt-ended dsDNA and 5'-overhung duplexes. Interestingly, RecQ[Bs] unwinds blunt-ended DNA withstructural features, including nicks, gaps, 5'-flaps, Kappa joints, synthetic replication forks, and Hollidayjunctions. We discuss these findings in the context of RecQ[Bs]'s possible functions in preserving genomicstability.", "metadata": {}}
+{"_id": "2919030", "title": "", "text": "SOD1 Integrates Signals from Oxygen and Glucose to Repress RespirationCu/Zn superoxide dismutase(SOD1) is an abundant enzyme that has been best studied as a regulator of antioxidant defense. Usingthe yeast Saccharomyces cerevisiae, we report that SOD1 transmits signals from oxygen and glucose torepress respiration. The mechanism involves SOD1-mediated stabilization of two casein kinase 1-gamma(CK1γ) homologs, Yck1p and Yck2p, required for respiratory repression. SOD1 binds a C-terminal degronwe identified in Yck1p/Yck2p and promotes kinase stability by catalyzing superoxide conversion toperoxide. The effects of SOD1 on CK1γ stability are also observed with mammalian SOD1 and CK1γ andin a human cell line. Therefore, in a single circuit, oxygen, glucose, and reactive oxygen can repressrespiration through SOD1/CK1γ signaling. Our data therefore may provide mechanistic insight into howrapidly proliferating cells and many cancers accomplish glucose-mediated repression of respiration infavor of aerobic glycolysis.", "metadata": {}}
+{"_id": "2931832", "title": "", "text": "The prognostic impact of the platelet distribution width-to-platelet count ratio in patients with breastcancerActivated platelets promote tumor cell growth, angiogenesis, and invasion. Platelet activity can beinferred by platelet volume indices (PVIs), which include platelet distribution width (PDW), mean plateletvolume (MPV), platelet distribution width-to-platelet count ratio (PDW/P), and mean plateletvolume-to-platelet count ratio. Platelets and platelet-related markers, such as the platelet-to-lymphocyteratio, have been found to be significant prognostic factors in patients with breast cancer. However, therole of PVIs for predicting survival in breast cancer remains unknown; hence, we performed thisretrospective analysis of 275 patients with breast cancer. PVIs were compared with clinicopathologicalvariables, and were assessed to identify independent indicators associated with disease-free survival(DFS) using the Cox proportional hazards model. An elevated PDW/P significantly correlated with age andHER2 status. Univariate analysis revealed that elevated PDW, MPV, and PDW/P as well as tumor size,nuclear grade, and lymph node involvement were significantly associated with inferior DFS rates (tumorsize: p<0.01; nuclear grade, lymph node involvement, PDW, MPV, and PDW/P: p<0.05). On multivariateanalysis, a large tumor size and elevated PDW/P were significant prognostic factors for DFS, with hazardratios of 3.24 (95% confidence interval [CI]: 1.24-8.47) and 2.99 (95% CI: 1.18-7.57), respectively(p<0.05). Our study is the first to reveal that an elevated PDW/P significantly reduces DFS in patientswith breast carcinoma. Measuring the PDW/P is simple, relatively inexpensive, and almost universallyavailable using routine blood counts; this makes it an attractive biomarker for improved risk assessment.", "metadata": {}}
+{"_id": "2947124", "title": "", "text": "Persistent LCMV infection is controlled by blockade of type I interferon signaling.During persistent viralinfections, chronic immune activation, negative immune regulator expression, an elevated interferonsignature, and lymphoid tissue destruction correlate with disease progression. We demonstrated thatblockade of type I interferon (IFN-I) signaling using an IFN-I receptor neutralizing antibody reducedimmune system activation, decreased expression of negative immune regulatory molecules, and restoredlymphoid architecture in mice persistently infected with lymphocytic choriomeningitis virus. IFN-Iblockade before and after establishment of persistent virus infection resulted in enhanced virus clearanceand was CD4 T cell-dependent. Hence, we demonstrate a direct causal link between IFN-I signaling,immune activation, negative immune regulator expression, lymphoid tissue disorganization, and viruspersistence. Our results suggest that therapies targeting IFN-I may help control persistent virusinfections.", "metadata": {}}
+{"_id": "2947540", "title": "", "text": "Lam6 Regulates the Extent of Contacts between OrganellesCommunication between organelles is crucialfor eukaryotic cells to function as one coherent unit. An important means of communication is throughmembrane contact sites, where two organelles come into close proximity allowing the transport of lipidsand small solutes between them. Contact sites are dynamic in size and can change in response toenvironmental or cellular stimuli; however, how this is regulated has been unclear. Here, we show thatSaccharomyces cerevisiae Lam6 resides in several central contact sites: ERMES (ER/mitochondriaencounter structure), vCLAMP (vacuole and mitochondria patch), and NVJ (nuclear vacuolar junction). Weshow that Lam6 is sufficient for expansion of contact sites under physiological conditions and necessaryfor coordination of contact site size. Given that Lam6 is part of a large protein family and is conserved invertebrates, our work opens avenues for investigating the underlying principles of organellecommunication.", "metadata": {}}
+{"_id": "2958458", "title": "", "text": "Endocrine regulation of human fetal growth: the role of the mother, placenta, and fetus.The environmentin which the fetus develops is critical for its survival and long-term health. The regulation of normalhuman fetal growth involves many multidirectional interactions between the mother, placenta, and fetus.The mother supplies nutrients and oxygen to the fetus via the placenta. The fetus influences the provisionof maternal nutrients via the placental production of hormones that regulate maternal metabolism. Theplacenta is the site of exchange between mother and fetus and regulates fetal growth via the productionand metabolism of growth-regulating hormones such as IGFs and glucocorticoids. Adequate trophoblastinvasion in early pregnancy and increased uteroplacental blood flow ensure sufficient growth of theuterus, placenta, and fetus. The placenta may respond to fetal endocrine signals to increase transport ofmaternal nutrients by growth of the placenta, by activation of transport systems, and by production ofplacental hormones to influence maternal physiology and even behavior. There are consequences of poorfetal growth both in the short term and long term, in the form of increased mortality and morbidity.Endocrine regulation of fetal growth involves interactions between the mother, placenta, and fetus, andthese effects may program long-term physiology.", "metadata": {}}
+{"_id": "2973910", "title": "", "text": "Endothelial-to-mesenchymal transition contributes to cardiac fibrosisCardiac fibrosis, associated with adecreased extent of microvasculature and with disruption of normal myocardial structures, results fromexcessive deposition of extracellular matrix, which is mediated by the recruitment of fibroblasts. Thesource of these fibroblasts is unclear and specific anti-fibrotic therapies are not currently available. Herewe show that cardiac fibrosis is associated with the emergence of fibroblasts originating from endothelialcells, suggesting an endothelial-mesenchymal transition (EndMT) similar to events that occur duringformation of the atrioventricular cushion in the embryonic heart. Transforming growth factor-β1 (TGF-β1)induced endothelial cells to undergo EndMT, whereas bone morphogenic protein 7 (BMP-7) preserved theendothelial phenotype. The systemic administration of recombinant human BMP-7 (rhBMP-7) significantlyinhibited EndMT and the progression of cardiac fibrosis in mouse models of pressure overload and chronicallograft rejection. Our findings show that EndMT contributes to the progression of cardiac fibrosis andthat rhBMP-7 can be used to inhibit EndMT and to intervene in the progression of chronic heart diseaseassociated with fibrosis.", "metadata": {}}
+{"_id": "2988714", "title": "", "text": "Coupled local translation and degradation regulate growth cone collapseLocal translation mediates axonalresponses to Semaphorin3A (Sema3A) and other guidance cues. However, only a subset of the axonalproteome is locally synthesized, whereas most proteins are trafficked from the soma. The reason whyonly specific proteins are locally synthesized is unknown. Here we show that local protein synthesis anddegradation are linked events in growth cones. We find that growth cones exhibit high levels ofubiquitination and that local signalling pathways trigger the ubiquitination and degradation of RhoA, amediator of Sema3A-induced growth cone collapse. Inhibition of RhoA degradation is sufficient to removethe protein-synthesis requirement for Sema3A-induced growth cone collapse. In addition to RhoA, wefind that locally translated proteins are the main targets of the ubiquitin-proteasome system in growthcones. Thus, local protein degradation is a major feature of growth cones and creates a requirement forlocal translation to replenish proteins needed to maintain growth cone responses.", "metadata": {}}
+{"_id": "2991954", "title": "", "text": "Cdk11 is a RanGTP-dependent microtubule stabilization factor that regulates spindle assemblyrateProduction of Ran-guanosine triphosphate (GTP) around chromosomes induces local nucleation andplus end stabilization of microtubules (MTs). The nuclear protein TPX2 is required for RanGTP-dependentMT nucleation. To find the MT stabilizer, we affinity purify nuclear localization signal (NLS)-containingproteins from Xenopus laevis egg extracts. This NLS protein fraction contains the MT stabilization activity.After further purification, we used mass spectrometry to identify proteins in active fractions, includingcyclin-dependent kinase 11 (Cdk11). Cdk11 localizes on spindle poles and MTs in Xenopus culture cellsand egg extracts. Recombinant Cdk11 demonstrates RanGTP-dependent MT stabilization activity,whereas a kinase-dead mutant does not. Inactivation of Cdk11 in egg extracts blocks RanGTP-dependentMT stabilization and dramatically decreases the spindle assembly rate. Simultaneous depletion of TPX2completely inhibits centrosome-dependent spindle assembly. Our results indicate that Cdk11 isresponsible for RanGTP-dependent MT stabilization around chromosomes and that this local stabilizationis essential for normal rates of spindle assembly and spindle function.", "metadata": {}}
+{"_id": "3001685", "title": "", "text": "Population dynamics of a pathogen: the conundrum of vivax malariaBuilding a mathematical model ofpopulation dynamics of pathogens within their host involves considerations of factors similar to those inecology, as pathogens can prey on cells in the host. But within the multicellular host, attacked cell typesare integrated with other cellular systems, which in turn intervene in the infection. For example, immuneresponses attempt to sense and then eliminate or contain pathogens, and homeostatic mechanisms try tocompensate for cell loss. This review focuses on modeling applied to malarias, diseases caused bysingle-cell eukaryote parasites that infect red blood cells, with special concern given to vivax malaria, adisease often thought to be benign (if sometimes incapacitating) because the parasite only attacks asmall proportion of red blood cells, the very youngest ones. However, I will use mathematical modeling toargue that depletion of this pool of red blood cells can be disastrous to the host if growth of the parasiteis not vigorously check by host immune responses. Also, modeling can elucidate aspects of new fieldobservations that indicate that vivax malaria is more dangerous than previously thought. ELECTRONICSUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12551-010-0034-3)contains supplementary material, which is available to authorized users.", "metadata": {}}
+{"_id": "3033830", "title": "", "text": "Identification and analysis of ribonuclease P and MRP RNA in a broad range of eukaryotesRNases P andMRP are ribonucleoprotein complexes involved in tRNA and rRNA processing, respectively. The RNAsubunits of these two enzymes are structurally related to each other and play an essential role in theenzymatic reaction. Both of the RNAs have a highly conserved helical region, P4, which is important inthe catalytic reaction. We have used a bioinformatics approach based on conserved elements tocomputationally analyze available genomic sequences of eukaryotic organisms and have identified a largenumber of novel nuclear RNase P and MRP RNA genes. For MRP RNA for instance, this investigationincreases the number of known sequences by a factor of three. We present secondary structure models ofmany of the predicted RNAs. Although all sequences are able to fold into the consensus secondarystructure of P and MRP RNAs, a striking variation in size is observed, ranging from a Nosema locustaeMRP RNA of 160 nt to much larger RNAs, e.g. a Plasmodium knowlesi P RNA of 696 nt. The P and MRPRNA genes appear in tandem in some protists, further emphasizing the close evolutionary relationship ofthese RNAs.", "metadata": {}}
+{"_id": "3034412", "title": "", "text": "Calcium absorption varies within the reference range for serum 25-hydroxyvitamin D.BACKGROUNDCalcium absorption is generally considered to be impaired under conditions of vitamin D deficiency, butthe vitamin D status that fully normalizes absorption is not known for humans. OBJECTIVE To quantifycalcium absorption at two levels of vitamin D repletion, using pharmacokinetic methods and commerciallymarketed calcium supplements. DESIGN Two experiments performed in the spring of the year, one yearapart. In the first, in which participants were pretreated with 25-hydroxyvitamin D (25OHD), mean serum25OHD concentration was 86.5 nmol/L; and in the other, with no pretreatment, mean serumconcentration was 50.2 nmol/L. Participants received 500 mg oral calcium loads as a part of a standardlow calcium breakfast. A low calcium lunch was provided at mid-day. Blood was obtained fasting and atfrequent intervals for 10 to 12 hours thereafter. METHODS Relative calcium absorption at the two 25OHDconcentrations was estimated from the area under the curve (AUC) for the load-induced increment inserum total calcium. RESULTS AUC(9) (+/- SEM), was 3.63 mg hr/dL +/- 0.234 in participants pretreatedwith 25OHD and 2.20 +/- 0.240 in those not pretreated (P < 0.001). In brief, absorption was 65% higherat serum 25OHD levels averaging 86.5 nmol/L than at levels averaging 50 nmol/L (both values within thenominal reference range for this analyte). CONCLUSIONS Despite the fact that the mean serum 25OHDlevel in the experiment without supplementation was within the current reference ranges, calciumabsorptive performance at 50 nmol/L was significantly reduced relative to that at a mean 25OHD level of86 nmol/L. Thus, individuals with serum 25-hydroxyvitamin D levels at the low end of the currentreference ranges may not be getting the full benefit from their calcium intake. We conclude that the lowerend of the current reference range is set too low.", "metadata": {}}
+{"_id": "3038933", "title": "", "text": "Evolution of virulence in opportunistic pathogens: generalism, plasticity, and controlStandard virulenceevolution theory assumes that virulence factors are maintained because they aid parasitic exploitation,increasing growth within and/or transmission between hosts. An increasing number of studies nowdemonstrate that many opportunistic pathogens (OPs) do not conform to these assumptions, withvirulence factors maintained instead because of advantages in non-parasitic contexts. Here we reviewvirulence evolution theory in the context of OPs and highlight the importance of incorporatingenvironments outside a focal virulence site. We illustrate that virulence selection is constrained bycorrelations between these external and focal settings and pinpoint drivers of key environmentalcorrelations, with a focus on generalist strategies and phenotypic plasticity. We end with a summary ofkey theoretical and empirical challenges to be met for a fuller understanding of OPs.", "metadata": {}}
+{"_id": "3052213", "title": "", "text": "Genome-Wide Profiling of H3K56 Acetylation and Transcription Factor Binding Sites in HumanAdipocytesThe growing epidemic of obesity and metabolic diseases calls for a better understanding ofadipocyte biology. The regulation of transcription in adipocytes is particularly important, as it is a targetfor several therapeutic approaches. Transcriptional outcomes are influenced by both histone modificationsand transcription factor binding. Although the epigenetic states and binding sites of several importanttranscription factors have been profiled in the mouse 3T3-L1 cell line, such data are lacking in humanadipocytes. In this study, we identified H3K56 acetylation sites in human adipocytes derived frommesenchymal stem cells. H3K56 is acetylated by CBP and p300, and deacetylated by SIRT1, all areproteins with important roles in diabetes and insulin signaling. We found that while almost half of thegenome shows signs of H3K56 acetylation, the highest level of H3K56 acetylation is associated withtranscription factors and proteins in the adipokine signaling and Type II Diabetes pathways. In order todiscover the transcription factors that recruit acetyltransferases and deacetylases to sites of H3K56acetylation, we analyzed DNA sequences near H3K56 acetylated regions and found that the E2Frecognition sequence was enriched. Using chromatin immunoprecipitation followed by high-throughputsequencing, we confirmed that genes bound by E2F4, as well as those by HSF-1 and C/EBPα, have higherthan expected levels of H3K56 acetylation, and that the transcription factor binding sites and acetylationsites are often adjacent but rarely overlap. We also discovered a significant difference between boundtargets of C/EBPα in 3T3-L1 and human adipocytes, highlighting the need to construct species-specificepigenetic and transcription factor binding site maps. This is the first genome-wide profile of H3K56acetylation, E2F4, C/EBPα and HSF-1 binding in human adipocytes, and will serve as an importantresource for better understanding adipocyte transcriptional regulation.", "metadata": {}}
+{"_id": "3052642", "title": "", "text": "Detecting and characterizing circular RNAsCircular RNA transcripts were first identified in the early 1990sbut knowledge of these species has remained limited, as their study through traditional methods of RNAanalysis has been difficult. Now, novel bioinformatic approaches coupled with biochemical enrichmentstrategies and deep sequencing have allowed comprehensive studies of circular RNA species. Recentstudies have revealed thousands of endogenous circular RNAs in mammalian cells, some of which arehighly abundant and evolutionarily conserved. Evidence is emerging that some circRNAs might regulatemicroRNA (miRNA) function, and roles in transcriptional control have also been suggested. Therefore,study of this class of noncoding RNAs has potential implications for therapeutic and research applications.We believe the key future challenge for the field will be to understand the regulation and function of theseunusual molecules.", "metadata": {}}
+{"_id": "3056682", "title": "", "text": "A classification of unstable angina revisited.Unstable angina is a critical phase of coronary heart diseasewith widely variable symptoms and prognosis. A decade ago, a classification of unstable angina based onclinical symptoms was introduced. This system was then validated by prospective clinical studies tocorrelate with the prognosis and was linked to angiographic and histological findings. It has been used tocategorize patients in many large clinical trials. In recent years, the pathophysiological roles of plateletactivation and inflammation in unstable angina have been elucidated. Subsequently, improved markers ofmyocardial injury, acute-phase proteins, and hemostatic markers that may be associated with clinicaloutcomes have been identified. Particularly, cardiac-specific troponin T and troponin I have been shownto represent the best predictors of early risk in patients with angina at rest. Accordingly, it is suggestedthat the original classification be extended by subclassifying one large group of unstable angina patients,ie, those with angina at rest within the past 48 hours (class IIIB), into troponin-positive (T(pos)) andtroponin-negative (T(neg)) patients. The 30-days risk for death and myocardial infarction is considered tobe up to 20% in class IIIB-T(pos) but <2% in class IIIB-T(neg) patients. Initial results suggest thattroponins may function as surrogate markers for thrombus formation and can effectively guide therapywith glycoprotein IIb/IIIa antagonists or low-molecular-weight heparins. These observations provideadditional impetus for adding the measurement of these markers to the clinical classification andrepresent a novel concept of treating these high-risk patients.", "metadata": {}}
+{"_id": "3067015", "title": "", "text": "Alcohol Intake and Blood Pressure: A Systematic Review Implementing a Mendelian RandomizationApproachBACKGROUND Alcohol has been reported to be a common and modifiable risk factor forhypertension. However, observational studies are subject to confounding by other behavioural andsociodemographic factors, while clinical trials are difficult to implement and have limited follow-up time.Mendelian randomization can provide robust evidence on the nature of this association by use of acommon polymorphism in aldehyde dehydrogenase 2 (ALDH2) as a surrogate for measuring alcoholconsumption. ALDH2 encodes a major enzyme involved in alcohol metabolism. Individuals homozygousfor the null variant (*2*2) experience adverse symptoms when drinking alcohol and consequently drinkconsiderably less alcohol than wild-type homozygotes (*1*1) or heterozygotes. We hypothesise that thispolymorphism may influence the risk of hypertension by affecting alcohol drinking behaviour. METHODSAND FINDINGS We carried out fixed effect meta-analyses of the ALDH2 genotype with blood pressure(five studies, n = 7,658) and hypertension (three studies, n = 4,219) using studies identified viasystematic review. In males, we obtained an overall odds ratio of 2.42 (95% confidence interval [CI]1.66-3.55, p = 4.8 x 10(-6)) for hypertension comparing *1*1 with *2*2 homozygotes and an odds ratioof 1.72 (95% CI 1.17-2.52, p = 0.006) comparing heterozygotes (surrogate for moderate drinkers) with*2*2 homozygotes. Systolic blood pressure was 7.44 mmHg (95% CI 5.39-9.49, p = 1.1 x 10(-12))greater among *1*1 than among *2*2 homozygotes, and 4.24 mmHg (95% CI 2.18-6.31, p = 0.00005)greater among heterozygotes than among *2*2 homozygotes. CONCLUSIONS These findings support thehypothesis that alcohol intake has a marked effect on blood pressure and the risk of hypertension.", "metadata": {}}
+{"_id": "3078080", "title": "", "text": "Rapid and Sensitive RT-QuIC Detection of Human Creutzfeldt-Jakob Disease Using CerebrospinalFluidUNLABELLED Fast, definitive diagnosis of Creutzfeldt-Jakob disease (CJD) is important in assessingpatient care options and transmission risks. Real-time quaking-induced conversion (RT-QuIC) assays ofcerebrospinal fluid (CSF) and nasal-brushing specimens are valuable in distinguishing CJD from non-CJDconditions but have required 2.5 to 5 days. Here, an improved RT-QuIC assay is described whichidentified positive CSF samples within 4 to 14 h with better analytical sensitivity. Moreover, analysis of 11CJD patients demonstrated that while 7 were RT-QuIC positive using the previous conditions, 10 werepositive using the new assay. In these and further analyses, a total of 46 of 48 CSF samples fromsporadic CJD patients were positive, while all 39 non-CJD patients were negative, giving 95.8%diagnostic sensitivity and 100% specificity. This second-generation RT-QuIC assay markedly improvedthe speed and sensitivity of detecting prion seeds in CSF specimens from CJD patients. This shouldenhance prospects for rapid and accurate ante mortem CJD diagnosis. IMPORTANCE A long-standingproblem in dealing with various neurodegenerative protein misfolding diseases is early and accuratediagnosis. This issue is particularly important with human prion diseases, such as CJD, because prions aredeadly, transmissible, and unusually resistant to decontamination. The recently developed RT-QuIC testallows for highly sensitive and specific detection of CJD in human cerebrospinal fluid and is being broadlyimplemented as a key diagnostic tool. However, as currently applied, RT-QuIC takes 2.5 to 5 days andmisses 11 to 23% of CJD cases. Now, we have markedly improved RT-QuIC analysis of human CSF suchthat CJD and non-CJD patients can be discriminated in a matter of hours rather than days with enhancedsensitivity. These improvements should allow for much faster, more accurate, and practical testing forCJD. In broader terms, our study provides a prototype for tests for misfolded protein aggregates thatcause many important amyloid diseases, such as Alzheimer's, Parkinson's, and tauopathies.", "metadata": {}}
+{"_id": "3078550", "title": "", "text": "Wortmannin, a phosphoinositide 3-kinase inhibitor, selectively enhances cytotoxicity ofreceptor-directed-toxin chimeras in vitro and in vivo.BACKGROUND Generalized resistance of someneoplastic cell lines to treatment with ligand-toxin chimeras has been attributed to an increased rate oflysosomal uptake and degradation following endocytosis of the chimera-receptor complex. Becausephosphoinositide 3-kinase (Pl 3-kinase) activity is known to play a role in intracellular trafficking,particularly from endosomes to lysosomes, we hypothesized that co-exposing cells to the Pl 3-kinaseinhibitor, wortmannin, might enhance cytotoxicity of ligand-toxin chimeras. METHODS In vitro,cytotoxicity of five receptor directed-toxin chimeras (bFGF-SAP, bFGF-PE, aFGF-PE, HBEGF-SAP,bFGF-gelonin) and an immunotoxin (11A8-SAP) was examined in the presence or absence of this Pl3-kinase inhibitor against a panel of human neoplastic cell lines: SK-MEL-5 (melanoma), PA-1 (ovarianteratocarcinoma), DU145 (prostatic carcinoma) and MCF-7 (breast carcinoma). In vivo, antitumor activityof a treatment regimen combining wortmannin (1 or 2 mg/kg i.p.) and bFGF-SAP (10 micrograms/kg i.v.)once a week for 4 weeks was evaluated compared to administration of each agent alone in C3H/HeN miceimplanted with the FSallC murine fibrosarcoma. RESULTS At concentrations greater than the reported Kifor Pl 3-kinase inhibition (1-10 microM), wortmannin enhanced cytotoxicity when combined with saporinor gelonin chimeras, but produced subadditive cytotoxicity when combined with Pseudomonas exotoxinchimeras. When low nanomolar concentrations selective for Pl 3-kinase inhibition (5-100 nM) wereexamined for effects on one receptor directed-toxin chimera, wortmannin dramatically enhancedbFGF-SAP cytotoxicity in three of the four cell lines. A different Pl 3-kinase inhibitor, LY294002 (Kiapproximately 1 microM), however, failed to potentiate bFGF-SAP. When administered to mice,wortmannin combined with bFGF-SAP resulted in a significant decrease in tumor volumes compared tovehicle-treated controls that was not observed in mice treated with either agent alone. CONCLUSIONSTaken together, these results suggest that although wortmannin increases the cytotoxic efficacy of somereceptor-directed chimeras, potentiation may occur through an alternative pathway not involving Pl3-kinase inhibition.", "metadata": {}}
+{"_id": "3083927", "title": "", "text": "Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk.We propose a modelwherein chronic stress results in glucocorticoid receptor resistance (GCR) that, in turn, results in failure todown-regulate inflammatory response. Here we test the model in two viral-challenge studies. In study 1,we assessed stressful life events, GCR, and control variables including baseline antibody to the challengevirus, age, body mass index (BMI), season, race, sex, education, and virus type in 276 healthy adultvolunteers. The volunteers were subsequently quarantined, exposed to one of two rhinoviruses, andfollowed for 5 d with nasal washes for viral isolation and assessment of signs/symptoms of a commoncold. In study 2, we assessed the same control variables and GCR in 79 subjects who were subsequentlyexposed to a rhinovirus and monitored at baseline and for 5 d after viral challenge for the production oflocal (in nasal secretions) proinflammatory cytokines (IL-1β, TNF-α, and IL-6). Study 1: After covaryingthe control variables, those with recent exposure to a long-term threatening stressful experiencedemonstrated GCR; and those with GCR were at higher risk of subsequently developing a cold. Study 2:With the same controls used in study 1, greater GCR predicted the production of more localproinflammatory cytokines among infected subjects. These data provide support for a model suggestingthat prolonged stressors result in GCR, which, in turn, interferes with appropriate regulation ofinflammation. Because inflammation plays an important role in the onset and progression of a wide rangeof diseases, this model may have broad implications for understanding the role of stress in health.", "metadata": {}}
+{"_id": "3085264", "title": "", "text": "Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP), a Neuron-Derived Peptide Regulating GlialGlutamate Transport and MetabolismIn the brain, glutamatergic neurotransmission is terminatedpredominantly by the rapid uptake of synaptically released glutamate into astrocytes through theNa(+)-dependent glutamate transporters GLT-1 and GLAST and its subsequent conversion into glutamineby the enzyme glutamine synthetase (GS). To date, several factors have been identified that rapidly alterglial glutamate uptake by post-translational modification of glutamate transporters. The only conditionknown to affect the expression of glial glutamate transporters and GS is the coculturing of glia withneurons. We now demonstrate that neurons regulate glial glutamate turnover via pituitary adenylatecyclase-activating polypeptide (PACAP). In the cerebral cortex PACAP is synthesized by neurons and actson the subpopulation of astroglia involved in glutamate turnover. Exposure of astroglia to PACAPincreased the maximal velocity of [(3)H]glutamate uptake by promoting the expression of GLT-1, GLAST,and GS. Moreover, the stimulatory effects of neuron-conditioned medium on glial glutamate transporterexpression were attenuated in the presence of PACAP-inactivating antibodies or the PACAP receptorantagonist PACAP 6-38. In contrast to PACAP, vasoactive intestinal peptide promoted glutamatetransporter expression only at distinctly higher concentrations, suggesting that PACAP exerts its effectson glial glutamate turnover via PAC1 receptors. Although PAC1 receptor-dependent activation of proteinkinase A (PKA) was sufficient to promote the expression of GLAST, the activation of both PKA and proteinkinase C (PKC) was required to promote GLT-1 expression optimally. Given the existence of various PAC1receptor isoforms that activate PKA and PKC to different levels, these findings point to a complexmechanism by which PACAP regulates glial glutamate transport and metabolism. Disturbances of theseregulatory mechanisms could represent a major cause for glutamate-associated neurological andpsychiatric disorders.", "metadata": {}}
+{"_id": "3090454", "title": "", "text": "Factors influencing B lymphopoiesis after allogeneic hematopoietic cell transplantation.In 93 allograftrecipients, the numbers of marrow B-cell precursors on days 80 and 365 correlated with the counts ofcirculating B cells, suggesting that the posttransplantation B-cell deficiency is at least in part due toinsufficient B lymphopoiesis. Factors that could affect B lymphopoiesis were evaluated. The number ofmarrow B-cell precursors on days 30 and 80 was at least 4-fold lower in patients with grade 2 to 4 acutegraft-versus-host disease (GVHD) compared with patients with grade 0 to 1 acute GVHD. The number ofB-cell precursors on day 365 was 18-fold lower in patients with extensive chronic GVHD compared withpatients with no or limited chronic GVHD. The number of B-cell precursors was not related to CD34 celldose, type of transplant (marrow versus blood stem cells), donor age, or patient age. It was concludedthat posttransplantation B-cell deficiency results in part from inhibition of B lymphopoiesis by GVHDand/or its treatment.", "metadata": {}}
+{"_id": "3093512", "title": "", "text": "Genetic variants rs1994016 and rs3825807 in ADAMTS7 affect its mRNA expression in atheroscleroticocclusive peripheral arterial diseaseAIM Peripheral artery disease (PAD) is a vascular disease affectingperipheral circulation. Recently, genome-wide association studies revealed a relationship between singlenucleotide polymorphisms (SNPs) in ADAMTS7 (a disintegrin and metalloprotease with thrombospondinmotif 7) and atherosclerosis. In this study, we aimed to determine ADAMTS7 expression in peripheralblood mononuclear cells (PBMCs) and the frequency of ADAMTS7 rs1994016 and rs3825807polymorphisms in a sample of Turkish patients with PAD, and to evaluate the association of matrixmetalloproteinase (MMP) levels with PAD development. METHODS In this case-control study,ADAMTS7mRNA and protein expression was determined using reverse transcription quantitative real-timepolymerase chain reaction (RT-qPCR) and western blot, respectively, and rs1994016 and rs3825807variants in ADAMTS7 were determined by real-time PCR in 115 PAD patients and 116 healthy controls.Plasma levels of nine MMPs were determined using a multiplex immunoassay system. RESULTSADAMTS7mRNA levels were significantly higher in PAD patients than in controls (t=-2.75, P=.007). Therewas no significant difference in the frequencies of rs1994016 and rs3825807 between PAD patients andcontrols (P>.05). In PAD patients, ADAMTS7mRNA levels were significantly increased for the CC genotypeof rs1994016 (t=-2.31, P=.026) and TT genotype of rs3825807 (t=-2.23, P=.032). Furthermore, plasmalevels of MMP-1, MMP-3, MMP-7, MMP-10, MMP-12, and MMP-13 were significantly higher in PAD patientsthan in controls (P<.05). CONCLUSION This is the first report of the relationship between PAD andADAMTS7 expression and the effects of the rs1994016 and rs3825807 variants on PAD development.ADAMTS7 may be associated with PAD development.", "metadata": {}}
+{"_id": "3095620", "title": "", "text": "Distinct Parietal and Temporal Pathways to the Homologues of Broca's Area in the MonkeyThehomologues of the two distinct architectonic areas 44 and 45 that constitute the anterior language zone(Broca's region) in the human ventrolateral frontal lobe were recently established in the macaquemonkey. Although we know that the inferior parietal lobule and the lateral temporal cortical regionproject to the ventrolateral frontal cortex, we do not know which of the several cortical areas found inthose regions project to the homologues of Broca's region in the macaque monkey and by means ofwhich white matter pathways. We have used the autoradiographic method, which permits theestablishment of the cortical area from which axons originate (i.e., the site of injection), the precisecourse of the axons in the white matter, and their termination within particular cortical areas, to examinethe parietal and temporal connections to area 44 and the two subdivisions of area 45 (i.e., areas 45A and45B). The results demonstrated a ventral temporo-frontal stream of fibers that originate from variousauditory, multisensory, and visual association cortical areas in the intermediate superolateral temporalregion. These axons course via the extreme capsule and target most strongly area 45 with a moremodest termination in area 44. By contrast, a dorsal stream of axons that originate from various corticalareas in the inferior parietal lobule and the adjacent caudal superior temporal sulcus was found to targetboth areas 44 and 45. These axons course in the superior longitudinal fasciculus, with some axonsoriginating from the ventral inferior parietal lobule and the adjacent superior temporal sulcus arching andforming a simple arcuate fasciculus. The cortex of the most rostral part of the inferior parietal lobule ispreferentially linked with the ventral premotor cortex (ventral area 6) that controls the orofacialmusculature. The cortex of the intermediate part of the inferior parietal lobule is linked with both areas44 and 45. These findings demonstrate the posterior parietal and temporal connections of theventrolateral frontal areas, which, in the left hemisphere of the human brain, were adapted for variousaspects of language production. These precursor circuits that are found in the nonlinguistic, nonhuman,primate brain also exist in the human brain. The possible reasons why these areas were adapted forlanguage use in the human brain are discussed. The results throw new light on the prelinguistic precursorcircuitry of Broca's region and help understand functional interactions between Broca's ventrolateralfrontal region and posterior parietal and temporal association areas.", "metadata": {}}
+{"_id": "3098821", "title": "", "text": "MIRA-seq for DNA methylation analysis of CpG islandsAIM To develop a reliable method for wholegenome analysis of DNA methylation. MATERIALS & METHODS Genome-scale analysis of DNAmethylation includes affinity-based approaches such as enrichment using methyl-CpG-binding proteins.One of these methods, the methylated-CpG island recovery assay (MIRA), is based on the high affinity ofthe MBD2b-MBD3L1 complex for CpG-methylated DNA. Here we provide a detailed description of MIRAand combine it with next generation sequencing platforms (MIRA-seq). RESULTS We assessed theperformance of MIRA-seq and compared the data with whole genome bisulfite sequencing. CONCLUSIONMIRA-seq is a reliable, genome-scale DNA methylation analysis platform for scoring DNA methylationdifferences at CpG-rich genomic regions. The method is not limited by primer or probe design and is costeffective.", "metadata": {}}
+{"_id": "3099497", "title": "", "text": "How many images are in an auditory scene?If an auditory scene consists of many spatially separatedsound sources, how many sound sources can be processed by the auditory system? Experiment Idetermined how many speech sources could be localized simultaneously on the azimuth plane. Differentwords were played from multiple loudspeakers, and listeners reported the total number of sound sourcesand their individual locations. In experiment II the accuracy of localizing one speech source in a mixtureof multiple speech sources was determined. An extra sound source was added to an existing set of soundsources, and the task was to localize that extra source. In experiment III the setup and task were thesame as in experiment I, except that the sounds were tones. The results showed that the maximumnumber of sound sources that listeners could perceive was limited to approximately four spatiallyseparated speech signals and three for tonal signals. The localization errors increased along with theincrease of total number of sound sources. When four or more speech sources already existed, theaccuracy in localizing an additional source was near chance.", "metadata": {}}
+{"_id": "3105781", "title": "", "text": "Mobilization of intracellular copper stores by the ctr2 vacuolar copper transporter.Copper plays anessential role in processes including signaling to the transcription and protein trafficking machinery,oxidative phosphorylation, iron mobilization, neuropeptide maturation, and normal development.Whereas much is known about intracellular mobilization of ions such as calcium, little information isavailable on how eukaryotic cells mobilize intracellular copper stores. We describe a mechanism by whichthe Saccharomyces cerevisiae Ctr2 protein provides bioavailable copper via mobilization of intracellularcopper stores. Whereas Ctr2 exhibits structural similarity to the Ctr1 plasma membrane copper importer,microscopic and biochemical fractionation studies localize Ctr2 to the vacuole membrane. Wedemonstrate that Ctr2 mobilizes vacuolar copper stores in a manner dependent on amino acid residuesconserved between the Ctr1 and Ctr2 copper transport family and that ctr2 Delta mutantshyper-accumulate vacuolar copper. Furthermore, a Ctr2 mutant that is mislocalized to the plasmamembrane stimulates extracellular copper uptake, supporting a direct role for Ctr2 in copper transportacross membranes. These studies identify a novel mechanism for copper mobilization and suggest thatorganisms cope with copper deprivation via the use of intracellular vesicular stores.", "metadata": {}}
+{"_id": "3107733", "title": "", "text": "Peroxisomes Are Signaling Platforms for Antiviral Innate ImmunityPeroxisomes have long beenestablished to play a central role in regulating various metabolic activities in mammalian cells. Theseorganelles act in concert with mitochondria to control the metabolism of lipids and reactive oxygenspecies. However, while mitochondria have emerged as an important site of antiviral signal transduction,a role for peroxisomes in immune defense is unknown. Here, we report that the RIG-I-like receptor (RLR)adaptor protein MAVS is located on peroxisomes and mitochondria. We find that peroxisomal andmitochondrial MAVS act sequentially to create an antiviral cellular state. Upon viral infection, peroxisomalMAVS induces the rapid interferon-independent expression of defense factors that provide short-termprotection, whereas mitochondrial MAVS activates an interferon-dependent signaling pathway withdelayed kinetics, which amplifies and stabilizes the antiviral response. The interferon regulatory factorIRF1 plays a crucial role in regulating MAVS-dependent signaling from peroxisomes. These resultsestablish that peroxisomes are an important site of antiviral signal transduction.", "metadata": {}}
+{"_id": "3112885", "title": "", "text": "Two-sided confidence intervals for the single proportion: comparison of seven methods. Stat. MedSimpleinterval estimate methods for proportions exhibit poor coverage and can produce evidently inappropriateintervals. Criteria appropriate to the evaluation of various proposed methods include: closeness of theachieved coverage probability to its nominal value; whether intervals are located too close to or toodistant from the middle of the scale; expected interval width; avoidance of aberrations such as limitsoutside [0,1] or zero width intervals; and ease of use, whether by tables, software or formulae. Sevenmethods for the single proportion are evaluated on 96,000 parameter space points. Intervals based ontail areas and the simpler score methods are recommended for use. In each case, methods are availablethat aim to align either the minimum or the mean coverage with the nominal 1 -alpha.", "metadata": {}}
+{"_id": "3113630", "title": "", "text": "Nuclear accumulation of HDAC4 in ATM deficiency promotes neurodegeneration inataxia-telangiectasiaAtaxia telangiectasia is a neurodegenerative disease caused by mutation of the Atmgene. Here we report that ataxia telangiectasia mutated (ATM) deficiency causes nuclear accumulation ofhistone deacetylase 4 (HDAC4) in neurons and promotes neurodegeneration. Nuclear HDAC4 binds tochromatin, as well as to myocyte enhancer factor 2A (MEF2A) and cAMP-responsive element bindingprotein (CREB), leading to histone deacetylation and altered neuronal gene expression. Blocking eitherHDAC4 activity or its nuclear accumulation blunts these neurodegenerative changes and rescues severalbehavioral abnormalities of ATM-deficient mice. Full rescue of the neurodegeneration, however, alsorequires the presence of HDAC4 in the cytoplasm, suggesting that the ataxia telangiectasia phenotyperesults both from a loss of cytoplasmic HDAC4 as well as its nuclear accumulation. To remaincytoplasmic, HDAC4 must be phosphorylated. The activity of the HDAC4 phosphatase, proteinphosphatase 2A (PP2A), is downregulated by ATM-mediated phosphorylation. In ATM deficiency,enhanced PP2A activity leads to HDAC4 dephosphorylation and the nuclear accumulation of HDAC4. Ourresults define a crucial role of the cellular localization of HDAC4 in the events leading to ataxiatelangiectasia neurodegeneration.", "metadata": {}}
+{"_id": "3118719", "title": "", "text": "Regulation and function of the E-cadherin/catenin complex in cells of the monocyte-macrophage lineageand DCs.E-cadherin is best characterized as adherens junction protein, which through homotypicinteractions contributes to the maintenance of the epithelial barrier function. In epithelial cells, thecytoplasmic tail of E-cadherin forms a dynamic complex with catenins and regulates several intracellularsignal transduction pathways, including Wnt/β-catenin, PI3K/Akt, Rho GTPase, and NF-κB signaling.Recent progress uncovered a novel and critical role for this adhesion molecule in mononuclear phagocytefunctions. E-cadherin regulates the maturation and migration of Langerhans cells, and its ligationprevents the induction of a tolerogenic state in bone marrow-derived dendritic cells (DCs). In thisrespect, the functionality of β-catenin could be instrumental in determining the balance betweenimmunogenicity and tolerogenicity of DCs in vitro and in vivo. Fusion of alternatively activatedmacrophages and osteoclasts is also E-cadherin-dependent. In addition, the E-cadherin ligands CD103and KLRG1 are expressed on DC-, T-, and NK-cell subsets and contribute to their interaction withE-cadherin-expressing DCs and macrophages. Here we discuss the regulation, function, and implicationsof E-cadherin expression in these central orchestrators of the immune system.", "metadata": {}}
+{"_id": "3127341", "title": "", "text": "Polymorphism and ligand dependent changes in human glucagon-like peptide-1 receptor (GLP-1R)function: allosteric rescue of loss of function mutation.The glucagon-like peptide-1 receptor (GLP-1R) is akey physiological regulator of insulin secretion and a major therapeutic target for the treatment of type IIdiabetes. However, regulation of GLP-1R function is complex with multiple endogenous peptides thatinteract with the receptor, including full-length (1-37) and truncated (7-37) forms of GLP-1 that can existin an amidated form (GLP-1(1-36)NH\u0000 and GLP-1(7-36)NH\u0000) and the related peptide oxyntomodulin. Inaddition, the GLP-1R possesses exogenous agonists, including exendin-4, and the allosteric modulator,compound 2 (6,7-dichloro-2-methylsulfonyl-3-tert-butylaminoquinoxaline). The complexity of thisligand-receptor system is further increased by the presence of several single nucleotide polymorphisms(SNPs) that are distributed across the receptor. We have investigated 10 GLP-1R SNPs, which werecharacterized in three physiologically relevant signaling pathways (cAMP accumulation, extracellularsignal-regulated kinase 1/2 phosphorylation, and intracellular Ca²\u0000 mobilization); ligand binding and cellsurface receptor expression were also determined. We demonstrate both ligand- and pathway-specificeffects for multiple SNPs, with the most dramatic effect observed for the Met¹\u0000\u0000 receptor variant. At theMet¹\u0000\u0000 variant, there was selective loss of peptide-induced responses across all pathways examined,but preservation of response to the small molecule compound 2. In contrast, at the Cys³³³ variant,peptide responses were preserved but there was attenuated response to compound 2. Strikingly, the lossof peptide function at the Met¹\u0000\u0000 receptor variant could be allosterically rescued by compound 2,providing proof-of-principle evidence that allosteric drugs could be used to treat patients with this loss offunction variant.", "metadata": {}}
+{"_id": "3140772", "title": "", "text": "Neuronal circuitry mechanism regulating adult quiescent neural stem cell fate decisionAdult neurogenesisarises from neural stem cells within specialized niches. Neuronal activity and experience, presumablyacting on this local niche, regulate multiple stages of adult neurogenesis, from neural progenitorproliferation to new neuron maturation, synaptic integration and survival. It is unknown whether localneuronal circuitry has a direct impact on adult neural stem cells. Here we show that, in the adult mousehippocampus, nestin-expressing radial glia-like quiescent neural stem cells (RGLs) respond tonically tothe neurotransmitter γ-aminobutyric acid (GABA) by means of γ2-subunit-containing GABAA receptors.Clonal analysis of individual RGLs revealed a rapid exit from quiescence and enhanced symmetricalself-renewal after conditional deletion of γ2. RGLs are in close proximity to terminals expressing 67-kDaglutamic acid decarboxylase (GAD67) of parvalbumin-expressing (PV+) interneurons and respondtonically to GABA released from these neurons. Functionally, optogenetic control of the activity of dentatePV+ interneurons, but not that of somatostatin-expressing or vasoactive intestinal polypeptide(VIP)-expressing interneurons, can dictate the RGL choice between quiescence and activation.Furthermore, PV+ interneuron activation restores RGL quiescence after social isolation, an experiencethat induces RGL activation and symmetrical division. Our study identifies a niche cell–signal–receptortrio and a local circuitry mechanism that control the activation and self-renewal mode of quiescent adultneural stem cells in response to neuronal activity and experience.", "metadata": {}}
+{"_id": "3150030", "title": "", "text": "Global vitamin D levels in relation to age, gender, skin pigmentation and latitude: an ecologicmeta-regression analysisWe performed a meta-analysis of cross-sectional studies on serum 25(OH)Dstatus globally. Serum 25(OH)D levels on average were 54 nmol/l, were higher in women than men, andhigher in Caucasians than in non-Caucasians. There was no trend in serum 25(OH)D level with latitude.Vitamin D deficiency was widespread. We studied vitamin D status (expressed as serum25-hydroxy-vitamin D [25(OH)D]) in native subjects worldwide. Meta-analysis and meta-regression ofstudies reporting on 25(OH)D in healthy subjects retrieved from Pubmed, Embase and Web of Scienceusing the terms “serum”, “25-hydroxy-vitamin D”, “cholecalciferol”, and “human”. A total of 394 studieswere included. The mean 25(OH)D level was 54 nmol/l (95% CI: 52–57 nmol/l). Women had borderlinesignificantly higher 25(OH)D levels than men, and Caucasians had higher levels than non-Caucasians.25(OH)D levels were higher in subjects aged >15 years than in younger subjects. Unadjusted there wasno significant decrease in 25(OH)D with latitude (slope of curve −0.03 ± 0.12 nmol/l per degree latitudenorth or south of equator, p = 0.8). There was a significant decline with latitude for Caucasians (−0.69 ±0.30 nmol/l per degree, p = 0.02), but not for non-Caucasians (0.03 ± 0.39 nmol/l per degree, p =0.14). After adjustment for age, gender, and ethnicity, no overall correlation was present between25(OH)D and latitude (−0.29 ± 0.24 nmol/l per degree, p = 0.23). There was no overall influence oflatitude on 25(OH)D. However, in separate analyses 25(OH)D decreased with latitude in Caucasians butnot in non-Caucasians. A widespread global vitamin D insufficiency was present compared with proposedthreshold levels.", "metadata": {}}
+{"_id": "3152612", "title": "", "text": "Identification and characterization of a novel monocyte/macrophage differentiation-dependent gene thatis responsive to lipopolysaccharide, ceramide, and lysophosphatidylcholine.A noveldifferentiation-dependent cDNA (DIF-2) has been isolated from human mononuclear phagocytes bydifferential display. The full-length cDNA was cloned and sequenced. DIF-2 consists of 156 amino acidsand has a predicted isoelectric point of 8.84. The mRNA is expressed in freshly isolated monocytes and isdownregulated significantly when monocytes are subjected to differentiation. A similardifferentiation-dependent downregulation is observed in normal hepatocytes compared toundifferentiated HepG2 cells. The mRNA expression in monocytes is sensitive to lipopolysaccharide andceramide which both strongly increase DIF-2 transcription, while lysophosphatidylcholine results in aweaker upregulation of DIF-2 expression. A DIF-2 homologous gene has been previously isolated frommouse fibroblasts and was shown to be a serum growth factor-inducible immediate early gene. Ourresults indicate that DIF-2 represents a gene which is regulated in differentiation processes and stronglyresponsive to lipopolysaccharide, ceramide and lysophosphatidylcholine.", "metadata": {}}
+{"_id": "3153673", "title": "", "text": "A Novel 3-Hydroxysteroid Dehydrogenase That Regulates Reproductive Development andLongevityEndogenous small molecule metabolites that regulate animal longevity are emerging as a novelmeans to influence health and life span. In C. elegans, bile acid-like steroids called the dafachronic acids(DAs) regulate developmental timing and longevity through the conserved nuclear hormone receptorDAF-12, a homolog of mammalian sterol-regulated receptors LXR and FXR. Using metabolic genetics,mass spectrometry, and biochemical approaches, we identify new activities in DA biosynthesis andcharacterize an evolutionarily conserved short chain dehydrogenase, DHS-16, as a novel3-hydroxysteroid dehydrogenase. Through regulation of DA production, DHS-16 controls DAF-12 activitygoverning longevity in response to signals from the gonad. Our elucidation of C. elegans bile acidbiosynthetic pathways reveals the possibility of novel ligands as well as striking biochemical conservationto other animals, which could illuminate new targets for manipulating longevity in metazoans.", "metadata": {}}
+{"_id": "3154880", "title": "", "text": "An Argonaute transports siRNAs from the cytoplasm to the nucleus.Ribonucleoprotein complexesconsisting of Argonaute-like proteins and small regulatory RNAs function in a wide range of biologicalprocesses. Many of these small regulatory RNAs are predicted to act, at least in part, within the nucleus.We conducted a genetic screen to identify factors essential for RNA interference (RNAi) in nuclei ofCaenorhabditis elegans and identified the Argonaute protein NRDE-3. In the absence of small interferingRNAs (siRNAs), NRDE-3 resides in the cytoplasm. NRDE-3 binds siRNAs generated by RNA-dependentRNA polymerases acting on messenger RNA templates in the cytoplasm and redistributes to the nucleus.Nuclear redistribution of NRDE-3 requires a functional nuclear localization signal, is required for nuclearRNAi, and results in NRDE-3 association with nuclear-localized nascent transcripts. Thus, specificArgonaute proteins can transport specific classes of small regulatory RNAs to distinct cellularcompartments to regulate gene expression.", "metadata": {}}
+{"_id": "3155374", "title": "", "text": "Phosphatidylinositol 4,5-Bisphosphate Functions as a Second Messenger that RegulatesCytoskeleton–Plasma Membrane AdhesionBinding interactions between the plasma membrane and thecytoskeleton define cell functions such as cell shape, formation of cell processes, cell movement, andendocytosis. Here we use optical tweezers tether force measurements and show that plasma membranephosphatidylinositol 4,5-bisphosphate (PIP2) acts as a second messenger that regulates the adhesionenergy between the cytoskeleton and the plasma membrane. Receptor stimuli that hydrolyze PIP2lowered adhesion energy, a process that could be mimicked by expressing PH domains that sequesterPIP2 or by targeting a 5'-PIP2-phosphatase to the plasma membrane to selectively lower plasmamembrane PIP2 concentration. Our study suggests that plasma membrane PIP2 controls dynamicmembrane functions and cell shape by locally increasing and decreasing the adhesion between theactin-based cortical cytoskeleton and the plasma membrane.", "metadata": {}}
+{"_id": "3155731", "title": "", "text": "Tissue-resident memory T cells: local specialists in immune defenceT cells have crucial roles in protectionagainst infection and cancer. Although the trafficking of memory T cells around the body is integral totheir capacity to provide immune protection, studies have shown that specialization of some memory Tcells into unique tissue-resident subsets gives the host enhanced regional immunity. In recent years,there has been considerable progress in our understanding of tissue-resident T cell development andfunction, revealing mechanisms for enhanced protective immunity that have the potential to influencerational vaccine design. This Review discusses the major advances and the emerging concepts in thisfield, summarizes what is known about the differentiation and the protective functions of tissue-residentmemory T cells in different tissues in the body and highlights key unanswered questions.", "metadata": {}}
+{"_id": "3173489", "title": "", "text": "Defective replication stress response inhibits lymphomagenesis and impairs lymphocytereconstitutionDNA replication stress promotes genome instability in cancer. However, the contribution ofthe replication stress response to the development of malignancies remains unresolved. The DNAreplication stress response protein SMARCAL1 stabilizes DNA replication forks and prevents replicationfork collapse, a cause of DNA breaks and apoptosis. While the fork regression/remodeling functions ofSMARCAL1 have been investigated, its in vivo functions in replication stress and cancer are unclear. Usinga gamma radiation (IR)-induced replication stress T-cell lymphoma mouse model, we observed asignificant inhibition of lymphomagenesis in mice lacking one or both alleles of Smarcal1. Notably, aquarter of the Smarcal1-deficient mice did not develop tumors. Moreover, hematopoietic stem/progenitorcells (HSPCs) and developing thymocytes in Smarcal1-deficient mice showed increased DNA damage andapoptosis during the proliferation burst following IR and an impaired ability to repopulate the thymusafter IR. Additionally, mice lacking Smarcal1 showed significant HSPC defects when challenged to respondto other replication stress stimuli. Thus, our data reveal the critical function of the DNA replication stressresponse and, specifically, Smarcal1 in hematopoietic cell survival and tumor development. Our resultsalso provide important insight into the immunodeficiency observed in individuals with mutations inSMARCAL1 by suggesting that it is an HSPC defect.", "metadata": {}}
+{"_id": "3174305", "title": "", "text": "Human DNA methylomes at base resolution show widespread epigenomic differencesDNA cytosinemethylation is a central epigenetic modification that has essential roles in cellular processes includinggenome regulation, development and disease. Here we present the first genome-wide,single-base-resolution maps of methylated cytosines in a mammalian genome, from both humanembryonic stem cells and fetal fibroblasts, along with comparative analysis of messenger RNA and smallRNA components of the transcriptome, several histone modifications, and sites of DNA–protein interactionfor several key regulatory factors. Widespread differences were identified in the composition andpatterning of cytosine methylation between the two genomes. Nearly one-quarter of all methylationidentified in embryonic stem cells was in a non-CG context, suggesting that embryonic stem cells mayuse different methylation mechanisms to affect gene regulation. Methylation in non-CG contexts showedenrichment in gene bodies and depletion in protein binding sites and enhancers. Non-CG methylationdisappeared upon induced differentiation of the embryonic stem cells, and was restored in inducedpluripotent stem cells. We identified hundreds of differentially methylated regions proximal to genesinvolved in pluripotency and differentiation, and widespread reduced methylation levels in fibroblastsassociated with lower transcriptional activity. These reference epigenomes provide a foundation for futurestudies exploring this key epigenetic modification in human disease and development.", "metadata": {}}
+{"_id": "3190689", "title": "", "text": "Laparoscopic adhesiolysis in patients with chronic abdominal pain: a blinded randomised controlledmulti-centre trial.BACKGROUND Laparoscopic adhesiolysis for chronic abdominal pain is controversial andis not evidence based. We aimed to test our hypothesis that laparoscopic adhesiolysis leads to substantialpain relief and improvement in quality of life in patients with adhesions and chronic abdominal pain.METHODS Patients had diagnostic laparoscopy for chronic abdominal pain attributed to adhesions; othercauses for their pain had been excluded. If adhesions were confirmed during diagnostic laparoscopy,patients were randomly assigned either to laparoscopic adhesiolysis or no treatment. Treatmentallocation was concealed from patients, and assessors were unaware of patients' treatment and outcome.Pain was assessed for 1 year by visual analogue score (VAS) score (scale 0-100), pain change score, useof analgesics, and quality of life score. Analysis was by intention to treat. FINDINGS Of 116 patientsenrolled for diagnostic laparoscopy, 100 were randomly allocated either laparoscopic adhesiolysis (52) orno treatment (48). Both groups reported substantial pain relief and a significantly improved quality of life,but there was no difference between the groups (mean change from baseline of VAS score at 12 months:difference 3 points, p=0.53; 95% CI -7 to 13). INTERPRETATION Although laparoscopic adhesiolysisrelieves chronic abdominal pain, it is not more beneficial than diagnostic laparoscopy alone. Therefore,laparoscopic adhesiolysis cannot be recommended as a treatment for adhesions in patients with chronicabdominal pain.", "metadata": {}}
+{"_id": "3202143", "title": "", "text": "Insulin Signaling and Dietary Restriction Differentially Influence the Decline of Learning and Memory withAgeOf all the age-related declines, memory loss is one of the most devastating. While conditions thatincrease longevity have been identified, the effects of these longevity-promoting factors on learning andmemory are unknown. Here we show that the C. elegans Insulin/IGF-1 receptor mutant daf-2 improvesmemory performance early in adulthood and maintains learning ability better with age but, surprisingly,demonstrates no extension in long-term memory with age. By contrast, eat-2 mutants, a model ofDietary Restriction (DR), exhibit impaired long-term memory in young adulthood but maintain this levelof memory longer with age. We find that crh-1, the C. elegans homolog of the CREB transcription factor,is required for long-term associative memory, but not for learning or short-term memory. The expressionof crh-1 declines with age and differs in the longevity mutants, and CREB expression and activitycorrelate with memory performance. Our results suggest that specific longevity treatments have acuteand long-term effects on cognitive functions that decline with age through their regulation of rate-limitinggenes required for learning and memory.", "metadata": {}}
+{"_id": "3203590", "title": "", "text": "Unique response pathways are established by allosteric interactions among nuclear hormonereceptorsHeterodimerization is a common paradigm among eukaryotic transcription factors. The 9-cisretinoic acid receptor (RXR) serves as a common heterodimerization partner for several nuclearreceptors, including the thyroid hormone receptor (T3R) and retinoic acid receptor (RAR). This raises thequestion as to whether these complexes possess dual hormonal responsiveness. We devised a strategy toexamine the transcriptional properties of each receptor individually or when tethered to a heterodimericpartner. We find that the intrinsic binding properties of RXR are masked in T3R-RXR and RAR-RXRheterodimers. In contrast, RXR is active as a non-DNA-binding cofactor with the NGFI-B/Nurr1 orphanreceptors. Heterodimerization of RXR with constitutively active NGFI-B/Nurr1 creates a novelhormone-dependent complex. These findings suggest that allosteric interactions among heterodimerscreate complexes with unique properties. We suggest that allostery is a critical feature underlying thegeneration of diversity in hormone response networks.", "metadata": {}}
+{"_id": "3205945", "title": "", "text": "Midlife and Late\u0000Life Vascular Risk Factors and White Matter Microstructural Integrity: TheAtherosclerosis Risk in Communities Neurocognitive StudyBACKGROUND Diffusion tensor imagingmeasures of white matter (WM) microstructural integrity appear to provide earlier indication of WM injurythan WM hyperintensities; however, risk factors for poor WM microstructural integrity have not beenestablished. Our study quantifies the association between vascular risk factors in midlife and late life withmeasures of late-life WM microstructural integrity. METHODS AND RESULTS We used data from 1851participants in ARIC (Atherosclerosis Risk in Communities Study) who completed 3-T magnetic resonanceimaging, including diffusion tensor imaging, as part of the ARIC Neurocognitive Study (ARIC-NCS). Wequantified the association among lipids, glucose, and blood pressure from the baseline ARIC visit(1987-1989, ages 44-65, midlife) and visit 5 of ARIC (2011-2013, ages 67-90, late life, concurrent withARIC-NCS) with regional and overall WM mean diffusivity and fractional anisotropy obtained at ARIC visit5 for ARIC participants. We also considered whether these associations were independent of or modifiedby WM hyperintensity volumes. We found that elevated blood pressure in midlife and late life andelevated glucose in midlife, but not late life, were associated with worse late-life WM microstructuralintegrity. These associations were independent of the degree of WM hyperintensity, and the associationbetween glucose and WM microstructural integrity appeared stronger for those with the least WMhyperintensity. There was little support for an adverse association between lipids and WM microstructuralintegrity. CONCLUSIONS Hypertension in both midlife and late life and elevated glucose in midlife arerelated to worse WM microstructural integrity in late life.", "metadata": {}}
+{"_id": "3210545", "title": "", "text": "KRAS gene amplification and overexpression but not mutation associates with aggressive and metastaticendometrial cancerBACKGROUND Three quarter of endometrial carcinomas are treated at early stage.Still, 15 to 20% of these patients experience recurrence, with little effect from systemic therapies. Homosapiens v-Ki-ras2 Kirsten rat sarcoma viral oncogenes homologue (KRAS) mutations have been reportedto have an important role in tumorigenesis for human cancers, but there is limited knowledge regardingclinical relevance of KRAS status in endometrial carcinomas. METHODS We have performed acomprehensive and integrated characterisation of genome-wide expression related to KRAS mutationsand copy-number alterations in primary- and metastatic endometrial carcinoma lesions in relation toclinical and histopathological data. A primary investigation set and clinical validation set was applied,consisting of 414 primary tumours and 61 metastatic lesions totally. RESULTS Amplification and gain ofKRAS present in 3% of the primary lesions and 18% of metastatic lesions correlated significantly withpoor outcome, high International Federation of Gynaecology and Obstetrics stage, non-endometrioidsubtype, high grade, aneuploidy, receptor loss and high KRAS mRNA levels, also found to be associatedwith aggressive phenotype. In contrast, KRAS mutations were present in 14.7% of primary lesions withno increase in metastatic lesions, and did not influence outcome, but was significantly associated withendometrioid subtype, low grade and obesity. CONCLUSION These results support that KRASamplification and KRAS mRNA expression, both increasing from primary to metastatic lesions, arerelevant for endometrial carcinoma disease progression.", "metadata": {}}
+{"_id": "3215494", "title": "", "text": "Hyperhomocysteinemia and atherosclerotic vascular disease: pathophysiology, screening, and treatment.off.Hyperhomocysteinemia has recently been identified as an important risk factor for atheroscleroticvascular disease. This article reviews homocysteine metabolism, causes of hyperhomocysteinemia, thepathophysiological findings of this disorder, and epidemiological studies of homocysteine and vasculardisease. Screening for hyperhomocysteinemia should be considered for patients at high risk for vasculardisease or abnormalities of homocysteine metabolism. For primary prevention of vascular disease,treatment of patients with homocysteine levels of 14 micromol/L or higher should be considered. Forsecondary prevention, treatment of patients with homocysteine levels of 11 micromol/L or higher shouldbe considered. Treatment is most conveniently administered as a folic acid supplement (400-1000microg) and a high-potency multivitamin that contains at least 400 microg of folate. Higher doses of folicacid and cyanocobalamin supplements may be required in some patients. Until prospective clinical trialdata become available, these conservative recommendations provide a safe, effective, andevidence-based approach to the diagnosis, evaluation, and management of patients withhyperhomocysteinemia.", "metadata": {}}
+{"_id": "3222122", "title": "", "text": "Best--worst scaling: What it can do for health care research and how to do it.Statements like \"quality ofcare is more highly valued than waiting time\" can neither be supported nor refuted by comparisons ofutility parameters from a traditional discrete choice experiment (DCE). Best--worst scaling can overcomethis problem because it asks respondents to perform a different choice task. However, whilst the natureof the best--worst task is generally understood, there are a number of issues relating to the design andanalysis of a best--worst choice experiment that require further exposition. This paper illustrates how toaggregate and analyse such data and using a quality of life pilot study demonstrates how richer insightscan be drawn by the use of best--worst tasks.", "metadata": {}}
+{"_id": "3222187", "title": "", "text": "Genetic variants and non-genetic factors predict circulating vitamin D levels in Hispanic and non-HispanicWhite women: the Breast Cancer Health Disparities Study.Genome-wide association studies (GWAS) haveidentified common polymorphisms in or near GC, CYP2R1, CYP24A1, and NADSYN1/DHCR7 genes to beassociated with circulating levels of 25-hydroxyvitamin D [25(OH)D] in European populations. Toreplicate these GWAS findings, we examined six selected polymorphisms from these regions and theirrelation with circulating 25(OH)D levels in 1,605 Hispanic women (629 U.S. Hispanics and 976 Mexicans)and 354 non-Hispanic White (NHW) women. We also assessed the potential interactions between thesevariants and known non-genetic predictors of 25(OH)D levels, including body mass index (BMI), sunlightexposure and vitamin D intake from diet and supplements. The minor alleles of the two GCpolymorphisms (rs7041 and rs2282679) were significantly associated with lower 25(OH)D levels in bothHispanic and NHW women. The CYP2R1 polymorphism, rs2060793, also was significantly associated with25(OH)D levels in both groups. We found no significant associations for the polymorphisms in theCYP24A1. In Hispanic controls, 25(OH)D levels were significantly associated with the rs12785878T andrs1790349G haplotype in the NADSYN1/DHCR7 region. Significant interactions between GC rs2282679and BMI and between rs12785878 and time spent in outdoor activities were observed. These resultsprovide further support for the contribution of common genetic variants to individual variability incirculating 25(OH)D levels. The observed interactions between SNPs and non-genetic factors warrantconfirmation.", "metadata": {}}
+{"_id": "3230361", "title": "", "text": "Generation and characterization of methyl-lysine histone antibodies.Publisher Summary This chaptersummarizes the development and characterization of rabbit polyclonal antibodies named histone that aredirected against the methylated H3-K9 position. It provides protocols for peptide design, rabbitimmunizations, and quality controls of methyl-lysine histone antibodies, followed by their in vivocharacterization using indirect IF of inter-and metaphase chromatin in wild-type (wt) and mutant mousecells that are deficient for the Suv39h histone methyltransferases (HMTases). Histone amino-termini(tails) protrude from the nucleosome core and are subject to a variety of post-translational modifications,including acetylation (on lysine residues), phosphorylation (on serine and threonine residues),methylation (on lysine and arginine residues), ubiquitination (on lysine residues), and ADP-ribosylation(on glutamic acid residues). In addition to their structural roles, histones play important functions in thecontrol of gene expression by regulating access to the underlying nucleosomal template. It is withoutdoubt that the development of high-quality, position-specific methyl-lysine histone antibodies can provideimportant tools for the further decoding of the epigenetic information, which is in part, indexed by distinctmethylation states of selective lysine residues in the histone amino-termini. A comparative analysisindicates significant discrepancies in the specificity and avidity of the available methyl-lysine histoneantibodies and highlights the need for extensive quality controls, such that experimental data can becorrectly interpreted despite the exquisite complexity of histone lysine methylation.", "metadata": {}}
+{"_id": "3230557", "title": "", "text": "The Hallmarks of AgingAging is characterized by a progressive loss of physiological integrity, leading toimpaired function and increased vulnerability to death. This deterioration is the primary risk factor formajor human pathologies, including cancer, diabetes, cardiovascular disorders, and neurodegenerativediseases. Aging research has experienced an unprecedented advance over recent years, particularly withthe discovery that the rate of aging is controlled, at least to some extent, by genetic pathways andbiochemical processes conserved in evolution. This Review enumerates nine tentative hallmarks thatrepresent common denominators of aging in different organisms, with special emphasis on mammalianaging. These hallmarks are: genomic instability, telomere attrition, epigenetic alterations, loss ofproteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cellexhaustion, and altered intercellular communication. A major challenge is to dissect theinterconnectedness between the candidate hallmarks and their relative contributions to aging, with thefinal goal of identifying pharmaceutical targets to improve human health during aging, with minimal sideeffects.", "metadata": {}}
+{"_id": "3270834", "title": "", "text": "A sensitive mass spectrometry platform identifies metabolic changes of life history traits in C.elegansAbnormal nutrient metabolism is a hallmark of aging, and the underlying genetic and nutritionalframework is rapidly being uncovered, particularly using C. elegans as a model. However, the directmetabolic consequences of perturbations in life history of C. elegans remain to be clarified. Based onrecent advances in the metabolomics field, we optimized and validated a sensitive mass spectrometry(MS) platform for identification of major metabolite classes in worms and applied it to study age and dietrelated changes. Using this platform that allowed detection of over 600 metabolites in a sample of 2500worms, we observed marked changes in fatty acids, amino acids and phospholipids during worm lifehistory, which were independent from the germ-line. Worms underwent a striking shift in lipidmetabolism after early adulthood that was at least partly controlled by the metabolic regulatorAAK-2/AMPK. Most amino acids peaked during development, except aspartic acid and glycine, whichaccumulated in aged worms. Dietary intervention also influenced worm metabolite profiles and theregulation was highly specific depending on the metabolite class. Altogether, these MS-based methodsare powerful tools to perform worm metabolomics for aging and metabolism-oriented studies.", "metadata": {}}
+{"_id": "3272084", "title": "", "text": "Characterisation of antibiotic prescriptions for acute respiratory tract infections in Danish generalpractice: a retrospective registry based cohort studyInappropriate use of antibiotics is contributing to theincreasing rates of antimicrobial resistance. Several Danish guidelines on antibiotic prescribing for acuterespiratory tract infections in general practice have been issued to promote rational prescribing ofantibiotics, however it is unclear if these recommendations are followed. We aimed to characterise thepattern of antibiotic prescriptions for patients diagnosed with acute respiratory tract infections, by meansof electronic prescriptions, labeled with clinical indications, from Danish general practice. Acuterespiratory tract infections accounted for 456,532 antibiotic prescriptions issued between July 2012 andJune 2013. Pneumonia was the most common indication with 178,354 prescriptions (39%), followed byacute tonsillitis (21%) and acute otitis media (19%). In total, penicillin V accounted for 58% of allprescriptions, followed by macrolides (18%) and amoxicillin (15%). The use of second-line agentsincreased with age for all indications, and comprised more than 40% of the prescriptions in patients aged>75 years. Women were more often prescribed antibiotics regardless of clinical indication. This is the firstDanish study to characterise antibiotic prescription patterns for acute respiratory tract infections by datalinkage of clinical indications. The findings confirm that penicillin V is the most commonly prescribedantibiotic agent for treatment of patients with an acute respiratory tract infection in Danish generalpractice. However, second-line agents like macrolides and amoxicillin with or without clavulanic acid areoverused. Strategies to improve the quality of antibiotic prescribing especially for pneumonia, acute otitismedia and acute rhinosinusitis are warranted. RESPIRATORY TRACT INFECTIONS TRACKING THEOVERUSE OF ANTIBIOTICS: Better adherence to guidelines for prescribing antibiotics for differentrespiratory tract infections are warranted in Danish general practice. The over-use of antibiotics,particularly so-called 'second-line' agents such as amoxicillin, increases resistance and may lead to apotentially catastrophic scenario where antibiotics are no longer effective. Exactly how widespread theover-use of antibiotics is for different infections, however, is not clear. Rune Aabenhus at the Universityof Copenhagen and co-workers analyzed primary care data regarding antibiotic prescriptions for acuterespiratory tract infections including pneumonia and ear infections in Denmark. They found that penicillinV-the current recommended first-line drug in Scandinavian countries-accounted for 58 per cent ofprescriptions, a figure which should be improved. Amoxicillin and macrolides were over-prescribed,particularly in elderly patients. The team also call for further analysis of prescriptions given byout-of-hours clinics.", "metadata": {}}
+{"_id": "3285059", "title": "", "text": "Lack of Skeletal Muscle IL-6 Affects Pyruvate Dehydrogenase Activity at Rest and during ProlongedExercisePyruvate dehydrogenase (PDH) plays a key role in the regulation of skeletal muscle substrateutilization. IL-6 is produced in skeletal muscle during exercise in a duration dependent manner and hasbeen reported to increase whole body fatty acid oxidation, muscle glucose uptake and decrease PDHaactivity in skeletal muscle of fed mice. The aim of the present study was to examine whether muscle IL-6contributes to exercise-induced PDH regulation in skeletal muscle. Skeletal muscle-specific IL-6 knockout(IL-6 MKO) mice and floxed littermate controls (control) completed a single bout of treadmill exercise for10, 60 or 120 min, with rested mice of each genotype serving as basal controls. The respiratory exchangeratio (RER) was overall higher (P<0.05) in IL-6 MKO than control mice during the 120 min of treadmillexercise, while RER decreased during exercise independent of genotype. AMPK and ACC phosphorylationalso increased with exercise independent of genotype. PDHa activity was in control mice higher (P<0.05)at 10 and 60 min of exercise than at rest but remained unchanged in IL-6 MKO mice. In addition, PDHaactivity was higher (P<0.05) in IL-6 MKO than control mice at rest and 60 min of exercise. Neither PDHphosphorylation nor acetylation could explain the genotype differences in PDHa activity. Together, thisprovides evidence that skeletal muscle IL-6 contributes to the regulation of PDH at rest and duringprolonged exercise and suggests that muscle IL-6 normally dampens carbohydrate utilization duringprolonged exercise via effects on PDH.", "metadata": {}}
+{"_id": "3285322", "title": "", "text": "Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breastcancer.PURPOSE Mutations in the BRCA1 and BRCA2 genes confer greater risk of developing breastcancer. We determined whether tumor pathologic features and clinical features differ in patients with andwithout BRCA mutations. PATIENTS AND METHODS Tumor pathologic features and clinical characteristicswere examined in 491 women with breast cancer who underwent genetic testing for BRCA mutationsbetween 1997 and 2006. A retrospective review of medical records was conducted to determine clinicalcharacteristics including ethnicity, age and clinical stage at diagnosis, age at parity, number of full-termpregnancies, use of oral contraceptives and hormone replacement therapy, and BRCA mutation status.Tumor pathology was reviewed to determine histologic type, tumor grade, and estrogen receptor,progesterone receptor, and HER-2/neu status. RESULTS Of the 491 patients with identified breastcancers, 391 patients were BRCA negative, and 86 patients were BRCA positive. Triple-negative breastcancer (ie, those with negative estrogen receptor, progesterone receptor, and HER-2/neu status) wasdiagnosed in 57.1% of the BRCA1-positive patients, 23.3% of the BRCA2-positive patients, and 13.8% ofthe BRCA-negative patients. BRCA1 mutation carriers had higher nuclear grade tumors than the othertwo groups (P < .001). Of the triple-negative cancer patients, BRCA2 mutation carriers were older whendiagnosed than BRCA1 mutation carriers and noncarriers (P < .01). CONCLUSION These results suggestthat tumors associated with BRCA1 mutations may be divided into two distinct groups, triple-negativeand non-triple-negative groups. Future studies should seek to determine whether patients with BRCA1mutations and triple-negative breast cancer respond to treatment better than BRCA-negative patientswith similar tumor pathology.", "metadata": {}}
+{"_id": "3308636", "title": "", "text": "Interferons: Success in anti-viral immunotherapy.The interferons (IFNs) are glycoproteins with strongantiviral activities that represent one of the first lines of host defense against invading pathogens. Theseproteins are classified into three groups, Type I, II and III IFNs, based on the structure of their receptorson the cell surface. Due to their ability to modulate immune responses, they have become attractivetherapeutic options to control chronic virus infections. In combination with other drugs, Type I IFNs areconsidered as \"standard of care\" in suppressing Hepatitis C (HCV) and Hepatitis B (HBV) infections, whileType III IFN has generated encouraging results as a treatment for HCV infection in phase III clinicaltrials. However, though effective, using IFNs as a treatment is not without the need for caution. IFNs aresuch powerful cytokines that affect a wide array of cell types; as a result, patients usually experienceunpleasant symptoms, with a percentage of patients suffering system wide effects. Thus, constantmonitoring is required for patients treated with IFN in order to reach the treatment goals of suppressingvirus infection and maintaining quality of life.", "metadata": {}}
+{"_id": "3315558", "title": "", "text": "Genetic analysis of human obesity in an Italian sample.An analysis of the genetic factors in obesity hasbeen carried out on a sample of nuclear families from Aosta (N. Italy). The families consisted of theparents and sibs of all elementary school children considered to be obese during a preliminary screeningand a similar sample of non-obese children and their nuclear families. The numbers of such families were67 and 112, respectively. Several tests were applied in order to examine the genetic contribution toobesity, and in particular to investigate the presence of a dominant major gene. Our conclusions are thatgenetic factors are certainly present. Several analyses suggest the presence of a dominant major genewith weak effect.", "metadata": {}}
+{"_id": "3321943", "title": "", "text": "The non-coding RNA landscape of human hematopoiesis and leukemiaNon-coding RNAs have emerged ascrucial regulators of gene expression and cell fate decisions. However, their expression patterns andregulatory functions during normal and malignant human hematopoiesis are incompletely understood.Here we present a comprehensive resource defining the non-coding RNA landscape of the humanhematopoietic system. Based on highly specific non-coding RNA expression portraits per blood cellpopulation, we identify unique fingerprint non-coding RNAs-such as LINC00173 in granulocytes-andassign these to critical regulatory circuits involved in blood homeostasis. Following the incorporation ofacute myeloid leukemia samples into the landscape, we further uncover prognostically relevantnon-coding RNA stem cell signatures shared between acute myeloid leukemia blasts and healthyhematopoietic stem cells. Our findings highlight the importance of the non-coding transcriptome in theformation and maintenance of the human blood hierarchy. While micro-RNAs are known regulators ofhaematopoiesis and leukemogenesis, the role of long non-coding RNAs is less clear. Here the authorsprovide a non-coding RNA expression landscape of the human hematopoietic system, highlighting theirrole in the formation and maintenance of the human blood hierarchy.", "metadata": {}}
+{"_id": "3329824", "title": "", "text": "Incidence and risk of central nervous system metastases as site of first recurrence in patients withHER2-positive breast cancer treated with adjuvant trastuzumab.BACKGROUND Central nervous system(CNS) disease as the site of first relapse after exposure to adjuvant trastuzumab has been reported. Wecarried out comprehensive meta-analysis to determine the risk of CNS metastases as the first site ofrecurrence in patients with HER2-positive breast cancer who received adjuvant trastuzumab. METHODSEligible studies include randomized trials of adjuvant trastuzumab administered for 1 year to patientswith HER2-positive breast cancer who reported CNS metastases as first site of disease recurrence.Statistical analyses were conducted to calculate the incidence, relative risk (RR), and 95% confidenceintervals (CIs) using fixed-effects inverse variance and random-effects models. RESULTS A total of 9020patients were included. The incidence of CNS metastases as first site of disease recurrence inHER2-positive patients receiving adjuvant trastuzumab was 2.56% (95% CI 2.07% to 3.01%) comparedwith 1.94% (95% CI 1.54% to 2.38%) in HER2-positive patients who did not receive adjuvanttrastuzumab. The RR of the CNS as first site of relapse in trastuzumab-treated patients was 1.35 (95% CI1.02-1.78, P = 0.038) compared with control arms without trastuzumab therapy. The ratio of CNSmetastases to total number of recurrence events was 16.94% (95% CI 10.85% to 24.07%) and 8.33%(95% CI 6.49% to 10.86%) for the trastuzumab-treated and control groups, respectively. No statisticallysignificant differences were found based on trastuzumab schedule or median follow-up time. No evidenceof publication bias was observed. CONCLUSIONS Adjuvant trastuzumab is associated with a significantincreased risk of CNS metastases as the site of first recurrence in HER2-positive breast cancer patients.", "metadata": {}}
+{"_id": "3330111", "title": "", "text": "Neutrophils in the activation and regulation of innate and adaptive immunityNeutrophils have long beenviewed as the final effector cells of an acute inflammatory response, with a primary role in the clearanceof extracellular pathogens. However, more recent evidence has extended the functions of these cells. Thenewly discovered repertoire of effector molecules in the neutrophil armamentarium includes a broad arrayof cytokines, extracellular traps and effector molecules of the humoral arm of the innate immune system.In addition, neutrophils are involved in the activation, regulation and effector functions of innate andadaptive immune cells. Accordingly, neutrophils have a crucial role in the pathogenesis of a broad rangeof diseases, including infections caused by intracellular pathogens, autoimmunity, chronic inflammationand cancer.", "metadata": {}}
+{"_id": "3346812", "title": "", "text": "Functions of DNA methylation: islands, start sites, gene bodies and beyondDNA methylation is frequentlydescribed as a 'silencing' epigenetic mark, and indeed this function of 5-methylcytosine was originallyproposed in the 1970s. Now, thanks to improved genome-scale mapping of methylation, we can evaluateDNA methylation in different genomic contexts: transcriptional start sites with or without CpG islands, ingene bodies, at regulatory elements and at repeat sequences. The emerging picture is that the functionof DNA methylation seems to vary with context, and the relationship between DNA methylation andtranscription is more nuanced than we realized at first. Improving our understanding of the functions ofDNA methylation is necessary for interpreting changes in this mark that are observed in diseases such ascancer.", "metadata": {}}
+{"_id": "3353748", "title": "", "text": "Metaplasia and transdifferentiation: from pure biology to the clinicTransformations from one tissue typeto another make up a well established set of phenomena that can be explained by the principles ofdevelopmental biology. Although these phenomena might be rare in nature, we can now imagine thepossibility of deliberately reprogramming cells from one tissue type to another by manipulating theexpression of transcription factors. This approach could generate new therapies for many humandiseases.", "metadata": {}}
+{"_id": "3355397", "title": "", "text": "Pioglitazone Use and Risk of Bladder Cancer and Other Common Cancers in Persons WithDiabetes.IMPORTANCE Studies suggest pioglitazone use may increase risk of cancers. OBJECTIVE Toexamine whether pioglitazone use for diabetes is associated with risk of bladder and 10 additionalcancers. DESIGN, SETTING, AND PARTICIPANTS Cohort and nested case-control analyses among personswith diabetes. A bladder cancer cohort followed 193,099 persons aged 40 years or older in 1997-2002until December 2012; 464 case patients and 464 matched controls were surveyed about additionalconfounders. A cohort analysis of 10 additional cancers included 236,507 persons aged 40 years or olderin 1997-2005 and followed until June 2012. Cohorts were from Kaiser Permanente Northern California.EXPOSURES Ever use, duration, cumulative dose, and time since initiation of pioglitazone as timedependent. MAIN OUTCOMES AND MEASURES Incident cancer, including bladder, prostate, femalebreast, lung/bronchus, endometrial, colon, non-Hodgkin lymphoma, pancreas, kidney/renal pelvis,rectum, and melanoma. RESULTS Among 193,099 persons in the bladder cancer cohort, 34,181 (18%)received pioglitazone (median duration, 2.8 years; range, 0.2-13.2 years) and 1261 had incident bladdercancer. Crude incidences of bladder cancer in pioglitazone users and nonusers were 89.8 and 75.9 per100,000 person-years, respectively. Ever use of pioglitazone was not associated with bladder cancer risk(adjusted hazard ratio [HR], 1.06; 95% CI, 0.89-1.26). Results were similar in case-control analyses(pioglitazone use: 19.6% among case patients and 17.5% among controls; adjusted odds ratio, 1.18;95% CI, 0.78-1.80). In adjusted analyses, there was no association with 8 of the 10 additional cancers;ever use of pioglitazone was associated with increased risk of prostate cancer (HR, 1.13; 95% CI,1.02-1.26) and pancreatic cancer (HR, 1.41; 95% CI, 1.16-1.71). Crude incidences of prostate andpancreatic cancer in pioglitazone users vs nonusers were 453.3 vs 449.3 and 81.1 vs 48.4 per 100,000person-years, respectively. No clear patterns of risk for any cancer were observed for time sinceinitiation, duration, or dose. CONCLUSIONS AND RELEVANCE Pioglitazone use was not associated with astatistically significant increased risk of bladder cancer, although an increased risk, as previouslyobserved, could not be excluded. The increased prostate and pancreatic cancer risks associated with everuse of pioglitazone merit further investigation to assess whether they are causal or are due to chance,residual confounding, or reverse causality.", "metadata": {}}
+{"_id": "3360421", "title": "", "text": "Embryonic stem cell lines from human blastocysts: somatic differentiation in vitroWe describe thederivation of pluripotent embryonic stem (ES) cells from human blastocysts. Two diploid ES cell lineshave been cultivated in vitro for extended periods while maintaining expression of markers characteristicof pluripotent primate cells. Human ES cells express the transcription factor Oct-4, essential fordevelopment of pluripotential cells in the mouse. When grafted into SCID mice, both lines give rise toteratomas containing derivatives of all three embryonic germ layers. Both cell lines differentiate in vitrointo extraembryonic and somatic cell lineages. Neural progenitor cells may be isolated fromdifferentiating ES cell cultures and induced to form mature neurons. Embryonic stem cells provide amodel to study early human embryology, an investigational tool for discovery of novel growth factors andmedicines, and a potential source of cells for use in transplantation therapy.", "metadata": {}}
+{"_id": "3360428", "title": "", "text": "Multipoint Kras oncogene mutations potentially indicate mucinous carcinoma on the entire spectrum ofmucinous ovarian neoplasmsKras mutation is a common phenomenon in many human neoplasms. Weaimed to assess the Kras mutational status along the histological continuum from normal ovaries to thedevelopment of benign, borderline and malignant ovarian mucinous neoplasms. We analyzed 41 cases ofmalignant, 10 cases of borderline, 7 cases of benign mucinous ovarian tumors and 7 cases of normalovarian tissue. The prevalence of Kras mutations in the normal ovary was 0.00% (n=0/7), while theprevalence in benign, borderline and malignant mucinous neoplasms was 57.14% (n=4/7), 90.00%(n=9/10) and 75.61% (n=31/41), respectively. Multiple Kras mutations were detected in 6 cases ofmucinous carcinoma, including 5 double mutations with G13D/V14I (n=1), G12V/G13S (n=1),G12D/G13S (n=3) and one triple mutation with A11V/G13N/V14I (n=1). We identified six cases with 3novel Kras mutations not previously described in the COSMIC database, which included A11V (n=3) andV14I (n=2) in mucinous carcinomas, and A11T (n=1) in a mucinous borderline tumor. In conclusion, Krasmutation appears to be one of the imperative events in the ovarian mucinous adenoma-borderlinetumor-carcinoma sequence, as increased numbers of Kras mutations have been shown to be thestrongest predictor of unequivocal malignancy in ovarian mucinous neoplasms.", "metadata": {}}
+{"_id": "3367829", "title": "", "text": "Identification and distinct regulation of yeast TATA box-containing genes.Despite being one of the firsteukaryotic transcriptional regulatory elements identified, the sequence of a native TATA box and itssignificance remain elusive. Applying criteria associated with TATA boxes we queried severalSaccharomyces genomes and arrived at the consensus TATA(A/T)A(A/T)(A/G). Approximately 20% ofyeast genes contain a TATA box. Strikingly, TATA box-containing genes are associated with responses tostress, are highly regulated, and preferentially utilize SAGA rather than TFIID when compared toTATA-less promoters. Transcriptional regulation in yeast appears to be mechanistically bipolar, possiblyreflecting a need to balance inducible stress-related responses with constitutive housekeeping functions.", "metadata": {}}
+{"_id": "3376731", "title": "", "text": "IL6 derived from cancer-associated fibroblasts promotes chemoresistance via CXCR7 in esophagealsquamous cell carcinomaVarious factors and cellular components in the tumor microenvironment are keydrivers associated with drug resistance in many cancers. Here, we analyzed the factors and molecularmechanisms involved in chemoresistance in patients with esophageal squamous cell carcinoma (ESCC).We found that interleukin 6 (IL6) derived mainly from cancer-associated fibroblasts played the mostimportant role in chemoresistance by upregulating C-X-C motif chemokine receptor 7 (CXCR7) expressionthrough signal transducer and activator of transcription 3/nuclear factor-κB pathway. CXCR7 knockdownresulted in the inhibition of IL6-induced proliferation and chemoresistance. In addition, CXCR7 silencingsignificantly decreased gene expression associated with stemness, chemoresistance andepithelial–mesenchymal transition and suppressed the proliferation ability of ESCC cells inthree-dimensional culture systems and angiogenesis assay. In clinical samples, ESCC patients with highexpression of CXCR7 and IL6 presented a significantly worse overall survival and progression-freesurvival upon receiving cisplatin after operation. These results suggest that the IL6–CXCR7 axis mayprovide a promising target for the treatment of ESCC.", "metadata": {}}
+{"_id": "3391547", "title": "", "text": "Myelodysplastic syndromes: revisiting the role of the bone marrow microenvironment in diseasepathogenesisMyelodysplastic syndromes are a heterogeneous group of diseases characterized byineffective hematopoiesis and the propensity to leukemic transformation. Their pathogenesis is complexand likely depends on interplay between aberrant hematopoietic cells and their microenvironment. Howniche cells play a role in disease evolution is poorly defined, but the delineation of the hematopoietic stemcell niche and the ability to interrogate its role in hematopoietic disease in animal models have furtheredour insights in recent years. The data support a view in which the microenvironment can play an activerole in the evolution of myelodysplasia and myeloproliferative disorders, thus providing further rationaleto explore therapeutic targeting of mesenchymal–hematopoietic interactions in these diseases.", "metadata": {}}
+{"_id": "3400973", "title": "", "text": "SMC complexes differentially compact mitotic chromosomes according to genomic contextStructuralmaintenance of chromosomes (SMC) protein complexes are key determinants of chromosomeconformation. Using Hi-C and polymer modelling, we study how cohesin and condensin, two deeplyconserved SMC complexes, organize chromosomes in the budding yeast Saccharomyces cerevisiae. Thecanonical role of cohesin is to co-align sister chromatids, while condensin generally compacts mitoticchromosomes. We find strikingly different roles for the two complexes in budding yeast mitosis. First,cohesin is responsible for compacting mitotic chromosome arms, independently of sister chromatidcohesion. Polymer simulations demonstrate that this role can be fully accounted for through cis-looping ofchromatin. Second, condensin is generally dispensable for compaction along chromosome arms. Instead,it plays a targeted role compacting the rDNA proximal regions and promoting resolution ofperi-centromeric regions. Our results argue that the conserved mechanism of SMC complexes is to formchromatin loops and that distinct SMC-dependent looping activities are selectively deployed toappropriately compact chromosomes.", "metadata": {}}
+{"_id": "3413083", "title": "", "text": "Patterns of chlamydia testing in different settings and implications for wider STI diagnosis and care: aprobability sample survey of the British populationBACKGROUND Following widespread rollout ofchlamydia testing to non-specialist and community settings in the UK, many individuals receive achlamydia test without being offered comprehensive STI and HIV testing. We assess sexual behaviouramong testers in different settings with a view to understanding their need for other STI diagnosticservices. METHODS A probability sample survey of the British population undertaken 2010-2012 (thethird National Survey of Sexual Attitudes and Lifestyles). We analysed weighted data on chlamydiatesting (past year), including location of most recent test, and diagnoses (past 5 years) from individualsaged 16-44 years reporting at least one sexual partner in the past year (4992 women, 3406 men).RESULTS Of the 26.8% (95% CI 25.4% to 28.2%) of women and 16.7% (15.5% to 18.1%) of menreporting a chlamydia test in the past year, 28.4% of women and 41.2% of men had tested ingenitourinary medicine (GUM), 41.1% and 20.7% of women and men respectively tested in generalpractice (GP) and the remainder tested in other non-GUM settings. Women tested outside GUM weremore likely to be older, in a relationship and to live in rural areas. Individuals tested outside GUMreported fewer risk behaviours; nevertheless, 11.0% (8.6% to 14.1%) of women and 6.8% (3.9% to11.6%) of men tested in GP and 13.2% (10.2% to 16.8%) and 9.6% (6.5% to 13.8%) of women andmen tested in other non-GUM settings reported 'unsafe sex', defined as two or more partners and nocondom use with any partner in the past year. Individuals treated for chlamydia outside GUM in the past5 years were less likely to report an HIV test in that time frame (women: 54.5% (42.7% to 65.7%) vs74.1% (65.9% to 80.9%) in GUM; men: 23.9% (12.7% to 40.5%) vs 65.8% (56.2% to 74.3%)).CONCLUSIONS Most chlamydia testing occurred in non-GUM settings, among populations reporting fewerrisk behaviours. However, there is a need to provide pathways to comprehensive STI care to the sizeableminority at higher risk.", "metadata": {}}
+{"_id": "3419709", "title": "", "text": "Treatment of nonalcoholic fatty liver disease: role of AMPK.Nonalcoholic fatty liver disease (NAFLD) is agrowing worldwide epidemic and an important risk factor for the development of insulin resistance, type 2diabetes, nonalcoholic steatohepatitis (NASH), and hepatic cellular carcinoma (HCC). Despite theprevalence of NAFLD, lifestyle interventions involving exercise and weight loss are the only acceptedtreatments for this disease. Over the last decade, numerous experimental compounds have been shownto improve NAFLD in preclinical animal models, and many of these therapeutics have been shown toincrease the activity of the cellular energy sensor AMP-activated protein kinase (AMPK). Because AMPKactivity is reduced by inflammation, obesity, and diabetes, increasing AMPK activity has been viewed as aviable therapeutic strategy to improve NAFLD. In this review, we propose three primary mechanisms bywhich AMPK activation may improve NAFLD. In addition, we examine the mechanisms by which AMPK isactivated. Finally, we identify 27 studies that have used AMPK activators to reduce NAFLD. Futureconsiderations for studies examining the relationship between AMPK and NAFLD are highlighted.", "metadata": {}}
+{"_id": "3419802", "title": "", "text": "Microenvironment-dependent growth of pre-neoplastic and malignant plasma cells in humanizedmiceMost human cancers, including myeloma, are preceded by a precursor state. There is an unmet needfor in vivo models to study the interaction of human preneoplastic cells in the bone marrowmicroenvironment with non-malignant cells. Here, we genetically humanized mice to permit the growth ofprimary human preneoplastic and malignant plasma cells together with non-malignant cells in vivo.Growth was largely restricted to the bone marrow, mirroring the pattern in patients with myeloma.Xenografts captured the genomic complexity of parental tumors and revealed additional somatic changes.Moreover, xenografts from patients with preneoplastic gammopathy showed progressive growth,suggesting that the clinical stability of these lesions may in part be due to growth controls extrinsic totumor cells. These data demonstrate a new approach to investigate the entire spectrum of human plasmacell neoplasia and illustrate the utility of humanized models for understanding the functional diversity ofhuman tumors.", "metadata": {}}
+{"_id": "3430789", "title": "", "text": "Effect of activated charcoal hemoperfusion on renal function in patients with paraquat poisoning.Thepresent study retrospectively analyzed 19 patients diagnosed with paraquat (PQ) poisoning with the aimto investigate the effect of activated charcoal hemoperfusion on renal function and PQ elimination. Theresults indicated that 7 patients died and 12 survived. Non-oliguric renal failure occurred in all of the 7patients who died. Among the 12 surviving patients, 10 had normal renal function and 2 developednon-oliguric renal failure. There was a linear correlation between plasma and urine paraquatconcentration prior to and during activated charcoal hemoperfusion. The equation parameters togetherwith the correlation coefficient on admission were as follows: Y=0.5820+1.7348X (R2=0.678; F=35.768;P<0.0001). The equation parameters together with the correlation coefficient were as follows duringactivated charcoal hemoperfusion: Y=0.6827+1.2649X (R2=0.626; F=50.308; P<0.0001). Therefore, itwas concluded that in patients with normal renal function, the elimination kinetics of PQ by the kidneyswere only associated with the plasma PQ concentration. Activated charcoal hemoperfusion had little effecton avoiding acute kidney injury in patients with severe PQ poisoning.", "metadata": {}}
+{"_id": "3435889", "title": "", "text": "Diabetes-induced effects on cardiomyocytes in chick embryonic heart micromass and mouse embryonicD3 differentiated stem cells.Diabetes mellitus during pregnancy is a considerable medical challenge, sinceit is related to \u0000augmented morbidity and mortality concerns for both the fetus \u0000and the pregnantwoman. Records show that the etiology of diabetic \u0000embryopathy is complicated, as many teratologicalfactors might be involved \u0000in the mechanisms of diabetes mellitus-induced congenital malformation. \u0000Inthis study, the potential cardiotoxic effect of hyperglycemia with hyperketonemia was investigated byusing two in vitro models; primary chick embryonic cardiomyocytes and stem cell derivedcardiomyocytes, where adverse effects were recorded in both systems. The cells were evaluated bychanges in beating activity, cell activity, protein content, ROS production, DNA damage anddifferentiating stem cell migration. The diabetic formulae used produced an increase in DNA damage anda decline in cell migration in mouse embryonic stem cells. These results provide an additional insight intoadverse effects during gestational diabetes mellitus and a recommendation for expectant mothers andmaternity staff to monitor glycaemic levels months ahead of conception. This study also supports therecommendation of using antioxidants during pregnancy to prevent DNA damage by the production ofROS, which might result in heart defects as well as other developmental anomalies.", "metadata": {}}
+{"_id": "3437084", "title": "", "text": "Motion magnificationWe present motion magnification, a technique that acts like a microscope for visualmotion. It can amplify subtle motions in a video sequence, allowing for visualization of deformations thatwould otherwise be invisible. To achieve motion magnification, we need to accurately measure visualmotions, and group the pixels to be modified. After an initial image registration step, we measure motionby a robust analysis of feature point trajectories, and segment pixels based on similarity of position,color, and motion. A novel measure of motion similarity groups even very small motions according tocorrelation over time, which often relates to physical cause. An outlier mask marks observations notexplained by our layered motion model, and those pixels are simply reproduced on the output from theoriginal registered observations. The motion of any selected layer may be magnified by a user-specifiedamount; texture synthesis fills-in unseen \"holes\" revealed by the amplified motions. The resultingmotion-magnified images can reveal or emphasize small motions in the original sequence, as wedemonstrate with deformations in load-bearing structures, subtle motions or balancing corrections ofpeople, and \"rigid\" structures bending under hand pressure.", "metadata": {}}
+{"_id": "3441524", "title": "", "text": "Human TRPML1 channel structures in open and closed conformationsTransient receptor potentialmucolipin 1 (TRPML1) is a Ca2+-releasing cation channel that mediates the calcium signalling andhomeostasis of lysosomes. Mutations in TRPML1 lead to mucolipidosis type IV, a severe lysosomalstorage disorder. Here we report two electron cryo-microscopy structures of full-length human TRPML1: a3.72-Å apo structure at pH 7.0 in the closed state, and a 3.49-Å agonist-bound structure at pH 6.0 in anopen state. Several aromatic and hydrophobic residues in pore helix 1, helices S5 and S6, and helix S6 ofa neighbouring subunit, form a hydrophobic cavity to house the agonist, suggesting a distinctagonist-binding site from that found in TRPV1, a TRP channel from a different subfamily. The opening ofTRPML1 is associated with distinct dilations of its lower gate together with a slight structural movement ofpore helix 1. Our work reveals the regulatory mechanism of TRPML channels, facilitates betterunderstanding of TRP channel activation, and provides insights into the molecular basis of mucolipidosistype IV pathogenesis.", "metadata": {}}
+{"_id": "3444507", "title": "", "text": "Integrative Genomics Viewer (IGV): high-performance genomics data visualization and explorationDatavisualization is an essential component of genomic data analysis. However, the size and diversity of thedata sets produced by today's sequencing and array-based profiling methods present major challenges tovisualization tools. The Integrative Genomics Viewer (IGV) is a high-performance viewer that efficientlyhandles large heterogeneous data sets, while providing a smooth and intuitive user experience at alllevels of genome resolution. A key characteristic of IGV is its focus on the integrative nature of genomicstudies, with support for both array-based and next-generation sequencing data, and the integration ofclinical and phenotypic data. Although IGV is often used to view genomic data from public sources, itsprimary emphasis is to support researchers who wish to visualize and explore their own data sets orthose from colleagues. To that end, IGV supports flexible loading of local and remote data sets, and isoptimized to provide high-performance data visualization and exploration on standard desktop systems.IGV is freely available for download from http://www.broadinstitute.org/igv, under a GNU LGPLopen-source license.", "metadata": {}}
+{"_id": "3446400", "title": "", "text": "Can genome engineering be used to target cancer-associated enhancers?Transcriptional misregulation isinvolved in the development of many diseases, especially neoplastic transformation. Distal regulatoryelements, such as enhancers, play a major role in specifying cell-specific transcription patterns in bothnormal and diseased tissues, suggesting that enhancers may be prime targets for therapeuticintervention. By focusing on modulating gene regulation mediated by cell type-specific enhancers, thereis hope that normal epigenetic patterning in an affected tissue could be restored with fewer side effectsthan observed with treatments employing relatively nonspecific inhibitors such as epigenetic drugs. Newmethods employing genomic nucleases and site-specific epigenetic regulators targeted to specificgenomic regions, using either artificial DNA-binding proteins or RNA-DNA interactions, may allow precisegenome engineering at enhancers. However, this field is still in its infancy and further refinements thatincrease specificity and efficiency are clearly required.", "metadata": {}}
+{"_id": "3462075", "title": "", "text": "Long\u0000Term Follow\u0000up of CD19 CAR Therapy in Acute Lymphoblastic LeukemiaBackgroundCD19\u0000specific chimeric antigen receptor (CAR) T cells induce high rates of initial response amongpatients with relapsed B\u0000cell acute lymphoblastic leukemia (ALL) and long\u0000term remissions in asubgroup of patients. Methods We conducted a phase 1 trial involving adults with relapsed B\u0000cell ALLwho received an infusion of autologous T cells expressing the 19\u000028z CAR at the Memorial SloanKettering Cancer Center (MSKCC). Safety and long\u0000term outcomes were assessed, as were theirassociations with demographic, clinical, and disease characteristics. Results A total of 53 adults received19\u000028z CAR T cells that were manufactured at MSKCC. After infusion, severe cytokine release syndromeoccurred in 14 of 53 patients (26%; 95% confidence interval [CI], 15 to 40); 1 patient died. Completeremission was observed in 83% of the patients. At a median follow\u0000up of 29 months (range, 1 to 65),the median event\u0000free survival was 6.1 months (95% CI, 5.0 to 11.5), and the median overall survivalwas 12.9 months (95% CI, 8.7 to 23.4). Patients with a low disease burden (<5% bone marrow blasts)before treatment had markedly enhanced remission duration and survival, with a median event\u0000freesurvival of 10.6 months (95% CI, 5.9 to not reached) and a median overall survival of 20.1 months (95%CI, 8.7 to not reached). Patients with a higher burden of disease (≥5% bone marrow blasts orextramedullary disease) had a greater incidence of the cytokine release syndrome and neurotoxic eventsand shorter long\u0000term survival than did patients with a low disease burden. Conclusions In the entirecohort, the median overall survival was 12.9 months. Among patients with a low disease burden, themedian overall survival was 20.1 months and was accompanied by a markedly lower incidence of thecytokine release syndrome and neurotoxic events after 19\u000028z CAR T\u0000cell infusion than was observedamong patients with a higher disease burden. (Funded by the Commonwealth Foundation for CancerResearch and others; ClinicalTrials.gov number, NCT01044069.)", "metadata": {}}
+{"_id": "3464191", "title": "", "text": "Periosteum contains skeletal stem cells with high bone regenerative potential controlled by PeriostinBoneregeneration relies on the activation of skeletal stem cells (SSCs) that still remain poorly characterized.Here, we show that periosteum contains SSCs with high bone regenerative potential compared to bonemarrow stromal cells/skeletal stem cells (BMSCs) in mice. Although periosteal cells (PCs) and BMSCs arederived from a common embryonic mesenchymal lineage, postnatally PCs exhibit greater clonogenicity,growth and differentiation capacity than BMSCs. During bone repair, PCs can efficiently contribute tocartilage and bone, and integrate long-term after transplantation. Molecular profiling uncovers genesencoding Periostin and other extracellular matrix molecules associated with the enhanced response toinjury of PCs. Periostin gene deletion impairs PC functions and fracture consolidation. Periostin-deficientperiosteum cannot reconstitute a pool of PCs after injury demonstrating the presence of SSCs withinperiosteum and the requirement of Periostin in maintaining this pool. Overall our results highlight theimportance of analyzing periosteum and PCs to understand bone phenotypes.", "metadata": {}}
+{"_id": "3468459", "title": "", "text": "Metabolism strikes back: metabolic flux regulates cell signaling.Mammalian cells depend on growth factorsignaling to take up nutrients; however, coordination of glucose and glutamine uptake has been amystery. In this issue of Genes & Development, Wellen and colleagues (pp. 2784-2799) show thatglucose flux through the hexosamine biosynthesis pathway regulates growth factor receptor glycosylationand enables glutamine consumption. This mechanism ensures that cells do not engage in anabolicmetabolism when nutrients are limiting, and highlights how substrate availability for protein modificationscan modulate cell signaling.", "metadata": {}}
+{"_id": "3471191", "title": "", "text": "Association of Pembrolizumab With Tumor Response and Survival Among Patients With AdvancedMelanoma.IMPORTANCE The programmed death 1 (PD-1) pathway limits immune responses tomelanoma and can be blocked with the humanized anti-PD-1 monoclonal antibody pembrolizumab.OBJECTIVE To characterize the association of pembrolizumab with tumor response and overall survivalamong patients with advanced melanoma. DESIGN, SETTINGS, AND PARTICIPANTS Open-label,multicohort, phase 1b clinical trials (enrollment, December 2011-September 2013). Median duration offollow-up was 21 months. The study was performed in academic medical centers in Australia, Canada,France, and the United States. Eligible patients were aged 18 years and older and had advanced ormetastatic melanoma. Data were pooled from 655 enrolled patients (135 from a nonrandomized cohort[n = 87 ipilimumab naive; n = 48 ipilimumab treated] and 520 from randomized cohorts [n = 226ipilimumab naive; n = 294 ipilimumab treated]). Cutoff dates were April 18, 2014, for safety analysesand October 18, 2014, for efficacy analyses. EXPOSURES Pembrolizumab 10 mg/kg every 2 weeks, 10mg/kg every 3 weeks, or 2 mg/kg every 3 weeks continued until disease progression, intolerable toxicity,or investigator decision. MAIN OUTCOMES AND MEASURES The primary end point was confirmedobjective response rate (best overall response of complete response or partial response) in patients withmeasurable disease at baseline per independent central review. Secondary end points included toxicity,duration of response, progression-free survival, and overall survival. RESULTS Among the 655 patients(median [range] age, 61 [18-94] years; 405 [62%] men), 581 had measurable disease at baseline. Anobjective response was reported in 194 of 581 patients (33% [95% CI, 30%-37%]) and in 60 of 133treatment-naive patients (45% [95% CI, 36% to 54%]). Overall, 74% (152/205) of responses wereongoing at the time of data cutoff; 44% (90/205) of patients had response duration for at least 1 yearand 79% (162/205) had response duration for at least 6 months. Twelve-month progression-free survivalrates were 35% (95% CI, 31%-39%) in the total population and 52% (95% CI, 43%-60%) amongtreatment-naive patients. Median overall survival in the total population was 23 months (95% CI, 20-29)with a 12-month survival rate of 66% (95% CI, 62%-69%) and a 24-month survival rate of 49% (95%CI, 44%-53%). In treatment-naive patients, median overall survival was 31 months (95% CI, 24 to notreached) with a 12-month survival rate of 73% (95% CI, 65%-79%) and a 24-month survival rate of60% (95% CI, 51%-68%). Ninety-two of 655 patients (14%) experienced at least 1 treatment-relatedgrade 3 or 4 adverse event (AE) and 27 of 655 (4%) patients discontinued treatment because of atreatment-related AE. Treatment-related serious AEs were reported in 59 patients (9%). There were nodrug-related deaths. CONCLUSIONS AND RELEVANCE Among patients with advanced melanoma,pembrolizumab administration was associated with an overall objective response rate of 33%, 12-monthprogression-free survival rate of 35%, and median overall survival of 23 months; grade 3 or 4treatment-related AEs occurred in 14%. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01295827.", "metadata": {}}
+{"_id": "3475317", "title": "", "text": "Inflammatory signaling in human Tuberculosis granulomas is spatially organizedGranulomas are thepathological hallmark of tuberculosis (TB). However, their function and mechanisms of formation remainpoorly understood. To understand the role of granulomas in TB, we analyzed the proteomes ofgranulomas from subjects with tuberculosis in an unbiased manner. Using laser-capture microdissection,mass spectrometry and confocal microscopy, we generated detailed molecular maps of humangranulomas. We found that the centers of granulomas have a pro-inflammatory environment that ischaracterized by the presence of antimicrobial peptides, reactive oxygen species and pro-inflammatoryeicosanoids. Conversely, the tissue surrounding the caseum has a comparatively anti-inflammatorysignature. These findings are consistent across a set of six human subjects and in rabbits. Although thebalance between systemic pro- and anti-inflammatory signals is crucial to TB disease outcome, here wefind that these signals are physically segregated within each granuloma. From the protein and lipidsnapshots of human and rabbit lesions analyzed here, we hypothesize that the pathologic response to TBis shaped by the precise anatomical localization of these inflammatory pathways during the developmentof the granuloma.", "metadata": {}}
+{"_id": "3493623", "title": "", "text": "Suppression of interferon-mediated anti-HBV response by single CpG methylation in the 5′-UTR ofTRIM22Objective Interferons (IFNs) mediate direct antiviral activity. They play a crucial role in the earlyhost immune response against viral infections. However, IFN therapy for HBV infection is less effectivethan for other viral infections. Design We explored the cellular targets of HBV in response to IFNs usingproteome-wide screening. Results Using LC-MS/MS, we identified proteins downregulated andupregulated by IFN treatment in HBV X protein (HBx)-stable and control cells. We found severalIFN-stimulated genes downregulated by HBx, including TRIM22, which is known as an antiretroviralprotein. We demonstrated that HBx suppresses the transcription of TRIM22 through a single CpGmethylation in its 5′-UTR, which further reduces the IFN regulatory factor-1 binding affinity, therebysuppressing the IFN-stimulated induction of TRIM22. Conclusions We verified our findings using a mousemodel, primary human hepatocytes and human liver tissues. Our data elucidate a mechanism by whichHBV evades the host innate immune system.", "metadata": {}}
+{"_id": "3495456", "title": "", "text": "Developmental Analysis of Bone Marrow Neutrophils Reveals Populations Specialized in Expansion,Trafficking, and Effector FunctionsSummary Neutrophils are specialized innate cells that require constantreplenishment from proliferative bone marrow (BM) precursors as a result of their short half\u0000life.Although it is established that neutrophils are derived from the granulocyte\u0000macrophage progenitor(GMP), the differentiation pathways from GMP to functional mature neutrophils are poorly defined. Usingmass cytometry (CyTOF) and cell\u0000cycle\u0000based analysis, we identified three neutrophil subsets withinthe BM: a committed proliferative neutrophil precursor (preNeu) which differentiates intonon\u0000proliferating immature neutrophils and mature neutrophils. Transcriptomic profiling and functionalanalysis revealed that preNeu require the C/EBP&egr; transcription factor for their generation from theGMP, and their proliferative program is substituted by a gain of migratory and effector function as theymature. preNeus expand under microbial and tumoral stress, and immature neutrophils are recruited tothe periphery of tumor\u0000bearing mice. In summary, our study identifies specialized BM granulocyticpopulations that ensure supply under homeostasis and stress responses. Graphical Abstract Figure. NoCaption available. HighlightsProliferation activity identifies committed neutrophil precursor in mice andhumansNeutrophil subsets possess distinct transcriptomic and functional signaturesDefect in neutrophildevelopment leads to impaired neutrophil\u0000mediated responsesIncreased circulating immatureneutrophils are associated with cancer progression &NA; The neutrophil differentiation pathway is poorlydefined. Evrard et. al. demonstrate a workflow of characterizing bone marrow neutrophil subsets on thebasis of their proliferative capacity and molecular signatures and thereby define the developmentaltrajectory and functional properties of neutrophils.", "metadata": {}}
+{"_id": "3504761", "title": "", "text": "TAK1-mediated autophagy and fatty acid oxidation prevent hepatosteatosis and tumorigenesis.The MAPkinase kinase kinase TGFβ-activated kinase 1 (TAK1) is activated by TLRs, IL-1, TNF, and TGFβ and inturn activates IKK-NF-κB and JNK, which regulate cell survival, growth, tumorigenesis, and metabolism.TAK1 signaling also upregulates AMPK activity and autophagy. Here, we investigated TAK1-dependentregulation of autophagy, lipid metabolism, and tumorigenesis in the liver. Fasted mice withhepatocyte-specific deletion of Tak1 exhibited severe hepatosteatosis with increased mTORC1 activityand suppression of autophagy compared with their WT counterparts. TAK1-deficient hepatocytesexhibited suppressed AMPK activity and autophagy in response to starvation or metformin treatment;however, ectopic activation of AMPK restored autophagy in these cells. Peroxisome proliferator-activatedreceptor α (PPARα) target genes and β-oxidation, which regulate hepatic lipid degradation, were alsosuppressed in hepatocytes lacking TAK1. Due to suppression of autophagy and β-oxidation, a high-fatdiet challenge aggravated steatohepatitis in mice with hepatocyte-specific deletion of Tak1. Notably,inhibition of mTORC1 restored autophagy and PPARα target gene expression in TAK1-deficient livers,indicating that TAK1 acts upstream of mTORC1. mTORC1 inhibition also suppressed spontaneous liverfibrosis and hepatocarcinogenesis in animals with hepatocyte-specific deletion of Tak1. These dataindicate that TAK1 regulates hepatic lipid metabolism and tumorigenesis via the AMPK/mTORC1 axis,affecting both autophagy and PPARα activity.", "metadata": {}}
+{"_id": "3506723", "title": "", "text": "Formins at the Junction.The actin cytoskeleton and adhesion junctions are physically and functionallycoupled at the cell-cell interface between epithelial cells. The actin regulatory complex Arp2/3 has anestablished role in the turnover of junctional actin; however, the role of formins, the largest group ofactin regulators, is less clear. Formins dynamically shape the actin cytoskeleton and have variousfunctions within cells. In this review we describe recent progress on how formins regulate actin dynamicsat cell-cell contacts and highlight formin functions during polarized protein traffic necessary forepithelialization.", "metadata": {}}
+{"_id": "3512154", "title": "", "text": "CRISPR adaptation biases explain preference for acquisition of foreign DNACRISPR-Cas (clustered,regularly interspaced short palindromic repeats coupled with CRISPR-associated proteins) is a bacterialimmunity system that protects against invading phages or plasmids. In the process of CRISPRadaptation, short pieces of DNA ('spacers') are acquired from foreign elements and integrated into theCRISPR array. So far, it has remained a mystery how spacers are preferentially acquired from the foreignDNA while the self chromosome is avoided. Here we show that spacer acquisition isreplication-dependent, and that DNA breaks formed at stalled replication forks promote spaceracquisition. Chromosomal hotspots of spacer acquisition were confined by Chi sites, which are sequenceoctamers highly enriched on the bacterial chromosome, suggesting that these sites limit spaceracquisition from self DNA. We further show that the avoidance of self is mediated by the RecBCDdouble-stranded DNA break repair complex. Our results suggest that, in Escherichia coli, acquisition ofnew spacers largely depends on RecBCD-mediated processing of double-stranded DNA breaks occurringprimarily at replication forks, and that the preference for foreign DNA is achieved through the higherdensity of Chi sites on the self chromosome, in combination with the higher number of forks on theforeign DNA. This model explains the strong preference to acquire spacers both from high copy plasmidsand from phages.", "metadata": {}}
+{"_id": "3514072", "title": "", "text": "High-resolution mapping of open chromatin in the rice genome.Gene expression is controlled by thecomplex interaction of transcription factors binding to promoters and other regulatory DNA elements. Onecommon characteristic of the genomic regions associated with regulatory proteins is a pronouncedsensitivity to DNase I digestion. We generated genome-wide high-resolution maps of DNase Ihypersensitive (DH) sites from both seedling and callus tissues of rice (Oryza sativa). Approximately 25%of the DH sites from both tissues were found in putative promoters, indicating that the vast majority ofthe gene regulatory elements in rice are not located in promoter regions. We found 58% more DH sites inthe callus than in the seedling. For DH sites detected in both the seedling and callus, 31% displayedsignificantly different levels of DNase I sensitivity within the two tissues. Genes that are differentiallyexpressed in the seedling and callus were frequently associated with DH sites in both tissues. The DNAsequences contained within the DH sites were hypomethylated, consistent with what is known aboutactive gene regulatory elements. Interestingly, tissue-specific DH sites located in the promoters showed ahigher level of DNA methylation than the average DNA methylation level of all the DH sites located in thepromoters. A distinct elevation of H3K27me3 was associated with intergenic DH sites. These resultssuggest that epigenetic modifications play a role in the dynamic changes of the numbers and DNase Isensitivity of DH sites during development.", "metadata": {}}
+{"_id": "3514540", "title": "", "text": "Prospective study of body fat distribution and the risk of endometrial cancer.BACKGROUND Epidemiologicstudies have found that overall obesity is positively related to endometrial cancer (EC) risk. However,data assessing the association between body fat distribution and risk of EC are still limited. METHODS Wefollowed 51,948 women who first reported waist circumference (WC) and hip circumference in 1986 inthe Nurses' Health Study. Waist-to-hip ratio (WHR) was calculated. RESULTS During 24 years offollow-up, 449 incident invasive EC cases were diagnosed. In a multivariate analysis without adjusting forbody mass index (BMI), the relative risks (RRs) for EC comparing extreme categories were 2.44 (95%confidence interval [CI] 1.72-3.45) for WC and 1.69 (95% CI=1.20-2.40) for WHR. However, afteradjustment of BMI, those positive associations were substantially attenuated and no longer significant;RR=1.08 (95% CI=0.69-1.67) for WC and 1.15 (95% CI=0.81-1.64) for WHR, respectively.CONCLUSION In our prospective cohort study, we found no independent association between body fatdistribution and the risk of EC after adjustment for BMI.", "metadata": {}}
+{"_id": "3524352", "title": "", "text": "Breast cancer clusters in the northeast United States: a geographic analysis.High breast cancer mortalityrates have been reported in the northeastern part of the United States, with recent attention focused onLong Island, New York. In this study, the authors investigate whether the high breast cancer mortality isevenly spread over the Northeast, in the sense that any observed clusters of deaths can be explained bychance alone, or whether there are clusters of statistical significance. Demographic data and age-specificbreast cancer mortality rates for women were obtained for all 244 counties in 11 northeastern states andfor the District of Columbia for 1988-1992. A recently developed spatial scan statistic is used, whichsearches for clusters of cases without specifying their size or location ahead of time, and which tests fortheir statistical significance while adjusting for the multiple testing inherent in such a procedure. Thebasic analysis is adjusted for age, with further analyses examining how the results are affected byincorporating race, urbanicity, and parity as confounding variables. There is a statistically significant andgeographically broad cluster of breast cancer deaths in the New York City-Philadelphia, Pennsylvania,metropolitan area (p = 0.0001), which has a 7.4% higher mortality rate than the rest of the Northeast.The cluster remains significant when race, urbanicity, and/or parity are included as confoundingvariables. Four smaller subclusters within this area are also significant on their own strength: Philadelphiawith suburbs (p = 0.0001), Long Island (p = 0.0001), central New Jersey (p = 0.0001), and northeasternNew Jersey (p = 0.0001). The elevated breast cancer mortality on Long Island might be viewed less as aunique local phenomenon and more as part of a more general situation involving large parts of the NewYork City-Philadelphia metropolitan area. The several known and hypothesized risk factors for which wecould not adjust and that may explain the detected cluster are most notably age at first birth, age atmenarche, age at menopause, breastfeeding, genetic mutations, and environmental factors.", "metadata": {}}
+{"_id": "3531388", "title": "", "text": "CD200R/CD200 Inhibits Osteoclastogenesis: New Mechanism of Osteoclast Control by Mesenchymal StemCells in HumanBone homeostasis is maintained by the balance between bone-forming osteoblasts andbone-degrading osteoclasts. Osteoblasts have a mesenchymal origin whereas osteoclasts belong to themyeloid lineage. Osteoclast and osteoblast communication occurs through soluble factors secretion,cell-bone interaction and cell-cell contact, which modulate their activities. CD200 is an immunoglobulinsuperfamilly member expressed on various types of cells including mesenchymal stem cells (MSCs).CD200 receptor (CD200R) is expressed on myeloid cells such as monocytes/macrophages. We assumethat CD200 could be a new molecule involved in the control of osteoclastogenesis and could play a role inMSC-osteoclast communication in humans. In this study, we demonstrated that soluble CD200 inhibitedthe differentiation of osteoclast precursors as well as their maturation in bone-resorbing cells in vitro.Soluble CD200 did not modify the monocyte phenotype but inhibited the receptor activator of nuclearfactor kappa-B ligand (RANKL) signaling pathway as well as the gene expression of osteoclast markerssuch as osteoclast-associated receptor (OSCAR) and nuclear factor of activated T cells cytoplasmic 1(NFATc1). Moreover, MSCs inhibited osteoclast formation, which depended on cell-cell contact and wasassociated with CD200 expression on the MSC surface. Our results clearly demonstrate that MSCs,through the expression of CD200, play a major role in the regulation of bone resorption and bonephysiology and that the CD200-CD200R couple could be a new target to control bone diseases.", "metadata": {}}
+{"_id": "3545805", "title": "", "text": "Tumor-specific Th17-polarized cells eradicate large established melanoma.CD4+ T cells can differentiateinto multiple effector subsets, but the potential roles of these subsets in anti-tumor immunity have notbeen fully explored. Seeking to study the impact of CD4+ T cell polarization on tumor rejection in a modelmimicking human disease, we generated a new MHC class II-restricted, T-cell receptor (TCR) transgenicmouse model in which CD4+ T cells recognize a novel epitope in tyrosinase-related protein 1 (TRP-1), anantigen expressed by normal melanocytes and B16 murine melanoma. Cells could be robustly polarizedinto Th0, Th1, and Th17 subtypes in vitro, as evidenced by cytokine, chemokine, and adhesion moleculeprofiles and by surface markers, suggesting the potential for differential effector function in vivo.Contrary to the current view that Th1 cells are most important in tumor rejection, we found thatTh17-polarized cells better mediated destruction of advanced B16 melanoma. Their therapeutic effectwas critically dependent on interferon-gamma (IFN-gamma) production, whereas depletion of interleukin(IL)-17A and IL-23 had little impact. Taken together, these data indicate that the appropriate in vitropolarization of effector CD4+ T cells is decisive for successful tumor eradication. This principle should beconsidered in designing clinical trials involving adoptive transfer-based immunotherapy of humanmalignancies.", "metadata": {}}
+{"_id": "3552753", "title": "", "text": "Defining community acquired pneumonia severity on presentation to hospital: an international derivationand validation study.BACKGROUND In the assessment of severity in community acquired pneumonia(CAP), the modified British Thoracic Society (mBTS) rule identifies patients with severe pneumonia butnot patients who might be suitable for home management. A multicentre study was conducted to deriveand validate a practical severity assessment model for stratifying adults hospitalised with CAP intodifferent management groups. METHODS Data from three prospective studies of CAP conducted in theUK, New Zealand, and the Netherlands were combined. A derivation cohort comprising 80% of the datawas used to develop the model. Prognostic variables were identified using multiple logistic regression with30 day mortality as the outcome measure. The final model was tested against the validation cohort.RESULTS 1068 patients were studied (mean age 64 years, 51.5% male, 30 day mortality 9%). Age>/=65 years (OR 3.5, 95% CI 1.6 to 8.0) and albumin <30 g/dl (OR 4.7, 95% CI 2.5 to 8.7) wereindependently associated with mortality over and above the mBTS rule (OR 5.2, 95% CI 2.7 to 10). A sixpoint score, one point for each of Confusion, Urea >7 mmol/l, Respiratory rate >/=30/min, lowsystolic(<90 mm Hg) or diastolic (</=60 mm Hg) Blood pressure), age >/=65 years (CURB-65 score)based on information available at initial hospital assessment, enabled patients to be stratified accordingto increasing risk of mortality: score 0, 0.7%; score 1, 3.2%; score 2, 3%; score 3, 17%; score 4, 41.5%and score 5, 57%. The validation cohort confirmed a similar pattern. CONCLUSIONS A simple six pointscore based on confusion, urea, respiratory rate, blood pressure, and age can be used to stratify patientswith CAP into different management groups.", "metadata": {}}
+{"_id": "3553087", "title": "", "text": "Mitochondrial iron chelation ameliorates cigarette-smoke induced bronchitis and emphysema inmiceChronic obstructive pulmonary disease (COPD) is linked to both cigarette smoking and geneticdeterminants. We have previously identified iron-responsive element-binding protein 2 (IRP2) as animportant COPD susceptibility gene and have shown that IRP2 protein is increased in the lungs ofindividuals with COPD. Here we demonstrate that mice deficient in Irp2 were protected from cigarettesmoke (CS)-induced experimental COPD. By integrating RNA immunoprecipitation followed by sequencing(RIP-seq), RNA sequencing (RNA-seq), and gene expression and functional enrichment clusteringanalysis, we identified Irp2 as a regulator of mitochondrial function in the lungs of mice. Irp2 increasedmitochondrial iron loading and levels of cytochrome c oxidase (COX), which led to mitochondrialdysfunction and subsequent experimental COPD. Frataxin-deficient mice, which had higher mitochondrialiron loading, showed impaired airway mucociliary clearance (MCC) and higher pulmonary inflammation atbaseline, whereas mice deficient in the synthesis of cytochrome c oxidase, which have reduced COX,were protected from CS-induced pulmonary inflammation and impairment of MCC. Mice treated with amitochondrial iron chelator or mice fed a low-iron diet were protected from CS-induced COPD.Mitochondrial iron chelation also alleviated CS-induced impairment of MCC, CS-induced pulmonaryinflammation and CS-associated lung injury in mice with established COPD, suggesting a criticalfunctional role and potential therapeutic intervention for the mitochondrial-iron axis in COPD.", "metadata": {}}
+{"_id": "3559136", "title": "", "text": "Cancer-Associated Fibroblasts Neutralize the Anti-tumor Effect of CSF1 Receptor Blockade by InducingPMN-MDSC Infiltration of Tumors.Tumor-associated macrophages (TAM) contribute to all aspects oftumor progression. Use of CSF1R inhibitors to target TAM is therapeutically appealing, but has had verylimited anti-tumor effects. Here, we have identified the mechanism that limited the effect of CSF1Rtargeted therapy. We demonstrated that carcinoma-associated fibroblasts (CAF) are major sources ofchemokines that recruit granulocytes to tumors. CSF1 produced by tumor cells caused HDAC2-mediateddownregulation of granulocyte-specific chemokine expression in CAF, which limited migration of thesecells to tumors. Treatment with CSF1R inhibitors disrupted this crosstalk and triggered a profoundincrease in granulocyte recruitment to tumors. Combining CSF1R inhibitor with a CXCR2 antagonistblocked granulocyte infiltration of tumors and showed strong anti-tumor effects.", "metadata": {}}
+{"_id": "3566945", "title": "", "text": "Phenotypic deficits in the HIV-1 envelope are associated with the maturation of a V2-directed broadlyneutralizing antibody lineageBroadly neutralizing antibodies (bnAbs) to HIV-1 can evolve after years of aniterative process of virus escape and antibody adaptation that HIV-1 vaccine design seeks to mimic. Toenable this, properties that render HIV-1 envelopes (Env) capable of eliciting bnAb responses need to bedefined. Here, we followed the evolution of the V2 apex directed bnAb lineage VRC26 in the HIV-1subtype C superinfected donor CAP256 to investigate the phenotypic changes of the virus populationscirculating before and during the early phases of bnAb induction. Longitudinal viruses that evolved fromthe VRC26-resistant primary infecting (PI) virus, the VRC26-sensitive superinfecting (SU) virus andensuing PI-SU recombinants revealed substantial phenotypic changes in Env, with a switch in Envproperties coinciding with early resistance to VRC26. Decreased sensitivity of SU-like viruses to VRC26was linked with reduced infectivity, altered entry kinetics and lower sensitivity to neutralization after CD4attachment. VRC26 maintained neutralization activity against cell-associated CAP256 virus, indicatingthat escape through the cell-cell transmission route is not a dominant escape pathway. Reduced fitness ofthe early escape variants and sustained sensitivity in cell-cell transmission are both features that limitvirus replication, thereby impeding rapid escape. This supports a scenario where VRC26 allowed onlypartial viral escape for a prolonged period, possibly increasing the time window for bnAb maturation.Collectively, our data highlight the phenotypic plasticity of the HIV-1 Env in evading bnAb pressure andthe need to consider phenotypic traits when selecting and designing Env immunogens. Combinations ofEnv variants with differential phenotypic patterns and bnAb sensitivity, as we describe here for CAP256,may maximize the potential for inducing bnAb responses by vaccination.", "metadata": {}}
+{"_id": "3572885", "title": "", "text": "High somatic mutation and neoantigen burden are correlated with decreased progression-free survival inmultiple myelomaTumor-specific mutations can result in immunogenic neoantigens, both of which havebeen correlated with responsiveness to immune checkpoint inhibitors in highly mutagenic cancers.However, early results of single-agent checkpoint inhibitors in multiple myeloma (MM) have beenunderwhelming. Therefore, we sought to understand the relationship between mutation and neoantigenlandscape of MM patients and responsiveness to therapies. Somatic mutation burden, neoantigen load,and response to therapy were determined using interim data from the MMRF CoMMpass study(NCT01454297) on 664 MM patients. In this population, the mean somatic and missense mutation loadswere 405.84(s=608.55) and 63.90(s=95.88) mutations per patient, respectively. There was a positivelinear relationship between mutation and neoantigen burdens (R2=0.862). The average predictedneoantigen load was 23.52(s=52.14) neoantigens with an average of 9.40(s=26.97) expressedneoantigens. Survival analysis revealed significantly shorter progression-free survival (PFS) in patientswith greater than average somatic missense mutation load (N=163, 0.493 vs 0.726 2-year PFS,P=0.0023) and predicted expressed neoantigen load (N=214, 0.555 vs 0.729 2-year PFS, P=0.0028).This pattern is maintained when stratified by disease stage and cytogenetic abnormalities. Therefore,high mutation and neoantigen load are clinically relevant risk factors that negatively impact survival ofMM patients under current standards of care.", "metadata": {}}
+{"_id": "3578380", "title": "", "text": "Postmarket Safety Events Among Novel Therapeutics Approved by the US Food and Drug AdministrationBetween 2001 and 2010Importance Postmarket safety events of novel pharmaceuticals and biologicsoccur when new safety risks are identified after initial regulatory approval of these therapeutics. Thesesafety events can change how novel therapeutics are used in clinical practice and inform patient andclinician decision making. Objectives To characterize the frequency of postmarket safety events amongnovel therapeutics approved by the US Food and Drug Administration (FDA), and to examine whether anynovel therapeutic characteristics known at the time of FDA approval were associated with increased risk.Design and Setting Cohort study of all novel therapeutics approved by the FDA between January 1, 2001,and December 31, 2010, followed up through February 28, 2017. Exposures Novel therapeuticcharacteristics known at the time of FDA approval, including drug class, therapeutic area, priority review,accelerated approval, orphan status, near–regulatory deadline approval, and regulatory review time.Main Outcomes and Measures A composite of (1) withdrawals due to safety concerns, (2) FDA issuance ofincremental boxed warnings added in the postmarket period, and (3) FDA issuance of safetycommunications. Results From 2001 through 2010, the FDA approved 222 novel therapeutics (183pharmaceuticals and 39 biologics). There were 123 new postmarket safety events (3 withdrawals, 61boxed warnings, and 59 safety communications) during a median follow-up period of 11.7 years(interquartile range [IQR], 8.7-13.8 years), affecting 71 (32.0%) of the novel therapeutics. The mediantime from approval to first postmarket safety event was 4.2 years (IQR, 2.5-6.0 years), and theproportion of novel therapeutics affected by a postmarket safety event at 10 years was 30.8% (95% CI,25.1%-37.5%). In multivariable analysis, postmarket safety events were statistically significantly morefrequent among biologics (incidence rate ratio [IRR] = 1.93; 95% CI, 1.06-3.52; P = .03), therapeuticsindicated for the treatment of psychiatric disease (IRR = 3.78; 95% CI, 1.77-8.06; P < .001), thosereceiving accelerated approval (IRR = 2.20; 95% CI, 1.15-4.21; P = .02), and those withnear–regulatory deadline approval (IRR = 1.90; 95% CI, 1.19-3.05; P = .008); events were statisticallysignificantly less frequent among those with regulatory review times less than 200 days (IRR = 0.46;95% CI, 0.24-0.87; P = .02). Conclusions and Relevance Among 222 novel therapeutics approved by theFDA from 2001 through 2010, 32% were affected by a postmarket safety event. Biologics, psychiatrictherapeutics, and accelerated and near–regulatory deadline approval were statistically significantlyassociated with higher rates of events, highlighting the need for continuous monitoring of the safety ofnovel therapeutics throughout their life cycle.", "metadata": {}}
+{"_id": "3580005", "title": "", "text": "Who is where at risk for Chronic Obstructive Pulmonary Disease? A spatial epidemiological analysis ofhealth insurance claims for COPD in Northeastern GermanyBACKGROUND Chronic obstructive pulmonarydisease (COPD) has a high prevalence rate in Germany and a further increase is expected within the nextyears. Although risk factors on an individual level are widely understood, only little is known about thespatial heterogeneity and population-based risk factors of COPD. Background knowledge about broader,population-based processes could help to plan the future provision of healthcare and preventionstrategies more aligned to the expected demand. The aim of this study is to analyze how the prevalenceof COPD varies across northeastern Germany on the smallest spatial-scale possible and to identify thelocation-specific population-based risk factors using health insurance claims of the AOK Nordost.METHODS To visualize the spatial distribution of COPD prevalence at the level of municipalities and urbandistricts, we used the conditional autoregressive Besag-York-Mollié (BYM) model. Geographicallyweighted regression modelling (GWR) was applied to analyze the location-specific ecological risk factorsfor COPD. RESULTS The sex- and age-adjusted prevalence of COPD was 6.5% in 2012 and varied widelyacross northeastern Germany. Population-based risk factors consist of the proportions of insurants aged65 and older, insurants with migration background, household size and area deprivation. The results ofthe GWR model revealed that the population at risk for COPD varies considerably across northeasternGermany. CONCLUSION Area deprivation has a direct and an indirect influence on the prevalence ofCOPD. Persons ageing in socially disadvantaged areas have a higher chance of developing COPD, evenwhen they are not necessarily directly affected by deprivation on an individual level. This underlines theimportance of considering the impact of area deprivation on health for planning of healthcare.Additionally, our results reveal that in some parts of the study area, insurants with migration backgroundand persons living in multi-persons households are at elevated risk of COPD.", "metadata": {}}
+{"_id": "3583084", "title": "", "text": "Large intergenic non-coding RNA-RoR modulates reprogramming of human induced pluripotent stemcellsThe conversion of lineage-committed cells to induced pluripotent stem cells (iPSCs) byreprogramming is accompanied by a global remodeling of the epigenome, resulting in altered patterns ofgene expression. Here we characterize the transcriptional reorganization of large intergenic non-codingRNAs (lincRNAs) that occurs upon derivation of human iPSCs and identify numerous lincRNAs whoseexpression is linked to pluripotency. Among these, we defined ten lincRNAs whose expression waselevated in iPSCs compared with embryonic stem cells, suggesting that their activation may promote theemergence of iPSCs. Supporting this, our results indicate that these lincRNAs are direct targets of keypluripotency transcription factors. Using loss-of-function and gain-of-function approaches, we found thatone such lincRNA (lincRNA-RoR) modulates reprogramming, thus providing a first demonstration forcritical functions of lincRNAs in the derivation of pluripotent stem cells.", "metadata": {}}
+{"_id": "3588621", "title": "", "text": "Extracellular vesicle isolation and characterization: toward clinical application.Two broad categories ofextracellular vesicles (EVs), exosomes and shed microvesicles (sMVs), which differ in size distribution aswell as protein and RNA profiles, have been described. EVs are known to play key roles in cell-cellcommunication, acting proximally as well as systemically. This Review discusses the nature of EVsubtypes, strategies for isolating EVs from both cell-culture media and body fluids, and procedures forquantifying EVs. We also discuss proteins selectively enriched in exosomes and sMVs that have thepotential for use as markers to discriminate between EV subtypes, as well as various applications of EVsin clinical diagnosis.", "metadata": {}}
+{"_id": "3590806", "title": "", "text": "Up-regulated NRIP2 in colorectal cancer initiating cells modulates the Wnt pathway by targetingRORβBACKGROUND Colorectal cancer remains one of the most common malignant tumors worldwide.Colorectal cancer initiating cells (CCICs) are a small subpopulation responsible for malignant behaviors ofcolorectal cancer. Aberrant activation of the Wnt pathways regulates the self-renewal of CCIC. However,the underlying mechanism(s) remain poorly understood. METHODS Via retroviral library screening, weidentified Nuclear Receptor-Interacting Protein 2 (NRIP2) as a novel interactor of the Wnt pathway fromenriched colorectal cancer colosphere cells. The expression levels of NRIP2 and retinoic acid-relatedorphan receptor β (RORβ) were further examined by FISH, qRT-PCR, IHC and Western blot. NRIP2overexpressed and knockdown colorectal cancer cells were produced to study the role of NRIP2 in Wntpathway. We also verified the binding between NRIP2 and RORβ and investigated the effect of RORβ onCCICs both in vitro and in vivo. Genechip-scanning speculated downstream target HBP1. Western blot,ChIP and luciferase reporter were carried to investigate the interaction between NRIP2, RORβ, and HBP1.RESULTS NRIP2 was significantly up-regulated in CCICs from both cell lines and primary colorectal cancertissues. Reinforced expression of NRIP2 increased Wnt activity, while silencing of NRIP2 attenuated Wntactivity. The transcription factor RORβ was a key target through which NRIP2 regulated Wnt pathwayactivity. RORβ was a transcriptional enhancer of inhibitor HBP1 of the Wnt pathway. NRIP2 preventedRORβ to bind with downstream HBP1 promoter regions and reduced the transcription of HBP1. This, inturn, attenuated the HBP1-dependent inhibition of TCF4-mediated transcription. CONCLUSIONS NRIP2 isa novel interactor of the Wnt pathway in colorectal cancer initiating cells. interactions between NRIP2,RORβ, and HBP1 mediate a new mechanism for CCIC self-renewal via the Wnt activity.", "metadata": {}}
+{"_id": "3591070", "title": "", "text": "Speed Limits for Nonvesicular Intracellular Sterol Transport.Sterol transport between the endoplasmicreticulum (ER) and plasma membrane (PM) occurs by nonvesicular mechanisms requiring sterol transportproteins (STPs). Here we examine the idea that transport is enhanced at membrane contact sites wherethe ER is closely apposed to the PM. We conclude that sterol desorption from the membrane, rather thanSTP-mediated diffusion, is rate limiting in the cellular context, so there is no apparent kinetic benefit tohaving STP-mediated sterol transfer occur at contact sites. Contact sites may instead compartmentalizelipid synthesis or transport machinery, providing opportunities for regulation.", "metadata": {}}
+{"_id": "3610080", "title": "", "text": "Misunderstandings in prescribing decisions in general practice: qualitative study.OBJECTIVES To identifyand describe misunderstandings between patients and doctors associated with prescribing decisions ingeneral practice. DESIGN Qualitative study. SETTING 20 general practices in the West Midlands andsouth east England. PARTICIPANTS 20 general practitioners and 35 consulting patients. MAIN OUTCOMEMEASURES Misunderstandings between patients and doctors that have potential or actual adverseconsequences for taking medicine. RESULTS 14 categories of misunderstanding were identified relating topatient information unknown to the doctor, doctor information unknown to the patient, conflictinginformation, disagreement about attribution of side effects, failure of communication about doctor'sdecision, and relationship factors. All the misunderstandings were associated with lack of patients'participation in the consultation in terms of the voicing of expectations and preferences or the voicing ofresponses to doctors' decisions and actions. They were all associated with potential or actual adverseoutcomes such as non-adherence to treatment. Many were based on inaccurate guesses andassumptions. In particular doctors seemed unaware of the relevance of patients' ideas about medicinesfor successful prescribing. CONCLUSIONS Patients' participation in the consultation and the adverseconsequences of lack of participation are important. The authors are developing an educationalintervention that builds on these findings.", "metadata": {}}
+{"_id": "3610282", "title": "", "text": "Phase-plate cryo-EM structure of a biased agonist-bound human GLP-1 receptor–Gs complexThe class Bglucagon-like peptide-1 (GLP-1) G protein-coupled receptor is a major target for the treatment of type 2diabetes and obesity. Endogenous and mimetic GLP-1 peptides exhibit biased agonism—a difference infunctional selectivity—that may provide improved therapeutic outcomes. Here we describe the structureof the human GLP-1 receptor in complex with the G protein-biased peptide exendin-P5 and a Gαsheterotrimer, determined at a global resolution of 3.3 Å. At the extracellular surface, the organization ofextracellular loop 3 and proximal transmembrane segments differs between our exendin-P5-boundstructure and previous GLP-1-bound GLP-1 receptor structure. At the intracellular face, there was asix-degree difference in the angle of the Gαs–α5 helix engagement between structures, which waspropagated across the G protein heterotrimer. In addition, the structures differed in the rate and extentof conformational reorganization of the Gαs protein. Our structure provides insights into the molecularbasis of biased agonism.", "metadata": {}}
+{"_id": "3613041", "title": "", "text": "Therapeutic equivalence of alendronate 70 mg once-weekly and alendronate 10 mg daily in the treatmentof osteoporosis. Alendronate Once-Weekly Study Group.Dosing convenience is a key element in theeffective management of any chronic disease, and is particularly important in the long-term managementof osteoporosis. Less frequent dosing with any medication may enhance compliance, thereby maximizingthe effectiveness of therapy. Animal data support the rationale that once-weekly dosing with alendronate70 mg (7 times the daily oral treatment dose) could provide similar efficacy to daily dosing withalendronate 10 mg due to its long duration of effect in bone. In addition, dog studies suggest that thepotential for esophageal irritation, observed with daily oral bisphosphonates, may be substantiallyreduced with once-weekly dosing. This dosing regimen would provide patients with increasedconvenience and would be likely to enhance patient compliance. We compared the efficacy and safety oftreatment with oral once-weekly alendronate 70 mg (N=519), twice-weekly alendronate 35 mg (N=369),and daily alendronate 10 mg (N=370) in a one-year, double-blind, multicenter study of postmenopausalwomen (ages 42 to 95) with osteoporosis (bone mineral density [BMD] of either lumbar spine or femoralneck at least 2.5 SDs below peak premenopausal mean, or prior vertebral or hip fracture). The primaryefficacy endpoint was the comparability of increases in lumbar spine BMD, using strict pre-definedequivalence criteria. Secondary endpoints included changes in BMD at the hip and total body and rate ofbone turnover, as assessed by biochemical markers. Both of the new regimens fully satisfied theequivalence criteria relative to daily therapy. Mean increases in lumbar spine BMD at 12 months were:5.1% (95% CI 4.8, 5.4) in the 70 mg once-weekly group, 5.2% (4.9, 5.6) in the 35 mg twice-weeklygroup, and 5.4% (5.0, 5.8) in the 10 mg daily treatment group. Increases in BMD at the total hip,femoral neck, trochanter, and total body were similar for the three dosing regimens. All three treatmentgroups similarly reduced biochemical markers of bone resorption (urinary N-telopeptides of type Icollagen) and bone formation (serum bone-specific alkaline phosphatase) into the middle of thepremenopausal reference range. All treatment regimens were well tolerated with a similar incidence ofupper GI adverse experiences. There were fewer serious upper GI adverse experiences and a trendtoward a lower incidence of esophageal events in the once-weekly dosing group compared to the dailydosing group. These data are consistent with preclinical animal models, and suggest that once-weeklydosing has the potential for improved upper GI tolerability. Clinical fractures, captured as adverseexperiences, were similar among the groups. We conclude that the alendronate 70 mg once-weeklydosing regimen will provide patients with a more convenient, therapeutically equivalent alternative todaily dosing, and may enhance compliance and long-term persistence with therapy.", "metadata": {}}
+{"_id": "3616843", "title": "", "text": "Association of Toll-Like Receptor 4 on Human Monocyte Subsets and Vulnerability Characteristics ofCoronary Plaque as Assessed by 64-Slice Multidetector Computed Tomography.BACKGROUND AlthoughToll-like receptor 4 (TLR-4) is involved in monocyte activation in patients with accelerated forms ofatherosclerosis, the relationship between the expression of TLR-4 on circulating monocytes and coronaryplaque vulnerability has not previously been evaluated. We investigated this relationship using 64-slicemultidetector computed tomography (MDCT) in patients with stable angina pectoris (SAP).Methods andResults:We enrolled 65 patients with SAP who underwent MDCT. Three monocyte subsets(CD14++CD16-, CD14++CD16+, and CD14+CD16+) and expression of TLR-4 were measured by flowcytometry. Intracoronary plaques were assessed by 64-slice MDCT. We defined vulnerability ofintracoronary plaques according to the presence of positive remodeling (remodeling index >1.05) and/orlow CT attenuation (<35 HU). The circulating CD14++CD16+monocytes more frequently expressedTLR-4 than CD14++CD16-and CD14+CD16+monocytes (P<0.001). The relative proportion of theexpression of TLR-4 on CD14++CD16+monocytes was significantly greater in patients with vulnerableplaque compared with those without (10.4 [4.1-14.5] % vs. 4.5 [2.8-7.8] %, P=0.012). In addition, therelative proportion of TLR-4 expression on CD14++CD16+monocytes positively correlated with theremodeling index (r=0.28, P=0.025) and negatively correlated with CT attenuation value (r=-0.31,P=0.013). CONCLUSIONS Upregulation of TLR-4 on CD14++CD16+monocytes might be associated withcoronary plaque vulnerability in patients with SAP.", "metadata": {}}
+{"_id": "3619372", "title": "", "text": "Expandable Cardiovascular Progenitor Cells Reprogrammed from Fibroblasts.Stem cell-based approachesto cardiac regeneration are increasingly viable strategies for treating heart failure. Generating abundantand functional autologous cells for transplantation in such a setting, however, remains a significantchallenge. Here, we isolated a cell population with extensive proliferation capacity and restrictedcardiovascular differentiation potentials during cardiac transdifferentiation of mouse fibroblasts. Theseinduced expandable cardiovascular progenitor cells (ieCPCs) proliferated extensively for more than 18passages in chemically defined conditions, with 10(5) starting fibroblasts robustly producing 10(16)ieCPCs. ieCPCs expressed cardiac signature genes and readily differentiated into functionalcardiomyocytes (CMs), endothelial cells (ECs), and smooth muscle cells (SMCs) in vitro, even afterlong-term expansion. When transplanted into mouse hearts following myocardial infarction, ieCPCsspontaneously differentiated into CMs, ECs, and SMCs and improved cardiac function for up to 12 weeksafter transplantation. Thus, ieCPCs are a powerful system to study cardiovascular specification andprovide strategies for regenerative medicine in the heart.", "metadata": {}}
+{"_id": "3619931", "title": "", "text": "Thyroid hormone inhibits lung fibrosis in mice by improving epithelial mitochondrial functionThyroidhormone (TH) is critical for the maintenance of cellular homeostasis during stress responses, but its rolein lung fibrosis is unknown. Here we found that the activity and expression of iodothyronine deiodinase 2(DIO2), an enzyme that activates TH, were higher in lungs from patients with idiopathic pulmonaryfibrosis than in control individuals and were correlated with disease severity. We also found thatDio2-knockout mice exhibited enhanced bleomycin-induced lung fibrosis. Aerosolized TH deliveryincreased survival and resolved fibrosis in two models of pulmonary fibrosis in mice (intratrachealbleomycin and inducible TGF-β1). Sobetirome, a TH mimetic, also blunted bleomycin-induced lungfibrosis. After bleomycin-induced injury, TH promoted mitochondrial biogenesis, improved mitochondrialbioenergetics and attenuated mitochondria-regulated apoptosis in alveolar epithelial cells both in vivo andin vitro. TH did not blunt fibrosis in Ppargc1a- or Pink1-knockout mice, suggesting dependence on thesepathways. We conclude that the antifibrotic properties of TH are associated with protection of alveolarepithelial cells and restoration of mitochondrial function and that TH may thus represent a potentialtherapy for pulmonary fibrosis.", "metadata": {}}
+{"_id": "3621011", "title": "", "text": "Tenomodulin promotes human adipocyte differentiation and beneficial visceral adipose tissueexpansion.Proper regulation of energy storage in adipose tissue is crucial for maintaining insulinsensitivity and molecules contributing to this process have not been fully revealed. Here we show thattype II transmembrane protein tenomodulin (TNMD) is upregulated in adipose tissue of insulin-resistantversus insulin-sensitive individuals, who were matched for body mass index (BMI). TNMD expressionincreases in human preadipocytes during differentiation, whereas silencing TNMD blocks adipogenesis.Upon high-fat diet feeding, transgenic mice overexpressing Tnmd develop increased epididymal whiteadipose tissue (eWAT) mass, and preadipocytes derived from Tnmd transgenic mice display greaterproliferation, consistent with elevated adipogenesis. In Tnmd transgenic mice, lipogenic genes areupregulated in eWAT, as is Ucp1 in brown fat, while liver triglyceride accumulation is attenuated. Despiteexpanded eWAT, transgenic animals display improved systemic insulin sensitivity, decreased collagendeposition and inflammation in eWAT, and increased insulin stimulation of Akt phosphorylation. Our datasuggest that TNMD acts as a protective factor in visceral adipose tissue to alleviate insulin resistance inobesity.", "metadata": {}}
+{"_id": "3623127", "title": "", "text": "Evidence for a limit to human lifespanDriven by technological progress, human life expectancy hasincreased greatly since the nineteenth century. Demographic evidence has revealed an ongoing reductionin old-age mortality and a rise of the maximum age at death, which may gradually extend humanlongevity. Together with observations that lifespan in various animal species is flexible and can beincreased by genetic or pharmaceutical intervention, these results have led to suggestions that longevitymay not be subject to strict, species-specific genetic constraints. Here, by analysing global demographicdata, we show that improvements in survival with age tend to decline after age 100, and that the age atdeath of the world’s oldest person has not increased since the 1990s. Our results strongly suggest thatthe maximum lifespan of humans is fixed and subject to natural constraints.", "metadata": {}}
+{"_id": "3654468", "title": "", "text": "Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on Glycemic Control inPatients With Type 2 Diabetes: A Randomized Clinical TrialImportance Glucagon-like peptide-1 (GLP-1)receptor agonists are effective therapies for the treatment of type 2 diabetes and are all currentlyavailable as an injection. Objectives To compare the effects of oral semaglutide with placebo (primary)and open-label subcutaneous semaglutide (secondary) on glycemic control in patients with type 2diabetes. Design, Setting, and Patients Phase 2, randomized, parallel-group, dosage-finding, 26-weektrial with 5-week follow-up at 100 sites (hospital clinics, general practices, and clinical research centers)in 14 countries conducted between December 2013 and December 2014. Of 1106 participants assessed,632 with type 2 diabetes and insufficient glycemic control using diet and exercise alone or a stable doseof metformin were randomized. Randomization was stratified by metformin use. Interventions Once-dailyoral semaglutide of 2.5 mg (n = 70), 5 mg (n = 70), 10 mg (n = 70), 20 mg (n = 70), 40-mg 4-weekdose escalation (standard escalation; n = 71), 40-mg 8-week dose escalation (slow escalation; n = 70),40-mg 2-week dose escalation (fast escalation, n = 70), oral placebo (n = 71; double-blind) oronce-weekly subcutaneous semaglutide of 1.0 mg (n = 70) for 26 weeks. Main Outcomes and MeasuresThe primary end point was change in hemoglobing A1c (HbA1c) from baseline to week 26. Secondary endpoints included change from baseline in body weight and adverse events. Results Baseline characteristicswere comparable across treatment groups. Of the 632 randomized patients (mean age, 57.1 years [SD,10.6]; men, 395 (62.7%); diabetes duration, 6.3 years [SD, 5.2]; body weight, 92.3 kg [SD, 16.8]; BMI,31.7 [SD, 4.3]), 583 (92%) completed the trial. Mean change in HbA1c level from baseline to week 26decreased with oral semaglutide (dosage-dependent range, −0.7% to −1.9%) and subcutaneoussemaglutide (−1.9%) and placebo (−0.3%); oral semaglutide reductions were significant vs placebo(dosage-dependent estimated treatment difference [ETD] range for oral semaglutide vs placebo, –0.4%to –1.6%; P = .01 for 2.5 mg, <.001 for all other dosages). Reductions in body weight were greater withoral semaglutide (dosage-dependent range, −2.1 kg to −6.9 kg) and subcutaneous semaglutide (−6.4kg) vs placebo (−1.2 kg), and significant for oral semaglutide dosages of 10 mg or more vs placebo(dosage-dependent ETD range, –0.9 to –5.7 kg; P < .001). Adverse events were reported by 63% to86% (371 of 490 patients) in the oral semaglutide groups, 81% (56 of 69 patients) in the subcutaneoussemaglutide group, and 68% (48 of 71 patients) in the placebo group; mild to moderate gastrointestinalevents were most common. Conclusions and Relevance Among patients with type 2 diabetes, oralsemaglutide resulted in better glycemic control than placebo over 26 weeks. These findings supportphase 3 studies to assess longer-term and clinical outcomes, as well as safety. Trial Registrationclinicaltrials.gov Identifier: NCT01923181", "metadata": {}}
+{"_id": "3662132", "title": "", "text": "Fast and accurate short read alignment with Burrows–Wheeler transformMOTIVATION The enormousamount of short reads generated by the new DNA sequencing technologies call for the development offast and accurate read alignment programs. A first generation of hash table-based methods has beendeveloped, including MAQ, which is accurate, feature rich and fast enough to align short reads from asingle individual. However, MAQ does not support gapped alignment for single-end reads, which makes itunsuitable for alignment of longer reads where indels may occur frequently. The speed of MAQ is also aconcern when the alignment is scaled up to the resequencing of hundreds of individuals. RESULTS Weimplemented Burrows-Wheeler Alignment tool (BWA), a new read alignment package that is based onbackward search with Burrows-Wheeler Transform (BWT), to efficiently align short sequencing readsagainst a large reference sequence such as the human genome, allowing mismatches and gaps. BWAsupports both base space reads, e.g. from Illumina sequencing machines, and color space reads from ABSOLiD machines. Evaluations on both simulated and real data suggest that BWA is approximately 10-20xfaster than MAQ, while achieving similar accuracy. In addition, BWA outputs alignment in the newstandard SAM (Sequence Alignment/Map) format. Variant calling and other downstream analyses afterthe alignment can be achieved with the open source SAMtools software package. AVAILABILITYhttp://maq.sourceforge.net.", "metadata": {}}
+{"_id": "3662510", "title": "", "text": "The financial cost of doctors emigrating from sub-Saharan Africa: human capital analysisOBJECTIVE Toestimate the lost investment of domestically educated doctors migrating from sub-Saharan Africancountries to Australia, Canada, the United Kingdom, and the United States. DESIGN Human capital costanalysis using publicly accessible data. SETTINGS Sub-Saharan African countries. PARTICIPANTS Ninesub-Saharan African countries with an HIV prevalence of 5% or greater or with more than one millionpeople with HIV/AIDS and with at least one medical school (Ethiopia, Kenya, Malawi, Nigeria, SouthAfrica, Tanzania, Uganda, Zambia, and Zimbabwe), and data available on the number of doctorspractising in destination countries. MAIN OUTCOME MEASURES The financial cost of educating a doctor(through primary, secondary, and medical school), assuming that migration occurred after graduation,using current country specific interest rates for savings converted to US dollars; cost according to thenumber of source country doctors currently working in the destination countries; and savings todestination countries of receiving trained doctors. RESULTS In the nine source countries the estimatedgovernment subsidised cost of a doctor's education ranged from $21,000 (£13,000; €15,000) in Ugandato $58,700 in South Africa. The overall estimated loss of returns from investment for all doctors currentlyworking in the destination countries was $2.17bn (95% confidence interval 2.13bn to 2.21bn), with costsfor each country ranging from $2.16m (1.55m to 2.78m) for Malawi to $1.41bn (1.38bn to 1.44bn) forSouth Africa. The ratio of the estimated compounded lost investment over gross domestic productshowed that Zimbabwe and South Africa had the largest losses. The benefit to destination countries ofrecruiting trained doctors was largest for the United Kingdom ($2.7bn) and United States ($846m).CONCLUSIONS Among sub-Saharan African countries most affected by HIV/AIDS, lost investment fromthe emigration of doctors is considerable. Destination countries should consider investing in measurabletraining for source countries and strengthening of their health systems.", "metadata": {}}
+{"_id": "3669694", "title": "", "text": "Chromatin modifying enzymes as modulators of reprogrammingGeneration of induced pluripotent stemcells (iPSCs) by somatic cell reprogramming involves global epigenetic remodelling. Whereas severalproteins are known to regulate chromatin marks associated with the distinct epigenetic states of cellsbefore and after reprogramming, the role of specific chromatin-modifying enzymes in reprogrammingremains to be determined. To address how chromatin-modifying proteins influence reprogramming, weused short hairpin RNAs (shRNAs) to target genes in DNA and histone methylation pathways, andidentified positive and negative modulators of iPSC generation. Whereas inhibition of the corecomponents of the polycomb repressive complex 1 and 2, including the histone 3 lysine 27methyltransferase EZH2, reduced reprogramming efficiency, suppression of SUV39H1, YY1 and DOT1Lenhanced reprogramming. Specifically, inhibition of the H3K79 histone methyltransferase DOT1L byshRNA or a small molecule accelerated reprogramming, significantly increased the yield of iPSC colonies,and substituted for KLF4 and c-Myc (also known as MYC). Inhibition of DOT1L early in the reprogrammingprocess is associated with a marked increase in two alternative factors, NANOG and LIN28, which playessential functional roles in the enhancement of reprogramming. Genome-wide analysis of H3K79me2distribution revealed that fibroblast-specific genes associated with the epithelial to mesenchymaltransition lose H3K79me2 in the initial phases of reprogramming. DOT1L inhibition facilitates the loss ofthis mark from genes that are fated to be repressed in the pluripotent state. These findings implicatespecific chromatin-modifying enzymes as barriers to or facilitators of reprogramming, and demonstratehow modulation of chromatin-modifying enzymes can be exploited to more efficiently generate iPSCs withfewer exogenous transcription factors.", "metadata": {}}
+{"_id": "3672261", "title": "", "text": "Natural variation in the parameters of innate immune cells is preferentially driven by genetic factorsThequantification and characterization of circulating immune cells provide key indicators of human health anddisease. To identify the relative effects of environmental and genetic factors on variation in theparameters of innate and adaptive immune cells in homeostatic conditions, we combined standardizedflow cytometry of blood leukocytes and genome-wide DNA genotyping of 1,000 healthy, unrelated peopleof Western European ancestry. We found that smoking, together with age, sex and latent infection withcytomegalovirus, were the main non-genetic factors that affected variation in parameters of humanimmune cells. Genome-wide association studies of 166 immunophenotypes identified 15 loci that showedenrichment for disease-associated variants. Finally, we demonstrated that the parameters of innate cellswere more strongly controlled by genetic variation than were those of adaptive cells, which were drivenby mainly environmental exposure. Our data establish a resource that will generate new hypotheses inimmunology and highlight the role of innate immunity in susceptibility to common autoimmune diseases.Both environmental factors and genetic factors influence human immunity. Albert and colleaguesleverage data from the Milieu Intérieur Consortium to comprehensively describe the effects of lifestyle,environment and genetics on human innate and adaptive immunity.", "metadata": {}}
+{"_id": "3680979", "title": "", "text": "The transcriptional program, functional heterogeneity, and clinical targeting of mast cellsMast cells areunique tissue-resident immune cells that express an array of receptors that can be activated by severalextracellular cues, including antigen-immunoglobulin E (IgE) complexes, bacteria, viruses, cytokines,hormones, peptides, and drugs. Mast cells constitute a small population in tissues, but their extraordinaryability to respond rapidly by releasing granule-stored and newly made mediators underpins theirimportance in health and disease. In this review, we document the biology of mast cells and introducenew concepts and opinions regarding their role in human diseases beyond IgE-mediated allergicresponses and antiparasitic functions. We bring to light recent discoveries and developments in mast cellresearch, including regulation of mast cell functions, differentiation, survival, and novel mouse models.Finally, we highlight the current and future opportunities for therapeutic intervention of mast cellfunctions in inflammatory diseases.", "metadata": {}}
+{"_id": "3684342", "title": "", "text": "LIN28B enhanced tumorigenesis in an autochthonous KRASG12V-driven lung carcinoma mousemodelLIN28B is a RNA-binding protein regulating predominantly let-7 microRNAs with essential functionsin inflammation, wound healing, embryonic stem cells, and cancer. LIN28B expression is associated withtumor initiation, progression, resistance, and poor outcome in several solid cancers, including lungcancer. However, the functional role of LIN28B, especially in non-small cell lung adenocarcinomas,remains elusive. Here, we investigated the effects of LIN28B expression on lung tumorigenesis usingLIN28B transgenic overexpression in an autochthonous KRASG12V-driven mouse model. We found thatLIN28B overexpression significantly increased the number of CD44+/CD326+ tumor cells, upregulatedVEGF-A and miR-21 and promoted tumor angiogenesis and epithelial-to-mesenchymal transition (EMT)accompanied by enhanced AKT phosphorylation and nuclear translocation of c-MYC. Moreover, LIN28Baccelerated tumor initiation and enhanced proliferation which led to a shortened overall survival. Inaddition, we analyzed lung adenocarcinomas of the Cancer Genome Atlas (TCGA) and found LIN28Bexpression in 24% of KRAS-mutated cases, which underscore the relevance of our model.", "metadata": {}}
+{"_id": "3690068", "title": "", "text": "Cost-effectiveness comparison between topical silver sulfadiazine and enclosed silver dressing forpartial-thickness burn treatment.The standard treatment of partial-thickness burns includes topical silverproducts such as silver sulfadiazine (SSD) cream and enclosed dressings including silver-impregnatedfoam (Mepilex Ag; Molnlycke Health Care, Gothenburg, Sweden) and silver-laden sheets (Aquacel Ag;ConvaTec, Skillman, NJ). The current state of health care is limited by resources, with an emphasis onevidence-based outcomes and cost-effective treatments. This study includes a decision analysis with anincremental cost-utility ratio comparing enclosed silver dressings with SSD in partial-thickness burnpatients with TBSA less than 20%. A comprehensive literature review was conducted to identify clinicallyrelevant health states in partial-thickness burn patients. These health states include successful healing,infection, and noninfected delayed healing requiring either surgery or conservative management. Theprobabilities of these health states were combined with Medicare CPT reimbursement codes (cost) andpatient-derived utilities to fit into the decision model. Utilities were obtained using a visual analog scaleduring patient interviews. Expected cost and quality-adjusted life years (QALYs) were calculated using theroll-back method. The incremental cost-utility ratio for enclosed silver dressing relative to SSD was$40,167.99/QALY. One-way sensitivity analysis of complication rates confirmed robustness of the model.Assuming a maximum willingness to pay $50,000/QALY, the complication rate for SSD must be 22% orhigher for enclosed silver dressing to be cost effective. By varying complication rates for SSD andenclosed silver dressings, the two-way sensitivity analysis demonstrated the cost effectiveness of usingenclosed silver dressing at the majority of complication rates for both treatment modalities. Enclosedsilver dressings are a cost-effective means of treating partial thickness burns.", "metadata": {}}
+{"_id": "3692112", "title": "", "text": "Randomized clinical study of Hydrofiber dressing with silver or silver sulfadiazine in the management ofpartial-thickness burns.This prospective, randomized study compared protocols of care using eitherAQUACEL Ag Hydrofiber (ConvaTec, a Bristol-Myers Squibb company, Skillman, NJ) dressing with silver(n = 42) or silver sulfadiazine (n = 42) for up to 21 days in the management of partial-thickness burnscovering 5% to 40% body surface area (BSA). AQUACEL Ag dressing was associated with less pain andanxiety during dressing changes, less burning and stinging during wear, fewer dressing changes, lessnursing time, and fewer procedural medications. Silver sulfadiazine was associated with greater flexibilityand ease of movement. Adverse events, including infection, were comparable between treatment groups.The AQUACEL Ag dressing protocol tended to have lower total treatment costs (Dollars 1040 vs. Dollars1180) and a greater rate of re-epithelialization (73.8% vs 60.0%), resulting in cost-effectiveness perburn healed of Dollars 1,409.06 for AQUACEL Ag dressing and Dollars 1,967.95 for silver sulfadiazine. Aprotocol of care with AQUACEL(R) Ag provided clinical and economic benefits compared with silversulfadiazine in patients with partial-thickness burns.", "metadata": {}}
+{"_id": "3698758", "title": "", "text": "Hepatitis C virus and blood transfusion: past and present risks.The risk of HCV transmission by blood andblood products has been greatly reduced since the early 1980's. Selection of non-remunerated donors,donor selection to prevent HIV transmission, initial surrogate testing in some regions, and introduction ofanti-HCV testing have all contributed to this. ALT surrogate testing has become obsolete since theintroduction of anti-HCV testing. The residual risk of HCV transmission due to donations in the anti-HCVwindow period at present is about 1 in 100 000 transfusions of cellular products, and transmission of HCVby plasma products treated with modern inactivation methods such as solvent-detergent treatment, hasnot been reported. Hemovigilance programmes, which are presently being installed, will provide moredata on the safety of blood transfusion. Introduction of HCV nucleic amplification technology (NAT) as aquality control of manufacturing pools for plasma products or as a form of blood donor screening byminipools is anticipated in many European countries for the coming year. Given industrial developments,NAT testing of individual blood donations may become available within the next 2 years. HCV NAT testingwill further annihilate the residual risk, and the cost-effectiveness will become relatively low incomparison with other public health measures.", "metadata": {}}
+{"_id": "3701541", "title": "", "text": "p62/SQSTM1 by Binding to Vitamin D Receptor Inhibits Hepatic Stellate Cell Activity, Fibrosis, and LiverCancer.Hepatic stellate cells (HSCs) play critical roles in liver fibrosis and hepatocellular carcinoma (HCC).Vitamin D receptor (VDR) activation in HSCs inhibits liver inflammation and fibrosis. We found thatp62/SQSTM1, a protein upregulated in liver parenchymal cells but downregulated in HCC-associatedHSCs, negatively controls HSC activation. Total body or HSC-specific p62 ablation potentiates HSCs andenhances inflammation, fibrosis, and HCC progression. p62 directly interacts with VDR and RXRpromoting their heterodimerization, which is critical for VDR:RXR target gene recruitment. Loss of p62 inHSCs impairs the repression of fibrosis and inflammation by VDR agonists. This demonstrates that p62 isa negative regulator of liver inflammation and fibrosis through its ability to promote VDR signaling inHSCs, whose activation supports HCC.", "metadata": {}}
+{"_id": "3707035", "title": "", "text": "Developing criteria for evaluation of geroprotectors as a key stage toward translation to the clinicIn thecoming decades, a massive shift in the aging segment of the population will have major social andeconomic consequences around the world. One way to offset this increase is to expedite the developmentof geroprotectors, substances that slow aging, repair age-associated damage and extend healthylifespan, or healthspan. While over 200 geroprotectors are now reported in model organisms and someare in human use for specific disease indications, the path toward determining whether they affect agingin humans remains obscure. Translation to the clinic is hampered by multiple issues including absence ofa common set of criteria to define, select, and classify these substances, given the complexity of theaging process and their enormous diversity in mechanism of action. Translational research efforts wouldbenefit from the formation of a scientific consensus on the following: the definition of 'geroprotector', theselection criteria for geroprotectors, a comprehensive classification system, and an analytical model.Here, we review current approaches to selection and put forth our own suggested selection criteria.Standardizing selection of geroprotectors will streamline discovery and analysis of new candidates, savingtime and cost involved in translation to clinic.", "metadata": {}}
+{"_id": "3710557", "title": "", "text": "β-Catenin Signaling and Roles in Liver Homeostasis, Injury, and Tumorigenesis.β-catenin (encoded byCTNNB1) is a subunit of the cell surface cadherin protein complex that acts as an intracellular signaltransducer in the WNT signaling pathway; alterations in its activity have been associated with thedevelopment of hepatocellular carcinoma and other liver diseases. Other than WNT, additional signalingpathways also can converge at β-catenin. β-catenin also interacts with transcription factors such as T-cellfactor, forkhead box protein O, and hypoxia inducible factor 1α to regulate the expression of targetgenes. We discuss the role of β-catenin in metabolic zonation of the adult liver. β-catenin also regulatesthe expression of genes that control metabolism of glucose, nutrients, and xenobiotics; alterations in itsactivity may contribute to the pathogenesis of nonalcoholic steatohepatitis. Alterations in β-cateninsignaling may lead to activation of hepatic stellate cells, which is required for fibrosis. Many hepatictumors such as hepatocellular adenomas, hepatocellular cancers, and hepatoblastomas have mutations inCTNNB1 that result in constitutive activation of β-catenin, so this molecule could be a therapeutic target.We discuss how alterations in β-catenin activity contribute to liver disease and how these might be usedin diagnosis and prognosis, as well as in the development of therapeutics.", "metadata": {}}
+{"_id": "3716075", "title": "", "text": "The global burden of dengue: an analysis from the Global Burden of Disease Study 2013.BACKGROUNDDengue is the most common arbovirus infection globally, but its burden is poorly quantified. Weestimated dengue mortality, incidence, and burden for the Global Burden of Disease Study 2013.METHODS We modelled mortality from vital registration, verbal autopsy, and surveillance data using theCause of Death Ensemble Modelling tool. We modelled incidence from officially reported cases, andadjusted our raw estimates for under-reporting based on published estimates of expansion factors. Intotal, we had 1780 country-years of mortality data from 130 countries, 1636 country-years of denguecase reports from 76 countries, and expansion factor estimates for 14 countries. FINDINGS We estimatedan average of 9221 dengue deaths per year between 1990 and 2013, increasing from a low of 8277(95% uncertainty estimate 5353-10 649) in 1992, to a peak of 11 302 (6790-13 722) in 2010. Thisyielded a total of 576 900 (330 000-701 200) years of life lost to premature mortality attributable todengue in 2013. The incidence of dengue increased greatly between 1990 and 2013, with the number ofcases more than doubling every decade, from 8·3 million (3·3 million-17·2 million) apparent cases in1990, to 58·4 million (23·6 million-121·9 million) apparent cases in 2013. When accounting for disabilityfrom moderate and severe acute dengue, and post-dengue chronic fatigue, 566 000 (186 000-1 415 000)years lived with disability were attributable to dengue in 2013. Considering fatal and non-fatal outcomestogether, dengue was responsible for 1·14 million (0·73 million-1·98 million) disability-adjusted life-yearsin 2013. INTERPRETATION Although lower than other estimates, our results offer more evidence that thetrue symptomatic incidence of dengue probably falls within the commonly cited range of 50 million to 100million cases per year. Our mortality estimates are lower than those presented elsewhere and should beconsidered in light of the totality of evidence suggesting that dengue mortality might, in fact, besubstantially higher. FUNDING Bill & Melinda Gates Foundation.", "metadata": {}}
+{"_id": "3720107", "title": "", "text": "Formin-mediated actin polymerization at cell–cell junctions stabilizes E-cadherin and maintainsmonolayer integrity during wound repairCadherin-mediated cell-cell adhesion is required for epithelialtissue integrity in homeostasis, during development, and in tissue repair. E-cadherin stability depends onF-actin, but the mechanisms regulating actin polymerization at cell-cell junctions remain poorlyunderstood. Here we investigated a role for formin-mediated actin polymerization at cell-cell junctions.We identify mDia1 and Fmnl3 as major factors enhancing actin polymerization and stabilizing E-cadherinat epithelial junctions. Fmnl3 localizes to adherens junctions downstream of Src and Cdc42 and itsdepletion leads to a reduction in F-actin and E-cadherin at junctions and a weakening of cell-celladhesion. Of importance, Fmnl3 expression is up-regulated and junctional localization increases duringcollective cell migration. Depletion of Fmnl3 or mDia1 in migrating monolayers results in dissociation ofleader cells and impaired wound repair. In summary, our results show that formin activity at epithelialcell-cell junctions is important for adhesion and the maintenance of epithelial cohesion during dynamicprocesses, such as wound repair.", "metadata": {}}
+{"_id": "3727986", "title": "", "text": "A mechanically active heterotypic E-cadherin/N-cadherin adhesion enables fibroblasts to drive cancer cellinvasionCancer-associated fibroblasts (CAFs) promote tumour invasion and metastasis. We show thatCAFs exert a physical force on cancer cells that enables their collective invasion. Force transmission ismediated by a heterophilic adhesion involving N-cadherin at the CAF membrane and E-cadherin at thecancer cell membrane. This adhesion is mechanically active; when subjected to force it triggers β-cateninrecruitment and adhesion reinforcement dependent on α-catenin/vinculin interaction. Impairment ofE-cadherin/N-cadherin adhesion abrogates the ability of CAFs to guide collective cell migration and blockscancer cell invasion. N-cadherin also mediates repolarization of the CAFs away from the cancer cells. Inparallel, nectins and afadin are recruited to the cancer cell/CAF interface and CAF repolarization is afadindependent. Heterotypic junctions between CAFs and cancer cells are observed in patient-derivedmaterial. Together, our findings show that a mechanically active heterophilic adhesion between CAFs andcancer cells enables cooperative tumour invasion.", "metadata": {}}
+{"_id": "3730196", "title": "", "text": "Long non-coding RNA HOTTIP promotes BCL-2 expression and induces chemoresistance in small cell lungcancer by sponging miR-216aDespite progress in treatment of small cell lung cancer (SCLC), itsmultidrug chemoresistance and poor prognosis still remain. Recently, we globally assessed longnon-coding RNAs (lncRNAs) for contributions to SCLC chemoresistance using microarray data, in vitro andin vivo assays. Here we reported that HOTTIP, encoding a lncRNA that is frequently amplified in SCLC,was associated with SCLC cell chemosensitivity, proliferation, and poor prognosis of SCLC patients.Moreover, mechanistic investigations showed that HOTTIP functioned as an oncogene in SCLCprogression by binding miR-216a and abrogating its tumor-suppressive function in this setting. On theother hand, HOTTIP increased the expression of anti-apoptotic factor BCL-2, another important targetgene of miR-216a, and jointly enhanced chemoresistance of SCLC by regulating BCL-2. Taken together,our study established a role for HOTTIP in SCLC progression and chemoresistance suggest its candidacyas a new diagnostic and prognostic biomarker for clinical management of SCLC.", "metadata": {}}
+{"_id": "3743071", "title": "", "text": "GSDS 2.0: an upgraded gene feature visualization serverUNLABELLED : Visualizing genes' structure andannotated features helps biologists to investigate their function and evolution intuitively. The GeneStructure Display Server (GSDS) has been widely used by more than 60 000 users since its firstpublication in 2007. Here, we reported the upgraded GSDS 2.0 with a newly designed interface, supportsfor more types of annotation features and formats, as well as an integrated visual editor for editing thegenerated figure. Moreover, a user-specified phylogenetic tree can be added to facilitate furtherevolutionary analysis. The full source code is also available for downloading. AVAILABILITY ANDIMPLEMENTATION Web server and source code are freely available at http://gsds.cbi.pku.edu.cn.CONTACT gaog@mail.cbi.pku.edu.cn or gsds@mail.cbi.pku.edu.cn   SUPPLEMENTARY INFORMATIONSupplementary data are available at Bioinformatics online.", "metadata": {}}
+{"_id": "3748310", "title": "", "text": "SLP-65 regulates immunoglobulin light chain gene recombination through the PI(3)K-PKB-FoxopathwayAlthough the essential role of the adaptor protein SLP-65 in pre-B cell differentiation isestablished, the molecular mechanism underlying its function is poorly understood. In this study, weuncover a link between SLP-65–dependent signaling and the phosphoinositide-3-OH kinase(PI(3)K)–protein kinase B (PKB)–Foxo pathway. We show that the forkhead box transcription factorFoxo3a promotes light chain rearrangement in pre-B cells. Our data suggest that PKB suppresses lightchain recombination by phosphorylating Foxo proteins, whereas reconstitution of SLP-65 functioncounteracts PKB activation and promotes Foxo3a and Foxo1 activity in pre-B cells. Together, these datailluminate a molecular function of SLP-65 and identify a key role for Foxo proteins in the regulation oflight chain recombination, receptor editing and B cell selection.", "metadata": {}}
+{"_id": "3752408", "title": "", "text": "A case-mix classification system for explaining healthcare costs using administrative data inItaly.BACKGROUND The Italian National Health Service (NHS) provides universal coverage to all citizens,granting primary and hospital care with a copayment system for outpatient and drug services. Financingof Local Health Trusts (LHTs) is based on a capitation system adjusted only for age, gender and area ofresidence. We applied a risk-adjustment system (Johns Hopkins Adjusted Clinical Groups System, ACG®System) in order to explain health care costs using routinely collected administrative data in the VenetoRegion (North-eastern Italy). METHODS All residents in the Veneto Region were included in the study.The ACG system was applied to classify the regional population based on the following informationsources for the year 2015: Hospital Discharges, Emergency Room visits, Chronic disease registry forcopayment exemptions, ambulatory visits, medications, the Home care database, and drug prescriptions.Simple linear regressions were used to contrast an age-gender model to models incorporating morecomprehensive risk measures aimed at predicting health care costs. RESULTS A simple age-gender modelexplained only 8% of the variance of 2015 total costs. Adding diagnoses-related variables provided a23% increase, while pharmacy based variables provided an additional 17% increase in explainedvariance. The adjusted R-squared of the comprehensive model was 6 times that of the simple age-gendermodel. CONCLUSIONS ACG System provides substantial improvement in predicting health care costswhen compared to simple age-gender adjustments. Aging itself is not the main determinant of theincrease of health care costs, which is better explained by the accumulation of chronic conditions and theresulting multimorbidity.", "metadata": {}}
+{"_id": "3756384", "title": "", "text": "EpCAM-regulated intramembrane proteolysis induces a cancer stem cell-like gene signature in hepatitis Bvirus-infected hepatocytes.BACKGROUND & AIMS Hepatocytes in which the hepatitis B virus (HBV) isreplicating exhibit loss of the chromatin modifying polycomb repressive complex 2 (PRC2), resulting inre-expression of specific, cellular PRC2-repressed genes. Epithelial cell adhesion molecule (EpCAM) is aPRC2-repressed gene, normally expressed in hepatic progenitors, but re-expressed in hepatic cancerstem cells (hCSCs). Herein, we investigated the functional significance of EpCAM re-expression inHBV-mediated hepatocarcinogenesis. METHODS Employing molecular approaches (transfections,fluorescence-activated cell sorting, immunoblotting, qRT-PCR), we investigated the role ofEpCAM-regulated intramembrane proteolysis (RIP) in HBV replicating cells in vitro, and in liver tumorsfrom HBV X/c-myc mice and chronically HBV infected patients. RESULTS EpCAM undergoes RIP in HBVreplicating cells, activating canonical Wnt signaling. Transfection of Wnt-responsive plasmid expressinggreen fluorescent protein (GFP) identified a GFP + population of HBV replicating cells. These GFP+/Wnt+cells exhibited cisplatin- and sorafenib-resistant growth resembling hCSCs, and increased expression ofpluripotency genes NANOG, OCT4, SOX2, and hCSC markers BAMBI, CD44 and CD133. These genes arereferred as EpCAM RIP and Wnt-induced hCSC-like gene signature. Interestingly, this gene signature isalso overexpressed in liver tumors of X/c-myc bitransgenic mice. Clinically, a group of HBV-associatedhepatocellular carcinomas was identified, exhibiting elevated expression of the hCSC-like gene signatureand associated with reduced overall survival post-surgical resection. CONCLUSIONS The hCSC-like genesignature offers promise as prognostic tool for classifying subtypes of HBV-induced HCCs. Since EpCAMRIP and Wnt signaling drive expression of this hCSC-like signature, inhibition of these pathways can beexplored as therapeutic strategy for this subtype of HBV-associated HCCs. LAY SUMMARY In this study,we provide evidence for a molecular mechanism by which chronic infection by the hepatitis B virus resultsin the development of poor prognosis liver cancer. Based on this mechanism our results suggest possibletherapeutic interventions.", "metadata": {}}
+{"_id": "3758260", "title": "", "text": "Parathyroid Hormone Directs Bone Marrow Mesenchymal Cell Fate.Intermittent PTH administration buildsbone mass and prevents fractures, but its mechanism of action is unclear. We genetically deleted thePTH/PTHrP receptor (PTH1R) in mesenchymal stem cells using Prx1Cre and found low bone formation,increased bone resorption, and high bone marrow adipose tissue (BMAT). Bone marrow adipocytes tracedto Prx1 and expressed classic adipogenic markers and high receptor activator of nuclear factor kappa Bligand (Rankl) expression. RANKL levels were also elevated in bone marrow supernatant and serum, butundetectable in other adipose depots. By cell sorting, Pref1+RANKL+ marrow progenitors were twice asgreat in mutant versus control marrow. Intermittent PTH administration to control mice reduced BMATsignificantly. A similar finding was noted in male osteoporotic patients. Thus, marrow adipocytes exhibitosteogenic and adipogenic characteristics, are uniquely responsive to PTH, and secrete RANKL. Thesestudies reveal an important mechanism for PTH's therapeutic action through its ability to directmesenchymal cell fate.", "metadata": {}}
+{"_id": "3761017", "title": "", "text": "Metformin attenuates blood-brain barrier disruption in mice following middle cerebral arteryocclusionBACKGROUND Metformin, a widely used hypoglycemic drug, reduces stroke incidence andalleviates chronic inflammation in clinical trials. However, the effect of metformin in ischemic stroke isunclear. Here, we investigated the effect of metformin on ischemic stroke in mice and further exploredthe possible underlying mechanisms. METHODS Ninety-eight adult male CD-1 mice underwent 90-minutetransient middle cerebral artery occlusion (tMCAO). Metformin (200 mg/kg) was administrated for up to14 days. Neurobehavioral outcomes, brain infarct volume, inflammatory factors, blood-brain barrier(BBB) permeability and AMPK signaling pathways were evaluated following tMCAO. Oxygen glucosedeprivation was performed on bEND.3 cells to explore the mechanisms of metformin in inhibitinginflammatory signaling pathways. RESULTS Infarct volume was reduced in metformin-treated micecompared to the control group following tMCAO (P < 0.05). Neurobehavioral outcomes were greatlyimproved in metformin-treated mice (P < 0.05). MPO+ cells, Gr1+ cells, MPO activity and BBBpermeability were decreased after metformin administration (P < 0.05). In addition, metformin activatedAMPK phosphorylation, inhibited NF-κB activation, down-regulated cytokine (IL-1β, IL-6, TNF-α) andICAM-1 expression following tMCAO (P < 0.05). Furthermore, metformin activated AMPK signalingpathway and alleviated oxygen-glucose deprivation-induced ICAM-1 expression in bEND.3 cells (P <0.05). Compound C, a selective AMPK inhibitor, eliminated this promotional effect. CONCLUSIONSMetformin down-regulated ICAM-1 in an AMPK-dependent manner, which could effectively preventischemia-induced brain injury by alleviating neutrophil infiltration, suggesting that metformin is apromising therapeutic agent in stroke therapy.", "metadata": {}}
+{"_id": "3765739", "title": "", "text": "Epstein-Barr Virus nuclear antigen 1 (EBNA1) confers resistance to apoptosis in EBV-positiveB-lymphoma cells through up-regulation of survivin.Resistance to apoptosis is an important component ofthe overall mechanism which drives the tumorigenic process. EBV is a ubiquitous humangamma-herpesvirus which preferentially establishes latent infection in viral infected B-lymphocytes.EBNA1 is typically expressed in most forms of EBV-positive malignancies and is important for replicationof the latent episome in concert with replication of the host cells. Here, we investigate the effects ofEBNA1 on survivin up-regulation in EBV-infected human B-lymphoma cells. We present evidence whichdemonstrates that EBNA1 forms a complex with Sp1 or Sp1-like proteins bound to their cis-element atthe survivin promoter. This enhances the activity of the complex and up-regulates survivin. Knockdown ofsurvivin and EBNA1 showed enhanced apoptosis in infected cells and thus supports a role for EBNA1 insuppressing apoptosis in EBV-infected cells. Here, we suggest that EBV encoded EBNA1 can contribute tothe oncogenic process by up-regulating the apoptosis suppressor protein, survivin in EBV-associatedB-lymphoma cells.", "metadata": {}}
+{"_id": "3770726", "title": "", "text": "Microfluidic platform to evaluate migration of cells from patients with DYT1 dystonia.BACKGROUNDMicrofluidic platforms for quantitative evaluation of cell biologic processes allow low cost and timeefficient research studies of biological and pathological events, such as monitoring cell migration byreal-time imaging. In healthy and disease states, cell migration is crucial in development and woundhealing, as well as to maintain the body's homeostasis. NEW METHOD The microfluidic chambers allowprecise measurements to investigate whether fibroblasts carrying a mutation in the TOR1A gene,underlying the hereditary neurologic disease--DYT1 dystonia, have decreased migration properties whencompared to control cells. RESULTS We observed that fibroblasts from DYT1 patients showedabnormalities in basic features of cell migration, such as reduced velocity and persistence of movement.COMPARISON WITH EXISTING METHOD The microfluidic method enabled us to demonstrate reducedpolarization of the nucleus and abnormal orientation of nuclei and Golgi inside the moving DYT1 patientcells compared to control cells, as well as vectorial movement of single cells. CONCLUSION We reporthere different assays useful in determining various parameters of cell migration in DYT1 patient cells as aconsequence of the TOR1A gene mutation, including a microfluidic platform, which provides a means toevaluate real-time vectorial movement with single cell resolution in a three-dimensional environment.", "metadata": {}}
+{"_id": "3770750", "title": "", "text": "Sugar-sweetened beverages and weight gain in children and adults: a systematic review andmeta-analysis.BACKGROUND The relation between sugar-sweetened beverages (SSBs) and body weightremains controversial. OBJECTIVE We conducted a systematic review and meta-analysis to summarizethe evidence in children and adults. DESIGN We searched PubMed, EMBASE, and Cochrane databasesthrough March 2013 for prospective cohort studies and randomized controlled trials (RCTs) that evaluatedthe SSB-weight relation. Separate meta-analyses were conducted in children and adults and for cohortsand RCTs by using random- and fixed-effects models. RESULTS Thirty-two original articles were includedin our meta-analyses: 20 in children (15 cohort studies, n = 25,745; 5 trials, n = 2772) and 12 in adults(7 cohort studies, n = 174,252; 5 trials, n = 292). In cohort studies, one daily serving increment of SSBswas associated with a 0.06 (95% CI: 0.02, 0.10) and 0.05 (95% CI: 0.03, 0.07)-unit increase in BMI inchildren and 0.22 kg (95% CI: 0.09, 0.34 kg) and 0.12 kg (95% CI: 0.10, 0.14 kg) weight gain in adultsover 1 y in random- and fixed-effects models, respectively. RCTs in children showed reductions in BMIgain when SSBs were reduced [random and fixed effects: -0.17 (95% CI: -0.39, 0.05) and -0.12 (95%CI: -0.22, -0.2)], whereas RCTs in adults showed increases in body weight when SSBs were added(random and fixed effects: 0.85 kg; 95% CI: 0.50, 1.20 kg). Sensitivity analyses of RCTs in childrenshowed more pronounced benefits in preventing weight gain in SSB substitution trials (compared withschool-based educational programs) and among overweight children (compared with normal-weightchildren). CONCLUSION Our systematic review and meta-analysis of prospective cohort studies and RCTsprovides evidence that SSB consumption promotes weight gain in children and adults.", "metadata": {}}
+{"_id": "3773719", "title": "", "text": "The tumorigenic potential of pluripotent stem cells: What can we do to minimize it?Human pluripotentstem cells (hPSCs) have the potential to fundamentally change the way that we go about treating andunderstanding human disease. Despite this extraordinary potential, these cells also have an innatecapability to form tumors in immunocompromised individuals when they are introduced in theirpluripotent state. Although current therapeutic strategies involve transplantation of only differentiatedhPSC derivatives, there is still a concern that transplanted cell populations could contain a smallpercentage of cells that are not fully differentiated. In addition, these cells have been frequently reportedto acquire genetic alterations that, in some cases, are associated with certain types of human cancers.Here, we try to separate the panic from reality and rationally evaluate the true tumorigenic potential ofthese cells. We also discuss a recent study examining the effect of culture conditions on the geneticintegrity of hPSCs. Finally, we present a set of sensible guidelines for minimizing the tumorigenicpotential of hPSC-derived cells. © 2016 The Authors. Inside the Cell published by Wiley Periodicals, Inc.", "metadata": {}}
+{"_id": "3776162", "title": "", "text": "Epidemiology of sepsis and septic shock in critical care units: comparison between sepsis-2 and sepsis-3populations using a national critical care databaseBackground New sepsis and septic shock definitionscould change the epidemiology of sepsis because of differences in criteria. We therefore compared thesepsis populations identified by the old and new definitions. Methods We used a high-quality, national,intensive care unit (ICU) database of 654 918 consecutive admissions to 189 adult ICUs in England, fromJanuary 2011 to December 2015. Primary outcome was acute hospital mortality. We compared old(Sepsis-2) and new (Sepsis-3) incidence, outcomes, trends in outcomes, and predictive validity of sepsisand septic shock populations. Results From among 197 724 Sepsis-2 severe sepsis and 197 142 Sepsis-3sepsis cases, we identified 153 257 Sepsis-2 septic shock and 39 262 Sepsis-3 septic shock cases. Theextrapolated population incidence of Sepsis-3 sepsis and Sepsis-3 septic shock was 101.8 and 19.3 per100 000 person-years, respectively, in 2015. Sepsis-2 severe sepsis and Sepsis-3 sepsis had similarincidence, similar mortality and showed significant risk-adjusted improvements in mortality over time.Sepsis-3 septic shock had a much higher Acute Physiology And Chronic Health Evaluation II (APACHE II)score, greater mortality and no risk-adjusted trends in mortality improvement compared with Sepsis-2septic shock. ICU admissions identified either as Sepsis-3 sepsis or septic shock and as Sepsis-2 severesepsis or septic shock had significantly greater risk-adjusted odds of death compared with non-sepsisadmissions (P<0.001). The predictive validity was greatest for Sepsis-3 septic shock. Conclusions In anICU database, compared with Sepsis-2, Sepsis-3 identifies a similar sepsis population with 92% overlapand much smaller septic shock population with improved predictive validity.", "metadata": {}}
+{"_id": "3788528", "title": "", "text": "Thymic expression of the golli-myelin basic protein gene in the SJL/J mouseThe T cell antigen-specificrepertoire is thought to be shaped by thymic expression of self molecules. Since a myelin basic protein(MBP)-like gene (golli-MBP) has been reported to be expressed by cells of the immune system, thepresent study was undertaken to determine whether the golli-MBP gene was expressed in the mousethymus and, if so, to characterize transcripts of this gene in this organ. Using exon-specific primers forMBP and golli-MBP, cDNA from thymus and other tissues was amplified, and the amplified productsanalyzed by Southern blotting with exon-specific oligonucleotide probes. The amplified products weresubcloned, and the inserts characterized by DNA sequencing. The thymic transcripts were found tocontain golli-MBP exons 1, 2, 3, 5A, 5B, 5C, 6, 7, 8, and 11.", "metadata": {}}
+{"_id": "3790895", "title": "", "text": "Urine microRNAs as biomarkers for bladder cancer: a diagnostic meta-analysisBACKGROUND Thediagnostic value of microRNA (miRNA) detection in patients with bladder cancer (BCa) is controversial.We performed a diagnostic meta-analysis to evaluate current evidence on the use of miRNA assays todiagnose BCa. METHODS We systematically searched PubMed, Embase, and Web of Science for studiespublished before March 31, 2015. The pooled sensitivity, specificity, positive and negative likelihoodratios, diagnostic odds ratio, and area under the curve (AUC) were calculated to evaluate the overall testperformance. Subgroup analyses were used to explore the between-study heterogeneity. Deeks' funnelplot asymmetry test was used to test publication bias. We applied the software of RevMan 5.2 and Stata11.0 to the meta-analysis. RESULTS A total of 23 studies from nine articles were included in themeta-analysis, with a total of 719 patients and 494 controls. The pooled sensitivity and specificity were0.75 (95% confidence interval [CI], 0.68-0.80) and 0.75 (95% CI, 0.70-0.80), respectively. The pooledpositive likelihood ratio was 3.03 (95% CI, 2.50-3.67); negative likelihood ratio was 0.33 (95% CI,0.27-0.42); and diagnostic odds ratio was 9.07 (95% CI, 6.35-12.95). The pooled AUC was 0.81 (95%CI, 0.78-0.85). Subgroup analyses indicated that the multiple miRNAs assays and urine supernatantassays showed high accuracies in diagnosing BCa. CONCLUSION The miRNA assays may serve aspotential noninvasive diagnostic tool for the detection of BCa. However, the clinical application of miRNAassays for BCa diagnosis still needs further validation by large prospective studies.", "metadata": {}}
+{"_id": "3801693", "title": "", "text": "Elevated Plasma Transforming Growth Factor &bgr;1 Levels Predict the Development of Hypertension inNormotensives: The 14-Year Follow-Up StudyBACKGROUND Transforming growth factor β1 (TGF-β1) is amultifunctional cytokine. There is growing evidence that TGF-β1 is involved in the pathogenesis ofhypertension and the development of target organ damage in hypertensives. Although several studieshave shown that TGF-β1 induced vascular hypertrophy and remodelling in various vascular diseases,there are no longitudinal data on hypertension in the epidemiological studies. The present study testedthe hypothesis whether elevated TGF-β1 levels can predict the development of hypertension. METHODSIn 2002-2004, 528 subjects received health examinations in Uku town, southwestern Japan. Weexamined blood pressure (BP), body mass index, and blood test. Data on fasting plasma TGF-β1 wereobtained from 528 individuals. Of these, 149 normotensives (BP <140/90 mm Hg withoutantihypertensive medications) at baseline were followed-up for 14 years. RESULTS Thereceiver-operating characteristic curve was used and the calculated cutoff value was 8.9 ng/ml. Of 149normotensives at baseline, 59 subjects developed hypertension. Plasma TGF-β1 levels were significantlyassociated with the development of hypertension after adjustment for confounding factors. To furtherexamine the association between them, we performed logistic regression analysis. We divided thebaseline plasma TGF-β1 levels into 2 groups using a cutoff value. The significant high odds ratio [3.582(95% confidence interval, 1.025-12.525)] for the development of hypertension was found in the highestgroup of TGF-β1 level vs. the lowest group after adjustment for confounders. CONCLUSIONS This is thefirst report demonstrating the causal relationship between them. Elevated plasma TGF-β1 levels predictedthe development of hypertension in normotensives in a population of community-dwelling Japanese.", "metadata": {}}
+{"_id": "3805841", "title": "", "text": "MYC Disrupts the Circadian Clock and Metabolism in Cancer Cells.The MYC oncogene encodes MYC, atranscription factor that binds the genome through sites termed E-boxes (5'-CACGTG-3'), which areidentical to the binding sites of the heterodimeric CLOCK-BMAL1 master circadian transcription factor.Hence, we hypothesized that ectopic MYC expression perturbs the clock by deregulating E-box-drivencomponents of the circadian network in cancer cells. We report here that deregulated expression of MYCor N-MYC disrupts the molecular clock in vitro by directly inducing REV-ERBα to dampen expression andoscillation of BMAL1, and this could be rescued by knockdown of REV-ERB. REV-ERBα expression predictspoor clinical outcome for N-MYC-driven human neuroblastomas that have diminished BMAL1 expression,and re-expression of ectopic BMAL1 in neuroblastoma cell lines suppresses their clonogenicity. Further,ectopic MYC profoundly alters oscillation of glucose metabolism and perturbs glutaminolysis. Our resultsdemonstrate an unsuspected link between oncogenic transformation and circadian and metabolicdysrhythmia, which we surmise to be advantageous for cancer.", "metadata": {}}
+{"_id": "3823862", "title": "", "text": "Integrated maps in quail (Coturnix japonica) confirm the high degree of synteny conservation withchicken (Gallus gallus) despite 35 million years of divergenceBackgroundBy comparing the quail genomewith that of chicken, chromosome rearrangements that have occurred in these two galliform species over35 million years of evolution can be detected. From a more practical point of view, the definition ofconserved syntenies helps to predict the position of genes in quail, based on information taken from thechicken sequence, thus enhancing the utility of this species in biological studies through a betterknowledge of its genome structure. A microsatellite and an Amplified Fragment Length Polymorphism(AFLP) genetic map were previously published for quail, as well as comparative cytogenetic data withchicken for macrochromosomes. Quail genomics will benefit from the extension and the integration ofthese maps. ResultsThe integrated linkage map presented here is based on segregation analysis of bothanonymous markers and functional gene loci in 1,050 quail from three independent F2 populations.Ninety-two loci are resolved into 14 autosomal linkage groups and a Z chromosome-specific linkagegroup, aligned with the quail AFLP map. The size of linkage groups ranges from 7.8 cM to 274.8 cM. Thetotal map distance covers 904.3 cM with an average spacing of 9.7 cM between loci. The coverage is notcomplete, as macrochromosome CJA08, the gonosome CJAW and 23 microchromosomes have no markerassigned yet. Significant sequence identities of quail markers with chicken enabled the alignment of thequail linkage groups on the chicken genome sequence assembly. This, together with interspecificFluorescence In Situ Hybridization (FISH), revealed very high similarities in marker order between thetwo species for the eight macrochromosomes and the 14 microchromosomes studied.ConclusionIntegrating the two microsatellite and the AFLP quail genetic maps greatly enhances thequality of the resulting information and will thus facilitate the identification of Quantitative Trait Loci(QTL). The alignment with the chicken chromosomes confirms the high conservation of gene order thatwas expected between the two species for macrochromosomes. By extending the comparative study tothe microchromosomes, we suggest that a wealth of information can be mined in chicken, to be used forgenome analyses in quail.", "metadata": {}}
+{"_id": "3825472", "title": "", "text": "Cadherin activity is required for activity-induced spine remodelingNeural activity induces the remodelingof pre- and postsynaptic membranes, which maintain their apposition through cell adhesion molecules.Among them, N-cadherin is redistributed, undergoes activity-dependent conformational changes, and isrequired for synaptic plasticity. Here, we show that depolarization induces the enlargement of the widthof spine head, and that cadherin activity is essential for this synaptic rearrangement. Dendritic spinesvisualized with green fluorescent protein in hippocampal neurons showed an expansion by the activationof AMPA receptor, so that the synaptic apposition zone may be expanded. N-cadherin-venus fusionprotein laterally dispersed along the expanding spine head. Overexpression of dominant-negative formsof N-cadherin resulted in the abrogation of the spine expansion. Inhibition of actin polymerization withcytochalasin D abolished the spine expansion. Together, our data suggest that cadherin-based adhesionmachinery coupled with the actin-cytoskeleton is critical for the remodeling of synaptic apposition zone.", "metadata": {}}
+{"_id": "3825750", "title": "", "text": "Aliskiren combined with losartan in type 2 diabetes and nephropathy.BACKGROUND Diabetic nephropathyis the leading cause of end-stage renal disease in developed countries. We evaluated the renoprotectiveeffects of dual blockade of the renin-angiotensin-aldosterone system by adding treatment with aliskiren,an oral direct renin inhibitor, to treatment with the maximal recommended dose of losartan (100 mgdaily) and optimal antihypertensive therapy in patients who had hypertension and type 2 diabetes withnephropathy. METHODS We enrolled 599 patients in this multinational, randomized, double-blind study.After a 3-month, open-label, run-in period during which patients received 100 mg of losartan daily,patients were randomly assigned to receive 6 months of treatment with aliskiren (150 mg daily for 3months, followed by an increase in dosage to 300 mg daily for another 3 months) or placebo, in additionto losartan. The primary outcome was a reduction in the ratio of albumin to creatinine, as measured in anearly-morning urine sample, at 6 months. RESULTS The baseline characteristics of the two groups weresimilar. Treatment with 300 mg of aliskiren daily, as compared with placebo, reduced the mean urinaryalbumin-to-creatinine ratio by 20% (95% confidence interval, 9 to 30; P<0.001), with a reduction of 50%or more in 24.7% of the patients who received aliskiren as compared with 12.5% of those who receivedplacebo (P<0.001). A small difference in blood pressure was seen between the treatment groups by theend of the study period (systolic, 2 mm Hg lower [P=0.07] and diastolic, 1 mm Hg lower [P=0.08] in thealiskiren group). The total numbers of adverse and serious adverse events were similar in the groups.CONCLUSIONS Aliskiren may have renoprotective effects that are independent of itsblood-pressure-lowering effect in patients with hypertension, type 2 diabetes, and nephropathy who arereceiving the recommended renoprotective treatment. (ClinicalTrials.gov number, NCT00097955[ClinicalTrials.gov].).", "metadata": {}}
+{"_id": "3828508", "title": "", "text": "Overweight in Celiac Disease: Prevalence, Clinical Characteristics, and Effect of a Gluten-FreeDietBACKGROUND:It is well established that a minority of celiac patients present with “classic” symptomsdue to malabsorption. However, few studies have focussed on the distribution of body mass index (BMI)in celiac populations and its relationship to clinical characteristics, or on its response to treatment.METHODS:We reviewed BMI measurements and other clinical and pathological characteristics from adatabase of 371 celiac patients diagnosed over a 10-yr period and seen by a single gastroenterologist. Toassess response to gluten exclusion, we compared BMI at diagnosis and after 2 yr treatment in patientswith serological support for dietary compliance. RESULTS:Mean BMI was 24.6 kg/m2 (range 16.3–43.5).Seventeen patients (5%) were underweight (BMI <18.5), 211 (57%) were normal, and 143 (39%) wereoverweight (BMI ≥25), including 48 (13% of all patients) in the obese range (BMI ≥30.0). There was asignificant association between low BMI and female gender, history of diarrhea, reduced hemoglobinconcentration, reduced bone mineral density (BMD), osteoporosis, and higher grades (subtotal/total) ofvillous atrophy. Of patients compliant with a gluten-free diet, 81% had gained weight after 2 yr, including82% of initially overweight patients. CONCLUSIONS:Few celiac patients are underweight at diagnosis anda large minority is overweight; these are less likely to present with classical features of diarrhea andreduced hemoglobin. Failed or delayed diagnosis of celiac disease may reflect lack of awareness of thislarge subgroup. The increase in weight of already overweight patients after dietary gluten exclusion is apotential cause of morbidity, and the gluten-free diet as conventionally prescribed needs to be modifiedaccordingly.", "metadata": {}}
+{"_id": "3829232", "title": "", "text": "Structural Studies of a Four-MBT Repeat Protein MBTD1BACKGROUND The Polycomb group (PcG) ofproteins is a family of important developmental regulators. The respective members function as largeprotein complexes involved in establishment and maintenance of transcriptional repression ofdevelopmental control genes. MBTD1, Malignant Brain Tumor domain-containing protein 1, is one suchPcG protein. MBTD1 contains four MBT repeats. METHODOLOGY/PRINCIPAL FINDINGS We havedetermined the crystal structure of MBTD1 (residues 130-566aa covering the 4 MBT repeats) at 2.5 Aresolution by X-ray crystallography. The crystal structure of MBTD1 reveals its similarity to anotherfour-MBT-repeat protein L3MBTL2, which binds lower methylated lysine histones. Fluorescencepolarization experiments confirmed that MBTD1 preferentially binds mono- and di-methyllysine histonepeptides, like L3MBTL1 and L3MBTL2. All known MBT-peptide complex structures characterized to date donot exhibit strong histone peptide sequence selectivity, and use a \"cavity insertion recognition mode\" torecognize the methylated lysine with the deeply buried methyl-lysine forming extensive interactions withthe protein while the peptide residues flanking methyl-lysine forming very few contacts [1]. Nevertheless,our mutagenesis data based on L3MBTL1 suggested that the histone peptides could not bind to MBTrepeats in any orientation. CONCLUSIONS The four MBT repeats in MBTD1 exhibits an asymmetricrhomboid architecture. Like other MBT repeat proteins characterized so far, MBTD1 binds mono- ordimethylated lysine histones through one of its four MBT repeats utilizing a semi-aromatic cage.ENHANCED VERSION This article can also be viewed as an enhanced version in which the text of thearticle is integrated with interactive 3D representations and animated transitions. Please note that a webplugin is required to access this enhanced functionality. Instructions for the installation and use of theweb plugin are available in Text S1.", "metadata": {}}
+{"_id": "3831884", "title": "", "text": "Glutamine supports pancreatic cancer growth through a Kras-regulated metabolic pathwayCancer cellshave metabolic dependencies that distinguish them from their normal counterparts. Among thesedependencies is an increased use of the amino acid glutamine to fuel anabolic processes. Indeed, thespectrum of glutamine-dependent tumours and the mechanisms whereby glutamine supports cancermetabolism remain areas of active investigation. Here we report the identification of a non-canonicalpathway of glutamine use in human pancreatic ductal adenocarcinoma (PDAC) cells that is required fortumour growth. Whereas most cells use glutamate dehydrogenase (GLUD1) to convert glutamine-derivedglutamate into α-ketoglutarate in the mitochondria to fuel the tricarboxylic acid cycle, PDAC relies on adistinct pathway in which glutamine-derived aspartate is transported into the cytoplasm where it can beconverted into oxaloacetate by aspartate transaminase (GOT1). Subsequently, this oxaloacetate isconverted into malate and then pyruvate, ostensibly increasing the NADPH/NADP(+) ratio which canpotentially maintain the cellular redox state. Importantly, PDAC cells are strongly dependent on thisseries of reactions, as glutamine deprivation or genetic inhibition of any enzyme in this pathway leads toan increase in reactive oxygen species and a reduction in reduced glutathione. Moreover, knockdown ofany component enzyme in this series of reactions also results in a pronounced suppression of PDACgrowth in vitro and in vivo. Furthermore, we establish that the reprogramming of glutamine metabolismis mediated by oncogenic KRAS, the signature genetic alteration in PDAC, through the transcriptionalupregulation and repression of key metabolic enzymes in this pathway. The essentiality of this pathway inPDAC and the fact that it is dispensable in normal cells may provide novel therapeutic approaches to treatthese refractory tumours.", "metadata": {}}
+{"_id": "3835423", "title": "", "text": "CD4+ T cell help guides formation of CD103+ lung-resident memory CD8+ T cells during influenza viralinfection.Tissue-resident memory T (Trm) cells provide enhanced protection against infection at mucosalsites. Here we found that CD4(+) T cells are important for the formation of functional lung-residentCD8(+) T cells after influenza virus infection. In the absence of CD4(+) T cells, CD8(+) T cells displayedreduced expression of CD103 (Itgae), were mislocalized away from airway epithelia, and demonstratedan impaired ability to recruit CD8(+) T cells to the lung airways upon heterosubtypic challenge. CD4(+) Tcell-derived interferon-γ was necessary for generating lung-resident CD103(+) CD8(+) Trm cells.Furthermore, expression of the transcription factor T-bet was increased in \"unhelped\" lung Trm cells, anda reduction in T-bet rescued CD103 expression in the absence of CD4(+) T cell help. Thus, CD4(+) Tcell-dependent signals are important to limit expression of T-bet and allow for the development ofCD103(+) CD8(+) Trm cells in the lung airways following respiratory infection.", "metadata": {}}
+{"_id": "3840043", "title": "", "text": "Inhibition of Apoptosis Overcomes Stage-Related Compatibility Barriers to Chimera Formation in MouseEmbryos.Cell types more advanced in development than embryonic stem cells, such as EpiSCs, fail tocontribute to chimeras when injected into pre-implantation-stage blastocysts, apparently because theinjected cells undergo apoptosis. Here we show that transient promotion of cell survival throughexpression of the anti-apoptotic gene BCL2 enables EpiSCs and Sox17+ endoderm progenitors tointegrate into blastocysts and contribute to chimeric embryos. Upon injection into blastocyst,BCL2-expressing EpiSCs contributed to all bodily tissues in chimeric animals while Sox17+ endodermprogenitors specifically contributed in a region-specific fashion to endodermal tissues. In addition, BCL2expression enabled rat EpiSCs to contribute to mouse embryonic chimeras, thereby forming interspecieschimeras that could survive to adulthood. Our system therefore provides a method to overcome cellularcompatibility issues that typically restrict chimera formation. Application of this type of approach couldbroaden the use of embryonic chimeras, including region-specific chimeras, for basic developmentalbiology research and regenerative medicine.", "metadata": {}}
+{"_id": "3845894", "title": "", "text": "Computational and Statistical Analyses of Amino Acid Usage and Physico-Chemical Properties of theTwelve Late Embryogenesis Abundant Protein ClassesLate Embryogenesis Abundant Proteins (LEAPs) areubiquitous proteins expected to play major roles in desiccation tolerance. Little is known about theirstructure - function relationships because of the scarcity of 3-D structures for LEAPs. The previousbuilding of LEAPdb, a database dedicated to LEAPs from plants and other organisms, led to theclassification of 710 LEAPs into 12 non-overlapping classes with distinct properties. Using this resource,numerous physico-chemical properties of LEAPs and amino acid usage by LEAPs have been computed andstatistically analyzed, revealing distinctive features for each class. This unprecedented analysis allowed arigorous characterization of the 12 LEAP classes, which differed also in multiple structural andphysico-chemical features. Although most LEAPs can be predicted as intrinsically disordered proteins, theanalysis indicates that LEAP class 7 (PF03168) and probably LEAP class 11 (PF04927) are natively foldedproteins. This study thus provides a detailed description of the structural properties of this protein familyopening the path toward further LEAP structure - function analysis. Finally, since each LEAP class can beclearly characterized by a unique set of physico-chemical properties, this will allow development ofsoftware to predict proteins as LEAPs.", "metadata": {}}
+{"_id": "3847200", "title": "", "text": "Direct Reprogramming of Hepatic Myofibroblasts into Hepatocytes In Vivo Attenuates Liver Fibrosis.Directinduction of induced hepatocytes (iHeps) from fibroblasts holds potential as a strategy for regenerativemedicine but until now has only been shown in culture settings. Here, we describe in vivo iHep formationusing transcription factor induction and genetic fate tracing in mouse models of chronic liver disease. Weshow that ectopic expression of the transcription factors FOXA3, GATA4, HNF1A, and HNF4A from apolycistronic lentiviral vector converts mouse myofibroblasts into cells with a hepatocyte phenotype. Invivo expression of the same set of transcription factors from a p75 neurotrophin receptor peptide(p75NTRp)-tagged adenovirus enabled the generation of hepatocyte-like cells from myofibroblasts infibrotic mouse livers and reduced liver fibrosis. We have therefore been able to convert pro-fibrogenicmyofibroblasts in the liver into hepatocyte-like cells with positive functional benefits. This direct in vivoreprogramming approach may open new avenues for the treatment of chronic liver disease.", "metadata": {}}
+{"_id": "3848469", "title": "", "text": "Epithelial to Mesenchymal Transition by TGFβ-1 Induction Increases Stemness Characteristics in PrimaryNon Small Cell Lung Cancer Cell LineBACKGROUND Cancer Stem Cells (CSCs) hypothesis asserts thatonly a small subset of cells within a tumour is capable of both tumour initiation and sustainment. TheEpithelial-Mesenchymal Transition (EMT) is an embryonic developmental program that is often activatedduring cancer invasion and metastasis. The aim of this study is to shed light on the relationship betweenEMT and CSCs by using LC31 lung cancer primary cell line. MATERIALS AND METHODS A549 and LC31cell lines were treated with 2 ng/ml TGFβ-1 for 30 days, and 80 days, respectively. To evaluate EMT,morphological changes were assessed by light microscopy, immunofluorescence and cytometry forfollowing markers: cytokeratins, e-cadherin, CD326 (epithelial markers) and CD90, and vimentin(mesenchymal markers). Moreover, RT-PCR for Slug, Twist and β-catenin genes were performed. OnTGFβ-1 treated and untreated LC31 cell lines, we performed stemness tests such as pneumospheresgrowth and stem markers expression such as Oct4, Nanog, Sox2, c-kit and CD133. Western Blot forCD133 and tumorigenicity assays using NOD/SCID mice were performed. RESULTS TGFβ-1 treated LC31cell line lost its epithelial morphology assuming a fibroblast-like appearance. The same results wereobtained for the A549 cell line (as control). Immunofluorescence and cytometry showed up-regulation ofvimentin and CD90 and down-regulation of cytocheratin, e-cadherin and CD326 in TGFβ-1 treated LC31and A549 cell lines. Slug, Twist and β-catenin m-RNA transcripts were up-regulated in TGFβ-1 treatedLC31 cell line confirming EMT. This cell line showed also over-expression of Oct4, Nanog, Sox2 andCD133, all genes of stemness. In addition, in TGFβ-1 treated LC31 cell line, an increasedpneumosphere-forming capacity and tumours-forming ability in NOD/SCID mice were detectable.CONCLUSIONS The induction of EMT by TGFβ-1 exposure, in primary lung cancer cell line results in theacquisition of mesenchymal profile and in the expression of stem cell markers.", "metadata": {}}
+{"_id": "3849194", "title": "", "text": "Dnmt3a and Dnmt3b Associate with Enhancers to Regulate Human Epidermal Stem Cell Homeostasis.Thegenome-wide localization and function of endogenous Dnmt3a and Dnmt3b in adult stem cells areunknown. Here, we show that in human epidermal stem cells, the two proteins bind in a histoneH3K36me3-dependent manner to the most active enhancers and are required to produce their associatedenhancer RNAs. Both proteins prefer super-enhancers associated to genes that either define theectodermal lineage or establish the stem cell and differentiated states. However, Dnmt3a and Dnmt3bdiffer in their mechanisms of enhancer regulation: Dnmt3a associates with p63 to maintain high levels ofDNA hydroxymethylation at the center of enhancers in a Tet2-dependent manner, whereas Dnmt3bpromotes DNA methylation along the body of the enhancer. Depletion of either protein inactivates theirtarget enhancers and profoundly affects epidermal stem cell function. Altogether, we reveal novelfunctions for Dnmt3a and Dnmt3b at enhancers that could contribute to their roles in disease andtumorigenesis.", "metadata": {}}
+{"_id": "3851329", "title": "", "text": "CDK inhibitors in cancer therapy: what is next?The pursuit for drugs that inhibit cyclin-dependent kinases(CDKs) has been an intense area of research for more than 15 years. The first-generation inhibitors,Flavopiridol and CY-202, are in late-stage clinical trials, but so far have demonstrated only modestactivity. Several second-generation inhibitors are now in clinical trials. Future approaches to determineclinical benefit need to incorporate both the lessons learned from these early compounds and informationrecently obtained from the genetic analysis of CDKs in preclinical models. Here we discuss key conceptsthat should be considered when validating the clinical utility of CDK inhibitors in cancer therapy.", "metadata": {}}
+{"_id": "3858268", "title": "", "text": "Lipid Desaturation Is a Metabolic Marker and Therapeutic Target of Ovarian Cancer Stem Cells.Lack ofsensitive single-cell analysis tools has limited the characterization of metabolic activity in cancer stemcells. By hyperspectral-stimulated Raman scattering imaging of single living cells and mass spectrometryanalysis of extracted lipids, we report here significantly increased levels of unsaturated lipids in ovariancancer stem cells (CSCs) as compared to non-CSCs. Higher lipid unsaturation levels were also detected inCSC-enriched spheroids compared to monolayer cultures of ovarian cancer cell lines or primary cells.Inhibition of lipid desaturases effectively eliminated CSCs, suppressed sphere formation in vitro, andblocked tumor initiation capacity in vivo. Mechanistically, we demonstrate that nuclear factor κB (NF-κB)directly regulates the expression levels of lipid desaturases, and inhibition of desaturases blocks NF-κBsignaling. Collectively, our findings reveal that increased lipid unsaturation is a metabolic marker forovarian CSCs and a target for CSC-specific therapy.", "metadata": {}}
+{"_id": "3863543", "title": "", "text": "Mesenchymal Inflammation Drives Genotoxic Stress in Hematopoietic Stem Cells and Predicts DiseaseEvolution in Human Pre-leukemia.Mesenchymal niche cells may drive tissue failure and malignanttransformation in the hematopoietic system, but the underlying molecular mechanisms and relevance tohuman disease remain poorly defined. Here, we show that perturbation of mesenchymal cells in a mousemodel of the pre-leukemic disorder Shwachman-Diamond syndrome (SDS) induces mitochondrialdysfunction, oxidative stress, and activation of DNA damage responses in hematopoietic stem andprogenitor cells. Massive parallel RNA sequencing of highly purified mesenchymal cells in the SDS mousemodel and a range of human pre-leukemic syndromes identified p53-S100A8/9-TLR inflammatorysignaling as a common driving mechanism of genotoxic stress. Transcriptional activation of this signalingaxis in the mesenchymal niche predicted leukemic evolution and progression-free survival inmyelodysplastic syndrome (MDS), the principal leukemia predisposition syndrome. Collectively, ourfindings identify mesenchymal niche-induced genotoxic stress in heterotypic stem and progenitor cellsthrough inflammatory signaling as a targetable determinant of disease outcome in human pre-leukemia.", "metadata": {}}
+{"_id": "3866315", "title": "", "text": "Novel Functional Sets of Lipid-Derived Mediators with Antiinflammatory Actions Generated from Omega-3Fatty Acids via Cyclooxygenase 2–Nonsteroidal Antiinflammatory Drugs and TranscellularProcessingAspirin therapy inhibits prostaglandin biosynthesis without directly acting on lipoxygenases,yet via acetylation of cyclooxygenase 2 (COX-2) it leads to bioactive lipoxins (LXs) epimeric at carbon 15(15-epi-LX, also termed aspirin-triggered LX [ATL]). Here, we report that inflammatory exudates frommice treated with ω-3 polyunsaturated fatty acid and aspirin (ASA) generate a novel array of bioactivelipid signals. Human endothelial cells with upregulated COX-2 treated with ASA converted C20:5 ω-3 to18R-hydroxyeicosapentaenoic acid (HEPE) and 15R-HEPE. Each was used by polymorphonuclearleukocytes to generate separate classes of novel trihydroxy-containing mediators, including 5-series15R-LX5 and 5,12,18R-triHEPE. These new compounds proved to be potent inhibitors of humanpolymorphonuclear leukocyte transendothelial migration and infiltration in vivo (ATL analogue >5,12,18R-triHEPE > 18R-HEPE). Acetaminophen and indomethacin also permitted 18R-HEPE and15R-HEPE generation with recombinant COX-2 as well as ω-5 and ω-9 oxygenations of other fatty acidsthat act on hematologic cells. These findings establish new transcellular routes for producing arrays ofbioactive lipid mediators via COX-2–nonsteroidal antiinflammatory drug–dependent oxygenations andcell–cell interactions that impact microinflammation. The generation of these and related compoundsprovides a novel mechanism(s) for the therapeutic benefits of ω-3 dietary supplementation, which maybe important in inflammation, neoplasia, and vascular diseases.", "metadata": {}}
+{"_id": "3868322", "title": "", "text": "Cholesteryl Ester Transfer Protein (CETP) Polymorphisms Affect mRNA Splicing, HDL Levels, andSex-Dependent Cardiovascular RiskPolymorphisms in and around the Cholesteryl Ester Transfer Protein(CETP) gene have been associated with HDL levels, risk for coronary artery disease (CAD), and responseto therapy. The mechanism of action of these polymorphisms has yet to be defined. We used mRNA allelicexpression and splice isoform measurements in human liver tissues to identify the genetic variantsaffecting CETP levels. Allelic CETP mRNA expression ratios in 56 human livers were strongly associatedwith several variants 2.5-7 kb upstream of the transcription start site (e.g., rs247616 p = 6.4 × 10(-5),allele frequency 33%). In addition, a common alternatively spliced CETP isoform lacking exon 9 (Δ9), hasbeen shown to prevent CETP secretion in a dominant-negative manner. The Δ 9 expression ranged from10 to 48% of total CETP mRNA in 94 livers. Increased formation of this isoform was exclusivelyassociated with an exon 9 polymorphism rs5883-C>T (p = 6.8 × 10(-10)) and intron 8 polymorphismrs9930761-T>C (5.6 × 10(-8)) (in high linkage disequilibrium with allele frequencies 6-7%). rs9930761changes a key splicing branch point nucleotide in intron 8, while rs5883 alters an exonic splicing enhancersequence in exon 9.The effect of these polymorphisms was evaluated in two clinical studies. In theWhitehall II study of 4745 subjects, both rs247616 and rs5883T/rs9930761C were independentlyassociated with increased HDL-C levels in males with similar effect size (rs247616 p = 9.6 × 10(-28) andrs5883 p = 8.6 × 10(-10), adjusted for rs247616). In an independent multiethnic US cohort ofhypertensive subjects with CAD (INVEST-GENE), rs5883T/rs9930761C alone were significantly associatedwith increased incidence of MI, stroke, and all-cause mortality in males (rs5883: OR 2.36 (CI 1.29-4.30),p = 0.005, n = 866). These variants did not reach significance in females in either study. Similar toearlier results linking low CETP activity with poor outcomes in males, our results suggest genetic,sex-dependent CETP splicing effects on cardiovascular risk by a mechanism independent of circulatingHDL-C levels.", "metadata": {}}
+{"_id": "3870062", "title": "", "text": "6-Sulphated Chondroitins Have a Positive Influence on Axonal RegenerationChondroitin sulphateproteoglycans (CSPGs) upregulated in the glial scar inhibit axon regeneration via their sulphatedglycosaminoglycans (GAGs). Chondroitin 6-sulphotransferase-1 (C6ST-1) is upregulated after injuryleading to an increase in 6-sulphated GAG. In this study, we ask if this increase in 6-sulphated GAG isresponsible for the increased inhibition within the glial scar, or whether it represents a partial reversion tothe permissive embryonic state dominated by 6-sulphated glycosaminoglycans (GAGs). Using C6ST-1knockout mice (KO), we studied post-injury changes in chondroitin sulphotransferase (CSST) expressionand the effect of chondroitin 6-sulphates on both central and peripheral axon regeneration. After CNSinjury, wild-type animals (WT) showed an increase in mRNA for C6ST-1, C6ST-2 and C4ST-1, but KO didnot upregulate any CSSTs. After PNS injury, while WT upregulated C6ST-1, KO showed an upregulation ofC6ST-2. We examined regeneration of nigrostriatal axons, which demonstrate mild spontaneous axonregeneration in the WT. KO showed many fewer regenerating axons and more axonal retraction than WT.However, in the PNS, repair of the median and ulnar nerves led to similar and normal levels of axonregeneration in both WT and KO. Functional tests on plasticity after the repair also showed no evidence ofenhanced plasticity in the KO. Our results suggest that the upregulation of 6-sulphated GAG after injurymakes the extracellular matrix more permissive for axon regeneration, and that the balance of differentCSs in the microenvironment around the lesion site is an important factor in determining the outcome ofnervous system injury.", "metadata": {}}
+{"_id": "3874000", "title": "", "text": "Tissue Mechanics Orchestrate Wnt-Dependent Human Embryonic Stem Cell Differentiation.Regenerativemedicine is predicated on understanding the mechanisms regulating development and applying theseconditions to direct stem cell fate. Embryogenesis is guided by cell-cell and cell-matrix interactions, but itis unclear how these physical cues influence stem cells in culture. We used human embryonic stem cells(hESCs) to examine whether mechanical features of the extracellular microenvironment coulddifferentially modulate mesoderm specification. We found that, on a hydrogel-based compliant matrix,hESCs accumulate β-catenin at cell-cell adhesions and show enhanced Wnt-dependent mesodermdifferentiation. Mechanistically, Src-driven ubiquitination of E-cadherin by Cbl-like ubiquitin ligasereleases P120-catenin to facilitate transcriptional activity of β-catenin, which initiates and reinforcesmesoderm differentiation. By contrast, on a stiff hydrogel matrix, hESCs show elevatedintegrin-dependent GSK3 and Src activity that promotes β-catenin degradation and inhibitsdifferentiation. Thus, we found that mechanical features of the microenvironmental matrix influencetissue-specific differentiation of hESCs by altering the cellular response to morphogens.", "metadata": {}}
+{"_id": "3878434", "title": "", "text": "Predictive performance of the quick Sequential Organ Failure Assessment score as a screening tool forsepsis, mortality, and intensive care unit admission in patients with febrile neutropeniaIn Sepsis-3, thequick Sequential Organ Failure Assessment (qSOFA) score was developed as criteria to use forrecognizing patients who may have poor outcomes. This study was performed to evaluate the predictiveperformance of the qSOFA score as a screening tool for sepsis, mortality, and intensive care unit (ICU)admission in patients with febrile neutropenia (FN). We also tried to compare its performance with that ofthe systemic inflammatory response syndrome (SIRS) criteria and Multinational Association of SupportiveCare in Cancer (MASCC) score for FN. We used a prospectively collected adult FN data registry. TheqSOFA and SIRS scores were calculated retrospectively using the preexisting data. The primary outcomewas the development of sepsis. The secondary outcomes were ICU admission and 28-day mortality. Ofthe 615 patients, 100 developed sepsis, 20 died, and 38 were admitted to ICUs. In multivariate analysis,qSOFA was an independent factor predicting sepsis and ICU admission. However, compared to theMASCC score, the area under the receiver operating curve of qSOFA was lower. qSOFA showed a lowsensitivity (0.14, 0.2, and 0.23) but high specificity (0.98, 0.97, and 0.97) in predicting sepsis, 28-daymortality, and ICU admission. Performance of the qSOFA score was inferior to that of the MASCC score.The preexisting risk stratification tool is more useful for predicting outcomes in patients with FN.", "metadata": {}}
+{"_id": "3882374", "title": "", "text": "LIN28 Regulates Stem Cell Metabolism and Conversion to Primed Pluripotency.The RNA-binding proteinsLIN28A and LIN28B play critical roles in embryonic development, tumorigenesis, and pluripotency, buttheir exact functions are poorly understood. Here, we show that, like LIN28A, LIN28B can functioneffectively with NANOG, OCT4, and SOX2 in reprogramming to pluripotency and that reactivation of bothendogenous LIN28A and LIN28B loci are required for maximal reprogramming efficiency. In humanfibroblasts, LIN28B is activated early during reprogramming, while LIN28A is activated later during thetransition to bona fide induced pluripotent stem cells (iPSCs). In murine cells, LIN28A and LIN28Bfacilitate conversion from naive to primed pluripotency. Proteomic and metabolomic analysis highlightedroles for LIN28 in maintaining the low mitochondrial function associated with primed pluripotency and inregulating one-carbon metabolism, nucleotide metabolism, and histone methylation. LIN28 binds tomRNAs of proteins important for oxidative phosphorylation and modulates protein abundance. Thus,LIN28A and LIN28B play cooperative roles in regulating reprogramming, naive/primed pluripotency, andstem cell metabolism.", "metadata": {}}
+{"_id": "3883485", "title": "", "text": "Genetic Drift Can Compromise Mitochondrial Replacement by Nuclear Transfer in HumanOocytes.Replacement of mitochondria through nuclear transfer between oocytes of two different womenhas emerged recently as a strategy for preventing inheritance of mtDNA diseases. Although experimentsin human oocytes have shown effective replacement, the consequences of small amounts of mtDNAcarryover have not been studied sufficiently. Using human mitochondrial replacement stem cell lines, weshow that, even though the low levels of heteroplasmy introduced into human oocytes by mitochondrialcarryover during nuclear transfer often vanish, they can sometimes instead result in mtDNA genotypicdrift and reversion to the original genotype. Comparison of cells with identical oocyte-derived nuclearDNA but different mtDNA shows that either mtDNA genotype is compatible with the nucleus and that driftis independent of mitochondrial function. Thus, although functional replacement of the mitochondrialgenome is possible, even low levels of heteroplasmy can affect the stability of the mtDNA genotype andcompromise the efficacy of mitochondrial replacement.", "metadata": {}}
+{"_id": "3893473", "title": "", "text": "TAL effectors are remote controls for gene activation.TAL (transcription activator-like) effectors constitutea novel class of DNA-binding proteins with predictable specificity. They are employed by Gram-negativeplant-pathogenic bacteria of the genus Xanthomonas which translocate a cocktail of different effectorproteins via a type III secretion system (T3SS) into plant cells where they serve as virulencedeterminants. Inside the plant cell, TALs localize to the nucleus, bind to target promoters, and induceexpression of plant genes. DNA-binding specificity of TALs is determined by a central domain of tandemrepeats. Each repeat confers recognition of one base pair (bp) in the DNA. Rearrangement of repeatmodules allows design of proteins with desired DNA-binding specificities. Here, we summarize how TALspecificity is encoded, first structural data and first data on site-specific TAL nucleases.", "metadata": {}}
+{"_id": "3896759", "title": "", "text": "Vascular heterogeneity and specialization in development and diseaseBlood and lymphatic vesselspervade almost all body tissues and have numerous essential roles in physiology and disease. The innerlining of these networks is formed by a single layer of endothelial cells, which is specialized according tothe needs of the tissue that it supplies. Whereas the general mechanisms of blood and lymphatic vesseldevelopment are being defined with increasing molecular precision, studies of the processes ofendothelial specialization remain mostly descriptive. Recent insights from genetic animal modelsilluminate how endothelial cells interact with each other and with their tissue environment, providingparadigms for vessel type- and organ-specific endothelial differentiation. Delineating these governingprinciples will be crucial for understanding how tissues develop and maintain, and how their functionbecomes abnormal in disease.", "metadata": {}}
+{"_id": "3898784", "title": "", "text": "Association of Intracerebral Hemorrhage Among Patients Taking Non–Vitamin K Antagonist vs Vitamin KAntagonist Oral Anticoagulants With In-Hospital MortalityImportance Although non–vitamin K antagonistoral anticoagulants (NOACs) are increasingly used to prevent thromboembolic disease, there are limiteddata on NOAC-related intracerebral hemorrhage (ICH). Objective To assess the association betweenpreceding oral anticoagulant use (warfarin, NOACs, and no oral anticoagulants [OACs]) and in-hospitalmortality among patients with ICH. Design, Setting, and Participants Retrospective cohort study of 141311 patients with ICH admitted from October 2013 to December 2016 to 1662 Get With TheGuidelines–Stroke hospitals. Exposures Anticoagulation therapy before ICH, defined as any use of OACswithin 7 days prior to hospital arrival. Main Outcomes and Measures In-hospital mortality. Results Among141 311 patients with ICH (mean [SD] age, 68.3 [15.3] years; 48.1% women), 15 036 (10.6%) weretaking warfarin and 4918 (3.5%) were taking NOACs preceding ICH, and 39 585 (28.0%) and 5783(4.1%) were taking concomitant single and dual antiplatelet agents, respectively. Patients with prior useof warfarin or NOACs were older and had higher prevalence of atrial fibrillation and prior stroke. AcuteICH stroke severity (measured by the National Institutes of Health Stroke Scale) was not significantlydifferent across the 3 groups (median, 9 [interquartile range, 2-21] for warfarin, 8 [2-20] for NOACs, and8 [2-19] for no OACs). The unadjusted in-hospital mortality rates were 32.6% for warfarin, 26.5% forNOACs, and 22.5% for no OACs. Compared with patients without prior use of OACs, the risk of in-hospitalmortality was higher among patients with prior use of warfarin (adjusted risk difference [ARD], 9.0%[97.5% CI, 7.9% to 10.1%]; adjusted odds ratio [AOR], 1.62 [97.5% CI, 1.53 to 1.71]) and higheramong patients with prior use of NOACs (ARD, 3.3% [97.5% CI, 1.7% to 4.8%]; AOR, 1.21 [97.5% CI,1.11-1.32]). Compared with patients with prior use of warfarin, patients with prior use of NOACs had alower risk of in-hospital mortality (ARD, −5.7% [97.5% CI, −7.3% to −4.2%]; AOR, 0.75 [97.5% CI,0.69 to 0.81]). The difference in mortality between NOAC-treated patients and warfarin-treated patientswas numerically greater among patients with prior use of dual antiplatelet agents (32.7% vs 47.1%;ARD, −15.0% [95.5% CI, −26.3% to −3.8%]; AOR, 0.50 [97.5% CI, 0.29 to 0.86]) than among thosetaking these agents without prior antiplatelet therapy (26.4% vs 31.7%; ARD, −5.0% [97.5% CI, −6.8%to −3.2%]; AOR, 0.77 [97.5% CI, 0.70 to 0.85]), although the interaction P value (.07) was notstatistically significant. Conclusions and Relevance Among patients with ICH, prior use of NOACs orwarfarin was associated with higher in-hospital mortality compared with no OACs. Prior use of NOACs,compared with prior use of warfarin, was associated with lower risk of in-hospital mortality.", "metadata": {}}
+{"_id": "3899896", "title": "", "text": "Elevated red blood cell distribution width contributes to poor prognosis in patients undergoing resectionfor nonmetastatic rectal cancerSeveral studies have reported that elevated red blood cell distributionwidth (RDW) was associated with the poor prognosis of different kinds of cancers. The aim of this studywas to investigate the prognostic role of RDW in patients undergoing resection for nonmetastatic rectalcancer. We retrospectively reviewed a database of 625 consecutive patients who underwent curativeresection for nonmetastatic rectal cancer at our institution from January 2009 to December 2014. Thecutoff value of RDW was calculated by receiver-operating characteristic curve. The results demonstratedthat patients in high RDW-cv group had a lower overall survival (OS) (P = .018) and disease-free survival(P = .004). We also observed that patients in high RDW-sd group were associated with significantly lowerOS (P = .033), whereas the disease-free survival (DFS) was not significantly different (P = .179).Inmultivariate analysis, we found elevated RDW-cv was associated poor DFS (hazard ratio [HR] = 1.56, P =.010) and RDW-sd can predict a worse OS (HR = 1.70, P = .009).We confirmed that elevated RDW canbe an independently prognostic factor in patients undergoing resection for nonmetastatic rectal cancer.So more intervention or surveillance might be paid to the patients with nonmetastatic rectal cancer andelevated RDW values in the future.", "metadata": {}}
+{"_id": "3903084", "title": "", "text": "Health workers cohort study: methods and study design.Objective: To examine different health outcomesthat are associated with specific lifestyle and genetic factors. Materials and methods: From March 2004 toApril 2006, a sample of employees from three different health and academic institutions, as well as theirfamily members, were enrolled in the study after providing informed consent. At baseline and follow-up(2010-2013), participants completed a self-administered questionnaire, a physical examination, andprovided blood samples. Results: A total of 10 729 participants aged 6 to 94 years were recruited atbaseline. Of these, 70% were females, and 50% were from the Mexican Social Security Institute. Nearly42% of the adults in the sample were overweight, while 20% were obese. Conclusion: Our study canoffer new insights into disease mechanisms and prevention through the analysis of risk factor informationin a large sample of Mexicans.", "metadata": {}}
+{"_id": "3912660", "title": "", "text": "Aberrant pro-atrial natriuretic peptide/corin/natriuretic peptide receptor signaling is present in maternalvascular endothelium in preeclampsia.OBJECTIVE Corin is a serine protease that converts pro-atrialnatriuretic peptide (pro-ANP) to atrial natriuretic peptide (ANP), a cardiac hormone that regulatessalt-water balance and blood pressure. ANP is degraded by natriuretic peptide receptor (NPR). This studywas to determine if aberrant pro-ANP/corin/NPR signaling is present in maternal vascular system inpreeclampsia. STUDY DESIGN Maternal venous blood was obtained from 197 pregnant women (84normotensive, 16 complicated with chronic hypertension (CHT), 11 mild and 86 severe preeclampsia).Plasma corin and pro-ANP concentrations were measured by enzyme-linked immunosorbent assay.Maternal subcutaneous fat tissue was obtained from 12 pregnant women with cesarean section delivery(6 normotensive and 6 preeclampsia). Vascular ANP and its receptors NPR-A, NPR-B, and NPR-Cexpression were examined by immunostaining of paraffin embedded subcutaneous fat tissue sections.RESULTS Corin concentrations were significantly higher in mild (2.78 ± 0.67 ng/ml, p < .05) and severe(2.53 ± 0.18 ng/ml, p < .01) preeclampsia than in normotensive (1.58 ± 0.08 ng/ml) and CHT (1.55 ±0.20 ng/ml) groups. Pro-ANP concentrations were significantly higher in CHT (1.59 ± 0.53 ng/ml, p <.05) and severe preeclampsia (1.42 ± 0.24 ng/ml, p < .01) than in normotensive (0.48 ± 0.06 ng/ml)and mild preeclampsia (0.52 ± 0.09 ng/ml) groups. ANP and NPR-B expression was undetectable inmaternal vessels from normotensive and preeclamptic pregnancies, but reduced NPR-A expression andincreased NPR-C expression was found in maternal vessel endothelium in preeclampsia. CONCLUSIONSANP is a vasodilator and NPR-C is a clearance receptor for ANP. The finding of upregulation of NPR-Cexpression suggests that circulating ANP clearance or degradation is increased in preeclampsia. Theseresults also suggest that pro-ANP/corin/NPR signaling is dominant in the vascular system inpreeclampsia.", "metadata": {}}
+{"_id": "3929361", "title": "", "text": "Optimising Strategies for Plasmodium falciparum Malaria Elimination in Cambodia: Primaquine, MassDrug Administration and Artemisinin ResistanceBACKGROUND Malaria elimination requires a variety ofapproaches individually optimized for different transmission settings. A recent field study in an area oflow seasonal transmission in South West Cambodia demonstrated dramatic reductions in malaria parasiteprevalence following both mass drug administration (MDA) and high treatment coverage of symptomaticpatients with artemisinin-piperaquine plus primaquine. This study employed multiple combined strategiesand it was unclear what contribution each made to the reductions in malaria. METHOD AND FINDINGS Amathematical model fitted to the trial results was used to assess the effects of the various components ofthese interventions, design optimal elimination strategies, and explore their interactions with artemisininresistance, which has recently been discovered in Western Cambodia. The modelling indicated that mostof the initial reduction of P. falciparum malaria resulted from MDA with artemisinin-piperaquine. Thesubsequent continued decline and near elimination resulted mainly from high coverage withartemisinin-piperaquine treatment. Both these strategies were more effective with the addition ofprimaquine. MDA with artemisinin combination therapy (ACT) increased the proportion of artemisininresistant infections, although much less than treatment of symptomatic cases with ACT, and this increasewas slowed by adding primaquine. Artemisinin resistance reduced the effectiveness of interventions usingACT when the prevalence of resistance was very high. The main results were robust to assumptions aboutprimaquine action, and immunity. CONCLUSIONS The key messages of these modelling results for policymakers were: high coverage with ACT treatment can produce a long-term reduction in malaria whereasthe impact of MDA is generally only short-term; primaquine enhances the effect of ACT in eliminatingmalaria and reduces the increase in proportion of artemisinin resistant infections; parasite prevalence is abetter surveillance measure for elimination programmes than numbers of symptomatic cases;combinations of interventions are most effective and sustained efforts are crucial for successfulelimination.", "metadata": {}}
+{"_id": "3930020", "title": "", "text": "Role of the Parasite-Derived Prostaglandin D2 in the Inhibition of Epidermal Langerhans Cell Migrationduring Schistosomiasis InfectionEpidermal Langerhans cells (LCs) play a key role in immune defensemechanisms and in numerous immunological disorders. In this report, we show that percutaneousinfection of C57BL/6 mice with the helminth parasite Schistosoma mansoni leads to the activation of LCsbut, surprisingly, to their retention in the epidermis. Moreover, using an experimental model of LCmigration induced by tumor necrosis factor (TNF)-α, we show that parasites transiently impair thedeparture of LCs from the epidermis and their subsequent accumulation as dendritic cells in the draininglymph nodes. The inhibitory effect is mediated by soluble lipophilic factors released by the parasites andnot by host-derived antiinflammatory cytokines, such as interleukin-10. We find that prostaglandin(PG)D2, but not the other major eicosanoids produced by the parasites, specifically impedes theTNF-α–triggered migration of LCs through the adenylate cyclase–coupled PGD2 receptor (DP receptor).Moreover, the potent DP receptor antagonist BW A868C restores LC migration in infected mice. Finally, ina model of contact allergen-induced LC migration, we show that activation of the DP receptor not onlyinhibits LC emigration but also dramatically reduces the contact hypersensitivity responses afterchallenge. Taken together, we propose that the inhibition of LC migration could represent an additionalstratagem for the schistosomes to escape the host immune system and that PGD2 may play a key role inthe control of cutaneous immune responses.", "metadata": {}}
+{"_id": "3935126", "title": "", "text": "Axicabtagene Ciloleucel CAR T\u0000Cell Therapy in Refractory Large B\u0000Cell LymphomaBackground In aphase 1 trial, axicabtagene ciloleucel (axi\u0000cel), an autologous anti\u0000CD19 chimeric antigen receptor(CAR) T\u0000cell therapy, showed efficacy in patients with refractory large B\u0000cell lymphoma after the failureof conventional therapy. Methods In this multicenter, phase 2 trial, we enrolled 111 patients with diffuselarge B\u0000cell lymphoma, primary mediastinal B\u0000cell lymphoma, or transformed follicular lymphoma whohad refractory disease despite undergoing recommended prior therapy. Patients received a target dose of2×106 anti\u0000CD19 CAR T cells per kilogram of body weight after receiving a conditioning regimen oflow\u0000dose cyclophosphamide and fludarabine. The primary end point was the rate of objective response(calculated as the combined rates of complete response and partial response). Secondary end pointsincluded overall survival, safety, and biomarker assessments. Results Among the 111 patients who wereenrolled, axi\u0000cel was successfully manufactured for 110 (99%) and administered to 101 (91%). Theobjective response rate was 82%, and the complete response rate was 54%.With a median follow\u0000up of15.4 months, 42% of the patients continued to have a response, with 40% continuing to have a completeresponse. The overall rate of survival at 18 months was 52%. The most common adverse events of grade3 or higher during treatment were neutropenia (in 78% of the patients), anemia (in 43%), andthrombocytopenia (in 38%). Grade 3 or higher cytokine release syndrome and neurologic eventsoccurred in 13% and 28% of the patients, respectively. Three of the patients died during treatment.Higher CAR T\u0000cell levels in blood were associated with response. Conclusions In this multicenter study,patients with refractory large B\u0000cell lymphoma who received CAR T\u0000cell therapy with axi\u0000cel had highlevels of durable response, with a safety profile that included myelosuppression, the cytokine releasesyndrome, and neurologic events. (Funded by Kite Pharma and the Leukemia and Lymphoma SocietyTherapy Acceleration Program; ZUMA\u00001 ClinicalTrials.gov number, NCT02348216.)", "metadata": {}}
+{"_id": "3943235", "title": "", "text": "Beta adrenergic blockade decreases the immunomodulatory effects of social disruption stressDuringphysiological or psychological stress, catecholamines produced by the sympathetic nervous system (SNS)regulate the immune system. Previous studies report that the activation of β-adrenergic receptors (βARs)mediates the actions of catecholamines and increases pro-inflammatory cytokine production in a numberof different cell types. The impact of the SNS on the immune modulation of social defeat has not beenexamined. The following studies were designed to determine whether SNS activation during socialdisruption stress (SDR) influences anxiety-like behavior as well as the activation, priming, andglucocorticoid resistance of splenocytes after social stress. CD-1 mice were exposed to one, three, or sixcycles of SDR and HPLC analysis of the plasma and spleen revealed an increase in catecholamines. Aftersix cycles of SDR the open field test was used to measure behaviors characteristic of anxiety andindicated that the social defeat induced increase in anxiety-like behavior was blocked by pre-treatmentwith the β-adrenergic antagonist propranolol. Pre-treatment with the β-adrenergic antagonist propranololdid not significantly alter corticosterone levels indicating no difference in activation of thehypothalamic-pituitary-adrenal axis. In addition to anxiety-like behavior the SDR induced splenomegalyand increase in plasma IL-6, TNFα, and MCP-1 were each reversed by pre-treatment with propranolol.Furthermore, flow cytometric analysis of cells from propranolol pretreated mice reduced the SDR-inducedincrease in the percentage of CD11b(+) splenic macrophages and significantly decreased the expressionof TLR2, TLR4, and CD86 on the surface of these cells. In addition, supernatants from 18h LPS-stimulatedex vivo cultures of splenocytes from propranolol-treated SDR mice contained less IL-6. Likewisepropranolol pre-treatment abrogated the glucocorticoid insensitivity of CD11b(+) cells ex vivo whencompared to splenocytes from SDR vehicle-treated mice. Together, this study demonstrates that theimmune activation and priming effects of SDR result, in part, as a consequence of SNS activation.", "metadata": {}}
+{"_id": "3944632", "title": "", "text": "Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone fortreatment of brain metastases: a randomized controlled trial.CONTEXT In patients with brain metastases,it is unclear whether adding up-front whole-brain radiation therapy (WBRT) to stereotactic radiosurgery(SRS) has beneficial effects on mortality or neurologic function compared with SRS alone. OBJECTIVE Todetermine if WBRT combined with SRS results in improvements in survival, brain tumor control,functional preservation rate, and frequency of neurologic death. DESIGN, SETTING, AND PATIENTSRandomized controlled trial of 132 patients with 1 to 4 brain metastases, each less than 3 cm indiameter, enrolled at 11 hospitals in Japan between October 1999 and December 2003. INTERVENTIONSPatients were randomly assigned to receive WBRT plus SRS (65 patients) or SRS alone (67 patients).MAIN OUTCOME MEASURES The primary end point was overall survival; secondary end points were braintumor recurrence, salvage brain treatment, functional preservation, toxic effects of radiation, and causeof death. RESULTS The median survival time and the 1-year actuarial survival rate were 7.5 months and38.5% (95% confidence interval, 26.7%-50.3%) in the WBRT + SRS group and 8.0 months and 28.4%(95% confidence interval, 17.6%-39.2%) for SRS alone (P = .42). The 12-month brain tumor recurrencerate was 46.8% in the WBRT + SRS group and 76.4% for SRS alone group (P<.001). Salvage braintreatment was less frequently required in the WBRT + SRS group (n = 10) than with SRS alone (n = 29)(P<.001). Death was attributed to neurologic causes in 22.8% of patients in the WBRT + SRS group andin 19.3% of those treated with SRS alone (P = .64). There were no significant differences in systemic andneurologic functional preservation and toxic effects of radiation. CONCLUSIONS Compared with SRSalone, the use of WBRT plus SRS did not improve survival for patients with 1 to 4 brain metastases, butintracranial relapse occurred considerably more frequently in those who did not receive WBRT.Consequently, salvage treatment is frequently required when up-front WBRT is not used. TRIALREGISTRATION umin.ac.jp/ctr Identifier: C000000412.", "metadata": {}}
+{"_id": "3952288", "title": "", "text": "RANK signals from CD4+3− inducer cells regulate development of Aire-expressing epithelial cells in thethymic medullaAire-expressing medullary thymic epithelial cells (mTECs) play a key role in preventingautoimmunity by expressing tissue-restricted antigens to help purge the emerging T cell receptorrepertoire of self-reactive specificities. Here we demonstrate a novel role for a CD4+3− inducer cellpopulation, previously linked to development of organized secondary lymphoid structures andmaintenance of T cell memory in the functional regulation of Aire-mediated promiscuous gene expressionin the thymus. CD4+3− cells are closely associated with mTECs in adult thymus, and in fetal thymus theirappearance is temporally linked with the appearance of Aire+ mTECs. We show that RANKL signals fromthis cell promote the maturation of RANK-expressing CD80−Aire− mTEC progenitors into CD80+Aire+mTECs, and that transplantation of RANK-deficient thymic stroma into immunodeficient hosts inducesautoimmunity. Collectively, our data reveal cellular and molecular mechanisms leading to the generationof Aire+ mTECs and highlight a previously unrecognized role for CD4+3−RANKL+ inducer cells inintrathymic self-tolerance.", "metadata": {}}
+{"_id": "3960385", "title": "", "text": "Proteomic approach to characterize biochemistry of meat quality defects.Proteomics can be used tocharacterize quality defects including pale, soft, and exudative (PSE) meat (pork and poultry), woodybroiler breast meat, reddish catfish fillets, meat toughness, and beef myoglobin oxidation. PSE broilermeat was characterized by 15 proteins that differed in abundance in comparison to normal broiler breastmeat, and eight proteins were differentially expressed in woody breast meat in comparison to normalbreast meat. Hemoglobin was the only protein that was differentially expressed between red and normalcatfish fillets. However, inducing low oxygen and/or heat stress conditions to catfish fillets did not lead tothe production of red fillets. Proteomic data provided information pertaining to the protein differencesthat exist in meat quality defects. However, these data need to be evaluated in conjunction withinformation pertaining to genetics, nutrition, environment of the live animal, muscle to meat conversion,meat quality analyses and sensory attributes to understand causality, protein biomarkers, and ultimatelyhow to prevent quality defects.", "metadata": {}}
+{"_id": "3973445", "title": "", "text": "Phosphorylation of Janus kinase 1 (JAK1) by AMP-activated protein kinase (AMPK) links energy sensing toanti-inflammatory signalingAdenosine 5′-monophosphate–activated protein kinase (AMPK) is a pivotalregulator of metabolism at cellular and organismal levels. AMPK also suppresses inflammation. We foundthat pharmacological activation of AMPK rapidly inhibited the Janus kinase (JAK)–signal transducer andactivator of transcription (STAT) pathway in various cells. In vitro kinase assays revealed that AMPKdirectly phosphorylated two residues (Ser515 and Ser518) within the Src homology 2 domain of JAK1.Activation of AMPK enhanced the interaction between JAK1 and 14-3-3 proteins in cultured vascularendothelial cells and fibroblasts, an effect that required the presence of Ser515 and Ser518 and wasabolished in cells lacking AMPK catalytic subunits. Mutation of Ser515 and Ser518 abolishedAMPK-mediated inhibition of JAK-STAT signaling stimulated by either the sIL-6Rα/IL-6 complex or theexpression of a constitutively active V658F-mutant JAK1 in human fibrosarcoma cells. Clinically usedAMPK activators metformin and salicylate enhanced the inhibitory phosphorylation of endogenous JAK1and inhibited STAT3 phosphorylation in primary vascular endothelial cells. Therefore, our findings reveala mechanism by which JAK1 function and inflammatory signaling may be suppressed in response tometabolic stress and provide a mechanistic rationale for the investigation of AMPK activators in a range ofdiseases associated with enhanced activation of the JAK-STAT pathway.", "metadata": {}}
+{"_id": "3981033", "title": "", "text": "IAP antagonists induce anti-tumor immunity in multiple myelomaThe cellular inhibitors of apoptosis(cIAP) 1 and 2 are amplified in about 3% of cancers and have been identified in multiple malignancies asbeing potential therapeutic targets as a result of their role in the evasion of apoptosis. Consequently,small-molecule IAP antagonists, such as LCL161, have entered clinical trials for their ability to inducetumor necrosis factor (TNF)-mediated apoptosis of cancer cells. However, cIAP1 and cIAP2 arerecurrently homozygously deleted in multiple myeloma (MM), resulting in constitutive activation of thenoncanonical nuclear factor (NF)-κB pathway. To our surprise, we observed robust in vivo anti-myelomaactivity of LCL161 in a transgenic myeloma mouse model and in patients with relapsed-refractory MM,where the addition of cyclophosphamide resulted in a median progression-free-survival of 10 months.This effect was not a result of direct induction of tumor cell death, but rather of upregulation oftumor-cell-autonomous type I interferon (IFN) signaling and a strong inflammatory response thatresulted in the activation of macrophages and dendritic cells, leading to phagocytosis of tumor cells.Treatment of a MM mouse model with LCL161 established long-term anti-tumor protection and inducedregression in a fraction of the mice. Notably, combination of LCL161 with the immune-checkpointinhibitor anti-PD1 was curative in all of the treated mice.", "metadata": {}}
+{"_id": "3981244", "title": "", "text": "Psychobiological Protective Factors Modifying the Association Between Age and Sexual Health in Men:Findings From the Men’s Health 40+ StudySexual health severely decreases with age. For males olderthan 40 years, erectile dysfunction (ED) is the most common sexual disorder. Although physical andpsychological risk factors for ED have been identified, protective factors are yet to be determined. Todate, no study has examined endocrine and psychosocial factors in parallel with regard to their modifyingeffect on the age-related increase in ED. Two hundred and seventy-one self-reporting healthy men agedbetween 40 and 75 years provided both psychometric data on sexual function and a set of potentialpsychosocial protective factors, and saliva samples for the analysis of steroid hormones andproinflammatory cytokines. Around 35% of the participants reported at least a mild form of ED. Directassociations with ED were identified for perceived general health, emotional support, relationship quality,intimacy motivation but not for steroid hormones or proinflammatory markers. Moderation analyses forthe association between age and ED revealed positive effects for testosterone (T),dehydroepiandrosterone (DHEA), perceived general health, emotional support, intimacy motivation, anda negative effect for interleukin-6 (all p < .05; f2 > .17). Group differences between older men with andwithout ED emerged for T, DHEA, and psychometric measures such as perceived general health,emotional support, satisfaction with life, and intimacy motivation (all p < .05; d > .3). Both psychosocialand endocrine parameters moderated the association between age and sexual health. Perceived generalhealth, emotional support, intimacy motivation, and relationship quality emerged as psychosocialprotective factors against ED. Higher T and DHEA and lower interleukin-6 levels also buffered against anage-related increase in ED.", "metadata": {}}
+{"_id": "3981613", "title": "", "text": "Patient-derived induced pluripotent stem cells in cancer research and precision oncologyTogether withrecent advances in the processing and culture of human tissue, bioengineering, xenotransplantation andgenome editing, Induced pluripotent stem cells (iPSCs) present a range of new opportunities for thestudy of human cancer. Here we discuss the main advantages and limitations of iPSC modeling, and howthe method intersects with other patient-derived models of cancer, such as organoids, organs-on-chipsand patient-derived xenografts (PDXs). We highlight the opportunities that iPSC models can providebeyond those offered by existing systems and animal models and present current challenges and crucialareas for future improvements toward wider adoption of this technology.", "metadata": {}}
+{"_id": "3981729", "title": "", "text": "Structural basis for sequence-specific recognition of DNA by TAL effectors.TAL (transcriptionactivator-like) effectors, secreted by phytopathogenic bacteria, recognize host DNA sequences through acentral domain of tandem repeats. Each repeat comprises 33 to 35 conserved amino acids and targets aspecific base pair by using two hypervariable residues [known as repeat variable diresidues (RVDs)] atpositions 12 and 13. Here, we report the crystal structures of an 11.5-repeat TAL effector in bothDNA-free and DNA-bound states. Each TAL repeat comprises two helices connected by a shortRVD-containing loop. The 11.5 repeats form a right-handed, superhelical structure that tracks along thesense strand of DNA duplex, with RVDs contacting the major groove. The 12th residue stabilizes the RVDloop, whereas the 13th residue makes a base-specific contact. Understanding DNA recognition by TALeffectors may facilitate rational design of DNA-binding proteins with biotechnological applications.", "metadata": {}}
+{"_id": "3984231", "title": "", "text": "Caveolin-1 deletion exacerbates cardiac interstitial fibrosis by promoting M2 macrophage activation inmice after myocardial infarction.Adverse remodeling following myocardial infarction (MI) leading to heartfailure is driven by an imbalanced resolution of inflammation. The macrophage cell is an important controlof post-MI inflammation, as macrophage subtypes secrete mediators to either promote inflammation andextend injury (M1 phenotype) or suppress inflammation and promote scar formation (M2 phenotype). Wehave previously shown that the absence of caveolin-1 (Cav1), a membrane scaffolding protein, isassociated with adverse cardiac remodeling in mice, but the mechanisms responsible remain to beelucidated. We explore here the role of Cav1 in the activation of macrophages using wild type C57BL6/J(WT) and Cav1(tm1Mls/J) (Cav1(-/-)) mice. By echocardiography, cardiac function was comparablebetween WT and Cav1(-/-) mice at 3days post-MI. In the absence of Cav1, there were a surprisinglyhigher percentage of M2 macrophages (arginase-1 positive) detected in the infarcted zone. Conversely,restoring Cav1 function after MI in WT mice by adding back the Cav1 scaffolding domain reduced the M2activation profile. Further, adoptive transfer of Cav1 null macrophages into WT mice on d3 post-MIexacerbated adverse cardiac remodeling at d14 post-MI. In vitro studies revealed that Cav1 nullmacrophages had a more pronounced M2 profile activation in response to IL-4 stimulation. In conclusion,Cav1 deletion promotes an array of maladaptive repair processes after MI, including increased TGF-βsignaling, increased M2 macrophage infiltration and dysregulation of the M1/M2 balance. Our data alsosuggest that cardiac remodeling can be improved by therapeutic intervention regulating Cav1 functionduring the inflammatory response phase.", "metadata": {}}
+{"_id": "3986403", "title": "", "text": "Lipid hydroperoxide measurement by oxidation of Fe2+ in the presence of xylenol orange. Comparisonwith the TBA assay and an iodometric methodStudy of the role of hydroperoxides and lipid peroxidation indisease requires simple and sensitive methods for direct hydroperoxide measurement. We report on atechnique for measuring hydroperoxide which relies upon the rapid hydroperoxide-mediated oxidation ofFe2+ under acidic conditions. Fe3+ forms a chromophore with xylenol orange which absorbs strongly at560 nm, yielding an apparent E560 (for H2O2, butyl hydroperoxide and cumene hydroperoxide) of4.3×104 M−1 cm−1. The assay was validated in a study of liposomal lipid peroxidation and shown to giveresults comparable with those obtained by an iodometric method or by measuring conjugated dienes. Theassay involving thiobarbituric acid, by comparison, underestimates lipid peroxidation and does notmeasure hydroperoxideper se.", "metadata": {}}
+{"_id": "4020950", "title": "", "text": "Roles of exosomes in cardioprotection.Exosomes are extracellular vesicles of endosomal origin whichhave emerged as key mediators of intercellular communication. All major cardiac cell types-includingcardiomyocytes, endothelial cells, and fibroblasts-release exosomes that modulate cellular functions.Exosomes released from human cardiac progenitor cells (CPCs) are cardioprotective and improve cardiacfunction after myocardial infarction to an extent comparable with that achieved by their parent cells.Cardiac progenitor cell-derived exosomes are enriched in cardioprotective microRNAs, particularlymiR-146a-3p. Circulating exosomes mediate remote ischaemic preconditioning. Moreover, they currentlyare being investigated as diagnostic markers. The discovery that cell-derived extracellular signallingorganelles mediate the paracrine effects of stem cells suggests that cell-free strategies could supplant celltransplantation. This review discusses emerging roles of exosomes in cardiovascular physiology, with afocus on cardioprotective activities of CPC-derived exosomes.", "metadata": {}}
+{"_id": "4036038", "title": "", "text": "The rate of change in declining steroid hormones: a new parameter of healthy aging in men?Research onhealthy aging in men has increasingly focused on age-related hormonal changes. Testosterone (T) declineis primarily investigated, while age-related changes in other sex steroids (dehydroepiandrosterone[DHEA], estradiol [E2], progesterone [P]) are mostly neglected. An integrated hormone parameterreflecting aging processes in men has yet to be identified. 271 self-reporting healthy men between 40and 75 provided both psychometric data and saliva samples for hormone analysis. Correlation analysisbetween age and sex steroids revealed negative associations for the four sex steroids (T, DHEA, E2, andP). Principal component analysis including ten salivary analytes identified a principal component mainlyunifying the variance of the four sex steroid hormones. Subsequent principal component analysisincluding the four sex steroids extracted the principal component of declining steroid hormones (DSH).Moderation analysis of the association between age and DSH revealed significant moderation effects forpsychosocial factors such as depression, chronic stress and perceived general health. In conclusion, theseresults provide further evidence that sex steroids decline in aging men and that the integrated hormoneparameter DSH and its rate of change can be used as biomarkers for healthy aging in men. Furthermore,the negative association of age and DSH is moderated by psychosocial factors.", "metadata": {}}
+{"_id": "4037034", "title": "", "text": "Development of a novel helper-dependent adenovirus-Epstein-Barr virus hybrid system for the stabletransformation of mammalian cells.Epstein-Barr virus (EBV) episomes are stably maintained inpermissive proliferating cell lines due to EBV nuclear antigen 1 (EBNA-1) protein-mediated replication andsegregation. Previous studies showed the ability of EBV episomes to confer long-term transgeneexpression and correct genetic defects in deficient cells. To achieve quantitative delivery of EBV episomesin vitro and in vivo, we developed a binary helper-dependent adenovirus (HDA)-EBV hybrid system thatconsists of one HDA vector for the expression of Cre recombinase and a second HDA vector that containsall of the sequences for the EBV episome flanked by loxP sites. Upon coinfection of cells, Cre expressedfrom the first vector recombined loxP sites on the second vector. The resulting circular EBV episomesexpressed a transgene and contained the EBV-derived family of repeats, an EBNA-1 expression cassette,and 19 kb of human DNA that functions as a replication origin in mammalian cells. This HDA-EBV hybridsystem transformed 40% of cultured cells. Transgene expression in proliferating cells was observed forover 20 weeks under conditions that selected for the expression of the transgene. In the absence ofselection, EBV episomes were lost at a rate of 8 to 10% per cell division. Successful delivery of EBVepisomes in vivo was demonstrated in the liver of transgenic mice expressing Cre from the albuminpromoter. This novel gene transfer system has the potential to confer long-term episomal transgeneexpression and therefore to correct genetic defects with reduced vector-related toxicity and withoutinsertional mutagenesis.", "metadata": {}}
+{"_id": "4067274", "title": "", "text": "Spliceosome assembly pathways for different types of alternative splicing converge during commitmentto splice site pairing in the A complex.Differential splice site pairing establishes alternative splicingpatterns resulting in the generation of multiple mRNA isoforms. This process is carried out by thespliceosome, which is activated by a series of sequential structural rearrangements of its five coresnRNPs. To determine when splice sites become functionally paired, we carried out a series of kinetic trapexperiments using pre-mRNAs that undergo alternative 5' splice site selection or alternative exoninclusion. We show that commitment to splice site pairing in both cases occurs in the A complex, which ischaracterized by the ATP-dependent association of the U2 snRNP with the branch point. Interestingly, thetiming of splice site pairing is independent of the intron or exon definition modes of splice siterecognition. Using the ATP analog ATPgammaS, we showed that ATP hydrolysis is required for splice sitepairing independent from U2 snRNP binding to the pre-mRNA. These results identify the A complex as thespliceosomal assembly step dedicated to splice site pairing and suggest that ATP hydrolysis locks splicesites into a splicing pattern after stable U2 snRNP association to the branch point.", "metadata": {}}
+{"_id": "4085204", "title": "", "text": "Transcripts of the MHM region on the chicken Z chromosome accumulate as non-coding RNA in thenucleus of female cells adjacent to the DMRT1 locusThe male hypermethylated (MHM) region, locatednear the middle of the short arm of the Z chromosome of chickens, consists of approximately 210 tandemrepeats of a BamHI 2.2-kb sequence unit. Cytosines of the CpG dinucleotides of this region areextensively methylated on the two Z chromosomes in the male but much less methylated on the single Zchromosome in the female. The state of methylation of the MHM region is established after fertilization byabout the 1-day embryonic stage. The MHM region is transcribed only in the female from the particularstrand into heterogeneous, high molecular-mass, non-coding RNA, which is accumulated at the site oftranscription, adjacent to the DMRT1 locus, in the nucleus. The transcriptional silence of the MHM regionin the male is most likely caused by the CpG methylation, since treatment of the male embryonicfibroblasts with 5-azacytidine results in hypo-methylation and active transcription of this region. In ZZWtriploid chickens, MHM regions are hypomethylated and transcribed on the two Z chromosomes, whereasMHM regions are hypermethylated and transcriptionally inactive on the three Z chromosomes in ZZZtriploid chickens, suggesting a possible role of the W chromosome on the state of the MHM region.", "metadata": {}}
+{"_id": "4138659", "title": "", "text": "Macropinocytosis of protein is an amino acid supply route in Ras-transformed cellsMacropinocytosis is ahighly conserved endocytic process by which extracellular fluid and its contents are internalized into cellsthrough large, heterogeneous vesicles known as macropinosomes. Oncogenic Ras proteins have beenshown to stimulate macropinocytosis but the functional contribution of this uptake mechanism to thetransformed phenotype remains unknown. Here we show that Ras-transformed cells usemacropinocytosis to transport extracellular protein into the cell. The internalized protein undergoesproteolytic degradation, yielding amino acids including glutamine that can enter central carbonmetabolism. Accordingly, the dependence of Ras-transformed cells on free extracellular glutamine forgrowth can be suppressed by the macropinocytic uptake of protein. Consistent with macropinocytosisrepresenting an important route of nutrient uptake in tumours, its pharmacological inhibitioncompromises the growth of Ras-transformed pancreatic tumour xenografts. These results identifymacropinocytosis as a mechanism by which cancer cells support their unique metabolic needs and pointto the possible exploitation of this process in the design of anticancer therapies.", "metadata": {}}
+{"_id": "4162857", "title": "", "text": "Linking Splicing to Pol II Transcription Stabilizes Pre-mRNAs and Influences Splicing PatternsRNAprocessing is carried out in close proximity to the site of transcription, suggesting a regulatory linkbetween transcription and pre-mRNA splicing. Using an in vitro transcription/splicing assay, wedemonstrate that an association of RNA polymerase II (Pol II) transcription and pre-mRNA splicing isrequired for efficient gene expression. Pol II-synthesized RNAs containing functional splice sites areprotected from nuclear degradation, presumably because the local concentration of the splicingmachinery is sufficiently high to ensure its association over interactions with nucleases. Furthermore, theprocess of transcription influences alternative splicing of newly synthesized pre-mRNAs. Because otherRNA polymerases do not provide similar protection from nucleases, and their RNA products displayaltered splicing patterns, the link between transcription and RNA processing is RNA Pol II-specific. Wepropose that the connection between transcription by Pol II and pre-mRNA splicing guarantees anextended half-life and proper processing of nascent pre-mRNAs.", "metadata": {}}
+{"_id": "4164929", "title": "", "text": "The emerging role of skeletal muscle extracellular matrix remodelling in obesity and exercise.Skeletalmuscle extracellular matrix remodelling has been proposed as a new feature associated with obesity andmetabolic dysfunction. Exercise training improves muscle function in obesity, which may be mediated byregulatory effects on the muscle extracellular matrix. This review examined available literature onskeletal muscle extracellular matrix remodelling during obesity and the effects of exercise. Anon-systematic literature review was performed on PubMed of publications from 1970 to 2015. A total of37 studies from humans and animals were retained. Studies reported overall increases in gene andprotein expression of different types of collagen, growth factors and enzymatic regulators of the skeletalmuscle extracellular matrix in obesity. Only two studies investigated the effects of exercise on skeletalmuscle extracellular matrix during obesity, with both suggesting a regulatory effect of exercise. Theeffects of exercise on muscle extracellular matrix seem to be influenced by the duration and type ofexercise training with variable effects from a single session compared with a longer duration of exercise.More studies are needed to elucidate the mechanisms behind skeletal muscle extracellular matrixremodelling during obesity and the effects of exercise.", "metadata": {}}
+{"_id": "4200695", "title": "", "text": "Effect of specific exercise strategy on need for surgery in patients with subacromial impingementsyndrome: randomised controlled studyOBJECTIVE To evaluate if a specific exercise strategy, targetingthe rotator cuff and scapula stabilisers, improves shoulder function and pain more than unspecificexercises in patients with subacromial impingement syndrome, thereby decreasing the need forarthroscopic subacromial decompression. DESIGN Randomised, participant and single assessor blinded,controlled study. SETTING Department of orthopaedics in a Swedish university hospital. PARTICIPANTS102 patients with long standing (over six months) persistent subacromial impingement syndrome inwhom earlier conservative treatment had failed, recruited through orthopaedic specialists.INTERVENTIONS The specific exercise strategy consisted of strengthening eccentric exercises for therotator cuff and concentric/eccentric exercises for the scapula stabilisers in combination with manualmobilisation. The control exercise programme consisted of unspecific movement exercises for the neckand shoulder. Patients in both groups received five to six individual guided treatment sessions during 12weeks. In between these supervised sessions the participants performed home exercises once or twice aday for 12 weeks. MAIN OUTCOME MEASURES The primary outcome was the Constant-Murley shoulderassessment score evaluating shoulder function and pain. Secondary outcomes were patients' globalimpression of change because of treatment and decision regarding surgery. RESULTS Most (97, 95%)participants completed the 12 week study. There was a significantly greater improvement in theConstant-Murley score in the specific exercise group than in the control exercise group (24 points (95%confidence interval 19 to 28.0) v 9 points (5 to 13); mean difference between group: 15 points (8.5 to20.6)). Significantly more patients in the specific exercise group reported successful outcome (defined aslarge improvement or recovered) in the patients' global assessment of change because of treatment:69% (35/51) v 24% (11/46); odds ratio 7.6, 3.1 to 18.9; P<0.001. A significantly lower proportion ofpatients in the specific exercise group subsequently chose to undergo surgery: 20% (10/51) v 63%(29/46); odds ratio 7.7, 3.1 to 19.4; P<0.001). CONCLUSION A specific exercise strategy, focusing onstrengthening eccentric exercises for the rotator cuff and concentric/eccentric exercises for the scapulastabilisers, is effective in reducing pain and improving shoulder function in patients with persistentsubacromial impingement syndrome. By extension, this exercise strategy reduces the need forarthroscopic subacromial decompression within the three month timeframe used in the study. TRIALREGISTRATION Clinical trials NCT01037673.", "metadata": {}}
+{"_id": "4231060", "title": "", "text": "Nucleotide sequence of an avian sarcoma virus oncogene (src) and proposed amino acid sequence forgene productThe transforming gene (src) of avian sarcoma virus (ASV) and adjacent regions of the viralgenome have been isolated by molecular cloning of viral DNA. Their nucleotide sequence encompassesthe whole of src and the portion of the gene env that encodes gp 37, one of two glycoproteins found inthe viral envelope. Src encodes a single, hydrophobic protein with structural features that conform toprevious descriptions of the gene product (pp60src). It appears that a single viral protein is responsiblefor both the initiation and maintenance of neoplastic transformation by avian sarcoma virus. Neither srcnor its product bear any obvious structural relationship to several other viral oncogenes and theirencoded proteins. Src is flanked by a repeated nucleotide sequence that may facilitate frequent deletionof the gene from the viral genome.", "metadata": {}}
+{"_id": "4246523", "title": "", "text": "Issues in design and interpretation of MDR-TB clinical trials: report of the first Global MDR-TB ClinicalTrials Landscape MeetingRecognizing that the current MDR-TB regimen is suboptimal and based onlow-quality evidence, the Global MDR-TB Clinical Trials Landscape Meeting was held in December, 2014to strategize about coordination of research and development of new treatment regimens for this diseasethat affects millions of people worldwide every year. Sixty international experts on multidrug-resistanttuberculosis (MDR-TB) met in Washington D.C. and Cape Town, South Africa to consider key MDR-TBtrial-related issues, including: standardization of definitions; clinical trial capacity building and; regimensoptimized to foster compliance, avoid the emergence of resistance and have clinical relevance for specialpopulations, including children and those co-infected with HIV. Underpinning all of this is the generationof a sufficient evidence base to facilitate regulatory approval and improved normative guidance.Participants discussed treatment combinations currently being studied in Phase 2B and Phase 3 trials aswell as other promising new regimens and combinations that may be evaluated in the near future. Theseinclude regimens designed specifically to enable shorter duration and all-oral treatment as a means ofmaximizing treatment completion. It is hoped that clear definition of these challenges will facilitate theprocess of identifying solutions that accelerate progress towards effective, non-toxic treatments that canbe programmatically implemented.", "metadata": {}}
+{"_id": "4254064", "title": "", "text": "Para-aortic splanchnopleura from early mouse embryos contains B1a cell progenitorsDEFINITIVEerythropoiesis in birds originates from stem cells that emerge in the splanchnopleural mesoderm near theembryonic aorta1–4. The yolk sac is still generally held to be the unique provider of haematopoietic stemcells during mammalian ontogeny5, although there may be an alternative intraembryonic source of stemcells in the mouse fetus6,7. Here we search for a possible non-yolk-sac source of stem cells by graftingintraembryonic splanchnopleura from 10- to 18-somite mouse embryos into adult immunodeficient SCIDmice. We find significant amounts of donor-derived serum IgM, normal numbers of IgM-secreting plasmacells, and the Bla (IgMa brightB220dullCD5+) cell subset to be fully reconstituted by donor progenitors 3to 6 months after engraftment. The haematogenic capacity revealed in our experiments is present in apreviously unrecognized site, the earliest described in the embryo, 12 hours before fetal livercolonization.", "metadata": {}}
+{"_id": "4256553", "title": "", "text": "Establishment in culture of pluripotential cells from mouse embryosPluripotential cells are present in amouse embryo until at least an early post-implantation stage, as shown by their ability to take part hi theformation of chimaeric animals1 and to form teratocarcinomas2. Until now it has not been possible toestablish progressively growing cultures of these cells in vitro, and cell lines have only been obtainedafter teratocarcinoma formation in vivo. We report here the establishment in tissue culture of pluripotentcell lines which have been isolated directly from in vitro cultures of mouse blastocysts. These cells areable to differentiate either in vitro or after innoculation into a mouse as a tumour in vivo. They have anormal karyotype.", "metadata": {}}
+{"_id": "4270992", "title": "", "text": "MHC class II interaction with CD4 mediated by a region analogous to the MHC class I binding site forCD8INTERACTIONS between major histocompatibility complex (MHC) molecules and the CD4 or CDScoreceptors have a major role in intrathymic T-cell selection1. On mature T cells, each of these twoglycoproteins is associated with a class-specific bias in MHC molecule recognition by the T-cell receptor.CD4+ T cells respond to antigen in association with MHC class II molecules and CD8+ T cells respond toantigen in association with MHC class I molecules. Physical interaction between the CD4/MHC class IImolecules and CD8/MHC class I molecules has been demonstrated by cell adhesion assay2–5, and abinding site for CDS on class I has been identified6,7. Here we demonstrate that a region of the MHCclass IIβ-chain β2 domain, structurally analogous to the CDS-binding loop in the MHC class I α3 domain,is critical for function with both mouse and human CD4.", "metadata": {}}
+{"_id": "4283694", "title": "", "text": "Instability and decay of the primary structure of DNAAlthough DNA is the carrier of genetic information, ithas limited chemical stability. Hydrolysis, oxidation and nonenzymatic methylation of DNA occur atsignificant ratesin vivo, and are counteracted by specific DNA repair processes. The spontaneous decay ofDNA is likely to be a major factor in mutagenesis, carcinogenesis and ageing, and also sets limits for therecovery of DNA fragments from fossils.", "metadata": {}}
+{"_id": "4300851", "title": "", "text": "Single-cell proteomic analysis of S. cerevisiae reveals the architecture of biological noiseA major goal ofbiology is to provide a quantitative description of cellular behaviour. This task, however, has beenhampered by the difficulty in measuring protein abundances and their variation. Here we present astrategy that pairs high-throughput flow cytometry and a library of GFP-tagged yeast strains to monitorrapidly and precisely protein levels at single-cell resolution. Bulk protein abundance measurements of>2,500 proteins in rich and minimal media provide a detailed view of the cellular response to theseconditions, and capture many changes not observed by DNA microarray analyses. Our single-cell dataargue that noise in protein expression is dominated by the stochastic production/destruction ofmessenger RNAs. Beyond this global trend, there are dramatic protein-specific differences in noise thatare strongly correlated with a protein's mode of transcription and its function. For example, proteins thatrespond to environmental changes are noisy whereas those involved in protein synthesis are quiet. Thus,these studies reveal a remarkable structure to biological noise and suggest that protein noise levels havebeen selected to reflect the costs and potential benefits of this variation.", "metadata": {}}
+{"_id": "4303075", "title": "", "text": "Direct conversion of fibroblasts to functional neurons by defined factorsCellular differentiation and lineagecommitment are considered to be robust and irreversible processes during development. Recent work hasshown that mouse and human fibroblasts can be reprogrammed to a pluripotent state with a combinationof four transcription factors. This raised the question of whether transcription factors could directly induceother defined somatic cell fates, and not only an undifferentiated state. We hypothesized thatcombinatorial expression of neural-lineage-specific transcription factors could directly convert fibroblastsinto neurons. Starting from a pool of nineteen candidate genes, we identified a combination of only threefactors, Ascl1, Brn2 (also called Pou3f2) and Myt1l, that suffice to rapidly and efficiently convert mouseembryonic and postnatal fibroblasts into functional neurons in vitro. These induced neuronal (iN) cellsexpress multiple neuron-specific proteins, generate action potentials and form functional synapses.Generation of iN cells from non-neural lineages could have important implications for studies of neuraldevelopment, neurological disease modelling and regenerative medicine.", "metadata": {}}
+{"_id": "4303939", "title": "", "text": "Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesityNon-alcoholic fatty liverdisease (NAFLD) is the hepatic manifestation of metabolic syndrome and the leading cause of chronicliver disease in the Western world. Twenty per cent of NAFLD individuals develop chronic hepaticinflammation (non-alcoholic steatohepatitis, NASH) associated with cirrhosis, portal hypertension andhepatocellular carcinoma, yet the causes of progression from NAFLD to NASH remain obscure. Here, weshow that the NLRP6 and NLRP3 inflammasomes and the effector protein IL-18 negatively regulateNAFLD/NASH progression, as well as multiple aspects of metabolic syndrome via modulation of the gutmicrobiota. Different mouse models reveal that inflammasome-deficiency-associated changes in theconfiguration of the gut microbiota are associated with exacerbated hepatic steatosis and inflammationthrough influx of TLR4 and TLR9 agonists into the portal circulation, leading to enhanced hepatictumour-necrosis factor (TNF)-α expression that drives NASH progression. Furthermore, co-housing ofinflammasome-deficient mice with wild-type mice results in exacerbation of hepatic steatosis and obesity.Thus, altered interactions between the gut microbiota and the host, produced by defective NLRP3 andNLRP6 inflammasome sensing, may govern the rate of progression of multiple metabolicsyndrome-associated abnormalities, highlighting the central role of the microbiota in the pathogenesis ofheretofore seemingly unrelated systemic auto-inflammatory and metabolic disorders.", "metadata": {}}
+{"_id": "4305576", "title": "", "text": "Chromatin remodelling at promoters suppresses antisense transcriptionChromatin allows the eukaryoticcell to package its DNA efficiently. To understand how chromatin structure is controlled across theSaccharomyces cerevisiae genome, we have investigated the role of the ATP-dependent chromatinremodelling complex Isw2 in positioning nucleosomes. We find that Isw2 functions adjacent to promoterregions where it repositions nucleosomes at the interface between genic and intergenic sequences.Nucleosome repositioning by Isw2 is directional and results in increased nucleosome occupancy of theintergenic region. Loss of Isw2 activity leads to inappropriate transcription, resulting in the generation ofboth coding and noncoding transcripts. Here we show that Isw2 repositions nucleosomes to enforcedirectionality on transcription by preventing transcription initiation from cryptic sites. Our analyses revealhow chromatin is organized on a global scale and advance our understanding of how transcription isregulated.", "metadata": {}}
+{"_id": "4306711", "title": "", "text": "The Human Mitochondrial DEAD-Box Protein DDX28 Resides in RNA Granules and Functions inMitoribosome Assembly.Human mitochondrial ribosomes are specialized in the synthesis of 13 proteins,which are fundamental components of the oxidative phosphorylation system. The pathway ofmitoribosome biogenesis, the compartmentalization of the process, and factors involved remain largelyunknown. Here, we have identified the DEAD-box protein DDX28 as an RNA granule component essentialfor the biogenesis of the mitoribosome large subunit (mt-LSU). DDX28 interacts with the 16S rRNA andthe mt-LSU. RNAi-mediated DDX28 silencing in HEK293T cells does not affect mitochondrial mRNAstability or 16S rRNA processing or modification. However, it leads to reduced levels of 16S rRNA andmt-LSU proteins, impaired mt-LSU assembly, deeply attenuated mitochondrial protein synthesis, andconsequent failure to assemble oxidative phosphorylation complexes. Our findings identify DDX28 asessential during the early stages of mitoribosome mt-LSU biogenesis, a process that takes place mainlynear the mitochondrial nucleoids, in the compartment defined by the RNA granules.", "metadata": {}}
+{"_id": "4311206", "title": "", "text": "Conversion of Adult Pancreatic α-cells to β-cells After Extreme β-cell LossPancreatic insulin-producingbeta-cells have a long lifespan, such that in healthy conditions they replicate little during a lifetime.Nevertheless, they show increased self-duplication after increased metabolic demand or after injury (thatis, beta-cell loss). It is not known whether adult mammals can differentiate (regenerate) new beta-cellsafter extreme, total beta-cell loss, as in diabetes. This would indicate differentiation from precursors oranother heterologous (non-beta-cell) source. Here we show beta-cell regeneration in a transgenic modelof diphtheria-toxin-induced acute selective near-total beta-cell ablation. If given insulin, the micesurvived and showed beta-cell mass augmentation with time. Lineage-tracing to label theglucagon-producing alpha-cells before beta-cell ablation tracked large fractions of regenerated beta-cellsas deriving from alpha-cells, revealing a previously disregarded degree of pancreatic cell plasticity. Suchinter-endocrine spontaneous adult cell conversion could be harnessed towards methods of producingbeta-cells for diabetes therapies, either in differentiation settings in vitro or in induced regeneration.", "metadata": {}}
+{"_id": "4312169", "title": "", "text": "Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastomaGlioblastomamultiforme (GBM) is a lethal brain tumour in adults and children. However, DNA copy number and geneexpression signatures indicate differences between adult and paediatric cases. To explore the geneticevents underlying this distinction, we sequenced the exomes of 48 paediatric GBM samples. Somaticmutations in the H3.3-ATRX-DAXX chromatin remodelling pathway were identified in 44% of tumours(21/48). Recurrent mutations in H3F3A, which encodes the replication-independent histone 3 variantH3.3, were observed in 31% of tumours, and led to amino acid substitutions at two critical positionswithin the histone tail (K27M, G34R/G34V) involved in key regulatory post-translational modifications.Mutations in ATRX (α-thalassaemia/mental retardation syndrome X-linked) and DAXX (death-domainassociated protein), encoding two subunits of a chromatin remodelling complex required for H3.3incorporation at pericentric heterochromatin and telomeres, were identified in 31% of samples overall,and in 100% of tumours harbouring a G34R or G34V H3.3 mutation. Somatic TP53 mutations wereidentified in 54% of all cases, and in 86% of samples with H3F3A and/or ATRX mutations. Screening of alarge cohort of gliomas of various grades and histologies (n = 784) showed H3F3A mutations to bespecific to GBM and highly prevalent in children and young adults. Furthermore, the presence ofH3F3A/ATRX-DAXX/TP53 mutations was strongly associated with alternative lengthening of telomeresand specific gene expression profiles. This is, to our knowledge, the first report to highlight recurrentmutations in a regulatory histone in humans, and our data suggest that defects of the chromatinarchitecture underlie paediatric and young adult GBM pathogenesis.", "metadata": {}}
+{"_id": "4313478", "title": "", "text": "Translational control of intron splicing in eukaryotesMost eukaryotic genes are interrupted by non-codingintrons that must be accurately removed from pre-messenger RNAs to produce translatable mRNAs.Splicing is guided locally by short conserved sequences, but genes typically contain many potential splicesites, and the mechanisms specifying the correct sites remain poorly understood. In most organisms,short introns recognized by the intron definition mechanism cannot be efficiently predicted solely on thebasis of sequence motifs. In multicellular eukaryotes, long introns are recognized through exon definitionand most genes produce multiple mRNA variants through alternative splicing. The nonsense-mediatedmRNA decay (NMD) pathway may further shape the observed sets of variants by selectively degradingthose containing premature termination codons, which are frequently produced in mammals. Here weshow that the tiny introns of the ciliate Paramecium tetraurelia are under strong selective pressure tocause premature termination of mRNA translation in the event of intron retention, and that the same biasis observed among the short introns of plants, fungi and animals. By knocking down the two P. tetraureliagenes encoding UPF1, a protein that is crucial in NMD, we show that the intrinsic efficiency of splicingvaries widely among introns and that NMD activity can significantly reduce the fraction of unsplicedmRNAs. The results suggest that, independently of alternative splicing, species with large intron numbersuniversally rely on NMD to compensate for suboptimal splicing efficiency and accuracy.", "metadata": {}}
+{"_id": "4319174", "title": "", "text": "Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesisAllhomeotherms use thermogenesis to maintain their core body temperature, ensuring that cellularfunctions and physiological processes can continue in cold environments. In the prevailing model ofthermogenesis, when the hypothalamus senses cold temperatures it triggers sympathetic discharge,resulting in the release of noradrenaline in brown adipose tissue and white adipose tissue. Acting via theβ(3)-adrenergic receptors, noradrenaline induces lipolysis in white adipocytes, whereas it stimulates theexpression of thermogenic genes, such as PPAR-γ coactivator 1a (Ppargc1a), uncoupling protein 1 (Ucp1)and acyl-CoA synthetase long-chain family member 1 (Acsl1), in brown adipocytes. However, the precisenature of all the cell types involved in this efferent loop is not well established. Here we report in mice anunexpected requirement for the interleukin-4 (IL-4)-stimulated program of alternative macrophageactivation in adaptive thermogenesis. Exposure to cold temperature rapidly promoted alternativeactivation of adipose tissue macrophages, which secrete catecholamines to induce thermogenic geneexpression in brown adipose tissue and lipolysis in white adipose tissue. Absence of alternativelyactivated macrophages impaired metabolic adaptations to cold, whereas administration of IL-4 increasedthermogenic gene expression, fatty acid mobilization and energy expenditure, all in amacrophage-dependent manner. Thus, we have discovered a role for alternatively activated macrophagesin the orchestration of an important mammalian stress response, the response to cold.", "metadata": {}}
+{"_id": "4319844", "title": "", "text": "Alternative Lengthening of Telomeres Mediated by Mitotic DNA Synthesis Engages Break-InducedReplication Processes.Alternative lengthening of telomeres (ALT) is a telomerase-independent telomeremaintenance mechanism that occurs in a subset of cancers. By analyzing telomerase-positive cells andtheir human TERC knockout-derived ALT human cell lines, we show that ALT cells harbor more fragiletelomeres representing telomere replication problems. ALT-associated replication defects trigger mitoticDNA synthesis (MiDAS) at telomeres in a RAD52-dependent, but RAD51-independent, manner. TelomericMiDAS is a conservative DNA synthesis process, potentially mediated by break-induced replication,similar to type II ALT survivors in Saccharomyces cerevisiae Replication stresses induced by ectopiconcogenic expression of cyclin E, G-quadruplexes, or R-loop formation facilitate the ALT pathway and leadto telomere clustering, a hallmark of ALT cancers. The TIMELESS/TIPIN complex suppresses telomereclustering and telomeric MiDAS, whereas the SMC5/6 complex promotes them. In summary, ALT cellsexhibit more telomere replication defects that result in persistent DNA damage responses at telomeres,leading to the engagement of telomeric MiDAS (spontaneous mitotic telomere synthesis) that is triggeredby DNA replication stress, a potential driver of genomic duplications in cancer.", "metadata": {}}
+{"_id": "4320111", "title": "", "text": "Light acts directly on organs and cells in culture to set the vertebrate circadian clock.The expression ofclock genes in vertebrates is widespread and not restricted to classical clock structures. The expression ofthe Clock gene in zebrafish shows a strong circadian oscillation in many tissues in vivo and in culture,showing that endogenous oscillators exist in peripheral organs. A defining feature of circadian clocks isthat they can be set or entrained to local time, usually by the environmental light-dark cycle. Animportant question is whether peripheral oscillators are entrained to local time by signals from centralpacemakers such as the eyes or are themselves directly light-responsive. Here we show that theperipheral organ clocks of zebrafish are set by light-dark cycles in culture. We also show that azebrafish-derived cell line contains a circadian oscillator, which is also directly light entrained.", "metadata": {}}
+{"_id": "4320424", "title": "", "text": "Small molecule inhibition of the KRAS–PDEδ interaction impairs oncogenic KRAS signallingThe KRASoncogene product is considered a major target in anticancer drug discovery. However, direct interferencewith KRAS signalling has not yet led to clinically useful drugs. Correct localization and signalling byfarnesylated KRAS is regulated by the prenyl-binding protein PDEδ, which sustains the spatialorganization of KRAS by facilitating its diffusion in the cytoplasm. Here we report that interfering withbinding of mammalian PDEδ to KRAS by means of small molecules provides a novel opportunity tosuppress oncogenic RAS signalling by altering its localization to endomembranes. Biochemical screeningand subsequent structure-based hit optimization yielded inhibitors of the KRAS–PDEδ interaction thatselectively bind to the prenyl-binding pocket of PDEδ with nanomolar affinity, inhibit oncogenic RASsignalling and suppress in vitro and in vivo proliferation of human pancreatic ductal adenocarcinoma cellsthat are dependent on oncogenic KRAS. Our findings may inspire novel drug discovery efforts aimed atthe development of drugs targeting oncogenic RAS.", "metadata": {}}
+{"_id": "4321295", "title": "", "text": "Evolution of novel cooperative swarming in the bacterium Myxococcus xanthusCooperation amongindividuals is necessary for evolutionary transitions to higher levels of biological organization. In suchtransitions, groups of individuals at one level (such as single cells) cooperate to form selective units at ahigher level (such as multicellular organisms). Though the evolution of cooperation is difficult to observedirectly in higher eukaryotes, microorganisms do offer such an opportunity. Here we report the evolutionof novel cooperative behaviour in experimental lineages of the bacterium Myxococcus xanthus. Wild-typestrains of M. xanthus exhibit socially dependent swarming across soft surfaces by a mechanism known as‘S-motility’ that requires the presence of extracellular type IV pili. In lineages of M. xanthus unable tomake pili, a new mechanistic basis for cooperative swarming evolved. Evolved swarming is mediated, atleast in part, by enhanced production of an extracellular fibril matrix that binds cells—and theirevolutionary interests—together. Though costly to individuals, fibril production greatly enhancedpopulation expansion in groups of interconnected cells. These results show that fundamental transitionsto primitive cooperation can readily occur in bacteria.", "metadata": {}}
+{"_id": "4321947", "title": "", "text": "Exon duplication and divergence in the human preproglucagon geneGlucagon is a 29-amino acidpancreatic hormone which counteracts the blood glucose-lowering action of insulin by stimulating hepaticglycogenolysis and gluconeogenesis1. The structure of the hamster pancreatic glucagon precursor hasrecently been determined from the sequence of a cloned cDNA2. Hamster preproglucagon is a 180-aminoacid protein which contains five functional regions; a signal or pre-peptide, an NH2-terminal peptide (alsocalled glicentin-related pancreatic peptide, GRPP), glucagon, and two carboxy-terminal glucagon-likepeptides (GLP-1 and GLP-2). The sequences of two non-allelic anglerfish pancreatic glucagonprecursors3–5 have also been determined and their organization is similar but not identical to thehamster protein; they lack the polypeptide segment corresponding to hamster GLP-2. The presence ofthree regions possessing internal homology, that is, glucagon, GLP-1 and GLP-2, within proglucagon, andthe absence of GLP-2 in the anglerfish precursors suggests that the structure of the preproglucagon genemight provide insight into the evolution of this polyprotein. We have isolated and sequenced the humanpreproglucagon gene and report here that the organization of the human precursor deduced from thissequence is identical to the hamster protein. The gene contains at least three intervening sequenceswhich divide the protein-coding portion of the gene into four regions corresponding to the signal peptideand part of the NH2-terminal peptide, the remainder of the NH2-terminal peptide and glucagon, GLP-1,and GLP-2. The data suggest that triplication and subsequent sequence divergence of an exon encodingglucagon or a glucagon-like peptide produced this polyprotein precursor.", "metadata": {}}
+{"_id": "4323425", "title": "", "text": "BH1 and BH2 domains of Bcl-2 are required for inhibition of apoptosis and heterodimerization withBaxBCL-2 was isolated from the t(14;18) chromosomal breakpoint in follicular B-cell lymphoma1–3. Bcl-2has the unique oncogenic role of extending cell survival by inhibiting a variety of apoptotic deaths4–13.An emerging family of Bcl-2 -related proteins share two highly conserved regions14–20 referred to hereas Bcl-2 homology 1 and 2 (BH1 and BH2) domains (Fig. 1). This includes Bax which heterodimerizeswith Bcl-2 and when overexpressed counteracts Bcl-214. We report here that site-specific mutagenesis ofBcl-2 establishes the two domains as novel dimerization motifs. Substitu-tion of Gly 145 in BHl domain orTrp 188 in BH2 domain completely abrogated Bcl-2's death-repressor activity in inter-leukin-3deprivation, γ-irradiation and glucocorticoid-induced apoptosis. Mutations that affected Bcl-2's functionalso disrupted its heterodimerization with Bax, yet still permitted Bcl-2 homo-dimerization. These resultsestablish a functional role for the BH1 and BH2 domains and suggest Bcl-2 exerts its action throughheterodimerization with Bax.", "metadata": {}}
+{"_id": "4323449", "title": "", "text": "KAP1 controls endogenous retroviruses in embryonic stem cellsMore than forty per cent of themammalian genome is derived from retroelements, of which about one-quarter are endogenousretroviruses (ERVs). Some are still active, notably in mice the highly polymorphic early transposon(ETn)/MusD and intracisternal A-type particles (IAP). ERVs are transcriptionally silenced during earlyembryogenesis by histone and DNA methylation (and reviewed in ref. 7), although the initiators of thisprocess, which is essential to protect genome integrity, remain largely unknown. KAP1 (KRAB-associatedprotein 1, also known as tripartite motif-containing protein 28, TRIM28) represses genes by recruiting thehistone methyltransferase SETDB1, heterochromatin protein 1 (HP1) and the NuRD histone deacetylasecomplex, but few of its physiological targets are known. Two lines of evidence suggest thatKAP1-mediated repression could contribute to the control of ERVs: first, KAP1 can trigger permanentgene silencing during early embryogenesis, and second, a KAP1 complex silences the retrovirus murineleukaemia virus in embryonic cells. Consistent with this hypothesis, here we show that KAP1 deletionleads to a marked upregulation of a range of ERVs, in particular IAP elements, in mouse embryonic stem(ES) cells and in early embryos. We further demonstrate that KAP1 acts synergistically with DNAmethylation to silence IAP elements, and that it is enriched at the 5′ untranslated region (5′UTR) of IAPgenomes, where KAP1 deletion leads to the loss of histone 3 lysine 9 trimethylation (H3K9me3), ahallmark of KAP1-mediated repression. Correspondingly, IAP 5′UTR sequences can impose in cisKAP1-dependent repression on a heterologous promoter in ES cells. Our results establish that KAP1controls endogenous retroelements during early embryonic development.", "metadata": {}}
+{"_id": "4324278", "title": "", "text": "The TOR signalling pathway controls nuclear localization of nutrient-regulated transcription factors.Therapamycin-sensitive TOR signalling pathway in Saccharomyces cerevisiae activates a cell-growth programin response to nutrients such as nitrogen and carbon. The TOR1 and TOR2 kinases (TOR) controlcytoplasmic protein synthesis and degradation through the conserved TAP42 protein. Uponphosphorylation by TOR, TAP42 binds and possibly inhibits type 2A and type-2A-related phosphatases;however, the mechanism by which TOR controls nuclear events such as global repression ofstarvation-specific transcription is unknown. Here we show that TOR prevents transcription of genesexpressed upon nitrogen limitation by promoting the association of the GATA transcription factor GLN3with the cytoplasmic protein URE2. The binding of GLN3 to URE2 requires TOR-dependentphosphorylation of GLN3. Phosphorylation and cytoplasmic retention of GLN3 are also dependent on theTOR effector TAP42, and are antagonized by the type-2A-related phosphatase SIT4. TOR inhibitsexpression of carbon-source-regulated genes by stimulating the binding of the transcriptional activatorsMSN2 and MSN4 to the cytoplasmic 14-3-3 protein BMH2. Thus, the TOR signalling pathway broadlycontrols nutrient metabolism by sequestering several transcription factors in the cytoplasm.", "metadata": {}}
+{"_id": "4325137", "title": "", "text": "Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptidesMurine embryonicstem (ES) cells are pluripotent cell lines established directly from the early embryo1,2 which cancontribute differentiated progeny to all adult tissues, including the germ-cell lineage3, afterre-incorporation into the normal embryo. They provide both a cellular vector for the generation oftransgenic animals4 and a useful system for the identification of polypeptide factors controllingdifferentiation processes in early development5. In particular, medium conditioned by Buffalo rat livercells contains a polypeptide factor, ES cell differentiation inhibitory activity (DIA), which specificallysuppresses the spontaneous differentiation of ES cells in vitro, thereby permitting their growth ashomogeneous stem cell populations in the absence of heterologous feeder cells6. ES cell pluripotentiality,including the ability to give rise to functional gametes, is preserved after prolonged culture in Buffalo ratliver media as a source of DIA7. Here, we report that purified DIA is related in structure and function tothe recently identified haemopoetic regulatory factors human interleukin for DA cells8,9 and leukaemiainhibitory factor10. DIA and human interleukin DA/leukaemia inhibitory factor have thus been identifiedas related multifunctional regulatory factors with distinct biological activities in both early embryonic andhaemopoetic stem cell systems.", "metadata": {}}
+{"_id": "4325398", "title": "", "text": "Pancreatic cancer genomes reveal aberrations in axon guidance pathway genesPancreatic cancer is ahighly lethal malignancy with few effective therapies. We performed exome sequencing and copy numberanalysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stageI and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumoursidentified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations.We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4,MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genesinvolved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms(ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data andanimal models provided supportive evidence for potential roles for these genetic aberrations incarcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in coresignalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in eachpathway. We also identified frequent and diverse somatic aberrations in genes described traditionally asembryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident inmurine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer,providing further supportive evidence for the potential involvement of axon guidance genes in pancreaticcarcinogenesis.", "metadata": {}}
+{"_id": "4326318", "title": "", "text": "Rejuvenation of aged progenitor cells by exposure to a young systemic environmentThe decline of tissueregenerative potential is a hallmark of ageing and may be due to age-related changes in tissue-specificstem cells. A decline in skeletal muscle stem cell (satellite cell) activity due to a loss of Notch signallingresults in impaired regeneration of aged muscle. The decline in hepatic progenitor cell proliferation owingto the formation of a complex involving cEBP-α and the chromatin remodelling factor brahma (Brm)inhibits the regenerative capacity of aged liver. To examine the influence of systemic factors on agedprogenitor cells from these tissues, we established parabiotic pairings (that is, a shared circulatorysystem) between young and old mice (heterochronic parabioses), exposing old mice to factors present inyoung serum. Notably, heterochronic parabiosis restored the activation of Notch signalling as well as theproliferation and regenerative capacity of aged satellite cells. The exposure of satellite cells from old miceto young serum enhanced the expression of the Notch ligand (Delta), increased Notch activation, andenhanced proliferation in vitro. Furthermore, heterochronic parabiosis increased aged hepatocyteproliferation and restored the cEBP-α complex to levels seen in young animals. These results suggest thatthe age-related decline of progenitor cell activity can be modulated by systemic factors that change withage.", "metadata": {}}
+{"_id": "4335423", "title": "", "text": "Continuous single-cell imaging of blood generation from haemogenic endotheliumDespite decades ofresearch, the identity of the cells generating the first haematopoietic cells in mammalian embryos isunknown. Indeed, whether blood cells arise from mesodermal cells, mesenchymal progenitors, bipotentendothelial–haematopoietic precursors or haemogenic endothelial cells remains controversial. Proximityof endothelial and blood cells at sites of embryonic haematopoiesis, as well as their similar geneexpression, led to the hypothesis of the endothelium generating blood. However, owing to lackingtechnology it has been impossible to observe blood cell emergence continuously at the single-cell level,and the postulated existence of haemogenic endothelial cells remains disputed. Here, using new imagingand cell-tracking methods, we show that embryonic endothelial cells can be haemogenic. By continuouslong-term single-cell observation of mouse mesodermal cells generating endothelial cell and bloodcolonies, it was possible to detect haemogenic endothelial cells giving rise to blood cells. Livingendothelial and haematopoietic cells were identified by simultaneous detection of morphology andmultiple molecular and functional markers. Detachment of nascent blood cells from endothelium is notdirectly linked to asymmetric cell division, and haemogenic endothelial cells are specified from cellsalready expressing endothelial markers. These results improve our understanding of the developmentalorigin of mammalian blood and the potential generation of haematopoietic stem cells from embryonicstem cells.", "metadata": {}}
+{"_id": "4335599", "title": "", "text": "Formation of germ-line chimaeras from embryo-derived teratocarcinoma cell linesThe recent availabilityin culture of embryo-derived pluripotential cells which exhibit both a normal karyotype and a highdifferentiative ability1–3 has encouraged us to assess the potential of these cells to form functional germcells following their incorporation into chimaeric mice. We report here the results of blastocyst injectionstudies using three independently isolated XY embryo-derived cell lines (EK.CP1, EK.CC1.1 and EKCC1.2)which produce a very high proportion (>50%) of live-born animals that are overtly chimaeric. Sevenchimaeric male mice, derived from these three lines, have, so far, proved to be functional germ-linechimaeras.", "metadata": {}}
+{"_id": "4336849", "title": "", "text": "Chloroquine resistance not linked to mdr-like genes in a Plasmodium falciparum crossCHLOROQUINE isthought to act against falciparum malaria by accumulating in the acid vesicles of the parasite andinterfering with their function1\u00004. Parasites resistant to chloroquine expel the drug rapidly in anunaltered form, thereby reducing levels of accumulation in the vesicles5. The discovery that verapamilpartially reverses chloroquine resistance in vitro 6 led to the proposal that efflux may involve anATP-driven P-glycoprotein pump similar to that in mammalian multidrug-resistant (mdr) tumor cell lines.Indeed, Plasmodium falciparum contains at least two mdr-like genes7,8, one of which has beensuggested to confer the chloroquine resistant (CQR) phenotype7,9,10. To determine if either of thesegenes is linked to chloroquine resistance, we performed a genetic cross between CQR andchloroquine-susceptible (CQS) clones of P. falciparum. Examination of 16 independent recombinantprogeny indicated that the rapid efflux phenotype is controlled by a single gene or a closely linked groupof genes. But, there was no linkage between the rapid efflux, CQR phenotype and either of the mdr-likeP. falciparum genes or amplification of those genes. These data indicate that the genetic locus governingchloroquine efflux and resistance is independent of the known mdr-like genes.", "metadata": {}}
+{"_id": "4340358", "title": "", "text": "Identification of a cold receptor reveals a general role for TRP channels in thermosensationThe cellularand molecular mechanisms that enable us to sense cold are not well understood. Insights into thisprocess have come from the use of pharmacological agents, such as menthol, that elicit a coolingsensation. Here we have characterized and cloned a menthol receptor from trigeminal sensory neuronsthat is also activated by thermal stimuli in the cool to cold range. This cold- and menthol-sensitivereceptor, CMR1, is a member of the TRP family of excitatory ion channels, and we propose that itfunctions as a transducer of cold stimuli in the somatosensory system. These findings, together with ourprevious identification of the heat-sensitive channels VR1 and VRL-1, demonstrate that TRP channelsdetect temperatures over a wide range and are the principal sensors of thermal stimuli in the mammalianperipheral nervous system.", "metadata": {}}
+{"_id": "4340509", "title": "", "text": "Surface mechanics mediate pattern formation in the developing retinaPattern formation of biologicalstructures involves organizing different types of cells into a spatial configuration. In this study, weinvestigate the physical basis of biological patterning of the Drosophila retina in vivo. We demonstratethat E- and N-cadherins mediate apical adhesion between retina epithelial cells. Differential expression ofN-cadherin within a sub-group of retinal cells (cone cells) causes them to form an overall shape thatminimizes their surface contact with surrounding cells. The cells within this group, in both normal andexperimentally manipulated conditions, pack together in the same way as soap bubbles do. The shapingof the cone cell group and packing of its components precisely imitate the physical tendency for surfacesto be minimized. Thus, simple patterned expression of N-cadherin results in a complex spatial pattern ofcells owing to cellular surface mechanics.", "metadata": {}}
+{"_id": "4343437", "title": "", "text": "Role of inscuteable in orienting asymmetric cell divisions in DrosophilaDrosophila neuroblasts andepithelial cells in the procephalic neurogenic region divide perpendicular to the surface, and segregate theproteins Numb and Prospero into the basal daughter cell. We demonstrate here that orientation of themitotic spindle and correct localization of Numb and Prospero in these cells require the inscuteable gene.Moreover, ectopic expression of inscuteable in other epithelial cells leads to spindle reorientation. TheInscuteable protein localizes to the apical cell cortex before mitosis, suggesting that Inscuteable functionsin establishing polarity for asymmetric cell division.", "metadata": {}}
+{"_id": "4343811", "title": "", "text": "Specific interference by ingested dsRNA.A genetic interference phenomenon in the nematodeCaenorhabditis elegans has been described in which expression of an individual gene can be specificallyreduced by microinjecting a corresponding fragment of double-stranded (ds) RNA. One striking feature ofthis process is a spreading effect: interference in a broad region of the animal is observed following theinjection of dsRNA into the extracellular body cavity. Here we show that C. elegans can respond in agene-specific manner to dsRNA encountered in the environment. C. elegans normally feed on bacteria,ingesting and grinding them in the pharynx and subsequently absorbing bacterial contents in the gut. Wefind that Escherichia coli bacteria expressing dsRNAs can confer specific interference effects on thenematode larvae that feed on them.", "metadata": {}}
+{"_id": "4345315", "title": "", "text": "Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3Missensemutations in the CIAS1 gene cause three autoinflammatory disorders: familial cold autoinflammatorysyndrome, Muckle–Wells syndrome and neonatal-onset multiple-system inflammatory disease. Cryopyrin(also called Nalp3), the product of CIAS1, is a member of the NOD-LRR protein family that has beenlinked to the activation of intracellular host defence signalling pathways. Cryopyrin forms a multi-proteincomplex termed ‘the inflammasome’, which contains the apoptosis-associated speck-like protein (ASC)and caspase-1, and promotes caspase-1 activation and processing of pro-interleukin (IL)-1β (ref. 4).Here we show the effect of cryopyrin deficiency on inflammasome function and immune responses.Cryopyrin and ASC are essential for caspase-1 activation and IL-1β and IL-18 production in response tobacterial RNA and the imidazoquinoline compounds R837 and R848. In contrast, secretion oftumour-necrosis factor-α and IL-6, as well as activation of NF-κB and mitogen-activated protein kinases(MAPKs) were unaffected by cryopyrin deficiency. Furthermore, we show that Toll-like receptors andcryopyrin control the secretion of IL-1β and IL-18 through different intracellular pathways. These resultsreveal a critical role for cryopyrin in host defence through bacterial RNA-mediated activation ofcaspase-1, and provide insights regarding the pathogenesis of autoinflammatory syndromes.", "metadata": {}}
+{"_id": "4345605", "title": "", "text": "Control of cortical GABA circuitry development by Nrg1 and ErbB4 signallingSchizophrenia is a complexdisorder that interferes with the function of several brain systems required for cognition and normal socialbehaviour. Although the most notable clinical aspects of the disease only become apparent during lateadolescence or early adulthood, many lines of evidence suggest that schizophrenia is aneurodevelopmental disorder with a strong genetic component. Several independent studies haveidentified neuregulin 1 (NRG1) and its receptor ERBB4 as important risk genes for schizophrenia,although their precise role in the disease process remains unknown. Here we show that Nrg1 and ErbB4signalling controls the development of inhibitory circuitries in the mammalian cerebral cortex bycell-autonomously regulating the connectivity of specific GABA (γ-aminobutyric acid)-containinginterneurons. In contrast to the prevalent view, which supports a role for these genes in the formationand function of excitatory synapses between pyramidal cells, we found that ErbB4 expression in themouse neocortex and hippocampus is largely confined to certain classes of interneurons. In particular,ErbB4 is expressed by many parvalbumin-expressing chandelier and basket cells, where it localizes toaxon terminals and postsynaptic densities receiving glutamatergic input. Gain- and loss-of-functionexperiments, both in vitro and in vivo, demonstrate that ErbB4 cell-autonomously promotes theformation of axo-axonic inhibitory synapses over pyramidal cells, and that this function is probablymediated by Nrg1. In addition, ErbB4 expression in GABA-containing interneurons regulates theformation of excitatory synapses onto the dendrites of these cells. By contrast, ErbB4 is dispensable forexcitatory transmission between pyramidal neurons. Altogether, our results indicate that Nrg1 and ErbB4signalling is required for the wiring of GABA-mediated circuits in the postnatal cortex, providing a newperspective to the involvement of these genes in the aetiology of schizophrenia.", "metadata": {}}
+{"_id": "4345757", "title": "", "text": "Obesity as a medical problem.Obesity is now so common within the world's population that it is beginningto replace undernutrition and infectious diseases as the most significant contributor to ill health. Inparticular, obesity is associated with diabetes mellitus, coronary heart disease, certain forms of cancer,and sleep-breathing disorders. Obesity is defined by a body-mass index (weight divided by square of theheight) of 30 kg m(-2) or greater, but this does not take into account the morbidity and mortalityassociated with more modest degrees of overweight, nor the detrimental effect of intra-abdominal fat.The global epidemic of obesity results from a combination of genetic susceptibility, increased availabilityof high-energy foods and decreased requirement for physical activity in modern society. Obesity shouldno longer be regarded simply as a cosmetic problem affecting certain individuals, but an epidemic thatthreatens global well being.", "metadata": {}}
+{"_id": "4346436", "title": "", "text": "Nonlinear Elasticity in Biological GelsUnlike most synthetic materials, biological materials often stiffen asthey are deformed. This nonlinear elastic response, critical for the physiological function of some tissues,has been documented since at least the 19th century, but the molecular structure and the designprinciples responsible for it are unknown. Current models for this response require geometrically complexordered structures unique to each material. In this Article we show that a much simpler molecular theoryaccounts for strain stiffening in a wide range of molecularly distinct biopolymer gels formed from purifiedcytoskeletal and extracellular proteins. This theory shows that systems of semi-flexible chains such asfilamentous proteins arranged in an open crosslinked meshwork invariably stiffen at low strains withoutthe need for a specific architecture or multiple elements with different intrinsic stiffnesses.", "metadata": {}}
+{"_id": "4346731", "title": "", "text": "Live-cell delamination counterbalances epithelial growth to limit tissue overcrowdingThe development andmaintenance of an epithelium requires finely balanced rates of growth and cell death. However, themechanical and biochemical mechanisms that ensure proper feedback control of tissue growth, whichwhen deregulated contribute to tumorigenesis, are poorly understood. Here we use the fly notum as amodel system to identify a novel process of crowding-induced cell delamination that balances growth toensure the development of well-ordered cell packing. In crowded regions of the tissue, a proportion ofcells undergo a serial loss of cell–cell junctions and a progressive loss of apical area, before beingsqueezed out by their neighbours. This path of delamination is recapitulated by a simple computationalmodel of epithelial mechanics, in which stochastic cell loss relieves overcrowding as the system tendstowards equilibrium. We show that this process of delamination is mechanistically distinct fromapoptosis-mediated cell extrusion and precedes the first signs of cell death. Overall, this analysis revealsa simple mechanism that buffers epithelia against variations in growth. Because live-cell delaminationconstitutes a mechanistic link between epithelial hyperplasia and cell invasion, this is likely to haveimportant implications for our understanding of the early stages of cancer development.", "metadata": {}}
+{"_id": "4347374", "title": "", "text": "Broad antiretroviral defence by human APOBEC3G through lethal editing of nascent reversetranscriptsViral replication usually requires that innate intracellular lines of defence be overcome, a taskusually accomplished by specialized viral gene products. The virion infectivity factor (Vif) protein ofhuman immunodeficiency virus (HIV) is required during the late stages of viral production to counter theantiviral activity of APOBEC3G (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G;also known as CEM15), a protein expressed notably in human T lymphocytes. When produced in thepresence of APOBEC3G, vif-defective virus is non-infectious. APOBEC3G is closely related to APOBEC1,the central component of an RNA-editing complex that deaminates a cytosine residue in apoB messengerRNA. APOBEC family members also have potent DNA mutator activity through dC deamination; however,whether the editing potential of APOBEC3G has any relevance to HIV inhibition is unknown. Here, wedemonstrate that it does, as APOBEC3G exerts its antiviral effect during reverse transcription to triggerG-to-A hypermutation in the nascent retroviral DNA. We also find that APOBEC3G can act on a broadrange of retroviruses in addition to HIV, suggesting that hypermutation by editing is a general innatedefence mechanism against this important group of pathogens.", "metadata": {}}
+{"_id": "4350400", "title": "", "text": "Generation of cell polarity in plants links endocytosis, auxin distribution and cell fatedecisionsDynamically polarized membrane proteins define different cell boundaries and have animportant role in intercellular communication—a vital feature of multicellular development. Efflux carriersfor the signalling molecule auxin from the PIN family are landmarks of cell polarity in plants and have acrucial involvement in auxin distribution-dependent development including embryo patterning,organogenesis and tropisms. Polar PIN localization determines the direction of intercellular auxin flow, yetthe mechanisms generating PIN polarity remain unclear. Here we identify an endocytosis-dependentmechanism of PIN polarity generation and analyse its developmental implications. Real-time PIN trackingshowed that after synthesis, PINs are initially delivered to the plasma membrane in a non-polar mannerand their polarity is established by subsequent endocytic recycling. Interference with PIN endocytosiseither by auxin or by manipulation of the Arabidopsis Rab5 GTPase pathway prevents PIN polarization.Failure of PIN polarization transiently alters asymmetric auxin distribution during embryogenesis andincreases the local auxin response in apical embryo regions. This results in ectopic expression of auxinpathway-associated root-forming master regulators in embryonic leaves and promotes homeotictransformation of leaves to roots. Our results indicate a two-step mechanism for the generation of PINpolar localization and the essential role of endocytosis in this process. It also highlights the link betweenendocytosis-dependent polarity of individual cells and auxin distribution-dependent cell fateestablishment for multicellular patterning.", "metadata": {}}
+{"_id": "4353857", "title": "", "text": "Congenital leptin deficiency is associated with severe early-onset obesity in humans.The extreme obesityof the obese (ob/ob) mouse is attributable to mutations in the gene encoding leptin, an adipocyte-specificsecreted protein which has profound effects on appetite and energy expenditure. We know of noequivalent evidence regarding leptin's role in the control of fat mass in humans. We have examined twoseverely obese children who are members of the same highly consanguineous pedigree. Their serumleptin levels were very low despite their markedly elevated fat mass and, in both, a homozygousframe-shift mutation involving the deletion of a single guanine nucleotide in codon 133 of the gene forleptin was found. The severe obesity found in these congenitally leptin-deficient subjects provides thefirst genetic evidence that leptin is an important regulator of energy balance in humans.", "metadata": {}}
+{"_id": "4361990", "title": "", "text": "Targeting of cell-surface β-amyloid precursor protein to lysosomes: alternative processing intoamyloid-bearing fragmentsPROGRESSIVE cerebral deposition of the amyloid β-peptide is an early andinvariant feature of Alzheimer's disease. The β-peptide is released by proteolytic cleavages from theβ-amyloid precursor protein (βAPP)1, a membrane-spanning glycoprotein expressed in most mammaliancells. Normal secretion of βAPP involves a cleavage in the β-peptide region2-3, releasing the solubleextramembranous portion4,5 and retaining a 10K C-terminal fragment in the membrane6. Because thissecretory pathway precludes β-amyloid formation, we searched for an alternative proteolytic processingpathway that can generate β-peptide-bearing fragments from full-length β APP. Incubation of livinghuman endothelial cells with a βAPP antibody revealed reinternalization of mature βAPP from the cellsurface and its targeting to endosomes/lysosomes. After cell-surface biotinylation, full-length biotinylatedβAPP was recovered inside the cells. Purification of lysosomes directly demonstrated the presence ofmature βAPP and an extensive array of β-peptide-containing proteolytic products. Our results define asecond processing pathway for βAPP and suggest that it may be responsible for generatingamyloid-bearing fragments in Alzheimer's disease.", "metadata": {}}
+{"_id": "4362729", "title": "", "text": "A keratin cytoskeletal protein regulates protein synthesis and epithelial cell growthCell growth, anincrease in mass and size, is a highly regulated cellular event. The Akt/mTOR (mammalian target ofrapamycin) signalling pathway has a central role in the control of protein synthesis and thus the growthof cells, tissues and organisms. A striking example of a physiological context requiring rapid cell growth istissue repair in response to injury. Here we show that keratin 17, an intermediate filament protein rapidlyinduced in wounded stratified epithelia, regulates cell growth through binding to the adaptor protein14-3-3σ. Mouse skin keratinocytes lacking keratin 17 (ref. 4) show depressed protein translation and areof smaller size, correlating with decreased Akt/mTOR signalling activity. Other signalling kinases havenormal activity, pointing to the specificity of this defect. Two amino acid residues located in theamino-terminal head domain of keratin 17 are required for the serum-dependent relocalization of14-3-3σ from the nucleus to the cytoplasm, and for the concomitant stimulation of mTOR activity and cellgrowth. These findings reveal a new and unexpected role for the intermediate filament cytoskeleton ininfluencing cell growth and size by regulating protein synthesis.", "metadata": {}}
+{"_id": "4363526", "title": "", "text": "Co-crystal structure of the HNF-3/fork head DNA-recognition motif resembles histone H5Thethree-dimensional structure of an HNF-3/fork head DNA-recognition motif complexed with DNA has beendetermined by X-ray crystallography at 2.5 \u0000 resolution. This α/β protein binds B-DNA as a monomer,through interactions with the DNA backbone and through both direct and water-mediated major andminor groove base contacts, inducing a 13° bend. The transcription factor fold is very similar to thestructure of histone H5. In its amino-terminal half, three α-helices adopt a compact structure thatpresents the third helix to the major groove. The remainder of the protein includes a twisted, antiparallelβ-structure and random coil that interacts with the minor groove.", "metadata": {}}
+{"_id": "4364884", "title": "", "text": "A Mechanism Linking Extra Centrosomes to Chromosomal InstabilityChromosomal instability (CIN) is ahallmark of many tumours and correlates with the presence of extra centrosomes. However, a directmechanistic link between extra centrosomes and CIN has not been established. It has been proposed thatextra centrosomes generate CIN by promoting multipolar anaphase, a highly abnormal division thatproduces three or more aneuploid daughter cells. Here we use long-term live-cell imaging to demonstratethat cells with multiple centrosomes rarely undergo multipolar cell divisions, and the progeny of thesedivisions are typically inviable. Thus, multipolar divisions cannot explain observed rates of CIN. Incontrast, we observe that CIN cells with extra centrosomes routinely undergo bipolar cell divisions, butdisplay a significantly increased frequency of lagging chromosomes during anaphase. To define themechanism underlying this mitotic defect, we generated cells that differ only in their centrosome number.We demonstrate that extra centrosomes alone are sufficient to promote chromosome missegregationduring bipolar cell division. These segregation errors are a consequence of cells passing through atransient 'multipolar spindle intermediate' in which merotelic kinetochore-microtubule attachment errorsaccumulate before centrosome clustering and anaphase. These findings provide a direct mechanistic linkbetween extra centrosomes and CIN, two common characteristics of solid tumours. We propose that thismechanism may be a common underlying cause of CIN in human cancer.", "metadata": {}}
+{"_id": "4366738", "title": "", "text": "Haematopoietic stem cells and early lymphoid progenitors occupy distinct bone marrow nichesAlthoughhaematopoietic stem cells (HSCs) are commonly assumed to reside within a specializedmicroenvironment, or niche, most published experimental manipulations of the HSC niche have affectedthe function of diverse restricted progenitors. This raises the fundamental question of whether HSCs andrestricted progenitors reside within distinct, specialized niches or whether they share a common niche.Here we assess the physiological sources of the chemokine CXCL12 for HSC and restricted progenitormaintenance. Cxcl12(DsRed) knock-in mice (DsRed-Express2 recombined into the Cxcl12 locus) showedthat Cxcl12 was primarily expressed by perivascular stromal cells and, at lower levels, by endothelialcells, osteoblasts and some haematopoietic cells. Conditional deletion of Cxcl12 from haematopoietic cellsor nestin-cre-expressing cells had little or no effect on HSCs or restricted progenitors. Deletion of Cxcl12from endothelial cells depleted HSCs but not myeloerythroid or lymphoid progenitors. Deletion of Cxcl12from perivascular stromal cells depleted HSCs and certain restricted progenitors and mobilized these cellsinto circulation. Deletion of Cxcl12 from osteoblasts depleted certain early lymphoid progenitors but notHSCs or myeloerythroid progenitors, and did not mobilize these cells into circulation. Different stem andprogenitor cells thus reside in distinct cellular niches in bone marrow: HSCs occupy a perivascular nicheand early lymphoid progenitors occupy an endosteal niche.", "metadata": {}}
+{"_id": "4373433", "title": "", "text": "Broad neutralization coverage of HIV by multiple highly potent antibodiesBroadly neutralizing antibodiesagainst highly variable viral pathogens are much sought after to treat or protect against global circulatingviruses. Here we probed the neutralizing antibody repertoires of four human immunodeficiency virus(HIV)-infected donors with remarkably broad and potent neutralizing responses and rescued 17 newmonoclonal antibodies that neutralize broadly across clades. Many of the new monoclonal antibodies arealmost tenfold more potent than the recently described PG9, PG16 and VRC01 broadly neutralizingmonoclonal antibodies and 100-fold more potent than the original prototype HIV broadly neutralizingmonoclonal antibodies. The monoclonal antibodies largely recapitulate the neutralization breadth found inthe corresponding donor serum and many recognize novel epitopes on envelope (Env) glycoproteingp120, illuminating new targets for vaccine design. Analysis of neutralization by the full complement ofanti-HIV broadly neutralizing monoclonal antibodies now available reveals that certain combinations ofantibodies should offer markedly more favourable coverage of the enormous diversity of global circulatingviruses than others and these combinations might be sought in active or passive immunization regimes.Overall, the isolation of multiple HIV broadly neutralizing monoclonal antibodies from several donors that,in aggregate, provide broad coverage at low concentrations is a highly positive indicator for the eventualdesign of an effective antibody-based HIV vaccine.", "metadata": {}}
+{"_id": "4373445", "title": "", "text": "Coordination of Rho GTPase activities during cell protrusionThe GTPases Rac1, RhoA and Cdc42 acttogether to control cytoskeleton dynamics. Recent biosensor studies have shown that all three GTPasesare activated at the front of migrating cells, and biochemical evidence suggests that they may regulateone another: Cdc42 can activate Rac1 (ref. 8), and Rac1 and RhoA are mutually inhibitory. However,their spatiotemporal coordination, at the seconds and single-micrometre dimensions typical of individualprotrusion events, remains unknown. Here we examine GTPase coordination in mouse embryonicfibroblasts both through simultaneous visualization of two GTPase biosensors and using a 'computationalmultiplexing' approach capable of defining the relationships between multiple protein activities visualizedin separate experiments. We found that RhoA is activated at the cell edge synchronous with edgeadvancement, whereas Cdc42 and Rac1 are activated 2 micro-m behind the edge with a delay of 40 s.This indicates that Rac1 and RhoA operate antagonistically through spatial separation and precise timing,and that RhoA has a role in the initial events of protrusion, whereas Rac1 and Cdc42 activate pathwaysimplicated in reinforcement and stabilization of newly expanded protrusions.", "metadata": {}}
+{"_id": "4378885", "title": "", "text": "Understanding mechanisms underlying human gene expression variation with RNAsequencingUnderstanding the genetic mechanisms underlying natural variation in gene expression is acentral goal of both medical and evolutionary genetics, and studies of expression quantitative trait loci(eQTLs) have become an important tool for achieving this goal. Although all eQTL studies so far haveassayed messenger RNA levels using expression microarrays, recent advances in RNA sequencing enablethe analysis of transcript variation at unprecedented resolution. We sequenced RNA from 69lymphoblastoid cell lines derived from unrelated Nigerian individuals that have been extensivelygenotyped by the International HapMap Project. By pooling data from all individuals, we generated a mapof the transcriptional landscape of these cells, identifying extensive use of unannotated untranslatedregions and more than 100 new putative protein-coding exons. Using the genotypes from the HapMapproject, we identified more than a thousand genes at which genetic variation influences overallexpression levels or splicing. We demonstrate that eQTLs near genes generally act by a mechanisminvolving allele-specific expression, and that variation that influences the inclusion of an exon is enrichedwithin and near the consensus splice sites. Our results illustrate the power of high-throughput sequencingfor the joint analysis of variation in transcription, splicing and allele-specific expression across individuals.", "metadata": {}}
+{"_id": "4380004", "title": "", "text": "Mesenchymal and haematopoietic stem cells form a unique bone marrow nicheThe cellular constituentsforming the haematopoietic stem cell (HSC) niche in the bone marrow are unclear, with studiesimplicating osteoblasts, endothelial and perivascular cells. Here we demonstrate that mesenchymal stemcells (MSCs), identified using nestin expression, constitute an essential HSC niche component. Nestin+MSCs contain all the bone-marrow colony-forming-unit fibroblastic activity and can be propagated asnon-adherent ‘mesenspheres’ that can self-renew and expand in serial transplantations. Nestin+ MSCsare spatially associated with HSCs and adrenergic nerve fibres, and highly express HSC maintenancegenes. These genes, and others triggering osteoblastic differentiation, are selectively downregulatedduring enforced HSC mobilization or β3 adrenoreceptor activation. Whereas parathormone administrationdoubles the number of bone marrow nestin+ cells and favours their osteoblastic differentiation, in vivonestin+ cell depletion rapidly reduces HSC content in the bone marrow. Purified HSCs home near nestin+MSCs in the bone marrow of lethally irradiated mice, whereas in vivo nestin+ cell depletion significantlyreduces bone marrow homing of haematopoietic progenitors. These results uncover an unprecedentedpartnership between two distinct somatic stem-cell types and are indicative of a unique niche in the bonemarrow made of heterotypic stem-cell pairs.", "metadata": {}}
+{"_id": "4380287", "title": "", "text": "Response to self antigen imprints regulatory memory in tissuesImmune homeostasis in tissues isachieved through a delicate balance between pathogenic T-cell responses directed at tissue-specificantigens and the ability of the tissue to inhibit these responses. The mechanisms by which tissues andthe immune system communicate to establish and maintain immune homeostasis are currently unknown.Clinical evidence suggests that chronic or repeated exposure to self antigen within tissues leads to anattenuation of pathological autoimmune responses, possibly as a means to mitigate inflammatorydamage and preserve function. Many human organ-specific autoimmune diseases are characterized bythe initial presentation of the disease being the most severe, with subsequent flares being of lesserseverity and duration. In fact, these diseases often spontaneously resolve, despite persistent tissueautoantigen expression. In the practice of antigen-specific immunotherapy, allergens or self antigens arerepeatedly injected in the skin, with a diminution of the inflammatory response occurring after eachsuccessive exposure. Although these findings indicate that tissues acquire the ability to attenuateautoimmune reactions upon repeated responses to antigens, the mechanism by which this occurs isunknown. Here we show that upon expression of self antigen in a peripheral tissue, thymus-derivedregulatory T cells (Treg cells) become activated, proliferate and differentiate into more potentsuppressors, which mediate resolution of organ-specific autoimmunity in mice. After resolution of theinflammatory response, activated Treg cells are maintained in the target tissue and are primed toattenuate subsequent autoimmune reactions when antigen is re-expressed. Thus, Treg cells function toconfer ‘regulatory memory’ to the target tissue. These findings provide a framework for understandinghow Treg cells respond when exposed to self antigen in peripheral tissues and offer mechanistic insightinto how tissues regulate autoimmunity.", "metadata": {}}
+{"_id": "4380451", "title": "", "text": "Reprogramming of human somatic cells to pluripotency with defined factorsPluripotency pertains to thecells of early embryos that can generate all of the tissues in the organism. Embryonic stem cells areembryo-derived cell lines that retain pluripotency and represent invaluable tools for research into themechanisms of tissue formation. Recently, murine fibroblasts have been reprogrammed directly topluripotency by ectopic expression of four transcription factors (Oct4, Sox2, Klf4 and Myc) to yieldinduced pluripotent stem (iPS) cells. Using these same factors, we have derived iPS cells from fetal,neonatal and adult human primary cells, including dermal fibroblasts isolated from a skin biopsy of ahealthy research subject. Human iPS cells resemble embryonic stem cells in morphology and geneexpression and in the capacity to form teratomas in immune-deficient mice. These data demonstrate thatdefined factors can reprogramme human cells to pluripotency, and establish a method wherebypatient-specific cells might be established in culture.", "metadata": {}}
+{"_id": "4381486", "title": "", "text": "Haematopoietic stem cells do not asymmetrically segregate chromosomes or retain BrdUStem cells areproposed to segregate chromosomes asymmetrically during self-renewing divisions so that older(‘immortal’) DNA strands are retained in daughter stem cells whereas newly synthesized strandssegregate to differentiating cells. Stem cells are also proposed to retain DNA labels, such as5-bromo-2-deoxyuridine (BrdU), either because they segregate chromosomes asymmetrically or becausethey divide slowly. However, the purity of stem cells among BrdU-label-retaining cells has not beendocumented in any tissue, and the ‘immortal strand hypothesis’ has not been tested in a system withdefinitive stem cell markers. Here we tested these hypotheses in haematopoietic stem cells (HSCs),which can be highly purified using well characterized markers. We administered BrdU to newborn mice,mice treated with cyclophosphamide and granulocyte colony-stimulating factor, and normal adult mice for4 to 10 days, followed by 70 days without BrdU. In each case, less than 6% of HSCs retained BrdU andless than 0.5% of all BrdU-retaining haematopoietic cells were HSCs, revealing that BrdU has poorspecificity and poor sensitivity as an HSC marker. Sequential administration of 5-chloro-2-deoxyuridineand 5-iodo-2-deoxyuridine indicated that all HSCs segregate their chromosomes randomly. Division ofindividual HSCs in culture revealed no asymmetric segregation of the label. Thus, HSCs cannot beidentified on the basis of BrdU-label retention and do not retain older DNA strands during division,indicating that these are not general properties of stem cells.", "metadata": {}}
+{"_id": "4385779", "title": "", "text": "Circadian Clocks in Human Red Blood CellsCircadian (\u000024 hour) clocks are fundamentally important forcoordinated physiology in organisms as diverse as cyanobacteria and humans. All current models of themolecular circadian clockwork in eukaryotic cells are based on transcription-translation feedback loops.Non-transcriptional mechanisms in the clockwork have been difficult to study in mammalian systems. Wecircumvented these problems by developing novel assays using human red blood cells, which have nonucleus (or DNA) and therefore cannot perform transcription. Our results show that transcription is notrequired for circadian oscillations in humans, and that non-transcriptional events seem to be sufficient tosustain cellular circadian rhythms. Using red blood cells, we found that peroxiredoxins, highly conservedantioxidant proteins, undergo \u000024-hour redox cycles, which persist for many days under constantconditions (that is, in the absence of external cues). Moreover, these rhythms are entrainable (that is,tunable by environmental stimuli) and temperature-compensated, both key features of circadianrhythms. We anticipate that our findings will facilitate more sophisticated cellular clock models,highlighting the interdependency of transcriptional and non-transcriptional oscillations in potentially alleukaryotic cells.", "metadata": {}}
+{"_id": "4387484", "title": "", "text": "G-protein-coupled receptor of Kaposi's sarcoma-associated herpesvirus is a viral oncogene andangiogenesis activator.The Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8) is a gamma-2herpesvirus that is implicated in the pathogenesis of Kaposi's sarcoma and of primary effusion B-celllymphomas (PELs). KSHV infects malignant and progenitor cells of Kaposi's sarcoma and PEL, it encodesputative oncogenes and genes that may cause Kaposi's sarcoma pathogenesis by stimulatingangiogenesis. The G-protein-coupled receptor encoded by an open reading frame (ORF 74) of KSHV isexpressed in Kaposi's sarcoma lesions and in PEL and stimulates signalling pathways linked to cellproliferation in a constitutive (agonist-independent) way. Here we show that signalling by this KSHVG-protein-coupled receptor leads to cell transformation and tumorigenicity, and induces a switch to anangiogenic phenotype mediated by vascular endothelial growth factor, an angiogenesis andKaposi's-spindle-cell growth factor. We find that this receptor can activate two protein kinases, JNK/SAPKand p38MAPK, by triggering signalling cascades like those induced by inflammatory cytokines that areangiogenesis activators and mitogens for Kaposi's sarcoma cells and B cells. We conclude that the KSHVG-protein-coupled receptor is a viral oncogene that can exploit cell signalling pathways to inducetransformation and angiogenesis in KSHV-mediated oncogenesis.", "metadata": {}}
+{"_id": "4387494", "title": "", "text": "Therapeutic potential of GSK-J4, a histone demethylase KDM6B/JMJD3 inhibitor, for acute myeloidleukemiaPURPOSE Acute myeloid leukemia (AML) is a heterogeneous disease with poor outcomes.Despite increased evidence shows that dysregulation of histone modification contributes to AML, specificdrugs targeting key histone modulators are not applied in the clinical treatment of AML. Here, weinvestigated whether targeting KDM6B, the demethylase of tri-methylated histone H3 lysine 27(H3K27me3), has a therapeutic potential for AML. METHODS A KDM6B-specific inhibitor, GSK-J4, wasapplied to treat the primary cells from AML patients and AML cell lines in vitro and in vivo.RNA-sequencing was performed to reveal the underlying mechanisms of inhibiting KDM6B for thetreatment of AML. RESULTS Here we observed that the mRNA expression of KDM6B was up-regulated inAML and positively correlated with poor survival. Treatment with GSK-J4 increased the global level ofH3K27me3 and reduced the proliferation and colony-forming ability of primary AML cells and AML celllines. GSK-J4 treatment significantly induced cell apoptosis and cell-cycle arrest in Kasumi-1 cells, anddisplayed a synergistic effect with cytosine arabinoside. Notably, injection of GSK-J4 attenuated thedisease progression in a human AML xenograft mouse model in vivo. Treatment with GSK-J4predominantly resulted in down-regulation of DNA replication and cell-cycle-related pathways, as well asabrogated the expression of critical cancer-promoting HOX genes. ChIP-qPCR validated an increasedenrichment of H3K27me3 in the transcription start sites of these HOX genes. CONCLUSIONS In summary,our findings suggest that targeting KDM6B with GSK-J4 has a therapeutic potential for the treatment ofAML.", "metadata": {}}
+{"_id": "4387784", "title": "", "text": "Structure of the proton-gated urea channel from the gastric pathogen Helicobacter pyloriHalf the world'spopulation is chronically infected with Helicobacter pylori, causing gastritis, gastric ulcers and anincreased incidence of gastric adenocarcinoma. Its proton-gated inner-membrane urea channel, HpUreI,is essential for survival in the acidic environment of the stomach. The channel is closed at neutral pH andopens at acidic pH to allow the rapid access of urea to cytoplasmic urease. Urease produces NH(3) andCO(2), neutralizing entering protons and thus buffering the periplasm to a pH of roughly 6.1 even ingastric juice at a pH below 2.0. Here we report the structure of HpUreI, revealing six protomersassembled in a hexameric ring surrounding a central bilayer plug of ordered lipids. Each protomerencloses a channel formed by a twisted bundle of six transmembrane helices. The bundle defines apreviously unobserved fold comprising a two-helix hairpin motif repeated three times around the centralaxis of the channel, without the inverted repeat of mammalian-type urea transporters. Both the channeland the protomer interface contain residues conserved in the AmiS/UreI superfamily, suggesting thepreservation of channel architecture and oligomeric state in this superfamily. Predominantly aromatic oraliphatic side chains line the entire channel and define two consecutive constriction sites in the middle ofthe channel. Mutation of Trp 153 in the cytoplasmic constriction site to Ala or Phe decreases theselectivity for urea in comparison with thiourea, suggesting that solute interaction with Trp 153contributes specificity. The previously unobserved hexameric channel structure described here provides anew model for the permeation of urea and other small amide solutes in prokaryotes and archaea.", "metadata": {}}
+{"_id": "4388082", "title": "", "text": "Drosophila oocyte localization is mediated by differential cadherin-based adhesion.In a Drosophila folliclethe oocyte always occupies a posterior position among a group of sixteen germline cells. Although theimportance of this cell arrangement for the subsequent formation of the anterior-posterior axis of theembryo is well documented, the molecular mechanism responsible for the posterior localization of theoocyte was unknown. Here we show that the homophilic adhesion molecule DE-cadherin mediates oocytepositioning. During follicle biogenesis, DE-cadherin is expressed in germline (including oocyte) andsurrounding follicle cells, with the highest concentration of DE-cadherin being found at the interfacebetween oocyte and posterior follicle cells. Mosaic analysis shows that DE-cadherin is required in bothgermline and follicle cells for correct oocyte localization, indicating that germline-soma interactions maybe involved in this process. By analysing the behaviour of the oocyte in follicles with a chimaeric follicularepithelium, we find that the position of the oocyte is determined by the position ofDE-cadherin-expressing follicle cells, to which the oocyte attaches itself selectively. Among theDE-cadherin positive follicle cells, the oocyte preferentially contacts those cells that express higher levelsof DE-cadherin. On the basis of these data, we propose that in wild-type follicles the oocyte competessuccessfully with its sister germline cells for contact to the posterior follicle cells, a sorting process drivenby different concentrations of DE-cadherin. This is, to our knowledge, the first in vivo example of acell-sorting process that depends on differential adhesion mediated by a cadherin.", "metadata": {}}
+{"_id": "4388470", "title": "", "text": "Somatic sex identity is cell-autonomous in the chickenIn the mammalian model of sex determination,embryos are considered to be sexually indifferent until the transient action of a sex-determining geneinitiates gonadal differentiation. Although this model is thought to apply to all vertebrates, this has yet tobe established. Here we have examined three lateral gynandromorph chickens (a rare, naturallyoccurring phenomenon in which one side of the animal appears male and the other female) to investigatethe sex-determining mechanism in birds. These studies demonstrated that gynandromorph birds aregenuine male:female chimaeras, and indicated that male and female avian somatic cells may have aninherent sex identity. To test this hypothesis, we transplanted presumptive mesoderm between embryosof reciprocal sexes to generate embryos containing male:female chimaeric gonads. In contrast to theoutcome for mammalian mixed-sex chimaeras, in chicken mixed-sex chimaeras the donor cells wereexcluded from the functional structures of the host gonad. In an example where female tissue wastransplanted into a male host, donor cells contributing to the developing testis retained a female identityand expressed a marker of female function. Our study demonstrates that avian somatic cells possess aninherent sex identity and that, in birds, sexual differentiation is substantively cell autonomous.", "metadata": {}}
+{"_id": "4389252", "title": "", "text": "Centrosome polarization delivers secretory granules to the immunological synapseCytotoxic Tlymphocytes (CTLs) destroy virally infected and tumorigenic cells by releasing the contents of specializedsecretory lysosomes—termed ‘lytic granules’—at the immunological synapse formed between the CTL andthe target. On contact with the target cell, the microtubule organizing centre of the CTL polarizes towardsthe target and granules move along microtubules in a minus-end direction towards the polarizedmicrotubule organizing centre. However, the final steps of secretion have remained unclear. Here weshow that CTLs do not require actin or plus-end microtubule motors for secretion, but instead thecentrosome moves to and contacts the plasma membrane at the central supramolecular activation clusterof the immunological synapse. Actin and IQGAP1 are cleared away from the synapse, and granules aredelivered directly to the plasma membrane. These data show that CTLs use a previously unreportedmechanism for delivering secretory granules to the immunological synapse, with granule secretioncontrolled by centrosome delivery to the plasma membrane.", "metadata": {}}
+{"_id": "4389394", "title": "", "text": "Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilizationThe p53 tumoursuppressor is a short-lived protein that is maintained at low levels in normal cells by Mdm2-mediatedubiquitination and subsequent proteolysis. Stabilization of p53 is crucial for its tumour suppressorfunction. However, the precise mechanism by which ubiquitinated p53 levels are regulated in vivo is notcompletely understood. By mass spectrometry of affinity-purified p53-associated factors, we haveidentified herpesvirus-associated ubiquitin-specific protease (HAUSP) as a novel p53-interacting protein.HAUSP strongly stabilizes p53 even in the presence of excess Mdm2, and also induces p53-dependent cellgrowth repression and apoptosis. Significantly, HAUSP has an intrinsic enzymatic activity that specificallydeubiquitinates p53 both in vitro and in vivo. In contrast, expression of a catalytically inactive pointmutant of HAUSP in cells increases the levels of p53 ubiquitination and destabilizes p53. These findingsreveal an important mechanism by which p53 can be stabilized by direct deubiquitination and also implythat HAUSP might function as a tumour suppressor in vivo through the stabilization of p53.", "metadata": {}}
+{"_id": "4391121", "title": "", "text": "Defective tryptophan catabolism underlies inflammation in mouse chronic granulomatous diseaseHalf acentury ago, chronic granulomatous disease (CGD) was first described as a disease fatally affecting theability of children to survive infections. Various milestone discoveries have since been made, from aninsufficient ability of patients’ leucocytes to kill microbes to the underlying genetic abnormalities. In thisinherited disorder, phagocytes lack NADPH oxidase activity and do not generate reactive oxygen species,most notably superoxide anion, causing recurrent bacterial and fungal infections. Patients with CGD alsosuffer from chronic inflammatory conditions, most prominently granuloma formation in hollow viscera.The precise mechanisms of the increased microbial pathogenicity have been unclear, and more so thereasons for the exaggerated inflammatory response. Here we show that a superoxide-dependent step intryptophan metabolism along the kynurenine pathway is blocked in CGD mice with lethal pulmonaryaspergillosis, leading to unrestrained Vγ1+ γδ T-cell reactivity, dominant production of interleukin(IL)-17, defective regulatory T-cell activity and acute inflammatory lung injury. Although beneficialeffects are induced by IL-17 neutralization or γδ T-cell contraction, complete cure and reversal of thehyperinflammatory phenotype are achieved by replacement therapy with a natural kynurenine distal tothe blockade in the pathway. Effective therapy, which includes co-administration of recombinantinterferon-γ (IFN-γ), restores production of downstream immunoactive metabolites and enables theemergence of regulatory Vγ4+ γδ and Foxp3+ αβ T cells. Therefore, paradoxically, the lack of reactiveoxygen species contributes to the hyperinflammatory phenotype associated with NADPH oxidasedeficiencies, through a dysfunctional kynurenine pathway of tryptophan catabolism. Yet, this conditioncan be reverted by reactivating the pathway downstream of the superoxide-dependent step.", "metadata": {}}
+{"_id": "4391685", "title": "", "text": "Experimental and theoretical study of mitotic spindle orientationThe architecture and adhesiveness of acell microenvironment is a critical factor for the regulation of spindle orientation in vivo. Using acombination of theory and experiments, we have investigated spindle orientation in HeLa (human) cells.Here we show that spindle orientation can be understood as the result of the action of cortical forcegenerators, which interact with spindle microtubules and are activated by cortical cues. We develop asimple physical description of this spindle mechanics, which allows us to calculate angular profiles of thetorque acting on the spindle, as well as the angular distribution of spindle orientations. Our modelaccounts for the preferred spindle orientation and the shape of the full angular distribution of spindleorientations observed in a large variety of different cellular microenvironment geometries. It alsocorrectly describes asymmetric spindle orientations, which are observed for certain distributions ofcortical cues. We conclude that, on the basis of a few simple assumptions, we can provide a quantitativedescription of the spindle orientation of adherent cells.", "metadata": {}}
+{"_id": "4391817", "title": "", "text": "CHROMOTHRIPSIS FROM DNA DAMAGE IN MICRONUCLEIGenome sequencing has uncovered a newmutational phenomenon in cancer and congenital disorders called chromothripsis. Chromothripsis ischaracterized by extensive genomic rearrangements and an oscillating pattern of DNA copy numberlevels, all curiously restricted to one or a few chromosomes. The mechanism for chromothripsis isunknown, but we previously proposed that it could occur through the physical isolation of chromosomesin aberrant nuclear structures called micronuclei. Here, using a combination of live cell imaging andsingle-cell genome sequencing, we demonstrate that micronucleus formation can indeed generate aspectrum of genomic rearrangements, some of which recapitulate all known features of chromothripsis.These events are restricted to the mis-segregated chromosome and occur within one cell division. Wedemonstrate that the mechanism for chromothripsis can involve the fragmentation and subsequentreassembly of a single chromatid from a micronucleus. Collectively, these experiments establish a newmutational process of which chromothripsis is one extreme outcome.", "metadata": {}}
+{"_id": "4392608", "title": "", "text": "DNA-binding factors shape the mouse methylome at distal regulatory regionsMethylation of cytosines isan essential epigenetic modification in mammalian genomes, yet the rules that govern methylationpatterns remain largely elusive. To gain insights into this process, we generated base-pair-resolutionmouse methylomes in stem cells and neuronal progenitors. Advanced quantitative analysis identifiedlow-methylated regions (LMRs) with an average methylation of 30%. These represent CpG-poor distalregulatory regions as evidenced by location, DNase I hypersensitivity, presence of enhancer chromatinmarks and enhancer activity in reporter assays. LMRs are occupied by DNA-binding factors and theirbinding is necessary and sufficient to create LMRs. A comparison of neuronal and stem-cell methylomesconfirms this dependency, as cell-type-specific LMRs are occupied by cell-type-specific transcriptionfactors. This study provides methylome references for the mouse and shows that DNA-binding factorslocally influence DNA methylation, enabling the identification of active regulatory regions.", "metadata": {}}
+{"_id": "4393153", "title": "", "text": "Molecular basis of RNA-dependent RNA polymerase II activityRNA polymerase (Pol) II catalysesDNA-dependent RNA synthesis during gene transcription. There is, however, evidence that Pol II alsopossesses RNA-dependent RNA polymerase (RdRP) activity. Pol II can use a homopolymeric RNAtemplate, can extend RNA by several nucleotides in the absence of DNA, and has been implicated in thereplication of the RNA genomes of hepatitis delta virus (HDV) and plant viroids. Here we show theintrinsic RdRP activity of Pol II with only pure polymerase, an RNA template–product scaffold andnucleoside triphosphates (NTPs). Crystallography reveals the template–product duplex in the siteoccupied by the DNA–RNA hybrid during transcription. RdRP activity resides at the active site used duringtranscription, but it is slower and less processive than DNA-dependent activity. RdRP activity is alsoobtained with part of the HDV antigenome. The complex of transcription factor IIS (TFIIS) with Pol II cancleave one HDV strand, create a reactive stem-loop in the hybrid site, and extend the new RNA 3′ end.Short RNA stem-loops with a 5′ extension suffice for activity, but their growth to a critical lengthapparently impairs processivity. The RdRP activity of Pol II provides a missing link in molecular evolution,because it suggests that Pol II evolved from an ancient replicase that duplicated RNA genomes.", "metadata": {}}
+{"_id": "4394525", "title": "", "text": "Bacteria activate sensory neurons that modulate pain and inflammationNociceptor sensory neurons arespecialized to detect potentially damaging stimuli, protecting the organism by initiating the sensation ofpain and eliciting defensive behaviours. Bacterial infections produce pain by unknown molecularmechanisms, although they are presumed to be secondary to immune activation. Here we demonstratethat bacteria directly activate nociceptors, and that the immune response mediated through TLR2,MyD88, T cells, B cells, and neutrophils and monocytes is not necessary for Staphylococcusaureus-induced pain in mice. Mechanical and thermal hyperalgesia in mice is correlated with live bacterialload rather than tissue swelling or immune activation. Bacteria induce calcium flux and action potentialsin nociceptor neurons, in part via bacterial N-formylated peptides and the pore-forming toxinα-haemolysin, through distinct mechanisms. Specific ablation of Nav1.8-lineage neurons, which includenociceptors, abrogated pain during bacterial infection, but concurrently increased local immuneinfiltration and lymphadenopathy of the draining lymph node. Thus, bacterial pathogens produce pain bydirectly activating sensory neurons that modulate inflammation, an unsuspected role for the nervoussystem in host-pathogen interactions.", "metadata": {}}
+{"_id": "4394817", "title": "", "text": "E2F1-3 Switch from Activators in Progenitor Cells to Repressors in Differentiating CellsIn the establishedmodel of mammalian cell cycle control, the retinoblastoma protein (Rb) functions to restrict cells fromentering S phase by binding and sequestering E2f activators (E2f1, E2f2 and E2f3), which are invariablyportrayed as the ultimate effectors of a transcriptional program that commit cells to enter and progressthrough S phase. Using a panel of tissue-specific cre-transgenic mice and conditional E2f alleles weexamined the effects of E2f1, E2f2 and E2f3 triple deficiency in murine embryonic stem cells, embryosand small intestines. We show that in normal dividing progenitor cells E2f1-3 function as transcriptionalactivators, but contrary to the current view, are dispensable for cell division and instead are necessary forcell survival. In differentiating cells E2f1-3 function in a complex with Rb as repressors to silence E2ftargets and facilitate exit from the cell cycle. The inactivation of Rb in differentiating cells resulted in aswitch of E2f1-3 from repressors to activators, leading to the superactivation of E2f responsive targetsand ectopic cell divisions. Loss of E2f1-3 completely suppressed these phenotypes caused by Rbdeficiency. This work contextualizes the activator versus repressor functions of E2f1-3 in vivo, revealingdistinct roles in dividing versus differentiating cells and in normal versus cancer-like cell cycles.", "metadata": {}}
+{"_id": "4396105", "title": "", "text": "K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactionsSomatic mutations in thesmall GTPase K-Ras are the most common activating lesions found in human cancer, and are generallyassociated with poor response to standard therapies. Efforts to target this oncogene directly have faceddifficulties owing to its picomolar affinity for GTP/GDP and the absence of known allosteric regulatorysites. Oncogenic mutations result in functional activation of Ras family proteins by impairing GTPhydrolysis. With diminished regulation by GTPase activity, the nucleotide state of Ras becomes moredependent on relative nucleotide affinity and concentration. This gives GTP an advantage over GDP andincreases the proportion of active GTP-bound Ras. Here we report the development of small moleculesthat irreversibly bind to a common oncogenic mutant, K-Ras(G12C). These compounds rely on themutant cysteine for binding and therefore do not affect the wild-type protein. Crystallographic studiesreveal the formation of a new pocket that is not apparent in previous structures of Ras, beneath theeffector binding switch-II region. Binding of these inhibitors to K-Ras(G12C) disrupts both switch-I andswitch-II, subverting the native nucleotide preference to favour GDP over GTP and impairing binding toRaf. Our data provide structure-based validation of a new allosteric regulatory site on Ras that istargetable in a mutant-specific manner.", "metadata": {}}
+{"_id": "4398832", "title": "", "text": "Cyclin A Regulates Kinetochore-Microtubules to Promote Faithful Chromosome SegregationThe mostconspicuous event in the cell cycle is the alignment of chromosomes in metaphase. Chromosomealignment fosters faithful segregation through the formation of bi-oriented attachments of kinetochoresto spindle microtubules. Notably, numerous kinetochore-microtubule (k-MT) attachment errors arepresent in early mitosis (prometaphase), and the persistence of those errors is the leading cause ofchromosome mis-segregation in aneuploid human tumour cells that continually mis-segregate wholechromosomes and display chromosomal instability. How robust error correction is achieved inprometaphase to ensure error-free mitosis remains unknown. Here we show that k-MT attachments inprometaphase cells are considerably less stable than in metaphase cells. The switch to more stable k-MTattachments in metaphase requires the proteasome-dependent destruction of cyclin A in prometaphase.Persistent cyclin A expression prevents k-MT stabilization even in cells with aligned chromosomes. Bycontrast, k-MTs are prematurely stabilized in cyclin-A-deficient cells. Consequently, cells lacking cyclin Adisplay higher rates of chromosome mis-segregation. Thus, the stability of k-MT attachments increasesdecisively in a coordinated fashion among all chromosomes as cells transit from prometaphase tometaphase. Cyclin A creates a cellular environment that promotes microtubule detachment fromkinetochores in prometaphase to ensure efficient error correction and faithful chromosome segregation.", "metadata": {}}
+{"_id": "4399268", "title": "", "text": "Induced pluripotent stem cells from a spinal muscular atrophy patientSpinal muscular atrophy is one ofthe most common inherited forms of neurological disease leading to infant mortality. Patients haveselective loss of lower motor neurons resulting in muscle weakness, paralysis and often death. Althoughpatient fibroblasts have been used extensively to study spinal muscular atrophy, motor neurons have aunique anatomy and physiology which may underlie their vulnerability to the disease process. Here wereport the generation of induced pluripotent stem cells from skin fibroblast samples taken from a childwith spinal muscular atrophy. These cells expanded robustly in culture, maintained the disease genotypeand generated motor neurons that showed selective deficits compared to those derived from the child’sunaffected mother. This is the first study to show that human induced pluripotent stem cells can be usedto model the specific pathology seen in a genetically inherited disease. As such, it represents a promisingresource to study disease mechanisms, screen new drug compounds and develop new therapies.", "metadata": {}}
+{"_id": "4399311", "title": "", "text": "A role for mitochondria in NLRP3 inflammasome activationAn inflammatory response initiated by theNLRP3 inflammasome is triggered by a variety of situations of host ‘danger’, including infection andmetabolic dysregulation. Previous studies suggested that NLRP3 inflammasome activity is negativelyregulated by autophagy and positively regulated by reactive oxygen species (ROS) derived from anuncharacterized organelle. Here we show that mitophagy/autophagy blockade leads to the accumulationof damaged, ROS-generating mitochondria, and this in turn activates the NLRP3 inflammasome. RestingNLRP3 localizes to endoplasmic reticulum structures, whereas on inflammasome activation both NLRP3and its adaptor ASC redistribute to the perinuclear space where they co-localize with endoplasmicreticulum and mitochondria organelle clusters. Notably, both ROS generation and inflammasomeactivation are suppressed when mitochondrial activity is dysregulated by inhibition of thevoltage-dependent anion channel. This indicates that NLRP3 inflammasome senses mitochondrialdysfunction and may explain the frequent association of mitochondrial damage with inflammatorydiseases.", "metadata": {}}
+{"_id": "4401289", "title": "", "text": "Break-induced telomere synthesis underlies alternative telomere maintenanceHomology-directed DNArepair is essential for genome maintenance through templated DNA synthesis. Alternative lengthening oftelomeres (ALT) necessitates homology-directed DNA repair to maintain telomeres in about 10–15% ofhuman cancers. How DNA damage induces assembly and execution of a DNA replication complex(break-induced replisome) at telomeres or elsewhere in the mammalian genome is poorly understood.Here we define break-induced telomere synthesis and demonstrate that it utilizes a specialized replisome,which underlies ALT telomere maintenance. DNA double-strand breaks enact nascent telomere synthesisby long-tract unidirectional replication. Proliferating cell nuclear antigen (PCNA) loading by replicationfactor C (RFC) acts as the initial sensor of telomere damage to establish predominance of DNApolymerase δ (Pol δ) through its POLD3 subunit. Break-induced telomere synthesis requires theRFC–PCNA–Pol δ axis, but is independent of other canonical replisome components, ATM and ATR, or thehomologous recombination protein Rad51. Thus, the inception of telomere damage recognition by thebreak-induced replisome orchestrates homology-directed telomere maintenance.", "metadata": {}}
+{"_id": "4402497", "title": "", "text": "Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNAInnateimmune defences are essential for the control of virus infection and are triggered through hostrecognition of viral macromolecular motifs known as pathogen-associated molecular patterns (PAMPs).Hepatitis C virus (HCV) is an RNA virus that replicates in the liver, and infects 200 million peopleworldwide. Infection is regulated by hepatic immune defences triggered by the cellular RIG-I helicase.RIG-I binds PAMP RNA and signals interferon regulatory factor 3 activation to induce the expression ofinterferon-α/β and antiviral/interferon-stimulated genes (ISGs) that limit infection. Here we identify thepolyuridine motif of the HCV genome 3′ non-translated region and its replication intermediate as thePAMP substrate of RIG-I, and show that this and similar homopolyuridine or homopolyriboadenine motifspresent in the genomes of RNA viruses are the chief feature of RIG-I recognition and immune triggeringin human and murine cells. 5′ terminal triphosphate on the PAMP RNA was necessary but not sufficientfor RIG-I binding, which was primarily dependent on homopolymeric ribonucleotide composition, linearstructure and length. The HCV PAMP RNA stimulated RIG-I-dependent signalling to induce a hepaticinnate immune response in vivo, and triggered interferon and ISG expression to suppress HCV infectionin vitro. These results provide a conceptual advance by defining specific homopolymeric RNA motifswithin the genome of HCV and other RNA viruses as the PAMP substrate of RIG-I, and demonstrateimmunogenic features of the PAMP–RIG-I interaction that could be used as an immune adjuvant forvaccine and immunotherapy approaches.", "metadata": {}}
+{"_id": "4404433", "title": "", "text": "Generation of transgenic non-human primates with germline transmissionThe common marmoset(Callithrix jacchus) is increasingly attractive for use as a non-human primate animal model in biomedicalresearch. It has a relatively high reproduction rate for a primate, making it potentially suitable fortransgenic modification. Although several attempts have been made to produce non-human transgenicprimates, transgene expression in the somatic tissues of live infants has not been demonstrated byobjective analyses such as polymerase chain reaction with reverse transcription or western blots. Here weshow that the injection of a self-inactivating lentiviral vector in sucrose solution into marmoset embryosresults in transgenic common marmosets that expressed the transgene in several organs. Notably, weachieved germline transmission of the transgene, and the transgenic offspring developed normally. Thesuccessful creation of transgenic marmosets provides a new animal model for human disease that has thegreat advantage of a close genetic relationship with humans. This model will be valuable to many fields ofbiomedical research.", "metadata": {}}
+{"_id": "4405194", "title": "", "text": "Induction of human neuronal cells by defined transcription factorsSomatic cell nuclear transfer, cellfusion, or expression of lineage-specific factors have been shown to induce cell-fate changes in diversesomatic cell types. We recently observed that forced expression of a combination of three transcriptionfactors, Brn2 (also known as Pou3f2), Ascl1 and Myt1l, can efficiently convert mouse fibroblasts intofunctional induced neuronal (iN) cells. Here we show that the same three factors can generate functionalneurons from human pluripotent stem cells as early as 6 days after transgene activation. When combinedwith the basic helix-loop-helix transcription factor NeuroD1, these factors could also convert fetal andpostnatal human fibroblasts into iN cells showing typical neuronal morphologies and expressing multipleneuronal markers, even after downregulation of the exogenous transcription factors. Importantly, thevast majority of human iN cells were able to generate action potentials and many matured to receivesynaptic contacts when co-cultured with primary mouse cortical neurons. Our data demonstrate thatnon-neural human somatic cells, as well as pluripotent stem cells, can be converted directly into neuronsby lineage-determining transcription factors. These methods may facilitate robust generation ofpatient-specific human neurons for in vitro disease modelling or future applications in regenerativemedicine.", "metadata": {}}
+{"_id": "4406819", "title": "", "text": "PAAR-repeat proteins sharpen and diversify the Type VI secretion system spikeThe bacterial type VIsecretion system (T6SS) is a large multicomponent, dynamic macromolecular machine that has animportant role in the ecology of many Gram-negative bacteria. T6SS is responsible for translocation of awide range of toxic effector molecules, allowing predatory cells to kill both prokaryotic as well aseukaryotic prey cells. The T6SS organelle is functionally analogous to contractile tails of bacteriophagesand is thought to attack cells by initially penetrating them with a trimeric protein complex called the VgrGspike. Neither the exact protein composition of the T6SS organelle nor the mechanisms of effectorselection and delivery are known. Here we report that proteins from the PAAR(proline-alanine-alanine-arginine) repeat superfamily form a sharp conical extension on the VgrG spike,which is further involved in attaching effector domains to the spike. The crystal structures of twoPAAR-repeat proteins bound to VgrG-like partners show that these proteins sharpen the tip of the T6SSspike complex. We demonstrate that PAAR proteins are essential for T6SS-mediated secretion and targetcell killing by Vibrio cholerae and Acinetobacter baylyi. Our results indicate a new model of the T6SSorganelle in which the VgrG-PAAR spike complex is decorated with multiple effectors that are deliveredsimultaneously into target cells in a single contraction-driven translocation event.", "metadata": {}}
+{"_id": "4407318", "title": "", "text": "Replication stress activates DNA repair synthesis in mitosisOncogene-induced DNA replication stress hasbeen implicated as a driver of tumorigenesis. Many chromosomal rearrangements characteristic of humancancers originate from specific regions of the genome called common fragile sites (CFSs). CFSs aredifficult-to-replicate loci that manifest as gaps or breaks on metaphase chromosomes (termed CFS‘expression’), particularly when cells have been exposed to replicative stress. The MUS81–EME1structure-specific endonuclease promotes the appearance of chromosome gaps or breaks at CFSsfollowing replicative stress. Here we show that entry of cells into mitotic prophase triggers therecruitment of MUS81 to CFSs. The nuclease activity of MUS81 then promotes POLD3-dependent DNAsynthesis at CFSs, which serves to minimize chromosome mis-segregation and non-disjunction. Wepropose that the attempted condensation of incompletely duplicated loci in early mitosis serves as thetrigger for completion of DNA replication at CFS loci in human cells. Given that this POLD3-dependentmitotic DNA synthesis is enhanced in aneuploid cancer cells that exhibit intrinsically high levels ofchromosomal instability (CIN+) and replicative stress, we suggest that targeting this pathway couldrepresent a new therapeutic approach.", "metadata": {}}
+{"_id": "4407385", "title": "", "text": "A specific amyloid-β protein assembly in the brain impairs memoryMemory function often declines withage, and is believed to deteriorate initially because of changes in synaptic function rather than loss ofneurons. Some individuals then go on to develop Alzheimer's disease with neurodegeneration. Here weuse Tg2576 mice, which express a human amyloid-β precursor protein (APP) variant linked to Alzheimer'sdisease, to investigate the cause of memory decline in the absence of neurodegeneration or amyloid-βprotein amyloidosis. Young Tg2576 mice (< 6 months old) have normal memory and lackneuropathology, middle-aged mice (6–14 months old) develop memory deficits without neuronal loss,and old mice (> 14 months old) form abundant neuritic plaques containing amyloid-β (refs 3–6). Wefound that memory deficits in middle-aged Tg2576 mice are caused by the extracellular accumulation of a56-kDa soluble amyloid-β assembly, which we term Aβ*56 (Aβ star 56). Aβ*56 purified from the brainsof impaired Tg2576 mice disrupts memory when administered to young rats. We propose that Aβ*56impairs memory independently of plaques or neuronal loss, and may contribute to cognitive deficitsassociated with Alzheimer's disease.", "metadata": {}}
+{"_id": "4407455", "title": "", "text": "Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell deathInflammatory caspases(caspase-1, -4, -5 and -11) are critical for innate defences. Caspase-1 is activated by ligands of variouscanonical inflammasomes, and caspase-4, -5 and -11 directly recognize bacterial lipopolysaccharide, bothof which trigger pyroptosis. Despite the crucial role in immunity and endotoxic shock, the mechanism forpyroptosis induction by inflammatory caspases is unknown. Here we identify gasdermin D (Gsdmd) bygenome-wide clustered regularly interspaced palindromic repeat (CRISPR)-Cas9 nuclease screens ofcaspase-11- and caspase-1-mediated pyroptosis in mouse bone marrow macrophages. GSDMD-deficientcells resisted the induction of pyroptosis by cytosolic lipopolysaccharide and known canonicalinflammasome ligands. Interleukin-1β release was also diminished in Gsdmd−/− cells, despite intactprocessing by caspase-1. Caspase-1 and caspase-4/5/11 specifically cleaved the linker between theamino-terminal gasdermin-N and carboxy-terminal gasdermin-C domains in GSDMD, which was requiredand sufficient for pyroptosis. The cleavage released the intramolecular inhibition on the gasdermin-Ndomain that showed intrinsic pyroptosis-inducing activity. Other gasdermin family members were notcleaved by inflammatory caspases but shared the autoinhibition; gain-of-function mutations in Gsdma3that cause alopecia and skin defects disrupted the autoinhibition, allowing its gasdermin-N domain totrigger pyroptosis. These findings offer insight into inflammasome-mediated immunity/diseases and alsochange our understanding of pyroptosis and programmed necrosis.", "metadata": {}}
+{"_id": "4409524", "title": "", "text": "Role of corin in trophoblast invasion and uterine spiral artery remodelling in pregnancyIn pregnancy,trophoblast invasion and uterine spiral artery remodelling are important for lowering maternal vascularresistance and increasing uteroplacental blood flow. Impaired spiral artery remodelling has beenimplicated in pre-eclampsia, a major complication of pregnancy, for a long time but the underlyingmechanisms remain unclear. Corin (also known as atrial natriuretic peptide-converting enzyme) is acardiac protease that activates atrial natriuretic peptide (ANP), a cardiac hormone that is important inregulating blood pressure. Unexpectedly, corin expression was detected in the pregnant uterus. Here weidentify a new function of corin and ANP in promoting trophoblast invasion and spiral artery remodelling.We show that pregnant corin- or ANP-deficient mice developed high blood pressure and proteinuria,characteristics of pre-eclampsia. In these mice, trophoblast invasion and uterine spiral artery remodellingwere markedly impaired. Consistent with this, the ANP potently stimulated human trophoblasts ininvading Matrigels. In patients with pre-eclampsia, uterine Corin messenger RNA and protein levels weresignificantly lower than that in normal pregnancies. Moreover, we have identified Corin gene mutations inpre-eclamptic patients, which decreased corin activity in processing pro-ANP. These results indicate thatcorin and ANP are essential for physiological changes at the maternal–fetal interface, suggesting thatdefects in corin and ANP function may contribute to pre-eclampsia.", "metadata": {}}
+{"_id": "4410181", "title": "", "text": "Metabolic rescue in pluripotent cells from patients with mtDNA diseaseMitochondria have a major role inenergy production via oxidative phosphorylation, which is dependent on the expression of critical genesencoded by mitochondrial (mt)DNA. Mutations in mtDNA can cause fatal or severely debilitating disorderswith limited treatment options. Clinical manifestations vary based on mutation type and heteroplasmy(that is, the relative levels of mutant and wild-type mtDNA within each cell). Here we generatedgenetically corrected pluripotent stem cells (PSCs) from patients with mtDNA disease. Multiple inducedpluripotent stem (iPS) cell lines were derived from patients with common heteroplasmic mutationsincluding 3243A>G, causing mitochondrial encephalomyopathy and stroke-like episodes (MELAS), and8993T>G and 13513G>A, implicated in Leigh syndrome. Isogenic MELAS and Leigh syndrome iPS celllines were generated containing exclusively wild-type or mutant mtDNA through spontaneous segregationof heteroplasmic mtDNA in proliferating fibroblasts. Furthermore, somatic cell nuclear transfer (SCNT)enabled replacement of mutant mtDNA from homoplasmic 8993T>G fibroblasts to generate correctedLeigh-NT1 PSCs. Although Leigh-NT1 PSCs contained donor oocyte wild-type mtDNA (human haplotypeD4a) that differed from Leigh syndrome patient haplotype (F1a) at a total of 47 nucleotide sites,Leigh-NT1 cells displayed transcriptomic profiles similar to those in embryo-derived PSCs carryingwild-type mtDNA, indicative of normal nuclear-to-mitochondrial interactions. Moreover, geneticallyrescued patient PSCs displayed normal metabolic function compared to impaired oxygen consumptionand ATP production observed in mutant cells. We conclude that both reprogramming approaches offercomplementary strategies for derivation of PSCs containing exclusively wild-type mtDNA, throughspontaneous segregation of heteroplasmic mtDNA in individual iPS cell lines or mitochondrial replacementby SCNT in homoplasmic mtDNA-based disease.", "metadata": {}}
+{"_id": "4411655", "title": "", "text": "The yeast Pif1p helicase removes telomerase from telomeric DNATelomeres are the physical ends ofeukaryotic chromosomes. Genetic studies have established that the baker's yeast Pif1p DNA helicase is anegative regulator of telomerase, the specialized reverse transcriptase that maintains telomeric DNA, butthe biochemical basis for this inhibition was unknown. Here we show that in vitro, Pif1p reduces theprocessivity of telomerase and releases telomerase from telomeric oligonucleotides. The releasedtelomerase is enzymatically active because it is able to lengthen a challenger oligonucleotide. In vivo,overexpression of Pif1p reduces telomerase association with telomeres, whereas depleting cells of Pif1pincreases the levels of telomere-bound Est1p, a telomerase subunit that is present on the telomere whentelomerase is active. We propose that Pif1p helicase activity limits telomerase action both in vivo and invitro by displacing active telomerase from DNA ends.", "metadata": {}}
+{"_id": "4411760", "title": "", "text": "Small regulatory RNAs inhibit RNA Polymerase II during the elongation phase of transcriptionEukaryoticcells express a wide variety of endogenous small regulatory RNAs that regulate heterochromatinformation, developmental timing, defence against parasitic nucleic acids and genome rearrangement.Many small regulatory RNAs are thought to function in nuclei. For instance, in plants and fungi, shortinterfering RNA (siRNAs) associate with nascent transcripts and direct chromatin and/or DNAmodifications. To understand further the biological roles of small regulatory RNAs, we conducted agenetic screen to identify factors required for RNA interference (RNAi) in Caenorhabditis elegans nuclei.Here we show that the gene nuclear RNAi defective-2 (nrde-2) encodes an evolutionarily conservedprotein that is required for siRNA-mediated silencing in nuclei. NRDE-2 associates with the Argonauteprotein NRDE-3 within nuclei and is recruited by NRDE-3/siRNA complexes to nascent transcripts thathave been targeted by RNAi. We find that nuclear-localized siRNAs direct an NRDE-2-dependent silencingof pre-messenger RNAs (pre-mRNAs) 3' to sites of RNAi, an NRDE-2-dependent accumulation of RNApolymerase (RNAP) II at genomic loci targeted by RNAi, and NRDE-2-dependent decreases in RNAP IIoccupancy and RNAP II transcriptional activity 3' to sites of RNAi. These results define NRDE-2 as acomponent of the nuclear RNAi machinery and demonstrate that metazoan siRNAs can silencenuclear-localized RNAs co-transcriptionally. In addition, these results establish a novel mode of RNAP IIregulation: siRNA-directed recruitment of NRDE factors that inhibit RNAP II during the elongation phaseof transcription.", "metadata": {}}
+{"_id": "4412772", "title": "", "text": "Cdk1 is sufficient to drive the mammalian cell cycleUnicellular organisms such as yeasts require a singlecyclin-dependent kinase, Cdk1, to drive cell division. In contrast, mammalian cells are thought to requirethe sequential activation of at least four different cyclin-dependent kinases, Cdk2, Cdk3, Cdk4 and Cdk6,to drive cells through interphase, as well as Cdk1 to proceed through mitosis. This model has beenchallenged by recent genetic evidence that mice survive in the absence of individual interphase Cdks.Moreover, most mouse cell types proliferate in the absence of two or even three interphase Cdks. Similarresults have been obtained on ablation of some of the activating subunits of Cdks, such as the D-type andE-type cyclins. Here we show that mouse embryos lacking all interphase Cdks (Cdk2, Cdk3, Cdk4 andCdk6) undergo organogenesis and develop to midgestation. In these embryos, Cdk1 binds to all cyclins,resulting in the phosphorylation of the retinoblastoma protein pRb and the expression of genes that areregulated by E2F transcription factors. Mouse embryonic fibroblasts derived from these embryosproliferate in vitro, albeit with an extended cell cycle due to inefficient inactivation of Rb proteins.However, they become immortal on continuous passage. We also report that embryos fail to develop tothe morula and blastocyst stages in the absence of Cdk1. These results indicate that Cdk1 is the onlyessential cell cycle Cdk. Moreover, they show that in the absence of interphase Cdks, Cdk1 can executeall the events that are required to drive cell division.", "metadata": {}}
+{"_id": "4414481", "title": "", "text": "Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respirationCalorie restriction(CR) extends lifespan in a wide spectrum of organisms and is the only regimen known to lengthen thelifespan of mammals. We established a model of CR in budding yeast Saccharomyces cerevisiae. In thissystem, lifespan can be extended by limiting glucose or by reducing the activity of the glucose-sensingcyclic-AMP-dependent kinase (PKA). Lifespan extension in a mutant with reduced PKA activity requiresSir2 and NAD (nicotinamide adenine dinucleotide). In this study we explore how CR activates Sir2 toextend lifespan. Here we show that the shunting of carbon metabolism toward the mitochondrialtricarboxylic acid cycle and the concomitant increase in respiration play a central part in this process. Wediscuss how this metabolic strategy may apply to CR in animals.", "metadata": {}}
+{"_id": "4414547", "title": "", "text": "Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancerImprovedsequencing technologies offer unprecedented opportunities for investigating the role of rare geneticvariation in common disease. However, there are considerable challenges with respect to study design,data analysis and replication. Using pooled next-generation sequencing of 507 genes implicated in therepair of DNA in 1,150 samples, an analytical strategy focused on protein-truncating variants (PTVs) anda large-scale sequencing case–control replication experiment in 13,642 individuals, here we show thatrare PTVs in the p53-inducible protein phosphatase PPM1D are associated with predisposition to breastcancer and ovarian cancer. PPM1D PTV mutations were present in 25 out of 7,781 cases versus 1 out of5,861 controls (P = 1.12 × 10−5), including 18 mutations in 6,912 individuals with breast cancer (P =2.42 × 10−4) and 12 mutations in 1,121 individuals with ovarian cancer (P = 3.10 × 10−9). Notably, allof the identified PPM1D PTVs were mosaic in lymphocyte DNA and clustered within a 370-base-pair regionin the final exon of the gene, carboxy-terminal to the phosphatase catalytic domain. Functional studiesdemonstrate that the mutations result in enhanced suppression of p53 in response to ionizing radiationexposure, suggesting that the mutant alleles encode hyperactive PPM1D isoforms. Thus, although themutations cause premature protein truncation, they do not result in the simple loss-of-function effecttypically associated with this class of variant, but instead probably have a gain-of-function effect. Ourresults have implications for the detection and management of breast and ovarian cancer risk. Moregenerally, these data provide new insights into the role of rare and of mosaic genetic variants in commonconditions, and the use of sequencing in their identification.", "metadata": {}}
+{"_id": "4416964", "title": "", "text": "Immunogenicity of induced pluripotent stem cellsInduced pluripotent stem cells (iPSCs), reprogrammedfrom somatic cells with defined factors, hold great promise for regenerative medicine as the renewablesource of autologous cells. Whereas it has been generally assumed that these autologous cells should beimmune-tolerated by the recipient from whom the iPSCs are derived, their immunogenicity has not beenvigorously examined. We show here that, whereas embryonic stem cells (ESCs) derived from inbredC57BL/6 (B6) mice can efficiently form teratomas in B6 mice without any evident immune rejection, theallogeneic ESCs from 129/SvJ mice fail to form teratomas in B6 mice due to rapid rejection by recipients.B6 mouse embryonic fibroblasts (MEFs) were reprogrammed into iPSCs by either retroviral approach(ViPSCs) or a novel episomal approach (EiPSCs) that causes no genomic integration. In contrast to B6ESCs, teratomas formed by B6 ViPSCs were mostly immune-rejected by B6 recipients. In addition, themajority of teratomas formed by B6 EiPSCs were immunogenic in B6 mice with T cell infiltration, andapparent tissue damage and regression were observed in a small fraction of teratomas. Global geneexpression analysis of teratomas formed by B6 ESCs and EiPSCs revealed a number of genes frequentlyoverexpressed in teratomas derived from EiPSCs, and several such gene products were shown tocontribute directly to the immunogenicity of the B6 EiPSC-derived cells in B6 mice. These findingsindicate that, in contrast to derivatives of ESCs, abnormal gene expression in some cells differentiatedfrom iPSCs can induce T-cell-dependent immune response in syngeneic recipients. Therefore, theimmunogenicity of therapeutically valuable cells derived from patient-specific iPSCs should be evaluatedbefore any clinic application of these autologous cells into the patients.", "metadata": {}}
+{"_id": "4417177", "title": "", "text": "Direct conversion of human fibroblasts to multilineage blood progenitorsAs is the case for embryo-derivedstem cells, application of reprogrammed human induced pluripotent stem cells is limited by ourunderstanding of lineage specification. Here we demonstrate the ability to generate progenitors andmature cells of the haematopoietic fate directly from human dermal fibroblasts without establishingpluripotency. Ectopic expression of OCT4 (also called POU5F1)-activated haematopoietic transcriptionfactors, together with specific cytokine treatment, allowed generation of cells expressing thepan-leukocyte marker CD45. These unique fibroblast-derived cells gave rise to granulocytic, monocytic,megakaryocytic and erythroid lineages, and demonstrated in vivo engraftment capacity. We note thatadult haematopoietic programs are activated, consistent with bypassing the pluripotent state to generateblood fate: this is distinct from haematopoiesis involving pluripotent stem cells, where embryonicprograms are activated. These findings demonstrate restoration of multipotency from human fibroblasts,and suggest an alternative approach to cellular reprogramming for autologous cell-replacement therapiesthat avoids complications associated with the use of human pluripotent stem cells.", "metadata": {}}
+{"_id": "4417558", "title": "", "text": "Mical links semaphorins to F-actin disassemblyHow instructive cues present on the cell surface have theirprecise effects on the actin cytoskeleton is poorly understood. Semaphorins are one of the largestfamilies of these instructive cues and are widely studied for their effects on cell movement, navigation,angiogenesis, immunology and cancer. Semaphorins/collapsins were characterized in part on the basis oftheir ability to drastically alter actin cytoskeletal dynamics in neuronal processes, but despiteconsiderable progress in the identification of semaphorin receptors and their signalling pathways, themolecules linking them to the precise control of cytoskeletal elements remain unknown. Recently, highlyunusual proteins of the Mical family of enzymes have been found to associate with the cytoplasmicportion of plexins, which are large cell-surface semaphorin receptors, and to mediate axon guidance,synaptogenesis, dendritic pruning and other cell morphological changes. Mical enzymes performreduction–oxidation (redox) enzymatic reactions and also contain domains found in proteins that regulatecell morphology. However, nothing is known of the role of Mical or its redox activity in mediatingmorphological changes. Here we report that Mical directly links semaphorins and their plexin receptors tothe precise control of actin filament (F-actin) dynamics. We found that Mical is both necessary andsufficient for semaphorin–plexin-mediated F-actin reorganization in vivo. Likewise, we purified Micalprotein and found that it directly binds F-actin and disassembles both individual and bundled actinfilaments. We also found that Mical utilizes its redox activity to alter F-actin dynamics in vivo and in vitro,indicating a previously unknown role for specific redox signalling events in actin cytoskeletal regulation.Mical therefore is a novel F-actin-disassembly factor that provides a molecular conduit through whichactin reorganization—a hallmark of cell morphological changes including axon navigation—can beprecisely achieved spatiotemporally in response to semaphorins.", "metadata": {}}
+{"_id": "4418070", "title": "", "text": "Novel Foxo1-dependent transcriptional programs control Treg cell functionRegulatory T (Treg) cells,characterized by expression of the transcription factor forkhead box P3 (Foxp3), maintain immunehomeostasis by suppressing self-destructive immune responses. Foxp3 operates as a late-actingdifferentiation factor controlling Treg cell homeostasis and function, whereas the early Treg-cell-lineagecommitment is regulated by the Akt kinase and the forkhead box O (Foxo) family of transcription factors.However, whether Foxo proteins act beyond the Treg-cell-commitment stage to control Treg cellhomeostasis and function remains largely unexplored. Here we show that Foxo1 is a pivotal regulator ofTreg cell function. Treg cells express high amounts of Foxo1 and display reduced T-cell-receptor-inducedAkt activation, Foxo1 phosphorylation and Foxo1 nuclear exclusion. Mice with Treg-cell-specific deletionof Foxo1 develop a fatal inflammatory disorder similar in severity to that seen in Foxp3-deficient mice,but without the loss of Treg cells. Genome-wide analysis of Foxo1 binding sites reveals \u0000300Foxo1-bound target genes, including the pro-inflammatory cytokine Ifng, that do not seem to be directlyregulated by Foxp3. These findings show that the evolutionarily ancient Akt–Foxo1 signalling modulecontrols a novel genetic program indispensable for Treg cell function.", "metadata": {}}
+{"_id": "4418112", "title": "", "text": "Functional screening identifies miRNAs inducing cardiac regenerationIn mammals, enlargement of theheart during embryonic development is primarily dependent on the increase in cardiomyocyte numbers.Shortly after birth, however, cardiomyocytes stop proliferating and further growth of the myocardiumoccurs through hypertrophic enlargement of the existing myocytes. As a consequence of the minimalrenewal of cardiomyocytes during adult life, repair of cardiac damage through myocardial regeneration isvery limited. Here we show that the exogenous administration of selected microRNAs (miRNAs) markedlystimulates cardiomyocyte proliferation and promotes cardiac repair. We performed a high-contentmicroscopy, high-throughput functional screening for human miRNAs that promoted neonatalcardiomyocyte proliferation using a whole-genome miRNA library. Forty miRNAs strongly increased bothDNA synthesis and cytokinesis in neonatal mouse and rat cardiomyocytes. Two of these miRNAs(hsa-miR-590 and hsa-miR-199a) were further selected for testing and were shown to promote cell cyclere-entry of adult cardiomyocytes ex vivo and to promote cardiomyocyte proliferation in both neonatal andadult animals. After myocardial infarction in mice, these miRNAs stimulated marked cardiac regenerationand almost complete recovery of cardiac functional parameters. The miRNAs identified hold great promisefor the treatment of cardiac pathologies consequent to cardiomyocyte loss.", "metadata": {}}
+{"_id": "4418269", "title": "", "text": "Specificity of sensory–motor connections encoded by Sema3e–Plxnd1 recognitionSpinal reflexes aremediated by synaptic connections between sensory afferents and motor neurons. The organization ofthese circuits shows several levels of specificity. Only certain classes of proprioceptive sensory neuronsmake direct, monosynaptic connections with motor neurons. Those that do are bound by rules of motorpool specificity: they form strong connections with motor neurons supplying the same muscle, but avoidmotor pools supplying antagonistic muscles. This pattern of connectivity is initially accurate and ismaintained in the absence of activity, implying that wiring specificity relies on the matching of recognitionmolecules on the surface of sensory and motor neurons. However, determinants of fine synapticspecificity here, as in most regions of the central nervous system, have yet to be defined. To address theorigins of synaptic specificity in these reflex circuits we have used molecular genetic methods tomanipulate recognition proteins expressed by subsets of sensory and motor neurons. We show here thata recognition system involving expression of the class 3 semaphorin Sema3e by selected motor neuronpools, and its high-affinity receptor plexin D1 (Plxnd1) by proprioceptive sensory neurons, is a criticaldeterminant of synaptic specificity in sensory–motor circuits in mice. Changing the profile ofSema3e–Plxnd1 signalling in sensory or motor neurons results in functional and anatomical rewiring ofmonosynaptic connections, but does not alter motor pool specificity. Our findings indicate that patterns ofmonosynaptic connectivity in this prototypic central nervous system circuit are constructed through arecognition program based on repellent signalling.", "metadata": {}}
+{"_id": "4418582", "title": "", "text": "A chromatin remodelling complex involved in transcription and DNA processing.The packaging of theeukaryotic genome in chromatin presents barriers that restrict the access of enzymes that process DNA.To overcome these barriers, cells possess a number of multi-protein, ATP-dependent chromatinremodelling complexes, each containing an ATPase subunit from the SNF2/SWI2 superfamily. Chromatinremodelling complexes function by increasing nucleosome mobility and are clearly implicated intranscription. Here we have analysed SNF2/SWI2- and ISWI-related proteins to identify remodellingcomplexes that potentially assist other DNA transactions. We purified a complex from Saccharomycescerevisiae that contains the Ino80 ATPase. The INO80 complex contains about 12 polypeptides includingtwo proteins related to the bacterial RuvB DNA helicase, which catalyses branch migration of Hollidayjunctions. The purified complex remodels chromatin, facilitates transcription in vitro and displays 3' to 5'DNA helicase activity. Mutants of ino80 show hypersensitivity to agents that cause DNA damage, inaddition to defects in transcription. These results indicate that chromatin remodelling driven by the Ino80ATPase may be connected to transcription as well as DNA damage repair.", "metadata": {}}
+{"_id": "4418878", "title": "", "text": "Oncogenic pathway signatures in human cancers as a guide to targeted therapiesThe development of anoncogenic state is a complex process involving the accumulation of multiple independent mutations thatlead to deregulation of cell signalling pathways central to the control of cell growth and cell fate. Theability to define cancer subtypes, recurrence of disease and response to specific therapies using DNAmicroarray-based gene expression signatures has been demonstrated in multiple studies. Various studieshave also demonstrated the potential for using gene expression profiles for the analysis of oncogenicpathways. Here we show that gene expression signatures can be identified that reflect the activationstatus of several oncogenic pathways. When evaluated in several large collections of human cancers,these gene expression signatures identify patterns of pathway deregulation in tumours and clinicallyrelevant associations with disease outcomes. Combining signature-based predictions across severalpathways identifies coordinated patterns of pathway deregulation that distinguish between specificcancers and tumour subtypes. Clustering tumours based on pathway signatures further defines prognosisin respective patient subsets, demonstrating that patterns of oncogenic pathway deregulation underliethe development of the oncogenic phenotype and reflect the biology and outcome of specific cancers.Predictions of pathway deregulation in cancer cell lines are also shown to predict the sensitivity totherapeutic agents that target components of the pathway. Linking pathway deregulation with sensitivityto therapeutics that target components of the pathway provides an opportunity to make use of theseoncogenic pathway signatures to guide the use of targeted therapeutics.", "metadata": {}}
+{"_id": "4421547", "title": "", "text": "CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus.The Insulin-likegrowth factor 2 (Igf2) and H19 genes are imprinted, resulting in silencing of the maternal and paternalalleles, respectively. This event is dependent upon an imprinted-control region two kilobases upstream ofH19 (refs 1, 2). On the paternal chromosome this element is methylated and required for the silencing ofH19 (refs 2-4). On the maternal chromosome the region is unmethylated and required for silencing of theIgf2 gene 90 kilobases upstream. We have proposed that the unmethylated imprinted-control region actsas a chromatin boundary that blocks the interaction of Igf2 with enhancers that lie 3' of H19 (refs 5, 6).This enhancer-blocking activity would then be lost when the region was methylated, thereby allowingexpression of Igf2 paternally. Here we show, using transgenic mice and tissue culture, that theunmethylated imprinted-control regions from mouse and human H19 exhibit enhancer-blocking activity.Furthermore, we show that CTCF, a zinc finger protein implicated in vertebrate boundary function, bindsto several sites in the unmethylated imprinted-control region that are essential for enhancer blocking.Consistent with our model, CTCF binding is abolished by DNA methylation. This is the first example, toour knowledge, of a regulated chromatin boundary in vertebrates.", "metadata": {}}
+{"_id": "4421578", "title": "", "text": "Broad and potent neutralization of HIV-1 by a gp41-specific human antibodyCharacterization of humanmonoclonal antibodies is providing considerable insight into mechanisms of broad HIV-1 neutralization.Here we report an HIV-1 gp41 membrane-proximal external region (MPER)-specific antibody, named10E8, which neutralizes \u000098% of tested viruses. An analysis of sera from 78 healthy HIV-1-infecteddonors demonstrated that 27% contained MPER-specific antibodies and 8% contained 10E8-likespecificities. In contrast to other neutralizing MPER antibodies, 10E8 did not bind phospholipids, was notautoreactive, and bound cell-surface envelope. The structure of 10E8 in complex with the complete MPERrevealed a site of vulnerability comprising a narrow stretch of highly conserved gp41-hydrophobicresidues and a critical arginine or lysine just before the transmembrane region. Analysis of resistantHIV-1 variants confirmed the importance of these residues for neutralization. The highly conserved MPERis a target of potent, non-self-reactive neutralizing antibodies, suggesting that HIV-1 vaccines should aimto induce antibodies to this region of HIV-1 envelope glycoprotein.", "metadata": {}}
+{"_id": "4421742", "title": "", "text": "Disruption of the Hepcidin/Ferroportin Regulatory System Causes Pulmonary Iron Overload andRestrictive Lung DiseaseEmerging evidence suggests that pulmonary iron accumulation is implicated in aspectrum of chronic lung diseases. However, the mechanism(s) involved in pulmonary iron deposition andits role in the in vivo pathogenesis of lung diseases remains unknown. Here we show that a pointmutation in the murine ferroportin gene, which causes hereditary hemochromatosis type 4(Slc40a1C326S), increases iron levels in alveolar macrophages, epithelial cells lining the conductingairways and lung parenchyma, and in vascular smooth muscle cells. Pulmonary iron overload isassociated with oxidative stress, restrictive lung disease with decreased total lung capacity and reducedblood oxygen saturation in homozygous Slc40a1C326S/C326S mice compared to wild-type controls.These findings implicate iron in lung pathology, which is so far not considered a classical iron-relateddisorder.", "metadata": {}}
+{"_id": "4421746", "title": "", "text": "Genome-wide genetic analysis of polyploidy in yeastPolyploidy, increased sets of chromosomes, occursduring development, cellular stress, disease and evolution. Despite its prevalence, little is known aboutthe physiological alterations that accompany polyploidy. We previously described ‘ploidy-specificlethality’, where a gene deletion that is not lethal in haploid or diploid budding yeast causes lethality intriploids or tetraploids. Here we report a genome-wide screen to identify ploidy-specific lethal functions.Only 39 out of 3,740 mutations screened exhibited ploidy-specific lethality. Almost all of these mutationsaffect genomic stability by impairing homologous recombination, sister chromatid cohesion, or mitoticspindle function. We uncovered defects in wild-type tetraploids predicted by the screen, and identifiedmechanisms by which tetraploidization affects genomic stability. We show that tetraploids have a highincidence of syntelic/monopolar kinetochore attachments to the spindle pole. We suggest that this defectcan be explained by mismatches in the ability to scale the size of the spindle pole body, spindle andkinetochores. Thus, geometric constraints may have profound effects on genome stability; thephenomenon described here may be relevant in a variety of biological contexts, including disease statessuch as cancer.", "metadata": {}}
+{"_id": "4421787", "title": "", "text": "Diverse and heritable lineage imprinting of early haematopoietic progenitorsHaematopoietic stem cells(HSCs) and their subsequent progenitors produce blood cells, but the precise nature and kinetics of thisproduction is a contentious issue. In one model, lymphoid and myeloid production branch after thelymphoid-primed multipotent progenitor (LMPP), with both branches subsequently producing dendriticcells. However, this model is based mainly on in vitro clonal assays and population-based tracking in vivo,which could miss in vivo single-cell complexity. Here we avoid these issues by using a new quantitativeversion of ‘cellular barcoding’ to trace the in vivo fate of hundreds of LMPPs and HSCs at the single-celllevel. These data demonstrate that LMPPs are highly heterogeneous in the cell types that they produce,separating into combinations of lymphoid-, myeloid- and dendritic-cell-biased producers. Conversely,although we observe a known lineage bias of some HSCs, most cellular output is derived from a smallnumber of HSCs that each generates all cell types. Crucially, in vivo analysis of the output of sibling cellsderived from single LMPPs shows that they often share a similar fate, suggesting that the fate of theseprogenitors was imprinted. Furthermore, as this imprinting is also observed for dendritic-cell-biasedLMPPs, dendritic cells may be considered a distinct lineage on the basis of separate ancestry. These datasuggest a ‘graded commitment’ model of haematopoiesis, in which heritable and diverse lineageimprinting occurs earlier than previously thought.", "metadata": {}}
+{"_id": "4422723", "title": "", "text": "Crowding induces live cell extrusion to maintain homeostatic cell numbers in epitheliaFor an epithelium toprovide a protective barrier, it must maintain homeostatic cell numbers by matching the number ofdividing cells with the number of dying cells. Although compensatory cell division can be triggered bydying cells, it is unknown how cell death might relieve overcrowding due to proliferation. When we triggerapoptosis in epithelia, dying cells are extruded to preserve a functional barrier. Extrusion occurs by cellsdestined to die signalling to surrounding epithelial cells to contract an actomyosin ring that squeezes thedying cell out. However, it is not clear what drives cell death during normal homeostasis. Here we show inhuman, canine and zebrafish cells that overcrowding due to proliferation and migration induces extrusionof live cells to control epithelial cell numbers. Extrusion of live cells occurs at sites where the highestcrowding occurs in vivo and can be induced by experimentally overcrowding monolayers in vitro. Likeapoptotic cell extrusion, live cell extrusion resulting from overcrowding also requires sphingosine1-phosphate signalling and Rho-kinase-dependent myosin contraction, but is distinguished by signallingthrough stretch-activated channels. Moreover, disruption of a stretch-activated channel, Piezo1, inzebrafish prevents extrusion and leads to the formation of epithelial cell masses. Our findings reveal thatduring homeostatic turnover, growth and division of epithelial cells on a confined substratum causeovercrowding that leads to their extrusion and consequent death owing to the loss of survival factors.These results suggest that live cell extrusion could be a tumour-suppressive mechanism that prevents theaccumulation of excess epithelial cells.", "metadata": {}}
+{"_id": "4422734", "title": "", "text": "Direct observation of ligand recognition by T cellsThe activation of T cells through interaction of theirT-cell receptors with antigenic peptide bound to major histocompatibility complex (MHC) on the surface ofantigen presenting cells (APCs) is a crucial step in adaptive immunity. Here we use three-dimensionalfluorescence microscopy to visualize individual peptide–I-Ek class II MHC complexes labelled with thephycobiliprotein phycoerythrin in an effort to characterize T-cell sensitivity and the requirements forforming an immunological synapse in single cells. We show that T cells expressing the CD4 antigenrespond with transient calcium signalling to even a single agonist peptide–MHC ligand, and that theorganization of molecules in the contact zone of the T cell and APC takes on the characteristics of animmunological synapse when only about ten agonists are present. This sensitivity is highly dependant onCD4, because blocking this molecule with antibodies renders T cells unable to detect less than about 30ligands.", "metadata": {}}
+{"_id": "4422868", "title": "", "text": "Crypt stem cells as the cells-of-origin of intestinal cancerIntestinal cancer is initiated byWnt-pathway-activating mutations in genes such as adenomatous polyposis coli (APC). As in mostcancers, the cell of origin has remained elusive. In a previously established Lgr5 (leucine-rich-repeatcontaining G-protein-coupled receptor 5) knockin mouse model, a tamoxifen-inducible Cre recombinase isexpressed in long-lived intestinal stem cells. Here we show that deletion of Apc in these stem cells leadsto their transformation within days. Transformed stem cells remain located at crypt bottoms, whilefuelling a growing microadenoma. These microadenomas show unimpeded growth and develop intomacroscopic adenomas within 3-5weeks. The distribution of Lgr5+ cells within stem-cell-derivedadenomas indicates that a stem cell/progenitor cell hierarchy is maintained in early neoplastic lesions.When Apc is deleted in short-lived transit-amplifying cells using a different cre mouse, the growth of theinduced microadenomas rapidly stalls. Even after 30weeks, large adenomas are very rare in these mice.We conclude that stem-cell-specific loss of Apc results in progressively growing neoplasia.", "metadata": {}}
+{"_id": "4423203", "title": "", "text": "Microbial engineering for the production of advanced biofuelsAdvanced biofuels produced bymicroorganisms have similar properties to petroleum-based fuels, and can 'drop in' to the existingtransportation infrastructure. However, producing these biofuels in yields high enough to be usefulrequires the engineering of the microorganism's metabolism. Such engineering is not based on just onespecific feedstock or host organism. Data-driven and synthetic-biology approaches can be used tooptimize both the host and pathways to maximize fuel production. Despite some success, challenges stillneed to be met to move advanced biofuels towards commercialization, and to compete with moreconventional fuels.", "metadata": {}}
+{"_id": "4423220", "title": "", "text": "Sperm chromatin proteomics identifies evolutionarily conserved fertility factorsMale infertility is along-standing enigma of significant medical concern. The integrity of sperm chromatin is a clinicalindicator of male fertility and in vitro fertilization potential: chromosome aneuploidy and DNAdecondensation or damage are correlated with reproductive failure. Identifying conserved proteinsimportant for sperm chromatin structure and packaging can reveal universal causes of infertility. Here wecombine proteomics, cytology and functional analysis in Caenorhabditis elegans to identify spermatogenicchromatin-associated proteins that are important for fertility. Our strategy employed multiple steps:purification of chromatin from comparable meiotic cell types, namely those undergoing spermatogenesisor oogenesis; proteomic analysis by multidimensional protein identification technology (MudPIT) offactors that co-purify with chromatin; prioritization of sperm proteins based on abundance; andsubtraction of common proteins to eliminate general chromatin and meiotic factors. Our approachreduced 1,099 proteins co-purified with spermatogenic chromatin, currently the most extensivecatalogue, to 132 proteins for functional analysis. Reduction of gene function through RNA interferencecoupled with protein localization studies revealed conserved spermatogenesis-specific proteins vital forDNA compaction, chromosome segregation, and fertility. Unexpected roles in spermatogenesis were alsodetected for factors involved in other processes. Our strategy to find fertility factors conserved from C.elegans to mammals achieved its goal: of mouse gene knockouts corresponding to nematode proteins,37% (7/19) cause male sterility. Our list therefore provides significant opportunity to identify causes ofmale infertility and targets for male contraceptives.", "metadata": {}}
+{"_id": "4423327", "title": "", "text": "Nanog safeguards pluripotency and mediates germline developmentNanog is a divergent homeodomainprotein found in mammalian pluripotent cells and developing germ cells. Deletion of Nanog causes earlyembryonic lethality, whereas constitutive expression enables autonomous self-renewal of embryonic stemcells. Nanog is accordingly considered a core element of the pluripotent transcriptional network. However,here we report that Nanog fluctuates in mouse embryonic stem cells. Transient downregulation of Nanogappears to predispose cells towards differentiation but does not mark commitment. By genetic deletionwe show that, although they are prone to differentiate, embryonic stem cells can self-renew indefinitelyin the permanent absence of Nanog. Expanded Nanog null cells colonize embryonic germ layers andexhibit multilineage differentiation both in fetal and adult chimaeras. Although they are also recruited tothe germ line, primordial germ cells lacking Nanog fail to mature on reaching the genital ridge. Thisdefect is rescued by repair of the mutant allele. Thus Nanog is dispensible for expression of somaticpluripotency but is specifically required for formation of germ cells. Nanog therefore acts primarily inconstruction of inner cell mass and germ cell states rather than in the housekeeping machinery ofpluripotency. We surmise that Nanog stabilizes embryonic stem cells in culture by resisting or reversingalternative gene expression states.", "metadata": {}}
+{"_id": "4423401", "title": "", "text": "Succinate is an inflammatory signal that induces IL-1β through HIF-1αMacrophages activated by theGram-negative bacterial product lipopolysaccharide switch their core metabolism from oxidativephosphorylation to glycolysis. Here we show that inhibition of glycolysis with 2-deoxyglucose suppresseslipopolysaccharide-induced interleukin-1β but not tumour-necrosis factor-α in mouse macrophages. Acomprehensive metabolic map of lipopolysaccharide-activated macrophages shows upregulation ofglycolytic and downregulation of mitochondrial genes, which correlates directly with the expressionprofiles of altered metabolites. Lipopolysaccharide strongly increases the levels of the tricarboxylic-acidcycle intermediate succinate. Glutamine-dependent anerplerosis is the principal source of succinate,although the ‘GABA (γ-aminobutyric acid) shunt’ pathway also has a role. Lipopolysaccharide-inducedsuccinate stabilizes hypoxia-inducible factor-1α, an effect that is inhibited by 2-deoxyglucose, withinterleukin-1β as an important target. Lipopolysaccharide also increases succinylation of several proteins.We therefore identify succinate as a metabolite in innate immune signalling, which enhancesinterleukin-1β production during inflammation.", "metadata": {}}
+{"_id": "4423559", "title": "", "text": "Planar cell polarity signalling couples cell division and morphogenesis during neurulationEnvironmentaland genetic aberrations lead to neural tube closure defects (NTDs) in 1 out of every 1,000 births. Mouseand frog models for these birth defects have indicated that Van Gogh-like 2 (Vangl2, also known asStrabismus) and other components of planar cell polarity (PCP) signalling might control neurulation bypromoting the convergence of neural progenitors to the midline. Here we show a novel role for PCPsignalling during neurulation in zebrafish. We demonstrate that non-canonical Wnt/PCP signallingpolarizes neural progenitors along the anteroposterior axis. This polarity is transiently lost during celldivision in the neural keel but is re-established as daughter cells reintegrate into the neuroepithelium.Loss of zebrafish Vangl2 (in trilobite mutants) abolishes the polarization of neural keel cells, disruptsre-intercalation of daughter cells into the neuroepithelium, and results in ectopic neural progenitoraccumulations and NTDs. Remarkably, blocking cell division leads to rescue of trilobite neural tubemorphogenesis despite persistent defects in convergence and extension. These results reveal a functionfor PCP signalling in coupling cell division and morphogenesis at neurulation and indicate a previouslyunrecognized mechanism that might underlie NTDs.", "metadata": {}}
+{"_id": "4424888", "title": "", "text": "The challenge of new drug discovery for tuberculosisTuberculosis (TB) is more prevalent in the worldtoday than at any other time in human history. Mycobacterium tuberculosis, the pathogen responsible forTB, uses diverse strategies to survive in a variety of host lesions and to evade immune surveillance. Akey question is how robust are our approaches to discovering new TB drugs, and what measures could betaken to reduce the long and protracted clinical development of new drugs. The emergence ofmulti-drug-resistant strains of M. tuberculosis makes the discovery of new molecular scaffolds a priority,and the current situation even necessitates the re-engineering and repositioning of some old drugfamilies to achieve effective control. Whatever the strategy used, success will depend largely on ourproper understanding of the complex interactions between the pathogen and its human host. In thisreview, we discuss innovations in TB drug discovery and evolving strategies to bring newer agents morequickly to patients.", "metadata": {}}
+{"_id": "4425507", "title": "", "text": "Subunit Arrangement and Phenylethanolamine Binding in GluN1/GluN2B NMDA ReceptorsSince it wasdiscovered that the anti-hypertensive agent ifenprodil has neuroprotective activity through its effects onNMDA (N-methyl-D-aspartate) receptors, a determined effort has been made to understand themechanism of action and to develop improved therapeutic compounds on the basis of this knowledge.Neurotransmission mediated by NMDA receptors is essential for basic brain development and function.These receptors form heteromeric ion channels and become activated after concurrent binding of glycineand glutamate to the GluN1 and GluN2 subunits, respectively. A functional hallmark of NMDA receptors isthat their ion-channel activity is allosterically regulated by binding of small compounds to theamino-terminal domain (ATD) in a subtype-specific manner. Ifenprodil and related phenylethanolaminecompounds, which specifically inhibit GluN1 and GluN2B NMDA receptors, have been intensely studied fortheir potential use in the treatment of various neurological disorders and diseases, including depression,Alzheimer's disease and Parkinson's disease. Despite considerable enthusiasm, mechanisms underlyingthe recognition of phenylethanolamines and ATD-mediated allosteric inhibition remain limited owing to alack of structural information. Here we report that the GluN1 and GluN2B ATDs form a heterodimer andthat phenylethanolamine binds at the interface between GluN1 and GluN2B, rather than within theGluN2B cleft. The crystal structure of the heterodimer formed between the GluN1b ATD from Xenopuslaevis and the GluN2B ATD from Rattus norvegicus shows a highly distinct pattern of subunitarrangement that is different from the arrangements observed in homodimeric non-NMDA receptors andreveals the molecular determinants for phenylethanolamine binding. Restriction of domain movement inthe bi-lobed structure of the GluN2B ATD, by engineering of an inter-subunit disulphide bond, markedlydecreases sensitivity to ifenprodil, indicating that conformational freedom in the GluN2B ATD is essentialfor ifenprodil-mediated allosteric inhibition of NMDA receptors. These findings pave the way for improvingthe design of subtype-specific compounds with therapeutic value for neurological disorders and diseases.", "metadata": {}}
+{"_id": "4427060", "title": "", "text": "Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease.Crohn's diseaseand ulcerative colitis, the two main types of chronic inflammatory bowel disease, are multifactorialconditions of unknown aetiology. A susceptibility locus for Crohn's disease has been mapped tochromosome 16. Here we have used a positional-cloning strategy, based on linkage analysis followed bylinkage disequilibrium mapping, to identify three independent associations for Crohn's disease: aframeshift variant and two missense variants of NOD2, encoding a member of the Apaf-1/Ced-4superfamily of apoptosis regulators that is expressed in monocytes. These NOD2 variants alter thestructure of either the leucine-rich repeat domain of the protein or the adjacent region. NOD2 activatesnuclear factor NF-kB; this activating function is regulated by the carboxy-terminal leucine-rich repeatdomain, which has an inhibitory role and also acts as an intracellular receptor for components of microbialpathogens. These observations suggest that the NOD2 gene product confers susceptibility to Crohn'sdisease by altering the recognition of these components and/or by over-activating NF-kB in monocytes,thus documenting a molecular model for the pathogenic mechanism of Crohn's disease that can now befurther investigated.", "metadata": {}}
+{"_id": "4427392", "title": "", "text": "Human cardiovascular progenitor cells develop from a KDR+ embryonic-stem-cell-derived populationThefunctional heart is comprised of distinct mesoderm-derived lineages including cardiomyocytes, endothelialcells and vascular smooth muscle cells. Studies in the mouse embryo and the mouse embryonic stem celldifferentiation model have provided evidence indicating that these three lineages develop from a commonFlk-1+ (kinase insert domain protein receptor, also known as Kdr) cardiovascular progenitor thatrepresents one of the earliest stages in mesoderm specification to the cardiovascular lineages. Todetermine whether a comparable progenitor is present during human cardiogenesis, we analysed thedevelopment of the cardiovascular lineages in human embryonic stem cell differentiation cultures. Herewe show that after induction with combinations of activin A, bone morphogenetic protein 4 (BMP4), basicfibroblast growth factor (bFGF, also known as FGF2), vascular endothelial growth factor (VEGF, alsoknown as VEGFA) and dickkopf homolog 1 (DKK1) in serum-free media, humanembryonic-stem-cell-derived embryoid bodies generate a KDRlow/C-KIT(CD117)neg population thatdisplays cardiac, endothelial and vascular smooth muscle potential in vitro and, after transplantation, invivo. When plated in monolayer cultures, these KDRlow/C-KITneg cells differentiate to generatepopulations consisting of greater than 50% contracting cardiomyocytes. Populations derived from theKDRlow/C-KITneg fraction give rise to colonies that contain all three lineages when plated inmethylcellulose cultures. Results from limiting dilution studies and cell-mixing experiments support theinterpretation that these colonies are clones, indicating that they develop from a cardiovascularcolony-forming cell. Together, these findings identify a human cardiovascular progenitor that defines oneof the earliest stages of human cardiac development.", "metadata": {}}
+{"_id": "4429118", "title": "", "text": "Cancer-related inflammationThe mediators and cellular effectors of inflammation are importantconstituents of the local environment of tumours. In some types of cancer, inflammatory conditions arepresent before a malignant change occurs. Conversely, in other types of cancer, an oncogenic changeinduces an inflammatory microenvironment that promotes the development of tumours. Regardless of itsorigin, 'smouldering' inflammation in the tumour microenvironment has many tumour-promoting effects.It aids in the proliferation and survival of malignant cells, promotes angiogenesis and metastasis,subverts adaptive immune responses, and alters responses to hormones and chemotherapeutic agents.The molecular pathways of this cancer-related inflammation are now being unravelled, resulting in theidentification of new target molecules that could lead to improved diagnosis and treatment.", "metadata": {}}
+{"_id": "4429388", "title": "", "text": "ESCRT-III recognition by VPS4 ATPasesThe ESCRT (endosomal sorting complex required for transport)pathway is required for terminal membrane fission events in several important biological processes,including endosomal intraluminal vesicle formation, HIV budding and cytokinesis. VPS4 ATPases performa key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysingtheir disassembly, possibly in conjunction with membrane fission. Here we show that the microtubuleinteracting and transport (MIT) domains of human VPS4A and VPS4B bind conserved sequence motifslocated at the carboxy termini of the CHMP1–3 class of ESCRT-III proteins. Structures of VPS4AMIT–CHMP1A and VPS4B MIT–CHMP2B complexes reveal that the C-terminal CHMP motif forms anamphipathic helix that binds in a groove between the last two helices of the tetratricopeptide-like repeat(TPR) of the VPS4 MIT domain, but in the opposite orientation to that of a canonical TPR interaction.Distinct pockets in the MIT domain bind three conserved leucine residues of the CHMP motif, andmutations that inhibit these interactions block VPS4 recruitment, impair endosomal protein sorting andrelieve dominant-negative VPS4 inhibition of HIV budding. Thus, our studies reveal how the VPS4ATPases recognize their CHMP substrates to facilitate the membrane fission events required for therelease of viruses, endosomal vesicles and daughter cells.", "metadata": {}}
+{"_id": "4429668", "title": "", "text": "Pif1 family helicases suppress genome instability at G-quadruplex motifsThe Saccharomyces cerevisiaePif1 helicase is the prototypical member of the Pif1 DNA helicase family, which is conserved from bacteriato humans. Here we show that exceptionally potent G-quadruplex unwinding is conserved among Pif1helicases. Moreover, Pif1 helicases from organisms separated by more than 3 billion years of evolutionsuppressed DNA damage at G-quadruplex motifs in yeast. The G-quadruplex-induced damage generatedin the absence of Pif1 helicases led to new genetic and epigenetic changes. Furthermore, when expressedin yeast, human PIF1 suppressed both G-quadruplex-associated DNA damage and telomere lengthening.", "metadata": {}}
+{"_id": "4429932", "title": "", "text": "Lysyl oxidase is essential for hypoxia-induced metastasisMetastasis is a multistep process responsible formost cancer deaths, and it can be influenced by both the immediate microenvironment (cell–cell orcell–matrix interactions) and the extended tumour microenvironment (for example vascularization).Hypoxia (low oxygen) is clinically associated with metastasis and poor patient outcome, although theunderlying processes remain unclear. Microarray studies have shown the expression of lysyl oxidase(LOX) to be elevated in hypoxic human tumour cells. Paradoxically, LOX expression is associated withboth tumour suppression and tumour progression, and its role in tumorigenesis seems dependent oncellular location, cell type and transformation status. Here we show that LOX expression is regulated byhypoxia-inducible factor (HIF) and is associated with hypoxia in human breast and head and necktumours. Patients with high LOX-expressing tumours have poor distant metastasis-free and overallsurvivals. Inhibition of LOX eliminates metastasis in mice with orthotopically grown breast cancertumours. Mechanistically, secreted LOX is responsible for the invasive properties of hypoxic humancancer cells through focal adhesion kinase activity and cell to matrix adhesion. Furthermore, LOX may berequired to create a niche permissive for metastatic growth. Our findings indicate that LOX is essential forhypoxia-induced metastasis and is a good therapeutic target for preventing and treating metastases.", "metadata": {}}
+{"_id": "4430962", "title": "", "text": "Identification of human brain tumour initiating cellsThe cancer stem cell (CSC) hypothesis suggests thatneoplastic clones are maintained exclusively by a rare fraction of cells with stem cell properties. Althoughthe existence of CSCs in human leukaemia is established, little evidence exists for CSCs in solid tumours,except for breast cancer. Recently, we prospectively isolated a CD133+ cell subpopulation from humanbrain tumours that exhibited stem cell properties in vitro. However, the true measures of CSCs are theircapacity for self renewal and exact recapitulation of the original tumour. Here we report the developmentof a xenograft assay that identified human brain tumour initiating cells that initiate tumours in vivo. Onlythe CD133+ brain tumour fraction contains cells that are capable of tumour initiation in NOD-SCID(non-obese diabetic, severe combined immunodeficient) mouse brains. Injection of as few as 100CD133+ cells produced a tumour that could be serially transplanted and was a phenocopy of the patient'soriginal tumour, whereas injection of 105 CD133- cells engrafted but did not cause a tumour. Thus, theidentification of brain tumour initiating cells provides insights into human brain tumour pathogenesis,giving strong support for the CSC hypothesis as the basis for many solid tumours, and establishes apreviously unidentified cellular target for more effective cancer therapies.", "metadata": {}}
+{"_id": "4432763", "title": "", "text": "Anthropometric reference data for international use: recommendations from a World Health OrganizationExpert Committee.The World Health Organization (WHO) convened an Expert Committee to reevaluatethe use of anthropometry at different ages for assessing health, nutrition, and social wellbeing. TheCommittee's task included identifying reference data for anthropometric indexes when appropriate, andproviding guidelines on how the data should be used. For fetal growth, the Committee recommended anexisting sex-specific multiracial reference. In view of the significant technical drawbacks of the currentNational Center for Health Statistics (NCHS)/WHO reference and its inadequacy for assessing the growthof breast-fed infants, the Committee recommended the development of a new reference concerningweight and length/height for infants and children, which will be a complex and costly undertaking. Properinterpretation of midupper arm circumference for preschoolers requires age-specific reference data. Toevaluate adolescent height-for-age, the Committee recommended the current NCHS/WHO reference. Useof the NCHS body mass index (BMI) data, with their upper percentile elevations and skewness, isundesirable for setting health goals; however, these data were provisionally recommended for definingobesity based on a combination of elevated BMI and high subcutaneous fat. The NCHS values wereprovisionally recommended as reference data for subscapular and triceps skinfold thicknesses. Guidelineswere also provided for adjusting adolescent anthropometric comparisons for maturational status.Currently, there is no need for adult reference data for BMI; interpretation should be based on pragmaticBMI cutoffs. Finally, the Committee noted that few normative anthropometric data exist for the elderly,especially for those > 80 y of age. Proper definitions of health status, function, and biologic age remain tobe developed for this group.", "metadata": {}}
+{"_id": "4434951", "title": "", "text": "Diverse interventions that extend mouse lifespan suppress shared age-associated epigenetic changes atcritical gene regulatory regionsBACKGROUND Age-associated epigenetic changes are implicated in aging.Notably, age-associated DNA methylation changes comprise a so-called aging \"clock\", a robust biomarkerof aging. However, while genetic, dietary and drug interventions can extend lifespan, their impact on theepigenome is uncharacterised. To fill this knowledge gap, we defined age-associated DNA methylationchanges at the whole-genome, single-nucleotide level in mouse liver and tested the impact oflongevity-promoting interventions, specifically the Ames dwarf Prop1 df/df mutation, calorie restrictionand rapamycin. RESULTS In wild-type mice fed an unsupplemented ad libitum diet, age-associatedhypomethylation was enriched at super-enhancers in highly expressed genes critical for liver function.Genes harbouring hypomethylated enhancers were enriched for genes that change expression with age.Hypermethylation was enriched at CpG islands marked with bivalent activating and repressing histonemodifications and resembled hypermethylation in liver cancer. Age-associated methylation changes aresuppressed in Ames dwarf and calorie restricted mice and more selectively and less specifically inrapamycin treated mice. CONCLUSIONS Age-associated hypo- and hypermethylation events occur atdistinct regulatory features of the genome. Distinct longevity-promoting interventions, specificallygenetic, dietary and drug interventions, suppress some age-associated methylation changes, consistentwith the idea that these interventions exert their beneficial effects, in part, by modulation of theepigenome. This study is a foundation to understand the epigenetic contribution to healthy aging andlongevity and the molecular basis of the DNA methylation clock.", "metadata": {}}
+{"_id": "4435369", "title": "", "text": "Extracellular vesicles for drug delivery.Extracellular vesicles (EVs) are cell-derived membrane vesicles,and represent an endogenous mechanism for intercellular communication. Since the discovery that EVsare capable of functionally transferring biological information, the potential use of EVs as drug deliveryvehicles has gained considerable scientific interest. EVs may have multiple advantages over currentlyavailable drug delivery vehicles, such as their ability to overcome natural barriers, their intrinsic celltargeting properties, and stability in the circulation. However, therapeutic applications of EVs as drugdelivery systems have been limited due to a lack of methods for scalable EV isolation and efficient drugloading. Furthermore, in order to achieve targeted drug delivery, their intrinsic cell targeting propertiesshould be tuned through EV engineering. Here, we review and discuss recent progress and remainingchallenges in the development of EVs as drug delivery vehicles.", "metadata": {}}
+{"_id": "4442799", "title": "", "text": "Effects of soy isoflavones and phytate on homocysteine, C-reactive protein, and iron status inpostmenopausal women.BACKGROUND Soy protein or its components may protect against theatherosclerotic cardiovascular disease (CVD) risk factors total homocysteine (tHcy), C-reactive protein(CRP), and excess body iron, which generally increase with menopause. OBJECTIVE The primaryobjective of this study was to determine the independent effect of the soy protein componentsisoflavones and phytate on CVD risk factors in postmenopausal women. The secondary objective was toidentify factors [blood lipids, oxidative stress indexes, serum ferritin, plasma folate, plasma vitamin B-12,and body mass index (BMI)] contributing to tHcy and CRP concentrations. DESIGN In a double-blind,6-wk study, 55 postmenopausal women aged 47-72 y were randomly assigned to 1 of 4 soy protein (40g/d) isolate treatments: native phytate and native isoflavone (n = 14), native phytate and low isoflavone(n = 13), low phytate and native isoflavone (n = 14), or low phytate and low isoflavone (n = 14). Wemeasured iron indexes, tHcy, CRP, and BMI. RESULTS Soy protein with native phytate significantlyreduced tHcy (P = 0.017), transferrin saturation (P = 0.027), and ferritin (P = 0.029), whereas soyprotein with native isoflavones had no effect on any variables. At baseline, BMI was highly correlated withtHcy (r = 0.39, P = 0.003) and CRP (r = 0.55, P < 0.0001), whereas HDL cholesterol was correlated withCRP (r = -0.30, P = 0.02). Multiple regression analysis showed that LDL cholesterol and BMI contributedsignificantly (R2= 19.9%, P = 0.003) to the overall variance in tHcy. CONCLUSION Consumingphytate-rich foods and maintaining a healthy weight may reduce atherosclerotic CVD risk factors inpostmenopausal women.", "metadata": {}}
+{"_id": "4444861", "title": "", "text": "Replication Fork Stability Confers Chemoresistance in BRCA-deficient CellsCells deficient in the Brca1 andBrca2 genes have reduced capacity to repair DNA double-strand breaks by homologous recombinationand consequently are hypersensitive to DNA-damaging agents, including cisplatin and poly(ADP-ribose)polymerase (PARP) inhibitors. Here we show that loss of the MLL3/4 complex protein, PTIP, protectsBrca1/2-deficient cells from DNA damage and rescues the lethality of Brca2-deficient embryonic stemcells. However, PTIP deficiency does not restore homologous recombination activity at double-strandbreaks. Instead, its absence inhibits the recruitment of the MRE11 nuclease to stalled replication forks,which in turn protects nascent DNA strands from extensive degradation. More generally, acquisition ofPARP inhibitors and cisplatin resistance is associated with replication fork protection in Brca2-deficienttumour cells that do not develop Brca2 reversion mutations. Disruption of multiple proteins, includingPARP1 and CHD4, leads to the same end point of replication fork protection, highlighting the complexitiesby which tumour cells evade chemotherapeutic interventions and acquire drug resistance.", "metadata": {}}
+{"_id": "4445629", "title": "", "text": "Plasma Corin as a Predictor of Cardiovascular Events in Patients With Chronic Heart Failure.OBJECTIVESThe aim of this study was to determine the prognostic value of plasma corin in patients with chronic heartfailure (CHF). BACKGROUND In recent years, accumulating evidence has indicated that corin plays acritical role in regulating blood pressure and cardiac function. METHODS We enrolled 1,148 consecutiveCHF patients in a prospective cohort study and explored the association between plasma corin levels andclinical prognosis using multivariate Cox regression analysis. RESULTS Patients with low corin levels(<458 pg/ml) were more likely to be women and to be hypertensive. Low corin was found to beassociated with an increase in New York Heart Association (NYHA) functional class and N-terminalpro-B-type natriuretic peptide (NT-proBNP) levels, and a decrease in left ventricular ejection fraction(LVEF) and the estimated glomerular filtration rate (eGFR). Multivariate Cox regression analysissuggested that log corin was an independent predictor of major adverse cardiac event(s) (MACE) (hazardratio: 0.62; 95% confidence interval: 0.39 to 0.95), together with age, diabetes, NYHA functional class,LVEF, eGFR, and log NT-proBNP. In addition, log corin was also a significant predictor for cardiovasculardeath (p = 0.041) and heart failure rehospitalization (p = 0.015) after adjustment for clinical variablesand established biomarkers of adverse prognosis. The Kaplan-Meier survival curves showed that low corinwas a significant predictor of MACE in patients with NT-proBNP levels above and below the median.CONCLUSIONS Our study demonstrates that plasma corin is a valuable prognostic marker of MACE inpatients with CHF, independent of established conventional risk factors.", "metadata": {}}
+{"_id": "4446814", "title": "", "text": "Cryo-EM structures of Tau filaments from Alzheimer’s disease brainAlzheimer's disease is the mostcommon neurodegenerative disease, and there are no mechanism-based therapies. The disease isdefined by the presence of abundant neurofibrillary lesions and neuritic plaques in the cerebral cortex.Neurofibrillary lesions comprise paired helical and straight tau filaments, whereas tau filaments withdifferent morphologies characterize other neurodegenerative diseases. No high-resolution structures oftau filaments are available. Here we present cryo-electron microscopy (cryo-EM) maps at 3.4-3.5 Åresolution and corresponding atomic models of paired helical and straight filaments from the brain of anindividual with Alzheimer's disease. Filament cores are made of two identical protofilaments comprisingresidues 306-378 of tau protein, which adopt a combined cross-β/β-helix structure and define the seedfor tau aggregation. Paired helical and straight filaments differ in their inter-protofilament packing,showing that they are ultrastructural polymorphs. These findings demonstrate that cryo-EM allows atomiccharacterization of amyloid filaments from patient-derived material, and pave the way for investigation ofa range of neurodegenerative diseases.", "metadata": {}}
+{"_id": "4447055", "title": "", "text": "Modulation of the proteoglycan receptor PTPσ promotes recovery after spinal cord injuryContusive spinalcord injury leads to a variety of disabilities owing to limited neuronal regeneration and functionalplasticity. It is well established that an upregulation of glial-derived chondroitin sulphate proteoglycans(CSPGs) within the glial scar and perineuronal net creates a barrier to axonal regrowth and sprouting.Protein tyrosine phosphatase σ (PTPσ), along with its sister phosphatase leukocyte commonantigen-related (LAR) and the nogo receptors 1 and 3 (NgR), have recently been identified as receptorsfor the inhibitory glycosylated side chains of CSPGs. Here we find in rats that PTPσ has a critical role inconverting growth cones into a dystrophic state by tightly stabilizing them within CSPG-rich substrates.We generated a membrane-permeable peptide mimetic of the PTPσ wedge domain that binds to PTPσ andrelieves CSPG-mediated inhibition. Systemic delivery of this peptide over weeks restored substantialserotonergic innervation to the spinal cord below the level of injury and facilitated functional recovery ofboth locomotor and urinary systems. Our results add a new layer of understanding to the critical role ofPTPσ in mediating the growth-inhibited state of neurons due to CSPGs within the injured adult spinalcord.", "metadata": {}}
+{"_id": "4447785", "title": "", "text": "A gp130–Src–YAP module links inflammation to epithelial regenerationInflammation promotesregeneration of injured tissues through poorly understood mechanisms, some of which involve interleukin(IL)-6 family members, the expression of which is elevated in many diseases including inflammatorybowel diseases and colorectal cancer. Here we show in mice and human cells that gp130, a co-receptorfor IL-6 cytokines, triggers activation of YAP and Notch, transcriptional regulators that control tissuegrowth and regeneration, independently of the gp130 effector STAT3. Through YAP and Notch, intestinalgp130 signalling stimulates epithelial cell proliferation, causes aberrant differentiation and confersresistance to mucosal erosion. gp130 associates with the related tyrosine kinases Src and Yes, which areactivated on receptor engagement to phosphorylate YAP and induce its stabilization and nucleartranslocation. This signalling module is strongly activated upon mucosal injury to promote healing andmaintain barrier function.", "metadata": {}}
+{"_id": "4449524", "title": "", "text": "Hemoglobin concentration in white, black, and Oriental children: is there a need for separate criteria inscreening for anemia?The concentration of hemoglobin in blacks was found to be 0.5 to 1.0 g/dl lowerthan that of income-matched whites in several large surveys. This difference could be a racialcharacteristic of blacks, or it might be due to a higher frequency of genetic traits such as thalassemiaminor and hemoglobinopathies, or to environmental factors such as iron deficiency. To help in makingthis distinction, we analyzed the data from multiphasic examinations (1973 to 1975) on 1718 white, 741black, and 315 Oriental healthy, nonindigent children between 5 and 14 years of age. In the entirepopulation, the median hemoglobin concentration averaged 0.5 g/dl lower in blacks than in whites of bothsexes (t test, P less than 0.001). The differences still averaged 0.5 g/dl (P less than 0.001) afterexclusion of all those with abnormal hemoglobin by electrophoresis (Hgb S and C) and those whose meancorpuscular volume was more than 5% below the normal mean for age (to exclude iron deficiency orthalassemia minor). The data strengthen the impression that blacks normally have a concentration ofhemoglobin averaging about 0.5 g/dl less than in whites. If this is the case, about 10% of normal blackswill be mistakenly designated anemic, if the same norms are applied.", "metadata": {}}
+{"_id": "4452318", "title": "", "text": "Divergent reprogramming routes lead to alternative stem-cell statesPluripotency is defined by the abilityof a cell to differentiate to the derivatives of all the three embryonic germ layers: ectoderm, mesodermand endoderm. Pluripotent cells can be captured via the archetypal derivation of embryonic stem cells orvia somatic cell reprogramming. Somatic cells are induced to acquire a pluripotent stem cell (iPSC) statethrough the forced expression of key transcription factors, and in the mouse these cells can fulfil thestrictest of all developmental assays for pluripotent cells by generating completely iPSC-derived embryosand mice. However, it is not known whether there are additional classes of pluripotent cells, or what thespectrum of reprogrammed phenotypes encompasses. Here we explore alternative outcomes of somaticreprogramming by fully characterizing reprogrammed cells independent of preconceived definitions ofiPSC states. We demonstrate that by maintaining elevated reprogramming factor expression levels,mouse embryonic fibroblasts go through unique epigenetic modifications to arrive at a stable,Nanog-positive, alternative pluripotent state. In doing so, we prove that the pluripotent spectrum canencompass multiple, unique cell states.", "metadata": {}}
+{"_id": "4452659", "title": "", "text": "Autophagy mediates degradation of nuclear laminaMacroautophagy (hereafter referred to as autophagy)is a catabolic membrane trafficking process that degrades a variety of cellular constituents and isassociated with human diseases. Although extensive studies have focused on autophagic turnover ofcytoplasmic materials, little is known about the role of autophagy in degrading nuclear components. Herewe report that the autophagy machinery mediates degradation of nuclear lamina components inmammals. The autophagy protein LC3/Atg8, which is involved in autophagy membrane trafficking andsubstrate delivery, is present in the nucleus and directly interacts with the nuclear lamina protein laminB1, and binds to lamin-associated domains on chromatin. This LC3-lamin B1 interaction does notdownregulate lamin B1 during starvation, but mediates its degradation upon oncogenic insults, such asby activated RAS. Lamin B1 degradation is achieved by nucleus-to-cytoplasm transport that deliverslamin B1 to the lysosome. Inhibiting autophagy or the LC3-lamin B1 interaction prevents activatedRAS-induced lamin B1 loss and attenuates oncogene-induced senescence in primary human cells. Ourstudy suggests that this new function of autophagy acts as a guarding mechanism protecting cells fromtumorigenesis.", "metadata": {}}
+{"_id": "4454788", "title": "", "text": "Pro-resolving lipid mediators are leads for resolution physiologyAdvances in our understanding of themechanisms that bring about the resolution of acute inflammation have uncovered a new genus ofpro-resolving lipid mediators that include the lipoxin, resolvin, protectin and maresin families, collectivelycalled specialized pro-resolving mediators. Synthetic versions of these mediators have potent bioactionswhen administered in vivo. In animal experiments, the mediators evoke anti-inflammatory and novelpro-resolving mechanisms, and enhance microbial clearance. Although they have been identified ininflammation resolution, specialized pro-resolving mediators are conserved structures that also functionin host defence, pain, organ protection and tissue remodelling. This Review covers the mechanisms ofspecialized pro-resolving mediators and omega-3 essential fatty acid pathways that could help us tounderstand their physiological functions.", "metadata": {}}
+{"_id": "4455466", "title": "", "text": "ZMYND11 links histone H3.3K36me3 to transcription elongation and tumour suppressionRecognition ofmodified histones by ‘reader’ proteins plays a critical role in the regulation of chromatin. H3K36trimethylation (H3K36me3) is deposited onto the nucleosomes in the transcribed regions after RNApolymerase II elongation. In yeast, this mark in turn recruits epigenetic regulators to reset the chromatinto a relatively repressive state, thus suppressing cryptic transcription. However, much less is knownabout the role of H3K36me3 in transcription regulation in mammals. This is further complicated by thetranscription-coupled incorporation of the histone variant H3.3 in gene bodies. Here we show that thecandidate tumour suppressor ZMYND11 specifically recognizes H3K36me3 on H3.3 (H3.3K36me3) andregulates RNA polymerase II elongation. Structural studies show that in addition to the trimethyl-lysinebinding by an aromatic cage within the PWWP domain, the H3.3-dependent recognition is mediated bythe encapsulation of the H3.3-specific ‘Ser 31’ residue in a composite pocket formed by the tandembromo–PWWP domains of ZMYND11. Chromatin immunoprecipitation followed by sequencing shows agenome-wide co-localization of ZMYND11 with H3K36me3 and H3.3 in gene bodies, and its occupancyrequires the pre-deposition of H3.3K36me3. Although ZMYND11 is associated with highly expressedgenes, it functions as an unconventional transcription co-repressor by modulating RNA polymerase II atthe elongation stage. ZMYND11 is critical for the repression of a transcriptional program that is essentialfor tumour cell growth; low expression levels of ZMYND11 in breast cancer patients correlate with worseprognosis. Consistently, overexpression of ZMYND11 suppresses cancer cell growth in vitro and tumourformation in mice. Together, this study identifies ZMYND11 as an H3.3-specific reader of H3K36me3 thatlinks the histone-variant-mediated transcription elongation control to tumour suppression.", "metadata": {}}
+{"_id": "4456756", "title": "", "text": "Autocrine BDNF–TrkB signalling within a single dendritic spineBrain-derived neurotrophic factor (BDNF)and its receptor TrkB are crucial for many forms of neuronal plasticity, including structural long-termpotentiation (sLTP), which is a correlate of an animal’s learning. However, it is unknown whether BDNFrelease and TrkB activation occur during sLTP, and if so, when and where. Here, using a fluorescenceresonance energy transfer-based sensor for TrkB and two-photon fluorescence lifetime imagingmicroscopy, we monitor TrkB activity in single dendritic spines of CA1 pyramidal neurons in culturedmurine hippocampal slices. In response to sLTP induction, we find fast (onset < 1 min) and sustained(>20 min) activation of TrkB in the stimulated spine that depends on NMDAR (N-methyl-d-aspartatereceptor) and CaMKII signalling and on postsynaptically synthesized BDNF. We confirm the presence ofpostsynaptic BDNF using electron microscopy to localize endogenous BDNF to dendrites and spines ofhippocampal CA1 pyramidal neurons. Consistent with these findings, we also show rapid,glutamate-uncaging-evoked, time-locked BDNF release from single dendritic spines using BDNF fused tosuperecliptic pHluorin. We demonstrate that this postsynaptic BDNF–TrkB signalling pathway is necessaryfor both structural and functional LTP. Together, these findings reveal a spine-autonomous, autocrinesignalling mechanism involving NMDAR–CaMKII-dependent BDNF release from stimulated dendriticspines and subsequent TrkB activation on these same spines that is crucial for structural and functionalplasticity.", "metadata": {}}
+{"_id": "4457160", "title": "", "text": "Whole genomes redefine the mutational landscape of pancreatic cancerPancreatic cancer remains one ofthe most lethal of malignancies and a major health burden. We performed whole-genome sequencing andcopy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomalrearrangements leading to gene disruption were prevalent, affecting genes known to be important inpancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreaticcarcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure)classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locallyrearranged, scattered and unstable. A significant proportion harboured focal amplifications, many ofwhich contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at lowindividual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenancegenes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNAmaintenance responded.", "metadata": {}}
+{"_id": "4457834", "title": "", "text": "Human oocytes reprogram adult somatic nuclei of a type 1 diabetic to diploid pluripotent stem cellsThetransfer of somatic cell nuclei into oocytes can give rise to pluripotent stem cells that are consistentlyequivalent to embryonic stem cells, holding promise for autologous cell replacement therapy. Althoughmethods to induce pluripotent stem cells from somatic cells by transcription factors are widely used inbasic research, numerous differences between induced pluripotent stem cells and embryonic stem cellshave been reported, potentially affecting their clinical use. Because of the therapeutic potential of diploidembryonic stem-cell lines derived from adult cells of diseased human subjects, we have systematicallyinvestigated the parameters affecting efficiency of blastocyst development and stem-cell derivation. Herewe show that improvements to the oocyte activation protocol, including the use of both kinase andtranslation inhibitors, and cell culture in the presence of histone deacetylase inhibitors, promotedevelopment to the blastocyst stage. Developmental efficiency varied between oocyte donors, and wasinversely related to the number of days of hormonal stimulation required for oocyte maturation, whereasthe daily dose of gonadotropin or the total number of metaphase II oocytes retrieved did not affectdevelopmental outcome. Because the use of concentrated Sendai virus for cell fusion induced an increasein intracellular calcium concentration, causing premature oocyte activation, we used diluted Sendai virusin calcium-free medium. Using this modified nuclear transfer protocol, we derived diploid pluripotentstem-cell lines from somatic cells of a newborn and, for the first time, an adult, a female with type 1diabetes.", "metadata": {}}
+{"_id": "4459491", "title": "", "text": "A three-dimensional human neural cell culture model of Alzheimer’s diseaseAlzheimer’s disease is themost common form of dementia, characterized by two pathological hallmarks: amyloid-β plaques andneurofibrillary tangles. The amyloid hypothesis of Alzheimer’s disease posits that the excessiveaccumulation of amyloid-β peptide leads to neurofibrillary tangles composed of aggregatedhyperphosphorylated tau. However, to date, no single disease model has serially linked these twopathological events using human neuronal cells. Mouse models with familial Alzheimer’s disease (FAD)mutations exhibit amyloid-β-induced synaptic and memory deficits but they do not fully recapitulate otherkey pathological events of Alzheimer’s disease, including distinct neurofibrillary tangle pathology. Humanneurons derived from Alzheimer’s disease patients have shown elevated levels of toxic amyloid-β speciesand phosphorylated tau but did not demonstrate amyloid-β plaques or neurofibrillary tangles. Here wereport that FAD mutations in β-amyloid precursor protein and presenilin 1 are able to induce robustextracellular deposition of amyloid-β, including amyloid-β plaques, in a human neural stem-cell-derivedthree-dimensional (3D) culture system. More importantly, the 3D-differentiated neuronal cells expressingFAD mutations exhibited high levels of detergent-resistant, silver-positive aggregates of phosphorylatedtau in the soma and neurites, as well as filamentous tau, as detected by immunoelectron microscopy.Inhibition of amyloid-β generation with β- or γ-secretase inhibitors not only decreased amyloid-βpathology, but also attenuated tauopathy. We also found that glycogen synthase kinase 3 (GSK3)regulated amyloid-β-mediated tau phosphorylation. We have successfully recapitulated amyloid-β and taupathology in a single 3D human neural cell culture system. Our unique strategy for recapitulatingAlzheimer’s disease pathology in a 3D neural cell culture model should also serve to facilitate thedevelopment of more precise human neural cell models of other neurodegenerative disorders.", "metadata": {}}
+{"_id": "4460880", "title": "", "text": "Mesenchymal-endothelial-transition contributes to cardiac neovascularizationEndothelial cells contributeto a subset of cardiac fibroblasts by undergoing endothelial-to-mesenchymal transition, but whethercardiac fibroblasts can adopt an endothelial cell fate and directly contribute to neovascularization aftercardiac injury is not known. Here, using genetic fate map techniques, we demonstrate that cardiacfibroblasts rapidly adopt an endothelial-cell-like phenotype after acute ischaemic cardiac injury.Fibroblast-derived endothelial cells exhibit anatomical and functional characteristics of native endothelialcells. We show that the transcription factor p53 regulates such a switch in cardiac fibroblast fate. Loss ofp53 in cardiac fibroblasts severely decreases the formation of fibroblast-derived endothelial cells, reducespost-infarct vascular density and worsens cardiac function. Conversely, stimulation of the p53 pathway incardiac fibroblasts augments mesenchymal-to-endothelial transition, enhances vascularity and improvescardiac function. These observations demonstrate that mesenchymal-to-endothelial transition contributesto neovascularization of the injured heart and represents a potential therapeutic target for enhancingcardiac repair.", "metadata": {}}
+{"_id": "4462079", "title": "", "text": "Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes.Recentevidence suggests that vitamin D intakes above current recommendations may be associated with betterhealth outcomes. However, optimal serum concentrations of 25-hydroxyvitamin D [25(OH)D] have notbeen defined. This review summarizes evidence from studies that evaluated thresholds for serum25(OH)D concentrations in relation to bone mineral density (BMD), lower-extremity function, dentalhealth, and risk of falls, fractures, and colorectal cancer. For all endpoints, the most advantageous serumconcentrations of 25(OH)D begin at 75 nmol/L (30 ng/mL), and the best are between 90 and 100 nmol/L(36-40 ng/mL). In most persons, these concentrations could not be reached with the currentlyrecommended intakes of 200 and 600 IU vitamin D/d for younger and older adults, respectively. Acomparison of vitamin D intakes with achieved serum concentrations of 25(OH)D for the purpose ofestimating optimal intakes led us to suggest that, for bone health in younger adults and all studiedoutcomes in older adults, an increase in the currently recommended intake of vitamin D is warranted. Anintake for all adults of > or =1000 IU (25 microg) [DOSAGE ERROR CORRECTED] vitamin D(cholecalciferol)/d is needed to bring vitamin D concentrations in no less than 50% of the population upto 75 nmol/L. The implications of higher doses for the entire adult population should be addressed infuture studies.", "metadata": {}}
+{"_id": "4462139", "title": "", "text": "Cohesin-dependent globules and heterochromatin shape 3D genome architecture in S. pombeEukaryoticgenomes are folded into three-dimensional structures, such as self-associating topological domains, theborders of which are enriched in cohesin and CCCTC-binding factor (CTCF) required for long-rangeinteractions. How local chromatin interactions govern higher-order folding of chromatin fibres and thefunction of cohesin in this process remain poorly understood. Here we perform genome-wide chromatinconformation capture (Hi-C) analysis to explore the high-resolution organization of theSchizosaccharomyces pombe genome, which despite its small size exhibits fundamental features found inother eukaryotes. Our analyses of wild-type and mutant strains reveal key elements of chromosomearchitecture and genome organization. On chromosome arms, small regions of chromatin locally interactto form 'globules'. This feature requires a function of cohesin distinct from its role in sister chromatidcohesion. Cohesin is enriched at globule boundaries and its loss causes disruption of local globulestructures and global chromosome territories. By contrast, heterochromatin, which loads cohesin atspecific sites including pericentromeric and subtelomeric domains, is dispensable for globule formationbut nevertheless affects genome organization. We show that heterochromatin mediates chromatin fibrecompaction at centromeres and promotes prominent inter-arm interactions within centromere-proximalregions, providing structural constraints crucial for proper genome organization. Loss of heterochromatinrelaxes constraints on chromosomes, causing an increase in intra- and inter-chromosomal interactions.Together, our analyses uncover fundamental genome folding principles that drive higher-orderchromosome organization crucial for coordinating nuclear functions.", "metadata": {}}
+{"_id": "4462155", "title": "", "text": "A temporal shift in the circuits mediating retrieval of fear memoryFear memories allow animals to avoiddanger, thereby increasing their chances of survival. Fear memories can be retrieved long after learning,but little is known about how retrieval circuits change with time. Here we show that the dorsal midlinethalamus of rats is required for the retrieval of auditory conditioned fear at late (24 hours, 7 days, 28days), but not early (0.5 hours, 6 hours) time points after learning. Consistent with this, theparaventricular nucleus of the thalamus (PVT), a subregion of the dorsal midline thalamus, showedincreased c-Fos expression only at late time points, indicating that the PVT is gradually recruited for fearretrieval. Accordingly, the conditioned tone responses of PVT neurons increased with time after training.The prelimbic (PL) prefrontal cortex, which is necessary for fear retrieval, sends dense projections to thePVT. Retrieval at late time points activated PL neurons projecting to the PVT, and optogenetic silencing ofthese projections impaired retrieval at late, but not early, time points. In contrast, silencing of PL inputsto the basolateral amygdala impaired retrieval at early, but not late, time points, indicating atime-dependent shift in retrieval circuits. Retrieval at late time points also activated PVT neuronsprojecting to the central nucleus of the amygdala, and silencing these projections at late, but not early,time points induced a persistent attenuation of fear. Thus, the PVT may act as a crucial thalamic noderecruited into cortico-amygdalar networks for retrieval and maintenance of long-term fear memories.", "metadata": {}}
+{"_id": "4462419", "title": "", "text": "Derivation of novel human ground state naive pluripotent stem cellsMouse embryonic stem (ES) cells areisolated from the inner cell mass of blastocysts, and can be preserved in vitro in a naiveinner-cell-mass-like configuration by providing exogenous stimulation with leukaemia inhibitory factor(LIF) and small molecule inhibition of ERK1/ERK2 and GSK3β signalling (termed 2i/LIF conditions).Hallmarks of naive pluripotency include driving Oct4 (also known as Pou5f1) transcription by its distalenhancer, retaining a pre-inactivation X chromosome state, and global reduction in DNA methylation andin H3K27me3 repressive chromatin mark deposition on developmental regulatory gene promoters. Uponwithdrawal of 2i/LIF, naive mouse ES cells can drift towards a primed pluripotent state resembling that ofthe post-implantation epiblast. Although human ES cells share several molecular features with naivemouse ES cells, they also share a variety of epigenetic properties with primed murine epiblast stem cells(EpiSCs). These include predominant use of the proximal enhancer element to maintain OCT4 expression,pronounced tendency for X chromosome inactivation in most female human ES cells, increase in DNAmethylation and prominent deposition of H3K27me3 and bivalent domain acquisition on lineageregulatory genes. The feasibility of establishing human ground state naive pluripotency in vitro withequivalent molecular and functional features to those characterized in mouse ES cells remains to bedefined. Here we establish defined conditions that facilitate the derivation of genetically unmodifiedhuman naive pluripotent stem cells from already established primed human ES cells, from somatic cellsthrough induced pluripotent stem (iPS) cell reprogramming or directly from blastocysts. The novel naivepluripotent cells validated herein retain molecular characteristics and functional properties that are highlysimilar to mouse naive ES cells, and distinct from conventional primed human pluripotent cells. Thisincludes competence in the generation of cross-species chimaeric mouse embryos that underwentorganogenesis following microinjection of human naive iPS cells into mouse morulas. Collectively, ourfindings establish new avenues for regenerative medicine, patient-specific iPS cell disease modelling andthe study of early human development in vitro and in vivo.", "metadata": {}}
+{"_id": "4462777", "title": "", "text": "Predicting immunogenic tumour mutations by combining mass spectrometry and exomesequencingHuman tumours typically harbour a remarkable number of somatic mutations. If presented onmajor histocompatibility complex class I molecules (MHCI), peptides containing these mutations couldpotentially be immunogenic as they should be recognized as ‘non-self’ neo-antigens by the adaptiveimmune system. Recent work has confirmed that mutant peptides can serve as T-cell epitopes. However,few mutant epitopes have been described because their discovery required the laborious screening ofpatient tumour-infiltrating lymphocytes for their ability to recognize antigen libraries constructedfollowing tumour exome sequencing. We sought to simplify the discovery of immunogenic mutantpeptides by characterizing their general properties. We developed an approach that combineswhole-exome and transcriptome sequencing analysis with mass spectrometry to identify neo-epitopes intwo widely used murine tumour models. Of the >1,300 amino acid changes identified, \u000013% werepredicted to bind MHCI, a small fraction of which were confirmed by mass spectrometry. The peptideswere then structurally modelled bound to MHCI. Mutations that were solvent-exposed and thereforeaccessible to T-cell antigen receptors were predicted to be immunogenic. Vaccination of mice confirmedthe approach, with each predicted immunogenic peptide yielding therapeutically active T-cell responses.The predictions also enabled the generation of peptide–MHCI dextramers that could be used to monitorthe kinetics and distribution of the anti-tumour T-cell response before and after vaccination. Thesefindings indicate that a suitable prediction algorithm may provide an approach for the pharmacodynamicmonitoring of T-cell responses as well as for the development of personalized vaccines in cancer patients.", "metadata": {}}
+{"_id": "4462919", "title": "", "text": "In vivo genome editing using Staphylococcus aureus Cas9The RNA-guided endonuclease Cas9 hasemerged as a versatile genome-editing platform. However, the size of the commonly used Cas9 fromStreptococcus pyogenes (SpCas9) limits its utility for basic research and therapeutic applications that usethe highly versatile adeno-associated virus (AAV) delivery vehicle. Here, we characterize six smaller Cas9orthologues and show that Cas9 from Staphylococcus aureus (SaCas9) can edit the genome withefficiencies similar to those of SpCas9, while being more than 1 kilobase shorter. We packaged SaCas9and its single guide RNA expression cassette into a single AAV vector and targeted the cholesterolregulatory gene Pcsk9 in the mouse liver. Within one week of injection, we observed >40% genemodification, accompanied by significant reductions in serum Pcsk9 and total cholesterol levels. Wefurther assess the genome-wide targeting specificity of SaCas9 and SpCas9 using BLESS, anddemonstrate that SaCas9-mediated in vivo genome editing has the potential to be efficient and specific.", "metadata": {}}
+{"_id": "4463588", "title": "", "text": "Effects of exercise intensity on cardiovascular fitness, total body composition, and visceral adiposity ofobese adolescents.BACKGROUND Little is known about how the intensity of exercise influencescardiovascular fitness and body composition, especially in obese adolescents. OBJECTIVE Our goal was todetermine the effects of physical training intensity on the cardiovascular fitness, percentage of body fat(%BF), and visceral adipose tissue (VAT) of obese adolescents. DESIGN Obese 13-16-y-olds (n = 80)were assigned to 1) biweekly lifestyle education (LSE), 2) LSE + moderate-intensity physical training, or3) LSE + high-intensity physical training. The intervention lasted 8 mo. Physical training was offered 5d/wk, and the target energy expenditure for all subjects in physical training groups was 1047 kJ (250kcal)/session. Cardiovascular fitness was measured with a multistage treadmill test, %BF withdual-energy X-ray absorptiometry, and VAT with magnetic resonance imaging. RESULTS The increase incardiovascular fitness in the high-intensity physical training group, but not in the moderate-intensitygroup, was significantly greater than that in the LSE alone group (P = 0.009); no other comparisons ofthe 3 groups were significant. Compared with the LSE alone group, a group composed of subjects in bothphysical training groups combined who attended training sessions >or=2 d/wk showed favorable changesin cardiovascular fitness (P < 0.001), %BF (P = 0.001), and VAT (P = 0.029). We found no evidence thatthe high-intensity physical training was more effective than the moderate-intensity physical training inenhancing body composition. CONCLUSIONS The cardiovascular fitness of obese adolescents wassignificantly improved by physical training, especially high-intensity physical training. The physicaltraining also reduced both visceral and total-body adiposity, but there was no clear effect of the intensityof physical training.", "metadata": {}}
+{"_id": "4463811", "title": "", "text": "Low methionine ingestion by rats extends life span.Dietary energy restriction has been a widely usedmeans of experimentally extending mammalian life span. We report here that lifelong reduction in theconcentration of a single dietary component, the essential amino acid L-methionine, from 0.86 to 0.17%of the diet results in a 30% longer life span of male Fischer 344 rats. Methionine restriction completelyabolished growth, although food intake was actually greater on a body weight basis. Studies of energyconsumption in early life indicated that the energy intake of 0.17% methionine-fed animals was nearnormal for animals of their size, although consumption per animal was below that of the much larger0.86% methionine-fed rats. Increasing the energy intake of rats fed 0.17% methionine failed to increasetheir rate of growth, whereas restricting 0.85% methionine-fed rats to the food intake of 0.17%methionine-fed animals did not materially reduce growth, indicating that food restriction was not a factorin life span extension in these experiments. The biochemically well-defined pathways of methioninemetabolism and utilization offer the potential for uncovering the precise mechanism(s) underlying thisspecific dietary restriction-related extension of life span.", "metadata": {}}
+{"_id": "4464565", "title": "", "text": "Epicatechin and a cocoa polyphenolic extract modulate gene expression in human Caco-2 cells.Weperformed a functional genomic analysis to study the effect of epicatechin and polyphenolic cocoa extractin the human colon adenocarcinoma cell line Caco-2. The specific Human Hematology/Immunology cDNAarrays by Clontech, containing 406 genes in duplicate, were used. The differentially expressed geneswere classified according to their level of expression, calculated as the ratio of the value obtained aftereach treatment relative to control cells, with a statistical significance of P < 0.05 (upregulated: ratio >1.5; downregulated: ratio < 0.6). Treatment with epicatechin decreased the expression of 21 genes andupregulated 24 genes. Upon incubation with the cocoa polyphenolic extract, 24 genes wereunderexpressed and 28 were overexpressed. The changes in expression for ferritin heavy polypeptide 1(FTH1), mitogen-activated protein kinase kinase 1 (MAPKK1), signal transducer and activator oftranscription 1 (STAT1), and topoisomerase 1 upon incubation with epicatechin, and for myeloid leukemiafactor 2 (MLF2), CCAAT/enhancer binding protein gamma (C/EBPG), MAPKK1, ATP-binding cassette,subfamily c member 1 (MRP1), STAT1, topoisomerase 1, and x-ray repair complementing defective repair1 (XRCC1) upon incubation with the cocoa polyphenolic extract were validated by RT-PCR. Changes in themessenger RNA levels for MAPKK1, STAT1, MRP1, and topoisomerase 1 upon incubation with eitherepicatechin or cocoa extract were further confirmed at the protein level by Western blotting. The changesin the expression of STAT1, MAPKK1, MRP1, and FTH1 genes, which are involved in the cellular responseto oxidative stress, are in agreement with the antioxidant properties of cocoa flavonoids. In addition, thechanges in the expression of C/EBPG, topoisomerase 1, MLF2, and XRCC1 suggest novel mechanisms ofaction of flavonoids at the molecular level.", "metadata": {}}
+{"_id": "4465608", "title": "", "text": "An atlas of active enhancers across human cell types and tissuesEnhancers control the correct temporaland cell-type-specific activation of gene expression in multicellular eukaryotes. Knowing their properties,regulatory activity and targets is crucial to understand the regulation of differentiation and homeostasis.Here we use the FANTOM5 panel of samples, covering the majority of human tissues and cell types, toproduce an atlas of active, in vivo-transcribed enhancers. We show that enhancers share properties withCpG-poor messenger RNA promoters but produce bidirectional, exosome-sensitive, relatively shortunspliced RNAs, the generation of which is strongly related to enhancer activity. The atlas is used tocompare regulatory programs between different cells at unprecedented depth, to identifydisease-associated regulatory single nucleotide polymorphisms, and to classify cell-type-specific andubiquitous enhancers. We further explore the utility of enhancer redundancy, which explains geneexpression strength rather than expression patterns. The online FANTOM5 enhancer atlas represents aunique resource for studies on cell-type-specific enhancers and gene regulation.", "metadata": {}}
+{"_id": "4465735", "title": "", "text": "Precision microbiome reconstitution restores bile acid mediated resistance to Clostridium difficileThegastrointestinal tracts of mammals are colonized by hundreds of microbial species that contribute tohealth, including colonization resistance against intestinal pathogens. Many antibiotics destroy intestinalmicrobial communities and increase susceptibility to intestinal pathogens. Among these, Clostridiumdifficile, a major cause of antibiotic-induced diarrhoea, greatly increases morbidity and mortality inhospitalized patients. Which intestinal bacteria provide resistance to C. difficile infection and their in vivoinhibitory mechanisms remain unclear. Here we correlate loss of specific bacterial taxa with developmentof infection, by treating mice with different antibiotics that result in distinct microbiota changes and leadto varied susceptibility to C. difficile. Mathematical modelling augmented by analyses of the microbiota ofhospitalized patients identifies resistance-associated bacteria common to mice and humans. Using theseplatforms, we determine that Clostridium scindens, a bile acid 7α-dehydroxylating intestinal bacterium, isassociated with resistance to C. difficile infection and, upon administration, enhances resistance toinfection in a secondary bile acid dependent fashion. Using a workflow involving mouse models, clinicalstudies, metagenomic analyses, and mathematical modelling, we identify a probiotic candidate thatcorrects a clinically relevant microbiome deficiency. These findings have implications for the rationaldesign of targeted antimicrobials as well as microbiome-based diagnostics and therapeutics forindividuals at risk of C. difficile infection.", "metadata": {}}
+{"_id": "4465762", "title": "", "text": "Transcription initiation complex structures elucidate DNA openingTranscription of eukaryoticprotein-coding genes begins with assembly of the RNA polymerase (Pol) II initiation complex andpromoter DNA opening. Here we report cryo-electron microscopy (cryo-EM) structures of yeast initiationcomplexes containing closed and open DNA at resolutions of 8.8 Å and 3.6 Å, respectively. DNA ispositioned and retained over the Pol II cleft by a network of interactions between the TATA-box-bindingprotein TBP and transcription factors TFIIA, TFIIB, TFIIE, and TFIIF. DNA opening occurs around the tip ofthe Pol II clamp and the TFIIE ‘extended winged helix’ domain, and can occur in the absence of TFIIH.Loading of the DNA template strand into the active centre may be facilitated by movements ofobstructing protein elements triggered by allosteric binding of the TFIIE ‘E-ribbon’ domain. The resultssuggest a unified model for transcription initiation with a key event, the trapping of open promoter DNAby extended protein–protein and protein–DNA contacts.", "metadata": {}}
+{"_id": "4467129", "title": "", "text": "Multiple mechanisms disrupt the let-7 microRNA family in neuroblastomaPoor prognosis in neuroblastomais associated with genetic amplification of MYCN. MYCN is itself a target of let-7, a tumour suppressorfamily of microRNAs implicated in numerous cancers. LIN28B, an inhibitor of let-7 biogenesis, isoverexpressed in neuroblastoma and has been reported to regulate MYCN. Here we show, however, thatLIN28B is dispensable in MYCN-amplified neuroblastoma cell lines, despite de-repression of let-7. Wefurther demonstrate that MYCN messenger RNA levels in amplified disease are exceptionally high andsufficient to sponge let-7, which reconciles the dispensability of LIN28B. We found that genetic loss oflet-7 is common in neuroblastoma, inversely associated with MYCN amplification, and independentlyassociated with poor outcomes, providing a rationale for chromosomal loss patterns in neuroblastoma.We propose that let-7 disruption by LIN28B, MYCN sponging, or genetic loss is a unifying mechanism ofneuroblastoma development with broad implications for cancer pathogenesis.", "metadata": {}}
+{"_id": "4468861", "title": "", "text": "Radiation and Dual Checkpoint Blockade Activates Non-Redundant Immune Mechanisms inCancerImmune checkpoint inhibitors result in impressive clinical responses, but optimal results willrequire combination with each other and other therapies. This raises fundamental questions aboutmechanisms of non-redundancy and resistance. Here we report major tumour regressions in a subset ofpatients with metastatic melanoma treated with an anti-CTLA4 antibody (anti-CTLA4) and radiation, andreproduced this effect in mouse models. Although combined treatment improved responses in irradiatedand unirradiated tumours, resistance was common. Unbiased analyses of mice revealed that resistancewas due to upregulation of PD-L1 on melanoma cells and associated with T-cell exhaustion. Accordingly,optimal response in melanoma and other cancer types requires radiation, anti-CTLA4 andanti-PD-L1/PD-1. Anti-CTLA4 predominantly inhibits T-regulatory cells (Treg cells), thereby increasing theCD8 T-cell to Treg (CD8/Treg) ratio. Radiation enhances the diversity of the T-cell receptor (TCR)repertoire of intratumoral T cells. Together, anti-CTLA4 promotes expansion of T cells, while radiationshapes the TCR repertoire of the expanded peripheral clones. Addition of PD-L1 blockade reverses T-cellexhaustion to mitigate depression in the CD8/Treg ratio and further encourages oligoclonal T-cellexpansion. Similarly to results from mice, patients on our clinical trial with melanoma showing high PD-L1did not respond to radiation plus anti-CTLA4, demonstrated persistent T-cell exhaustion, and rapidlyprogressed. Thus, PD-L1 on melanoma cells allows tumours to escape anti-CTLA4-based therapy, and thecombination of radiation, anti-CTLA4 and anti-PD-L1 promotes response and immunity through distinctmechanisms.", "metadata": {}}
+{"_id": "4469125", "title": "", "text": "G-protein-independent coupling of MC4R to Kir7.1 in hypothalamic neuronsThe regulated release ofanorexigenic α-melanocyte stimulating hormone (α-MSH) and orexigenic Agouti-related protein (AgRP)from discrete hypothalamic arcuate neurons onto common target sites in the central nervous system hasa fundamental role in the regulation of energy homeostasis. Both peptides bind with high affinity to themelanocortin-4 receptor (MC4R); existing data show that α-MSH is an agonist that couples the receptorto the Gαs signalling pathway, while AgRP binds competitively to block α-MSH binding and blocks theconstitutive activity mediated by the ligand-mimetic amino-terminal domain of the receptor. Here weshow that, in mice, regulation of firing activity of neurons from the paraventricular nucleus of thehypothalamus (PVN) by α-MSH and AgRP can be mediated independently of Gαs signalling byligand-induced coupling of MC4R to closure of inwardly rectifying potassium channel, Kir7.1. Furthermore,AgRP is a biased agonist that hyperpolarizes neurons by binding to MC4R and opening Kir7.1,independently of its inhibition of α-MSH binding. Consequently, Kir7.1 signalling appears to be central tomelanocortin-mediated regulation of energy homeostasis within the PVN. Coupling of MC4R to Kir7.1 mayexplain unusual aspects of the control of energy homeostasis by melanocortin signalling, including thegene dosage effect of MC4R and the sustained effects of AgRP on food intake.", "metadata": {}}
+{"_id": "4474874", "title": "", "text": "Role of ghrelin in the relationship between hyperphagia and accelerated gastric emptying in diabeticmice.BACKGROUND & AIMS Ghrelin is an orexigenic peptide with gastroprokinetic effects. Mice withstreptozotocin (STZ)-induced diabetes exhibit hyperphagia, altered gastric emptying, and increasedplasma ghrelin levels. We investigated the causative role of ghrelin herein by comparing changes inghrelin receptor knockout (growth hormone secretagogue receptor [GHS-R](-/-)) and wild-type(GHS-R(+/+)) mice with STZ-induced diabetes. METHODS Gastric emptying was measured with the[(13)C]octanoic acid breath test. The messenger RNA (mRNA) expression of neuropeptide Y (NPY),agouti-related peptide (AgRP), and proopiomelanocortin was quantified by real-time reverse-transcriptionpolymerase chain reaction. Neural contractions were elicited by electrical field stimulation in fundicsmooth muscle strips. RESULTS Diabetes increased plasma ghrelin levels to a similar extent in bothgenotypes. Hyperphagia was more pronounced in GHS-R(+/+) than in GHS-R(-/-) mice between days 12and 21. Increases in NPY and AgRP mRNA expression were less pronounced in diabetic GHS-R(-/-) thanin GHS-R(+/+) mice from day 15 on, whereas decreases in proopiomelanocortin mRNA levels weresimilar in both genotypes. Gastric emptying was accelerated to a similar extent in both genotypes,starting on day 16. In fundic smooth muscle strips of diabetic GHS-R(+/+) and GHS-R(-/-) mice,neuronal relaxations were reduced, whereas contractions were increased; this increase was related to anincreased affinity of muscarinic and tachykinergic receptors. CONCLUSIONS Diabetic hyperphagia isregulated by central mechanisms in which the ghrelin-signaling pathway affects the expression of NPYand AgRP in the hypothalamus. The acceleration of gastric emptying, which is not affected by ghrelinsignaling, is not the cause of diabetic hyperphagia and probably involves local contractility changes in thefundus.", "metadata": {}}
+{"_id": "4483571", "title": "", "text": "Human serum 25-hydroxycholecalciferol response to extended oral dosing withcholecalciferol.BACKGROUND The cholecalciferol inputs required to achieve or maintain any given serum25-hydroxycholecalciferol concentration are not known, particularly within ranges comparable to theprobable physiologic supply of the vitamin. OBJECTIVES The objectives were to establish the quantitativerelation between steady state cholecalciferol input and the resulting serum 25-hydroxycholecalciferolconcentration and to estimate the proportion of the daily requirement during winter that is met bycholecalciferol reserves in body tissue stores. DESIGN Cholecalciferol was administered daily in controlledoral doses labeled at 0, 25, 125, and 250 micro g cholecalciferol for approximately 20 wk during thewinter to 67 men living in Omaha (41.2 degrees N latitude). The time course of serum25-hydroxycholecalciferol concentration was measured at intervals over the course of treatment.RESULTS From a mean baseline value of 70.3 nmol/L, equilibrium concentrations of serum25-hydroxycholecalciferol changed during the winter months in direct proportion to the dose, with a slopeof approximately 0.70 nmol/L for each additional 1 micro g cholecalciferol input. The calculated oral inputrequired to sustain the serum 25-hydroxycholecalciferol concentration present before the study (ie, in theautumn) was 12.5 micro g (500 IU)/d, whereas the total amount from all sources (supplement, food,tissue stores) needed to sustain the starting 25-hydroxycholecalciferol concentration was estimated atapproximately 96 micro g (approximately 3800 IU)/d. By difference, the tissue stores providedapproximately 78-82 micro g/d. CONCLUSIONS Healthy men seem to use 3000-5000 IU cholecalciferol/d,apparently meeting > 80% of their winter cholecalciferol need with cutaneously synthesizedaccumulations from solar sources during the preceding summer months. Current recommended vitamin Dinputs are inadequate to maintain serum 25-hydroxycholecalciferol concentration in the absence ofsubstantial cutaneous production of vitamin D.", "metadata": {}}
+{"_id": "4489217", "title": "", "text": "Intratumor heterogeneity and branched evolution revealed by multiregion sequencing.BACKGROUNDIntratumor heterogeneity may foster tumor evolution and adaptation and hinder personalized-medicinestrategies that depend on results from single tumor-biopsy samples. METHODS To examine intratumorheterogeneity, we performed exome sequencing, chromosome aberration analysis, and ploidy profiling onmultiple spatially separated samples obtained from primary renal carcinomas and associated metastaticsites. We characterized the consequences of intratumor heterogeneity using immunohistochemicalanalysis, mutation functional analysis, and profiling of messenger RNA expression. RESULTS Phylogeneticreconstruction revealed branched evolutionary tumor growth, with 63 to 69% of all somatic mutationsnot detectable across every tumor region. Intratumor heterogeneity was observed for a mutation withinan autoinhibitory domain of the mammalian target of rapamycin (mTOR) kinase, correlating with S6 and4EBP phosphorylation in vivo and constitutive activation of mTOR kinase activity in vitro. Mutationalintratumor heterogeneity was seen for multiple tumor-suppressor genes converging on loss of function;SETD2, PTEN, and KDM5C underwent multiple distinct and spatially separated inactivating mutationswithin a single tumor, suggesting convergent phenotypic evolution. Gene-expression signatures of goodand poor prognosis were detected in different regions of the same tumor. Allelic composition and ploidyprofiling analysis revealed extensive intratumor heterogeneity, with 26 of 30 tumor samples from fourtumors harboring divergent allelic-imbalance profiles and with ploidy heterogeneity in two of four tumors.CONCLUSIONS Intratumor heterogeneity can lead to underestimation of the tumor genomics landscapeportrayed from single tumor-biopsy samples and may present major challenges to personalized-medicineand biomarker development. Intratumor heterogeneity, associated with heterogeneous protein function,may foster tumor adaptation and therapeutic failure through Darwinian selection. (Funded by the MedicalResearch Council and others.).", "metadata": {}}
+{"_id": "4492358", "title": "", "text": "Succession of microbial consortia in the developing infant gut microbiome.The colonization process of theinfant gut microbiome has been called chaotic, but this view could reflect insufficient documentation ofthe factors affecting the microbiome. We performed a 2.5-y case study of the assembly of the humaninfant gut microbiome, to relate life events to microbiome composition and function. Sixty fecal sampleswere collected from a healthy infant along with a diary of diet and health status. Analysis of >300,00016S rRNA genes indicated that the phylogenetic diversity of the microbiome increased gradually overtime and that changes in community composition conformed to a smooth temporal gradient. In contrast,major taxonomic groups showed abrupt shifts in abundance corresponding to changes in diet or health.Community assembly was nonrandom: we observed discrete steps of bacterial succession punctuated bylife events. Furthermore, analysis of ≈ 500,000 DNA metagenomic reads from 12 fecal samples revealedthat the earliest microbiome was enriched in genes facilitating lactate utilization, and that functionalgenes involved in plant polysaccharide metabolism were present before the introduction of solid food,priming the infant gut for an adult diet. However, ingestion of table foods caused a sustained increase inthe abundance of Bacteroidetes, elevated fecal short chain fatty acid levels, enrichment of genesassociated with carbohydrate utilization, vitamin biosynthesis, and xenobiotic degradation, and a morestable community composition, all of which are characteristic of the adult microbiome. This studyrevealed that seemingly chaotic shifts in the microbiome are associated with life events; however,additional experiments ought to be conducted to assess how different infants respond to similar lifeevents.", "metadata": {}}
+{"_id": "4500832", "title": "", "text": "gamma-tocopherol, the major form of vitamin E in the US diet, deserves moreattention.gamma-tocopherol is the major form of vitamin E in many plant seeds and in the US diet, buthas drawn little attention compared with alpha-tocopherol, the predominant form of vitamin E in tissuesand the primary form in supplements. However, recent studies indicate that gamma-tocopherol may beimportant to human health and that it possesses unique features that distinguish it fromalpha-tocopherol. gamma-Tocopherol appears to be a more effective trap for lipophilic electrophiles thanis alpha-tocopherol. gamma-Tocopherol is well absorbed and accumulates to a significant degree in somehuman tissues; it is metabolized, however, largely to2,7,8-trimethyl-2-(beta-carboxyethyl)-6-hydroxychroman (gamma-CEHC), which is mainly excreted inthe urine. gamma-CEHC, but not the corresponding metabolite derived from alpha-tocopherol, hasnatriuretic activity that may be of physiologic importance. Both gamma-tocopherol and gamma-CEHC,but not alpha-tocopherol, inhibit cyclooxygenase activity and, thus, possess antiinflammatory properties.Some human and animal studies indicate that plasma concentrations of gamma-tocopherol are inverselyassociated with the incidence of cardiovascular disease and prostate cancer. These distinguishing featuresof gamma-tocopherol and its metabolite suggest that gamma-tocopherol may contribute significantly tohuman health in ways not recognized previously. This possibility should be further evaluated, especiallyconsidering that high doses of alpha-tocopherol deplete plasma and tissue gamma-tocopherol, in contrastwith supplementation with gamma-tocopherol, which increases both. We review current information onthe bioavailability, metabolism, chemistry, and nonantioxidant activities of gamma-tocopherol andepidemiologic data concerning the relation between gamma-tocopherol and cardiovascular disease andcancer.", "metadata": {}}
+{"_id": "4505748", "title": "", "text": "Disclosure of APOE genotype for risk of Alzheimer's disease.BACKGROUND The apolipoprotein E (APOE)genotype provides information on the risk of Alzheimer's disease, but the genotyping of patients and theirfamily members has been discouraged. We examined the effect of genotype disclosure in a prospective,randomized, controlled trial. METHODS We randomly assigned 162 asymptomatic adults who had aparent with Alzheimer's disease to receive the results of their own APOE genotyping (disclosure group) ornot to receive such results (nondisclosure group). We measured symptoms of anxiety, depression, andtest-related distress 6 weeks, 6 months, and 1 year after disclosure or nondisclosure. RESULTS Therewere no significant differences between the two groups in changes in time-averaged measures of anxiety(4.5 in the disclosure group and 4.4 in the nondisclosure group, P=0.84), depression (8.8 and 8.7,respectively; P=0.98), or test-related distress (6.9 and 7.5, respectively; P=0.61). Secondarycomparisons between the nondisclosure group and a disclosure subgroup of subjects carrying the APOEepsilon4 allele (which is associated with increased risk) also revealed no significant differences. However,the epsilon4-negative subgroup had a significantly lower level of test-related distress than did theepsilon4-positive subgroup (P=0.01). Subjects with clinically meaningful changes in psychologicaloutcomes were distributed evenly among the nondisclosure group and the epsilon4-positive andepsilon4-negative subgroups. Baseline scores for anxiety and depression were strongly associated withpost-disclosure scores of these measures (P<0.001 for both comparisons). CONCLUSIONS The disclosureof APOE genotyping results to adult children of patients with Alzheimer's disease did not result insignificant short-term psychological risks. Test-related distress was reduced among those who learnedthat they were APOE epsilon4-negative. Persons with high levels of emotional distress before undergoinggenetic testing were more likely to have emotional difficulties after disclosure. (ClinicalTrials.gov number,NCT00571025.)", "metadata": {}}
+{"_id": "4506414", "title": "", "text": "Blood pressure and incidence of twelve cardiovascular diseases: lifetime risks, healthy life-years lost, andage-specific associations in 1·25 million peopleBACKGROUND The associations of blood pressure with thedifferent manifestations of incident cardiovascular disease in a contemporary population have not beencompared. In this study, we aimed to analyse the associations of blood pressure with 12 differentpresentations of cardiovascular disease. METHODS We used linked electronic health records from 1997 to2010 in the CALIBER (CArdiovascular research using LInked Bespoke studies and Electronic healthRecords) programme to assemble a cohort of 1·25 million patients, 30 years of age or older and initiallyfree from cardiovascular disease, a fifth of whom received blood pressure-lowering treatments. Westudied the heterogeneity in the age-specific associations of clinically measured blood pressure with 12acute and chronic cardiovascular diseases, and estimated the lifetime risks (up to 95 years of age) andcardiovascular disease-free life-years lost adjusted for other risk factors at index ages 30, 60, and 80years. This study is registered at ClinicalTrials.gov, number NCT01164371. FINDINGS During 5·2 yearsmedian follow-up, we recorded 83,098 initial cardiovascular disease presentations. In each age group,the lowest risk for cardiovascular disease was in people with systolic blood pressure of 90-114 mm Hgand diastolic blood pressure of 60-74 mm Hg, with no evidence of a J-shaped increased risk at lowerblood pressures. The effect of high blood pressure varied by cardiovascular disease endpoint, fromstrongly positive to no effect. Associations with high systolic blood pressure were strongest forintracerebral haemorrhage (hazard ratio 1·44 [95% CI 1·32-1·58]), subarachnoid haemorrhage (1·43[1·25-1·63]), and stable angina (1·41 [1·36-1·46]), and weakest for abdominal aortic aneurysm (1·08[1·00-1·17]). Compared with diastolic blood pressure, raised systolic blood pressure had a greater effecton angina, myocardial infarction, and peripheral arterial disease, whereas raised diastolic blood pressurehad a greater effect on abdominal aortic aneurysm than did raised systolic pressure. Pulse pressureassociations were inverse for abdominal aortic aneurysm (HR per 10 mm Hg 0·91 [95% CI 0·86-0·98])and strongest for peripheral arterial disease (1·23 [1·20-1·27]). People with hypertension (blood pressure≥140/90 mm Hg or those receiving blood pressure-lowering drugs) had a lifetime risk of overallcardiovascular disease at 30 years of age of 63·3% (95% CI 62·9-63·8) compared with 46·1%(45·5-46·8) for those with normal blood pressure, and developed cardiovascular disease 5·0 years earlier(95% CI 4·8-5·2). Stable and unstable angina accounted for most (43%) of the cardiovasculardisease-free years of life lost associated with hypertension from index age 30 years, whereas heart failureand stable angina accounted for the largest proportion (19% each) of years of life lost from index age 80years. INTERPRETATION The widely held assumptions that blood pressure has strong associations withthe occurrence of all cardiovascular diseases across a wide age range, and that diastolic and systolicassociations are concordant, are not supported by the findings of this high-resolution study. Despitemodern treatments, the lifetime burden of hypertension is substantial. These findings emphasise theneed for new blood pressure-lowering strategies, and will help to inform the design of randomised trialsto assess them. FUNDING Medical Research Council, National Institute for Health Research, andWellcome Trust.", "metadata": {}}
+{"_id": "4506702", "title": "", "text": "Can Online Consumers Contribute to Drug Knowledge? A Mixed-Methods Comparison ofConsumer-Generated and Professionally Controlled Psychotropic Medication Information on theInternetBACKGROUND Ongoing initiatives to filter online health searches exclude consumer-generatedcontent from search returns, though its inferiority compared with professionally controlled content is notdemonstrated. The antidepressant escitalopram and the antipsychotic quetiapine have ranked over thelast 5 years as top-selling agents in their respective drug classes. Both drugs have various off-labelmental health and non-mental health uses, ranging from the relief of insomnia and migraines to thetreatment of severe developmental disorders. OBJECTIVE Our objective was to describe the mostfrequently reported effects of escitalopram and quetiapine in online consumer reviews, to compare themwith effects described in professionally controlled commercial health websites, and to gauge the usabilityof online consumer medication reviews. METHODS A stratified simple random sample of 960 consumerreviews was selected from all 6998 consumer reviews of the two drugs in 2 consumer-generated(www.askapatient.com and www.crazymeds.us) and 2 professionally controlled (www.webmd.com andwww.revolutionhealth.com) health websites. Professional medication descriptions included all standardinformation on the medications from the latter 2 websites. All textual data were inductively coded formedication effects, and intercoder agreement was assessed. Chi-square was used to test for associationsbetween consumer-reported effects and website origination. RESULTS Consumers taking eitherescitalopram (n = 480) or quetiapine (n = 480) most frequently reported symptom improvement (30.4%or 146/480, 24.8% or 119/480) or symptom worsening (15.8% or 76/480, 10.2% or 49/480), changes insleep (36% or 173/480, 60.6% or 291/480) and changes in weight and appetite (22.5% or 108/480,30.8% or 148/480). More consumers posting reviews on consumer-generated rather than professionallycontrolled websites reported symptom worsening on quetiapine (17.3% or 38/220 versus 5% or 11/220,P < .001), while more consumers posting on professionally controlled websites reported symptomimprovement (32.7% or 72/220 versus 21.4% or 47/220, P = .008). Professional descriptions morefrequently listed physical adverse effects and warnings about suicidal ideation while consumer reviewsemphasized effects disrupting daily routines and provided richer descriptions of effects in context. Themost recent 20 consumer reviews on each drug from each website (n = 80) were comparable to the fullsample of reviews in the frequency of commonly reported effects. CONCLUSION Consumer reviews andprofessional medication descriptions generally reported similar effects of two psychotropic medicationsbut differed in their descriptions and in frequency of reporting. Professional medication descriptions offerthe advantage of a concise yet comprehensive listing of drug effects, while consumer reviews offergreater context and situational examples of how effects may manifest in various combinations and tovarying degrees. The dispersion of consumer reviews across websites limits their integration, but a briefbrowsing strategy on the two target medications nonetheless retrieved representative consumer content.Current strategies for filtering online health searches to return only trusted or approved websites mayinappropriately address the challenge to identify quality health sources on the Internet because suchstrategies unduly limit access to an entire complementary source for health information.", "metadata": {}}
+{"_id": "4515975", "title": "", "text": "Effect of supplemental zinc on the growth and serum zinc concentrations of prepubertal children: ameta-analysis of randomized controlled trials.BACKGROUND Multiple studies have been carried out toassess the effect of zinc supplementation on children's growth. The results of these studies areinconsistent, and the factors responsible for these varied outcomes are unknown. OBJECTIVEMeta-analyses of randomized controlled intervention trials were therefore completed to assess the effectof zinc supplementation on the physical growth and serum zinc concentrations of prepubertal children.DESIGN A total of 33 acceptable studies with appropriate data were identified by MEDLINE (NationalLibrary of Medicine, Bethesda, MD) searches and other methods. Weighted mean effect sizes (expressedin SD units) were calculated for changes in height, weight, weight-for-height, and serum zincconcentration by using random-effects models; factors associated with effect sizes were explored bymeta-regression techniques. RESULTS Zinc supplementation produced highly significant, positiveresponses in height and weight increments, with effect sizes of 0.350 (95% CI: 0.189, 0.511) and 0.309(0.178, 0.439), respectively. There was no significant effect of zinc on weight-for-height indexes[weighted mean effect size: -0.018 (-0.132, 0.097)]. Zinc supplementation caused a large increase in thechildren's serum zinc concentrations, with an effect size of 0.820 (0.499, 1.14). Growth responses weregreater in children with low initial weight-for-age z scores and in those aged >6 mo with low initialheight-for-age z scores. CONCLUSIONS Interventions to improve children's zinc nutriture should beconsidered in populations at risk of zinc deficiency, especially where there are elevated rates ofunderweight or stunting. The population mean serum zinc concentration is a useful indicator of thesuccessful delivery and absorption of zinc supplements in children.", "metadata": {}}
+{"_id": "4530659", "title": "", "text": "Mechanisms of Age-Related Macular DegenerationAge-related macular degeneration (AMD), aprogressive condition that is untreatable in up to 90% of patients, is a leading cause of blindness in theelderly worldwide. The two forms of AMD, wet and dry, are classified based on the presence or absence ofblood vessels that have disruptively invaded the retina, respectively. A detailed understanding of themolecular mechanisms underlying wet AMD has led to several robust FDA-approved therapies. Incontrast, there are no approved treatments for dry AMD. In this review, we provide insight into thecritical effector pathways mediating each form of the disease. A recurring theme that spans most aspectsof AMD pathogenesis is defective immune modulation in the classically immune-privileged ocular haven.Interestingly, the latest advances in AMD research also highlight common molecular disease pathwayswith other neurodegenerative disorders. Finally, the therapeutic potential of intervening at knownmechanistic steps of AMD pathogenesis is discussed.", "metadata": {}}
+{"_id": "4544916", "title": "", "text": "The N-end rule pathway regulates pathogen responses in plants.To efficiently counteract pathogens,plants rely on a complex set of immune responses that are tightly regulated to allow the timelyactivation, appropriate duration and adequate amplitude of defense programs. The coordination of theplant immune response is known to require the activity of the ubiquitin/proteasome system, whichcontrols the stability of proteins in eukaryotes. Here, we demonstrate that the N-end rule pathway, asubset of the ubiquitin/proteasome system, regulates the defense against a wide range of bacterial andfungal pathogens in the model plant Arabidopsis thaliana. We show that this pathway positively regulatesthe biosynthesis of plant-defense metabolites such as glucosinolates, as well as the biosynthesis andresponse to the phytohormone jasmonic acid, which plays a key role in plant immunity. Our results alsosuggest that the arginylation branch of the N-end rule pathway regulates the timing and amplitude of thedefense program against the model pathogen Pseudomonas syringae AvrRpm1.", "metadata": {}}
+{"_id": "4547102", "title": "", "text": "H3K9 demethylase KDM4E is an epigenetic regulator for bovine embryonic development and a defectivefactor for nuclear reprogramming.Aberrant epigenetic reprogramming often results in developmentaldefects in somatic cell nuclear transfer (SCNT) embryos during embryonic genome activation (EGA).Bovine eight-cell SCNT embryos exhibit global hypermethylation of histone H3 lysine 9 tri- anddi-methylation (H3K9me3/2), but the intrinsic reason for this remains elusive. Here, we provide evidencethat two H3K9 demethylase genes, lysine-specific demethylase 4D (KDM4D) and 4E (KDM4E), are relatedto active H3K9me3/2 demethylation in in vitro fertilized (IVF) embryos and are deficiently expressed incloned embryos at the time of EGA. Moreover, KDM4E plays a more crucial role in IVF and SCNTembryonic development, and overexpression of KDM4E can restore the global transcriptome, improveblastocyst formation and increase the cloning efficiency of SCNT embryos. Our results thereby indicatethat KDM4E can function as a crucial epigenetic regulator of EGA and as an internal defective factorresponsible for persistent H3K9me3/2 barriers to SCNT-mediated reprogramming. Furthermore, we showthat interactions between RNA and KDM4E are essential for H3K9 demethylation during EGA. Theseobservations advance the understanding of incomplete nuclear reprogramming and are of greatimportance for transgenic cattle procreation.", "metadata": {}}
+{"_id": "4550036", "title": "", "text": "Risk of gestational hypertension in relation to folic acid supplementation during pregnancy.The authorsinvestigated the association between folic acid supplementation and gestational hypertension. The studypopulation included women with nonmalformed infants in the United States and Canada who wereparticipating in the Slone Epidemiology Center Birth Defects Study between 1993 and 2000. Women wereinterviewed within 6 months after delivery about sociodemographic and medical factors, the occurrenceof hypertension with or without preeclampsia, and multivitamin use in pregnancy. Relative risks, adjustedfor weight, parity, twin pregnancy, diabetes, smoking, education, and family income, were estimatedusing Cox regression models. Of 2,100 women, 204 (9.7%) reported gestational hypertension (onsetafter the 20th week of gestation). The multivariate-adjusted relative risk of developing gestationalhypertension during the month after folic acid supplementation, compared with not using folic acid duringthat same month, was 0.55 (95% confidence interval: 0.39, 0.79). This finding suggests that folicacid-containing multivitamins may reduce the risk of gestational hypertension.", "metadata": {}}
+{"_id": "4561402", "title": "", "text": "Aire regulates negative selection of organ-specific T cellsAutoimmune polyendocrinopathy syndrome type1 is a recessive Mendelian disorder resulting from mutations in a novel gene, AIRE, and is characterizedby a spectrum of organ-specific autoimmune diseases. It is not known what tolerance mechanisms aredefective as a result of AIRE mutation. By tracing the fate of autoreactive CD4+ T cells with high affinityfor a pancreatic antigen in transgenic mice with an Aire mutation, we show here that Aire deficiencycauses almost complete failure to delete the organ-specific cells in the thymus. These results indicate thatautoimmune polyendocrinopathy syndrome 1 is caused by failure of a specialized mechanism for deletingforbidden T cell clones, establishing a central role for this tolerance mechanism.", "metadata": {}}
+{"_id": "4583180", "title": "", "text": "Extracellular Acidic pH Activates the Sterol Regulatory Element-Binding Protein 2 to Promote TumorProgression.Conditions of the tumor microenvironment, such as hypoxia and nutrient starvation, playcritical roles in cancer progression. However, the role of acidic extracellular pH in cancer progression isnot studied as extensively as that of hypoxia. Here, we show that extracellular acidic pH (pH 6.8)triggered activation of sterol regulatory element-binding protein 2 (SREBP2) by stimulating nucleartranslocation and promoter binding to its targets, along with intracellular acidification. Interestingly,inhibition of SREBP2, but not SREBP1, suppressed the upregulation of low pH-induced cholesterolbiosynthesis-related genes. Moreover, acyl-CoA synthetase short-chain family member 2 (ACSS2), adirect SREBP2 target, provided a growth advantage to cancer cells under acidic pH. Furthermore, acidicpH-responsive SREBP2 target genes were associated with reduced overall survival of cancer patients.Thus, our findings show that SREBP2 is a key transcriptional regulator of metabolic genes andprogression of cancer cells, partly in response to extracellular acidification.", "metadata": {}}
+{"_id": "4587978", "title": "", "text": "Mutation of the Human Circadian Clock Gene CRY1 in Familial Delayed Sleep Phase DisorderPatterns ofdaily human activity are controlled by an intrinsic circadian clock that promotes \u000024 hr rhythms in manybehavioral and physiological processes. This system is altered in delayed sleep phase disorder (DSPD), acommon form of insomnia in which sleep episodes are shifted to later times misaligned with the societalnorm. Here, we report a hereditary form of DSPD associated with a dominant coding variation in the corecircadian clock gene CRY1, which creates a transcriptional inhibitor with enhanced affinity for circadianactivator proteins Clock and Bmal1. This gain-of-function CRY1 variant causes reduced expression of keytranscriptional targets and lengthens the period of circadian molecular rhythms, providing a mechanisticlink to DSPD symptoms. The allele has a frequency of up to 0.6%, and reverse phenotyping of unrelatedfamilies corroborates late and/or fragmented sleep patterns in carriers, suggesting that it affects sleepbehavior in a sizeable portion of the human population.", "metadata": {}}
+{"_id": "4611267", "title": "", "text": "Lateral Hypothalamic Signaling Mechanisms Underlying Feeding Stimulation: Differential Contributions ofSrc Family Tyrosine Kinases to Feeding Triggered Either by NMDA Injection or by Food DeprivationIn rats,feeding can be triggered experimentally using many approaches. Included among these are (1) fooddeprivation and (2) acute microinjection of the neurotransmitter l-glutamate (Glu) or its receptor agonistNMDA into the lateral hypothalamic area (LHA). Under both paradigms, the NMDA receptor (NMDA-R)within the LHA appears critically involved in transferring signals encoded by Glu to stimulate feeding.However, the intracellular mechanisms underlying this signal transfer are unknown. Becauseprotein-tyrosine kinases (PTKs) participate in NMDA-R signaling mechanisms, we determined PTKinvolvement in LHA mechanisms underlying both types of feeding stimulation through food intake andbiochemical measurements. LHA injections of PTK inhibitors significantly suppressed feeding elicited byLHA NMDA injection (up to 69%) but only mildly suppressed deprivation feeding (24%), suggesting thatPTKs may be less critical for signals underlying this feeding behavior. Conversely, food deprivation butnot NMDA injection produced marked increases in apparent activity for Src PTKs and in the expression ofPyk2, an Src-activating PTK. When considered together, the behavioral and biochemical resultsdemonstrate that, although it is easier to suppress NMDA-elicited feeding by PTK inhibitors, fooddeprivation readily drives PTK activity in vivo. The latter result may reflect greater PTK recruitment byneurotransmitter receptors, distinct from the NMDA-R, that are activated during deprivation-elicited butnot NMDA-elicited feeding. These results also demonstrate how the use of only one feeding stimulationparadigm may fail to reveal the true contributions of signaling molecules to pathways underlying feedingbehavior in vivo.", "metadata": {}}
+{"_id": "4627816", "title": "", "text": "Relationship between advanced glycation end\u0000product accumulation and low skeletal muscle mass inJapanese men and womenAIM The present study aimed to investigate the relationship between advancedglycation end-product accumulation and skeletal muscle mass among middle-aged and older Japanesemen and women. METHODS A total of 132 participants enrolled in this cross-sectional study. Skinautofluorescence was assessed as a measure of advanced glycation-end products. Appendicular skeletalmuscle mass was measured using dual-energy X-ray absorptiometry, and skeletal muscle index wascalculated by dividing appendicular skeletal muscle mass by height squared. Participants were dividedinto two groups (low skeletal muscle index and normal skeletal muscle index) using the Asian WorkingGroup for Sarcopenia's skeletal muscle index criteria for diagnosing sarcopenia. Multivariate logisticregression analysis and the area under the receiver operating characteristic curve were used todetermine significant factors associated with low skeletal muscle index. RESULTS Participants consisted of70 men (mean age 57 ± 10 years) and 62 women (mean age 60 ± 11 years). There were 31 and 101participants in the low and normal skeletal muscle index groups, respectively. Skin autofluorescence wassignificantly higher in the low skeletal muscle index group compared with the normal skeletal muscleindex group (P < 0.01). Skin autofluorescence was a significant independent factor associated with lowskeletal muscle index based on multivariate logistic regression analysis (odds ratio 15.7, 95% confidenceinterval 1.85-133.01; P = 0.012). The cut-off for skin autofluorescence was 2.45 arbitrary units, with asensitivity of 0.75 and specificity of 0.91. CONCLUSIONS Skin autofluorescence was an independentfactor associated with low skeletal muscle index among middle-aged and older Japanese men andwomen. Geriatr Gerontol Int 2017; 17: 785-790.", "metadata": {}}
+{"_id": "4632921", "title": "", "text": "Large-Scale Profiling Reveals the Influence of Genetic Variation on Gene Expression in Human InducedPluripotent Stem Cells.In this study, we used whole-genome sequencing and gene expression profiling of215 human induced pluripotent stem cell (iPSC) lines from different donors to identify genetic variantsassociated with RNA expression for 5,746 genes. We were able to predict causal variants for theseexpression quantitative trait loci (eQTLs) that disrupt transcription factor binding and validated a subsetof them experimentally. We also identified copy-number variant (CNV) eQTLs, including some that appearto affect gene expression by altering the copy number of intergenic regulatory regions. In addition, wewere able to identify effects on gene expression of rare genic CNVs and regulatory single-nucleotidevariants and found that reactivation of gene expression on the X chromosome depends on genechromosomal position. Our work highlights the value of iPSCs for genetic association analyses andprovides a unique resource for investigating the genetic regulation of gene expression in pluripotent cells.", "metadata": {}}
+{"_id": "4641348", "title": "", "text": "Ethanol extract of Allium fistulosum inhibits development of non-alcoholic fatty liverdiseaseBACKGROUND/OBJECTIVES Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronicliver disease and is closely associated with metabolic syndrome. In the present study, we observed theeffect of ethanol extract of Allium fistulosum (EAF) on NAFLD and have suggested the possibility of usingEAF as a natural product for application in the development of a treatment for NAFLD.MATERIALS/METHODS The preventive effect on hepatic lipid accumulation was estimated by using anoleic acid (OA)-induced NAFLD model in vitro and a Western diet (high-fat high-sucrose; WD)-inducedobese mouse model. Animals were divided into three groups (n = 7): normal diet group (ND), WD group,and WD plus 1% EAF group. RESULTS EAF reduced OA-stimulated lipid accumulation in HepG2 cells inthe absence of cellular cytotoxicity and significantly blocked transcriptional activation of sterol regulatoryelement-binding protein 1 and fatty acid synthase genes. Subsequently, we investigated these effects invivo in mice fed either ND or WD in the presence or absence of EAF supplementation. In comparison tothe ND controls, the WD-fed mice exhibited increases in body weight, liver weight, epididymal fat weight,and accumulation of fat in hepatocytes, and these effects were significantly attenuated by EAFsupplementation. CONCLUSIONS Allium fistulosum attenuates the development of NAFLD, and EAF elicitsanti-lipogenic activity in liver. Therefore, EAF represents a promising candidate for use in thedevelopment of novel therapeutic drugs or drug combinations for the prevention and treatment of NAFLD.", "metadata": {}}
+{"_id": "4647303", "title": "", "text": "Cardiovascular risk factors in childhood and carotid artery intima-media thickness in adulthood: theCardiovascular Risk in Young Finns Study.CONTEXT Exposure to cardiovascular risk factors duringchildhood and adolescence may be associated with the development of atherosclerosis later in life.OBJECTIVE To study the relationship between cardiovascular risk factors measured in childhood andadolescence and common carotid artery intima-media thickness (IMT), a marker of preclinicalatherosclerosis, measured in adulthood. DESIGN, SETTING, AND PARTICIPANTS Population-based,prospective cohort study conducted at 5 centers in Finland among 2229 white adults aged 24 to 39 yearswho were examined in childhood and adolescence at ages 3 to 18 years in 1980 and reexamined 21 yearslater, between September 2001 and January 2002. MAIN OUTCOME MEASURES Association betweencardiovascular risk variables (levels of low-density lipoprotein cholesterol [LDL-C], high-densitylipoprotein cholesterol [HDL-C], and triglycerides; LDL-C/HDL-C ratio; systolic and diastolic bloodpressure; body mass index; smoking) measured in childhood and adulthood and common carotid arteryIMT measured in adulthood. RESULTS In multivariable models adjusted for age and sex, IMT in adulthoodwas significantly associated with childhood LDL-C levels (P =.001), systolic blood pressure (P<.001),body mass index (P =.007), and smoking (P =.02), and with adult systolic blood pressure (P<.001), bodymass index (P<.001), and smoking (P =.004). The number of risk factors measured in 12- to 18-year-oldadolescents, including high levels (ie, extreme age- and sex-specific 80th percentile) of LDL-C, systolicblood pressure, body mass index, and cigarette smoking, were directly related to carotid IMT measured inyoung adults at ages 33 through 39 years (P<.001 for both men and women), and remained significantafter adjustment for contemporaneous risk variables. The number of risk factors measured at ages 3 to 9years demonstrated a weak direct relationship with carotid IMT at ages 24 to 30 years in men (P =.02)but not in women (P =.63). CONCLUSIONS Risk factor profile assessed in 12- to 18-year-old adolescentspredicts adult common carotid artery IMT independently of contemporaneous risk factors. These findingssuggest that exposure to cardiovascular risk factors early in life may induce changes in arteries thatcontribute to the development of atherosclerosis.", "metadata": {}}
+{"_id": "4653837", "title": "", "text": "MicroRNA-29 induces cellular senescence in aging muscle through multiple signaling pathwaysThemechanisms underlying the development of aging-induced muscle atrophy are unclear. By microRNAarray and individual qPCR analyses, we found significant up-regulation of miR-29 in muscles of agedrodents vs. results in young. With aging, p85α, IGF-1 and B-myb muscle levels were lower while theexpression of certain cell arrest proteins (p53, p16 and pRB) increased. When miR-29 was expressed inmuscle progenitor cells (MPC), their proliferation was impaired while SA-βgal expression increasedsignifying the development of senescence. Impaired MPC proliferation resulted from interactions betweenmiR-29 and the 3'-UTR of p85a, IGF-1 and B-myb, suppressing the translation of these mediators ofmyoblast proliferation. In vivo, electroporation of miR-29 into muscles of young mice suppressed theproliferation and increased levels of cellular arrest proteins, recapitulating aging-induced responses inmuscle. A potential stimulus of miR-29 expression is Wnt-3a since we found that exogenous Wnt-3astimulated miR-29 expression 2.7-fold in primary cultures of MPCs. Thus, aging-induced musclesenescence results from activation of miR-29 by Wnt-3a leading to suppressed expression of severalsignaling proteins (p85α, IGF-1 and B-myb) that act coordinately to impair the proliferation of MPCscontributing to muscle atrophy. The increase in miR-29 provides a potential mechanism for aging-inducedsarcopenia.", "metadata": {}}
+{"_id": "4658268", "title": "", "text": "Rictor, a Novel Binding Partner of mTOR, Defines a Rapamycin-Insensitive and Raptor-IndependentPathway that Regulates the CytoskeletonThe mammalian TOR (mTOR) pathway integrates nutrient- andgrowth factor-derived signals to regulate growth, the process whereby cells accumulate mass andincrease in size. mTOR is a large protein kinase and the target of rapamycin, an immunosuppressant thatalso blocks vessel restenosis and has potential anticancer applications. mTOR interacts with the raptorand GbetaL proteins to form a complex that is the target of rapamycin. Here, we demonstrate that mTORis also part of a distinct complex defined by the novel protein rictor (rapamycin-insensitive companion ofmTOR). Rictor shares homology with the previously described pianissimo from D. discoidieum, STE20pfrom S. pombe, and AVO3p from S. cerevisiae. Interestingly, AVO3p is part of a rapamycin-insensitiveTOR complex that does not contain the yeast homolog of raptor and signals to the actin cytoskeletonthrough PKC1. Consistent with this finding, the rictor-containing mTOR complex contains GbetaL but notraptor and it neither regulates the mTOR effector S6K1 nor is it bound by FKBP12-rapamycin. We findthat the rictor-mTOR complex modulates the phosphorylation of Protein Kinase C alpha (PKCalpha) andthe actin cytoskeleton, suggesting that this aspect of TOR signaling is conserved between yeast andmammals.", "metadata": {}}
+{"_id": "4662264", "title": "", "text": "Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase.Thephosphorylation of the human estrogen receptor (ER) serine residue at position 118 is required for fullactivity of the ER activation function 1 (AF-1). This Ser118 is phosphorylated by mitogen-activatedprotein kinase (MAPK) in vitro and in cells treated with epidermal growth factor (EGF) and insulin-likegrowth factor (IGF) in vivo. Overexpression of MAPK kinase (MAPKK) or of the guanine nucleotide bindingprotein Ras, both of which activate MAPK, enhanced estrogen-induced and antiestrogen(tamoxifen)-induced transcriptional activity of wild-type ER, but not that of a mutant ER with an alaninein place of Ser118. Thus, the activity of the amino-terminal AF-1 of the ER is modulated by thephosphorylation of Ser118 through the Ras-MAPK cascade of the growth factor signaling pathways.", "metadata": {}}
+{"_id": "4664540", "title": "", "text": "Regulation of the antimicrobial response by NLR proteins.Nucleotide-binding, oligomerization domain(NOD)-like receptor (NLR) proteins are a family of innate immune receptors that play a pivotal role inmicrobial sensing, leading to the initiation of antimicrobial immune responses. Dysregulation of thefunction of multiple NLR family members has been linked, both in mice and humans, to a propensity forinfection and autoinflammatory disease. Despite our increased understanding of NLR function andinteractions, many aspects related to mechanisms of sensing, downstream signaling, and in vivofunctions remain elusive. In this review, we focus on key members of the NLR family, describing theiractivation by diverse microbes, downstream effector functions, and interactions with each other and withother innate sensor protein families. Also discussed is the role of microbial sensing by NLR receptorsleading to activation of the adaptive immune arm that collaborates in the antimicrobial defense.", "metadata": {}}
+{"_id": "4678846", "title": "", "text": "Acetylcysteine for prevention of acute deterioration of renal function following elective coronaryangiography and intervention: a randomized controlled trial.CONTEXT The antioxidant acetylcysteineprevents acute contrast nephrotoxicity in patients with impaired renal function who undergo computedtomography scanning. However, its role in coronary angiography is unclear. OBJECTIVE To determinewhether oral acetylcysteine prevents acute deterioration in renal function in patients with moderate renalinsufficiency who undergo elective coronary angiography. DESIGN AND SETTING Prospective,randomized, double-blind, placebo-controlled trial conducted from May 2000 to December 2001 at theGrantham Hospital at the University of Hong Kong. PARTICIPANTS Two hundred Chinese patients agedmean (SD) 68 (6.5) years with stable moderate renal insufficiency (creatinine clearance <60 mL/min[1.00 mL/s]) who were undergoing elective coronary angiography with or without intervention.INTERVENTION Participants were randomly assigned to receive oral acetylcysteine(600 mg twice per day;n = 102) or matching placebo tablets (n = 98) on the day before and the day of angiography. All patientsreceived low-osmolality contrast agent. MAIN OUTCOME MEASURES Occurrence of more than a 25%increase in serum creatinine level within 48 hours after contrast administration; change in creatinineclearance and serum creatinine level. RESULTS Twelve control patients (12%) and 4 acetylcysteinepatients (4%) developed a more than 25% increase in serum creatinine level within 48 hours aftercontrast administration (relative risk, 0.32; 95% confidence interval [CI], 0.10-0.96; P =.03). Serumcreatinine was lower in the acetylcysteine group (1.22 mg/dL [107.8 micromol/L]; 95% CI, 1.11-1.33mg/dL vs 1.38 mg/dL [122.9 micromol/L]; 95% CI, 1.27-1.49 mg/dL; P =.006) during the first 48 hoursafter angiography. Acetylcysteine treatment significantly increased creatinine clearance from 44.8mL/min (0.75 mL/s) (95% CI, 42.7-47.6 mL/min) to 58.9 mL/min (0.98 mL/s) (95% CI, 55.6-62.3mL/min) 2 days after the contrast administration (P<.001). The increase was not significant in the controlgroup (from 42.1 to 44.1 mL/min [0.70 to 0.74 mL/s]; P =.15). The benefit of acetylcysteine wasconsistent among various patient subgroups and persistent for at least 7 days. There were no majortreatment-related adverse events. CONCLUSION Acetylcysteine protects patients with moderate chronicrenal insufficiency from contrast-induced deterioration in renal function after coronary angiographicprocedures, with minimal adverse effects and at a low cost.", "metadata": {}}
+{"_id": "4679264", "title": "", "text": "DNA Methylation in the Human Cerebral Cortex Is Dynamically Regulated throughout the Life Span andInvolves Differentiated NeuronsThe role of DNA cytosine methylation, an epigenetic regulator ofchromatin structure and function, during normal and pathological brain development and aging remainsunclear. Here, we examined by MethyLight PCR the DNA methylation status at 50 loci, encompassingprimarily 5′ CpG islands of genes related to CNS growth and development, in temporal neocortex of 125subjects ranging in age from 17 weeks of gestation to 104 years old. Two psychiatric diseasecohorts—defined by chronic neurodegeneration (Alzheimer's) or lack thereof (schizophrenia)—wereincluded. A robust and progressive rise in DNA methylation levels across the lifespan was observed for8/50 loci (GABRA2, GAD1, HOXA1, NEUROD1, NEUROD2, PGR, STK11, SYK) typically in conjunction withdeclining levels of the corresponding mRNAs. Another 16 loci were defined by a sharp rise in DNAmethylation levels within the first few months or years after birth. Disease-associated changes werelimited to 2/50 loci in the Alzheimer's cohort, which appeared to reflect an acceleration of the age-relatedchange in normal brain. Additionally, methylation studies on sorted nuclei provided evidence forbidirectional methylation events in cortical neurons during the transition from childhood to advanced age,as reflected by significant increases at 3, and a decrease at 1 of 10 loci. Furthermore, the DNMT3a denovo DNA methyl-transferase was expressed across all ages, including a subset of neurons residing inlayers III and V of the mature cortex. Therefore, DNA methylation is dynamically regulated in the humancerebral cortex throughout the lifespan, involves differentiated neurons, and affects a substantial portionof genes predominantly by an age-related increase.", "metadata": {}}
+{"_id": "4680262", "title": "", "text": "Mulberry leaves (Morus alba L.) ameliorate obesity-induced hepatic lipogenesis, fibrosis, and oxidativestress in high-fat diet-fed miceObesity is associated with chronic diseases such as fatty liver, type 2diabetes, cardiovascular disease, and severe metabolic syndrome. Obesity causes metabolic impairmentincluding excessive lipid accumulation and fibrosis in the hepatic tissue as well as the increase inoxidative stress. In order to investigate the effect of mulberry leaf (Morus alba L.) extract (MLE) onobesity-induced oxidative stress, lipogenesis, and fibrosis in liver, MLE has been gavaged for 12 weeks inhigh-fat diet (HFD)-induced obese mice. MLE treatment significantly ameliorated LXRα-mediatedlipogenesis and hepatic fibrosis markers such as α-smooth muscle actin, while MLE up-regulatedlipolysis-associated markers such as lipoprotein lipase in the HFD-fed mice. Moreover, MLE normalizedthe activities of antioxidant enzymes including heme oxygenase-1 and glutathione peroxidase inaccordance with protein levels of 4-hydroxynonenal in the HFD-fed mice. MLE has beneficial effects onobesity-related fatty liver disease by regulation of hepatic lipid metabolism, fibrosis, and antioxidantdefense system. MLE supplementation might be a potential therapeutic approach for obesity-relateddisease including non-alcoholic fatty liver disease.", "metadata": {}}
+{"_id": "4687948", "title": "", "text": "HMG-CoA reductase inhibitors and the risk of hip fractures in elderly patients.CONTEXT Recent animalstudies have found that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) lipid-lowering drugs(statins) substantially increase bone formation, but whether statin use in humans results in clinicallymeaningful bone formation or a reduction in the risk of osteoporotic fractures is not known. OBJECTIVETo determine whether the use of statins is associated with reduced hip fracture risk. DESIGN Case-controlstudy. SETTING AND PATIENTS A total of 6110 New Jersey residents aged 65 years or older and enrolledin Medicare and either Medicaid or the Pharmacy Assistance for the Aged and Disabled program. Casepatients (n=1222) underwent surgical repair of a hip fracture in 1994. Control patients (n=4888) wereidentified at a ratio of 4:1 and frequency-matched to case patients for age and sex. MAIN OUTCOMEMEASURE Adjusted odds ratio (OR) of hip fracture by statin use in the 180 days and 3 years prior to theindex date (the earliest date of admission for surgery), adjusted for demographic and clinicalcharacteristics and health care utilization. RESULTS Use of statins in either the prior 180 days (adjustedOR, 0.50; 95% confidence interval [CI], 0.33-0.76) or prior 3 years (adjusted OR, 0.57; 95% CI,0.40-0.82) was associated with a significant reduction in the risk of hip fracture, even after controlling forvariables such as race, insurance status, psychoactive medications, estrogen and thiazide use, ischemicheart disease, cancer, and diabetes mellitus. No significant relationship was observed between use ofnonstatin lipid-lowering agents and hip fracture risk. Clear relationships were observed between thedegree of reduction in hip fracture risk and the extent of statin use; there was no evidence of suchrelationships with nonstatin lipid-lowering agents. After adjusting for extent of statin use in the prior 3years, current use (on the index date) was associated with a 71% reduction in risk (adjusted OR, 0.29;95% CI, 0.10-0.81). The relationship between statin use and hip fracture risk persisted after controllingfor variables such as the number of medications, the Charlson comorbidity index score, andhospitalization or nursing home stay in the last 180 days, as well as after excluding patients who were ina nursing home prior to their index date or who died in the year after their index date. Use of nonstatinlipid-lowering agents was not observed to be associated with reduction in hip fracture risk in any of thesealternative models or analyses. CONCLUSIONS These findings support an association between statin useby elderly patients and reduction in the risk of hip fracture. Controlled trials are needed to exclude thepossibility of unmeasured confounders. JAMA. 2000;283:3211-3216", "metadata": {}}
+{"_id": "4688277", "title": "", "text": "The quality of modern cross-sectional ecologic studies: a bibliometric review.The ecologic study design isroutinely used by epidemiologists in spite of its limitations. It is presently unknown how well thechallenges of the design are dealt with in epidemiologic research. The purpose of this bibliometric reviewwas to critically evaluate the characteristics, statistical methods, and reporting of results of moderncross-sectional ecologic papers. A search through 6 major epidemiology journals identified allcross-sectional ecologic studies published since January 1, 2000. A total of 125 articles met the inclusionrequirements and were assessed via common evaluative criteria. It was found that a considerablenumber of cross-sectional ecologic studies use unreliable methods or contain statistical oversights; mostinvestigators who adjusted their outcomes for age or sex did so improperly (64%), statistical validity wasa potential issue for 20% of regression models, and simple linear regression was the most commonanalytic approach (31%). Many authors omitted important information when discussing the ecologicnature of their study (31%), the choice of study design (58%), and the susceptibility of their research tothe ecological fallacy (49%). These results suggest that there is a need for an international set ofguidelines that standardizes reporting on ecologic studies. Additionally, greater attention should be givento the relevant biostatistical literature.", "metadata": {}}
+{"_id": "4688340", "title": "", "text": "Efficacy of Beta1 Integrin and EGFR Targeting in Sphere-Forming Human Head and Neck CancerCellsBACKGROUND Resistance to radiotherapy continues to be a limiting factor in the treatment of cancerincluding head and neck squamous cell carcinoma (HNSCC). Simultaneous targeting of β1 integrin andEGFR was shown to have a higher radiosensitizing potential than mono-targeting in the majority of testedHNSCC cancer models. As tumor-initiating cells (TIC) are thought to play a key role for therapy resistanceand recurrence and can be enriched in sphere forming conditions, this study investigated the efficacy ofβ1 integrin/EGFR targeting without and in combination with X-ray irradiation on the behavior ofsphere-forming cells (SFC). METHODS HNSCC cell lines (UTSCC15, UTSCC5, Cal33, SAS) were injectedsubcutaneously into nude mice for tumor up-take and plated for primary and secondary sphere formationunder non-adhesive conditions which is thought to reflect the enrichment of SFC and their self-renewalcapacity, respectively. Treatment was accomplished by inhibitory antibodies for β1 integrin (AIIB2) andEGFR (Cetuximab) as well as X-ray irradiation (2 - 6 Gy single doses). Further, flow cytometry for TICmarker expression and cell cycling as well as Western blotting for DNA repair protein expression andphosphorylation were employed. RESULTS We found higher primary and secondary sphere formingcapacity of SAS cells relative to other HNSCC cell lines, which was in line with the tumor up-take rates ofSAS versus UTSCC15 cells. AIIB2 and Cetuximab administration had minor cytotoxic and noradiosensitizing effects on SFC. Intriguingly, secondary SAS spheres, representing the fraction ofsurviving SFC upon passaging, showed greatly enhanced radiosensitivity compared to primary spheres.Intriguingly, neither AIIB2 nor Cetuximab significantly altered basal sphere forming capacity andradiosensitivity. While an increased accumulation of G0/G1 phase cells was observable in secondary SASspheres, DNA double strand break repair indicated no difference on the basis of significantly enhancedATM and Chk2 dephosphorylation upon irradiation. CONCLUSIONS In the HNSCC model, sphere-formingconditions select for cells, which are unsusceptible to both anti-β1 integrin and anti-EGFR inhibitoryantibodies. With regard to primary and secondary sphere formation, our data suggest that both of theseSFC fractions express distinct survival strategies independent from β1 integrin and EGFR and that futurework is warranted to better understand SFC survival and enrichment before and after treatment tountangle the underlying mechanisms for identifying novel, druggable cancer targets in SFC.", "metadata": {}}
+{"_id": "4695046", "title": "", "text": "AnxietyOBJECTIVES To examine the effect of routinely administered psychiatric questionnaires on therecognition, management, and outcome of psychiatric disorders in non-psychiatric settings. DATASOURCES Embase, Medline, PsycLIT, Cinahl, Cochrane Controlled Trials Register, and hand searches ofkey journals. METHODS A systematic review of randomised controlled trials of the administration androutine feedback of psychiatric screening and outcome questionnaires to clinicians in non-psychiatricsettings. Narrative overview of key design features and end points, together with a random effectsquantitative synthesis of comparable studies. MAIN OUTCOME MEASURES Recognition of psychiatricdisorders after feedback of questionnaire results; interventions for psychiatric disorders; and outcome ofpsychiatric disorders. RESULTS Nine randomised studies were identified that examined the use ofcommon psychiatric instruments in primary care and general hospital settings. Studies compared theeffect of the administration of these instruments followed by the feedback of the results to clinicians, withadministration with no feedback. Meta-analytic pooling was possible for four of these studies (2457participants), which measured the effect of feedback on the recognition of depressive disorders. Routineadministration and feedback of scores for all patients (irrespective of score) did not increase the overallrate of recognition of mental disorders such as anxiety and depression (relative risk of detection ofdepression by clinician after feedback 0.95, 95% confidence interval 0.83 to 1.09). Two studies showedthat routine administration followed by selective feedback for only high scorers increased the rate ofrecognition of depression (relative risk of detection of depression after feedback 2.64, 1.62 to 4.31). Thisincreased recognition, however, did not translate into an increased rate of intervention. Overall, studiesof routine administration of psychiatric measures did not show an effect on patient outcome.CONCLUSIONS The routine measurement of outcome is a costly exercise. Little evidence shows that it isof benefit in improving psychosocial outcomes of those with psychiatric disorder managed innon-psychiatric settings.", "metadata": {}}
+{"_id": "4695107", "title": "", "text": "The challenges of overcoming antibiotic resistance: Plant extracts as potential sources of antimicrobialand resistance modifying agentsThe problem of antibiotic resistance, which has limited the use of cheapand old antibiotics, has necessitated the need for a continued search for new antimicrobial compounds.Understanding the mechanisms of resistance is important in the development of strategies to solving theproblem. Active efflux of drugs, alteration of target sites and enzymatic degradations are the strategiesby which pathogenic bacteria acquire or develop intrinsic resistance to antibiotics. Multi-drug resistance(MDR) pumps, capable of recognizing and expelling a variety of structurally unrelated compounds fromthe bacterial cell and conferring resistance to a wide range of antibiotics have since been characterized inmany gram positive and gram negative pathogens like Staphylococcus aureus, Pseudomonas aeruginosa,Escherichia coli and, more recently, in mycobacteria. The ability of some chemical compounds (calledMDR inhibitors or resistance modifying agents) to modify the resistance phenotype in bacteria by workingsynergistically with antibiotics in vitro has since been observed. The search for such compounds whichcan be combined with antibiotics in the treatment of drug resistant infections may be an alternative toovercoming the problem of resistance in bacteria. Crude extracts of medicinal plants stand out asveritable sources of potential resistance modifying agents and the African biosphere promises to be apotential source of such compounds owing to its rich plant species diversity.", "metadata": {}}
+{"_id": "4700428", "title": "", "text": "The effect of N-acetylcysteine in the nucleus accumbens on neurotransmission and relapse tococaine.BACKGROUND Relapse to cocaine seeking has been linked with low glutamate in the nucleusaccumbens core (NAcore) causing potentiation of synaptic glutamate transmission from prefrontal cortex(PFC) afferents. Systemic N-acetylcysteine (NAC) has been shown to restore glutamate homeostasis,reduce relapse to cocaine seeking, and depotentiate PFC-NAcore synapses. Here, we examine the effectsof NAC applied directly to the NAcore on relapse and neurotransmission in PFC-NAcore synapses, as wellas the involvement of the metabotropic glutamate receptors 2/3 (mGluR2/3) and 5 (mGluR5). METHODSRats were trained to self-administer cocaine for 2 weeks and following extinction received eitherintra-accumbens NAC or systemic NAC 30 or 120 minutes, respectively, before inducing reinstatementwith a conditioned cue or a combined cue and cocaine injection. We also recorded postsynaptic currentsusing in vitro whole cell recordings in acute slices and measured cystine and glutamate uptake in primaryglial cultures. RESULTS NAC microinjection into the NAcore inhibited the reinstatement of cocaineseeking. In slices, a low concentration of NAC reduced the amplitude of evoked glutamatergic synapticcurrents in the NAcore in an mGluR2/3-dependent manner, while high doses of NAC increased amplitudein an mGluR5-dependent manner. Both effects depended on NAC uptake through cysteine transportersand activity of the cysteine/glutamate exchanger. Finally, we showed that by blocking mGluR5 theinhibition of cocaine seeking by NAC was potentiated. CONCLUSIONS The effect of NAC on relapse tococaine seeking depends on the balance between stimulating mGluR2/3 and mGluR5 in the NAcore, andthe efficacy of NAC can be improved by simultaneously inhibiting mGluR5.", "metadata": {}}
+{"_id": "4701662", "title": "", "text": "A phospholipid transfer function of ER-mitochondria encounter structure revealed in vitroAs phospholipidsare synthesized mainly in the endoplasmic reticulum (ER) and mitochondrial inner membranes, how cellsproperly distribute specific phospholipids to diverse cellular membranes is a crucial problem formaintenance of organelle-specific phospholipid compositions. Although the ER-mitochondria encounterstructure (ERMES) was proposed to facilitate phospholipid transfer between the ER and mitochondria,such a role of ERMES is still controversial and awaits experimental demonstration. Here we developed anovel in vitro assay system with isolated yeast membrane fractions to monitor phospholipid exchangebetween the ER and mitochondria. With this system, we found that phospholipid transport between theER and mitochondria relies on membrane intactness, but not energy sources such as ATP, GTP or themembrane potential across the mitochondrial inner membrane. We further found that lack of the ERMEScomponent impairs the phosphatidylserine transport from the ER to mitochondria, but not thephosphatidylethanolamine transport from mitochondria to the ER. This in vitro assay system thus offers apowerful tool to analyze the non-vesicular phospholipid transport between the ER and mitochondria.", "metadata": {}}
+{"_id": "4702639", "title": "", "text": "An integrin β3–KRAS–RalB complex drives tumour stemness and resistance to EGFR inhibitionTumourcells, with stem-like properties, are highly aggressive and often show drug resistance. Here, we revealthat integrin αvβ3 serves as a marker of breast, lung and pancreatic carcinomas with stem-like propertiesthat are highly resistant to receptor tyrosine kinase inhibitors such as erlotinib. This was observed in vitroand in mice bearing patient-derived tumour xenografts or in clinical specimens from lung cancer patientswho had progressed on erlotinib. Mechanistically, αvβ3, in the unliganded state, recruits KRAS and RalBto the tumour cell plasma membrane, leading to the activation of TBK1 and NF-κB. In fact, αvβ3expression and the resulting KRAS–RalB–NF-κB pathway were both necessary and sufficient for tumourinitiation, anchorage independence, self-renewal and erlotinib resistance. Pharmacological targeting ofthis pathway with bortezomib reversed both tumour stemness and erlotinib resistance. These findings notonly identify αvβ3 as a marker/driver of carcinoma stemness but also reveal a therapeutic strategy tosensitize such tumours to RTK inhibition.", "metadata": {}}
+{"_id": "4709641", "title": "", "text": "Gain of toxic Apolipoprotein E4 effects in Human iPSC-Derived Neurons Is Ameliorated by aSmall-Molecule Structure CorrectorEfforts to develop drugs for Alzheimer's disease (AD) have shownpromise in animal studies, only to fail in human trials, suggesting a pressing need to study AD in humanmodel systems. Using human neurons derived from induced pluripotent stem cells that expressedapolipoprotein E4 (ApoE4), a variant of the APOE gene product and the major genetic risk factor for AD,we demonstrated that ApoE4-expressing neurons had higher levels of tau phosphorylation, unrelated totheir increased production of amyloid-β (Aβ) peptides, and that they displayed GABAergic neurondegeneration. ApoE4 increased Aβ production in human, but not in mouse, neurons. Converting ApoE4 toApoE3 by gene editing rescued these phenotypes, indicating the specific effects of ApoE4. Neurons thatlacked APOE behaved similarly to those expressing ApoE3, and the introduction of ApoE4 expressionrecapitulated the pathological phenotypes, suggesting a gain of toxic effects from ApoE4. Treatment ofApoE4-expressing neurons with a small-molecule structure corrector ameliorated the detrimental effects,thus showing that correcting the pathogenic conformation of ApoE4 is a viable therapeutic approach forApoE4-related AD.", "metadata": {}}
+{"_id": "4729644", "title": "", "text": "LncRNA NEAT1/let-7a-5p axis regulates the cisplatin resistance in nasopharyngeal carcinoma by targetingRsf-1 and modulating the Ras-MAPK pathway.The long non-coding RNA nuclear paraspeckle assemblytranscript 1 (NEAT1) was reported to be upregulated and be involved in oncogenic growth and drugresistance in nasopharyngeal carcinoma (NPC). However, the exact roles of NEAT1 and its underlyingmechanisms in the drug resistance of NPC remain largely unclear. In this study, the expressions ofNEAT1, let-72-5p and Rsf-1 mRNA were detected by reverse transcription-quantitative polymerase chainreaction (RT-qPCR). The effects of NEAT1 and let-72-5p on cell proliferation and cisplatin resistance ofNPC cells were investigated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT)assay and 5-ethynyl-20-deoxyuridine (EdU) assay. Western blot analysis was performed to detect theprotein levels of Rsf-1, Ras, p-Raf1, Raf1, p-MEK1, MEK1, p-ERK1/2 and ERK1/2. Xenograft tumor assaywas done to elucidate the role of NEAT1 involved in NPC tumor growth in vivo. We found that NEAT1 wasupregulated and let-7a-5p was downregulated in NPC tissues, as well as NPC cell lines. Inhibition ofNEAT1 markedly repressed the cisplatin resistance of NPC cells. NEAT1 was demonstrated to interact withlet-7a-5p. Besides, a negative correlation between NEAT1 and let-7a-5p expression was observed in NPCtissues. Rsf-1 was confirmed as a target of let-7a-5p. NEAT1 remarkably reversed the inhibitory effect oflet-7q-5p on the cisplatin resistance of NPC cells in vitro. Additionally, NEAT1 knockdown inhibited theRas-MAPK pathway in NPC cells. NEAT1 knockdown suppressed tumor growth in the presence of cisplatinin vivo. Overall, these findings suggest that NEAT1/let-7a-5p axis regulates the cisplatin resistance inNPC by targeting Rsf-1 and modulating the Ras-MAPK signaling pathway.", "metadata": {}}
+{"_id": "4740447", "title": "", "text": "Antibacterial peptide microcin J25 inhibits transcription by binding within and obstructing the RNApolymerase secondary channel.The antibacterial peptide microcin J25 (MccJ25) inhibits transcription bybacterial RNA polymerase (RNAP). Biochemical results indicate that inhibition of transcription occurs atthe level of NTP uptake or NTP binding by RNAP. Genetic results indicate that inhibition of transcriptionrequires an extensive determinant, comprising more than 50 amino acid residues, within the RNAPsecondary channel (also known as the \"NTP-uptake channel\" or \"pore\"). Biophysical results indicate thatinhibition of transcription involves binding of MccJ25 within the RNAP secondary channel. Molecularmodeling indicates that binding of MccJ25 within the RNAP secondary channel obstructs the RNAPsecondary channel. We conclude that MccJ25 inhibits transcription by binding within and obstructing theRNAP secondary channel--acting essentially as a \"cork in a bottle. \" Obstruction of the RNAP secondarychannel represents an attractive target for drug discovery.", "metadata": {}}
+{"_id": "4767806", "title": "", "text": "Exploring and exploiting the systemic effects of deregulated replication licensing.Maintenance andaccurate propagation of the genetic material are key features for physiological development andwellbeing. The replication licensing machinery is crucial for replication precision as it ensures thatreplication takes place once per cell cycle. Thus, the expression status of the components comprising thereplication licensing apparatus is tightly regulated to avoid re-replication; a form of replication stress thatleads to genomic instability, a hallmark of cancer. In the present review we discuss the mechanistic basisof replication licensing deregulation, which leads to systemic effects, exemplified by its role incarcinogenesis and a variety of genetic syndromes. In addition, new insights demonstrate that above aparticular threshold, the replication licensing factor Cdc6 acts as global transcriptional regulator, outliningnew lines of exploration. The role of the putative replication licensing factor ChlR1/DDX11, mutated in theWarsaw Breakage Syndrome, in cancer is also considered. Finally, future perspectives focused on thepotential therapeutic advantage by targeting replication licensing factors, and particularly Cdc6, arediscussed.", "metadata": {}}
+{"_id": "4784069", "title": "", "text": "Regulatory principles of pluripotency: from the ground state up.Pluripotency is the remarkable capacity ofa single cell to engender all the specialized cell types of an adult organism. This property can be capturedindefinitely through derivation of self-renewing embryonic stem cells (ESCs), which represent aninvaluable platform to investigate cell fate decisions and disease. Recent advances have revealed thatmanipulation of distinct signaling cues can render ESCs in a uniform \"ground state\" of pluripotency, whichmore closely recapitulates the pluripotent naive epiblast. Here we discuss the extrinsic and intrinsicregulatory principles that underpin the nature of pluripotency and consider the emerging spectrum ofpluripotent states.", "metadata": {}}
+{"_id": "4791384", "title": "", "text": "Neonatal Mortality Levels for 193 Countries in 2009 with Trends since 1990: A Systematic Analysis ofProgress, Projections, and PrioritiesBACKGROUND Historically, the main focus of studies of childhoodmortality has been the infant and under-five mortality rates. Neonatal mortality (deaths <28 days of age)has received limited attention, although such deaths account for about 41% of all child deaths. To betterassess progress, we developed annual estimates for neonatal mortality rates (NMRs) and neonatal deathsfor 193 countries for the period 1990-2009 with forecasts into the future. METHODS AND FINDINGS Wecompiled a database of mortality in neonates and children (<5 years) comprising 3,551 country-years ofinformation. Reliable civil registration data from 1990 to 2009 were available for 38 countries. Astatistical model was developed to estimate NMRs for the remaining 155 countries, 17 of which had nonational data. Country consultation was undertaken to identify data inputs and review estimates. In2009, an estimated 3.3 million babies died in the first month of life-compared with 4.6 million neonataldeaths in 1990-and more than half of all neonatal deaths occurred in five countries of the world (44% ofglobal livebirths): India 27.8% (19.6% of global livebirths), Nigeria 7.2% (4.5%), Pakistan 6.9% (4.0%),China 6.4% (13.4%), and Democratic Republic of the Congo 4.6% (2.1%). Between 1990 and 2009, theglobal NMR declined by 28% from 33.2 deaths per 1,000 livebirths to 23.9. The proportion of child deathsthat are in the neonatal period increased in all regions of the world, and globally is now 41%. While NMRswere halved in some regions of the world, Africa's NMR only dropped 17.6% (43.6 to 35.9).CONCLUSIONS Neonatal mortality has declined in all world regions. Progress has been slowest in theregions with high NMRs. Global health programs need to address neonatal deaths more effectively ifMillennium Development Goal 4 (two-thirds reduction in child mortality) is to be achieved.", "metadata": {}}
+{"_id": "4795303", "title": "", "text": "Neuroprotective Effects of Four Phenylethanoid Glycosides on H2O2-Induced Apoptosis on PC12 Cells viathe Nrf2/ARE PathwayNuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factoragainst oxidative stress and neurodegenerative disorders. Phenylethanoid glycosides (PhGs; salidroside,acteoside, isoacteoside, and echinacoside) exhibit antioxidant and neuroprotective bioactivities. Thisstudy was performed to investigate the neuroprotective effect and molecular mechanism of PhGs. PhGspretreatment significantly suppressed H\u0000O\u0000-induced cytotoxicity in PC12 cells by triggering the nucleartranslocation of Nrf2 and reversing the downregulated protein expression of heme oxygenase 1 (HO-1),NAD(P)H quinone oxidoreductase 1 (NQO1), glutamate cysteine ligase-catalytic subunit (GCLC), andglutamate-cysteine ligase modifier subunit (GCLM). Nrf2 siRNA or HO-1 inhibitor zinc protoporphyrin(ZnPP) reduced the neuroprotective effect. PhGs showed potential interaction with the Nrf2 binding site inKelch-like ECH-association protein 1 (Keap1). This result may support the hypothesis that PhGs areactivators of Nrf2. We demonstrated the potential binding between PhGs and the Keap1-activatedNrf2/ARE pathway, and that PhGs with more glycosides had enhanced effects.", "metadata": {}}
+{"_id": "4810810", "title": "", "text": "Mortality risk attributable to high and low ambient temperature: a multicountry observationalstudyBACKGROUND Although studies have provided estimates of premature deaths attributable to eitherheat or cold in selected countries, none has so far offered a systematic assessment across the wholetemperature range in populations exposed to different climates. We aimed to quantify the total mortalityburden attributable to non-optimum ambient temperature, and the relative contributions from heat andcold and from moderate and extreme temperatures. METHODS We collected data for 384 locations inAustralia, Brazil, Canada, China, Italy, Japan, South Korea, Spain, Sweden, Taiwan, Thailand, UK, andUSA. We fitted a standard time-series Poisson model for each location, controlling for trends and day ofthe week. We estimated temperature-mortality associations with a distributed lag non-linear model with21 days of lag, and then pooled them in a multivariate metaregression that included country indicatorsand temperature average and range. We calculated attributable deaths for heat and cold, defined astemperatures above and below the optimum temperature, which corresponded to the point of minimummortality, and for moderate and extreme temperatures, defined using cutoffs at the 2·5th and 97·5thtemperature percentiles. FINDINGS We analysed 74,225,200 deaths in various periods between 1985 and2012. In total, 7·71% (95% empirical CI 7·43-7·91) of mortality was attributable to non-optimumtemperature in the selected countries within the study period, with substantial differences betweencountries, ranging from 3·37% (3·06 to 3·63) in Thailand to 11·00% (9·29 to 12·47) in China. Thetemperature percentile of minimum mortality varied from roughly the 60th percentile in tropical areas toabout the 80-90th percentile in temperate regions. More temperature-attributable deaths were caused bycold (7·29%, 7·02-7·49) than by heat (0·42%, 0·39-0·44). Extreme cold and hot temperatures wereresponsible for 0·86% (0·84-0·87) of total mortality. INTERPRETATION Most of the temperature-relatedmortality burden was attributable to the contribution of cold. The effect of days of extreme temperaturewas substantially less than that attributable to milder but non-optimum weather. This evidence hasimportant implications for the planning of public-health interventions to minimise the healthconsequences of adverse temperatures, and for predictions of future effect in climate-change scenarios.FUNDING UK Medical Research Council.", "metadata": {}}
+{"_id": "4816339", "title": "", "text": "Survivin is not required for the endomitotic cell cycle of megakaryocytes.Survivin is a member of thechromosome passenger complex, which plays an important role in chromosome alignment, separation,and cytokinesis. Although survivin is required for the proliferation and survival of hematopoietic stem andprogenitor cells, the extent to which it is necessary for endomitosis of megakaryocytes remainscontroversial. To determine whether survivin is required for polyploidization, we analyzed mice with amegakaryocyte-specific deletion. PF4-Cre/survivin(fl/fl) mice harbored normal platelet counts withmegakaryocytes that reached ploidy states comparable with those of control littermates. The CD41(+)cells within these animals showed little excision but increased annexin V staining, implying that survivin isrequired for survival of megakaryocyte progenitors in vivo. In contrast, megakaryocytes in which survivinwas excised ex vivo showed robust excision and an increased degree of polyploidization. These resultsdemonstrate that survivin is necessary for survival of megakaryocyte progenitors, but is not required forpolyploidization of committed megakaryocytes.", "metadata": {}}
+{"_id": "4820792", "title": "", "text": "β1 integrin mediates an alternative survival pathway in breast cancer cells resistant tolapatinibINTRODUCTION The overexpression of human epidermal growth factor receptor (HER)-2 in 20%of human breast cancers and its association with aggressive growth has led to widespread use ofHER2-targeted therapies, such as trastuzumab (T) and lapatinib (L). Despite the success of these drugs,their efficacy is limited in patients whose tumors demonstrate de novo or acquired resistance totreatment. The β1 integrin resides on the membrane of the breast cancer cell, activating severalelements of breast tumor progression including proliferation and survival. METHODS We developed apanel of HER2-overexpressing cell lines resistant to L, T, and the potent LT combination throughlong-term exposure and validated these models in 3D culture. Parental and L/T/LT-resistant cells weresubject to HER2 and β1 integrin inhibitors in 3D and monitored for 12 days, followed by quantification ofcolony number. Parallel experiments were conducted where cells were either stained for Ki-67 andTerminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) or harvested for protein andanalyzed by immunoblot. Results were subjected to statistical testing using analysis of variance andlinear contrasts, followed by adjustment with the Sidak method. RESULTS Using multiple cell linesincluding BT474 and HCC1954, we reveal that in L and LT resistance, where phosphorylation ofEGFR/HER1, HER2, and HER3 are strongly inhibited, kinases downstream of β1 integrin--including focaladhesion kinase (FAK) and Src--are up-regulated. Blockade of β1 by the antibody AIIB2 abrogates thisup-regulation and functionally achieves significant growth inhibition of L and LT resistant cells in 3D,without dramatically affecting the parental cells. SiRNA against β1 as well as pharmacologic inhibition ofFAK achieve the same growth inhibitory effect. In contrast, trastuzumab-resistant cells, which retain highlevels of phosphorylated EGFR/HER1, HER2, and HER3, are only modestly growth-inhibited by AIIB2.CONCLUSIONS Our data suggest that HER2 activity, which is suppressed in resistance involving L but notT alone, dictates whether β1 mediates an alternative pathway driving resistance. Our findings justifyclinical studies investigating the inhibition of β1 or its downstream signaling moieties as strategies toovercome acquired L and LT resistance.", "metadata": {}}
+{"_id": "4824840", "title": "", "text": "Incidence and Trends of Sepsis in US Hospitals Using Clinical vs Claims Data, 2009-2014ImportanceEstimates from claims-based analyses suggest that the incidence of sepsis is increasing and mortalityrates from sepsis are decreasing. However, estimates from claims data may lack clinical fidelity and canbe affected by changing diagnosis and coding practices over time. Objective To estimate the US nationalincidence of sepsis and trends using detailed clinical data from the electronic health record (EHR) systemsof diverse hospitals. Design, Setting, and Population Retrospective cohort study of adult patientsadmitted to 409 academic, community, and federal hospitals from 2009-2014. Exposures Sepsis wasidentified using clinical indicators of presumed infection and concurrent acute organ dysfunction, adaptingThird International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) criteria for objective andconsistent EHR-based surveillance. Main Outcomes and Measures Sepsis incidence, outcomes, and trendsfrom 2009-2014 were calculated using regression models and compared with claims-based estimatesusing International Classification of Diseases, Ninth Revision, Clinical Modification codes for severe sepsisor septic shock. Case-finding criteria were validated against Sepsis-3 criteria using medical recordreviews. Results A total of 173 690 sepsis cases (mean age, 66.5 [SD, 15.5] y; 77 660 [42.4%] women)were identified using clinical criteria among 2 901 019 adults admitted to study hospitals in 2014 (6.0%incidence). Of these, 26 061 (15.0%) died in the hospital and 10 731 (6.2%) were discharged to hospice.From 2009-2014, sepsis incidence using clinical criteria was stable (+0.6% relative change/y [95% CI,−2.3% to 3.5%], P = .67) whereas incidence per claims increased (+10.3%/y [95% CI, 7.2% to 13.3%],P < .001). In-hospital mortality using clinical criteria declined (−3.3%/y [95% CI, −5.6% to −1.0%], P =.004), but there was no significant change in the combined outcome of death or discharge to hospice(−1.3%/y [95% CI, −3.2% to 0.6%], P = .19). In contrast, mortality using claims declined significantly(−7.0%/y [95% CI, −8.8% to −5.2%], P < .001), as did death or discharge to hospice (−4.5%/y [95%CI, −6.1% to −2.8%], P < .001). Clinical criteria were more sensitive in identifying sepsis than claims(69.7% [95% CI, 52.9% to 92.0%] vs 32.3% [95% CI, 24.4% to 43.0%], P < .001), with comparablepositive predictive value (70.4% [95% CI, 64.0% to 76.8%] vs 75.2% [95% CI, 69.8% to 80.6%], P =.23). Conclusions and Relevance In clinical data from 409 hospitals, sepsis was present in 6% of adulthospitalizations, and in contrast to claims-based analyses, neither the incidence of sepsis nor thecombined outcome of death or discharge to hospice changed significantly between 2009-2014. Thefindings also suggest that EHR-based clinical data provide more objective estimates than claims-baseddata for sepsis surveillance.", "metadata": {}}
+{"_id": "4828631", "title": "", "text": "Body-mass index and risk of 22 specific cancers: a population-based cohort study of 5·24 million UKadultsBACKGROUND High body-mass index (BMI) predisposes to several site-specific cancers, but alarge-scale systematic and detailed characterisation of patterns of risk across all common cancersadjusted for potential confounders has not previously been undertaken. We aimed to investigate the linksbetween BMI and the most common site-specific cancers. METHODS With primary care data fromindividuals in the Clinical Practice Research Datalink with BMI data, we fitted Cox models to investigateassociations between BMI and 22 of the most common cancers, adjusting for potential confounders. Wefitted linear then non-linear (spline) models; investigated effect modification by sex, menopausal status,smoking, and age; and calculated population effects. FINDINGS 5·24 million individuals were included;166,955 developed cancers of interest. BMI was associated with 17 of 22 cancers, but effects variedsubstantially by site. Each 5 kg/m(2) increase in BMI was roughly linearly associated with cancers of theuterus (hazard ratio [HR] 1·62, 99% CI 1·56-1·69; p<0·0001), gallbladder (1·31, 1·12-1·52; p<0·0001),kidney (1·25, 1·17-1·33; p<0·0001), cervix (1·10, 1·03-1·17; p=0·00035), thyroid (1·09, 1·00-1·19;p=0·0088), and leukaemia (1·09, 1·05-1·13; p≤0·0001). BMI was positively associated with liver (1·19,1·12-1·27), colon (1·10, 1·07-1·13), ovarian (1·09, 1.04-1.14), and postmenopausal breast cancers(1·05, 1·03-1·07) overall (all p<0·0001), but these effects varied by underlying BMI or individual-levelcharacteristics. We estimated inverse associations with prostate and premenopausal breast cancer risk,both overall (prostate 0·98, 0·95-1·00; premenopausal breast cancer 0·89, 0·86-0·92) and innever-smokers (prostate 0·96, 0·93-0·99; premenopausal breast cancer 0·89, 0·85-0·94). By contrast,for lung and oral cavity cancer, we observed no association in never smokers (lung 0·99, 0·93-1·05; oralcavity 1·07, 0·91-1·26): inverse associations overall were driven by current smokers and ex-smokers,probably because of residual confounding by smoking amount. Assuming causality, 41% of uterine and10% or more of gallbladder, kidney, liver, and colon cancers could be attributable to excess weight. Weestimated that a 1 kg/m(2) population-wide increase in BMI would result in 3790 additional annual UKpatients developing one of the ten cancers positively associated with BMI. INTERPRETATION BMI isassociated with cancer risk, with substantial population-level effects. The heterogeneity in the effectssuggests that different mechanisms are associated with different cancer sites and different patientsubgroups. FUNDING National Institute for Health Research, Wellcome Trust, and Medical ResearchCouncil.", "metadata": {}}
+{"_id": "4828984", "title": "", "text": "Cryo-EM structure of a herpesvirus capsid at 3.1 ÅStructurally and genetically, human herpesviruses areamong the largest and most complex of viruses. Using cryo–electron microscopy (cryo-EM) with anoptimized image reconstruction strategy, we report the herpes simplex virus type 2 (HSV-2) capsidstructure at 3.1 angstroms, which is built up of about 3000 proteins organized into three types of hexons(central, peripentonal, and edge), pentons, and triplexes. Both hexons and pentons contain the majorcapsid protein, VP5; hexons also contain a small capsid protein, VP26; and triplexes comprise VP23 andVP19C. Acting as core organizers, VP5 proteins form extensive intermolecular networks, involvingmultiple disulfide bonds (about 1500 in total) and noncovalent interactions, with VP26 proteins andtriplexes that underpin capsid stability and assembly. Conformational adaptations of these proteinsinduced by their microenvironments lead to 46 different conformers that assemble into a massivequasisymmetric shell, exemplifying the structural and functional complexity of HSV.", "metadata": {}}
+{"_id": "4833016", "title": "", "text": "Asymptotic and resampling strategies for assessing and comparing indirect effects in multiple mediatormodels.Hypotheses involving mediation are common in the behavioral sciences. Mediation exists when apredictor affects a dependent variable indirectly through at least one intervening variable, or mediator.Methods to assess mediation involving multiple simultaneous mediators have received little attention inthe methodological literature despite a clear need. We provide an overview of simple and multiplemediation and explore three approaches that can be used to investigate indirect processes, as well asmethods for contrasting two or more mediators within a single model. We present an illustrative example,assessing and contrasting potential mediators of the relationship between the helpfulness of socializationagents and job satisfaction. We also provide SAS and SPSS macros, as well as Mplus and LISREL syntax,to facilitate the use of these methods in applications.", "metadata": {}}
+{"_id": "4841908", "title": "", "text": "Distinct Metabolomic Signatures Are Associated with Longevity in HumansAlterations in metabolisminfluence lifespan in experimental models, but data in humans are lacking. Here we use liquidchromatography/mass spectrometry to quantify 217 plasma metabolites and examine their relation tolongevity in a large cohort of men and women followed for up to 20 years. We find that, higherconcentrations of the citric acid cycle intermediate, isocitrate, and the bile acid, taurocholate, areassociated with lower odds of longevity, defined as attaining 80 years of age. Higher concentrations ofisocitrate, but not taurocholate, are also associated with worse cardiovascular health at baseline, as wellas risk of future cardiovascular disease and death. None of the metabolites identified are associated withcancer risk. Our findings suggest that some, but not all, metabolic pathways related to human longevityare linked to the risk of common causes of death.", "metadata": {}}
+{"_id": "4854076", "title": "", "text": "The expanding problem of adipose depot remodeling and postnatal adipocyte progenitor recruitment.Therising incidence of obesity and associated metabolic diseases has increased the urgency in understandingall aspects of adipose tissue biology. This includes the function of adipocytes, how adipose tissue expandsin obesity, and how expanded adipose tissues in adults can impact physiology. Here, we highlight thegrowing appreciation for the importance of de novo adipocyte differentiation to adipose tissue expansionin adult humans and animals. We detail recent efforts to identify adipose precursor populations thatcontribute to the physiological postnatal recruitment of white, brown, and beige adipocytes in mice, andsummarize new data that reveal the complexity of adipose tissue development in vivo.", "metadata": {}}
+{"_id": "4856149", "title": "", "text": "Clonal competition in BcrAbl-driven leukemia: how transplantations can accelerate clonalconversionBACKGROUND Clonal competition in cancer describes the process in which the progeny of acell clone supersedes or succumbs to other competing clones due to differences in their functionalcharacteristics, mostly based on subsequently acquired mutations. Even though the patterns of thosemutations are well explored in many tumors, the dynamical process of clonal selection is underexposed.METHODS We studied the dynamics of clonal competition in a BcrAbl-induced leukemia using aγ-retroviral vector library encoding the oncogene in conjunction with genetic barcodes. To this end, westudied the growth dynamics of transduced cells on the clonal level both in vitro and in vivo intransplanted mice. RESULTS While we detected moderate changes in clonal abundancies in vitro, weobserved monoclonal leukemias in 6/30 mice after transplantation, which intriguingly were caused byonly two different BcrAbl clones. To analyze the success of these clones, we applied a mathematicalmodel of hematopoietic tissue maintenance, which indicated that a differential engraftment capacity ofthese two dominant clones provides a possible explanation of our observations. These findings werefurther supported by additional transplantation experiments and increased BcrAbl transcript levels in bothclones. CONCLUSION Our findings show that clonal competition is not an absolute process based onmutations, but highly dependent on selection mechanisms in a given environmental context.", "metadata": {}}
+{"_id": "4857085", "title": "", "text": "Open Babel: An open chemical toolboxBACKGROUND A frequent problem in computational modeling isthe interconversion of chemical structures between different formats. While standard interchange formatsexist (for example, Chemical Markup Language) and de facto standards have arisen (for example,SMILES format) , the need to interconvert formats is a continuing problem due to the multitude ofdifferent application areas for chemistry data, differences in the data stored by different formats (0Dversus 3D, for example), and competition between software along with a lack of vendor-neutral formats.RESULTS We discuss, for the first time, Open Babel, an open-source chemical toolbox that speaks themany languages of chemical data. Open Babel version 2.3 interconverts over 110 formats. The need torepresent such a wide variety of chemical and molecular data requires a library that implements a widerange of cheminformatics algorithms, from partial charge assignment and aromaticity detection, to bondorder perception and canonicalization. We detail the implementation of Open Babel, describe keyadvances in the 2.3 release, and outline a variety of uses both in terms of software products and scientificresearch, including applications far beyond simple format interconversion. CONCLUSIONS Open Babelpresents a solution to the proliferation of multiple chemical file formats. In addition, it provides a varietyof useful utilities from conformer searching and 2D depiction, to filtering, batch conversion, andsubstructure and similarity searching. For developers, it can be used as a programming library to handlechemical data in areas such as organic chemistry, drug design, materials science, and computationalchemistry. It is freely available under an open-source license from http://openbabel.org.", "metadata": {}}
+{"_id": "4857093", "title": "", "text": "Young adolescents' nutrition assessment on computer (YANA-C)Objective:To assess the relative validityand acceptability of the computerised 24-h recall ‘Young Adolescent's Nutrition Assessment on Computer(YANA-C)’.Design:Food and nutrient intakes assessed with YANA-C were compared with food records(study 1) and 24-h dietary recall interviews (study 2).Main outcome measures:Intakes of food groups(fruit, fruit juice, vegetables, potatoes, bread, cereals, milk, cheese, other milk products, soft drinks, dietsoft drinks, sugar/sweets, pastry/cookies, savoury snacks, butter/sauces, eggs, fish, meat) and nutrients(energy, carbohydrates, protein, fat, fiber, calcium, vitamin C and iron).Subjects and setting:A total of237 pupils (11–14 y) from two primary and four secondary schools (study 1: n=136; study 2: n=101) inBelgium-Flanders. Results:YANA-C proved to agree well with both standard methods in categorizingsubjects in consumers and nonconsumers (κstudy 1=0.48–0.92; κstudy 2=0.38–0.90). Spearman'scorrelations for energy and nutrient intakes ranged between 0.44 and 0.79 for study 1 and between 0.44and 0.86 for study 2. Nutrient and energy intakes were in general (excluding calcium) significantly higherin YANA-C in comparison with the food record, but not in comparison with the interview (only fiber).Statistics used to investigate whether YANA-C agreed with the other methods in rankingportions/amounts in consumers only were fair to moderate for most of the food groups (weighted κ study1=0.11–0.55; study 2=0.04–0.73); amounts in consumers only, were significantly lower in YANA-Cagainst both standards for cereals; amounts were significantly higher in YANA-C against the food recordfor milk, soft drinks, sugar/sweets and savoury snacks and against the interview for potatoes. Only a fewpupils evaluated the program negatively. Conclusion:YANA-C is a promising method to collect detaileddietary information from young adolescents with relatively low staff resources, useful in many nutritionresearch applications.", "metadata": {}}
+{"_id": "4883040", "title": "", "text": "Antiretroviral Therapy for Prevention of Tuberculosis in Adults with HIV: A Systematic Review andMeta-AnalysisBACKGROUND Human immunodeficiency virus (HIV) infection is the strongest risk factor fordeveloping tuberculosis and has fuelled its resurgence, especially in sub-Saharan Africa. In 2010, therewere an estimated 1.1 million incident cases of tuberculosis among the 34 million people living with HIVworldwide. Antiretroviral therapy has substantial potential to prevent HIV-associated tuberculosis. Weconducted a systematic review of studies that analysed the impact of antiretroviral therapy on theincidence of tuberculosis in adults with HIV infection. METHODS AND FINDINGS PubMed, Embase, AfricanIndex Medicus, LILACS, and clinical trial registries were systematically searched. Randomised controlledtrials, prospective cohort studies, and retrospective cohort studies were included if they comparedtuberculosis incidence by antiretroviral therapy status in HIV-infected adults for a median of over 6 mo indeveloping countries. For the meta-analyses there were four categories based on CD4 counts atantiretroviral therapy initiation: (1) less than 200 cells/µl, (2) 200 to 350 cells/µl, (3) greater than 350cells/µl, and (4) any CD4 count. Eleven studies met the inclusion criteria. Antiretroviral therapy isstrongly associated with a reduction in the incidence of tuberculosis in all baseline CD4 count categories:(1) less than 200 cells/µl (hazard ratio [HR] 0.16, 95% confidence interval [CI] 0.07 to 0.36), (2) 200 to350 cells/µl (HR 0.34, 95% CI 0.19 to 0.60), (3) greater than 350 cells/µl (HR 0.43, 95% CI 0.30 to0.63), and (4) any CD4 count (HR 0.35, 95% CI 0.28 to 0.44). There was no evidence of hazard ratiomodification with respect to baseline CD4 count category (p = 0.20). CONCLUSIONS Antiretroviraltherapy is strongly associated with a reduction in the incidence of tuberculosis across all CD4 countstrata. Earlier initiation of antiretroviral therapy may be a key component of global and nationalstrategies to control the HIV-associated tuberculosis syndemic. REVIEW REGISTRATION InternationalProspective Register of Systematic Reviews CRD42011001209 Please see later in the article for theEditors' Summary.", "metadata": {}}
+{"_id": "4886637", "title": "", "text": "Diabetes, metabolic syndrome, and breast cancer: a review of the current evidence.Incidences of breastcancer, type 2 diabetes, and metabolic syndrome have increased over the past decades with the obesityepidemic, especially in industrialized countries. Insulin resistance, hyperinsulinemia, and changes in thesignaling of growth hormones and steroid hormones associated with diabetes may affect the risk ofbreast cancer. We reviewed epidemiologic studies of the association between type 2 diabetes and risk ofbreast cancer and the available evidence on the role of hormonal mediators of an association betweendiabetes and breast cancer. The combined evidence supports a modest association between type 2diabetes and the risk of breast cancer, which appears to be more consistent among postmenopausal thanamong premenopausal women. Despite many proposed potential pathways, the mechanisms underlyingan association between diabetes and breast cancer risk remain unclear, particularly because the 2diseases share several risk factors, including obesity, a sedentary lifestyle, and possibly intake ofsaturated fat and refined carbohydrates, that may confound this association. Although the metabolicsyndrome is closely related to diabetes and embraces additional components that might influence breastcancer risk, the role of the metabolic syndrome in breast carcinogenesis has not been studied and thusremains unknown.", "metadata": {}}
+{"_id": "4889228", "title": "", "text": "Loss of TDP43 inhibits progression of triple-negative breast cancer in coordination with SRSF3Aberrantalternative splicing has been highlighted as a potential hallmark of cancer. Here, we identify TDP43 (TARDNA-binding protein 43) as an important splicing regulator responsible for the unique splicing profile intriple-negative breast cancer (TNBC). Clinical data demonstrate that TDP43 is highly expressed in TNBCwith poor prognosis. Knockdown of TDP43 inhibits tumor progression, including proliferation andmetastasis, and overexpression of TDP43 promotes proliferation and malignancy of mammary epithelialcells. Deep sequencing analysis and functional experiments indicate that TDP43 alters most splicingevents with splicing factor SRSF3 (serine/arginine-rich splicing factor 3), in the regulation of TNBCprogression. The TDP43/SRSF3 complex controls specific splicing events, including downstream genesPAR3 and NUMB The effect of reduced metastasis and proliferation upon the knockdown of TDP43 orSRSF3 is mediated by the splicing regulation of PAR3 and NUMB exon 12, respectively. The TDP43/SRSF3complex and downstream PAR3 isoform are potential therapeutic targets for TNBC.", "metadata": {}}
+{"_id": "4890578", "title": "", "text": "Atherosclerotic plaque rupture--pathologic basis of plaque stability and instability.Time for primary reveiw27 days   Atherosclerosis continues to be one of the main subjects in pathology research. The intriguingcomplexity of its pathogenesis as well as the importance of its clinical sequelae provide a rationale for this[1]. A large number of diseases with totally different clinical presentations are basically atherosclerosisrelated, and among these, myocardial infarction, stroke, abdominal aneurysms and lower limb ischemiadetermine to a large extent the morbidity and mortality in Western style populations. But, despite thisbroad spectrum of clinical disease, most of the acute manifestations of atherosclerosis share a commonpathogenetic feature: rupture of an atherosclerotic plaque [2–4]. Plaque disruptions may vary greatly inextent from tiny fissures or erosions of the plaque surface to deep intimal tears which extend into the softlipid core of lesions; in all these instances, at least some degree of thrombus formation occurs [5, 6]. Theabdominal aorta is the arterial site most prominently involved in the process of plaque formation, andalso of plaque complications. In this large diameter vessel the process of plaque disruption andthrombosis is not ended by luminal occlusion, and may lead to extensive surface ulcerations comprisinglarge areas of the aortic wall, as can be observed in many autopsy cases at older age. Apart from theundisputable role of atherosclerosis in abdominal aneurysm formation [7], mural thrombosis leads to asurprisingly low rate of clinically significant complications in these patients, although cholesterol embolican be regularly found in their kidneys and skin at autopsy. Still, it is presently unclear what impact thevarious biologically active mediators released from eroded aortic surfaces may have on the human body.In contrast, in small diameter vessels such as coronary arteries, occlusive thrombosis is a frequent andoften fatal complication of plaque …   * Corresponding author. Tel.: +31-20-5665-633; fax:+31-20-914-738; e-mail a.c.vanderwal@amc.uva.nl", "metadata": {}}
+{"_id": "4896726", "title": "", "text": "Pioneer factor Pax7 deploys a stable enhancer repertoire for specification of cell fatePioneer transcriptionfactors establish new cell-fate competence by triggering chromatin remodeling. However, many featuresof pioneer action, such as their kinetics and stability, remain poorly defined. Here, we show that Pax7, byopening a unique repertoire of enhancers, is necessary and sufficient for specification of one pituitarylineage. Pax7 binds its targeted enhancers rapidly, but chromatin remodeling and gene activation areslower. Enhancers opened by Pax7 show a loss of DNA methylation and acquire stable epigeneticmemory, as evidenced by binding of nonpioneer factors after Pax7 withdrawal. This work shows thattransient Pax7 expression is sufficient for stable specification of cell identity. Analysis of Pax7 dynamicsduring pituitary lineage specification shows that Pax7 binds rapidly at uniquely marked heterochromatinpioneer sites and initiates chromatin opening that remains stable after Pax7 withdrawal, with loss of DNAhypermethylation at pioneered enhancers.", "metadata": {}}
+{"_id": "4899981", "title": "", "text": "Human cancer cells utilize mitotic DNA synthesis to resist replication stress at telomeres regardless oftheir telomere maintenance mechanismTelomeres resemble common fragile sites (CFSs) in that they aredifficult-to-replicate and exhibit fragility in mitosis in response to DNA replication stress. At CFSs, thisfragility is associated with a delay in the completion of DNA replication until early mitosis, whereuponcells are proposed to switch to a RAD52-dependent form of break-induced replication. Here, we show thatthis mitotic DNA synthesis (MiDAS) is also a feature of human telomeres. Telomeric MiDAS is notrestricted to those telomeres displaying overt fragility, and is a feature of a wide range of cell linesirrespective of whether their telomeres are maintained by telomerase or by the alternative lengthening oftelomeres (ALT) mechanism. MiDAS at telomeres requires RAD52, and is mechanistically similar toCFS-associated MiDAS, with the notable exception that telomeric MiDAS does not require theMUS81-EME1 endonuclease. We propose a model whereby replication stress initiates a RAD52-dependentform of break-induced replication that bypasses a requirement for MUS81-EME1 to complete DNAsynthesis in mitosis.", "metadata": {}}
+{"_id": "4910408", "title": "", "text": "Low drug levels and thrombotic complications in high\u0000risk atrial fibrillation patients treated with directoral anticoagulantsEssentials Direct oral anticoagulants (DOACs) do not require laboratory monitoringcurrently. DOAC specific measurements were performed at trough in patients with atrial fibrillation.Patients who developed thromboembolic events showed lower DOAC plasma levels. This study supportsthe concept of measuring DOAC levels at steady state. SUMMARY Background Direct oral anticoagulants(DOACs) are administered at fixed doses without the need for dose adjustment according to laboratorytesting. High interindividual variability in drug blood levels has been shown with all DOACs. To evaluate apossible relationship between DOAC C-trough anticoagulant levels and thromboembolic events, 565consecutive naive patients with atrial fibrillation (AF) were enrolled in this study performed within theSTART Laboratory Registry. Methods DOAC-specific measurements (diluted thrombin time oranti-activated factor II calibrated for dabigatran; anti-activated FX calibrated for rivaroxaban orapixaban) at C-trough were performed locally at steady state within 15-25 days after the start oftreatment. For each DOAC, the interval of C-trough levels, from the limit of quantification to the highestvalue, was subdivided into four equal classes, and results were attributed to these classes; the medianvalues of results were also calculated. Thromboembolic complications occurring during 1 year of follow-upwere recorded. Results Thromboembolic events (1.8%) occurred in 10 patients who had baselineC-trough levels in the lowest class of drug levels. The incidence of thromboembolic events amongpatients with DOAC C-trough levels in the lowest level class was 2.4%, and that in the remaining groupswas 0%. The patients with thrombotic complications also had a higher mean CHA2 DS2 -VASc score thanthat of the total patient population: 5.3 (95% confidence interval [CI] 4.3-6.3 versus 3.0 (95% CI2.9-3.1). Conclusion In this study cohort, thrombotic complications occurred only in DOAC-treated AFpatients who had very low C-trough levels, with a relatively high CHA2 DS2 -VASc score. Larger studiesare warranted to confirm these preliminary observations.", "metadata": {}}
+{"_id": "4911006", "title": "", "text": "Consensus guidelines for the detection of immunogenic cell death.Apoptotic cells have long beenconsidered as intrinsically tolerogenic or unable to elicit immune responses specific for deadcell-associated antigens. However, multiple stimuli can trigger a functionally peculiar type of apoptoticdemise that does not go unnoticed by the adaptive arm of the immune system, which we named\"immunogenic cell death\" (ICD). ICD is preceded or accompanied by the emission of a series ofimmunostimulatory damage-associated molecular patterns (DAMPs) in a precise spatiotemporalconfiguration. Several anticancer agents that have been successfully employed in the clinic for decades,including various chemotherapeutics and radiotherapy, can elicit ICD. Moreover, defects in thecomponents that underlie the capacity of the immune system to perceive cell death as immunogenicnegatively influence disease outcome among cancer patients treated with ICD inducers. Thus, ICD hasprofound clinical and therapeutic implications. Unfortunately, the gold-standard approach to detect ICDrelies on vaccination experiments involving immunocompetent murine models and syngeneic cancer cells,an approach that is incompatible with large screening campaigns. Here, we outline strategies conceivedto detect surrogate markers of ICD in vitro and to screen large chemical libraries for putative ICDinducers, based on a high-content, high-throughput platform that we recently developed. Such a platformallows for the detection of multiple DAMPs, like cell surface-exposed calreticulin, extracellular ATP andhigh mobility group box 1 (HMGB1), and/or the processes that underlie their emission, such asendoplasmic reticulum stress, autophagy and necrotic plasma membrane permeabilization. We surmisethat this technology will facilitate the development of next-generation anticancer regimens, which killmalignant cells and simultaneously convert them into a cancer-specific therapeutic vaccine.", "metadata": {}}
+{"_id": "4920376", "title": "", "text": "Long-Term ERK Inhibition in KRAS-Mutant Pancreatic Cancer Is Associated with MYC Degradation andSenescence-like Growth Suppression.Induction of compensatory mechanisms and ERK reactivation haslimited the effectiveness of Raf and MEK inhibitors in RAS-mutant cancers. We determined that directpharmacologic inhibition of ERK suppressed the growth of a subset of KRAS-mutant pancreatic cancer celllines and that concurrent phosphatidylinositol 3-kinase (PI3K) inhibition caused synergistic cell death.Additional combinations that enhanced ERK inhibitor action were also identified. Unexpectedly, long-termtreatment of sensitive cell lines caused senescence, mediated in part by MYC degradation and p16reactivation. Enhanced basal PI3K-AKT-mTOR signaling was associated with de novo resistance to ERKinhibitor, as were other protein kinases identified by kinome-wide siRNA screening and a geneticgain-of-function screen. Our findings reveal distinct consequences of inhibiting this kinase cascade at thelevel of ERK.", "metadata": {}}
+{"_id": "4926049", "title": "", "text": "TRF2 Recruits RTEL1 to Telomeres in S Phase to Promote T-Loop UnwindingThe helicase RTEL1 promotest-loop unwinding and suppresses telomere fragility to maintain the integrity of vertebrate telomeres. Aninteraction between RTEL1 and PCNA is important to prevent telomere fragility, but how RTEL1 engageswith the telomere to promote t-loop unwinding is unclear. Here, we establish that the shelterin proteinTRF2 recruits RTEL1 to telomeres in S phase, which is required to prevent catastrophic t-loop processingby structure-specific nucleases. We show that the TRF2-RTEL1 interaction is mediated by ametal-coordinating C4C4 motif in RTEL1, which is compromised by the Hoyeraal-Hreidarsson syndrome(HHS) mutation, RTEL1(R1264H). Conversely, we define a TRF2(I124D) substitution mutation within theTRFH domain of TRF2, which eliminates RTEL1 binding and phenocopies the RTEL1(R1264H) mutation,giving rise to aberrant t-loop excision, telomere length heterogeneity, and loss of the telomere as a circle.These results implicate TRF2 in the recruitment of RTEL1 to facilitate t-loop disassembly at telomeres in Sphase.", "metadata": {}}
+{"_id": "4928057", "title": "", "text": "Macrophages Facilitate Electrical Conduction in the HeartOrgan-specific functions of tissue-residentmacrophages in the steady-state heart are unknown. Here, we show that cardiac macrophages facilitateelectrical conduction through the distal atrioventricular node, where conducting cells densely interspersewith elongated macrophages expressing connexin 43. When coupled to spontaneously beatingcardiomyocytes via connexin-43-containing gap junctions, cardiac macrophages have a negative restingmembrane potential and depolarize in synchrony with cardiomyocytes. Conversely, macrophages renderthe resting membrane potential of cardiomyocytes more positive and, according to computationalmodeling, accelerate their repolarization. Photostimulation of channelrhodopsin-2-expressingmacrophages improves atrioventricular conduction, whereas conditional deletion of connexin 43 inmacrophages and congenital lack of macrophages delay atrioventricular conduction. In the Cd11bDTRmouse, macrophage ablation induces progressive atrioventricular block. These observations implicatemacrophages in normal and aberrant cardiac conduction.", "metadata": {}}
+{"_id": "4928282", "title": "", "text": "A Tunable Diffusion\u0000Consumption Mechanism of Cytokine Propagation Enables Plasticity in Cell\u0000to\u0000CellCommunication in the Immune System&NA; Immune cells communicate by exchanging cytokines toachieve a context\u0000appropriate response, but the distances over which such communication happens arenot known. Here, we used theoretical considerations and experimental models of immune responses invitro and in vivo to quantify the spatial extent of cytokine communications in dense tissues. Weestablished that competition between cytokine diffusion and consumption generated spatial niches of highcytokine concentrations with sharp boundaries. The size of these self\u0000assembled niches scaled with thedensity of cytokine\u0000consuming cells, a parameter that gets tuned during immune responses. In vivo, wemeasured interactions on length scales of 80–120 &mgr;m, which resulted in a high degree ofcell\u0000to\u0000cell variance in cytokine exposure. Such heterogeneous distributions of cytokines were a sourceof non\u0000genetic cell\u0000to\u0000cell variability that is often overlooked in single\u0000cell studies. Our findings thusprovide a basis for understanding variability in the patterning of immune responses by diffusible factors.Graphical Abstract Figure. No caption available. HighlightsCytokine penetration in tissues is governed bya diffusion\u0000consumption mechanismSpherical cytokine niches are generated around cytokine\u0000producingcellsThe characteristic niche size depends on the density of cytokine consumersCytokine niches are asource of variability in otherwise identical cells &NA; Cytokine\u0000mediated communication allows immunecells to achieve a context\u0000appropriate response, but the distance over which this communicationhappens is unclear. Oyler\u0000Yaniv et al. (2017) show that a simple diffusion\u0000consumption mechanismquantitatively describes the spatial spread of cytokines in vivo and results in localized niches of highcytokine concentrations that contribute to cell\u0000to\u0000cell variability.", "metadata": {}}
+{"_id": "4932668", "title": "", "text": "Cardiac neural crest contributes to cardiomyogenesis in zebrafish.In birds and mammals, cardiac neuralcrest is essential for heart development and contributes to conotruncal cushion formation and outflowtract septation. The zebrafish prototypical heart lacks outflow tract septation, raising the question ofwhether cardiac neural crest exists in zebrafish. Here, results from three distinct lineage-labelingapproaches identify zebrafish cardiac neural crest cells and indicate that these cells have the ability togenerate MF20-positive muscle cells in the myocardium of the major chambers during development.Fate-mapping demonstrates that cardiac neural crest cells originate both from neural tube regionsanalogous to those found in birds, as well as from a novel region rostral to the otic vesicle. In contrast toother vertebrates, cardiac neural crest invades the myocardium in all segments of the heart, includingoutflow tract, atrium, atrioventricular junction, and ventricle in zebrafish. Three distinct groups ofpremigratory neural crest along the rostrocaudal axis have different propensities to contribute to differentsegments in the heart and are correspondingly marked by unique combinations of gene expressionpatterns. Zebrafish will serve as a model for understanding interactions between cardiac neural crest andcardiovascular development.", "metadata": {}}
+{"_id": "4939312", "title": "", "text": "Sodium Hydroxide Production from Seawater Desalination Brine: Process Design and EnergyEfficiency.The ability to increase pH is a crucial need for desalination pretreatment (especially in reverseosmosis) and for other industries, but processes used to raise pH often incur significant emissions andnonrenewable resource use. Alternatively, waste brine from desalination can be used to create sodiumhydroxide, via appropriate concentration and purification pretreatment steps, for input into thechlor-alkali process. In this work, an efficient process train (with variations) is developed and modeled forsodium hydroxide production from seawater desalination brine using membrane chlor-alkali electrolysis.The integrated system includes nanofiltration, concentration via evaporation or mechanical vaporcompression, chemical softening, further ion-exchange softening, dechlorination, and membraneelectrolysis. System productivity, component performance, and energy consumption of the NaOHproduction process are highlighted, and their dependencies on electrolyzer outlet conditions and brinerecirculation are investigated. The analysis of the process also includes assessment of the energyefficiency of major components, estimation of system operating expense and comparison with similarprocesses. The brine-to-caustic process is shown to be technically feasible while offering severaladvantages, that is, the reduced environmental impact of desalination through lessened brine discharge,and the increase in the overall water recovery ratio of the reverse osmosis facility. Additionally, best-useconditions are given for producing caustic not only for use within the plant, but also in excess amounts forpotential revenue.", "metadata": {}}
+{"_id": "4942718", "title": "", "text": "High-Throughput Genetic Screens Identify a Large and Diverse Collection of New Sporulation Genes inBacillus subtilisThe differentiation of the bacterium Bacillus subtilis into a dormant spore is among themost well-characterized developmental pathways in biology. Classical genetic screens performed over thepast half century identified scores of factors involved in every step of this morphological process. Morerecently, transcriptional profiling uncovered additional sporulation-induced genes required for successfulspore development. Here, we used transposon-sequencing (Tn-seq) to assess whether there were anysporulation genes left to be discovered. Our screen identified 133 out of the 148 genes with knownsporulation defects. Surprisingly, we discovered 24 additional genes that had not been previouslyimplicated in spore formation. To investigate their functions, we used fluorescence microscopy to surveyearly, middle, and late stages of differentiation of null mutants from the B. subtilis ordered knockoutcollection. This analysis identified mutants that are delayed in the initiation of sporulation, defective inmembrane remodeling, and impaired in spore maturation. Several mutants had novel sporulationphenotypes. We performed in-depth characterization of two new factors that participate in cell-cellsignaling pathways during sporulation. One (SpoIIT) functions in the activation of σE in the mother cell;the other (SpoIIIL) is required for σG activity in the forespore. Our analysis also revealed that as many as36 sporulation-induced genes with no previously reported mutant phenotypes are required for timelyspore maturation. Finally, we discovered a large set of transposon insertions that trigger prematureinitiation of sporulation. Our results highlight the power of Tn-seq for the discovery of new genes andnovel pathways in sporulation and, combined with the recently completed null mutant collection, open thedoor for similar screens in other, less well-characterized processes.", "metadata": {}}
+{"_id": "4951831", "title": "", "text": "Psychobiological mechanisms underlying the social buffering of the hypothalamic-pituitary-adrenocorticalaxis: a review of animal models and human studies across development.Discovering the stress-bufferingeffects of social relationships has been one of the major findings in psychobiology in the last century.However, an understanding of the underlying neurobiological and psychological mechanisms of thisbuffering is only beginning to emerge. An important avenue of this research concerns the neurocircuitrythat can regulate the activity of the hypothalamic-pituitary-adrenocortical (HPA) axis. The present reviewis a translational effort aimed at integrating animal models and human studies of the social regulation ofthe HPA axis from infancy to adulthood, specifically focusing on the process that has been named socialbuffering. This process has been noted across species and consists of a dampened HPA axis stressresponse to threat or challenge that occurs with the presence or assistance of a conspecific. We describeaspects of the relevant underlying neurobiology when enough information exists and expose major gapsin our understanding across all domains of the literatures we aimed to integrate. We provide a workingconceptual model focused on the role of oxytocinergic systems and prefrontal neural networks as 2 of theputative biological mediators of this process, and propose that the role of early experiences is critical inshaping later social buffering effects. This synthesis points to both general future directions and specificexperiments that need to be conducted to build a more comprehensive model of the HPA social bufferingeffect across the life span that incorporates multiple levels of analysis: neuroendocrine, behavioral, andsocial.", "metadata": {}}
+{"_id": "4959368", "title": "", "text": "Elevation of circulating branched-chain amino acids is an early event in human pancreaticadenocarcinoma developmentMost patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosedwith advanced disease and survive less than 12 months. PDAC has been linked with obesity and glucoseintolerance, but whether changes in circulating metabolites are associated with early cancer progressionis unknown. To better understand metabolic derangements associated with early disease, we profiledmetabolites in prediagnostic plasma from individuals with pancreatic cancer (cases) and matched controlsfrom four prospective cohort studies. We find that elevated plasma levels of branched-chain amino acids(BCAAs) are associated with a greater than twofold increased risk of future pancreatic cancer diagnosis.This elevated risk was independent of known predisposing factors, with the strongest associationobserved among subjects with samples collected 2 to 5 years before diagnosis, when occult disease isprobably present. We show that plasma BCAAs are also elevated in mice with early-stage pancreaticcancers driven by mutant Kras expression but not in mice with Kras-driven tumors in other tissues, andthat breakdown of tissue protein accounts for the increase in plasma BCAAs that accompanies early-stagedisease. Together, these findings suggest that increased whole-body protein breakdown is an early eventin development of PDAC.", "metadata": {}}
+{"_id": "4961038", "title": "", "text": "Effective Use of PI3K and MEK Inhibitors to Treat Mutant K-Ras G12D and PIK3CA H1047R Murine LungCancersSomatic mutations that activate phosphoinositide 3-kinase (PI3K) have been identified in thep110-alpha catalytic subunit (encoded by PIK3CA). They are most frequently observed in two hotspots:the helical domain (E545K and E542K) and the kinase domain (H1047R). Although the p110-alphamutants are transforming in vitro, their oncogenic potential has not been assessed in geneticallyengineered mouse models. Furthermore, clinical trials with PI3K inhibitors have recently been initiated,and it is unknown if their efficacy will be restricted to specific, genetically defined malignancies. In thisstudy, we engineered a mouse model of lung adenocarcinomas initiated and maintained by expression ofp110-alpha H1047R. Treatment of these tumors with NVP-BEZ235, a dual pan-PI3K and mammaliantarget of rapamycin (mTOR) inhibitor in clinical development, led to marked tumor regression as shownby positron emission tomography-computed tomography, magnetic resonance imaging and microscopicexamination. In contrast, mouse lung cancers driven by mutant Kras did not substantially respond tosingle-agent NVP-BEZ235. However, when NVP-BEZ235 was combined with a mitogen-activated proteinkinase kinase (MEK) inhibitor, ARRY-142886, there was marked synergy in shrinking these Kras-mutantcancers. These in vivo studies suggest that inhibitors of the PI3K-mTOR pathway may be active incancers with PIK3CA mutations and, when combined with MEK inhibitors, may effectively treat KRASmutated lung cancers.", "metadata": {}}
+{"_id": "4979184", "title": "", "text": "Transdifferentiation of glioblastoma cells into vascular endothelial cells.Glioblastoma (GBM) is the mostmalignant brain tumor and is highly resistant to intensive combination therapies and anti-VEGF therapies.To assess the resistance mechanism to anti-VEGF therapy, we examined the vessels of GBMs in tumorsthat were induced by the transduction of p53(+/-) heterozygous mice with lentiviral vectors containingoncogenes and the marker GFP in the hippocampus of GFAP-Cre recombinase (Cre) mice. We weresurprised to observe GFP(+) vascular endothelial cells (ECs). Transplantation of mouse GBM cellsrevealed that the tumor-derived endothelial cells (TDECs) originated from tumor-initiating cells and didnot result from cell fusion of ECs and tumor cells. An in vitro differentiation assay suggested that hypoxiais an important factor in the differentiation of tumor cells to ECs and is independent of VEGF. TDECformation was not only resistant to an anti-VEGF receptor inhibitor in mouse GBMs but it led to anincrease in their frequency. A xenograft model of human GBM spheres from clinical specimens and directclinical samples from patients with GBM also showed the presence of TDECs. We suggest that the TDEC isan important player in the resistance to anti-VEGF therapy, and hence a potential target for GBM therapy.", "metadata": {}}
+{"_id": "4993011", "title": "", "text": "Ribosomal DNA copy loss and repeat instability in ATRX-mutated cancersATRX (alpha thalassemia/mentalretardation X-linked) complexes with DAXX to deposit histone variant H3.3 into repetitiveheterochromatin. Recent genome sequencing studies in cancers have revealed mutations in ATRX andtheir association with ALT (alternative lengthening of telomeres) activation. Here we report depletion ofATRX in mouse ES cells leads to selective loss in ribosomal RNA gene (rDNA) copy number. Supportingthis, ATRX-mutated human ALT-positive tumors also show a substantially lower rDNA copy thanALT-negative tumors. Further investigation shows that the rDNA copy loss and repeat instability arecaused by a disruption in H3.3 deposition and thus a failure in heterochromatin formation at rDNArepeats in the absence of ATRX. We also find that ATRX-depleted cells are reduced in ribosomal RNAtranscription output and show increased sensitivity to RNA polymerase I (Pol I) transcription inhibitorCX5461. In addition, human ALT-positive cancer cell lines are also more sensitive to CX5461 treatment.Our study provides insights into the contribution of ATRX loss of function to tumorigenesis through theloss of rDNA stability and suggests the therapeutic potential of targeting Pol I transcription in ALTcancers.", "metadata": {}}
+{"_id": "4999387", "title": "", "text": "Combining indoor residual spraying and insecticide-treated nets for malaria control in Africa: a review ofpossible outcomes and an outline of suggestions for the futureInsecticide-treated nets (ITNs) and indoorresidual spraying (IRS) are currently the preferred methods of malaria vector control. In many cases,these methods are used together in the same households, especially to suppress transmission inholoendemic and hyperendemic scenarios. Though widespread, there has been limited evidencesuggesting that such co-application confers greater protective benefits than either ITNs or IRS when usedalone. Since both methods are insecticide-based and intradomicilliary, this article hypothesises thatoutcomes of their combination would depend on effects of the candidate active ingredients on mosquitoesthat enter or those that attempt to enter houses. It is suggested here that enhanced household levelprotection can be achieved if the ITNs and IRS have divergent yet complementary properties, e.g. highlydeterrent IRS compounds coupled with highly toxic ITNs. To ensure that the problem of insecticideresistance is avoided, the ITNs and IRS products should preferably be of different insecticide classes, e.g.pyrethroid-based nets combined with organophosphate or carbamate based IRS. The overall communitybenefits would however depend also on other factors such as proportion of people covered by theinterventions and the behaviour of vector species. This article concludes by emphasizing the need forbasic and operational research, including mathematical modelling to evaluate IRS/ITN combinations incomparison to IRS alone or ITNs alone.", "metadata": {}}
+{"_id": "4999633", "title": "", "text": "Membrane estrogen receptor-α levels in MCF-7 breast cancer cells predict cAMP and proliferationresponses17β-estradiol (E2) can rapidly induce cAMP production, but the conditions under which thesecAMP levels are best measured and the signaling pathways responsible for the consequent proliferativeeffects on breast cancer cells are not fully understood. To help resolve these issues, we compared cAMPmechanistic responses in MCF-7 cell lines selected for low (mERlow) and high (mERhigh) expression ofthe membrane form of estrogen receptor (mER)-α, and thus addressed the receptor subform involved incAMP signaling. MCF-7 cells were immunopanned and subsequently separated by fluorescence activatedcell sorting into mERhigh (mER-α-enriched) and mERlow (mER-α-depleted) populations. Unique(compared with previously reported) incubation conditions at 4°C were found to be optimal fordemonstrating E2-induced cAMP production. Time-dependent and dose-dependent effects of E2 on cAMPproduction were determined for both cell subpopulations. The effects of forskolin, 8-CPT cAMP, proteinkinase A inhibitor (H-89), and adenylyl cyclase inhibitor (SQ 22,536) on E2-induced cell proliferation wereassessed using the crystal violet assay. We demonstrated a rapid and transient cAMP increase after 1pmol/l E2 stimulation in mERhigh cells; at 4°C these responses were much more reliable and robust thanat 37°C (the condition most often used). The loss of cAMP at 37°C was not due to export.3-Isobutyl-1-methylxanthine (IBMX; 1 mmol/l) only partially preserved cAMP, suggesting that multiplephosphodiesterases modulate its level. The accumulated cAMP was consistently much higher in mERhighcells than in mERlow cells, implicating mER-α levels in the process. ICI172,780 blocked the E2-inducedresponse and 17α-estradiol did not elicit the response, also suggesting activity through an estrogenreceptor. E2 dose-dependent cAMP production, although biphasic in both cell types, was responsive to50-fold higher E2 concentrations in mERhigh cells. Proliferation of mERlow cells was stimulated over thewhole range of E2concentrations, whereas the number of mERhigh cells was greatly decreased atconcentrations above 1 nmol/l, suggesting that estrogen over-stimulation can lead to cell death, as haspreviously been reported, and that mER-α participates. E2-mediated activation of adenylyl cyclase anddownstream participation of protein kinase A were shown to be involved in these responses. RapidmER-α-mediated nongenomic signaling cascades generate cAMP and downstream signaling events, whichcontribute to the regulation of breast cancer cell number.", "metadata": {}}
+{"_id": "5002665", "title": "", "text": "The embryonic cell lineage of the nematode Caenorhabditis elegans.The embryonic cell lineage ofCaenorhabditis elegans has been traced from zygote to newly hatched larva, with the result that theentire cell lineage of this organism is now known. During embryogenesis 671 cells are generated; in thehermaphrodite 113 of these (in the male 111) undergo programmed death and the remainder eitherdifferentiate terminally or become postembryonic blast cells. The embryonic lineage is highly invariant, asare the fates of the cells to which it gives rise. In spite of the fixed relationship between cell ancestry andcell fate, the correlation between them lacks much obvious pattern. Thus, although most neurons arisefrom the embryonic ectoderm, some are produced by the mesoderm and a few are sisters to muscles;again, lineal boundaries do not necessarily coincide with functional boundaries. Nevertheless, cell ablationexperiments (as well as previous cell isolation experiments) demonstrate substantial cell autonomy in atleast some sections of embryogenesis. We conclude that the cell lineage itself, complex as it is, plays animportant role in determining cell fate. We discuss the origin of the repeat units (partial segments) in thebody wall, the generation of the various orders of symmetry, the analysis of the lineage in terms ofsublineages, and evolutionary implications.", "metadata": {}}
+{"_id": "5003144", "title": "", "text": "Self-Reactive B Cells in the Germinal Center Reaction.Maintenance of immunological self-tolerancerequires lymphocytes carrying self-reactive antigen receptors to be selectively prevented from mountingdestructive or inflammatory effector responses. Classically, self-tolerance is viewed in terms of theremoval, editing, or silencing of B and T cells that have formed self-reactive antigen receptors duringtheir early development. However, B cells activated by foreign antigen can enter germinal centers (GCs),where they further modify their antigen receptor by somatic hypermutation (SHM) of theirimmunoglobulin genes. The inevitable emergence of activated, self-reactive GC B cells presents a uniquechallenge to the maintenance of self-tolerance that must be rapidly countered to avoid autoantibodyproduction. Here we discuss current knowledge of the mechanisms that enforce B cell self-tolerance, withparticular focus on the control of self-reactive GC B cells. We also consider how self-reactive GC B cellscan escape self-tolerance to initiate autoantibody production or instead be redeemed via SHM and used inproductive antibody responses.", "metadata": {}}
+{"_id": "5035827", "title": "", "text": "Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases.Humanaging is characterized by a chronic, low-grade inflammation, and this phenomenon has been termed as\"inflammaging. \" Inflammaging is a highly significant risk factor for both morbidity and mortality in theelderly people, as most if not all age-related diseases share an inflammatory pathogenesis. Nevertheless,the precise etiology of inflammaging and its potential causal role in contributing to adverse healthoutcomes remain largely unknown. The identification of pathways that control age-related inflammationacross multiple systems is therefore important in order to understand whether treatments that modulateinflammaging may be beneficial in old people. The session on inflammation of the Advances inGerosciences meeting held at the National Institutes of Health/National Institute on Aging in Bethesda onOctober 30 and 31, 2013 was aimed at defining these important unanswered questions aboutinflammaging. This article reports the main outcomes of this session.", "metadata": {}}
+{"_id": "5035851", "title": "", "text": "Cryptochromes Enabling Plants and Animals to Determine Circadian TimeCryptochromes areflavin-containing blue light photoreceptors related to photolyases-they are found in both plants andanimals and have recently been described for bacteria. In plants, cryptochromes perform a variety offunctions including the entrainment of circadian rhythms. They serve a similar role in Drosophila andmammals, where the cryptochromes also perform an additional function as an essential component of thecircadian clock.", "metadata": {}}
+{"_id": "5085118", "title": "", "text": "Neural crest-derived stem cells migrate and differentiate into cardiomyocytes after myocardialinfarction.OBJECTIVE We recently demonstrated that primitive neural crest-derived (NC) cells migratefrom the cardiac neural crest during embryonic development and remain in the heart as dormant stemcells, with the capacity to differentiate into various cell types, including cardiomyocytes. Here, weexamined the migration and differentiation potential of these cells on myocardial infarction (MI).METHODS AND RESULTS We obtained double-transgenic mice by crossing protein-0 promoter-Cre micewith Floxed-enhanced green fluorescent protein mice, in which the NC cells express enhanced greenfluorescent protein. In the neonatal heart, NC stem cells (NCSCs) were localized predominantly in theoutflow tract, but they were also distributed in a gradient from base to apex throughout the ventricularmyocardium. Time-lapse video analysis revealed that the NCSCs were migratory. Some NCSCs persistedin the adult heart. On MI, NCSCs accumulated at the ischemic border zone area (BZA), which expressesmonocyte chemoattractant protein-1 (MCP-1). Ex vivo cell migration assays demonstrated that MCP-1induced NCSC migration and that this chemotactic effect was significantly depressed by an anti-MCP-1antibody. Small NC cardiomyocytes first appeared in the BZA 2 weeks post-MI and gradually increased innumber thereafter. CONCLUSIONS These results suggested that NCSCs migrate into the BZA viaMCP-1/CCR2 signaling and contribute to the provision of cardiomyocytes for cardiac regeneration afterMI.", "metadata": {}}
+{"_id": "5094468", "title": "", "text": "Mitochondria as sensors and regulators of calcium signallingDuring the past two decades calcium (Ca2+)accumulation in energized mitochondria has emerged as a biological process of utmost physiologicalrelevance. Mitochondrial Ca2+ uptake was shown to control intracellular Ca2+ signalling, cellmetabolism, cell survival and other cell-type specific functions by buffering cytosolic Ca2+ levels andregulating mitochondrial effectors. Recently, the identity of mitochondrial Ca2+ transporters has beenrevealed, opening new perspectives for investigation and molecular intervention.", "metadata": {}}
+{"_id": "5099266", "title": "", "text": "Caspase-11 promotes the fusion of phagosomes harboring pathogenic bacteria with lysosomes bymodulating actin polymerization.Inflammasomes are multiprotein complexes that include members of theNLR (nucleotide-binding domain leucine-rich repeat containing) family and caspase-1. Once bacterialmolecules are sensed within the macrophage, the inflammasome is assembled, mediating the activationof caspase-1. Caspase-11 mediates caspase-1 activation in response to lipopolysaccharide and bacterialtoxins, and yet its role during bacterial infection is unknown. Here, we demonstrated that caspase-11 wasdispensable for caspase-1 activation in response to Legionella, Salmonella, Francisella, and Listeria. Wealso determined that active mouse caspase-11 was required for restriction of L. pneumophila infection.Similarly, human caspase-4 and caspase-5, homologs of mouse caspase-11, cooperated to restrict L.pneumophila infection in human macrophages. Caspase-11 promoted the fusion of the L. pneumophilavacuole with lysosomes by modulating actin polymerization through cofilin. However, caspase-11 wasdispensable for the fusion of lysosomes with phagosomes containing nonpathogenic bacteria, uncoveringa fundamental difference in the trafficking of phagosomes according to their cargo.", "metadata": {}}
+{"_id": "5106691", "title": "", "text": "Adipocyte inflammation is essential for healthy adipose tissue expansion and remodeling.Chronicinflammation constitutes an important link between obesity and its pathophysiological sequelae. Incontrast to the belief that inflammatory signals exert a fundamentally negative impact on metabolism, weshow that proinflammatory signaling in the adipocyte is in fact required for proper adipose tissueremodeling and expansion. Three mouse models with an adipose tissue-specific reduction inproinflammatory potential were generated that display a reduced capacity for adipogenesis in vivo, whilethe differentiation potential is unaltered in vitro. Upon high-fat-diet exposure, the expansion of visceraladipose tissue is prominently affected. This is associated with decreased intestinal barrier function,increased hepatic steatosis, and metabolic dysfunction. An impaired local proinflammatory response inthe adipocyte leads to increased ectopic lipid accumulation, glucose intolerance, and systemicinflammation. Adipose tissue inflammation is therefore an adaptive response that enables safe storage ofexcess nutrients and contributes to a visceral depot barrier that effectively filters gut-derived endotoxin.", "metadata": {}}
+{"_id": "5107861", "title": "", "text": "Chronic variable stress activates hematopoietic stem cellsExposure to psychosocial stress is a risk factorfor many diseases, including atherosclerosis. Although incompletely understood, interaction between thepsyche and the immune system provides one potential mechanism linking stress and disease inceptionand progression. Known cross-talk between the brain and immune system includes thehypothalamic-pituitary-adrenal axis, which centrally drives glucocorticoid production in the adrenalcortex, and the sympathetic-adrenal-medullary axis, which controls stress-induced catecholamine releasein support of the fight-or-flight reflex. It remains unknown, however, whether chronic stress changeshematopoietic stem cell activity. Here we show that stress increases proliferation of these most primitivehematopoietic progenitors, giving rise to higher levels of disease-promoting inflammatory leukocytes. Wefound that chronic stress induced monocytosis and neutrophilia in humans. While investigating the sourceof leukocytosis in mice, we discovered that stress activates upstream hematopoietic stem cells. Underconditions of chronic variable stress in mice, sympathetic nerve fibers released surplus noradrenaline,which signaled bone marrow niche cells to decrease CXCL12 levels through the β3-adrenergic receptor.Consequently, hematopoietic stem cell proliferation was elevated, leading to an increased output ofneutrophils and inflammatory monocytes. When atherosclerosis-prone Apoe(-/-) mice were subjected tochronic stress, accelerated hematopoiesis promoted plaque features associated with vulnerable lesionsthat cause myocardial infarction and stroke in humans.", "metadata": {}}
+{"_id": "5108807", "title": "", "text": "CNTF reverses obesity-induced insulin resistance by activating skeletal muscle AMPKCiliary neurotrophicfactor (CNTF) induces weight loss and improves glucose tolerance in humans and rodents. CNTF isthought to act centrally by inducing hypothalamic neurogenesis to modulate food intake and peripherallyby altering hepatic gene expression, in a manner similar to that of leptin. Here, we show that CNTFsignals through the CNTFRα–IL-6R–gp130β receptor complex to increase fatty-acid oxidation and reduceinsulin resistance in skeletal muscle by activating AMP-activated protein kinase (AMPK), independent ofsignaling through the brain. Thus, our findings further show that the antiobesogenic effects of CNTF in theperiphery result from direct effects on skeletal muscle, and that these peripheral effects are notsuppressed by diet-induced or genetic models of obesity, an essential requirement for the therapeutictreatment of obesity-related diseases.", "metadata": {}}
+{"_id": "5114282", "title": "", "text": "The Global Spread of Hepatitis C Virus 1a and 1b: A Phylodynamic and PhylogeographicAnalysisBACKGROUND Hepatitis C virus (HCV) is estimated to affect 130-180 million people worldwide.Although its origin is unknown, patterns of viral diversity suggest that HCV genotype 1 probablyoriginated from West Africa. Previous attempts to estimate the spatiotemporal parameters of the virus,both globally and regionally, have suggested that epidemic HCV transmission began in 1900 and grewsteadily until the late 1980s. However, epidemiological data suggest that the expansion of HCV may haveoccurred after the Second World War. The aim of our study was to elucidate the timescale and route ofthe global spread of HCV. METHODS AND FINDINGS We show that the rarely sequenced HCV region(E2P7NS2) is more informative for molecular epidemiology studies than the more commonly used NS5Bregion. We applied phylodynamic methods to a substantial set of new E2P7NS2 and NS5B sequences,together with all available global HCV sequences with information in both of these genomic regions, inorder to estimate the timescale and nature of the global expansion of the most prevalent HCV subtypes,1a and 1b. We showed that transmission of subtypes 1a and 1b \"exploded\" between 1940 and 1980, withthe spread of 1b preceding that of 1a by at least 16 y (95% confidence interval 15-17). Phylogeographicanalysis of all available NS5B sequences suggests that HCV subtypes 1a and 1b disseminated from thedeveloped world to the developing countries. CONCLUSIONS The evolutionary rate of HCV appears fasterthan previously suggested. The global spread of HCV coincided with the widespread use of transfusedblood and blood products and with the expansion of intravenous drug use but slowed prior to the wideimplementation of anti-HCV screening. Differences in the transmission routes associated with subtypes 1aand 1b provide an explanation of the relatively earlier expansion of 1b. Our data show that the mostplausible route of the HCV dispersal was from developed countries to the developing world. Please seelater in the article for the Editors' Summary.", "metadata": {}}
+{"_id": "5114940", "title": "", "text": "Pharmacological interventions for smoking cessation: an overview and networkmeta-analysis.BACKGROUND Smoking is the leading preventable cause of illness and premature deathworldwide. Some medications have been proven to help people to quit, with three licensed for thispurpose in Europe and the USA: nicotine replacement therapy (NRT), bupropion, and varenicline. Cytisine(a treatment pharmacologically similar to varenicline) is also licensed for use in Russia and some of theformer socialist economy countries. Other therapies, including nortriptyline, have also been tested foreffectiveness. OBJECTIVES How do NRT, bupropion and varenicline compare with placebo and with eachother in achieving long-term abstinence (six months or longer)? How do the remaining treatmentscompare with placebo in achieving long-term abstinence? How do the risks of adverse and seriousadverse events (SAEs) compare between the treatments, and are there instances where the harms mayoutweigh the benefits? METHODS The overview is restricted to Cochrane reviews, all of which includerandomised trials. Participants are usually adult smokers, but we exclude reviews of smoking cessationfor pregnant women and in particular disease groups or specific settings. We cover nicotine replacementtherapy (NRT), antidepressants (bupropion and nortriptyline), nicotine receptor partial agonists(varenicline and cytisine), anxiolytics, selective type 1 cannabinoid receptor antagonists (rimonabant),clonidine, lobeline, dianicline, mecamylamine, Nicobrevin, opioid antagonists, nicotine vaccines, andsilver acetate. Our outcome for benefit is continuous or prolonged abstinence at least six months from thestart of treatment. Our outcome for harms is the incidence of serious adverse events associated witheach of the treatments. We searched the Cochrane Database of Systematic Reviews (CDSR) in TheCochrane Library, for any reviews with 'smoking' in the title, abstract or keyword fields. The last searchwas conducted in November 2012. We assessed methodological quality using a revised version of theAMSTAR scale. For NRT, bupropion and varenicline we conducted network meta-analyses, comparingeach with the others and with placebo for benefit, and varenicline and bupropion for risks of seriousadverse events. MAIN RESULTS We identified 12 treatment-specific reviews. The analyses covered 267studies, involving 101,804 participants. Both NRT and bupropion were superior to placebo (odds ratios(OR) 1.84; 95% credible interval (CredI) 1.71 to 1.99, and 1.82; 95% CredI 1.60 to 2.06 respectively).Varenicline increased the odds of quitting compared with placebo (OR 2.88; 95% CredI 2.40 to 3.47).Head-to-head comparisons between bupropion and NRT showed equal efficacy (OR 0.99; 95% CredI 0.86to 1.13). Varenicline was superior to single forms of NRT (OR 1.57; 95% CredI 1.29 to 1.91), and tobupropion (OR 1.59; 95% CredI 1.29 to 1.96). Varenicline was more effective than nicotine patch (OR1.51; 95% CredI 1.22 to 1.87), than nicotine gum (OR 1.72; 95% CredI 1.38 to 2.13), and than 'other'NRT (inhaler, spray, tablets, lozenges; OR 1.42; 95% CredI 1.12 to 1.79), but was not more effectivethan combination NRT (OR 1.06; 95% CredI 0.75 to 1.48). Combination NRT also outperformed singleformulations. The four categories of NRT performed similarly against each other, apart from 'other' NRT,which was marginally more effective than NRT gum (OR 1.21; 95% CredI 1.01 to 1.46). Cytisine (anicotine receptor partial agonist) returned positive findings (risk ratio (RR) 3.98; 95% CI 2.01 to 7.87),without significant adverse events or SAEs. Across the 82 included and excluded bupropion trials, ourestimate of six seizures in the bupropion arms versus none in the placebo arms was lower than theexpected rate (1:1000), at about 1:1500. SAE meta-analysis of the bupropion studies demonstrated noexcess of neuropsychiatric (RR 0.88; 95% CI 0.31 to 2.50) or cardiovascular events (RR 0.77; 95% CI0.37 to 1.59). SAE meta-analysis of 14 varenicline trials found no difference between the varenicline andplacebo arms (RR 1.06; 95% CI 0.72 to 1.55), and subgroup analyses detected no significant excess ofneuropsychiatric events (RR 0.53; 95% CI 0.17 to 1.67), or of cardiac events (RR 1.26; 95% CI 0.62 to2.56). Nortriptyline increased the chances of quitting (RR 2.03; 95% CI 1.48 to 2.78). Neithernortriptyline nor bupropion were shown to enhance the effect of NRT compared with NRT alone. Clonidineincreased the chances of quitting (RR 1.63; 95% CI 1.22 to 2.18), but this was offset by adose-dependent rise in adverse events. Mecamylamine in combination with NRT may increase thechances of quitting, but the current evidence is inconclusive. Other treatments failed to demonstrate a", "metadata": {}}
+{"_id": "5116145", "title": "", "text": "A library of yeast transcription factor motifs reveals a widespread function for Rsc3 in targetingnucleosome exclusion at promoters.The sequence specificity of DNA-binding proteins is the primarymechanism by which the cell recognizes genomic features. Here, we describe systematic determination ofyeast transcription factor DNA-binding specificities. We obtained binding specificities for 112 DNA-bindingproteins representing 19 distinct structural classes. One-third of the binding specificities have not beenpreviously reported. Several binding sequences have striking genomic distributions relative totranscription start sites, supporting their biological relevance and suggesting a role in promoterarchitecture. Among these are Rsc3 binding sequences, containing the core CGCG, which are foundpreferentially approximately 100 bp upstream of transcription start sites. Mutation of RSC3 results in adramatic increase in nucleosome occupancy in hundreds of proximal promoters containing a Rsc3 bindingelement, but has little impact on promoters lacking Rsc3 binding sequences, indicating that Rsc3 plays abroad role in targeting nucleosome exclusion at yeast promoters.", "metadata": {}}
+{"_id": "5123516", "title": "", "text": "EphA3 maintains tumorigenicity and is a therapeutic target in glioblastoma multiforme.Significantendeavor has been applied to identify functional therapeutic targets in glioblastoma (GBM) to halt thegrowth of this aggressive cancer. We show that the receptor tyrosine kinase EphA3 is frequentlyoverexpressed in GBM and, in particular, in the most aggressive mesenchymal subtype. Importantly,EphA3 is highly expressed on the tumor-initiating cell population in glioma and appears critically involvedin maintaining tumor cells in a less differentiated state by modulating mitogen-activated protein kinasesignaling. EphA3 knockdown or depletion of EphA3-positive tumor cells reduced tumorigenic potential toa degree comparable to treatment with a therapeutic radiolabelled EphA3-specific monoclonal antibody.These results identify EphA3 as a functional, targetable receptor in GBM.", "metadata": {}}
+{"_id": "5132358", "title": "", "text": "Chimeric antigen receptor-modified T cells for acute lymphoid leukemia.Chimeric antigenreceptor-modified T cells with specificity for CD19 have shown promise in the treatment of chroniclymphocytic leukemia (CLL). It remains to be established whether chimeric antigen receptor T cells haveclinical activity in acute lymphoblastic leukemia (ALL). Two children with relapsed and refractorypre-B-cell ALL received infusions of T cells transduced with anti-CD19 antibody and a T-cell signalingmolecule (CTL019 chimeric antigen receptor T cells), at a dose of 1.4×10(6) to 1.2×10(7) CTL019 cellsper kilogram of body weight. In both patients, CTL019 T cells expanded to a level that was more than1000 times as high as the initial engraftment level, and the cells were identified in bone marrow. Inaddition, the chimeric antigen receptor T cells were observed in the cerebrospinal fluid (CSF), where theypersisted at high levels for at least 6 months. Eight grade 3 or 4 adverse events were noted. Thecytokine-release syndrome and B-cell aplasia developed in both patients. In one child, thecytokine-release syndrome was severe; cytokine blockade with etanercept and tocilizumab was effectivein reversing the syndrome and did not prevent expansion of chimeric antigen receptor T cells or reduceantileukemic efficacy. Complete remission was observed in both patients and is ongoing in one patient at11 months after treatment. The other patient had a relapse, with blast cells that no longer expressedCD19, approximately 2 months after treatment. Chimeric antigen receptor-modified T cells are capable ofkilling even aggressive, treatment-refractory acute leukemia cells in vivo. The emergence of tumor cellsthat no longer express the target indicates a need to target other molecules in addition to CD19 in somepatients with ALL.", "metadata": {}}
+{"_id": "5132461", "title": "", "text": "Extended-connectivity fingerprints.Extended-connectivity fingerprints (ECFPs) are a novel class oftopological fingerprints for molecular characterization. Historically, topological fingerprints weredeveloped for substructure and similarity searching. ECFPs were developed specifically forstructure-activity modeling. ECFPs are circular fingerprints with a number of useful qualities: they can bevery rapidly calculated; they are not predefined and can represent an essentially infinite number ofdifferent molecular features (including stereochemical information); their features represent the presenceof particular substructures, allowing easier interpretation of analysis results; and the ECFP algorithm canbe tailored to generate different types of circular fingerprints, optimized for different uses. While the useof ECFPs has been widely adopted and validated, a description of their implementation has not previouslybeen presented in the literature.", "metadata": {}}
+{"_id": "5137019", "title": "", "text": "Suppressor of cytokine signaling 3 inhibits antiviral IFN-beta signaling to enhance HIV-1 replication inmacrophages.HIV-1 replication within macrophages of the CNS often results in cognitive and motorimpairment, which is known as HIV-associated dementia (HAD) in its most severe form. IFN-betasuppresses viral replication within these cells during early CNS infection, but the effect is transient. HIV-1eventually overcomes this protective innate immune response to resume replication through an unknownmechanism, initiating the progression toward HAD. In this article, we show that Suppressor of CytokineSignaling (SOCS)3, a molecular inhibitor of IFN signaling, may allow HIV-1 to evade innate immunitywithin the CNS. We found that SOCS3 is elevated in an in vivo SIV/macaque model of HAD and that thepattern of expression correlates with recurrence of viral replication and onset of CNS disease. In vitro, theHIV-1 regulatory protein transactivator of transcription induces SOCS3 in human and murinemacrophages in a NF-kappaB-dependent manner. SOCS3 expression attenuates the response ofmacrophages to IFN-beta at proximal levels of pathway activation and downstream antiviral geneexpression and consequently overcomes the inhibitory effect of IFN-beta on HIV-1 replication. Thesestudies indicate that SOCS3 expression, induced by stimuli present in the HIV-1-infected brain, such astransactivator of transcription, inhibits antiviral IFN-beta signaling to enhance HIV-1 replication inmacrophages. This consequence of SOCS3 expression in vitro, supported by a correlation with increasedviral load and onset of CNS disease in vivo, suggests that SOCS3 may allow HIV-1 to evade the protectiveinnate immune response within the CNS, allowing the recurrence of viral replication and, ultimately,promoting progression toward HAD.", "metadata": {}}
+{"_id": "5144381", "title": "", "text": "Molecular model of the human 26S proteasome.The 26S proteasome plays a fundamental role ineukaryotic homeostasis by undertaking the highly controlled degradation of a wide range of proteins,including key cellular regulators such as those controlling cell-cycle progression and apoptosis. Here wereport the structure of the human 26S proteasome determined by cryo-electron microscopy andsingle-particle analysis, with secondary structure elements identified both in the 20S proteolytic coreregion and in the 19S regulatory particle. We have used this information together with crystal structures,homology models, and other biochemical information to construct a molecular model of the complete 26Sproteasome. This model allows for a detailed description of the 20S core within the 26S proteasome andredefines the overall assignment of subunits within the 19S regulatory particle. The informationpresented here provides a strong basis for a mechanistic understanding of the 26S proteasome.", "metadata": {}}
+{"_id": "5145974", "title": "", "text": "Urinary bisphenol A concentrations and early reproductive health outcomes among women undergoingIVF.STUDY QUESTION In women undergoing IVF, are urinary bisphenol A (BPA) concentrationsassociated with ovarian response and early reproductive outcomes, including oocyte maturation andfertilization, Day 3 embryo quality and blastocyst formation? SUMMARY ANSWER Higher urinary BPAconcentrations were found to be associated with decreased ovarian response, number of fertilized oocytesand decreased blastocyst formation. WHAT IS KNOWN ALREADY Experimental animal and in vitro studieshave reported associations between BPA exposure and adverse reproductive outcomes. We previouslyreported an association between urinary BPA and decreased ovarian response [peak serum estradiol(E(2)) and oocyte count at the time of retrieval] in women undergoing IVF; however, there are limitedhuman data on reproductive health outcomes, such as fertilization and embryo development. STUDYDESIGN, SIZE AND DURATION Prospective preconception cohort study. One hundred and seventy-fourwomen aged 18-45 years and undergoing 237 IVF cycles were recruited at the Massachusetts GeneralHospital Fertility Center, Boston, MA, USA, between November 2004 and August 2010. These womenwere followed until they either had a live birth or discontinued treatment. Cryothaw and donor egg cycleswere not included in the analysis. PARTICIPANTS/MATERIALS, SETTING AND METHODS Urinary BPAconcentrations were measured by online solid-phase extraction-high-performance liquidchromatography-isotope dilution-tandem mass spectrometry. Mixed effect models, poisson regressionand multivariate logistic regression models were used wherever appropriate to evaluate the associationbetween cycle-specific urinary BPA concentrations and measures of ovarian response, oocyte maturation(metaphase II), fertilization, embryo quality and cleavage rate. We accounted for correlation amongmultiple IVF cycles in the same woman using generalized estimating equations. MAIN RESULTS AND THEROLE OF CHANCE The geometric mean (SD) for urinary BPA concentrations was 1.50 (2.22) µg/l. Afteradjustment for age and other potential confounders (Day 3 serum FSH, smoking, BMI), there was asignificant linear dose-response association between increased urinary BPA concentrations and decreasednumber of oocytes (overall and mature), decreased number of normally fertilized oocytes and decreasedE(2) levels (mean decreases of 40, 253 and 471 pg/ml for urinary BPA quartiles 2, 3 and 4, whencompared with the lowest quartile, respectively; P-value for trend = 0.001). The mean number of oocytesand normally fertilized oocytes decreased by 24 and 27%, respectively, for the highest versus the lowestquartile of urinary BPA (trend test P < 0.001 and 0.002, respectively). Women with urinary BPA abovethe lowest quartile had decreased blastocyst formation (trend test P-value = 0.08). LIMITATIONS ANDREASONS FOR CAUTION Potential limitations include exposure misclassification due to the very shorthalf-life of BPA and its high variability over time; uncertainty about the generalizability of the results tothe general population of women conceiving naturally and limited sample. WIDER IMPLICATIONS OF THEFINDINGS The results from this extended study, using IVF as a model to study early reproductive healthoutcomes in humans, indicate a negative dose-response association between urinary BPA concentrationsand serum peak E(2) and oocyte yield, confirming our previous findings. In addition, we foundsignificantly decreased metaphase II oocyte count and number of normally fertilizing oocytes and asuggestive association between BPA urinary concentrations and decreased blastocyst formation, thusindicating that BPA may alter reproductive function in susceptible women undergoing IVF. STUDYFUNDING/COMPETING INTEREST(S) This work was supported by grants ES009718 and ES000002 fromthe National Institute of Environmental Health Sciences and grant OH008578 from the National Institutefor Occupational Safety and Health. None of the authors has actual or potential competing financialinterests. DISCLAIMER The findings and conclusions in this report are those of the authors and do notnecessarily represent the views of the Centers for Disease Control and Prevention.", "metadata": {}}
+{"_id": "5151024", "title": "", "text": "Cost-effectiveness of options for the diagnosis of high blood pressure in primary care: a modellingstudy.BACKGROUND The diagnosis of hypertension has traditionally been based on blood-pressuremeasurements in the clinic, but home and ambulatory measurements better correlate with cardiovascularoutcome, and ambulatory monitoring is more accurate than both clinic and home monitoring indiagnosing hypertension. We aimed to compare the cost-effectiveness of different diagnostic strategiesfor hypertension. METHODS We did a Markov model-based probabilistic cost-effectiveness analysis. Weused a hypothetical primary-care population aged 40 years or older with a screening blood-pressuremeasurement greater than 140/90 mm Hg and risk-factor prevalence equivalent to the generalpopulation. We compared three diagnostic strategies-further blood pressure measurement in the clinic, athome, and with an ambulatory monitor-in terms of lifetime costs, quality-adjusted life years, andcost-effectiveness. FINDINGS Ambulatory monitoring was the most cost-effective strategy for thediagnosis of hypertension for men and women of all ages. It was cost-saving for all groups (from -£56[95% CI -105 to -10] in men aged 75 years to -£323 [-389 to -222] in women aged 40 years) andresulted in more quality-adjusted life years for men and women older than 50 years (from 0·006 [0·000to 0·015] for women aged 60 years to 0·022 [0·012 to 0·035] for men aged 70 years). This finding wasrobust when assessed with a wide range of deterministic sensitivity analyses around the base case, butwas sensitive if home monitoring was judged to have equal test performance to ambulatory monitoring orif treatment was judged effective irrespective of whether an individual was hypertensive.INTERPRETATION Ambulatory monitoring as a diagnostic strategy for hypertension after an initial raisedreading in the clinic would reduce misdiagnosis and save costs. Additional costs from ambulatorymonitoring are counterbalanced by cost savings from better targeted treatment. Ambulatory monitoringis recommended for most patients before the start of antihypertensive drugs. FUNDING National Institutefor Health Research and the National Institute for Health and Clinical Excellence.", "metadata": {}}
+{"_id": "5152028", "title": "", "text": "Folic acid improves endothelial function in coronary artery disease via mechanisms largely independent ofhomocysteine lowering.BACKGROUND Homocysteine is a risk factor for coronary artery disease (CAD),although a causal relation remains to be proven. The importance of determining direct causality rests inthe fact that plasma homocysteine can be safely and inexpensively reduced by 25% with folic acid. Thisreduction is maximally achieved by doses of 0.4 mg/d. High-dose folic acid (5 mg/d) improves endothelialfunction in CAD, although the mechanism is controversial. It has been proposed that improvement occursthrough reduction in total (tHcy) or free (non-protein bound) homocysteine (fHcy). We investigated theeffects of folic acid on endothelial function before a change in homocysteine in patients with CAD.METHODS AND RESULTS A randomized, placebo-controlled study of folic acid (5 mg/d) for 6 weeks wasundertaken in 33 patients. Endothelial function, assessed by flow-mediated dilatation (FMD), wasmeasured before, at 2 and 4 hours after the first dose of folic acid, and after 6 weeks of treatment.Plasma folate increased markedly by 1 hour (200 compared with 25.8 nmol/L; P<0.001). FMD improvedat 2 hours (83 compared with 47 microm; P<0.001) and was largely complete by 4 hours (101 comparedwith 51 microm; P<0.001). tHcy did not significantly differ acutely (4-hour tHcy, 9.56 compared with9.79 micromol/L; P=NS). fHcy did not differ at 3 hours but was slightly reduced at 4 hours (1.55compared with 1.78 micromol/L; P=0.02). FMD improvement did not correlate with reductions in eitherfHcy or tHcy at any time. CONCLUSIONS These data suggest that folic acid improves endothelial functionin CAD acutely by a mechanism largely independent of homocysteine.", "metadata": {}}
+{"_id": "5172048", "title": "", "text": "Focal adhesion kinase links mechanical force to skin fibrosis via inflammatory signalingExuberantfibroproliferation is a common complication after injury for reasons that are not well understood. One keycomponent of wound repair that is often overlooked is mechanical force, which regulates cell-matrixinteractions through intracellular focal adhesion components, including focal adhesion kinase (FAK). Herewe report that FAK is activated after cutaneous injury and that this process is potentiated by mechanicalloading. Fibroblast-specific FAK knockout mice have substantially less inflammation and fibrosis thancontrol mice in a model of hypertrophic scar formation. We show that FAK acts throughextracellular-related kinase (ERK) to mechanically trigger the secretion of monocyte chemoattractantprotein-1 (MCP-1, also known as CCL2), a potent chemokine that is linked to human fibrotic disorders.Similarly, MCP-1 knockout mice form minimal scars, indicating that inflammatory chemokine pathwaysare a major mechanism by which FAK mechanotransduction induces fibrosis. Small-molecule inhibition ofFAK blocks these effects in human cells and reduces scar formation in vivo through attenuated MCP-1signaling and inflammatory cell recruitment. These findings collectively indicate that physical forceregulates fibrosis through inflammatory FAK–ERK–MCP-1 pathways and that molecular strategiestargeting FAK can effectively uncouple mechanical force from pathologic scar formation.", "metadata": {}}
+{"_id": "5185871", "title": "", "text": "Prognostic Accuracy of the SOFA Score, SIRS Criteria, and qSOFA Score for In-Hospital Mortality AmongAdults With Suspected Infection Admitted to the Intensive Care UnitImportance The Sepsis-3 Criteriaemphasized the value of a change of 2 or more points in the Sequential [Sepsis-related] Organ FailureAssessment (SOFA) score, introduced quick SOFA (qSOFA), and removed the systemic inflammatoryresponse syndrome (SIRS) criteria from the sepsis definition. Objective Externally validate and assess thediscriminatory capacities of an increase in SOFA score by 2 or more points, 2 or more SIRS criteria, or aqSOFA score of 2 or more points for outcomes among patients who are critically ill with suspectedinfection. Design, Setting, and Participants Retrospective cohort analysis of 184 875 patients with aninfection-related primary admission diagnosis in 182 Australian and New Zealand intensive care units(ICUs) from 2000 through 2015. Exposures SOFA, qSOFA, and SIRS criteria applied to data collectedwithin 24 hours of ICU admission. Main Outcomes and Measures The primary outcome was in-hospitalmortality. In-hospital mortality or ICU length of stay (LOS) of 3 days or more was a composite secondaryoutcome. Discrimination was assessed using the area under the receiver operating characteristic curve(AUROC). Adjusted analyses were performed using a model of baseline risk determined using variablesindependent of the scoring systems. Results Among 184 875 patients (mean age, 62.9 years [SD, 17.4];women, 82 540 [44.6%]; most common diagnosis bacterial pneumonia, 32 634 [17.7%]), a total of 34578 patients (18.7%) died in the hospital, and 102 976 patients (55.7%) died or experienced an ICU LOSof 3 days or more. SOFA score increased by 2 or more points in 90.1%; 86.7% manifested 2 or moreSIRS criteria, and 54.4% had a qSOFA score of 2 or more points. SOFA demonstrated significantlygreater discrimination for in-hospital mortality (crude AUROC, 0.753 [99% CI, 0.750-0.757]) than SIRScriteria (crude AUROC, 0.589 [99% CI, 0.585-0.593]) or qSOFA (crude AUROC, 0.607 [99% CI,0.603-0.611]). Incremental improvements were 0.164 (99% CI, 0.159-0.169) for SOFA vs SIRS criteriaand 0.146 (99% CI, 0.142-0.151) for SOFA vs qSOFA (P <.001). SOFA (AUROC, 0.736 [99% CI,0.733-0.739]) outperformed the other scores for the secondary end point (SIRS criteria: AUROC, 0.609[99% CI, 0.606-0.612]; qSOFA: AUROC, 0.606 [99% CI, 0.602-0.609]). Incremental improvementswere 0.127 (99% CI, 0.123-0.131) for SOFA vs SIRS criteria and 0.131 (99% CI, 0.127-0.134) for SOFAvs qSOFA (P <.001). Findings were consistent for both outcomes in multiple sensitivity analyses.Conclusions and Relevance Among adults with suspected infection admitted to an ICU, an increase inSOFA score of 2 or more had greater prognostic accuracy for in-hospital mortality than SIRS criteria orthe qSOFA score. These findings suggest that SIRS criteria and qSOFA may have limited utility forpredicting mortality in an ICU setting.", "metadata": {}}
+{"_id": "5222182", "title": "", "text": "Predictors of mammographic density: insights gained from a novel regression analysis of a twinstudy.Understanding which factors influence mammographically dense and nondense areas is importantbecause percent mammographic density adjusted for age is a strong, continuously distributed risk factorfor breast cancer, especially when adjusted for weight or body mass index. Using computer-assistedmethods, we measured mammographically dense areas for 571 monozygotic and 380 dizygotic Australianand North American twin pairs ages 40 to 70 years. We used a novel regression modeling approach inwhich each twin's measure of dense and nondense area was regressed against one or both of the twin'sand co-twin's covariates. The nature of changes to regression estimates with the inclusion of the twinand/or co-twin's covariates can be evaluated for consistency with causal and/or other models. By causal,we mean that if it were possible to vary a covariate experimentally then the expected value of theoutcome measure would change. After adjusting for the individual's weight, the co-twin associations withweight were attenuated, consistent with a causal effect of weight on mammographic measures, which inabsolute log cm(2)/kg was thrice stronger for nondense than dense area. After adjusting for weight, laterage at menarche, and greater height were associated with greater dense and lesser nondense areas in amanner inconsistent with causality. The associations of dense and nondense areas with parity areconsistent with a causal effect and/or within-person confounding. The associations betweenmammographic density measures and height are consistent with shared early life environmental factorsthat predispose to both height and percent mammographic density and possibly breast cancer risk.", "metadata": {}}
+{"_id": "5223817", "title": "", "text": "Shaping the landscape of the Escherichia coli chromosome: replication-transcription encounters in cellswith an ectopic replication originEach cell division requires the unwinding of millions of DNA base pairs toallow chromosome duplication and gene transcription. As DNA replication and transcription share thesame template, conflicts between both processes are unavoidable and head-on collisions are thought tobe particularly problematic. Surprisingly, a recent study reported unperturbed cell cycle progression inEscherichia coli cells with an ectopic replication origin in which highly transcribed rrn operons were forcedto be replicated opposite to normal. In this study we have re-generated a similar strain and found thedoubling time to be twice that of normal cells. Replication profiles of this background revealed significantdeviations in comparison to wild-type profiles, particularly in highly transcribed regions and thetermination area. These deviations were alleviated by mutations that either inactivate the terminationarea or destabilise RNA polymerase complexes and allow their easier displacement by replication forks.Our data demonstrate that head-on replication-transcription conflicts are highly problematic. Indeed,analysis of the replication profile of the previously published E. coli construct revealed a chromosomalrearrangement that alleviates replication-transcription conflicts in an intriguingly simple way. Our datasupport the idea that avoiding head-on collisions has significantly contributed to shaping the distinctarchitecture of bacterial chromosomes.", "metadata": {}}
+{"_id": "5236443", "title": "", "text": "Epithelial–mesenchymal transitions in tumour progressionWithout epithelial–mesenchymal transitions, inwhich polarized epithelial cells are converted into motile cells, multicellular organisms would be incapableof getting past the blastula stage of embryonic development. However, this important developmentalprogramme has a more sinister role in tumour progression. Epithelial–mesenchymal transition provides anew basis for understanding the progression of carcinoma towards dedifferentiated and more malignantstates.", "metadata": {}}
+{"_id": "5238341", "title": "", "text": "Platelets at the interface of thrombosis, inflammation, and cancer.Although once primarily recognized forits roles in hemostasis and thrombosis, the platelet has been increasingly recognized as a multipurposecell. Indeed, circulating platelets have the ability to influence a wide range of seemingly unrelatedpathophysiologic events. Here, we highlight some of the notable observations that link platelets toinflammation, reinforcing the platelet's origin from a lower vertebrate cell type with both hemostatic andimmunologic roles. In addition, we consider the relevance of platelets in cancer biology by focusing on thehallmarks of cancer and the ways platelets can influence multistep development of tumors. Beyond itstraditional role in hemostasis and thrombosis, the platelet's involvement in the interplay betweenhemostasis, thrombosis, inflammation, and cancer is likely complex, yet extremely important in eachdisease process. The existence of animal models of platelet dysfunction and currently used antiplatelettherapies provide a framework for understanding mechanistic insights into a wide range ofpathophysiologic events. Thus, the basic scientist studying platelet function can think beyond thetraditional hemostasis and thrombosis paradigms, while the practicing hematologist must appreciateplatelet relevance in a wide range of disease processes.", "metadata": {}}
+{"_id": "5252837", "title": "", "text": "Cellular roles of DNA topoisomerases: a molecular perspectiveDNA topoisomerases are the magicians ofthe DNA world — by allowing DNA strands or double helices to pass through each other, they can solve allof the topological problems of DNA in replication, transcription and other cellular transactions. Extensivebiochemical and structural studies over the past three decades have provided molecular models of howthe various subfamilies of DNA topoisomerase manipulate DNA. In this review, the cellular roles of theseenzymes are examined from a molecular point of view.", "metadata": {}}
+{"_id": "5253987", "title": "", "text": "MicroRNA sponges: progress and possibilities.The microRNA (miRNA) \"sponge\" method was introducedthree years ago as a means to create continuous miRNA loss of function in cell lines and transgenicorganisms. Sponge RNAs contain complementary binding sites to a miRNA of interest, and are producedfrom transgenes within cells. As with most miRNA target genes, a sponge's binding sites are specific tothe miRNA seed region, which allows them to block a whole family of related miRNAs. This transgenicapproach has proven to be a useful tool to probe miRNA functions in a variety of experimental systems.Here we will discuss the ways sponge and related constructs can be optimized and review recentapplications of this method with particular emphasis on stable expression in cancer studies and intransgenic animals.", "metadata": {}}
+{"_id": "5254463", "title": "", "text": "Wip1 phosphatase regulates p53-dependent apoptosis of stem cells and tumorigenesis in the mouseintestine.Colorectal cancer is one of the major causes of cancer-related deaths. To gain further insightsinto the mechanisms underlying its development, we investigated the role of Wip1 phosphatase, which ishighly expressed in intestinal stem cells, in the mouse model of APC(Min)-driven polyposis. We found thatWip1 removal increased the life span of APC(Min) mice through a significant suppression of polypformation. This protection was dependent on the p53 tumor suppressor, which plays a putative role in theregulation of apoptosis of intestinal stem cells. Activation of apoptosis in stem cells of Wip1-deficientmice, but not wild-type APC(Min) mice, increased when the Wnt pathway was constitutively activated. Wepropose, therefore, that the Wip1 phosphatase regulates homeostasis of intestinal stem cells. In turn,Wip1 loss suppresses APC(Min)-driven polyposis by lowering the threshold for p53-dependent apoptosisof stem cells, thus preventing their conversion into tumor-initiating stem cells.", "metadata": {}}
+{"_id": "5254741", "title": "", "text": "The shunt problem: control of functional shunting in normal and tumour vasculatureNetworks of bloodvessels in normal and tumour tissues have heterogeneous structures, with widely varying blood flowpathway lengths. To achieve efficient blood flow distribution, mechanisms for the structural adaptation ofvessel diameters must be able to inhibit the formation of functional shunts (whereby short pathwaysbecome enlarged and flow bypasses long pathways). Such adaptation requires information about tissuemetabolic status to be communicated upstream to feeding vessels, through conducted responses. Wepropose that impaired vascular communication in tumour microvascular networks, leading to functionalshunting, is a primary cause of dysfunctional microcirculation and local hypoxia in cancer. We suggestthat anti-angiogenic treatment of tumours may restore vascular communication and thereby improve ornormalize flow distribution in tumour vasculature.", "metadata": {}}
+{"_id": "5256564", "title": "", "text": "Pharmacological Blockade of ASCT2-dependent Glutamine Transport Leads To Anti-tumor Efficacy inPreclinical ModelsThe unique metabolic demands of cancer cells underscore potentially fruitfulopportunities for drug discovery in the era of precision medicine. However, therapeutic targeting ofcancer metabolism has led to surprisingly few new drugs to date. The neutral amino acid glutamineserves as a key intermediate in numerous metabolic processes leveraged by cancer cells, includingbiosynthesis, cell signaling, and oxidative protection. Herein we report the preclinical development ofV-9302, a competitive small molecule antagonist of transmembrane glutamine flux that selectively andpotently targets the amino acid transporter ASCT2. Pharmacological blockade of ASCT2 with V-9302resulted in attenuated cancer cell growth and proliferation, increased cell death, and increased oxidativestress, which collectively contributed to antitumor responses in vitro and in vivo. This is the first study, toour knowledge, to demonstrate the utility of a pharmacological inhibitor of glutamine transport inoncology, representing a new class of targeted therapy and laying a framework for paradigm-shiftingtherapies targeting cancer cell metabolism.", "metadata": {}}
+{"_id": "5260382", "title": "", "text": "An Antidepressant Decreases CSF Aβ Production in Healthy Individuals and in Transgenic ADMiceSerotonin signaling suppresses generation of amyloid-β (Aβ) in vitro and in animal models ofAlzheimer’s disease (AD). We show that in an aged transgenic AD mouse model (APP/PS1 plaque-bearingmice), the antidepressant citalopram, a selective serotonin reuptake inhibitor, decreased Aβ in braininterstitial fluid in a dose-dependent manner. Growth of individual amyloid plaques was assessed inplaque-bearing mice that were chronically administered citalopram. Citalopram arrested the growth ofpreexisting plaques and reduced the appearance of new plaques by 78%. In healthy human volunteers,citalopram’s effects on Aβ production and Aβ concentrations in cerebrospinal fluid (CSF) were measuredprospectively using stable isotope labeling kinetics, with CSF sampling during acute dosing of citalopram.Aβ production in CSF was slowed by 37% in the citalopram group compared to placebo. This change wasassociated with a 38% decrease in total CSF Aβ concentrations in the drug-treated group. The ability tosafely decrease Aβ concentrations is potentially important as a preventive strategy for AD. This studydemonstrates key target engagement for future AD prevention trials.", "metadata": {}}
+{"_id": "5262240", "title": "", "text": "Variations in the quality and sustainability of long-term glycaemic control with continuous subcutaneousinsulin infusion.AIMS To investigate the pattern of changes in HbA1c in people with Type 1 diabetesmanaged by long-term Continuous subcutaneous insulin infusion. METHODS We studied HbA1c changesusing computerized clinic records in 35 adult people with Type 1 diabetes and an elevated HbA1c (≥ 64mmol/mol, 8.0%) on multiple daily insulin injections, who were then switched to continuoussubcutaneous insulin infusion for at least 5 years. RESULTS We identified three subgroups with similarbaseline HbA1c but different long-term responses to pump therapy: group A--those with improvementfollowed by deterioration (57%); group B--those with improvement that was sustained throughout the 5years (31%); and group C-those where HbA1c did not change significantly from baseline (12%). Thepatients in group C had a higher BMI: 31.0 ± 5.2 vs. 25.9 ± 3.3 vs. 25.2 ± 3.1 kg/m² (group C vs. groupA and group B; P = 0.02). CONCLUSIONS Improved glycaemic control with continuous subcutaneousinsulin infusion was maintained over 5 years by 88% of people with Type 1 diabetes in this study, butthere were variations in the long-term efficacy, with some people improving and worsening, othersmaintaining strict control and a few subcutaneous insulin infusion 'non-responders'.", "metadata": {}}
+{"_id": "5266423", "title": "", "text": "Historical review: megakaryopoiesis and thrombopoiesis.The study of thrombopoiesis has evolved greatlysince an era when platelets were termed \"the dust of the blood,\" only about 100 years ago. During thistime megakaryocytes were identified as the origin of blood platelets; marrow-derived megakaryocyticprogenitor cells were functionally defined and then purified; and the primary regulator of the process,thrombopoietin, was cloned and characterized and therapeutic thrombopoietic agents developed. Duringthis journey we continue to learn that the physiologic mechanisms that drive proplatelet formation can berecapitulated in cell-free systems and their biochemistry evaluated; the molecular underpinnings ofendomitosis are being increasingly understood; the intracellular signals sent by engagement of a largenumber of megakaryocyte surface receptors have been defined; and many of the transcription factorsthat drive megakaryocytic fate determination have been identified and experimentally manipulated. Whilesome of these biologic processes mimic those seen in other cell types, megakaryocytes and plateletspossess enough unique developmental features that we are virtually assured that continued study ofthrombopoiesis will yield innumerable clinical and scientific insights for many decades to come.", "metadata": {}}
+{"_id": "5268462", "title": "", "text": "Obesity and Its Metabolic Complications: The Role of Adipokines and the Relationship between Obesity,Inflammation, Insulin Resistance, Dyslipidemia and Nonalcoholic Fatty Liver DiseaseAccumulatingevidence indicates that obesity is closely associated with an increased risk of metabolic diseases such asinsulin resistance, type 2 diabetes, dyslipidemia and nonalcoholic fatty liver disease. Obesity results froman imbalance between food intake and energy expenditure, which leads to an excessive accumulation ofadipose tissue. Adipose tissue is now recognized not only as a main site of storage of excess energyderived from food intake but also as an endocrine organ. The expansion of adipose tissue produces anumber of bioactive substances, known as adipocytokines or adipokines, which trigger chronic low-gradeinflammation and interact with a range of processes in many different organs. Although the precisemechanisms are still unclear, dysregulated production or secretion of these adipokines caused by excessadipose tissue and adipose tissue dysfunction can contribute to the development of obesity-relatedmetabolic diseases. In this review, we focus on the role of several adipokines associated with obesity andthe potential impact on obesity-related metabolic diseases. Multiple lines evidence provides valuableinsights into the roles of adipokines in the development of obesity and its metabolic complications.Further research is still required to fully understand the mechanisms underlying the metabolic actions of afew newly identified adipokines.", "metadata": {}}
+{"_id": "5270265", "title": "", "text": "Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistancepathwaysTrastuzumab is a successful rationally designed ERBB2-targeted therapy. However, about halfof individuals with ERBB2-overexpressing breast cancer do not respond to trastuzumab-based therapies,owing to various resistance mechanisms. Clinically applicable regimens for overcoming trastuzumabresistance of different mechanisms are not yet available. We show that the nonreceptor tyrosine kinasec-SRC (SRC) is a key modulator of trastuzumab response and a common node downstream of multipletrastuzumab resistance pathways. We find that SRC is activated in both acquired and de novotrastuzumab-resistant cells and uncover a novel mechanism of SRC regulation involvingdephosphorylation by PTEN. Increased SRC activation conferred considerable trastuzumab resistance inbreast cancer cells and correlated with trastuzumab resistance in patients. Targeting SRC in combinationwith trastuzumab sensitized multiple lines of trastuzumab-resistant cells to trastuzumab and eliminatedtrastuzumab-resistant tumors in vivo, suggesting the potential clinical application of this strategy toovercome trastuzumab resistance.", "metadata": {}}
+{"_id": "5271210", "title": "", "text": "MicroRNAs: new tools for diagnosis, prognosis, and therapy in hepatocellular carcinoma?MicroRNAs(miRNAs) are evolutionarily conserved small noncoding RNAs involved in the regulation of geneexpression and protein translation. Many studies have shown that they play a crucial role in driving organand tissue differentiation during embryogenesis and in the fine-tuning of fundamental biologicalprocesses, such as proliferation and apoptosis. Growing evidence indicates that their deregulation playsan important role in cancer onset and progression as well, where they act as oncogenes oroncosuppressors. In this review, we highlight the most recent findings regarding the role of miRNAs inhepatocellular carcinoma (HCC) by analyzing the possible mechanisms by which they contribute to thisneoplasm. Moreover, we discuss the possible role of circulating miRNAs as biomarkers, a field that needsurgent improvement in the clinical surveillance of HCC, and the fascinating possibility of using them astherapeutic targets or drugs themselves.", "metadata": {}}
+{"_id": "5273056", "title": "", "text": "A vertebrate gene, ticrr, is an essential checkpoint and replication regulator.Eukaryotes have numerouscheckpoint pathways to protect genome fidelity during normal cell division and in response to DNAdamage. Through a screen for G2/M checkpoint regulators in zebrafish, we identified ticrr (forTopBP1-interacting, checkpoint, and replication regulator), a previously uncharacterized gene that isrequired to prevent mitotic entry after treatment with ionizing radiation. Ticrr deficiency isembryonic-lethal in the absence of exogenous DNA damage because it is essential for normal cell cycleprogression. Specifically, the loss of ticrr impairs DNA replication and disrupts the S/M checkpoint,leading to premature mitotic entry and mitotic catastrophe. We show that the human TICRR orthologassociates with TopBP1, a known checkpoint protein and a core component of the DNA replicationpreinitiation complex (pre-IC), and that the TICRR-TopBP1 interaction is stable without chromatin andrequires BRCT motifs essential for TopBP1's replication and checkpoint functions. Most importantly, wefind that ticrr deficiency disrupts chromatin binding of pre-IC, but not prereplication complex,components. Taken together, our data show that TICRR acts in association with TopBP1 and plays anessential role in pre-IC formation. It remains to be determined whether Ticrr represents the vertebrateortholog of the yeast pre-IC component Sld3, or a hitherto unknown metazoan replication and checkpointregulator.", "metadata": {}}
+{"_id": "5278233", "title": "", "text": "A maternally methylated CpG island in KvLQT1 is associated with an antisense paternal transcript andloss of imprinting in Beckwith-Wiedemann syndrome.Loss of imprinting at IGF2, generally through anH19-independent mechanism, is associated with a large percentage of patients with the overgrowth andcancer predisposition condition Beckwith-Wiedemann syndrome (BWS). Imprinting control elements areproposed to exist within the KvLQT1 locus, because multiple BWS-associated chromosomerearrangements disrupt this gene. We have identified an evolutionarily conserved, maternally methylatedCpG island (KvDMR1) in an intron of the KvLQT1 gene. Among 12 cases of BWS with normal H19methylation, 5 showed demethylation of KvDMR1 in fibroblast or lymphocyte DNA; whereas, in 4 cases ofBWS with H19 hypermethylation, methylation at KvDMRl was normal. Thus, inactivation of H19 andhypomethylation at KvDMR1 (or an associated phenomenon) represent distinct epigenetic anomaliesassociated with biallelic expression of IGF2. Reverse transcription-PCR analysis of the human andsyntenic mouse loci identified the presence of a KvDMR1-associated RNA transcribed exclusively from thepaternal allele and in the opposite orientation with respect to the maternally expressed KvLQT1 gene. Wepropose that KvDMR1 and/or its associated antisense RNA (KvLQT1-AS) represents an additionalimprinting control element or center in the human 11p15.5 and mouse distal 7 imprinted domains.", "metadata": {}}
+{"_id": "5284188", "title": "", "text": "Alarming levels of drug-resistant tuberculosis in Belarus: results of a survey in MinskResistance toanti-tuberculosis (TB) medicines is a major public health threat in most countries of the former SovietUnion. As no representative and quality-assured information on the magnitude of this problem existed inBelarus, a survey was conducted in the capital city of Minsk. Between November 2009 and December2010, 156 consecutively diagnosed new and 68 previously treated culture-positive TB patients residing inMinsk were enrolled in the survey. Mycobacterium tuberculosis isolates were obtained from each patientand tested for susceptibility to first- and second-line anti-TB drugs. Multidrug-resistant (MDR)-TB wasfound in 35.3% (95% CI 27.7-42.8) of new patients and 76.5% (95% CI 66.1-86.8) of those previouslytreated. Overall, nearly one in two patients enrolled had MDR-TB. Extensively drug-resistant TB wasreported in 15 of the 107 MDR-TB patients (14.0%, 95% CI 7.3-20.7). Patients <35 yrs of age haveshown a two times higher odds ratio of multidrug-resistant TB than those aged >35 yrs. The findings ofthis survey in Minsk city are alarming and represent the highest proportions of MDR-TB ever recorded inthe world. This study greatly contributes to the understanding of the burden of drug-resistant TB in urbanareas of Belarus.", "metadata": {}}
+{"_id": "5289038", "title": "", "text": "Partitioning regulatory mechanisms of within-host malaria dynamics using the effective propagationnumber.Immune clearance and resource limitation (via red blood cell depletion) shape the peaks andtroughs of malaria parasitemia, which in turn affect disease severity and transmission. Quantitativelypartitioning the relative roles of these effects through time is challenging. Using data from rodentmalaria, we estimated the effective propagation number, which reflects the relative importance ofcontrasting within-host control mechanisms through time and is sensitive to the inoculating parasitedose. Our analysis showed that the capacity of innate responses to restrict initial parasite growthsaturates with parasite dose and that experimentally enhanced innate immunity can affect parasitedensity indirectly via resource depletion. Such a statistical approach offers a tool to improve targeting ofdrugs or vaccines for human therapy by revealing the dynamics and interactions of within-host regulatorymechanisms.", "metadata": {}}
+{"_id": "5293024", "title": "", "text": "Life is sweet: candy consumption and longevity.Our attitude towards candy—“if it tastes that good, itcan't be healthy”—betrays society's puritanical stance towards pleasure. Candy has been blamed forvarious ills, including hyperactivity in children; however, clinical trials have not supportedthis.1  Candy—sugar confectionery and chocolate—is not a recent invention: the ancient Arabs, Chinese,and Egyptians candied fruits and nuts in honey, and the Aztecs made a chocolate drink from the bean ofthe cacao tree. Today, Americans gratify themselves with, on average, 5.4 kg of sugar candy and 6.5 kgof chocolate per person annually.2  Since candy has existed for centuries, we surmised that it cannot betotally unhealthy. We decided to investigate whether candy consumption was associated with longevity.Subjects were from the Harvard alumni health study, an ongoing study of men entering HarvardUniversity as undergraduates between 1916 and 1950. We included 7841 men, free of cardiovasculardisease and cancer, who responded to a health survey …", "metadata": {}}
+{"_id": "5304891", "title": "", "text": "Inter-individual variability and genetic influences on cytokine responses to bacteria and fungiLittle isknown about the inter-individual variation of cytokine responses to different pathogens in healthyindividuals. To systematically describe cytokine responses elicited by distinct pathogens and to determinethe effect of genetic variation on cytokine production, we profiled cytokines produced by peripheral bloodmononuclear cells from 197 individuals of European origin from the 200 Functional Genomics (200FG)cohort in the Human Functional Genomics Project (http://www.humanfunctionalgenomics.org), obtainedover three different years. We compared bacteria- and fungi-induced cytokine profiles and found thatmost cytokine responses were organized around a physiological response to specific pathogens, ratherthan around a particular immune pathway or cytokine. We then correlated genome-widesingle-nucleotide polymorphism (SNP) genotypes with cytokine abundance and identified six cytokinequantitative trait loci (QTLs). Among them, a cytokine QTL at the NAA35-GOLM1 locus markedlymodulated interleukin (IL)-6 production in response to multiple pathogens and was associated withsusceptibility to candidemia. Furthermore, the cytokine QTLs that we identified were enriched amongSNPs previously associated with infectious diseases and heart diseases. These data reveal and begin toexplain the variability in cytokine production by human immune cells in response to pathogens.", "metadata": {}}
+{"_id": "5321708", "title": "", "text": "Integrins promote cytokinesis through the RSK signaling axis.Cytokinesis is the final stage in cell division.Although integrins can regulate cytokinesis, the mechanisms involved are not fully understood. In thisstudy, we demonstrate that integrin-regulated ERK (extracellular signal-related kinase) and RSK (p90ribosomal S6 kinase) signaling promotes successful cytokinesis. Inhibiting the activation of ERK and RSKin CHO cells by a mutation in the integrin β1 cytoplasmic tail or with pharmacological inhibitors results inthe accumulation of cells with midbodies and the formation of binucleated cells. Activation of ERK andRSK signaling by the expression of constitutively active RAF1 suppresses the mutant phenotype in aRSK-dependent manner. Constitutively active RSK2 also restores cytokinesis inhibited by the mutantintegrin. Importantly, the regulatory role of the RSK pathway is not specific to CHO cells. MCF-10Ahuman mammary epithelial cells and HPNE human pancreatic ductal epithelial cells exhibit a similardependence on RSK for successful cytokinesis. In addition, depriving mitotic MCF10A cells ofintegrin-mediated adhesion by incubating them in suspension suppressed ERK and RSK activation andresulted in a failure of cytokinesis. Furthermore, inhibition of RSK or integrins within the 3D context of adeveloping salivary gland organ explant also leads to an accumulation of epithelial cells with midbodies,suggesting a similar defect in cytokinesis. Interestingly, neither ERK nor RSK regulates cytokinesis inhuman fibroblasts, suggesting cell-type specificity. Taken together, our results identify the integrin-RSKsignaling axis as an important regulator of cytokinesis in epithelial cells. We propose that the properinteraction of cells with their microenvironment through integrins contributes to the maintenance ofgenomic stability by promoting the successful completion of cytokinesis.", "metadata": {}}
+{"_id": "5323845", "title": "", "text": "Sympathetic neural mechanisms in normal and hypertensive pregnancy in humans.BACKGROUND Directrecordings from peripheral sympathetic nerves have shown an increased sympathetic drive inpregnancy-induced hypertension (PIH) and preeclampsia (PE). It is unknown whether sympathetic driveis altered in normal pregnancy, when arterial blood pressure can be normal or relatively low. The aim ofthis study was to measure and compare peripheral sympathetic discharge, its vasoconstrictor effect andits baroreceptor control, during pregnancy and postpartum in women with normal pregnancy (NP) andPIH and in normotensive nonpregnant (NN) women. METHODS AND RESULTS Twenty-one women withNP, 18 women with PIH, and 21 NN women had muscle sympathetic nerve activity assessed frommultiunit discharges (MSNA) and from single units with defined vasoconstrictor properties (s-MSNA). Thes-MSNA in NP (38+/-6.6 impulses/100 beats) was greater (P<0.05) than in NN women (19+/-1.8impulses/100 beats) despite similar age and body weight but less than in PIH women (P<0.001)(146+/-23.5 impulses/100 beats). MSNA followed a similar trend. Cardiac baroreceptor reflex sensitivity(BRS) was impaired in NP and PIH women relative to NN. After delivery, sympathetic activity decreasedto values similar to those obtained in NN, and there was an increase in BRS. In women with NP, thedecrease in sympathetic output occurred despite an insignificant change in blood pressure.CONCLUSIONS Central sympathetic output was increased in women with normal pregnancy and was evengreater in the hypertensive pregnant group. The findings suggest that the moderate sympathetichyperactivity during the latter months of normal pregnancy may help to return the arterial pressure tononpregnant levels, although when the increase in activity is excessive, hypertension may ensue.", "metadata": {}}
+{"_id": "5339554", "title": "", "text": "Barriers to recruiting urban African American women into research studies in community settings.Thisqualitative study identified barriers to African American women's participation in a community-basedbehavioral intervention trial to increase mammography screening. Four themes emerged from focusgroup discussions with community agency providers and research team members. These themes were(1) going to the gatekeepers; (2) knowing the culture; (3) location is everything; and (4) protocols,policies, and possibilities. A checklist of actions that nurse researchers could consider to increase AfricanAmerican women's participation in community trials is provided.", "metadata": {}}
+{"_id": "5372432", "title": "", "text": "Geographical access to healthcare in Northern England and post-mortem diagnosis ofcancer.BACKGROUND There is some previous evidence that diagnosis of cancer at death, recorded asregistry death certificate only records, is associated with problems of access to care. METHODS Recordsfrom the Northern and Yorkshire Cancer Registry for patients registered with breast, colorectal, lung,ovarian or prostate cancer between 1994 and 2002 were supplemented with measures of travel time togeneral practitioner and hospital services, and social deprivation. Logistic regression was used to identifypredictors of records where diagnosis was at death. RESULTS There was no association between the oddsdiagnosis at death and access to primary care. For all sites except breast, the highest odds of being acancer diagnosed at death fell among those living in the highest quartile of hospital travel time, althoughit was only statistically significant for colorectal and ovary tumours. Those in the most deprived andfurthest travel time to hospital quartile were 2.6 times more likely to be a diagnosis at death casecompared with those in the most affluent and proximal areas. CONCLUSIONS There is some evidencethat poorer geographical access to tertiary care, in particular when coupled with social disadvantages,may be associated with increased odds of diagnosis at death.", "metadata": {}}
+{"_id": "5372773", "title": "", "text": "Enhanced monocyte Fc phagocytosis by a homologue of interleukin-10 encoded by humancytomegalovirus.Human cytomegalovirus (HCMV) expresses several homologues of human interleukin 10(hIL-10) possessing immunomodulatory properties which may promote viral infection by modulating thefunction of myeloid cells. We examined the phenotype and phagocytic capability of human monocytesexposed to hIL-10, an HCMV-encoded hIL-10 homologue expressed during the productive phase ofinfection (cmvIL-10), and a differentially spliced form of cmvIL-10 expressed during latent and productivephases of infection, (LAcmvIL-10). hIL-10 and cmvIL-10 upregulated expression of Fcgamma receptors,stimulated phagocytosis of IgG-opsonised erythrocytes and decreased MHC class II (HLA-DR) expressionon purified monocytes within 24 h. In contrast, LAcmvIL-10 decreased HLA-DR expression at later times(48 h and 72 h) but did not increase Fcgamma receptor expression. We conclude that cmvIL-10 promotesdifferentiation of monocytes towards a pro-phagocytic phenotype and that LAcmvIL-10 does not affectmonocytes by the same mechanism as cmvIL-10. The significance of these properties to cytomegaloviruspathogenesis is discussed.", "metadata": {}}
+{"_id": "5373138", "title": "", "text": "3D Chromosome Regulatory Landscape of Human Pluripotent Cells.In this study, we describe the 3Dchromosome regulatory landscape of human naive and primed embryonic stem cells. To devise this map,we identified transcriptional enhancers and insulators in these cells and placed them within the context ofcohesin-associated CTCF-CTCF loops using cohesin ChIA-PET data. The CTCF-CTCF loops we identifiedform a chromosomal framework of insulated neighborhoods, which in turn form topologically associatingdomains (TADs) that are largely preserved during the transition between the naive and primed states.Regulatory changes in enhancer-promoter interactions occur within insulated neighborhoods during cellstate transition. The CTCF anchor regions we identified are conserved across species, influence geneexpression, and are a frequent site of mutations in cancer cells, underscoring their functional importancein cellular regulation. These 3D regulatory maps of human pluripotent cells therefore provide a foundationfor future interrogation of the relationships between chromosome structure and gene control indevelopment and disease.", "metadata": {}}
+{"_id": "5377059", "title": "", "text": "Functional analysis via standardized whole-blood stimulation systems defines the boundaries of a healthyimmune response to complex stimuli.Standardization of immunophenotyping procedures has become ahigh priority. We have developed a suite of whole-blood, syringe-based assay systems that can be usedto reproducibly assess induced innate or adaptive immune responses. By eliminating preanalytical errorsassociated with immune monitoring, we have defined the protein signatures induced by (1) medicallyrelevant bacteria, fungi, and viruses; (2) agonists specific for defined host sensors; (3) clinicallyemployed cytokines; and (4) activators of T cell immunity. Our results provide an initial assessment ofhealthy donor reference values for induced cytokines and chemokines and we report the failure to releaseinterleukin-1α as a common immunological phenotype. The observed naturally occurring variation of theimmune response may help to explain differential susceptibility to disease or response to therapeuticintervention. The implementation of a general solution for assessment of functional immune responseswill help support harmonization of clinical studies and data sharing.", "metadata": {}}
+{"_id": "5377642", "title": "", "text": "SATB1 Expression Governs Epigenetic Repression of PD\u00001 in Tumor\u0000Reactive T Cells&NA; Despite theimportance of programmed cell death\u00001 (PD\u00001) in inhibiting T cell effector activity, the mechanismsregulating its expression remain poorly defined. We found that the chromatin organizer special AT\u0000richsequence\u0000binding protein\u00001 (Satb1) restrains PD\u00001 expression induced upon T cell activation byrecruiting a nucleosome remodeling deacetylase (NuRD) complex to Pdcd1 regulatory regions. Satb1deficienct T cells exhibited a 40\u0000fold increase in PD\u00001 expression. Tumor\u0000derived transforming growthfactor &bgr; (Tgf\u0000&bgr;) decreased Satb1 expression through binding of Smad proteins to the Satb1promoter. Smad proteins also competed with the Satb1\u0000NuRD complex for binding to Pdcd1 enhancers,releasing Pdcd1 expression from Satb1\u0000mediated repression, Satb1\u0000deficient tumor\u0000reactive T cellslost effector activity more rapidly than wild\u0000type lymphocytes at tumor beds expressing PD\u00001 ligand(CD274), and these differences were abrogated by sustained CD274 blockade. Our findings suggest thatSatb1 functions to prevent premature T cell exhaustion by regulating Pdcd1 expression upon T cellactivation. Dysregulation of this pathway in tumor\u0000infiltrating T cells results in diminished anti\u0000tumorimmunity. Graphical Abstract Figure. No caption available. HighlightsT cell activation increased theexpression of Satb1 in mature CD8+ and CD4+ T cellsRecruitment of the NuRD repression complex bySatb1 inhibits expression of Pdcd1In tumors, TGF\u0000&bgr; inhibits Satb1 expression in T cells, increasingPdcd1 expressionSatb1−/− T cells express high amounts of PD\u00001 and have decreased anti\u0000tumoractivity &NA; Stephen et al. show that the chromatin organizer Satb1 controls expression levels of PD\u00001upon T cell activation through the recruitment of a de\u0000acetylase complex to regulatory regions of thePdcd1 gene. Tumor\u0000derived TGF\u0000&bgr; dysregulates this pathway, unleashing PD\u00001 expression intumor\u0000infiltrating T cells and decreasing anti\u0000tumor immunity.", "metadata": {}}
+{"_id": "5386514", "title": "", "text": "Activation of the NLRP3 inflammasome in dendritic cells induces IL-1β–dependent adaptive immunityagainst tumorsThe therapeutic efficacy of anticancer chemotherapies may depend on dendritic cells(DCs), which present antigens from dying cancer cells to prime tumor-specific interferon-γ(IFN-γ)–producing T lymphocytes. Here we show that dying tumor cells release ATP, which then acts onP2X7 purinergic receptors from DCs and triggers the NOD-like receptor family, pyrin domain containing-3protein (NLRP3)-dependent caspase-1 activation complex ('inflammasome'), allowing for the secretion ofinterleukin-1β (IL-1β). The priming of IFN-γ–producing CD8+ T cells by dying tumor cells fails in theabsence of a functional IL-1 receptor 1 and in Nlpr3-deficient (Nlrp3−/−) or caspase-1–deficient(Casp-1−/−) mice unless exogenous IL-1β is provided. Accordingly, anticancer chemotherapy turned outto be inefficient against tumors established in purinergic receptor P2rx7−/− or Nlrp3−/− or Casp1−/−hosts. Anthracycline-treated individuals with breast cancer carrying a loss-of-function allele of P2RX7developed metastatic disease more rapidly than individuals bearing the normal allele. These resultsindicate that the NLRP3 inflammasome links the innate and adaptive immune responses against dyingtumor cells.", "metadata": {}}
+{"_id": "5389095", "title": "", "text": "Mfge8 promotes obesity by mediating the uptake of dietary fats and serum fatty acidsFatty acids areintegral mediators of energy storage, membrane formation and cell signaling. The pathways thatorchestrate uptake of fatty acids remain incompletely understood. Expression of the integrin ligand Mfge8is increased in human obesity and in mice on a high-fat diet, but its role in obesity is unknown. We showhere that Mfge8 promotes the absorption of dietary triglycerides and the cellular uptake of fatty acid andthat Mfge8-deficient (Mfge8−/−) mice are protected from diet-induced obesity, steatohepatitis andinsulin resistance. Mechanistically, we found that Mfge8 coordinates fatty acid uptake through αvβ3integrin– and αvβ5 integrin–dependent phosphorylation of Akt by phosphatidylinositide-3 kinase andmTOR complex 2, leading to translocation of Cd36 and Fatp1 from cytoplasmic vesicles to the cellsurface. Collectively, our results imply a role for Mfge8 in regulating the absorption and storage of dietaryfats, as well as in the development of obesity and its complications.", "metadata": {}}
+{"_id": "5389523", "title": "", "text": "RAD52 Facilitates Mitotic DNA Synthesis Following Replication Stress.Homologous recombination (HR) isnecessary to counteract DNA replication stress. Common fragile site (CFS) loci are particularly sensitiveto replication stress and undergo pathological rearrangements in tumors. At these loci, replication stressfrequently activates DNA repair synthesis in mitosis. This mitotic DNA synthesis, termed MiDAS, requiresthe MUS81-EME1 endonuclease and a non-catalytic subunit of the Pol-delta complex, POLD3. Here, weexamine the contribution of HR factors in promoting MiDAS in human cells. We report that RAD51 andBRCA2 are dispensable for MiDAS but are required to counteract replication stress at CFS loci duringS-phase. In contrast, MiDAS is RAD52 dependent, and RAD52 is required for the timely recruitment ofMUS81 and POLD3 to CFSs in early mitosis. Our results provide further mechanistic insight into MiDASand define a specific function for human RAD52. Furthermore, selective inhibition of MiDAS may comprisea potential therapeutic strategy to sensitize cancer cells undergoing replicative stress.", "metadata": {}}
+{"_id": "5395426", "title": "", "text": "Excitotoxic brain injury in adult zebrafish stimulates neurogenesis and long-distance neuronalintegration.Zebrafish maintain a greater capacity than mammals for central nervous system repair afterinjury. Understanding differences in regenerative responses between different vertebrate species mayshed light on mechanisms to improve repair in humans. Quinolinic acid is an excitotoxin that has beenused to induce brain injury in rodents for modeling Huntington's disease and stroke. When injected intothe adult rodent striatum, this toxin stimulates subventricular zone neurogenesis and neuroblastmigration to injury. However, most new neurons fail to survive and lesion repair is minimal. We usedquinolinic acid to lesion the adult zebrafish telencephalon to study reparative processes. We also usedconditional transgenic lineage mapping of adult radial glial stem cells to explore survival and integrationof neurons generated after injury. Telencephalic lesioning with quinolinic acid, and to a lesser extentvehicle injection, produced cell death, microglial infiltration, increased cell proliferation, and enhancedneurogenesis in the injured hemisphere. Lesion repair was more complete with quinolinic acid injectionthan after vehicle injection. Fate mapping of her4-expressing radial glia showed injury-induced expansionof radial glial stem cells that gave rise to neurons which migrated to injury, survived at least 8 weeks andformed long-distance projections that crossed the anterior commissure and synapsed in the contralateralhemisphere. These findings suggest that quinolinic acid lesioning of the zebrafish brain stimulates adultneural stem cells to produce robust regeneration with long-distance integration of new neurons. Thismodel should prove useful for elucidating reparative mechanisms that can be applied to restorativetherapies for mammalian brain injury.", "metadata": {}}
+{"_id": "5398179", "title": "", "text": "Germinal Center T Follicular Helper Cells Are Highly Permissive to HIV-1 and Alter Their Phenotype duringVirus Replication.HIV-1 replication is concentrated within CD4(+) T cells in B cell follicles of secondarylymphoid tissues during asymptomatic disease. Limited data suggest that a subset of T follicular helpercells (TFH) within germinal centers (GC) is highly permissive to HIV-1. Whether GC TFH are the majorHIV-1 virus-producing cells in vivo has not been established. In this study, we investigated TFHpermissivity to HIV-1 ex vivo by spinoculating and culturing tonsil cells with HIV-1 GFP reporter viruses.Using flow cytometry, higher percentages of GC TFH (CXCR5(high)PD-1(high)) andCXCR5(+)programmed cell death-1 (PD-1)(low) cells were GFP(+) than non-GC TFH(CXCR5(+)PD-1(intermediate)) or extrafollicular (EF) (CXCR5(-)) cells. When sorted prior tospinoculation, however, GC TFH were substantially more permissive than CXCR5(+)PD-1(low) or EF cells,suggesting that many GC TFH transition to a CXCR5(+)PD-1(low) phenotype during productive infection.In situ hybridization on inguinal lymph node sections from untreated HIV-1-infected individuals withoutAIDS revealed higher frequencies of HIV-1 RNA(+) cells in GC than non-GC regions of follicle or EFregions. Superinfection of HIV-1-infected individuals' lymph node cells with GFP reporter virus confirmedthe permissivity of follicular cells ex vivo. Lymph node immunostaining revealed 96% ofCXCR5(+)CD4(+) cells were located in follicles. Within sorted lymph node cells from four HIV-infectedindividuals, CXCR5(+) subsets harbored 11-66-fold more HIV-1 RNA than CXCR5(-) subsets, asdetermined by RT PCR. Thus, GC TFH are highly permissive to HIV-1, but downregulate PD-1 and, to alesser extent, CXCR5 during HIV-1 replication. These data further implicate GC TFH as the majorHIV-1-producing cells in chronic asymptomatic HIV-1 infection.", "metadata": {}}
+{"_id": "5402581", "title": "", "text": "Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomizedplacebo-controlled trials.CONTEXT Atypical antipsychotic medications are widely used to treat delusions,aggression, and agitation in people with Alzheimer disease and other dementia; however, concerns havearisen about the increased risk for cerebrovascular adverse events, rapid cognitive decline, and mortalitywith their use. OBJECTIVE To assess the evidence for increased mortality from atypical antipsychotic drugtreatment for people with dementia. DATA SOURCES MEDLINE (1966 to April 2005), the CochraneControlled Trials Register (2005, Issue 1), meetings presentations (1997-2004), and information fromthe sponsors were searched using the terms for atypical antipsychotic drugs (aripiprazole, clozapine,olanzapine, quetiapine, risperidone, and ziprasidone), dementia, Alzheimer disease, and clinical trial.STUDY SELECTION Published and unpublished randomized placebo-controlled, parallel-group clinical trialsof atypical antipsychotic drugs marketed in the United States to treat patients with Alzheimer disease ordementia were selected by consensus of the authors. DATA EXTRACTION Trials, baseline characteristics,outcomes, all-cause dropouts, and deaths were extracted by one reviewer; treatment exposure wasobtained or estimated. Data were checked by a second reviewer. DATA SYNTHESIS Fifteen trials (9unpublished), generally 10 to 12 weeks in duration, including 16 contrasts of atypical antipsychotic drugswith placebo met criteria (aripiprazole [n = 3], olanzapine [n = 5], quetiapine [n = 3], risperidone [n =5]). A total of 3353 patients were randomized to study drug and 1757 were randomized to placebo.Outcomes were assessed using standard methods (with random- or fixed-effects models) to calculateodds ratios (ORs) and risk differences based on patients randomized and relative risks based on totalexposure to treatment. There were no differences in dropouts. Death occurred more often amongpatients randomized to drugs (118 [3.5%] vs 40 [2.3%]. The OR by meta-analysis was 1.54; 95%confidence interval [CI], 1.06-2.23; P = .02; and risk difference was 0.01; 95% CI, 0.004-0.02; P = .01).Sensitivity analyses did not show evidence for differential risks for individual drugs, severity, sampleselection, or diagnosis. CONCLUSIONS Atypical antipsychotic drugs may be associated with a smallincreased risk for death compared with placebo. This risk should be considered within the context ofmedical need for the drugs, efficacy evidence, medical comorbidity, and the efficacy and safety ofalternatives. Individual patient analyses modeling survival and causes of death are needed.", "metadata": {}}
+{"_id": "5403286", "title": "", "text": "PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutictargetingPhosphatidylinositol 3-kinases (PI3Ks) are crucial coordinators of intracellular signalling inresponse to extracellular stimuli. Hyperactivation of PI3K signalling cascades is one of the most commonevents in human cancers. In this Review, we discuss recent advances in our knowledge of the roles ofspecific PI3K isoforms in normal and oncogenic signalling, the different ways in which PI3K can beupregulated, and the current state and future potential of targeting this pathway in the clinic.", "metadata": {}}
+{"_id": "5406411", "title": "", "text": "Amphiregulin enhances regulatory T cell-suppressive function via the epidermal growth factorreceptor.Epidermal growth factor receptor (EGFR) is known to be critically involved in tissue developmentand homeostasis as well as in the pathogenesis of cancer. Here we showed that Foxp3(+) regulatory T(Treg) cells express EGFR under inflammatory conditions. Stimulation with the EGF-like growth factorAmphiregulin (AREG) markedly enhanced Treg cell function in vitro, and in a colitis and tumor vaccinationmodel we showed that AREG was critical for efficient Treg cell function in vivo. In addition, mastcell-derived AREG fully restored optimal Treg cell function. These findings reveal EGFR as a component inthe regulation of local immune responses and establish a link between mast cells and Treg cells.Targeting of this immune regulatory mechanism may contribute to the therapeutic successes ofEGFR-targeting treatments in cancer patients.", "metadata": {}}
+{"_id": "5409325", "title": "", "text": "Gonadotrope-specific deletion of Dicer results in severely suppressed gonadotropins and fertilitydefects.Pituitary gonadotropins follicle-stimulating hormone and luteinizing hormone are heterodimericglycoproteins expressed in gonadotropes. They act on gonads and promote their development andfunctions including steroidogenesis and gametogenesis. Although transcriptional regulation ofgonadotropin subunits has been well studied, the post-transcriptional regulation of gonadotropin subunitsis not well understood. To test if microRNAs regulate the hormone-specific gonadotropin β subunits invivo, we deleted Dicer in gonadotropes by a Cre-lox genetic approach. We found that many of theDICER-dependent microRNAs, predicted in silico to bind gonadotropin β subunit mRNAs, were suppressedin purified gonadotropes of mutant mice. Loss of DICER-dependent microRNAs in gonadotropes resultedin profound suppression of gonadotropin-β subunit proteins and, consequently, the heterodimerichormone secretion. In addition to suppression of basal levels, interestingly, thepost-gonadectomy-induced rise in pituitary gonadotropin synthesis and secretion were both abolished inmutants, indicating a defective gonadal negative feedback control. Furthermore, mutants lacking Dicer ingonadotropes displayed severely reduced fertility and were rescued with exogenous hormones confirmingthat the fertility defects were secondary to suppressed gonadotropins. Our studies reveal thatDICER-dependent microRNAs are essential for gonadotropin homeostasis and fertility in mice. Our studiesalso implicate microRNAs in gonadal feedback control of gonadotropin synthesis and secretion. Thus,DICER-dependent microRNAs confer a new layer of transcriptional and post-transcriptional regulation ingonadotropes to orchestrate the hypothalamus-pituitary-gonadal axis physiology.", "metadata": {}}
+{"_id": "5409905", "title": "", "text": "Sequential histone-modifying activities determine the robustness of transdifferentiationNaturalinterconversions between distinct somatic cell types have been reported in species as diverse as jellyfishand mice. The efficiency and reproducibility of some reprogramming events represent unexploitedavenues in which to probe mechanisms that ensure robust cell conversion. We report that a conservedH3K27me3/me2 demethylase, JMJD-3.1, and the H3K4 methyltransferase Set1 complex cooperate toensure invariant transdifferentiation (Td) of postmitotic Caenorhabditis elegans hindgut cells into motorneurons. At single-cell resolution, robust conversion requires stepwise histone-modifying activities,functionally partitioned into discrete phases of Td through nuclear degradation of JMJD-3.1 andphase-specific interactions with transcription factors that have conserved roles in cell plasticity andterminal fate selection. Our results draw parallels between epigenetic mechanisms underlying robust Tdin nature and efficient cell reprogramming in vitro.", "metadata": {}}
+{"_id": "5415832", "title": "", "text": "Normal and leukemic stem cell niches: insights and therapeutic opportunities.Hematopoietic stem cells(HSCs) rely on instructive cues from the bone marrow (BM) niche to maintain their quiescence and adaptblood production to the organism's needs. Alterations in the BM niche are commonly observed in bloodmalignancies and directly contribute to the aberrant function of disease-initiating leukemic stem cells(LSCs). Here, we review recent insights into the cellular and molecular determinants of the normal HSCniche and describe how genetic changes in stromal cells and leukemia-induced BM niche remodelingcontribute to blood malignancies. Moreover, we discuss how these findings can be applied tonon-cell-autonomous therapies targeting the LSC niche.", "metadata": {}}
+{"_id": "5431268", "title": "", "text": "Role of common hypnotics on the phenotypic causes of obstructive sleep apnoea: paradoxical effects ofzolpidem.Hypnotics are contraindicated in obstructive sleep apnoea (OSA) because of concerns ofpharyngeal muscle relaxation and delayed arousal worsening hypoxaemia. However, human data arelacking. This study aimed to determine the effects of three common hypnotics on the respiratory arousalthreshold, genioglossus muscle responsiveness and upper airway collapsibility during sleep.21 individualswith and without OSA (18-65 years) completed 84 detailed sleep studies after receiving temazepam (10mg), zolpidem (10 mg), zopiclone (7.5 mg) and placebo on four occasions in a randomised, double-blind,placebo-controlled, crossover trial (ACTRN12612001004853).The arousal threshold increased withzolpidem and zopiclone versus placebo (mean±sd -18.3±10 and -19.1±9 versus -14.6±7 cmH2O;p=0.02 and p<0.001) but not with temazepam (-16.8±9 cmH2O; p=0.17). Genioglossus muscle activityduring stable non-REM sleep and responsiveness during airway narrowing was not different withtemazepam and zopiclone versus placebo but, paradoxically, zolpidem increased median muscleresponsiveness three-fold during airway narrowing (median -0.15 (interquartile range -1.01 to -0.04)versus -0.05 (-0.29 to -0.03)% maximum EMG per cmH2O epiglottic pressure; p=0.03). The upperairway critical closing pressure did not change with any of the hypnotics. These doses of commonhypnotics have differential effects on the respiratory arousal threshold but do not reduce upper airwaymuscle activity or alter airway collapsibility during sleep. Rather, muscle activity increases during airwaynarrowing with zolpidem.", "metadata": {}}
+{"_id": "5433667", "title": "", "text": "Clinical human papillomavirus detection forecasts cervical cancer risk in women over 18 years offollow-up.PURPOSE To describe the long-term (≥ 10 years) benefits of clinical human papillomavirus(HPV) DNA testing for cervical precancer and cancer risk prediction. METHODS Cervicovaginal lavagescollected from 19,512 women attending a health maintenance program were retrospectively tested forHPV using a clinical test. HPV positives were tested for HPV16 and HPV18 individually using a researchtest. A Papanicolaou (Pap) result classified as atypical squamous cells of undetermined significance(ASC-US) or more severe was considered abnormal. Women underwent follow-up prospectively withroutine annual Pap testing up to 18 years. Cumulative incidence rates (CIRs) of ≥ grade 3 cervicalintraepithelial neoplasia (CIN3+) or cancer for enrollment test results were calculated. RESULTS Abaseline negative HPV test provided greater reassurance against CIN3+ over the 18-year follow-up thana normal Pap (CIR, 0.90% v 1.27%). Although both baseline Pap and HPV tests predicted who woulddevelop CIN3+ within the first 2 years of follow-up, only HPV testing predicted who would develop CIN3+10 to 18 years later (P = .004). HPV16- and HPV18-positive women with normal Pap were at elevatedrisk of CIN3+ compared with other HPV-positive women with normal Pap and were at similar risk ofCIN3+ compared with women with a low-grade squamous intraepithelial Pap. CONCLUSION HPV testingto rule out cervical disease followed by Pap testing and possibly combined with the detection of HPV16and HPV18 among HPV positives to identify those at immediate risk of CIN3+ would be an efficientalgorithm for cervical cancer screening, especially in women age 30 years or older.", "metadata": {}}
+{"_id": "5436081", "title": "", "text": "MG53 nucleates assembly of cell membrane repair machineryDynamic membrane repair and remodellingis an elemental process that maintains cell integrity and mediates efficient cellular function. Here wereport that MG53, a muscle-specific tripartite motif family protein (TRIM72), is a component of thesarcolemmal membrane-repair machinery. MG53 interacts with phosphatidylserine to associate withintracellular vesicles that traffic to and fuse with sarcolemmal membranes. Mice null for MG53 showprogressive myopathy and reduced exercise capability, associated with defective membrane-repaircapacity. Injury of the sarcolemmal membrane leads to entry of the extracellular oxidative environmentand MG53 oligomerization, resulting in recruitment of MG53-containing vesicles to the injury site. Aftervesicle translocation, entry of extracellular Ca2+ facilitates vesicle fusion to reseal the membrane. Ourdata indicate that intracellular vesicle translocation and Ca2+-dependent membrane fusion are distinctsteps involved in the repair of membrane damage and that MG53 may initiate the assembly of themembrane repair machinery in an oxidation-dependent manner.", "metadata": {}}
+{"_id": "5448119", "title": "", "text": "A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci forsystemic lupus erythematosusGenome-wide association studies have recently identified at least 15susceptibility loci for systemic lupus erythematosus (SLE). To confirm additional risk loci, we selectedSNPs from 2,466 regions that showed nominal evidence of association to SLE (P < 0.05) in agenome-wide study and genotyped them in an independent sample of 1,963 cases and 4,329 controls.This replication effort identified five new SLE susceptibility loci (P < 5 × 10−8): TNIP1 (odds ratio (OR) =1.27), PRDM1 (OR = 1.20), JAZF1 (OR = 1.20), UHRF1BP1 (OR = 1.17) and IL10 (OR = 1.19). Weidentified 21 additional candidate loci with P≤ 1 × 10−5. A candidate screen of alleles previouslyassociated with other autoimmune diseases suggested five loci (P < 1 × 10−3) that may contribute toSLE: IFIH1, CFB, CLEC16A, IL12B and SH2B3. These results expand the number of confirmed andcandidate SLE susceptibility loci and implicate several key immunologic pathways in SLE pathogenesis.", "metadata": {}}
+{"_id": "5468807", "title": "", "text": "ARID1A-mutated ovarian cancers depend on HDAC6 activityARID1A, encoding a subunit of the SWI/SNFchromatin-remodelling complex, is the most frequently mutated epigenetic regulator across all humancancers. ARID1A and TP53 mutations are typically mutually exclusive. Therapeutic approaches thatcorrelate with this genetic characteristic remain to be explored. Here, we show that HDAC6 activity isessential in ARID1A-mutated ovarian cancers. Inhibition of HDAC6 activity using a clinically applicablesmall-molecule inhibitor significantly improved the survival of mice bearing ARID1A-mutated tumours.This correlated with the suppression of growth and dissemination of ARID1A-mutated, but not wild-type,tumours. The dependence on HDAC6 activity in ARID1A-mutated cells correlated with a directtranscriptional repression of HDAC6 by ARID1A. HDAC6 inhibition selectively promoted apoptosis ofARID1A-mutated cells. HDAC6 directly deacetylates Lys120 of p53, a pro-apoptotic post-translationalmodification. Thus, ARID1A mutation inactivates the apoptosis-promoting function of p53 by upregulatingHDAC6. Together, these results indicate that pharmacological inhibition of HDAC6 is a therapeuticstrategy for ARID1A-mutated cancers.", "metadata": {}}
+{"_id": "5473074", "title": "", "text": "Solution NMR structure of the TatA component of the twin-arginine protein transport system fromgram-positive bacterium Bacillus subtilis.The twin-arginine transport (Tat) system translocates foldedproteins across the bacterial cytoplasmic or chloroplast thylakoid membrane of plants. The Tat system inmost Gram-positive bacteria consists of two essential components, the TatA and TatC proteins. TatA isconsidered to be a bifunctional subunit, which can form a protein-conducting channel byself-oligomerization and can also participate in substrate recognition. However, the molecular mechanismunderlying protein translocation remains elusive. Herein, we report the solution structure of the TatA(d)protein from Bacillus subtilis by NMR spectroscopy, the first structure of the Tat system at atomicresolution. TatA(d) shows an L-shaped structure formed by a transmembrane helix and an amphipathichelix, while the C-terminal tail is largely unstructured. Our results strongly support the postulatedtopology of TatA(d) in which the transmembrane helix is inserted into the lipid bilayer while theamphipathic helix lies at the membrane-water interface. Moreover, the structure of TatA(d) revealed thestructural importance of several conserved residues at the hinge region, thus shedding new light onfurther elucidation of the protein transport mechanism of the Tat system.", "metadata": {}}
+{"_id": "5476778", "title": "", "text": "Autoimmunity due to molecular mimicry as a cause of neurological diseaseOne hypothesis that couplesinfection with autoimmune disease is molecular mimicry. Molecular mimicry is characterized by animmune response to an environmental agent that cross-reacts with a host antigen, resulting in disease.This hypothesis has been implicated in the pathogenesis of diabetes, lupus and multiple sclerosis (MS).There is limited direct evidence linking causative agents with pathogenic immune reactions in thesediseases. Our study establishes a clear link between viral infection, autoimmunity and neurologicaldisease in humans. As a model for molecular mimicry, we studied patients with human T-lymphotropicvirus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a disease that canbe indistinguishable from MS (refs. 5,6,7). HAM/TSP patients develop antibodies to neurons. Wehypothesized these antibodies would identify a central nervous system (CNS) autoantigen.Immunoglobulin G isolated from HAM/TSP patients identified heterogeneous nuclear ribonuclearprotein-A1 (hnRNP-A1) as the autoantigen. Antibodies to hnRNP-A1 cross-reacted with HTLV-1-tax, theimmune response to which is associated with HAM/TSP (refs. 5,9). Immunoglobulin G specifically stainedhuman Betz cells, whose axons are preferentially damaged. Infusion of autoantibodies in brain sectionsinhibited neuronal firing, indicative of their pathogenic nature. These data demonstrate the importance ofmolecular mimicry between an infecting agent and hnRNP-A1 in autoimmune disease of the CNS.", "metadata": {}}
+{"_id": "5483793", "title": "", "text": "Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancerAntigen-specific CD8+T-cell tolerance, induced by myeloid-derived suppressor cells (MDSCs), is one of the main mechanisms oftumor escape. Using in vivo models, we show here that MDSCs directly disrupt the binding of specificpeptide–major histocompatibility complex (pMHC) dimers to CD8-expressing T cells through nitration oftyrosines in a T-cell receptor (TCR)-CD8 complex. This process makes CD8-expressing T cells unable tobind pMHC and to respond to the specific peptide, although they retain their ability to respond tononspecific stimulation. Nitration of TCR-CD8 is induced by MDSCs through hyperproduction of reactiveoxygen species and peroxynitrite during direct cell-cell contact. Molecular modeling suggests specific sitesof nitration that might affect the conformational flexibility of TCR-CD8 and its interaction with pMHC.These data identify a previously unknown mechanism of T-cell tolerance in cancer that is also pertinent tomany pathological conditions associated with accumulation of MDSCs.", "metadata": {}}
+{"_id": "5484763", "title": "", "text": "A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40phox and selective defects in neutrophil NADPH oxidase activity.Chronic granulomatous disease (CGD),an immunodeficiency with recurrent pyogenic infections and granulomatous inflammation, results fromloss of phagocyte superoxide production by recessive mutations in any 1 of 4 genes encoding subunits ofthe phagocyte NADPH oxidase. These include gp91(phox) and p22(phox), which form themembrane-integrated flavocytochrome b, and cytosolic subunits p47(phox) and p67(phox). A fifthsubunit, p40(phox), plays an important role in phagocytosis-induced superoxide production via a phoxhomology (PX) domain that binds to phosphatidylinositol 3-phosphate (PtdIns(3)P). We report the firstcase of autosomal recessive mutations in NCF4, the gene encoding p40(phox), in a boy who presentedwith granulomatous colitis. His neutrophils showed a substantial defect in intracellular superoxideproduction during phagocytosis, whereas extracellular release of superoxide elicited by phorbol ester orformyl-methionyl-leucyl-phenylalanine (fMLF) was unaffected. Genetic analysis of NCF4 showedcompound heterozygosity for a frameshift mutation with premature stop codon and a missense mutationpredicting a R105Q substitution in the PX domain. Parents and a sibling were healthy heterozygouscarriers. p40(phox)R105Q lacked binding to PtdIns(3)P and failed to reconstitute phagocytosis-inducedoxidase activity in p40(phox)-deficient granulocytes, with premature loss of p40(phox)R105Q fromphagosomes. Thus, p40(phox) binding to PtdIns(3)P is essential for phagocytosis-induced oxidantproduction in human neutrophils and its absence can be associated with disease.", "metadata": {}}
+{"_id": "5487448", "title": "", "text": "Birth weight and mammographic density among postmenopausal women in Sweden.Birth weight is asignificant predictor of breast cancer risk in adult life and mammary gland mass could be an intermediatestage in this long process. We have studied the association of birth size measurements withmammographic density, a marker of mammary gland mass. For a population-based sample of 893postmenopausal women without previous cancer in Sweden, we retrieved information on birth size frombirth records and their most recent mammography. Film mammograms of the medio-lateral oblique viewwere digitized and the Cumulus software was used for computer-assisted semi-automated thresholding ofmammographic density. Results were analyzed using generalized linear models controlling for possibleconfounders. Mean percent mammographic density increased when comparing the extreme categories ofbirth weight (from 15.6% to 18.6%) and head circumference (from 15.5% to 20.4%), and thecorresponding linear trends were statistically significant (p values 0.02 and 0.007, respectively). Theassociations were particularly strong when the cutoff for high versus low mammographic density was setat the relatively high value of 50%. Compared to women weighing 3001-3500 grams at birth, womenwith birth weights >4000g were at almost 3-fold risk of developing high mammographic density (oddsratio: 2.9, 95% confidence interval 1.1 to 7.9). No association with mammographic density was evidentwith respect to birth length which, however, is known to be less accurately measured. These resultsindicate that adult breast density, a powerful predictor of breast cancer risk, has intrauterine roots, asreflected in birth size.", "metadata": {}}
+{"_id": "5492542", "title": "", "text": "Oral ciclopirox olamine displays biological activity in a phase I study in patients with advancedhematologic malignancies.The antimycotic ciclopirox olamine is an intracellular iron chelator that hasanticancer activity in vitro and in vivo. We developed an oral formulation of ciclopirox olamine andconducted the first-in-human phase I study of this drug in patients with relapsed or refractoryhematologic malignancies (Trial registration ID: NCT00990587). Patients were treated with 5-80 mg/m²oral ciclopirox olamine once daily for five days in 21-day treatment cycles. Pharmacokinetic andpharmacodynamic companion studies were performed in a subset of patients. Following definition of thehalf-life of ciclopirox olamine, an additional cohort was enrolled and treated with 80 mg/m² ciclopiroxolamine four times daily. Adverse events and clinical response were monitored throughout the trial.Twenty-three patients received study treatment. Ciclopirox was rapidly absorbed and cleared with a shorthalf-life. Plasma concentrations of an inactive ciclopirox glucuronide metabolite were greater than thoseof ciclopirox. Repression of survivin expression was observed in peripheral blood cells isolated frompatients treated once daily with ciclopirox olamine at doses greater than 10 mg/m², demonstratingbiological activity of the drug. Dose-limiting gastrointestinal toxicities were observed in patients receiving80 mg/m² four times daily, and no dose limiting toxicity was observed at 40 mg/m² once daily.Hematologic improvement was observed in two patients. Once-daily dosing of oral ciclopirox olamine waswell tolerated in patients with relapsed or refractory hematologic malignancies, and further optimizationof dosing regimens is warranted in this patient population.", "metadata": {}}
+{"_id": "5500086", "title": "", "text": "Cancer cell–autonomous contribution of type I interferon signaling to the efficacy of chemotherapySomeof the anti-neoplastic effects of anthracyclines in mice originate from the induction of innate and Tcell–mediated anticancer immune responses. Here we demonstrate that anthracyclines stimulate therapid production of type I interferons (IFNs) by malignant cells after activation of the endosomal patternrecognition receptor Toll-like receptor 3 (TLR3). By binding to IFN-α and IFN-β receptors (IFNARs) onneoplastic cells, type I IFNs trigger autocrine and paracrine circuitries that result in the release ofchemokine (C-X-C motif) ligand 10 (CXCL10). Tumors lacking Tlr3 or Ifnar failed to respond tochemotherapy unless type I IFN or Cxcl10, respectively, was artificially supplied. Moreover, a type IIFN–related signature predicted clinical responses to anthracycline-based chemotherapy in severalindependent cohorts of patients with breast carcinoma characterized by poor prognosis. Our data suggestthat anthracycline-mediated immune responses mimic those induced by viral pathogens. We surmise thatsuch 'viral mimicry' constitutes a hallmark of successful chemotherapy.", "metadata": {}}
+{"_id": "5503194", "title": "", "text": "alphaE-catenin controls cerebral cortical size by regulating the hedgehog signaling pathway.Duringdevelopment, cells monitor and adjust their rates of accumulation to produce organs of predeterminedsize. We show here that central nervous system-specific deletion of the essential adherens junction gene,alphaE-catenin, causes abnormal activation of the hedgehog pathway, resulting in shortening of the cellcycle, decreased apoptosis, and cortical hyperplasia. We propose that alphaE-catenin connectscell-density-dependent adherens junctions with the developmental hedgehog pathway and that thisconnection may provide a negative feedback loop controlling the size of developing cerebral cortex.", "metadata": {}}
+{"_id": "5508750", "title": "", "text": "Molecular regulation of effector and memory T cell differentiationImmunological memory is a cardinalfeature of adaptive immunity and an important goal of vaccination strategies. Here we highlight advancesin the understanding of the diverse T lymphocyte subsets that provide acute and long-term protectionfrom infection. These include new insights into the transcription factors, and the upstream 'pioneering'factors that regulate their accessibility to key sites of gene regulation, as well as metabolic regulatorsthat contribute to the differentiation of effector and memory subsets; ontogeny and definingcharacteristics of tissue-resident memory lymphocytes; and origins of the remarkable heterogeneityexhibited by activated T cells. Collectively, these findings underscore progress in delineating theunderlying pathways that control diversification in T cell responses but also reveal gaps in the knowledge,as well as the challenges that arise in the application of this knowledge to rationally elicit desired T cellresponses through vaccination and immunotherapy.", "metadata": {}}
+{"_id": "5511240", "title": "", "text": "Liver-resident macrophage necroptosis orchestrates type 1 microbicidal inflammation andtype-2-mediated tissue repair during bacterial infection.Kupffer cells, the phagocytes of fetal origin thatline the liver sinusoids, are key contributors of host defense against enteroinvasive bacteria. Here, wefound that infection by Listeria monocytogenes induced the early necroptotic death of Kupffer cells, whichwas followed by monocyte recruitment and an anti-bacterial type 1 inflammatory response. Kupffer celldeath also triggered a type 2 response that involved the hepatocyte-derived alarmin interleukin-33(IL-33) and basophil-derived interleukin-4 (IL-4). This led to the alternative activation of themonocyte-derived macrophages recruited to the liver, which thereby replaced ablated Kupffer cells andrestored liver homeostasis. Kupffer cell death is therefore a key signal orchestrating type 1 microbicidalinflammation and type-2-mediated liver repair upon infection. This indicates that beyond the classicaldichotomy of type 1 and type 2 responses, these responses can develop sequentially in the context of abacterial infection and act interdependently, orchestrating liver immune responses and return tohomeostasis, respectively.", "metadata": {}}
+{"_id": "5519177", "title": "", "text": "Gene regulation in the immune system by long noncoding RNAsLong noncoding RNAs (lncRNAs) areemerging as critical regulators of gene expression in the immune system. Studies have shown thatlncRNAs are expressed in a highly lineage-specific manner and control the differentiation and function ofinnate and adaptive cell types. In this Review, we focus on mechanisms used by lncRNAs to regulategenes encoding products involved in the immune response, including direct interactions with chromatin,RNA and proteins. In addition, we address new areas of lncRNA biology, such as the functions ofenhancer RNAs, circular RNAs and chemical modifications to RNA in cellular processes. We emphasizecritical gaps in knowledge and future prospects for the roles of lncRNAs in the immune system andautoimmune disease.", "metadata": {}}
+{"_id": "5531479", "title": "", "text": "The Ly49Q receptor plays a crucial role in neutrophil polarization and migration by regulating rafttrafficking.Neutrophils rapidly undergo polarization and directional movement to infiltrate the sites ofinfection and inflammation. Here, we show that an inhibitory MHC I receptor, Ly49Q, was crucial for theswift polarization of and tissue infiltration by neutrophils. During the steady state, Ly49Q inhibitedneutrophil adhesion by preventing focal-complex formation, likely by inhibiting Src and PI3 kinases.However, in the presence of inflammatory stimuli, Ly49Q mediated rapid neutrophil polarization andtissue infiltration in an ITIM-domain-dependent manner. These opposite functions appeared to bemediated by distinct use of effector phosphatase SHP-1 and SHP-2. Ly49Q-dependent polarization andmigration were affected by Ly49Q regulation of membrane raft functions. We propose that Ly49Q ispivotal in switching neutrophils to their polarized morphology and rapid migration upon inflammation,through its spatiotemporal regulation of membrane rafts and raft-associated signaling molecules.", "metadata": {}}
+{"_id": "5548081", "title": "", "text": "Prevalence of Kaposi sarcoma-associated herpesvirus infection in homosexual men at beginning of andduring the HIV epidemic.CONTEXT Some studies have inferred that an epidemic of Kaposisarcoma-associated herpesvirus (KSHV) infection in homosexual men in the United States occurredconcurrently with that of human immunodeficiency virus (HIV), but there have been no directmeasurements of KSHV prevalence at the beginning of the HIV epidemic. OBJECTIVES To determine theprevalence of KSHV infection in homosexual men in San Francisco, Calif, at the beginning of the HIVepidemic in 1978 and 1979 and to examine changes in prevalence of KSHV at time points from 1978through 1996 in light of changes in sexual behavior. DESIGN, SETTING, AND PARTICIPANTS Analysis of aclinic-based sample (n = 398) derived from the San Francisco City Clinic Cohort (ages 18-66 years) (n =2666 for analyses herein) and from population-based samples from the San Francisco Men's Health Study(MHS) (ages 25-54 years) (n = 825 and 252) and the San Francisco Young Men's Health Study (YMHS)(ages 18-29 years) (n = 428-976, and 557); behavioral studies were longitudinal and KSHV prevalencestudies were cross-sectional. MAIN OUTCOME MEASURES Antibodies against KSHV and HIV; sexualbehaviors. RESULTS The prevalence of KSHV infection in 1978 and 1979 was 26.5% of 235 (a randomsample) overall (weighted for HIV infection) vs 6.9% (128/1842) for HIV in the San Francisco City ClinicCohort sample. The prevalence of KSHV infection remained essentially unchanged between an MHSsample of 252 in 1984 and 1985 (29.6%) and a YMHS sample of 557 in 1995 and 1996 (26.4%), whileHIV prevalence dropped from 49.5% of 825 in 1984 and 1985 (MHS) to 17.6% of 428 in 1992 and 1993(YMHS). The proportion of men practicing unprotected receptive anal intercourse with 1 or more partnersdeclined from 54% to 11% during the 1984 through 1993 period (MHS) with similar though slightlyhigher values in the YMHS in 1992 and 1993; whereas for unprotected oral intercourse it ranged between60% and 90% in the 1984 through 1996 period (MHS and YMHS). CONCLUSIONS Infection with KSHVwas already highly prevalent in homosexual men when the HIV epidemic began in San Francisco, and itsprevalence has been maintained at a nearly constant level. Any declines in the incidence of Kaposisarcoma do not appear to be caused by a decline in KSHV transmission.", "metadata": {}}
+{"_id": "5551138", "title": "", "text": "Nortriptyline for smoking cessation: a review.This article reviews the efficacy of nortriptyline for smokingcessation based on a meta-analysis of the Cochrane Library. Six placebo-controlled trials have shownnortriptyline (75-100 mg) doubles quit rates (OR = 2.1). Between 4% and 12% of smokers dropped outbecause of adverse events, but no serious adverse events occurred. The efficacy of nortriptyline did notappear to be related to its antidepressant actions. Nortriptyline is an efficacious aid to smoking cessationwith a magnitude of effect similar to that for bupropion and nicotine replacement therapies. Whethernortriptyline produces serious side effects at these doses in healthy, nondepressed smokers remainsunclear because it has been tested in only 500 smokers. The finding that nortriptyline and bupropion areeffective for smoking cessation but that selective serotonin-reuptake inhibitors are not suggests thatdopaminergic or adrenergic, but not serotonergic, activity is important for cessation efficacy. Until furtherstudies can verify a low incidence of significant adverse events, nortriptyline should be a second-linetreatment for smoking cessation.", "metadata": {}}
+{"_id": "5556809", "title": "", "text": "Emotion dysregulation in attention deficit hyperactivity disorder.Although it has long been recognized thatmany individuals with attention deficit hyperactivity disorder (ADHD) also have difficulties with emotionregulation, no consensus has been reached on how to conceptualize this clinically challenging domain.The authors examine the current literature using both quantitative and qualitative methods. Three keyfindings emerge. First, emotion dysregulation is prevalent in ADHD throughout the lifespan and is a majorcontributor to impairment. Second, emotion dysregulation in ADHD may arise from deficits in orientingtoward, recognizing, and/or allocating attention to emotional stimuli; these deficits implicate dysfunctionwithin a striato-amygdalo-medial prefrontal cortical network. Third, while current treatments for ADHDoften also ameliorate emotion dysregulation, a focus on this combination of symptoms reframes clinicalquestions and could stimulate novel therapeutic approaches. The authors then consider three models toexplain the overlap between emotion dysregulation and ADHD: emotion dysregulation and ADHD arecorrelated but distinct dimensions; emotion dysregulation is a core diagnostic feature of ADHD; and thecombination constitutes a nosological entity distinct from both ADHD and emotion dysregulation alone.The differing predictions from each model can guide research on the much-neglected population ofpatients with ADHD and emotion dysregulation.", "metadata": {}}
+{"_id": "5558754", "title": "", "text": "Use of serum C reactive protein and procalcitonin concentrations in addition to symptoms and signs topredict pneumonia in patients presenting to primary care with acute cough: diagnostic studyOBJECTIVESTo quantify the diagnostic accuracy of selected inflammatory markers in addition to symptoms and signsfor predicting pneumonia and to derive a diagnostic tool. DESIGN Diagnostic study performed between2007 and 2010. Participants had their history taken, underwent physical examination and measurementof C reactive protein (CRP) and procalcitonin in venous blood on the day they first consulted, andunderwent chest radiography within seven days. SETTING Primary care centres in 12 European countries.PARTICIPANTS Adults presenting with acute cough. MAIN OUTCOME MEASURES Pneumonia asdetermined by radiologists, who were blind to all other information when they judged chest radiographs.RESULTS Of 3106 eligible patients, 286 were excluded because of missing or inadequate chestradiographs, leaving 2820 patients (mean age 50, 40% men) of whom 140 (5%) had pneumonia.Re-assessment of a subset of 1675 chest radiographs showed agreement in 94% (κ 0.45, 95%confidence interval 0.36 to 0.54). Six published \"symptoms and signs models\" varied in theirdiscrimination (area under receiver operating characteristics curve (ROC) ranged from 0.55 (95%confidence interval 0.50 to 0.61) to 0.71 (0.66 to 0.76)). The optimal combination of clinical predictionitems derived from our patients included absence of runny nose and presence of breathlessness, cracklesand diminished breath sounds on auscultation, tachycardia, and fever, with an ROC area of 0.70 (0.65 to0.75). Addition of CRP at the optimal cut off of >30 mg/L increased the ROC area to 0.77 (0.73 to 0.81)and improved the diagnostic classification (net reclassification improvement 28%). In the 1556 patientsclassified according to symptoms, signs, and CRP >30 mg/L as \"low risk\" (<2.5%) for pneumonia, theprevalence of pneumonia was 2%. In the 132 patients classified as \"high risk\" (>20%), the prevalence ofpneumonia was 31%. The positive likelihood ratio of low, intermediate, and high risk for pneumonia was0.4, 1.2, and 8.6 respectively. Measurement of procalcitonin added no relevant additional diagnosticinformation. A simplified diagnostic score based on symptoms, signs, and CRP >30 mg/L resulted inproportions of pneumonia of 0.7%, 3.8%, and 18.2% in the low, intermediate, and high risk grouprespectively. CONCLUSIONS A clinical rule based on symptoms and signs to predict pneumonia inpatients presenting to primary care with acute cough performed best in patients with mild or severeclinical presentation. Addition of CRP concentration at the optimal cut off of >30 mg/L improveddiagnostic information, but measurement of procalcitonin concentration did not add clinically relevantinformation in this group.", "metadata": {}}
+{"_id": "5560962", "title": "", "text": "Somatic Mutations of the Immunoglobulin Framework Are Generally Required for Broad and Potent HIV-1NeutralizationBroadly neutralizing antibodies (bNAbs) to HIV-1 can prevent infection and are therefore ofgreat importance for HIV-1 vaccine design. Notably, bNAbs are highly somatically mutated and generatedby a fraction of HIV-1-infected individuals several years after infection. Antibodies typically accumulatemutations in the complementarity determining region (CDR) loops, which usually contact the antigen. TheCDR loops are scaffolded by canonical framework regions (FWRs) that are both resistant to and lesstolerant of mutations. Here, we report that in contrast to most antibodies, including those with limitedHIV-1 neutralizing activity, most bNAbs require somatic mutations in their FWRs. Structural andfunctional analyses reveal that somatic mutations in FWR residues enhance breadth and potency byproviding increased flexibility and/or direct antigen contact. Thus, in bNAbs, FWRs play an essential rolebeyond scaffolding the CDR loops and their unusual contribution to potency and breadth should beconsidered in HIV-1 vaccine design.", "metadata": {}}
+{"_id": "5567005", "title": "", "text": "Etiology of type 1 diabetes.Recent genetic mapping and gene-phenotype studies have revealed thegenetic architecture of type 1 diabetes. At least ten genes so far can be singled out as strong causalcandidates. The known functions of these genes indicate the primary etiological pathways of this disease,including HLA class II and I molecules binding to preproinsulin peptides and T cell receptors, T and B cellactivation, innate pathogen-viral responses, chemokine and cytokine signaling, and T regulatory andantigen-presenting cell functions. This review considers research in the field of type 1 diabetes towardidentifying disease mechanisms using genetic approaches. The expression and functions of thesepathways, and, therefore, disease susceptibility, will be influenced by epigenetic and environmentalfactors. Certain inherited immune phenotypes will be early precursors of type 1 diabetes and could beuseful in future clinical trials.", "metadata": {}}
+{"_id": "5567223", "title": "", "text": "Plasticity of epithelial stem cells in tissue regenerationTissues rely upon stem cells for homeostasis andrepair. Recent studies show that the fate and multilineage potential of epithelial stem cells can changedepending on whether a stem cell exists within its resident niche and responds to normal tissuehomeostasis, whether it is mobilized to repair a wound, or whether it is taken from its niche andchallenged to de novo tissue morphogenesis after transplantation. In this Review, we discuss howdifferent populations of naturally lineage-restricted stem cells and committed progenitors can displayremarkable plasticity and reversibility and reacquire long-term self-renewing capacities and multilineagedifferentiation potential during physiological and regenerative conditions. We also discuss the implicationsof cellular plasticity for regenerative medicine and for cancer.", "metadata": {}}
+{"_id": "5572127", "title": "", "text": "Atm-deficient mice exhibit increased sensitivity to dextran sulfate sodium-induced colitis characterized byelevated DNA damage and persistent immune activation.The role of ataxia telangiectasia mutated (ATM),a DNA double-strand break recognition and response protein, in inflammation and inflammatory diseasesis unclear. We have previously shown that high levels of systemic DNA damage are induced by intestinalinflammation in wild-type mice. To determine the effect of Atm deficiency in inflammation, we inducedexperimental colitis in Atm(-/-), Atm(+/-), and wild-type mice via dextran sulfate sodium (DSS)administration. Atm(-/-) mice had higher disease activity indices and rates of mortality compared withheterozygous and wild-type mice. Systemic DNA damage and immune response were characterized inperipheral blood throughout and after three cycles of treatment. Atm(-/-) mice showed increasedsensitivity to levels of DNA strand breaks in peripheral leukocytes, as well as micronucleus formation inerythroblasts, compared with heterozygous and wild-type mice, especially during remission periods andafter the end of treatment. Markers of reactive oxygen and nitrogen species-mediated damage, including8-oxoguanine and nitrotyrosine, were present both in the distal colon and in peripheral leukocytes, withAtm(-/-) mice manifesting more 8-oxoguanine formation than wild-type mice. Atm(-/-) mice showedgreater upregulation of inflammatory cytokines and significantly higher percentages of activated CD69+and CD44+ T cells in the peripheral blood throughout treatment. ATM, therefore, may be a criticalimmunoregulatory factor dampening the deleterious effects of chronic DSS-induced inflammation,necessary for systemic genomic stability and homeostasis of the gut epithelial barrier.", "metadata": {}}
+{"_id": "5573975", "title": "", "text": "Activin–like kinase–3 activity is important for kidney regeneration and reversal of fibrosisMoleculesassociated with the transforming growth factor β (TGF-β) superfamily, such as bone morphogenicproteins (BMPs) and TGF-β, are key regulators of inflammation, apoptosis and cellular transitions. Herewe show that the BMP receptor activin-like kinase 3 (Alk3) is elevated early in diseased kidneys afterinjury. We also found that its deletion in the tubular epithelium leads to enhanced TGF-β1-Smad familymember 3 (Smad3) signaling, epithelial damage and fibrosis, suggesting a protective role forAlk3-mediated signaling in the kidney. A structure-function analysis of the BMP-Alk3-BMP receptor, type2 (BMPR2) ligand-receptor complex, along with synthetic organic chemistry, led us to construct a libraryof small peptide agonists of BMP signaling that function through the Alk3 receptor. One such peptideagonist, THR-123, suppressed inflammation, apoptosis and the epithelial-to-mesenchymal transitionprogram and reversed established fibrosis in five mouse models of acute and chronic renal injury.THR-123 acts specifically through Alk3 signaling, as mice with a targeted deletion for Alk3 in their tubularepithelium did not respond to therapy with THR-123. Combining THR-123 and the angiotensin-convertingenzyme inhibitor captopril had an additive therapeutic benefit in controlling renal fibrosis. Our studiesshow that BMP signaling agonists constitute a new line of therapeutic agents with potential utility in theclinic to induce regeneration, repair and reverse established fibrosis.", "metadata": {}}
+{"_id": "5579368", "title": "", "text": "COHCAP: an integrative genomic pipeline for single-nucleotide resolution DNA methylationanalysisCOHCAP (City of Hope CpG Island Analysis Pipeline) is an algorithm to analyze single-nucleotideresolution DNA methylation data produced by either an Illumina methylation array or targeted bisulfitesequencing. The goal of the COHCAP algorithm is to identify CpG islands that show a consistent pattern ofmethylation among CpG sites. COHCAP is currently the only DNA methylation package that providesintegration with gene expression data to identify a subset of CpG islands that are most likely to regulatedownstream gene expression, and it can generate lists of differentially methylated CpG islands with\u000050% concordance with gene expression from both cell line data and heterogeneous patient data. Forexample, this article describes known breast cancer biomarkers (such as estrogen receptor) with anegative correlation between DNA methylation and gene expression. COHCAP also provides visualizationfor quality control metrics, regions of differential methylation and correlation between methylation andgene expression. This software is freely available at https://sourceforge.net/projects/cohcap/.", "metadata": {}}
+{"_id": "5586392", "title": "", "text": "Subgrouping of patients with neuropathic pain according to pain-related sensory abnormalities: a firststep to a stratified treatment approach.BACKGROUND Patients with neuropathic pain present with variouspain-related sensory abnormalities. These sensory features form different patterns or mosaics-thesensory profile-in individual patients. One hypothesis for the development of sensory profiles is thatdistinct pathophysiological mechanisms of pain generation produce specific sensory abnormalities.Several controlled trials of promising new drugs have produced negative results, but these findings couldhave been a result of heterogeneity in the patient population. Subgrouping patients on the basis ofindividual sensory profiles could reduce this heterogeneity and improve trial design. RECENTDEVELOPMENTS A statistical categorisation of patients with neuropathic pain showed that subgroups ofpatients with distinct sensory profiles who perceive their pain differently do exist across a range ofneuropathic disorders, although some distinct disorder-specific profiles were also detected. Results of thefirst clinical trials to use the subgroup approach at baseline could show a superior effect of the studydrugs in specific subgroups, rather than in the entire cohort of patients. WHERE NEXT?: A newclassification of neuropathic pain should take into account subgroups of patients with different sensoryprofiles. Sensory phenotyping has the potential to improve clinical trial design by enriching the studypopulation with potential treatment responders, and might lead to a stratified treatment approach andultimately to personalised treatment.", "metadata": {}}
+{"_id": "5596332", "title": "", "text": "The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).IMPORTANCEDefinitions of sepsis and septic shock were last revised in 2001. Considerable advances have since beenmade into the pathobiology (changes in organ function, morphology, cell biology, biochemistry,immunology, and circulation), management, and epidemiology of sepsis, suggesting the need forreexamination. OBJECTIVE To evaluate and, as needed, update definitions for sepsis and septic shock.PROCESS A task force (n = 19) with expertise in sepsis pathobiology, clinical trials, and epidemiology wasconvened by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine.Definitions and clinical criteria were generated through meetings, Delphi processes, analysis of electronichealth record databases, and voting, followed by circulation to international professional societies,requesting peer review and endorsement (by 31 societies listed in the Acknowledgment). KEY FINDINGSFROM EVIDENCE SYNTHESIS Limitations of previous definitions included an excessive focus oninflammation, the misleading model that sepsis follows a continuum through severe sepsis to shock, andinadequate specificity and sensitivity of the systemic inflammatory response syndrome (SIRS) criteria.Multiple definitions and terminologies are currently in use for sepsis, septic shock, and organ dysfunction,leading to discrepancies in reported incidence and observed mortality. The task force concluded the termsevere sepsis was redundant. RECOMMENDATIONS Sepsis should be defined as life-threatening organdysfunction caused by a dysregulated host response to infection. For clinical operationalization, organdysfunction can be represented by an increase in the Sequential [Sepsis-related] Organ FailureAssessment (SOFA) score of 2 points or more, which is associated with an in-hospital mortality greaterthan 10%. Septic shock should be defined as a subset of sepsis in which particularly profound circulatory,cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsisalone. Patients with septic shock can be clinically identified by a vasopressor requirement to maintain amean arterial pressure of 65 mm Hg or greater and serum lactate level greater than 2 mmol/L (>18mg/dL) in the absence of hypovolemia. This combination is associated with hospital mortality ratesgreater than 40%. In out-of-hospital, emergency department, or general hospital ward settings, adultpatients with suspected infection can be rapidly identified as being more likely to have poor outcomestypical of sepsis if they have at least 2 of the following clinical criteria that together constitute a newbedside clinical score termed quickSOFA (qSOFA): respiratory rate of 22/min or greater, alteredmentation, or systolic blood pressure of 100 mm Hg or less. CONCLUSIONS AND RELEVANCE Theseupdated definitions and clinical criteria should replace previous definitions, offer greater consistency forepidemiologic studies and clinical trials, and facilitate earlier recognition and more timely management ofpatients with sepsis or at risk of developing sepsis.", "metadata": {}}
+{"_id": "5597586", "title": "", "text": "Stem cell transplantation in patients with autonomic neuropathy due to primary (AL)amyloidosis.OBJECTIVES Patients with AL amyloidosis can benefit from high-dose chemotherapy andautologous stem cell transplantation (ASCT). Transplantation can be challenging due to fluid shifts,sepsis, and cardiac dysrhythmias. Amyloidosis may present with autonomic neuropathy (AN) that rendersperitransplant care problematic. The purpose of this study was to determine the outcome of patients withAN during and after ASCT. METHODS We performed a case-control study of patients with AL amyloidosiswith associated AN and compared them to a large matched cohort without AN who also underwent ASCT.RESULTS We identified 13 patients with AN who underwent ASCT and a matched control group of 95patients without AN. Patients with AN had more organs involved (median 2.5 vs 1, p < 0.001) and theconditioning dose of melphalan was often reduced by 30% compared to controls without AN (p =0.0015). Median duration of hospitalization was similar for both cohorts, as were engraftment kinetics.Atrial fibrillation occurred in all patients with AN but in only 1 control patient (p < 0.0001). Median overallsurvival (OS) for patients with AN was 29 months but >60 months for controls (p < 0.0001). Onunivariate analysis, cardiac involvement (p = 0.0132), AN (p = 0.0011), glomerular filtration rate (p =0.038), number of organs involved (p = 0.0064), and NT-pro-BNP (p = 0.039) all had an impact on OS.On multivariate analysis, AN retained an independent adverse impact on OS. CONCLUSIONS Patients withautonomic neuropathy secondary to AL amyloidosis can undergo autologous stem cell transplantationwith relative safety. Autonomic neuropathy is an independent, adverse determinant of survival in thesepatients.", "metadata": {}}
+{"_id": "5612738", "title": "", "text": "MicroRNA-148a regulates LDL receptor and ABCA1 expression to control circulating lipoprotein levelsThehepatic low-density lipoprotein receptor (LDLR) pathway is essential for clearing circulating LDLcholesterol (LDL-C). Whereas the transcriptional regulation of LDLR is well characterized, thepost-transcriptional mechanisms that govern LDLR expression are just beginning to emerge. Here wedevelop a high-throughput genome-wide screening assay to systematically identify microRNAs (miRNAs)that regulate LDLR activity in human hepatic cells. From this screen we identified and characterizedmiR-148a as a negative regulator of LDLR expression and activity and defined a sterol regulatoryelement–binding protein 1 (SREBP1)-mediated pathway through which miR-148a regulates LDL-Cuptake. In mice, inhibition of miR-148a increased hepatic LDLR expression and decreased plasma LDL-C.Moreover, we found that miR-148a regulates hepatic expression of ATP-binding cassette, subfamily A,member 1 (ABCA1) and circulating high-density lipoprotein cholesterol (HDL-C) levels in vivo. Thesestudies uncover a role for miR-148a as a key regulator of hepatic LDL-C clearance through directmodulation of LDLR expression and demonstrate the therapeutic potential of inhibiting miR-148a toameliorate an elevated LDL-C/HDL-C ratio, a prominent risk factor for cardiovascular disease.", "metadata": {}}
+{"_id": "5633876", "title": "", "text": "BRACHYURY and CDX2 Mediate BMP-Induced Differentiation of Human and Mouse Pluripotent Stem Cellsinto Embryonic and Extraembryonic LineagesBMP is thought to induce hESC differentiation towardmultiple lineages including mesoderm and trophoblast. The BMP-induced trophoblast phenotype is along-standing paradox in stem cell biology. Here we readdressed BMP function in hESCs and mouseepiblast-derived cells. We found that BMP4 cooperates with FGF2 (via ERK) to induce mesoderm and toinhibit endoderm differentiation. These conditions induced cells with high levels of BRACHYURY (BRA) thatcoexpressed CDX2. BRA was necessary for and preceded CDX2 expression; both genes were essential forexpression not only of mesodermal genes but also of trophoblast-associated genes. Maximal expressionof the latter was seen in the absence of FGF but these cells coexpressed mesodermal genes andmoreover they differed in cell surface and epigenetic properties from placental trophoblast. We concludethat BMP induces human and mouse pluripotent stem cells primarily to form mesoderm, rather thantrophoblast, acting through BRA and CDX2.", "metadata": {}}
+{"_id": "5633957", "title": "", "text": "Degradation of Cellular miR-27 by a Novel, Highly Abundant Viral Transcript Is Important for EfficientVirus Replication In VivoCytomegaloviruses express large amounts of viral miRNAs during lytic infection,yet, they only modestly alter the cellular miRNA profile. The most prominent alteration upon lytic murinecytomegalovirus (MCMV) infection is the rapid degradation of the cellular miR-27a and miR-27b. Here, wereport that this regulation is mediated by the \u00001.7 kb spliced and highly abundant MCMV m169transcript. Specificity to miR-27a/b is mediated by a single, apparently optimized, miRNA binding sitelocated in its 3'-UTR. This site is easily and efficiently retargeted to other cellular and viral miRNAs bytarget site replacement. Expression of the 3'-UTR of m169 by an adenoviral vector was sufficient tomediate its function, indicating that no other viral factors are essential in this process. Degradation ofmiR-27a/b was found to be accompanied by 3'-tailing and -trimming. Despite its dramatic effect onmiRNA stability, we found this interaction to be mutual, indicating potential regulation of m169 bymiR-27a/b. Most interestingly, three mutant viruses no longer able to target miR-27a/b, either due tomiRNA target site disruption or target site replacement, showed significant attenuation in multiple organsas early as 4 days post infection, indicating that degradation of miR-27a/b is important for efficient MCMVreplication in vivo.", "metadata": {}}
+{"_id": "5641851", "title": "", "text": "Social and geographical factors affecting access to treatment of colorectal cancer: a cancer registrystudyOBJECTIVE Cancer outcomes vary between and within countries with patients from deprivedbackgrounds known to have inferior survival. The authors set out to explore the effect of deprivation inrelation to the accessibility of hospitals offering diagnostic and therapeutic services on stage atpresentation and receipt of treatment. DESIGN Analysis of a Cancer Registry Database. Data includedstage and treatment details from the first 6 months. The socioeconomic status of the immediate area ofresidence and the travel time from home to hospital was derived from the postcode. SETTINGPopulation-based study of patients resident in a large area in the north of England. PARTICIPANTS 39 619patients with colorectal cancer diagnosed between 1994 and 2002. OUTCOMES MEASURED Stage ofdiagnosis and receipt of treatment in relation to deprivation and distance from hospital. RESULTS Patientsin the most deprived quartile were significantly more likely to be diagnosed at stage 4 for rectal cancer(OR 1.516, p<0.05) but less so for colonic cancer. There was a trend for both sites for patients in themost deprived quartile to be less likely to receive chemotherapy for stage 4 disease. Patients with coloniccancer were very significantly less likely to receive any treatment if they came from any but the mostaffluent area (ORs 0.639, 0.603 and 0.544 in increasingly deprived quartiles), this may have beenexacerbated if the hospital was distant from their residence (OR for forth quartile for both travel anddeprivation 0.731, not significant). The effect was less for rectal cancer and no effect of distance wasseen. CONCLUSIONS Residing in a deprived area is associated with tendencies to higher stage atdiagnosis and especially in the case of colonic cancer to reduced receipt of treatment. These observationsare consistent with other findings and indicate that access to diagnosis requires further investigation.", "metadata": {}}
+{"_id": "5649538", "title": "", "text": "Development of candidate genomic markers to select breast cancer patients for dasatinib therapy.Patientselection is important for targeted therapies, yet phase I/II trials are often underpowered for developingpredictors of drug response. The goal of this research was to define genomic predictors for dasatinib thatcould be prospectively tested in early-phase clinical trials. Gene expression profiles of dasatinib-sensitiveand dasatinib-resistant cell lines (n = 23) were compared to develop a dasatinib-sensitivity index(modified DS index). A Src pathway activity index (revised Src index) was defined using genes inducedby the Src transfection of mammary epithelial cells and was optimized to be reproducible across cell linesand human specimens. A dasatinib target index was devised using the weighted sum of 19 kinases thatbind to dasatinib with variable affinity. The performance of these prediction models was assessed inindependent cell lines with known dasatinib sensitivity. The feasibility of applying these genomic tests tohuman samples was evaluated on 133 biopsies of primary breast cancers. The modified DS index showed90% accuracy in independent breast cancer cell lines (n = 12) and the target index, but not the revisedSrc index signature, also distinguished dasatinib-sensitive and dasatinib-resistant cells (P = 0.0024). Thegenomic predictors showed acceptable reproducibility in replicate cell line and human gene expressiondata. When all three predictors were applied to the same 133 patient samples, the predictors identifieddifferent patient subsets as potentially sensitive. We defined three conceptually different potentialpredictors of dasatinib response that were reproducible across cell lines and human data. These candidatemarkers are being tested in a clinical trial to determine their utility.", "metadata": {}}
+{"_id": "5650232", "title": "", "text": "BEDTools: a flexible suite of utilities for comparing genomic featuresMOTIVATION Testing for correlationsbetween different sets of genomic features is a fundamental task in genomics research. However,searching for overlaps between features with existing web-based methods is complicated by the massivedatasets that are routinely produced with current sequencing technologies. Fast and flexible tools aretherefore required to ask complex questions of these data in an efficient manner. RESULTS This articleintroduces a new software suite for the comparison, manipulation and annotation of genomic features inBrowser Extensible Data (BED) and General Feature Format (GFF) format. BEDTools also supports thecomparison of sequence alignments in BAM format to both BED and GFF features. The tools are extremelyefficient and allow the user to compare large datasets (e.g. next-generation sequencing data) with bothpublic and custom genome annotation tracks. BEDTools can be combined with one another as well as withstandard UNIX commands, thus facilitating routine genomics tasks as well as pipelines that can quicklyanswer intricate questions of large genomic datasets. AVAILABILITY AND IMPLEMENTATION BEDToolswas written in C++. Source code and a comprehensive user manual are freely available athttp://code.google.com/p/bedtools   CONTACT aaronquinlan@gmail.com;imh4y@virginia.edu   SUPPLEMENTARY INFORMATION Supplementary data are available atBioinformatics online.", "metadata": {}}
+{"_id": "5687200", "title": "", "text": "Vegetarian diet improves insulin resistance and oxidative stress markers more than conventional diet insubjects with Type 2 diabetesAIMS The aim of this study was to compare the effects of calorie-restrictedvegetarian and conventional diabetic diets alone and in combination with exercise on insulin resistance,visceral fat and oxidative stress markers in subjects with Type 2 diabetes. METHODS A 24-week,randomized, open, parallel design was used. Seventy-four patients with Type 2 diabetes were randomlyassigned to either the experimental group (n = 37), which received a vegetarian diet, or the controlgroup (n = 37), which received a conventional diabetic diet. Both diets were isocaloric, calorie restricted(-500 kcal/day). All meals during the study were provided. The second 12 weeks of the diet werecombined with aerobic exercise. Participants were examined at baseline, 12 weeks and 24 weeks.Primary outcomes were: insulin sensitivity measured by hyperinsulinaemic isoglycaemic clamp; volumeof visceral and subcutaneous fat measured by magnetic resonance imaging; and oxidative stressmeasured by thiobarbituric acid reactive substances. Analyses were by intention to treat. RESULTSForty-three per cent of participants in the experimental group and 5% of participants in the control groupreduced diabetes medication (P < 0.001). Body weight decreased more in the experimental group than inthe control group [-6.2 kg (95% CI -6.6 to -5.3) vs. -3.2 kg (95% CI -3.7 to -2.5); interaction group ×time P = 0.001]. An increase in insulin sensitivity was significantly greater in the experimental group thanin the control group [30% (95% CI 24.5-39) vs. 20% (95% CI 14-25), P = 0.04]. A reduction in bothvisceral and subcutaneous fat was greater in the experimental group than in the control group (P = 0.007and P = 0.02, respectively). Plasma adiponectin increased (P = 0.02) and leptin decreased (P = 0.02) inthe experimental group, with no change in the control group. Vitamin C, superoxide dismutase andreduced glutathione increased in the experimental group (P = 0.002, P < 0.001 and P = 0.02,respectively). Differences between groups were greater after the addition of exercise training. Changes ininsulin sensitivity and enzymatic oxidative stress markers correlated with changes in visceral fat.CONCLUSIONS A calorie-restricted vegetarian diet had greater capacity to improve insulin sensitivitycompared with a conventional diabetic diet over 24 weeks. The greater loss of visceral fat andimprovements in plasma concentrations of adipokines and oxidative stress markers with this diet may beresponsible for the reduction of insulin resistance. The addition of exercise training further augmented theimproved outcomes with the vegetarian diet.", "metadata": {}}
+{"_id": "5691302", "title": "", "text": "Antidepressant use and risk of adverse outcomes in older people: population based cohortstudyOBJECTIVES To investigate the association between antidepressant treatment and risk of severalpotential adverse outcomes in older people with depression and to examine risks by class ofantidepressant, duration of use, and dose. DESIGN Cohort study of people aged 65 and over diagnosedas having depression. SETTING 570 general practices in the United Kingdom supplying data to theQResearch primary care database. PARTICIPANTS 60,746 patients diagnosed as having a new episode ofdepression between the ages of 65 and 100 years from 1 January 1996 to 31 December 2007 andfollowed up until 31 December 2008. MAIN OUTCOME MEASURES Hazard ratios associated withantidepressant use for all cause mortality, attempted suicide/self harm, myocardial infarction,stroke/transient ischaemic attack, falls, fractures, upper gastrointestinal bleeding, epilepsy/seizures, roadtraffic accidents, adverse drug reactions, and hyponatraemia, adjusted for a range of potentialconfounding variables. Hazard ratios were calculated for antidepressant class (tricyclic and relatedantidepressants, selective serotonin reuptake inhibitors, other antidepressants), dose, and duration ofuse and for commonly prescribed individual drugs. RESULTS 54,038 (89.0%) patients received at leastone prescription for an antidepressant during follow-up. A total of 1,398,359 antidepressant prescriptionswere issued: 764,659 (54.7%) for selective serotonin reuptake inhibitors, 442,192 (31.6%) for tricyclicantidepressants, 2203 (0.2%) for monoamine oxidase inhibitors, and 189,305 (13.5%) for the group ofother antidepressants. The associations with the adverse outcomes differed significantly between theantidepressant classes for seven outcomes. Selective serotonin reuptake inhibitors were associated withthe highest adjusted hazard ratios for falls (1.66, 95% confidence interval 1.58 to 1.73) andhyponatraemia (1.52, 1.33 to 1.75) compared with when antidepressants were not being used. Thegroup of other antidepressants was associated with the highest adjusted hazard ratios for all causemortality (1.66, 1.56 to 1.77), attempted suicide/self harm (5.16, 3.90 to 6.83), stroke/transientischaemic attack (1.37, 1.22 to 1.55), fracture (1.64, 1.46 to 1.84), and epilepsy/seizures (2.24, 1.60 to3.15), compared with when antidepressants were not being used. Tricyclic antidepressants did not havethe highest hazard ratio for any of the outcomes. Significantly different associations also existed betweenthe individual drugs for the same seven outcomes; trazodone (tricyclic antidepressant), mirtazapine, andvenlafaxine (both in the group of other antidepressants) were associated with the highest rates for someof these outcomes. Absolute risks over 1 year for all cause mortality were 7.04% for patients while nottaking antidepressants, 8.12% for those taking tricyclic antidepressants, 10.61% for selective serotoninreuptake inhibitors, and 11.43% for other antidepressants. CONCLUSIONS Selective serotonin reuptakeinhibitors and drugs in the group of other antidepressants were associated with an increased risk ofseveral adverse outcomes compared with tricyclic antidepressants. Among individual drugs, trazodone,mirtazapine, and venlafaxine were associated with the highest risks for some outcomes. As this is anobservational study, it is susceptible to confounding by indication, channelling bias, and residualconfounding, so differences in characteristics between patients prescribed different antidepressant drugsthat could account for some of the associations between the drugs and the adverse outcomes mayremain. Further research is needed to confirm these findings, but the risks and benefits of differentantidepressants should be carefully evaluated when these drugs are prescribed to older people.", "metadata": {}}
+{"_id": "5698494", "title": "", "text": "The benefits of statins in people without established cardiovascular disease but with cardiovascular riskfactors: meta-analysis of randomised controlled trialsOBJECTIVES To investigate whether statins reduceall cause mortality and major coronary and cerebrovascular events in people without establishedcardiovascular disease but with cardiovascular risk factors, and whether these effects are similar in menand women, in young and older (>65 years) people, and in people with diabetes mellitus. DESIGNMeta-analysis of randomised trials. DATA SOURCES Cochrane controlled trials register, Embase, andMedline. Data abstraction Two independent investigators identified studies on the clinical effects of statinscompared with a placebo or control group and with follow-up of at least one year, at least 80% or moreparticipants without established cardiovascular disease, and outcome data on mortality and majorcardiovascular disease events. Heterogeneity was assessed using the Q and I(2) statistics. Publicationbias was assessed by visual examination of funnel plots and the Egger regression test. RESULTS 10 trialsenrolled a total of 70 388 people, of whom 23 681 (34%) were women and 16 078 (23%) had diabetesmellitus. Mean follow-up was 4.1 years. Treatment with statins significantly reduced the risk of all causemortality (odds ratio 0.88, 95% confidence interval 0.81 to 0.96), major coronary events (0.70, 0.61 to0.81), and major cerebrovascular events (0.81, 0.71 to 0.93). No evidence of an increased risk of cancerwas observed. There was no significant heterogeneity of the treatment effect in clinical subgroups.CONCLUSION In patients without established cardiovascular disease but with cardiovascular risk factors,statin use was associated with significantly improved survival and large reductions in the risk of majorcardiovascular events.", "metadata": {}}
+{"_id": "5700349", "title": "", "text": "Mechanical coupling between transsynaptic N-cadherin adhesions and actin flow stabilizes dendriticspinesThe morphology of neuronal dendritic spines is a critical indicator of synaptic function. It isregulated by several factors, including the intracellular actin/myosin cytoskeleton and transcellularN-cadherin adhesions. To examine the mechanical relationship between these molecular components, weperformed quantitative live-imaging experiments in primary hippocampal neurons. We found that actinturnover and structural motility were lower in dendritic spines than in immature filopodia and increasedupon expression of a nonadhesive N-cadherin mutant, resulting in an inverse relationship between spinemotility and actin enrichment. Furthermore, the pharmacological stimulation of myosin II induced therearward motion of actin structures in spines, showing that myosin II exerts tension on the actin network.Strikingly, the formation of stable, spine-like structures enriched in actin was induced at contactsbetween dendritic filopodia and N-cadherin-coated beads or micropatterns. Finally, computer simulationsof actin dynamics mimicked various experimental conditions, pointing to the actin flow rate as animportant parameter controlling actin enrichment in dendritic spines. Together these data demonstratethat a clutch-like mechanism between N-cadherin adhesions and the actin flow underlies the stabilizationof dendritic filopodia into mature spines, a mechanism that may have important implications in synapseinitiation, maturation, and plasticity in the developing brain.", "metadata": {}}
+{"_id": "5702790", "title": "", "text": "Phosphate and R2D2 restrict the substrate specificity of Dicer-2, an ATP-driven ribonuclease.DrosophilaDicer-2 generates small interfering RNAs (siRNAs) from long double-stranded RNA (dsRNA), whereasDicer-1 produces microRNAs (miRNAs) from pre-miRNA. What makes the two Dicers specific for theirbiological substrates? We find that purified Dicer-2 can efficiently cleave pre-miRNA, but that inorganicphosphate and the Dicer-2 partner protein R2D2 inhibit pre-miRNA cleavage. Dicer-2 contains C-terminalRNase III domains that mediate RNA cleavage and an N-terminal helicase motif, whose function isunclear. We show that Dicer-2 is a dsRNA-stimulated ATPase that hydrolyzes ATP to ADP; ATP hydrolysisis required for Dicer-2 to process long dsRNA, but not pre-miRNA. Wild-type Dicer-2, but not a mutantdefective in ATP hydrolysis, can generate siRNAs faster than it can dissociate from a long dsRNAsubstrate. We propose that the Dicer-2 helicase domain uses ATP to generate many siRNAs from a singlemolecule of dsRNA before dissociating from its substrate.", "metadata": {}}
+{"_id": "5704562", "title": "", "text": "Therapeutic potential of mood stabilizers lithium and valproic acid: beyond bipolar disorder.The moodstabilizers lithium and valproic acid (VPA) are traditionally used to treat bipolar disorder (BD), a severemental illness arising from complex interactions between genes and environment that drive deficits incellular plasticity and resiliency. The therapeutic potential of these drugs in other central nervous systemdiseases is also gaining support. This article reviews the various mechanisms of action of lithium and VPAgleaned from cellular and animal models of neurologic, neurodegenerative, and neuropsychiatricdisorders. Clinical evidence is included when available to provide a comprehensive perspective of the fieldand to acknowledge some of the limitations of these treatments. First, the review describes how action atthese drugs' primary targets--glycogen synthase kinase-3 for lithium and histone deacetylases forVPA--induces the transcription and expression of neurotrophic, angiogenic, and neuroprotective proteins.Cell survival signaling cascades, oxidative stress pathways, and protein quality control mechanisms mayfurther underlie lithium and VPA's beneficial actions. The ability of cotreatment to augmentneuroprotection and enhance stem cell homing and migration is also discussed, as are microRNAs as newtherapeutic targets. Finally, preclinical findings have shown that the neuroprotective benefits of theseagents facilitate anti-inflammation, angiogenesis, neurogenesis, blood-brain barrier integrity, anddisease-specific neuroprotection. These mechanisms can be compared with dysregulated diseasemechanisms to suggest core cellular and molecular disturbances identifiable by specific risk biomarkers.Future clinical endeavors are warranted to determine the therapeutic potential of lithium and VPA acrossthe spectrum of central nervous system diseases, with particular emphasis on a personalized medicineapproach toward treating these disorders.", "metadata": {}}
+{"_id": "5710820", "title": "", "text": "The feasibility of malaria elimination in South AfricaBACKGROUND Following the last major malariaepidemic in 2000, malaria incidence in South Africa has declined markedly. The decrease has been soemphatic that South Africa now meets the World Health Organization (WHO) threshold for malariaelimination. Given the Millennium Development Goal of reversing the spread of malaria by 2015, SouthAfrica is being urged to adopt an elimination agenda. This study aimed to determine the appropriatenessof implementing a malaria elimination programme in present day South Africa. METHODS An assessmentof the progress made by South Africa in terms of implementing an integrated malaria control programmeacross the three malaria-endemic provinces was undertaken. Vector control and case management datawere analysed from the period of 2000 until 2011. RESULTS Both malaria-related morbidity and mortalityhave decreased significantly across all three malaria-endemic provinces since 2000. The greatest declinewas seen in KwaZulu-Natal where cases decreased from 42,276 in 2000 to 380 in 2010 and deathsdropped from 122 in 2000 to six in 2010. Although there has been a 49.2 % (8,553 vs 4,214) decrease inthe malaria cases reported in Limpopo Province, currently it is the largest contributor to the malariaincidence in South Africa. Despite all three provinces reporting average insecticide spray coverage of over80%, malaria incidence in both Mpumalanga and Limpopo remains above the elimination threshold.Locally transmitted case numbers have declined in all three malaria provinces but imported case numbershave been increasing. Knowledge gaps in vector distribution, insecticide resistance status and drug usagewere also identified. CONCLUSIONS Malaria elimination in South Africa is a realistic possibility if certaincriteria are met. Firstly, there must be continued support for the existing malaria control programmes toensure the gains made are sustained. Secondly, cross border malaria control initiatives with neighbouringcountries must be strongly encouraged and supported to reduce malaria in the region and the importationof malaria into South Africa. Thirdly, operational research, particularly on vector distribution andinsecticide resistance status must be conducted as a matter of urgency, and finally, the surveillancesystems must be refined to ensure the information required to inform an elimination agenda are routinelycollected.", "metadata": {}}
+{"_id": "5735492", "title": "", "text": "The epidemiology of sexually transmitted co-infections in HIV-positive and HIV-negativeAfrican-Caribbean women in TorontoBACKGROUND HIV disproportionately affects African-Caribbeanwomen in Canada but the frequency and distribution of sexually transmitted infections in this communityhave not been previously studied. METHODS We recruited women based on HIV status through a Torontocommunity health centre. Participants completed a socio-behavioural questionnaire using AudioComputer Assisted Self-Interview (ACASI) and provided blood for syphilis, HIV, hepatitis B and C, herpessimplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), and human cytomegalovirus (CMV)serology, urine for chlamydia and gonorrhea molecular testing and vaginal secretions for bacterialvaginosis (BV) and human papillomavirus (HPV). Differences in prevalence were assessed for statisticalsignificance using chi-square. RESULTS We recruited 126 HIV-positive and 291 HIV-negative women,with a median age of 40 and 31 years, respectively (p < 0.001). Active HBV infection and lifetimeexposure to HBV infection were more common in HIV-positive women (4.8% vs. 0.34%, p = 0.004; and47.6% vs. 21.2%, p < 0.0001), as was a self-reported history of HBV vaccination (66.1% vs. 44.0%, p =0.0001). Classical STIs were rare in both groups; BV prevalence was low and did not vary by HIV status.HSV-2 infection was markedly more frequent in HIV-positive (86.3%) than HIV-negative (46.6%) women(p < 0.0001). Vaginal HPV infection was also more common in HIV-positive than in HIV-negative women(50.8% vs. 22.6%, p < 0.0001) as was infection with high-risk oncogenic HPV types (48.4% vs. 17.3%,p < 0.0001). CONCLUSIONS Classical STIs were infrequent in this clinic-based population ofAfrican-Caribbean women in Toronto. However, HSV-2 prevalence was higher than that reported inprevious studies in the general Canadian population and was strongly associated with HIV infection, aswas infection with hepatitis B and HPV.", "metadata": {}}
+{"_id": "5752492", "title": "", "text": "Characterization of Programmed Death-1 Homologue-1 (PD-1H) Expression and Function in Normal andHIV Infected IndividualsChronic immune activation that persists despite anti-retroviral therapy (ART) isthe strongest predictor of disease progression in HIV infection. Monocyte/macrophages in HIV-infectedindividuals are known to spontaneously secrete cytokines, although neither the mechanism nor themolecules involved are known. Here we show that overexpression of the newly described co-stimulatorymolecule, PD1 homologue (PD-1H) in human monocyte/macrophages is sufficient to induce spontaneoussecretion of multiple cytokines. The process requires signaling via PD-1H as cytokine secretion could beabrogated by deletion of the cytoplasmic domain. Such overexpression of PD-1H, associated withspontaneous cytokine expression is seen in monocytes from chronically HIV-infected individuals and thiscorrelates with immune activation and CD4 depletion, but not viral load. Moreover, antigen presentationby PD-1H-overexpressing monocytes results in enhanced cytokine secretion by HIV-specific T cells. Theseresults suggest that PD-1H might play a crucial role in modulating immune activation and immuneresponse in HIV infection.", "metadata": {}}
+{"_id": "5760247", "title": "", "text": "A conserved mechanism for centromeric nucleosome recognition by centromere proteinCENP-C.Chromosome segregation during mitosis requires assembly of the kinetochore complex at thecentromere. Kinetochore assembly depends on specific recognition of the histone variant CENP-A in thecentromeric nucleosome by centromere protein C (CENP-C). We have defined the determinants of thisrecognition mechanism and discovered that CENP-C binds a hydrophobic region in the CENP-A tail anddocks onto the acidic patch of histone H2A and H2B. We further found that the more broadly conservedCENP-C motif uses the same mechanism for CENP-A nucleosome recognition. Our findings reveal aconserved mechanism for protein recruitment to centromeres and a histone recognition mode whereby adisordered peptide binds the histone tail through hydrophobic interactions facilitated by nucleosomedocking.", "metadata": {}}
+{"_id": "5764562", "title": "", "text": "Chemical tools for biomolecular imaging.The visualization of biologically relevant molecules and activitiesinside living cells continues to transform cell biology into a truly quantitative science. However, despitethe spectacular achievements in some areas of cell biology, the majority of cellular processes still operateinvisibly, not illuminated by even our brightest laser beams. Further progress therefore will depend notonly on improvements in instrumentation but also increasingly on the development of new fluorophoresand fluorescent sensors to target these activities. In the following, we review some of the recentapproaches to generating such sensors, the methods to attach them to selected biomolecules, and theirapplications to various biological problems.", "metadata": {}}
+{"_id": "5765455", "title": "", "text": "Reactive oxygen species, DNA damage, and error-prone repair: a model for genomic instability withprogression in myeloid leukemia?Myelodysplastic syndromes (MDS) comprise a heterogeneous group ofdisorders characterized by ineffective hematopoiesis, with an increased propensity to develop acutemyelogenous leukemia (AML). The molecular basis for MDS progression is unknown, but a key element inMDS disease progression is loss of chromosomal material (genomic instability). Using our two-step mousemodel for myeloid leukemic disease progression involving overexpression of human mutant NRAS andBCL2 genes, we show that there is a stepwise increase in the frequency of DNA damage leading to anincreased frequency of error-prone repair of double-strand breaks (DSB) by nonhomologous end-joining.There is a concomitant increase in reactive oxygen species (ROS) in these transgenic mice with diseaseprogression. Importantly, RAC1, an essential component of the ROS-producing NADPH oxidase, isdownstream of RAS, and we show that ROS production in NRAS/BCL2 mice is in part dependent on RAC1activity. DNA damage and error-prone repair can be decreased or reversed in vivo by N-acetyl cysteineantioxidant treatment. Our data link gene abnormalities to constitutive DNA damage and increased DSBrepair errors in vivo and provide a mechanism for an increase in the error rate of DNA repair with MDSdisease progression. These data suggest treatment strategies that target RAS/RAC pathways and ROSproduction in human MDS/AML.", "metadata": {}}
+{"_id": "5774746", "title": "", "text": "A link between inflammation and metastasis: serum amyloid A1 and A3 induce metastasis, and aretargets of metastasis-inducing S100A4S100A4 is implicated in metastasis and chronic inflammation, butits function remains uncertain. Here we establish an S100A4-dependent link between inflammation andmetastatic tumor progression. We found that the acute-phase response proteins serum amyloid A (SAA)1 and SAA3 are transcriptional targets of S100A4 via Toll-like receptor 4 (TLR4)/nuclear factor-κBsignaling. SAA proteins stimulated the transcription of RANTES (regulated upon activation normal T-cellexpressed and presumably secreted), G-CSF (granulocyte-colony-stimulating factor) and MMP2 (matrixmetalloproteinase 2), MMP3, MMP9 and MMP13. We have also shown for the first time that SAA stimulatetheir own transcription as well as that of proinflammatory S100A8 and S100A9 proteins. Moreover, theystrongly enhanced tumor cell adhesion to fibronectin, and stimulated migration and invasion of humanand mouse tumor cells. Intravenously injected S100A4 protein induced expression of SAA proteins andcytokines in an organ-specific manner. In a breast cancer animal model, ectopic expression of SAA1 orSAA3 in tumor cells potently promoted widespread metastasis formation accompanied by a massiveinfiltration of immune cells. Furthermore, coordinate expression of S100A4 and SAA in tumor samplesfrom colorectal carcinoma patients significantly correlated with reduced overall survival. These data showthat SAA proteins are effectors for the metastasis-promoting functions of S100A4, and serve as a linkbetween inflammation and tumor progression.", "metadata": {}}
+{"_id": "5775033", "title": "", "text": "Pyruvate dehydrogenase activity and acetyl group accumulation during exercise after differentdiets.Pyruvate dehydrogenase activity (PDHa) and acetyl group accumulation were examined in humanskeletal muscle at rest and during exercise after different diets. Five males cycled at 75% of maximal O2uptake (VO2 max) to exhaustion after consuming a low-carbohydrate diet (LCD) for 3 days and again 1-2wk later for the same duration after consuming a high-carbohydrate diet (HCD) for 3 days. Resting PDHawas lower after a LCD (0.20 +/- 0.04 vs. 0.69 +/- 0.05 mmol.min-1.kg wet wt-1; P < 0.05) andcoincided with a greater intramuscular acetyl-CoA-to-CoASH ratio, acetyl-CoA content, andacetylcarnitine content. PDHa increased during exercise in both conditions but at a lower rate in the LCDcondition compared with the HCD condition (1.46 +/- 0.25 vs. 2.65 +/- 0.23 mmol.min-1.kg wet wt-1 at16 min and 1.88 +/- 0.20 vs. 3.11 +/- 0.14 at the end of exercise; P < 0.05). During exercise muscleacetyl-CoA and acetylcarnitine content and the acetyl-CoA-to-CoASH ratio decreased in the LCD conditionbut increased in the HCD condition. Under resting conditions PDHa was influenced by the availability offat or carbohydrate fuels acting through changes in the acetyl-CoA-to-CoASH ratio. However, duringexercise the activation of PDHa occurred independent of changes in the acetyl-CoA-to-CoASH ratio,suggesting that other factors are more important.", "metadata": {}}
+{"_id": "5782614", "title": "", "text": "Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplasticsyndromes.Recent genetic analyses of large populations have revealed that somatic mutations inhematopoietic cells leading to clonal expansion are commonly acquired during human aging. Clonallyrestricted hematopoiesis is associated with an increased risk of subsequent diagnosis of myeloid orlymphoid neoplasia and increased all-cause mortality. Although myelodysplastic syndromes (MDS) aredefined by cytopenias, dysplastic morphology of blood and marrow cells, and clonal hematopoiesis, mostindividuals who acquire clonal hematopoiesis during aging will never develop MDS. Therefore, acquisitionof somatic mutations that drive clonal expansion in the absence of cytopenias and dysplastichematopoiesis can be considered clonal hematopoiesis of indeterminate potential (CHIP), analogous tomonoclonal gammopathy of undetermined significance and monoclonal B-cell lymphocytosis, which areprecursor states for hematologic neoplasms but are usually benign and do not progress. Becausemutations are frequently observed in healthy older persons, detection of an MDS-associated somaticmutation in a cytopenic patient without other evidence of MDS may cause diagnostic uncertainty. Herewe discuss the nature and prevalence of CHIP, distinction of this state from MDS, and current areas ofuncertainty regarding diagnostic criteria for myeloid malignancies.", "metadata": {}}
+{"_id": "5783785", "title": "", "text": "DNA Methylation mediated down-regulating of MicroRNA-33b and its role in gastric cancerThe discoveryof microRNAs (miRNAs) provides a new and powerful tool for studying the mechanism, diagnosis andtreatment of human cancers. Currently, down-regulation of tumor suppressive miRNAs by CpG islandhypermethylation is emerging as a common hallmark of cancer. Here, we reported that thedown-regulation of miR-33b was associated with pM stage of gastric cancer (GC) patients. Ectopicexpression of miR-33b in HGC-27 and MGC-803 cells inhibited cell proliferation, migration and invasion,which might be due to miR-33b targeting oncogene c-Myc. Moreover, enhanced methylation level of theCpG island upstream of miR-33b in GC patients with down-regulated miR-33b was confirmed bymethylation-specific PCR (MSP) amplification. Furthermore, re-introduction of miR-33b significantlysuppressed tumorigenesis of GC cells in the nude mice. In conclusion, miR-33b acts as a tumorsuppressor and hypermethylation of the CpG island upstream of miR-33b is responsible for itsdown-regulation in gastric cancer.", "metadata": {}}
+{"_id": "5785219", "title": "", "text": "Modulation of glucose metabolism in macrophages by products of nitric oxide synthase.Nitric oxide (NO)is a product of L-arginine metabolism that suppresses cellular oxidative metabolism through the inhibitionof tricarboxylic acid cycle and electron transport chain enzymes. The impact of NO synthase (NOS)activity on specific pathways of glucose metabolism in freshly harvested and overnight-cultured ratresident peritoneal macrophages, at rest and after stimulation with zymosan, was investigated usingradiolabeled glucose. NOS activity was modulated through the L-arginine concentration in culture mediaand the use of its specific inhibitor, NG-monomethyl-L-arginine, and quantitated using radiolabeledL-arginine. Results demonstrated that NOS activity was associated with increased glucose disappearance,glycolysis, and hexose monophosphate shunt activity and, in line with the known inhibition of oxidativemetabolism associated with the production of NO, with a decrease in the flux of glucose and butyratecarbon through the tricarboxylic acid cycle. In addition, the relative increase in glucose utilization thatfollows zymosan stimulation was enhanced by treatments that suppressed NOS activity. These resultsdemonstrate that the characteristics of glucose metabolism by macrophages are, to a significant extent,determined by products of NOS.", "metadata": {}}
+{"_id": "5798227", "title": "", "text": "SOCS1/JAB is a negative regulator of LPS-induced macrophage activation.Bacterial lipopolysaccharide(LPS) triggers innate immune responses through Toll-like receptor (TLR) 4. We show here that thesuppressor of cytokine-signaling-1 (SOCS1/JAB) is rapidly induced by LPS and negatively regulates LPSsignaling. SOCS1(+/-) mice or SOCS1(-/-) mice with interferon-gamma (IFNgamma)-deficientbackground were more sensitive to LPS-induced lethal effects than were wild-type littermates.LPS-induced NO(2)(-) synthesis and TNFalpha production were augmented in SOCS1(-/-) macrophages.Furthermore, LPS tolerance, a protection mechanism against endotoxin shock, was also strikingly reducedin SOCS1(-/-) cells. LPS-induced I-kappaB and p38 phosphorylation was upregulated in SOCS1(-/-)macrophages, and forced expression of SOCS1 suppressed LPS-induced NF-kappaB activation. Thus,SOCS1 directly suppresses TLR4 signaling and modulates innate immunity.", "metadata": {}}
+{"_id": "5800138", "title": "", "text": "Bacteria-triggered CD4+ T Regulatory Cells Suppress Helicobacter hepaticus–induced ColitisWe havepreviously demonstrated that interleukin (IL)-10–deficient (IL-10 knockout [KO]) but not wild-type (WT)mice develop colitis after infection with Helicobacter hepaticus . Here, we show that infectedrecombination activating gene (RAG) KO mice develop intestinal inflammation after reconstitution withCD4+ T cells from IL-10 KO animals and that the cotransfer of CD4+ T cells from H. hepaticus –infectedbut not uninfected WT mice prevents this colitis. The disease-protective WT CD4+ cells are containedwithin the CD45RBlow fraction and unexpectedly were found in both the CD25+ and the CD25−subpopulations of these cells, their frequency being higher in the latter. The mechanism by which CD25+and CD25− CD45RBlow CD4+ cells block colitis involves IL-10 and not transforming growth factor(TGF)-β, as treatment with anti–IL-10R but not anti–TGF-β monoclonal antibody abrogated theirprotective effect. In vitro, CD45RBlow CD4+ cells from infected WT mice were shown to produce IL-10and suppress interferon-γ production by IL-10 KO CD4+ cells in an H. hepaticus antigen–specific manner.Together, our data support the concept that H. hepaticus infection results in the induction in WT mice ofregulatory T cells that prevent bacteria-induced colitis. The induction of such cells in response to gut floramay be a mechanism protecting normal individuals against inflammatory bowel disease.", "metadata": {}}
+{"_id": "5811042", "title": "", "text": "The NLRP12 Sensor Negatively Regulates Autoinflammatory Disease by Modulating Interleukin-4Production in T Cells.Missense mutations in the nucleotide-binding oligomerization domain (NOD)-likereceptor pyrin domain containing family of gene 12 (Nlrp12) are associated with periodic fever syndromesand atopic dermatitis in humans. Here, we have demonstrated a crucial role for NLRP12 in negativelyregulating pathogenic T cell responses. Nlrp12(-/-) mice responded to antigen immunization withhyperinflammatory T cell responses. Furthermore, transfer of CD4(+)CD45RB(hi)Nlrp12(-/-) T cells intoimmunodeficient mice led to more severe colitis and atopic dermatitis. NLRP12 deficiency did not,however, cause exacerbated ascending paralysis during experimental autoimmune encephalomyelitis(EAE); instead, Nlrp12(-/-) mice developed atypical neuroinflammatory symptoms that werecharacterized by ataxia and loss of balance. Enhanced T-cell-mediated interleukin-4 (IL-4) productionpromotes the development of atypical EAE disease in Nlrp12(-/-) mice. These results define anunexpected role for NLRP12 as an intrinsic negative regulator of T-cell-mediated immunity and identifyaltered NF-κB regulation and IL-4 production as key mediators of NLRP12-associated disease.", "metadata": {}}
+{"_id": "5821617", "title": "", "text": "Shc coordinates signals from intercellular junctions and integrins to regulate flow-inducedinflammationAtherosclerotic plaques develop in regions of the vasculature associated with chronicinflammation due to disturbed flow patterns. Endothelial phenotype modulation by flow requires theintegration of numerous mechanotransduction pathways, but how this is achieved is not well understood.We show here that, in response to flow, the adaptor protein Shc is activated and associates with cell-celland cell-matrix adhesions. Shc activation requires the tyrosine kinases vascular endothelial growth factorreceptor 2 and Src. Shc activation and its vascular endothelial cadherin (VE-cadherin) association arematrix independent. In contrast, Shc binding to integrins requires VE-cadherin but occurs only on specificmatrices. Silencing Shc results in reduction in both matrix-independent and matrix-dependent signals.Furthermore, Shc regulates flow-induced inflammatory signaling by activating nuclear factorkappaB-dependent signals that lead to atherogenesis. In vivo, Shc is activated in atherosclerosis-proneregions of arteries, and its activation correlates with areas of atherosclerosis. Our results support a modelin which Shc orchestrates signals from cell-cell and cell-matrix adhesions to elicit flow-inducedinflammatory signaling.", "metadata": {}}
+{"_id": "5824955", "title": "", "text": "SIRT1 Redistribution on Chromatin Promotes Genomic Stability but Alters Gene Expression duringAgingGenomic instability and alterations in gene expression are hallmarks of eukaryotic aging. The yeasthistone deacetylase Sir2 silences transcription and stabilizes repetitive DNA, but during aging or inresponse to a DNA break, the Sir complex relocalizes to sites of genomic instability, resulting in thedesilencing of genes that cause sterility, a characteristic of yeast aging. Using embryonic stem cells, weshow that mammalian Sir2, SIRT1, represses repetitive DNA and a functionally diverse set of genesacross the mouse genome. In response to DNA damage, SIRT1 dissociates from these loci and relocalizesto DNA breaks to promote repair, resulting in transcriptional changes that parallel those in the agingmouse brain. Increased SIRT1 expression promotes survival in a mouse model of genomic instability andsuppresses age-dependent transcriptional changes. Thus, DNA damage-induced redistribution of SIRT1and other chromatin-modifying proteins may be a conserved mechanism of aging in eukaryotes.", "metadata": {}}
+{"_id": "5824985", "title": "", "text": "Bariatric Surgery in the United Kingdom: A Cohort Study of Weight Loss and Clinical Outcomes in RoutineClinical Care.BACKGROUND Bariatric surgery is becoming a more widespread treatment for obesity.Comprehensive evidence of the long-term effects of contemporary surgery on a broad range of clinicaloutcomes in large populations treated in routine clinical practice is lacking. The objective of this studywas to measure the association between bariatric surgery, weight, body mass index, and obesity-relatedco-morbidities. METHODS AND FINDINGS This was an observational retrospective cohort study usingdata from the United Kingdom Clinical Practice Research Datalink. All 3,882 patients registered in thedatabase and with bariatric surgery on or before 31 December 2014 were included and matched bypropensity score to 3,882 obese patients without surgery. The main outcome measures were change inweight and body mass index over 4 y; incident diagnoses of type 2 diabetes mellitus (T2DM),hypertension, angina, myocardial infarction (MI), stroke, fractures, obstructive sleep apnoea, and cancer;mortality; and resolution of hypertension and T2DM. Weight measures were available for 3,847 patientsbetween 1 and 4 mo, 2,884 patients between 5 and 12 mo, and 2,258 patients between 13 and 48 mopost-procedure. Bariatric surgery patients exhibited rapid weight loss for the first four postoperativemonths, at a rate of 4.98 kg/mo (95% CI 4.88-5.08). Slower weight loss was sustained to the end of 4 y.Gastric bypass (6.56 kg/mo) and sleeve gastrectomy (6.29 kg/mo) were associated with greater initialweight reduction than gastric banding (2.77 kg/mo). Protective hazard ratios (HRs) were detected forbariatric surgery for incident T2DM, 0.68 (95% CI 0.55-0.83); hypertension, 0.35 (95% CI 0.27-0.45);angina, 0.59 (95% CI 0.40-0.87);MI, 0.28 (95% CI 0.10-0.74); and obstructive sleep apnoea, 0.55(95% CI 0.40-0.87). Strong associations were found between bariatric surgery and the resolution ofT2DM, with a HR of 9.29 (95% CI 6.84-12.62), and between bariatric surgery and the resolution ofhypertension, with a HR of 5.64 (95% CI 2.65-11.99). No association was detected between bariatricsurgery and fractures, cancer, or stroke. Effect estimates for mortality found no protective associationwith bariatric surgery overall, with a HR of 0.97 (95% CI 0.66-1.43). The data used were recorded for themanagement of patients in primary care and may be subject to inaccuracy, which would tend to lead tounderestimates of true relative effect sizes. CONCLUSIONS Bariatric surgery as delivered in the UKhealthcare system is associated with dramatic weight loss, sustained at least 4 y after surgery. Thisweight loss is accompanied by substantial improvements in pre-existing T2DM and hypertension, as wellas a reduced risk of incident T2DM, hypertension, angina, MI, and obstructive sleep apnoea. Widening theavailability of bariatric surgery could lead to substantial health benefits for many people who are morbidlyobese.", "metadata": {}}
+{"_id": "5828251", "title": "", "text": "Notch signalling acts in postmitotic avian myogenic cells to control MyoD activation.During Drosophilamyogenesis, Notch signalling acts at multiple steps of the muscle differentiation process. In vertebrates,Notch activation has been shown to block MyoD activation and muscle differentiation in vitro, suggestingthat this pathway may act to maintain the cells in an undifferentiated proliferative state. In this paper, weaddress the role of Notch signalling in vivo during chick myogenesis. We first demonstrate that theNotch1 receptor is expressed in postmitotic cells of the myotome and that the Notch ligands Delta1 andSerrate2 are detected in subsets of differentiating myogenic cells and are thus in position to signal toNotch1 during myogenic differentiation. We also reinvestigate the expression of MyoD and Myf5 duringavian myogenesis, and observe that Myf5 is expressed earlier than MyoD, consistent with previous resultsin the mouse. We then show that forced expression of the Notch ligand, Delta1, during early myogenesis,using a retroviral system, has no effect on the expression of the early myogenic markers Pax3 and Myf5,but causes strong down-regulation of MyoD in infected somites. Although Delta1 overexpression resultsin the complete lack of differentiated muscles, detailed examination of the infected embryos shows thatinitial formation of a myotome is not prevented, indicating that exit from the cell cycle has not beenblocked. These results suggest that Notch signalling acts in postmitotic myogenic cells to control a criticalstep of muscle differentiation.", "metadata": {}}
+{"_id": "5835149", "title": "", "text": "Hepatitis C virus infection in a large cohort of homosexually active men: independent associations withHIV-1 infection and injecting drug use but not sexual behaviour.OBJECTIVE To determine the prevalenceand risk factors for hepatitis C virus (HCV) infection in a cohort of homosexually active men, withparticular reference to assessing sexual transmission. DESIGN Prevalence based on cross-sectionaltesting for HCV (c100 protein) antibody in a cohort using sera stored between 1984 and 1989, andassessment of risk factors using a case-control analysis based on questionnaire data from HCV positiveand negative subjects. SUBJECTS/SETTING 1038 homosexually active men who were participating in aprospective study established to identify risk factors for AIDS. They had been recruited through privateand public primary care and sexually transmissible disease (STD) services in central Sydney. MAINOUTCOME MEASURES Prevalence of HCV antibody and its association with human immunodeficiency virustype 1 (HIV-1) infection and other STDs, number of sexual partners, sexual practices and recreationaldrug use. RESULTS Overall, 7.6% of subjects tested were seropositive for HCV antibody. In univariateanalysis, HCV infection was significantly associated with injecting drug use (IDU) (OR = 8.18, p <0.0001) and HIV infection (OR = 3.14, p < 0.0001) and with self reported history of syphilis (OR = 1.88,p = 0.016), anogenital herpes (OR = 1.93, p = 0.017), gonorrhoea (OR = 2.43, p = 0.009) and hepatitisB (OR = 1.92, p = 0.010). In case control analysis, similar sexual behaviours (partner numbers andpractices) were reported by HCV positive and HCV negative subjects except that HCV negative subjectsmore frequently reported engaging than HCV positive subject in unprotected receptive anal intercoursewithout ejaculation (OR = 0.61, p = 0.034), unprotected insertive (OR = 0.59, p = 0.039) and receptive(OR = 0.56, p = 0.016) oro-anal intercourse (rimming) and insertive fisting (OR = 0.48, p = 0.034). Inmultiple logistic regression analyses, only HIV-1 infection (OR = 3.18, p < 0.0001) and IDU in theprevious six months (OR = 7.24, p < 0.0001) remained significantly associated with the presence of HCVantibody. CONCLUSIONS IDU was the major behavioural risk factor for HCV infection. If sexual oranother from of transmission did occur, it may have been facilitated by concurrent HIV-1 infection.", "metadata": {}}
+{"_id": "5838067", "title": "", "text": "Analysis of human cytomegalovirus-encoded microRNA activity during infection.MicroRNAs (miRNAs) areexpressed in a wide variety of organisms, ranging from plants to animals, and are key posttranscriptionalregulators of gene expression. Virally encoded miRNAs are unique in that they could potentially targetboth viral and host genes. Indeed, we have previously demonstrated that a human cytomegalovirus(HCMV)-encoded miRNA, miR-UL112, downregulates the expression of a host immune gene, MICB.Remarkably, it was shown that the same miRNA also downregulates immediate-early viral genes and thatits ectopic expression resulted in reduced viral replication and viral titers. The targets for most of the viralmiRNAs, and hence their functions, are still unknown. Here we demonstrate that miR-UL112 also targetsthe UL114 gene, and we present evidence that the reduction of UL114 by miR-UL112 reduces its activityas uracil DNA glycosylase but only minimally affects virus growth. In addition, we show that twoadditional HCMV-encoded miRNAs, miR-US25-1 and miR-US25-2, reduce the viral replication and DNAsynthesis not only of HCMV but also of other viruses, suggesting that these two miRNAs target cellulargenes that are essential for virus growth. Thus, we suggest that in addition to miR-UL112, two additionalHCMV miRNAs control the life cycle of the virus.", "metadata": {}}
+{"_id": "5839365", "title": "", "text": "Anti-obesity drugs: past, present and futureThe ideal anti-obesity drug would produce sustained weightloss with minimal side effects. The mechanisms that regulate energy balance have substantial built-inredundancy, overlap considerably with other physiological functions, and are influenced by social, hedonicand psychological factors that limit the effectiveness of pharmacological interventions. It is thereforeunsurprising that anti-obesity drug discovery programmes have been littered with false starts, failures inclinical development, and withdrawals due to adverse effects that were not fully appreciated at the timeof launch. Drugs that target pathways in metabolic tissues, such as adipocytes, liver and skeletal muscle,have shown potential in preclinical studies but none has yet reached clinical development. Recentimprovements in the understanding of peptidergic signalling of hunger and satiety from thegastrointestinal tract mediated by ghrelin, cholecystokinin (CCK), peptide YY (PYY) and glucagon-likepeptide-1 (GLP-1), and of homeostatic mechanisms related to leptin and its upstream pathways in thehypothalamus, have opened up new possibilities. Although some have now reached clinical development,it is uncertain whether they will meet the strict regulatory hurdles required for licensing of an anti-obesitydrug. However, GLP-1 receptor agonists have already succeeded in diabetes treatment and, owing totheir attractive body-weight-lowering effects in humans, will perhaps also pave the way for otheranti-obesity agents. To succeed in developing drugs that control body weight to the extent seen followingsurgical intervention, it seems obvious that a new paradigm is needed. In other therapeutic arenas, suchas diabetes and hypertension, lower doses of multiple agents targeting different pathways often yieldbetter results than strategies that modify one pathway alone. Some combination approaches usingpeptides and small molecules have now reached clinical trials, although recent regulatory experiencesuggests that large challenges lie ahead. In future, this polytherapeutic strategy could possibly rivalsurgery in terms of efficacy, safety and sustainability of weight loss.", "metadata": {}}
+{"_id": "5849439", "title": "", "text": "Cytochemical Analysis of Pollen Development in Wild-Type Arabidopsis and a Male-SterileMutant.Microsporogenesis has been examined in wild-type Arabidopsis thaliana and the nuclearmale-sterile mutant BM3 by cytochemical staining. The mutant lacks adenine phosphoribosyltransferase,an enzyme of the purine salvage pathway that converts adenine to AMP. Pollen development in themutant began to diverge from wild type just after meiosis, as the tetrads of microspores were releasedfrom their callose walls. The first indication of abnormal pollen development in the mutant was a darkerstaining of the microspore wall due to an incomplete synthesis of the intine. Vacuole formation wasdelayed and irregular in the mutant, and the majority of the mutant microspores failed to undergo mitoticdivisions. Enzyme activities of alcohol dehydrogenase and esterases decreased in the mutant soon aftermeiosis and were undetectable in mature pollen grains of the mutant. RNA accumulation was alsodiminished. These results are discussed in relation to the possible role(s) of adenine salvage in pollendevelopment.", "metadata": {}}
+{"_id": "5850219", "title": "", "text": "Prevalence, risk factors, and uptake of interventions for sexually transmitted infections in Britain: findingsfrom the National Surveys of Sexual Attitudes and Lifestyles (Natsal)BACKGROUND Population-basedestimates of prevalence, risk distribution, and intervention uptake inform delivery of control programmesfor sexually transmitted infections (STIs). We undertook the third National Survey of Sexual Attitudes andLifestyles (Natsal-3) after implementation of national sexual health strategies, and describe theepidemiology of four STIs in Britain (England, Scotland, and Wales) and the uptake of interventions.METHODS Between Sept 6, 2010 and Aug 31, 2012 , we did a probability sample survey of 15,162women and men aged 16-74 years in Britain. Participants were interviewed with computer-assistedface-to-face and self-completion questionnaires. Urine from a sample of participants aged 16-44 yearswho reported at least one sexual partner over the lifetime was tested for the presence of Chlamydiatrachomatis, type-specific human papillomavirus (HPV), Neisseria gonorrhoeae, and HIV antibody. Wedescribe age-specific and sex-specific prevalences of infection and intervention uptake, in relation todemographic and behavioural factors, and explore changes since Natsal-1 (1990-91) and Natsal-2(1999-2001). FINDINGS Of 8047 eligible participants invited to provide a urine sample, 4828 (60%)agreed. We excluded 278 samples, leaving 4550 (94%) participants with STI test results. Chlamydiaprevalence was 1·5% (95% CI 1·1-2·0) in women and 1·1% (0·7-1·6) in men. Prevalences in individualsaged 16-24 years were 3·1% (2·2-4·3) in women and 2·3% (1·5-3·4) in men. Area-level deprivation andhigher numbers of partners, especially without use of condoms, were risk factors. However, 60·4%(45·5-73·7) of chlamydia in women and 43·3% (25·9-62·5) in men was in individuals who had had onepartner in the past year. Among sexually active 16-24-year-olds, 54·2% (51·4-56·9) of women and34·6% (31·8-37·4) of men reported testing for chlamydia in the past year, with testing higher in thosewith more partners. High-risk HPV was detected in 15·9% (14·4-17·5) of women, similar to in Natsal-2.Coverage of HPV catch-up vaccination was 61·5% (58·2-64·7). Prevalence of HPV types 16 and 18 inwomen aged 18-20 years was lower in Natsal-3 than Natsal-2 (5·8% [3·9-8·6] vs 11·3% [6·8-18·2];age-adjusted odds ratio 0·44 [0·21-0·94]). Gonorrhoea (<0·1% prevalence in women and men) and HIV(0·1% prevalence in women and 0·2% in men) were uncommon and restricted to participants withrecognised high-risk factors. Since Natsal-2, substantial increases were noted in attendance at sexualhealth clinics (from 6·7% to 21·4% in women and from 7·7% to 19·6% in men) and HIV testing (from8·7% to 27·6% in women and from 9·2% to 16·9% in men) in the past 5 years. INTERPRETATION STIswere distributed heterogeneously, requiring general and infection-specific interventions. Increases intesting and attendance at sexual health clinics, especially in people at highest risk, are encouraging.However, STIs persist both in individuals accessing and those not accessing services. Our findings provideempirical evidence to inform future sexual health interventions and services. FUNDING Grants from theUK Medical Research Council and the Wellcome Trust, with support from the Economic and SocialResearch Council and the Department of Health.", "metadata": {}}
+{"_id": "5855168", "title": "", "text": "Cancer Pharmacogenomics and Pharmacoepidemiology: Setting a Research Agenda to AccelerateTranslationRecent advances in genomic research have demonstrated a substantial role for genomicfactors in predicting response to cancer therapies. Researchers in the fields of cancer pharmacogenomicsand pharmacoepidemiology seek to understand why individuals respond differently to drug therapy, interms of both adverse effects and treatment efficacy. To identify research priorities as well as theresources and infrastructure needed to advance these fields, the National Cancer Institute (NCI)sponsored a workshop titled \"Cancer Pharmacogenomics: Setting a Research Agenda to AccelerateTranslation\" on July 21, 2009, in Bethesda, MD. In this commentary, we summarize and discuss fivescience-based recommendations and four infrastructure-based recommendations that were identified as aresult of discussions held during this workshop. Key recommendations include 1) supporting the routinecollection of germline and tumor biospecimens in NCI-sponsored clinical trials and in some observationaland population-based studies; 2) incorporating pharmacogenomic markers into clinical trials; 3)addressing the ethical, legal, social, and biospecimen- and data-sharing implications of pharmacogenomicand pharmacoepidemiologic research; and 4) establishing partnerships across NCI, with other federalagencies, and with industry. Together, these recommendations will facilitate the discovery and validationof clinical, sociodemographic, lifestyle, and genomic markers related to cancer treatment response andadverse events, and they will improve both the speed and efficiency by which new pharmacogenomic andpharmacoepidemiologic information is translated into clinical practice.", "metadata": {}}
+{"_id": "5860364", "title": "", "text": "Differential transcription of the orphan receptor RORbeta in nuclear extracts derived from Neuro2A andHeLa cells.An important model system for studying the process leading to productive transcription isprovided by the superfamily of nuclear receptors, which are for the most part ligand-controlledtranscription factors. Over the past years several 'orphan' nuclear receptors have been isolated for whichno ligand has yet been identified. Very little is known about how these 'orphan' receptors regulatetranscription. In this study we have analysed the biochemical and transcriptional properties of theneuronally expressed orphan nuclear receptor RORbeta (NR1F2) and compared them with the retinoicacid receptor heterodimer RXRalpha-RARalpha (NR2B1-NR1B1) and Gal-VP16 in vitro. Although RORbetabinds to its DNA-binding sites with comparatively low affinity, it efficiently directs transcription in nuclearextracts derived from a neuronal cell line, Neuro2A, but not in nuclear extracts from non-neuronal HeLacells. In contrast, RXRalpha-RARalpha and the acidic transcription factor Gal-VP16 support transcriptionin Neuro2A and HeLa nuclear extracts equally efficiently. These observations point to a different(co)factor requirement for transactivation by members of the NR1 subfamily of nuclear receptors.", "metadata": {}}
+{"_id": "5864770", "title": "", "text": "Estrogens, progestogens, normal breast cell proliferation, and breast cancer risk.Epidemiologic studiessuggest that ovarian hormones contribute to the development of breast cancer at all stages. Earlymenopause and premenopausal obesity reduces the risk while postmenopausal obesity and menopausalestrogen replacement therapy increases the risk. Combined oral contraceptives and Depo-Provera do notreduce the risk. It appears that estrogens and progestogens act through and with proto-oncogenes andgrowth factors to affect breast cell proliferation and breast cancer etiology. Animal studies suggest thatestrogen causes interlobular ductal cell division and progesterone causes increased terminal duct lobularunit cell division in the luteal phase. Most breast carcinomas originate from terminal duct lobular unitcells. During pregnancy, these cells fully multiply. Their reproduction is also increased during the lutealphase. Yet, there is considerable interpersonal variation. No studies examining breast cell division havecompared cell division rates with serum hormone concentrations, however. The peak of mitosis occursabout 3 days before breast cell death in the late luteal and very early follicular phases. Other researchsuggests that breast stem cell proliferation is linked to breast cancer development. Endocrine therapyreduces mitotic activity, indicating the estrogen and progesterone receptor content of breast cancers.Hormone-dependent breast cancer cell lines are all estrogen-dependent. Progesterone can block theestrogen-dependent cell lines which act like endometrial cells. The results of the various breast cellproliferation studies in relation to breast cancer are unclear and research identifying a molecularexplanation would help in understanding the different findings.", "metadata": {}}
+{"_id": "5867846", "title": "", "text": "Analysis of the interaction of primate retroviruses with the human RNA interference machinery.Thequestion of whether retroviruses, including human immunodeficiency virus type 1 (HIV-1), interact withthe cellular RNA interference machinery has been controversial. Here, we present data showing thatneither HIV-1 nor human T-cell leukemia virus type 1 (HTLV-1) expresses significant levels of either smallinterfering RNAs or microRNAs in persistently infected T cells. We also demonstrate that the retroviralnuclear transcription factors HIV-1 Tat and HTLV-1 Tax, as well as the Tas transactivator encoded byprimate foamy virus, fail to inhibit RNA interference in human cells. Moreover, the stable expression ofphysiological levels of HIV-1 Tat did not globally inhibit microRNA production or expression in infectedhuman cells. Together, these data argue that HIV-1 and HTLV-1 neither induce the production of viralsmall interfering RNAs or microRNAs nor repress the cellular RNA interference machinery in infected cells.", "metadata": {}}
+{"_id": "5884524", "title": "", "text": "Impact of diabetes on long-term prognosis in patients with unstable angina and non-Q-wave myocardialinfarction: results of the OASIS (Organization to Assess Strategies for Ischemic Syndromes)Registry.BACKGROUND Although unstable coronary artery disease is the most common reason foradmission to a coronary care unit, the long-term prognosis of patients with this diagnosis is unknown.This is particularly true for patients with diabetes mellitus, who are known to have a high morbidity andmortality after an acute myocardial infarction. METHODS AND RESULTS Prospectively collected data from6 different countries in the Organization to Assess Strategies for Ischemic Syndromes (OASIS) registrywere analyzed to determine the 2-year prognosis of diabetic and nondiabetic patients who werehospitalized with unstable angina or non-Q-wave myocardial infarction. Overall, 1718 of 8013 registrypatients (21%) had diabetes. Diabetic patients had a higher rate of coronary bypass surgery thannondiabetic patients (23% versus 20%, P:<0.001) but had similar rates of catheterization andangioplasty. Diabetes independently predicted mortality (relative risk [RR], 1.57; 95% CI, 1.38 to 1.81;P:<0.001), as well as cardiovascular death, new myocardial infarction, stroke, and new congestive heartfailure. Moreover, compared with their nondiabetic counterparts, women had a significantly higher riskthan men (RR, 1.98; 95% CI, 1.60 to 2.44; and RR, 1.28; 95% CI, 1.06 to 1.56, respectively).Interestingly, diabetic patients without prior cardiovascular disease had the same event rates for alloutcomes as nondiabetic patients with previous vascular disease. CONCLUSIONS Hospitalization forunstable angina or non-Q-wave myocardial infarction predicts a high 2-year morbidity and mortality; thisis especially evident for patients with diabetes. Diabetic patients with no previous cardiovascular diseasehave the same long-term morbidity and mortality as nondiabetic patients with established cardiovasculardisease after hospitalization for unstable coronary artery disease.", "metadata": {}}
+{"_id": "5885376", "title": "", "text": "Strain improvement by metabolic engineering: lysine production as a case study for systems biology.Acentral goal of systems biology is the elucidation of cell function and physiology through the integrateduse of broad based genomic and physiological data. Such systemic approaches have been employedextensively in the past, as they are a central element of metabolic flux analysis, the distribution of kineticcontrol in pathways, and the key differentiating characteristic of metabolic engineering. In one casestudy, these tools have been applied to the improvement of lysine-producing strains of Corynebacteriumglutamicum. The systematic study of the physiology of this organism allowed the identification of specificmetabolic targets and subsequently led to significant improvements in product yield and productivity.This case study can serve as a guide for the development of systems biology tools for the utilization oflarge volumes of cell- and genome-wide transcriptional and physiological data.", "metadata": {}}
+{"_id": "5912283", "title": "", "text": "Cognitive behavioral therapy vs zopiclone for treatment of chronic primary insomnia in older adults: arandomized controlled trial.CONTEXT Insomnia is a common condition in older adults and is associatedwith a number of adverse medical, social, and psychological consequences. Previous research hassuggested beneficial outcomes of both psychological and pharmacological treatments, but blindedplacebo-controlled trials comparing the effects of these treatments are lacking. OBJECTIVE To examineshort- and long-term clinical efficacy of cognitive behavioral therapy (CBT) and pharmacologicaltreatment in older adults experiencing chronic primary insomnia. DESIGN, SETTING, AND PARTICIPANTSA randomized, double-blinded, placebo-controlled trial of 46 adults (mean age, 60.8 y; 22 women) withchronic primary insomnia conducted between January 2004 and December 2005 in a single Norwegianuniversity-based outpatient clinic for adults and elderly patients. INTERVENTION CBT (sleep hygiene,sleep restriction, stimulus control, cognitive therapy, and relaxation; n = 18), sleep medication (7.5-mgzopiclone each night; n = 16), or placebo medication (n = 12). All treatment duration was 6 weeks, andthe 2 active treatments were followed up at 6 months. MAIN OUTCOME MEASURES Ambulant clinicalpolysomnographic data and sleep diaries were used to determine total wake time, total sleep time, sleepefficiency, and slow-wave sleep (only assessed using polysomnography) on all 3 assessment points.RESULTS CBT resulted in improved short- and long-term outcomes compared with zopiclone on 3 out of 4outcome measures. For most outcomes, zopiclone did not differ from placebo. Participants receiving CBTimproved their sleep efficiency from 81.4% at pretreatment to 90.1% at 6-month follow-up comparedwith a decrease from 82.3% to 81.9% in the zopiclone group. Participants in the CBT group spent muchmore time in slow-wave sleep (stages 3 and 4) compared with those in other groups, and spent less timeawake during the night. Total sleep time was similar in all 3 groups; at 6 months, patients receiving CBThad better sleep efficiency using polysomnography than those taking zopiclone. CONCLUSION Theseresults suggest that interventions based on CBT are superior to zopiclone treatment both in short- andlong-term management of insomnia in older adults. TRIAL REGISTRATION clinicaltrials.gov Identifier:NCT00295386.", "metadata": {}}
+{"_id": "5914739", "title": "", "text": "Local changes in lipid environment of TCR microclusters regulate membrane binding by the CD3εcytoplasmic domainThe CD3ε and ζ cytoplasmic domains of the T cell receptor bind to the inner leaflet ofthe plasma membrane (PM), and a previous nuclear magnetic resonance structure showed that bothtyrosines of the CD3ε immunoreceptor tyrosine-based activation motif partition into the bilayer.Electrostatic interactions between acidic phospholipids and clusters of basic CD3ε residues werepreviously shown to be essential for CD3ε and ζ membrane binding. Phosphatidylserine (PS) is the mostabundant negatively charged lipid on the inner leaflet of the PM and makes a major contribution tomembrane binding by the CD3ε cytoplasmic domain. Here, we show that TCR triggering by peptide--MHCcomplexes induces dissociation of the CD3ε cytoplasmic domain from the plasma membrane. Release ofthe CD3ε cytoplasmic domain from the membrane is accompanied by a substantial focal reduction innegative charge and available PS in TCR microclusters. These changes in the lipid composition of TCRmicroclusters even occur when TCR signaling is blocked with a Src kinase inhibitor. Local changes in thelipid composition of TCR microclusters thus render the CD3ε cytoplasmic domain accessible during earlystages of T cell activation.", "metadata": {}}
+{"_id": "5921065", "title": "", "text": "Humans and great apes share a large frontal cortexSome of the outstanding cognitive capabilities ofhumans are commonly attributed to a disproportionate enlargement of the human frontal lobe duringevolution. This claim is based primarily on comparisons between the brains of humans and of otherprimates, to the exclusion of most great apes. We compared the relative size of the frontal cortices inliving specimens of several primate species, including all extant hominoids, using magnetic resonanceimaging. Human frontal cortices were not disproportionately large in comparison to those of the greatapes. We suggest that the special cognitive abilities attributed to a frontal advantage may be due todifferences in individual cortical areas and to a richer interconnectivity, none of which required anincrease in the overall relative size of the frontal lobe during hominid evolution.", "metadata": {}}
+{"_id": "5922085", "title": "", "text": "Virus-Plus-Susceptibility Gene Interaction Determines Crohn's Disease Gene Atg16L1 Phenotypes inIntestineIt is unclear why disease occurs in only a small proportion of persons carrying common riskalleles of disease susceptibility genes. Here we demonstrate that an interaction between a specific virusinfection and a mutation in the Crohn's disease susceptibility gene Atg16L1 induces intestinal pathologiesin mice. This virus-plus-susceptibility gene interaction generated abnormalities in granule packaging andunique patterns of gene expression in Paneth cells. Further, the response to injury induced by the toxicsubstance dextran sodium sulfate was fundamentally altered to include pathologies resembling aspects ofCrohn's disease. These pathologies triggered by virus-plus-susceptibility gene interaction were dependenton TNFalpha and IFNgamma and were prevented by treatment with broad spectrum antibiotics. Thus, weprovide a specific example of how a virus-plus-susceptibility gene interaction can, in combination withadditional environmental factors and commensal bacteria, determine the phenotype of hosts carryingcommon risk alleles for inflammatory disease.", "metadata": {}}
+{"_id": "5927534", "title": "", "text": "CaMKII Triggers the Diffusional Trapping of Surface AMPARs through Phosphorylation of StargazinTheCa(2+)/calmodulin-dependent protein kinase II (CaMKII) is critically required for the synapticrecruitment of AMPA-type glutamate receptors (AMPARs) during both development and plasticity.However, the underlying mechanism is unknown. Using single-particle tracking of AMPARs, we show thatCaMKII activation and postsynaptic translocation induce the synaptic trapping of AMPARs diffusing in themembrane. AMPAR immobilization requires both phosphorylation of the auxiliary subunit Stargazin andits binding to PDZ domain scaffolds. It does not depend on the PDZ binding domain of GluA1 AMPARsubunit nor its phosphorylation at Ser831. Finally, CaMKII-dependent AMPAR immobilization regulatesshort-term plasticity. Thus, NMDA-dependent Ca(2+) influx in the post-synapse triggers a CaMKII- andStargazin-dependent decrease in AMPAR diffusional exchange at synapses that controls synaptic function.", "metadata": {}}
+{"_id": "5935987", "title": "", "text": "Epigenetics in diabetic nephropathy, immunity and metabolismWhen it comes to the epigenome, there isa fine line between clarity and confusion-walk that line and you will discover another fascinating level oftranscription control. With the genetic code representing the cornerstone of rules for information that isencoded to proteins somewhere above the genome level there is a set of rules by which chemicalinformation is also read. These epigenetic modifications show a different side of the genetic code that isdiverse and regulated, hence modifying genetic transcription transiently, ranging from short- tolong-term alterations. While this complexity brings exquisite control it also poses a formidable challengeto efforts to decode mechanisms underlying complex disease. Recent technological and computationaladvances have improved unbiased acquisition of epigenomic patterns to improve our understanding ofthe complex chromatin landscape. Key to resolving distinct chromatin signatures of diabetic complicationsis the identification of the true physiological targets of regulatory proteins, such as reader proteins thatrecognise, writer proteins that deposit and eraser proteins that remove specific chemical moieties. Buthow might a diverse group of proteins regulate the diabetic landscape from an epigenomic perspective?Drawing from an ever-expanding compendium of experimental and clinical studies, this review details thecurrent state-of-play and provides a perspective of chromatin-dependent mechanisms implicated indiabetic complications, with a special focus on diabetic nephropathy. We hypothesise a codified signatureof the diabetic epigenome and provide examples of prime candidates for chemical modification. As for thepharmacological control of epigenetic marks, we explore future strategies to expedite and refine thesearch for clinically relevant discoveries. We also consider the challenges associated with therapeuticstrategies targeting epigenetic pathways.", "metadata": {}}
+{"_id": "5939172", "title": "", "text": "Drinking pattern and mortality: the Italian Risk Factor and Life Expectancy pooling project.PURPOSE Toanalyze the relationship between an aspect of drinking pattern (i.e., drinking with or without meals) andrisk of all-cause and specific-cause mortality. METHODS The Risk Factors and Life Expectancy Study, is apooling of a series of epidemiological studies conducted in Italy. Eight-thousand six-hundred andforty-seven men and 6521 women, age 30-59 at baseline, and free of cardiovascular disease, werefollowed for mortality from all causes, cardiovascular and noncardiovascular, during an average follow-upof 7 years. RESULTS Drinkers of wine outside meals exhibited higher death rates from all causes,noncardiovascular diseases, and cancer, as compared to drinkers of wine with meals. This associationwas independent from the cardiovascular disease (CVD) risk factors measured at baseline and theamount of alcohol consumed and seemed to be stronger in women as compared to men. CONCLUSIONSThe present results indicate that drinking patterns may have important health implications, and attentionshould be given to this aspect of alcohol use and its relationship to health outcomes. The relationshipbetween alcohol consumption and disease has been the focus of intensive scientific investigation (1-9).Most studies to date, however, have limitations. A major drawback is that limited information has beencollected regarding the complex issue of alcohol consumption. In many studies, ascertainment of alcoholconsumption frequently focused only on quantity of alcohol consumed without considering the manydifferent components of alcohol consumption, particularly drinking pattern (10-12). It has beenhypothesized, and preliminary data support the notion, that drinking pattern could have importantinfluences on determining the health effects of alcohol (13,14). The present study examines therelationship between one aspect of drinking pattern (drinking wine outside meals) and mortality in a largecohort of men and women.", "metadata": {}}
+{"_id": "5944514", "title": "", "text": "Pointing in the right direction: new developments in the field of planar cell polarityPlanar cell polarity(PCP) is observed in an array of developmental processes that involve collective cell movement and tissueorganization, and its disruption can lead to severe developmental defects. Recent studies in flies andvertebrates have identified new functions for PCP as well as new signalling components, and haveproposed new mechanistic models. However, despite this progress, the search to simplify principles ofunderstanding continues and important mechanistic uncertainties still pose formidable challenges.", "metadata": {}}
+{"_id": "5953485", "title": "", "text": "ADAR1 Forms a Complex with Dicer to Promote MicroRNA Processing and RNA-Induced GeneSilencingAdenosine deaminases acting on RNA (ADARs) are involved in RNA editing that convertsadenosine residues to inosine specifically in double-stranded RNAs. In this study, we investigated theinteraction of the RNA editing mechanism with the RNA interference (RNAi) machinery and found thatADAR1 forms a complex with Dicer through direct protein-protein interaction. Most importantly, ADAR1increases the maximum rate (Vmax) of pre-microRNA (miRNA) cleavage by Dicer and facilitates loadingof miRNA onto RNA-induced silencing complexes, identifying a new role of ADAR1 in miRNA processingand RNAi mechanisms. ADAR1 differentiates its functions in RNA editing and RNAi by the formation ofeither ADAR1/ADAR1 homodimer or Dicer/ADAR1 heterodimer complexes, respectively. As expected, theexpression of miRNAs is globally inhibited in ADAR1(-/-) mouse embryos, which, in turn, alters theexpression of their target genes and might contribute to their embryonic lethal phenotype.", "metadata": {}}
+{"_id": "5956016", "title": "", "text": "Interchangeability of Biosimilars: A European PerspectiveMany of the best-selling ‘blockbuster’ biologicalmedicinal products are, or will soon be, facing competition from similar biological medicinal products(biosimilars) in the EU. Biosimilarity is based on the comparability concept, which has been usedsuccessfully for several decades to ensure close similarity of a biological product before and after amanufacturing change. Over the last 10 years, experience with biosimilars has shown that even complexbiotechnology-derived proteins can be copied successfully. Most best-selling biologicals are used forchronic treatment. This has triggered intensive discussion on the interchangeability of a biosimilar with itsreference product, with the main concern being immunogenicity. We explore the theoretical basis of thepresumed risks of switching between a biosimilar and its reference product and the available data onswitches. Our conclusion is that a switch between comparable versions of the same active substanceapproved in accordance with EU legislation is not expected to trigger or enhance immunogenicity. On thebasis of current knowledge, it is unlikely and very difficult to substantiate that two products, comparableon a population level, would have different safety or efficacy in individual patients upon a switch. Ourconclusion is that biosimilars licensed in the EU are interchangeable.", "metadata": {}}
+{"_id": "5956380", "title": "", "text": "Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomasGliomasarising in the brainstem and thalamus are devastating tumors that are difficult to surgically resect. Todetermine the genetic and epigenetic landscape of these tumors, we performed exomic sequencing of 14brainstem gliomas (BSGs) and 12 thalamic gliomas. We also performed targeted mutational analysis ofan additional 24 such tumors and genome-wide methylation profiling of 45 gliomas. This study led to thediscovery of tumor-specific mutations in PPM1D, encoding wild-type p53-induced protein phosphatase 1D(WIP1), in 37.5% of the BSGs that harbored hallmark H3F3A mutations encoding p. Lys27Metsubstitutions. PPM1D mutations were mutually exclusive with TP53 mutations in BSG and attenuated p53activation in vitro. PPM1D mutations were truncating alterations in exon 6 that enhanced the ability ofPPM1D to suppress the activation of the DNA damage response checkpoint protein CHK2. These resultsdefine PPM1D as a frequent target of somatic mutation and as a potential therapeutic target in brainstemgliomas.", "metadata": {}}
+{"_id": "5966635", "title": "", "text": "Crystal structure of a nucleosome core particle containing the variant histone H2A.ZActivation oftranscription within chromatin has been correlated with the incorporation of the essential histone variantH2A.Z into nucleosomes. H2A.Z and other histone variants may establish structurally distinctchromosomal domains; however, the molecular mechanism by which they function is largely unknown.Here we report the 2.6 Å crystal structure of a nucleosome core particle containing the histone variantH2A.Z. The overall structure is similar to that of the previously reported 2.8 Å nucleosome structurecontaining major histone proteins. However, distinct localized changes result in the subtle destabilizationof the interaction between the (H2A.Z–H2B) dimer and the (H3–H4)2 tetramer. Moreover, H2A.Znucleosomes have an altered surface that includes a metal ion. This altered surface may lead to changesin higher order structure, and/or could result in the association of specific nuclear proteins with H2A.Z.Finally, incorporation of H2A.Z and H2A within the same nucleosome is unlikely, due to significantchanges in the interface between the two H2A.Z–H2B dimers.", "metadata": {}}
+{"_id": "5979056", "title": "", "text": "Dendritic Cell KLF2 Expression Regulates T Cell Activation and Proatherogenic ImmuneResponses.Dendritic cells (DCs) have been implicated as important regulators of innate and adaptiveinflammation in many diseases, including atherosclerosis. However, the molecular mechanisms by whichDCs mitigate or promote inflammatory pathogenesis are only partially understood. Previous studies haveshown an important anti-inflammatory role for the transcription factor Krüppel-like factor 2 (KLF2) inregulating activation of various cell types that participate in atherosclerotic lesion development, includingendothelial cells, macrophages, and T cells. We used a pan-DC, CD11c-specific cre-lox gene knockoutmouse model to assess the role of KLF2 in DC activation, function, and control of inflammation in thecontext of hypercholesterolemia and atherosclerosis. We found that KLF2 deficiency enhanced surfaceexpression of costimulatory molecules CD40 and CD86 in DCs and promoted increased T cell proliferationand apoptosis. Transplant of bone marrow from mice with KLF2-deficient DCs into Ldlr-/- miceaggravated atherosclerosis compared with control mice, most likely due to heightened vascularinflammation evidenced by increased DC presence within lesions, enhanced T cell activation and cytokineproduction, and increased cell death in atherosclerotic lesions. Taken together, these data indicate thatKLF2 governs the degree of DC activation and hence the intensity of proatherogenic T cell responses.", "metadata": {}}
+{"_id": "5991309", "title": "", "text": "Targeting tumor-necrosis factor receptor pathways for tumor immunotherapyWith the success ofipilimumab and promise of programmed death-1 pathway-targeted agents, the field of tumorimmunotherapy is expanding rapidly. Newer targets for clinical development include select members ofthe tumor necrosis factor receptor (TNFR) family. Agonist antibodies to these co-stimulatory moleculestarget both T and B cells, modulating T-cell activation and enhancing immune responses. In vitro and invivo preclinical data have provided the basis for continued development of 4-1BB, OX40,glucocorticoid-induced TNFR-related gene, herpes virus entry mediator, and CD27 as potential therapiesfor patients with cancer. In this review, we summarize the immune response to tumors, considerpreclinical and early clinical data on select TNFR family members, discuss potential translationalchallenges and suggest possible combination therapies with the aim of inducing durable antitumorresponses.", "metadata": {}}
+{"_id": "5993745", "title": "", "text": "Plasma soluble corin in patients with heart failure.BACKGROUND Corin is a transmembrane protease thatprocesses natriuretic peptides in the heart. Like many membrane proteins, corin is shed from the cellsurface. METHODS AND RESULTS In this study, we obtained plasma samples from healthy controls andpatients with heart failure (HF) and acute myocardial infarction. Soluble corin levels in plasma weremeasured by an ELISA method. In healthy adults (n=198), plasma corin levels were 690 pg/mL (SD, 260pg/mL). The corin levels did not differ significantly among different age groups. In patients with HF(n=291), plasma corin levels were significantly lower compared with that of healthy controls (365 pg/mL[SD, 259]; P<0.001). The reduction in plasma corin levels seemed to correlate with the severity of HF. Inpatients of New York Heart Association classes II, III, and IV, plasma corin levels were 450 pg/mL (SD,281 pg/mL; n=69), 377 pg/mL (SD, 270 pg/mL; n=132), and 282 pg/mL (SD, 194 pg/mL; n=90),respectively (P<0.001 class II vs class IV; P<0.05 class III vs class IV). In contrast, plasma corin levelsin patients with acute myocardial infarction (n=73) were similar to that of healthy controls (678 pg/mL[SD, 285 pg/mL]; P>0.05). CONCLUSIONS Soluble corin was detected in human plasma. Plasma corinlevels were reduced significantly in patients with HF but not in those with acute myocardial infarction. Ourresults indicate that corin deficiency may contribute to the pathogenesis of HF and that plasma corin maybe used as a biomarker in the diagnosis of HF.", "metadata": {}}
+{"_id": "6000423", "title": "", "text": "The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype.Despitegenetic heterogeneity, myelodysplastic syndromes (MDSs) share features of cytological dysplasia andineffective hematopoiesis. We report that a hallmark of MDSs is activation of the NLRP3 inflammasome,which drives clonal expansion and pyroptotic cell death. Independent of genotype, MDS hematopoieticstem and progenitor cells (HSPCs) overexpress inflammasome proteins and manifest activated NLRP3complexes that direct activation of caspase-1, generation of interleukin-1β (IL-1β) and IL-18, andpyroptotic cell death. Mechanistically, pyroptosis is triggered by the alarmin S100A9 that is found inexcess in MDS HSPCs and bone marrow plasma. Further, like somatic gene mutations, S100A9-inducedsignaling activates NADPH oxidase (NOX), increasing levels of reactive oxygen species (ROS) that initiatecation influx, cell swelling, and β-catenin activation. Notably, knockdown of NLRP3 or caspase-1,neutralization of S100A9, and pharmacologic inhibition of NLRP3 or NOX suppress pyroptosis, ROSgeneration, and nuclear β-catenin in MDSs and are sufficient to restore effective hematopoiesis. Thus,alarmins and founder gene mutations in MDSs license a common redox-sensitive inflammasome circuit,which suggests new avenues for therapeutic intervention.", "metadata": {}}
+{"_id": "6036535", "title": "", "text": "Structural Brain Correlates Associated with Professional Handball PlayingBACKGROUND There is no doubtthat good bimanual performance is very important for skilled handball playing. The control of thenon-dominant hand is especially demanding since efficient catching and throwing needs both hands.METHODOLOGY/HYPOTHESES We investigated training-induced structural neuroplasticity in professionalhandball players using several structural neuroimaging techniques and analytic approaches and alsoprovide a review of the literature about sport-induced structural neuroplastic alterations. Structural brainadaptations were expected in regions relevant for motor and somatosensory processing such as the greymatter (GM) of the primary/secondary motor (MI/supplementary motor area, SMA) and somatosensorycortex (SI/SII), basal ganglia, thalamus, and cerebellum and in the white matter (WM) of thecorticospinal tract (CST) and corpus callosum, stronger in brain regions controlling the non-dominant lefthand. RESULTS Increased GM volume in handball players compared with control subjects were found inthe right MI/SI, bilateral SMA/cingulate motor area, and left intraparietal sulcus. Fractional anisotropy(FA) and axial diffusivity were increased within the right CST in handball players compared with controlwomen. Age of handball training commencement correlated inversely with GM volume in the right and leftMI/SI and years of handball training experience correlated inversely with radial diffusivity in the rightCST. Subcortical structures tended to be larger in handball players. The anatomical measures of the brainregions associated with handball playing were positively correlated in handball players, but notinterrelated in control women. DISCUSSION/CONCLUSION Training-induced structural alterations werefound in the somatosensory-motor network of handball players, more pronounced in the right hemispherecontrolling the non-dominant left hand. Correlations between handball training-related measures andanatomical differences suggest neuroplastic adaptations rather than a genetic predisposition for a ballplaying affinity. Investigations of neuroplasticity specifically in sportsmen might help to understand theneural mechanisms of expertise in general.", "metadata": {}}
+{"_id": "6040392", "title": "", "text": "The role of epigenetics in aging and age-related diseasesThe role of epigenetics in aging and age-relateddiseases is a key issue in molecular physiology and medicine because certain epigenetic factors arethought to mediate, at least in part, the relationship between the genome and the environment. An activerole for epigenetics in aging must meet two prior conditions: there must be specific epigenetic changesduring aging and they must be functionally associated with the aged phenotype. Assuming that specificepigenetic modifications can have a direct functional outcome in aging, it is also essential to establishwhether they depend on genetic, environmental or stochastic factors, and if they can be transmitted fromone generation to the next. Here we discuss current knowledge about these matters and future directionsin the field.", "metadata": {}}
+{"_id": "6042706", "title": "", "text": "Effects of a high-fat diet exposure in utero on the metabolic syndrome-like phenomenon in mouseoffspring through epigenetic changes in adipocytokine gene expression.The links between obesity inparents and their offspring and the role of genes and a shared environment are not completelyunderstood. Adipocytokines such as leptin and adiponectin play important roles in glucose and lipidmetabolism. Therefore, we examined whether the offspring from dams exposed to a high-fat diet duringpregnancy (OH mice) exhibited hypertension, insulin resistance, and hyperlipidemia along with epigeneticchanges in the expression of adipocytokine genes. OH mice were significantly heavier than the offspringof dams exposed to a control diet during pregnancy (OC mice) from 14 wk of age after an increasedcaloric intake from 8 wk. OH mice exhibited higher blood pressure and worse glucose tolerance than theOC mice at 24 wk. Total triglyceride and leptin levels were significantly higher and the adiponectin levelwas significantly lower in OH compared with OC mice at 12 wk of age. This was associated with changesin leptin and adiponectin expression in white adipose tissue. There were lower acetylation and highermethylation levels of histone H3 at lysine 9 of the promoter of adiponectin in adipose tissues of OH miceat 2 wk of age as well as at 12 and 24 wk of age compared with OC mice. In contrast, methylation ofhistone 4 at lysine 20 in the leptin promoter was significantly higher in OH compared with OC mice. Thus,exposure to a high-fat diet in utero might cause a metabolic syndrome-like phenomenon throughepigenetic modifications of adipocytokine, adiponectin, and leptin gene expression.", "metadata": {}}
+{"_id": "6054657", "title": "", "text": "Highly efficient miRNA-mediated reprogramming of mouse and human somatic cells topluripotency.Transcription factor-based cellular reprogramming has opened the way to convertingsomatic cells to a pluripotent state, but has faced limitations resulting from the requirement fortranscription factors and the relative inefficiency of the process. We show here that expression of themiR302/367 cluster rapidly and efficiently reprograms mouse and human somatic cells to an iPSC statewithout a requirement for exogenous transcription factors. This miRNA-based reprogramming approach istwo orders of magnitude more efficient than standard Oct4/Sox2/Klf4/Myc-mediated methods. Mouse andhuman miR302/367 iPSCs display similar characteristics to Oct4/Sox2/Klf4/Myc-iPSCs, includingpluripotency marker expression, teratoma formation, and, for mouse cells, chimera contribution andgermline contribution. We found that miR367 expression is required for miR302/367-mediatedreprogramming and activates Oct4 gene expression, and that suppression of Hdac2 is also required.Thus, our data show that miRNA and Hdac-mediated pathways can cooperate in a powerful way toreprogram somatic cells to pluripotency.", "metadata": {}}
+{"_id": "6057195", "title": "", "text": "Unmet needs and depression among carers of people newly diagnosed with cancer.AIMS The aims of thisanalysis were to examine levels of unmet needs and depression among carers of people newly diagnosedwith cancer and to identify groups who may be at higher risk, by examining relationships withdemographic characteristics. METHODS One hundred and fifty dyads of people newly diagnosed withcancer and their carers, aged 18 years and older, were recruited from four Australian hospitals. Peoplewith cancer receiving adjuvant cancer treatment with curative intent, were eligible to participate. Carerscompleted the Supportive Care Needs Survey-Partners & Caregivers (SCNS-P&C45), and both carers andpatients completed the Centre of Epidemiologic-Depression Scale (CES-D). RESULTS Overall, 57% ofcarers reported at least one, 37% at least three, 31% at least five, and 15% at least 10 unmet needs;the most commonly endorsed unmet needs were in the domains of information and health care serviceneeds. Thirty percent of carers and 36% of patients were at risk of clinical depression. A weak tomoderate positive relationship was observed between unmet needs and carer depression (r=0.30,p<0.001). Carer levels of unmet needs were significantly associated with carer age, hospital type,treatment type, cancer type, living situation, relationship status (in both uni- and multi-factor analysis);person with cancer age and carer level of education (in unifactor analysis only); but not with carer genderor patient gender (in both uni- and multi-factor analyses). CONCLUSION Findings highlight theimportance of developing tailored programmes to systematically assist carers who are supportingpatients through the early stages of cancer treatment.", "metadata": {}}
+{"_id": "6061927", "title": "", "text": "Glucose Sensing in L Cells: A Primary Cell StudyGlucagon-like peptide-1 (GLP-1) is an enteric hormonethat stimulates insulin secretion and improves glycaemia in type 2 diabetes. Although GLP-1-basedtreatments are clinically available, alternative strategies to increase endogenous GLP-1 release from Lcells are hampered by our limited physiological understanding of this cell type. By generating transgenicmice with L cell-specific expression of a fluorescent protein, we studied the characteristics of primary Lcells by electrophysiology, fluorescence calcium imaging, and expression analysis and show that single Lcells are electrically excitable and glucose responsive. Sensitivity to tolbutamide and low-millimolarconcentrations of glucose and alpha-methylglucopyranoside, assessed in single L cells and by hormonesecretion from primary cultures, suggested that GLP-1 release is regulated by the activity of sodiumglucose cotransporter 1 and ATP-sensitive K(+) channels, consistent with their high expression levels inpurified L cells by quantitative RT-PCR. These and other pathways identified using this approach willprovide exciting opportunities for future physiological and therapeutic exploration.", "metadata": {}}
+{"_id": "6070278", "title": "", "text": "Total atherosclerotic burden by whole body magnetic resonance angiography predicts major adversecardiovascular events.OBJECTIVE The purpose of the present study was to investigate the relationshipbetween the Total Atherosclerotic Score (TAS), a measurement of the overall atherosclerotic burden ofthe arterial tree by whole body magnetic resonance angiography (WBMRA), and the risk of major adversecardiovascular events (MACE), defined as cardiac death, myocardial infarction, stroke and/or coronaryrevascularization, assuming that TAS predicts MACE. METHODS AND RESULTS 305 randomly selected 70year-old subjects (47% women) underwent WBMRA. Their atherosclerotic burden was evaluated and TAS> 0, that is atherosclerotic changes, were found in 68% of subjects. During follow-up (mean 4.8 years),MACE occurred in 25 subjects (8.2%). Adjusting for multiple risk factors, TAS was associated with MACE(OR 8.86 for any degree of vessel lumen abnormality, 95%CI 1.14-69.11, p = 0.037). In addition, TASimproved discrimination and reclassification when added to the Framingham risk score (FRS), and ROC(Receiver Operator Curve) increased from 0.681 to 0.750 (p = 0.0421). CONCLUSION In apopulation-based sample of 70 year old men and women WBMRA, with TAS, predicted MACEindependently of major cardiovascular risk factors.", "metadata": {}}
+{"_id": "6076903", "title": "", "text": "Regulation of ADMP and BMP2/4/7 at Opposite Embryonic Poles Generates a Self-RegulatingMorphogenetic FieldEmbryos have the ability to self-regulate and regenerate normal structures afterbeing sectioned in half. How is such a morphogenetic field established? We discovered that quadrupleknockdown of ADMP and BMP2/4/7 in Xenopus embryos eliminates self-regulation, causing ubiquitousneural induction throughout the ectoderm. ADMP transcription in the Spemann organizer is activated atlow BMP levels. When ventral BMP2/4/7 signals are depleted, Admp expression increases, allowing forself-regulation. ADMP has BMP-like activity and signals via the ALK-2 receptor. It is unable to signaldorsally because of inhibition by Chordin. The ventral BMP antagonists Sizzled and Bambi further refinethe pattern. By transplanting dorsal or ventral wild-type grafts into ADMP/BMP2/4/7-depleted hosts, wedemonstrate that both poles serve as signaling centers that can induce histotypic differentiation overconsiderable distances. We conclude that dorsal and ventral BMP signals and their extracellularantagonists expressed under opposing transcriptional regulation provide a molecular mechanism forembryonic self-regulation.", "metadata": {}}
+{"_id": "6077214", "title": "", "text": "Genetic control of mosquitoes.Genetics can potentially provide new, species-specific, environmentallyfriendly methods for mosquito control. Genetic control strategies aim either to suppress targetpopulations or to introduce a harm-reducing novel trait. Different approaches differ considerably in theirproperties, especially between self-limiting strategies, where the modification has limited persistence,and self-sustaining strategies, which are intended to persist indefinitely in the target population and mayinvade other populations. Several methods with different molecular biology are under development andthe first field trials have been completed successfully.", "metadata": {}}
+{"_id": "6078882", "title": "", "text": "Colorectal Cancers from Distinct Ancestral Populations Show Variations in BRAF Mutation FrequencyIt hasbeen demonstrated for some cancers that the frequency of somatic oncogenic mutations may vary inancestral populations. To determine whether key driver alterations might occur at different frequencies incolorectal cancer, we applied a high-throughput genotyping platform (OncoMap) to query 385 mutationsacross 33 known cancer genes in colorectal cancer DNA from 83 Asian, 149 Black and 195 White patients.We found that Asian patients had fewer canonical oncogenic mutations in the genes tested (60% vs Black79% (P = 0.011) and White 77% (P = 0.015)), and that BRAF mutations occurred at a higher frequencyin White patients (17% vs Asian 4% (P = 0.004) and Black 7% (P = 0.014)). These results suggest thatthe use of genomic approaches to elucidate the different ancestral determinants harbored by patientpopulations may help to more precisely and effectively treat colorectal cancer.", "metadata": {}}
+{"_id": "6079486", "title": "", "text": "Direct neuronal reprogramming: learning from and for development.The key signalling pathways andtranscriptional programmes that instruct neuronal diversity during development have largely beenidentified. In this Review, we discuss how this knowledge has been used to successfully reprogrammevarious cell types into an amazing array of distinct types of functional neurons. We further discuss theextent to which direct neuronal reprogramming recapitulates embryonic development, and examine theparticular barriers to reprogramming that may exist given a cell's unique developmental history. Weconclude with a recently proposed model for cell specification called the 'Cook Islands' model, andconsider whether it is a fitting model for cell specification based on recent results from the directreprogramming field.", "metadata": {}}
+{"_id": "6082738", "title": "", "text": "Cell fusion hypothesis of the cancer stem cell.A major advance in recent cancer research is theidentification of tumor cells with stem cell-like properties. Cancer stem cells (CSCs) often represent a rarepopulation in the tumor mass and possess the exclusive ability to initiate the growth of a heterogeneoustumor. The origin of CSCs remains elusive and is likely to be cancer type specific. One possible butunder-appreciated potential mechanism for the generation of CSCs is through fusion between stem cellsand differentiated cells. The cell fusion hypothesis of CSCs adds an important functional underpinning tothe potential multifaceted roles of cell fusion in the initiation and progression of cancer.", "metadata": {}}
+{"_id": "6083952", "title": "", "text": "Antidepressant fluoxetine enhances glucocorticoid receptor function in vitro by modulating membranesteroid transporters.1. Incubation of LMCAT fibroblast cells with antidepressants potentiatesglucocorticoid receptor (GR)-mediated gene transcription in the presence of dexamethasone and cortisol,but not of corticosterone. We have shown that antidepressants do so by inhibiting the LMCAT cellmembrane steroid transporter (which is virtually identical to the multidrug resistance P-glycoprotein) andthus by increasing dexamethasone or cortisol intracellular concentrations. However, previousexperiments with the antidepressant fluoxetine in the presence of dexamethasone have producednegative results (Pariante et al. (2001). Br. J. Pharmacol., 134, 1335-1343). 2. We have sincere-examined the effects of fluoxetine on GR-mediated gene transcription in the presence ofdexamethasone. Moreover, we have examined the effects of fluoxetine on GR-mediated genetranscription in the presence of cortisol and corticosterone, and on the intracellular accumulation ofradioactive cortisol and corticosterone. Finally, we have examined the effects of fluoxetine on inhibition ofP-glycoprotein activity in Caco-2 cells. 3. We now find that fluoxetine (1-10 micro M) enhancesGR-mediated gene transcription in the presence of dexamethasone and cortisol (+140-170%), but not ofcorticosterone, and increases the intracellular accumulation of (3)H-cortisol (+5-15%), but not of(3)H-corticosterone. Moreover, fluoxetine (10 micro M) induces approximately 30% inhibition of PGPactivity in Caco-2 cells. 4. Our results show that fluoxetine, like other antidepressants, inhibits membranesteroid transporters.", "metadata": {}}
+{"_id": "6085365", "title": "", "text": "Physician knowledge levels and barriers to coronary risk prevention in women: survey results from theWomen and Heart Disease Physician Education Initiative.BACKGROUND Few studies have examinedwhether physician knowledge, attitudes, or practice patterns might contribute to gender disparities in theprimary prevention of coronary heart disease (CHD), including among physicians caring for the largestnumber of reproductive-age women, obstetricians and gynecologists (OB/GYNs). We sought to identifybarriers affecting the provision of recommended coronary risk factor therapies in women. METHODS Wesurveyed internists and OB/GYNs who attended Grand Rounds presentations developed for the New YorkState Women and Heart Disease Physician Education Initiative. This program was designed to improvescreening and management of coronary risk factors in women. Attendees were asked to complete a7-minute questionnaire. RESULTS The mean age of the 529 respondents was 40.3 years (standarddeviation = 12.3), 75.1% were internists (n=378), and 42.7% (n=226) were women. Physicianscorrectly responded to 71.5% of the 13 questions assessing knowledge of coronary risk prevention(range, 4-13). Almost one third of internists and half of the OB/GYNs did not know that tobacco use wasthe leading cause of myocardial infarction in young women. For patients who smoked tobacco, only twothirds of internists and 55.4% of OB/GYNs reported suggesting a quit date (p=.007). After controlling forcovariates, physicians who did not perceive time as a barrier were more likely to discuss smokingcessation (odds ratio=1.7 [1.1-2.7]). CONCLUSIONS Among the internists and OB/GYNs surveyed, timewas perceived as a barrier to implementing risk prevention. These physicians also underestimated theimpact of tobacco use as a risk factor for CHD in young women. To lessen gender disparities in CHDprevention, both specialties need time-efficient educational programs that reflect specialty differences.", "metadata": {}}
+{"_id": "6106004", "title": "", "text": "Separation of mother and daughter cells.Publisher Summary The budding yeast Saccharomycescerevisiae ( S. cerevisiae ) divides asymmetrically. In vegetative growth, yeast cells reproduce bybudding, and the position where the bud forms ultimately determines the plane of cell division. Thischapter describes the detailed procedures for the separation and isolation of mothers and daughters.These protocols have been used by investigators studying aging, bud site selection, and other aspects ofasymmetric cell division. The chapter describes the procedures for performing life span analysis bymicromanipulation and the steps for the large-scale collection of old cells. At the beginning and the end ofa life span, it can be difficult to distinguish mothers from daughters. At most points in the life span,daughter cells are smaller than the mothers that produced them. In addition, mother cells will generallybud a second time before their daughter cells form their first bud. One method for effective isolation ofvirgin daughter cells from mother cells, but not for recovery of old mothers, is called a “baby machine. ”Mother cells are attached to a membrane and allowed to divide. Daughter cells from these attached cellsare eluted continuously by washing the membrane.", "metadata": {}}
+{"_id": "6108481", "title": "", "text": "Postnatal development of adipocyte cellularity in the normal rat.It has been shown by severalinvestigators that adipocyte number is stable in mature human beings and several species of rodents.Although the number of new cells appearing in the adipose depot can be measured histometrically and byCoulter counting of osmium-fixed cells, such methods do not distinguish between \"lipid filling\" ofpreexistent adipocytes and synthesis of new adipocytes. The experiments reported here using in vivoinjection of [(3)H]thymidine show that synthesis of new adipocytes in the Sprague-Dawley rat continuesafter birth and ceases before sexual maturity. Furthermore, during the second and third postnatal weeks,a \"bed\" of preadipocytes is synthesized. Preadipocytes may take as long as 30 days to appear as matureadipocytes.", "metadata": {}}
+{"_id": "6112053", "title": "", "text": "Withdrawal Symptoms after Selective Serotonin Reuptake Inhibitor Discontinuation: A SystematicReviewBackground: Selective serotonin reuptake inhibitors (SSRI) are widely used in medical practice.They have been associated with a broad range of symptoms, whose clinical meaning has not been fullyappreciated. Methods: The PRISMA guidelines were followed to conduct a systematic review of theliterature. Titles, abstracts, and topics were searched using the following terms: ‘withdrawal symptoms'OR ‘withdrawal syndrome' OR ‘discontinuation syndrome' OR ‘discontinuation symptoms', AND ‘SSRI' OR‘serotonin' OR ‘antidepressant' OR ‘paroxetine' OR ‘fluoxetine' OR ‘sertraline' OR ‘fluvoxamine' OR‘citalopram' OR ‘escitalopram'. The electronic research literature databases included CINAHL, theCochrane Library, PubMed and Web-of-Science from inception of each database to July 2014. Results:There were 15 randomized controlled studies, 4 open trials, 4 retrospective investigations, and 38 casereports. The prevalence of the syndrome was variable, and its estimation was hindered by a lack of caseidentification in many studies. Symptoms typically occur within a few days from drug discontinuation andlast a few weeks, also with gradual tapering. However, many variations are possible, including late onsetand/or longer persistence of disturbances. Symptoms may be easily misidentified as signs of impendingrelapse. Conclusions: Clinicians need to add SSRI to the list of drugs potentially inducing withdrawalsymptoms upon discontinuation, together with benzodiazepines, barbiturates, and other psychotropicdrugs. The term ‘discontinuation syndrome' that is currently used minimizes the potential vulnerabilitiesinduced by SSRI and should be replaced by ‘withdrawal syndrome'.", "metadata": {}}
+{"_id": "6121555", "title": "", "text": "Sphingosine Kinase 1 Regulates the Akt/FOXO3a/Bim Pathway and Contributes to Apoptosis Resistance inGlioma CellsThe aim of this study was to investigate the mechanism through which Sphingosine kinase-1(SPHK1) exerts its anti-apoptosis activity in glioma cancer cells. We here report that dysregulation ofSPHK1 alters the sensitivity of glioma to apoptosis both in vitro and in vivo. Further mechanistic studyexamined the expression of Bcl-2 family members, including Bcl-2, Mcl-1, Bax and Bim, inSPHK1-overexpressing glioma cells and revealed that only pro-apoptotic Bim was downregulated bySPHK1. Moreover, the transcriptional level of Bim was also altered by SPHK1 in glioma cells. We nextconfirmed the correlation between SPHK1 and Bim expression in primary glioma specimens. Importantly,increasing SPHK1 expression in glioma cells markedly elevated Akt activity and phosphorylatedinactivation of FOXO3a, which led to downregulation of Bim. A pharmacological approach showed thatthese effects of SPHK1 were dependent on phosphatidylinositol 3-kinase (PI3K). Furthermore, effects ofSPHK1 on Akt/FOXO3a/Bim pathway could be reversed by SPHK1 specific RNA interference or SPHK1inhibitor. Collectively, our results indicate that regulation of the Akt/FOXO3a/Bim pathway may be anovel mechanism by which SPHK1 protects glioma cells from apoptosis, thereby involved in gliomatumorigenesis.", "metadata": {}}
+{"_id": "6121668", "title": "", "text": "COX-2 and survivin are overexpressed and positively correlated in endometrial carcinoma.OBJECTIVES Toinvestigate the expressions of survivin and Cyclooxygenase-2 (COX-2), and their possible correlations inthe development of endometrial adenocarcinoma (EC). We also looked at their association with classicalprognostic factors in EC. To our knowledge, this is the first time survivin expression is investigated interms of its relation to COX-2 in the developmental pathway of EC. METHODS Archived tissue samples of50 EC, 30 endometrial hyperplasia and 20 proliferative endometrium were selected andimmunohistochemically analyzed for survivin and COX-2 expression. RESULTS Both survivin and COX-2were overexpressed in hyperplasia and endometrial adenocarcinoma cases compared to proliferativeendometrium, which was statistically significant (p=0.01, p=0.02, respectively). Among EC cases,survivin and COX-2 were strongly positive in 38 (76%) and 30 (60%) patients, respectively.Furthermore, we found survivin and COX-2 to be positively correlated, which was also statisticallysignificant (p=0.0001, r=0.46). Neither survivin nor COX-2 expression was correlated with classicalprognostic factors of endometrial carcinoma such as myometrial invasion, grade or lymph nodemetastasis (p>0.05). Neither COX-2 nor survivin had an impact on overall survival (p>0.05).CONCLUSIONS Both survivin and COX-2 are overexpressed, and they seem to be early events in theoccurrence of EC. Moreover, protein products of these two genes are positively correlated. COX-2 andsurvivin might share a common molecular pathway or enhance each other's actions in the developmentalpathway of EC. Molecular basis of such a relationship should be further investigated in endometrialcarcinogenesis.", "metadata": {}}
+{"_id": "6123521", "title": "", "text": "Structural plasticity of the adult brain: how animal models help us understand brain changes indepression and systemic disorders related to depressionThe brain interprets experiences and translatesthem into behavioral and physiological responses. Stressful events are those which are threatening or, atthe very least, unexpected and surprising, and the physiological and behavioral responses are intended topromote adaptation via a process called \"allostasis. \" Chemical mediators of allostasis include cortisol andadrenalin from the adrenal glands, other hormones, and neurotransmitters, the parasympathetic andsympathetic nervous systems, and cytokines and chemokines from the immune system. Two brainstructures, the amygdala and hippocampus, play key roles in interpreting what is stressful anddetermining appropriate responses. The hippocampus, a key structure for memories of events andcontexts, expresses receptors that enable it to respond to glucocorticoid hormones in the blood, itundergoes atrophy in a number of psychiatric disorders; it also responds to stressors with changes inexcitability, decreased dendritic branching, and reduction in number of neurons in the dentate gyrus. Theamygdala, which is important for \"emotional memories, \" becomes hyperactive in posttraumatic stressdisorder and depressive illness, in animal models of stress, there is evidence for growth and hypertrophyof nerve cells in the amygdala. Changes in the brain after acute and chronic stressors mirror the patternseen in the metabolic, cardiovascular, and immune systems, that is, short-term adaptation (allostasis)followed by long-term damage (allostatic load), eg, atherosclerosis, fat deposition obesity, bonedemineralization, and impaired immune function. Allostatic load of this kind is seen in major depressiveillness and may also be expressed in other chronic anxiety and mood disorders.", "metadata": {}}
+{"_id": "6123924", "title": "", "text": "CCR7 provides localized access to IL-2 and defines homeostatically distinct regulatory T cellsubsetsImmune tolerance and activation depend on precise control over the number and function ofimmunosuppressive Foxp3(+) regulatory T (T reg) cells, and the importance of IL-2 in maintainingtolerance and preventing autoimmunity is clear. However, the homeostatic requirement for IL-2 amongspecific populations of peripheral T reg cells remains poorly understood. We show that IL-2 selectivelymaintains a population of quiescent CD44(lo)CD62L(hi) T reg cells that gain access to paracrine IL-2produced in the T cell zones of secondary lymphoid tissues due to their expression of the chemokinereceptor CCR7. In contrast, CD44(hi)CD62L(lo)CCR7(lo) T reg cells that populate nonlymphoid tissues donot access IL-2-prevalent regions in vivo and are insensitive to IL-2 blockade; instead, their maintenancedepends on continued signaling through the co-stimulatory receptor ICOS (inducible co-stimulator). Thus,we define a fundamental homeostatic subdivision in T reg cell populations based on their localization andprovide an integrated framework for understanding how T reg cell abundance and function are controlledby unique signals in different tissue environments.", "metadata": {}}
+{"_id": "6128334", "title": "", "text": "Assessing sequence comparison methods with reliable structurally identified distant evolutionaryrelationships.Pairwise sequence comparison methods have been assessed using proteins whoserelationships are known reliably from their structures and functions, as described in the SCOP database[Murzin, A. G., Brenner, S. E., Hubbard, T. & Chothia C. (1995) J. Mol. Biol. 247, 536-540]. Theevaluation tested the programs BLAST [Altschul, S. F., Gish, W., Miller, W., Myers, E. W. & Lipman, D. J.(1990). J. Mol. Biol. 215, 403-410], WU-BLAST2 [Altschul, S. F. & Gish, W. (1996) Methods Enzymol.266, 460-480], FASTA [Pearson, W. R. & Lipman, D. J. (1988) Proc. Natl. Acad. Sci. USA 85, 2444-2448],and SSEARCH [Smith, T. F. & Waterman, M. S. (1981) J. Mol. Biol. 147, 195-197] and their scoringschemes. The error rate of all algorithms is greatly reduced by using statistical scores to evaluatematches rather than percentage identity or raw scores. The E-value statistical scores of SSEARCH andFASTA are reliable: the number of false positives found in our tests agrees well with the scores reported.However, the P-values reported by BLAST and WU-BLAST2 exaggerate significance by orders ofmagnitude. SSEARCH, FASTA ktup = 1, and WU-BLAST2 perform best, and they are capable of detectingalmost all relationships between proteins whose sequence identities are >30%. For more distantly relatedproteins, they do much less well; only one-half of the relationships between proteins with 20-30%identity are found. Because many homologs have low sequence similarity, most distant relationshipscannot be detected by any pairwise comparison method; however, those which are identified may beused with confidence.", "metadata": {}}
+{"_id": "6129301", "title": "", "text": "Evaluation of a mental health outreach service for homeless families.AIMS To describe the characteristicsof homeless children and families seen by the mental health outreach service (MHOS), to evaluate theimpact of this service on the short term psychosocial functioning of children and parents, and to establishperceptions of, and satisfaction with, the service. METHODS Twenty seven children from 23 families whowere in receipt of the MHOS and 27 children from 23 families residing in other hostels where no suchservice was available were studied. The MHOS was delivered by a clinical nurse specialist with expertisein child mental health, who offered the following interventions: assessment and brief treatment of mentalhealth disorders in children; liaison with agencies; and training of homeless centre staff. RESULTSChildren in the experimental group had a significantly higher decrease in Strengths and DifficultiesQuestionnaire (SDQ) total scores. Having received the intervention was the strongest predictor ofimprovement in SDQ total scores. There was no significant impact on parental mental health (GeneralHealth Questionnaire) scores. Homeless families and staff expressed high satisfaction with the MHOS.CONCLUSION This MHOS for homeless families is an innovative intervention which meets the complexand multiple needs of a vulnerable population unable to access mainstream mental health services. Theprimary objective of the service was to improve child mental health problems; however, the servicedeveloped in a responsive way by meeting social and practical needs of families in addition to its clinicalrole.", "metadata": {}}
+{"_id": "6137330", "title": "", "text": "Evaluation of individuals with pulmonary nodules: when is it lung cancer? Diagnosis and management oflung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practiceguidelines.OBJECTIVES The objective of this article is to update previous evidence-basedrecommendations for evaluation and management of individuals with solid pulmonary nodules and togenerate new recommendations for those with nonsolid nodules. METHODS We updated prior literaturereviews, synthesized evidence, and formulated recommendations by using the methods described in the\"Methodology for Development of Guidelines for Lung Cancer\" in the American College of ChestPhysicians Lung Cancer Guidelines, 3rd ed. RESULTS We formulated recommendations for evaluatingsolid pulmonary nodules that measure > 8 mm in diameter, solid nodules that measure ≤ 8 mm indiameter, and subsolid nodules. The recommendations stress the value of assessing the probability ofmalignancy, the utility of imaging tests, the need to weigh the benefits and harms of differentmanagement strategies (nonsurgical biopsy, surgical resection, and surveillance with chest CT imaging),and the importance of eliciting patient preferences. CONCLUSIONS Individuals with pulmonary nodulesshould be evaluated and managed by estimating the probability of malignancy, performing imaging teststo better characterize the lesions, evaluating the risks associated with various management alternatives,and eliciting their preferences for management.", "metadata": {}}
+{"_id": "6144337", "title": "", "text": "AgDscam, a Hypervariable Immunoglobulin Domain-Containing Receptor of the       Anopheles gambiaeInnate Immune SystemActivation of the insect innate immune system is dependent on a limited numberof pattern recognition receptors (PRRs) capable of interacting with pathogen-associated molecularpattern. Here we report a novel role of an alternatively spliced hypervariable immunoglobulindomain-encoding gene, Dscam, in generating a broad range of PRRs implicated in immune defense in themalaria vector Anopheles gambiae. The mosquito Down syndrome cell adhesion molecule gene,AgDscam, has a complex genome organization with 101 exons that can produce over 31,000 potentialalternative splice forms with different combinations of adhesive domains and interaction specificities.AgDscam responds to infection by producing pathogen challenge-specific splice form repertoires.Transient silencing of AgDscam compromises the mosquito's resistance to infections with bacteria and themalaria parasite Plasmodium. AgDscam is mediating phagocytosis of bacteria with which it can associateand defend against in a splice form–specific manner. AgDscam is a hypervariable PRR of the A. gambiaeinnate immune system.", "metadata": {}}
+{"_id": "6144969", "title": "", "text": "Enterovirus-induced gene expression profile is critical for human pancreatic islet destructionVirallyinduced inflammatory responses, beta cell destruction and release of beta cell autoantigens may lead toautoimmune reactions culminating in type 1 diabetes. Therefore, viral capability to induce beta cell deathand the nature of virus-induced immune responses are among key determinants of diabetogenic viruses.We hypothesised that enterovirus infection induces a specific gene expression pattern that results in isletdestruction and that such a host response pattern is not shared among all enterovirus infections butvaries between virus strains. The changes in global gene expression and secreted cytokine profilesinduced by lytic or benign enterovirus infections were studied in primary human pancreatic islet usingDNA microarrays and viral strains either isolated at the clinical onset of type 1 diabetes or capable ofcausing a diabetes-like condition in mice. The expression of pro-inflammatory cytokine genes (IL-1-α,IL-1-β and TNF-α) that also mediate cytokine-induced beta cell dysfunction correlated with the lyticpotential of a virus. Temporally increasing gene expression levels of double-stranded RNA recognitionreceptors, antiviral molecules, cytokines and chemokines were detected for all studied virus strains. Lyticcoxsackievirus B5 (CBV-5)-DS infection also downregulated genes involved in glycolysis and insulinsecretion. The results suggest a distinct, virus-strain-specific, gene expression pattern leading topancreatic islet destruction and pro-inflammatory effects after enterovirus infection. However, neitherviral replication nor cytotoxic cytokine production alone are sufficient to induce necrotic cell death. Morelikely the combined effect of these and possibly cellular energy depletion lie behind theenterovirus-induced necrosis of islets.", "metadata": {}}
+{"_id": "6148876", "title": "", "text": "Islet1 derivatives in the heart are of both neural crest and second heart field origin.RATIONALE Islet1(Isl1) has been proposed as a marker of cardiac progenitor cells derived from the second heart field andis utilized to identify and purify cardiac progenitors from murine and human specimens for ex vivoexpansion. The use of Isl1 as a specific second heart field marker is dependent on its exclusion fromother cardiac lineages such as neural crest. OBJECTIVE Determine whether Isl1 is expressed by cardiacneural crest. METHODS AND RESULTS We used an intersectional fate-mapping system using theRC::FrePe allele, which reports dual Flpe and Cre recombination. Combining Isl1(Cre/+), a SHF driver,and Wnt1::Flpe, a neural crest driver, with Rc::FrePe reveals that some Isl1 derivatives in the cardiacoutflow tract derive from Wnt1-expressing neural crest progenitors. In contrast, no overlap was observedbetween Wnt1-derived neural crest and an alternative second heart field driver, Mef2c-AHF-Cre.CONCLUSIONS Isl1 is not restricted to second heart field progenitors in the developing heart but alsolabels cardiac neural crest. The intersection of Isl1 and Wnt1 lineages within the heart provides a caveatto using Isl1 as an exclusive second heart field cardiac progenitor marker and suggests that someIsl1-expressing progenitor cells derived from embryos, embryonic stem cultures, or induced pluripotentstem cultures may be of neural crest lineage.", "metadata": {}}
+{"_id": "6153754", "title": "", "text": "Review of the secondary injury theory of acute spinal cord trauma with emphasis on vascularmechanisms.In patients with spinal cord injury, the primary or mechanical trauma seldom causes totaltransection, even though the functional loss may be complete. In addition, biochemical and pathologicalchanges in the cord may worsen after injury. To explain these phenomena, the concept of the secondaryinjury has evolved for which numerous pathophysiological mechanisms have been postulated. This paperreviews the concept of secondary injury with special emphasis on vascular mechanisms. Evidence ispresented to support the theory of secondary injury and the hypothesis that a key mechanism isposttraumatic ischemia with resultant infarction of the spinal cord. Evidence for the role of vascularmechanisms has been obtained from a variety of models of acute spinal cord injury in several species.Many different angiographic methods have been used for assessing microcirculation of the cord and formeasuring spinal cord blood flow after trauma. With these techniques, the major systemic and localvascular effects of acute spinal cord injury have been identified and implicated in the etiology ofsecondary injury. The systemic effects of acute spinal cord injury include hypotension and reducedcardiac output. The local effects include loss of autoregulation in the injured segment of the spinal cordand a marked reduction of the microcirculation in both gray and white matter, especially in hemorrhagicregions and in adjacent zones. The microcirculatory loss extends for a considerable distance proximal anddistal to the site of injury. Many studies have shown a dose-dependent reduction of spinal cord blood flowvarying with the severity of injury, and a reduction of spinal cord blood flow which worsens with timeafter injury. The functional deficits due to acute spinal cord injury have been measuredelectrophysiologically with techniques such as motor and somatosensory evoked potentials and havebeen found proportional to the degree of posttraumatic ischemia. The histological effects include earlyhemorrhagic necrosis leading to major infarction at the injury site. These posttraumatic vascular effectscan be treated. Systemic normotension can be restored with volume expansion or vasopressors, andspinal cord blood flow can be improved with dopamine, steroids, nimodipine, or volume expansion. Thecombination of nimodipine and volume expansion improves posttraumatic spinal cord blood flow andspinal cord function measured by evoked potentials. These results provide strong evidence thatposttraumatic ischemia is an important secondary mechanism of injury, and that it can be counteracted.", "metadata": {}}
+{"_id": "6157371", "title": "", "text": "Chronophin mediates an ATP-sensing mechanism for cofilin dephosphorylation and neuronal cofilin-actinrod formation.Actin and its key regulatory component, cofilin, are found together in large rod-shapedassemblies in neurons subjected to energy stress. Such inclusions are also enriched in Alzheimer'sdisease brain, and appear in transgenic models of neurodegeneration. Neuronal insults, such as energyloss and/or oxidative stress, result in rapid dephosphorylation of the cellular cofilin pool prior to itsassembly into rod-shaped inclusions. Although these events implicate a role for phosphatases in cofilinrod formation, a mechanism linking energy stress, phosphocofilin turnover, and subsequent rod assemblyhas been elusive. We demonstrate the ATP-sensitive interaction of the cofilin phosphatase chronophin(CIN) with the chaperone hsp90 to form a biosensor that mediates cofilin/actin rod formation. Our resultssuggest a model whereby attenuated interactions between CIN and hsp90 during ATP depletion enhanceCIN-dependent cofilin dephosphorylation and consequent rod assembly, thereby providing a mechanismfor the formation of pathological actin/cofilin aggregates during neurodegenerative energy flux.", "metadata": {}}
+{"_id": "6157837", "title": "", "text": "Renal considerations in angiotensin converting enzyme inhibitor therapy: a statement for healthcareprofessionals from the Council on the Kidney in Cardiovascular Disease and the Council for High BloodPressure Research of the American Heart Association.Angiotensin converting enzyme (ACE) inhibitors arenow one of the most frequently used classes of antihypertensive drugs. Beyond their utility in themanagement of hypertension, their use has been extended to the long-term management of patientswith congestive heart failure (CHF), as well as diabetic and nondiabetic nephropathies. Although ACEinhibitor therapy usually improves renal blood flow (RBF) and sodium excretion rates in CHF and reducesthe rate of progressive renal injury in chronic renal disease, its use can also be associated with asyndrome of “functional renal insufficiency” and/or hyperkalemia. This form of acute renal failure (ARF)most commonly develops shortly after initiation of ACE inhibitor therapy but can be observed aftermonths or years of therapy, even in the absence of prior ill effects. ARF is most likely to occur when renalperfusion pressure cannot be sustained because of substantial decreases in mean arterial pressure (MAP)or when glomerular filtration rate (GFR) is highly angiotensin II (Ang II) dependent. Conditions thatpredict an adverse hemodynamic effect of ACE inhibitors in patients with CHF are preexisting hypotensionand low cardiac filling pressures. The GFR is especially dependent on Ang II during extracellular fluid(ECF) volume depletion, high-grade bilateral renal artery stenosis, or stenosis of a dominant or singlekidney, as in a renal transplant recipient. Understanding the pathophysiological mechanisms and thecommon risk factors for ACE inhibitor–induced functional ARF is critical, because preventive strategies forARF exist, and if effectively used, they may permit use of these compounds in a less restricted fashion.Under normal physiological conditions, renal autoregulation adjusts renal vascular resistance, so that RBFand GFR remain constant over a wide range of MAPs.1 The intrinsic renal autoregulation mechanism isadjusted by Ang II and the sympathetic nervous system. When renal perfusion pressure falls (as in …", "metadata": {}}
+{"_id": "6158879", "title": "", "text": "Greater clinical benefit of more intensive oral antiplatelet therapy with prasugrel in patients with diabetesmellitus in the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition withprasugrel-Thrombolysis in Myocardial Infarction 38.BACKGROUND Patients with diabetes mellitus (DM)are at high risk for recurrent cardiovascular events after acute coronary syndromes, in part because ofincreased platelet reactivity. The Trial to Assess Improvement in Therapeutic Outcomes by OptimizingPlatelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) showed anoverall reduction in ischemic events with more intensive antiplatelet therapy with prasugrel than withclopidogrel but with more bleeding. We compared prasugrel with clopidogrel among subjects with DM inTRITON-TIMI 38. METHODS AND RESULTS We classified 13 608 subjects on the basis of preexistinghistory of DM and further according to insulin use. Prespecified analyses of the primary (cardiovasculardeath, nonfatal myocardial infarction, or nonfatal stroke) and key secondary end points, including netclinical benefit (death, nonfatal myocardial infarction, nonfatal stroke, and nonfatal TIMI major bleeding)were compared by use of the log-rank test. We found that 3146 subjects had a preexisting history of DM,including 776 receiving insulin. The primary end point was reduced significantly with prasugrel amongsubjects without DM (9.2% versus 10.6%; hazard ratio [HR], 0.86; P=0.02) and with DM (12.2% versus17.0%; HR, 0.70; P<0.001, P(interaction)=0.09). A benefit for prasugrel was observed among DMsubjects on insulin (14.3% versus 22.2%; HR, 0.63; P=0.009) and those not on insulin (11.5% versus15.3%; HR, 0.74; P=0.009). Myocardial infarction was reduced with prasugrel by 18% among subjectswithout DM (7.2% versus 8.7%; HR, 0.82; P=0.006) and by 40% among subjects with DM (8.2% versus13.2%; HR, 0.60; P<0.001, P(interaction)=0.02). Although TIMI major hemorrhage was increasedamong subjects without DM on prasugrel (1.6% versus 2.4%; HR, 1.43; P=0.02), the rates were similaramong subjects with DM for clopidogrel and prasugrel (2.6% versus 2.5%; HR, 1.06; P=0.81,P(interaction)=0.29). Net clinical benefit with prasugrel was greater for subjects with DM (14.6% versus19.2%; HR, 0.74; P=0.001) than for subjects without DM (11.5% versus 12.3%; HR, 0.92; P=0.16,P(interaction)=0.05). CONCLUSIONS Subjects with DM tended to have a greater reduction in ischemicevents without an observed increase in TIMI major bleeding and therefore a greater net treatment benefitwith prasugrel compared with clopidogrel. These data demonstrate that the more intensive oralantiplatelet therapy provided with prasugrel is of particular benefit to patients with DM.", "metadata": {}}
+{"_id": "6163801", "title": "", "text": "Kinetics of early T cell receptor signaling regulate the pathway of lytic granule delivery to the secretorydomain.Cytolytic granules mediate killing of virus-infected cells by cytotoxic T lymphocytes. We showhere that the granules can take long or short paths to the secretory domain. Both paths utilized the sameintracellular molecular events, which have different spatial and temporal arrangements and are regulatedby the kinetics of Ca(2+)-mediated signaling. Rapid signaling caused swift granule concentration near themicrotubule-organizing center (MTOC) and subsequent delivery by the polarized MTOC directly to thesecretory domain-the shortest path. Indolent signaling led to late recruitment of granules that movedalong microtubules to the periphery of the synapse and then moved tangentially to fuse at the outer edgeof the secretory domain-a longer path. The short pathway is associated with faster granule release andmore efficient killing than the long pathway. Thus, the kinetics of early signaling regulates the quality ofthe T cell cytolytic response.", "metadata": {}}
+{"_id": "6171953", "title": "", "text": "Sirtuin-1 is a nutrient-dependent modulator of inflammationInflammation accompanies obesity and itscomorbidities-type 2 diabetes, non-alcoholic fatty liver disease and atherosclerosis, among others-andmay contribute to their pathogenesis. Yet the cellular machinery that links nutrient sensing toinflammation remains incompletely characterized. The protein deacetylase sirtuin-1 (SirT1) is activatedby energy depletion and plays a critical role in the mammalian response to fasting. More recently it hasbeen implicated in the repression of inflammation. SirT1 mRNA and protein expression are suppressed inobese rodent and human white adipose tissue, while experimental reduction of SirT1 in adipocytes andmacrophages causes low-grade inflammation that mimics that observed in obesity. Thus suppression ofSirT1 during overnutrition may be critical to the development of obesity-associated inflammation. Thiseffect is attributable to multiple actions of SirT1, including direct deacetylation of NFκB and chromatinremodeling at inflammatory gene promoters. In this work, we report that SirT1 is also suppressed bydiet-induced obesity in macrophages, which are key contributors to the ontogeny of metabolicinflammation. Thus, SirT1 may be a common mechanism by which cells sense nutrient status andmodulate inflammatory signaling networks in accordance with organismal energy availability.", "metadata": {}}
+{"_id": "6173523", "title": "", "text": "A culture-independent sequence-based metagenomics approach to the investigation of an outbreak ofShiga-toxigenic Escherichia coli O104:H4.IMPORTANCE Identification of the bacterium responsible for anoutbreak can aid in disease management. However, traditional culture-based diagnosis can be difficult,particularly if no specific diagnostic test is available for an outbreak strain. OBJECTIVE To explore thepotential of metagenomics, which is the direct sequencing of DNA extracted from microbiologicallycomplex samples, as an open-ended clinical discovery platform capable of identifying and characterizingbacterial strains from an outbreak without laboratory culture. DESIGN, SETTING, AND PATIENTS In aretrospective investigation, 45 samples were selected from fecal specimens obtained from patients withdiarrhea during the 2011 outbreak of Shiga-toxigenic Escherichia coli (STEC) O104:H4 in Germany.Samples were subjected to high-throughput sequencing (August-September 2012), followed by a3-phase analysis (November 2012-February 2013). In phase 1, a de novo assembly approach wasdeveloped to obtain a draft genome of the outbreak strain. In phase 2, the depth of coverage of theoutbreak strain genome was determined in each sample. In phase 3, sequences from each sample werecompared with sequences from known bacteria to identify pathogens other than the outbreak strain.MAIN OUTCOMES AND MEASURES The recovery of genome sequence data for the purposes ofidentification and characterization of the outbreak strain and other pathogens from fecal samples.RESULTS During phase 1, a draft genome of the STEC outbreak strain was obtained. During phase 2, theoutbreak strain genome was recovered from 10 samples at greater than 10-fold coverage and from 26samples at greater than 1-fold coverage. Sequences from the Shiga-toxin genes were detected in 27 of40 STEC-positive samples (67%). In phase 3, sequences from Clostridium difficile, Campylobacter jejuni,Campylobacter concisus, and Salmonella enterica were recovered. CONCLUSIONS AND RELEVANCE Theseresults suggest the potential of metagenomics as a culture-independent approach for the identification ofbacterial pathogens during an outbreak of diarrheal disease. Challenges include improving diagnosticsensitivity, speeding up and simplifying workflows, and reducing costs.", "metadata": {}}
+{"_id": "6176498", "title": "", "text": "Biomarkers of endothelial dysfunction and risk of type 2 diabetes mellitus.CONTEXT Endothelialdysfunction occurs in diagnosed type 2 diabetes mellitus but may also precede development of diabetes.OBJECTIVE To determine whether elevated plasma levels of biomarkers reflecting endothelial dysfunction(E-selectin; intercellular adhesion molecule 1 [ICAM-1]; and vascular cell adhesion molecule 1 [VCAM-1])predict development of type 2 diabetes in initially nondiabetic women. DESIGN AND SETTINGProspective, nested case-control study within the Nurses' Health Study, an ongoing US study initiated in1976. PARTICIPANTS Of 121 700 women initially enrolled, 32 826 provided blood samples in 1989-1990;of those free of diabetes, cardiovascular disease, or cancer at baseline, 737 developed incident diabetesby 2000. Controls (n = 785) were selected according to matched age, fasting status, and race. MAINOUTCOME MEASURE Risk of confirmed clinically diagnosed type 2 diabetes by baseline levels ofE-selectin, ICAM-1, and VCAM-1. RESULTS Baseline median levels of the biomarkers were significantlyhigher among cases than among controls (E-selectin, 61.2 vs 45.4 ng/mL; ICAM-1, 264.9 vs 247.0ng/mL; VCAM-1, 545.4 vs 526.0 ng/mL [all P values < or =.004]). Elevated E-selectin and ICAM-1 levelspredicted incident diabetes in logistic regression models conditioned on matching criteria and adjusted forbody mass index (BMI), family history of diabetes, smoking, diet score, alcohol intake, activity index, andpostmenopausal hormone use. The adjusted relative risks for incident diabetes in the top quintile vs thebottom quintiles were 5.43 for E-selectin (95% confidence interval [CI], 3.47-8.50), 3.56 for ICAM-1(95% CI, 2.28-5.58), and 1.12 for VCAM-1 (95% CI, 0.76-1.66). Adjustment for waist circumferenceinstead of BMI or further adjustment for baseline levels of C-reactive protein, fasting insulin, andhemoglobin A(1c) or exclusion of cases diagnosed during the first 4 years of follow-up did not alter theseassociations. CONCLUSION Endothelial dysfunction predicts type 2 diabetes in women independent ofother known risk factors, including obesity and subclinical inflammation.", "metadata": {}}
+{"_id": "6182947", "title": "", "text": "Nrf2 protects human alveolar epithelial cells against injury induced by influenza A virusBACKGROUNDInfluenza A virus (IAV) infection primarily targets respiratory epithelial cells and produces clinicaloutcomes ranging from mild upper respiratory infection to severe pneumonia. Recent studies have shownthe importance of lung antioxidant defense systems against injury by IAV. Nuclear factor-erythroid 2related factor 2 (Nrf2) activates the majority of antioxidant genes. METHODS Alveolar type II (ATII) cellsand alveolar macrophages (AM) were isolated from human lungs not suitable for transplantation anddonated for medical research. In some studies ATII cells were transdifferentiated to alveolar type I-like(ATI-like) cells. Alveolar epithelial cells were infected with A/PR/8/34 (PR8) virus. We analyzed PR8 virusproduction, influenza A nucleoprotein levels, ROS generation and expression of antiviral genes.Immunocytofluorescence was used to determine Nrf2 translocation and western blotting to detect Nrf2,HO-1 and caspase 1 and 3 cleavage. We also analyzed ingestion of PR8 virus infected apoptotic ATII cellsby AM, cytokine levels by ELISA, glutathione levels, necrosis and apoptosis by TUNEL assay. Moreover,we determined the critical importance of Nrf2 using adenovirus Nrf2 (AdNrf2) or Nrf2 siRNA tooverexpress or knockdown Nrf2, respectively. RESULTS We found that IAV induced oxidative stress,cytotoxicity and apoptosis in ATI-like and ATII cells. We also found that AM can ingest PR8 virus-inducedapoptotic ATII cells (efferocytosis) but not viable cells, whereas ATII cells did not ingest these apoptoticcells. PR8 virus increased ROS production, Nrf2, HO-1, Mx1 and OAS1 expression and Nrf2 translocationto the nucleus. Nrf2 knockdown with siRNA sensitized ATI-like cells and ATII cells to injury induced byIAV and overexpression of Nrf2 with AdNrf2 protected these cells. Furthermore, Nrf2 overexpressionfollowed by infection with PR8 virus decreased virus replication, influenza A nucleoprotein expression,antiviral response and oxidative stress. However, AdNrf2 did not increase IFN-λ1 (IL-29) levels.CONCLUSIONS Our results indicate that IAV induces alveolar epithelial injury and that Nrf2 protects thesecells from the cytopathic effects of IAV likely by increasing the expression of antioxidant genes.Identifying the pathways involved in protecting cells from injury during influenza infection may beparticularly important for developing new therapeutic strategies.", "metadata": {}}
+{"_id": "6190603", "title": "", "text": "Dynamics in the plasma membrane: how to combine fluidity and order.Cell membranes are fascinatingsupramolecular aggregates that not only form a barrier between compartments but also harbor manychemical reactions essential to the existence and functioning of a cell. Here, it is proposed to review themolecular dynamics and mosaic organization of the plasma membrane, which are thought to haveimportant functional implications. We will first summarize the basic concepts of Brownian diffusion andlipid domain formation in model membranes and then track the development of ideas and tools in thisfield, outlining key results obtained on the dynamic processes at work in membrane structure andassembly. We will focus in particular on findings made using fluorescent labeling and imaging proceduresto record these dynamic processes. We will also discuss a few examples showing the impact of lateraldiffusion on cell signal transduction, and outline some future methodological challenges which must bemet before we can answer some of the questions arising in this field of research.", "metadata": {}}
+{"_id": "6191684", "title": "", "text": "Management of chronic tension-type headache with tricyclic antidepressant medication, stressmanagement therapy, and their combination: a randomized controlled trial.CONTEXT Chronictension-type headaches are characterized by near-daily headaches and often are difficult to manage inprimary practice. Behavioral and pharmacological therapies each appear modestly effective, but data arelacking on their separate and combined effects. OBJECTIVE To evaluate the clinical efficacy of behavioraland pharmacological therapies, singly and combined, for chronic tension-type headaches. DESIGN ANDSETTING Randomized placebo-controlled trial conducted from August 1995 to January 1998 at 2outpatient sites in Ohio. PARTICIPANTS Two hundred three adults (mean age, 37 years; 76% women)with diagnosis of chronic tension-type headaches (mean, 26 headache d/mo). INTERVENTIONSParticipants were randomly assigned to receive tricyclic antidepressant (amitriptyline hydrochloride, up to100 mg/d, or nortriptyline hydrochloride, up to 75 mg/d) medication (n = 53), placebo (n = 48), stressmanagement (eg, relaxation, cognitive coping) therapy (3 sessions and 2 telephone contacts) plusplacebo (n = 49), or stress management therapy plus antidepressant medication (n = 53). MAINOUTCOME MEASURES Monthly headache index scores calculated as the mean of pain ratings (0-10 scale)recorded by participants in a daily diary 4 times per day; number of days per month with at leastmoderate pain (pain rating >/=5), analgesic medication use, and Headache Disability Inventory scores,compared by intervention group. RESULTS Tricyclic antidepressant medication and stress managementtherapy each produced larger reductions in headache activity, analgesic medication use, andheadache-related disability than placebo, but antidepressant medication yielded more rapidimprovements in headache activity. Combined therapy was more likely to produce clinically significant(>/=50%) reductions in headache index scores (64% of participants) than antidepressant medication(38% of participants; P =.006), stress management therapy (35%; P =.003), or placebo (29%; P=.001). On other measures the combined therapy and its 2 component therapies produced similaroutcomes. CONCLUSIONS Our results indicate that antidepressant medication and stress managementtherapy are each modestly effective in treating chronic tension-type headaches. Combined therapy mayimprove outcome relative to monotherapy.", "metadata": {}}
+{"_id": "6202834", "title": "", "text": "Maximum likelihood estimates of species trees: how accuracy of phylogenetic inference depends upon thedivergence history and sampling design.The understanding that gene trees are often in discord with eachother and with the species trees that contain them has led researchers to methods that incorporate theinherent stochasticity of genetic processes in the phylogenetic estimation procedure. Recently developedmethods for species-tree estimation that not only consider the retention and sorting of ancestralpolymorphism but also quantify the actual probabilities of incomplete lineage sorting are expected toprovide an improvement over earlier summary-statistic based approaches that discard much of theinformation content of gene trees. However, these new methods have yet to be tested on trulychallenging evolutionary histories such as those marked by recent rapid speciation where high levels ofincomplete lineage sorting and discord among gene trees predominate. Here, we test a newmaximum-likelihood method that incorporates stochastic models of both nucleotide substitution andlineage sorting for species-tree estimation. Using a simulation approach, we consider a broad range ofspecies-tree topologies under 2 scenarios representing moderate and severe incomplete lineage sorting.We show that the maximum-likelihood method results in more accurate species trees than asummary-statistic based approach, demonstrating that information contained in discordant gene treescan be effectively extracted using a full probabilistic model. Moreover, we demonstrate that the shape ofthe original species tree (i.e., the relative lengths of internal branches) has a significant impact onwhether the species tree is estimated accurately. In the speciation histories explored here, it is not justthe recent origin of species that affects the accuracy of the estimates but the variance in relative speciesdivergence times as well. Additionally, we show that sampling effort (number of individuals and/or loci)and sampling design (ratio of individuals to loci) are both important factors affecting the accuracy ofspecies-tree estimates, which is again affected by the relative timing of divergence among species. Theinherent difficulties of estimating relationships when species have undergone a recent radiation arediscussed, and in particular, the limitations with maximum-likelihood estimates of species trees that donot consider uncertainty in the estimated gene trees of individual loci. Thus, despite substantialimprovements over current summary-statistic based approaches, and the increased sophistication ofprocedures that incorporate the process of gene lineage coalescence, recent radiations still appear topose daunting challenges for phylogenetics.", "metadata": {}}
+{"_id": "6207111", "title": "", "text": "Relationship of soft drink consumption to global overweight, obesity, and diabetes: a cross-nationalanalysis of 75 countries.OBJECTIVES We estimated the relationship between soft drink consumption andobesity and diabetes worldwide. METHODS We used multivariate linear regression to estimate theassociation between soft drink consumption and overweight, obesity, and diabetes prevalence in 75countries, controlling for other foods (cereals, meats, fruits and vegetables, oils, and total calories),income, urbanization, and aging. Data were obtained from the Euromonitor Global Market InformationDatabase, the World Health Organization, and the International Diabetes Federation. Bottled waterconsumption, which increased with per-capita income in parallel to soft drink consumption, served as anatural control group. RESULTS Soft drink consumption increased globally from 9.5 gallons per personper year in 1997 to 11.4 gallons in 2010. A 1% rise in soft drink consumption was associated with anadditional 4.8 overweight adults per 100 (adjusted B; 95% confidence interval [CI] = 3.1, 6.5), 2.3obese adults per 100 (95% CI = 1.1, 3.5), and 0.3 adults with diabetes per 100 (95% CI = 0.1, 0.8).These findings remained robust in low- and middle-income countries. CONCLUSIONS Soft drinkconsumption is significantly linked to overweight, obesity, and diabetes worldwide, including in low- andmiddle-income countries.", "metadata": {}}
+{"_id": "6209599", "title": "", "text": "Extensive translation of circular RNAs driven by N6-methyladenosineExtensive pre-mRNA back-splicinggenerates numerous circular RNAs (circRNAs) in human transcriptome. However, the biological functionsof these circRNAs remain largely unclear. Here we report that N6-methyladenosine (m6A), the mostabundant base modification of RNA, promotes efficient initiation of protein translation from circRNAs inhuman cells. We discover that consensus m6A motifs are enriched in circRNAs and a single m6A site issufficient to drive translation initiation. This m6A-driven translation requires initiation factor eIF4G2 andm6A reader YTHDF3, and is enhanced by methyltransferase METTL3/14, inhibited by demethylase FTO,and upregulated upon heat shock. Further analyses through polysome profiling, computational predictionand mass spectrometry reveal that m6A-driven translation of circRNAs is widespread, with hundreds ofendogenous circRNAs having translation potential. Our study expands the coding landscape of humantranscriptome, and suggests a role of circRNA-derived proteins in cellular responses to environmentalstress.", "metadata": {}}
+{"_id": "6212802", "title": "", "text": "Simvastatin reduces CD40 expression in an experimental model of early arterialization of saphenous veingraft.BACKGROUND Saphenous vein graft (VG) failure occurs more frequently compared with arterialgrafts, and graft thrombosis represents the main cause of early occlusion. Because CD40-CD40L pathwayCD40 represents a culprit link between local inflammation and coagulation cascade, we investigate therole of CD40 and its soluble ligand (sCD40L) in the immediate in vitro response of VG to arterialpressures, and the potential effects of Simvastatin (Merck Sharp&Dohme, White-house Station, NJ)supplementation. METHODS Samples of saphenous vein and of internal mammary artery (IMA) wereobtained from sixteen patients without history of statin therapy. Segments underwent pulsatile pressuredistension and culture with or without supplementation of Simvastatin. CD40 and sCD40L were assessedin tissue lysate and in culture supernatant, respectively. sCD40L serum concentrations were alsomeasured. RESULTS During the course of the experiment, the CD40 expression was significantly lower inIMA samples compared with both distended and not distended VG. Pressure distension up-regulated theproduction of CD40 in VG segments after 24 and 48 h. Statin supplementation significantly reduced theexpression of CD40 in both venous (P < 0.001) and arterial samples (P < 0.001). This effect ofSimvastatin was not affected by the treatment with L-NAME, but it was reversed by the addition ofmevalonic acid. Mean sCD40L content in culture supernatants increased over time, suggesting that notonly platelets but also the vessel wall is a source of CD40 and sCD40L. CONCLUSIONS Simvastatintreatment modulates endothelial CD40-sCD40L in both venous and arterial grafts, and therefore mayrepresent a useful tool in the pharmacological prevention of graft failure.", "metadata": {}}
+{"_id": "6219790", "title": "", "text": "Cancer Cell Membrane-Coated Nanoparticles for Anticancer Vaccination and Drug DeliveryCell-derivednanoparticles have been garnering increased attention due to their ability to mimic many of the naturalproperties displayed by their source cells. This top-down engineering approach can be applied toward thedevelopment of novel therapeutic strategies owing to the unique interactions enabled through theretention of complex antigenic information. Herein, we report on the biological functionalization ofpolymeric nanoparticles with a layer of membrane coating derived from cancer cells. The resultingcore-shell nanostructures, which carry the full array of cancer cell membrane antigens, offer a robustplatform with applicability toward multiple modes of anticancer therapy. We demonstrate that by couplingthe particles with an immunological adjuvant, the resulting formulation can be used to promote atumor-specific immune response for use in vaccine applications. Moreover, we show that by takingadvantage of the inherent homotypic binding phenomenon frequently observed among tumor cells themembrane functionalization allows for a unique cancer targeting strategy that can be utilized for drugdelivery applications.", "metadata": {}}
+{"_id": "6227220", "title": "", "text": "Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as amitokineDespite growing interest and a recent surge in papers, the role of autophagy in glucose and lipidmetabolism is unclear. We produced mice with skeletal muscle–specific deletion of Atg7 (encodingautophagy-related 7). Unexpectedly, these mice showed decreased fat mass and were protected fromdiet-induced obesity and insulin resistance; this phenotype was accompanied by increased fatty acidoxidation and browning of white adipose tissue (WAT) owing to induction of fibroblast growth factor 21(Fgf21). Mitochondrial dysfunction induced by autophagy deficiency increased Fgf21 expression throughinduction of Atf4, a master regulator of the integrated stress response. Mitochondrial respiratory chaininhibitors also induced Fgf21 in an Atf4-dependent manner. We also observed induction of Fgf21,resistance to diet-induced obesity and amelioration of insulin resistance in mice with autophagydeficiency in the liver, another insulin target tissue. These findings suggest that autophagy deficiency andsubsequent mitochondrial dysfunction promote Fgf21 expression, a hormone we consequently term a'mitokine', and together these processes promote protection from diet-induced obesity and insulinresistance.", "metadata": {}}
+{"_id": "6250701", "title": "", "text": "Laboratory prediction of the requirement for renal replacement in acute falciparum malariaBACKGROUNDAcute renal failure is a common complication of severe malaria in adults, and without renal replacementtherapy (RRT), it carries a poor prognosis. Even when RRT is available, delaying its initiation mayincrease mortality. Earlier identification of patients who will need RRT may improve outcomes. METHODProspectively collected data from two intervention studies in adults with severe malaria were analysedfocusing on laboratory features on presentation and their association with a later requirement for RRT. Inparticular, laboratory indices of acute tubular necrosis (ATN) and acute kidney injury (AKI) that are usedin other settings were examined. RESULTS Data from 163 patients were available for analysis. Whetheror not the patients should have received RRT (a retrospective assessment determined by threeindependent reviewers) was used as the reference. Forty-three (26.4%) patients met criteria for dialysis,but only 19 (44.2%) were able to receive this intervention due to the limited availability of RRT. Patientswith impaired renal function on admission (creatinine clearance < 60 ml/min) (n = 84) had theirlaboratory indices of ATN/AKI analysed. The plasma creatinine level had the greatest area under the ROCcurve (AUC): 0.83 (95% confidence interval 0.74-0.92), significantly better than the AUCs for, urinarysodium level, the urea to creatinine ratio (UCR), the fractional excretion of urea (FeUN) and the urinaryneutrophil gelatinase-associated lipocalcin (NGAL) level. The AUC for plasma creatinine was also greaterthan the AUC for blood urea nitrogen level, the fractional excretion of sodium (FeNa), the renal failureindex (RFI), the urinary osmolality, the urine to plasma creatinine ratio (UPCR) and the creatinineclearance, although the difference for these variables did not reach statistical significance. CONCLUSIONSIn adult patients with severe malaria and impaired renal function on admission, none of the evaluatedlaboratory indices was superior to the plasma creatinine level when used to predict a later requirementfor renal replacement therapy.", "metadata": {}}
+{"_id": "6251620", "title": "", "text": "Antineutrophil cytoplasmic antibodies (ANCA).Antineutrophil cytoplasmic antibodies (ANCA) are asensitive and specific marker for ANCA-associated systemic vasculitis. Using indirect immunofluorescenceon ethanol-fixed neutrophils, two major fluoroscopic patterns can be recognised: a diffuse cytoplasmicstaining (C-ANCA), and a perinuclear/nuclear staining (P-ANCA). In patients with vasculitis, more of 90%of C-ANCA are directed against proteinase 3 (PR3-ANCA) whereas approximately 80-90% of P-ANCArecognise myelperoxidase (MPO-ANCA). Although C-ANCA (PR3-ANCA) is preferentially associated withWegener's granulomatosis (WG), and P-ANCA (MPO-ANCA) with microscopic polyangiitis (MPA),idiopathic necrotising crescentic glomerulonephritis (iNCGN) and Churg-Strauss syndrome (CSS), there isnot absolute specificity. Between 10-20% of patients with classical WG show P-ANCA (MPO-ANCA), andeven a larger percentage of patients with MPA or CSS have C-ANCA (PR3-ANCA). Furthermore, it shouldbe stressed that approximately 10-20% of patients with WG or MPA (and 40-50% of cases of CSS) havenegative assay for ANCA. The best diagnostic performance is obtained when indirect immunofluorescenceis combined with PR3 and MPO-specific ELISAs. ANCA with different and unknown antigen specificity arefound in a variety of conditions other than AASV, including inflammatory bowel diseases, otherautoimmune diseases, and infections where their clinical significance is unclear. ANCA levels are useful tomonitor disease activity but should not be used by themselves to guide treatment. A significant increasein ANCA titres, or the reappearance of ANCA, should alert the clinicians and lead to a stricter patientcontrol.", "metadata": {}}
+{"_id": "6259170", "title": "", "text": "Emerging functional cross-talk between the Keap1-Nrf2 system and mitochondriaNuclear factorerythroid-derived 2-related factor 2 (Nrf2) was originally identified as a positive regulator of drugdetoxifying enzyme gene expression during exposure to environmental electrophiles. Currently, Nrf2 isknown to regulate the expression of hundreds of cytoprotective genes to counteract endogenously orexogenously generated oxidative stress. Furthermore, when activated in human tumors by somaticmutations, Nrf2 confers growth advantages and chemoresistance by regulating genes involved in variousprocesses such as the pentose phosphate pathway and nucleotide synthesis in addition to antioxidantproteins. Interestingly, increasing evidence shows that Nrf2 is associated with mitochondrial biogenesisduring environmental stresses in certain tissues such as the heart. Furthermore, SKN-1, a functionalhomolog of Nrf2 in C. elegans, is activated by mitochondrial reactive oxygen species and extends lifespan by promoting mitochondrial homeostasis (i.e., mitohormesis). Similarly, Nrf2 activation was recentlyobserved in the heart of surfeit locus protein 1 (Surf1) -/- mice in which cellular respiration wasdecreased due to cytochrome c oxidase defects. In this review, we critically examine the relationshipbetween Nrf2 and mitochondria and argue that the Nrf2 stress pathway intimately communicates withmitochondria to maintain cellular homeostasis during oxidative stress.", "metadata": {}}
+{"_id": "6264468", "title": "", "text": "Regulation of pluripotency by RNA binding proteins.Establishment, maintenance, and exit frompluripotency require precise coordination of a cell's molecular machinery. Substantial headway has beenmade in deciphering many aspects of this elaborate system, particularly with respect to epigenetics,transcription, and noncoding RNAs. Less attention has been paid to posttranscriptional regulatoryprocesses such as alternative splicing, RNA processing and modification, nuclear export, regulation oftranscript stability, and translation. Here, we introduce the RNA binding proteins that enable theposttranscriptional regulation of gene expression, summarizing current and ongoing research on theirroles at different regulatory points and discussing how they help script the fate of pluripotent stem cells.", "metadata": {}}
+{"_id": "6268106", "title": "", "text": "The ubiquitin ligase Drosophila Mind bomb promotes Notch signaling by regulating the localization andactivity of Serrate and Delta.The receptor Notch and its ligands of the Delta/Serrate/LAG2 (DSL) familyare the central components in the Notch pathway, a fundamental cell signaling system that regulatespattern formation during animal development. Delta is directly ubiquitinated by Drosophila and XenopusNeuralized, and by zebrafish Mind bomb, two unrelated RING-type E3 ubiquitin ligases with commonabilities to promote Delta endocytosis and signaling activity. Although orthologs of both Neuralized andMind bomb are found in most metazoan organisms, their relative contributions to Notch signaling in anysingle organism have not yet been assessed. We show here that a Drosophila ortholog of Mind bomb(D-mib) is a positive component of Notch signaling that is required for multiple Neuralized-independent,Notch-dependent developmental processes. Furthermore, we show that D-mib associates physically andfunctionally with both Serrate and Delta. We find that D-mib uses its ubiquitin ligase activity to promoteDSL ligand activity, an activity that is correlated with its ability to induce the endocytosis and degradationof both Delta and Serrate (see also Le Borgne et al., 2005). We further demonstrate that D-mib canfunctionally replace Neuralized in multiple cell fate decisions that absolutely require endogenousNeuralized, a testament to the highly similar activities of these two unrelated ubiquitin ligases inregulating Notch signaling. We conclude that ubiquitination of Delta and Serrate by Neuralized and D-mibis an obligate feature of DSL ligand activation throughout Drosophila development.", "metadata": {}}
+{"_id": "6270720", "title": "", "text": "Myeloid differentiation factor-88/interleukin-1 signaling controls cardiac fibrosis and heart failureprogression in inflammatory dilated cardiomyopathy.RATIONALE The myeloid differentiation factor(MyD)88/interleukin (IL)-1 axis activates self-antigen-presenting cells and promotes autoreactive CD4(+)T-cell expansion in experimental autoimmune myocarditis, a mouse model of inflammatory heart disease.OBJECTIVE The aim of this study was to determine the role of MyD88 and IL-1 in the progression of acutemyocarditis to an end-stage heart failure. METHODS AND RESULTS Using alpha-myosin heavy chainpeptide (MyHC-alpha)-loaded, activated dendritic cells, we induced myocarditis in wild-type andMyD88(-/-) mice with similar distributions of heart-infiltrating cell subsets and comparable CD4(+) T-cellresponses. Injection of complete Freund's adjuvant (CFA) or MyHC-alpha/CFA into diseased micepromoted cardiac fibrosis, induced ventricular dilation, and impaired heart function in wild-type but not inMyD88(-/-) mice. Experiments with chimeric mice confirmed the bone marrow origin of the fibroblastsreplacing inflammatory infiltrates and showed that MyD88 and IL-1 receptor type I signaling on bonemarrow-derived cells was critical for development of cardiac fibrosis during progression to heart failure.CONCLUSIONS Our findings indicate a critical role of MyD88/IL-1 signaling in the bone marrowcompartment in postinflammatory cardiac fibrosis and heart failure and point to novel therapeuticstrategies against inflammatory cardiomyopathy.", "metadata": {}}
+{"_id": "6277638", "title": "", "text": "Mechanisms of Life Span Extension by Rapamycin in the Fruit Fly Drosophila melanogasterThe target ofrapamycin (TOR) pathway is a major nutrient-sensing pathway that, when genetically downregulated,increases life span in evolutionarily diverse organisms including mammals. The central component of thispathway, TOR kinase, is the target of the inhibitory drug rapamycin, a highly specific and well-describeddrug approved for human use. We show here that feeding rapamycin to adult Drosophila produces the lifespan extension seen in some TOR mutants. Increase in life span by rapamycin was associated withincreased resistance to both starvation and paraquat. Analysis of the underlying mechanisms revealedthat rapamycin increased longevity specifically through the TORC1 branch of the TOR pathway, throughalterations to both autophagy and translation. Rapamycin could increase life span of weak insulin/Igfsignaling (IIS) pathway mutants and of flies with life span maximized by dietary restriction, indicatingadditional mechanisms.", "metadata": {}}
+{"_id": "6280907", "title": "", "text": "Conversion of vascular endothelial cells into multipotent stem-like cellsMesenchymal stem cells can giverise to several cell types, but varying results depending on isolation methods and tissue source have ledto controversies about their usefulness in clinical medicine. Here we show that vascular endothelial cellscan transform into multipotent stem-like cells by an activin-like kinase-2 (ALK2) receptor–dependentmechanism. In lesions from individuals with fibrodysplasia ossificans progressiva (FOP), a disease inwhich heterotopic ossification occurs as a result of activating ALK2 mutations, or from transgenic miceexpressing constitutively active ALK2, chondrocytes and osteoblasts expressed endothelial markers.Lineage tracing of heterotopic ossification in mice using a Tie2-Cre construct also suggested anendothelial origin of these cell types. Expression of constitutively active ALK2 in endothelial cells causedendothelial-to-mesenchymal transition and acquisition of a stem cell–like phenotype. Similar results wereobtained by treatment of untransfected endothelial cells with the ligands transforming growth factor-β2(TGF-β2) or bone morphogenetic protein-4 (BMP4) in an ALK2-dependent manner. These stem-like cellscould be triggered to differentiate into osteoblasts, chondrocytes or adipocytes. We suggest thatconversion of endothelial cells to stem-like cells may provide a new approach to tissue engineering.", "metadata": {}}
+{"_id": "6285534", "title": "", "text": "miR-302 Is Required for Timing of Neural Differentiation, Neural Tube Closure, and EmbryonicViabilityThe evolutionarily conserved miR-302 family of microRNAs is expressed during early mammalianembryonic development. Here, we report that deletion of miR-302a-d in mice results in a fully penetrantlate embryonic lethal phenotype. Knockout embryos have an anterior neural tube closure defectassociated with a thickened neuroepithelium. The neuroepithelium shows increased progenitorproliferation, decreased cell death, and precocious neuronal differentiation. mRNA profiling at multipletime points during neurulation uncovers a complex pattern of changing targets over time. Overexpressionof one of these targets, Fgf15, in the neuroepithelium of the chick embryo induces precocious neuronaldifferentiation. Compound mutants between mir-302 and the related mir-290 locus have a syntheticlethal phenotype prior to neurulation. Our results show that mir-302 helps regulate neurulation bysuppressing neural progenitor expansion and precocious differentiation. Furthermore, these resultsuncover redundant roles for mir-290 and mir-302 early in development.", "metadata": {}}
+{"_id": "6290112", "title": "", "text": "Low copy number of the salivary amylase gene predisposes to obesityCommon multi-allelic copy numbervariants (CNVs) appear enriched for phenotypic associations compared to their biallelic counterparts.Here we investigated the influence of gene dosage effects on adiposity through a CNV association studyof gene expression levels in adipose tissue. We identified significant association of a multi-allelic CNVencompassing the salivary amylase gene (AMY1) with body mass index (BMI) and obesity, and wereplicated this finding in 6,200 subjects. Increased AMY1 copy number was positively associated withboth amylase gene expression (P = 2.31 × 10(-14)) and serum enzyme levels (P < 2.20 × 10(-16)),whereas reduced AMY1 copy number was associated with increased BMI (change in BMI per estimatedcopy = -0.15 (0.02) kg/m(2); P = 6.93 × 10(-10)) and obesity risk (odds ratio (OR) per estimated copy= 1.19, 95% confidence interval (CI) = 1.13-1.26; P = 1.46 × 10(-10)). The OR value of 1.19 per copyof AMY1 translates into about an eightfold difference in risk of obesity between subjects in the top (copynumber > 9) and bottom (copy number < 4) 10% of the copy number distribution. Our study provides afirst genetic link between carbohydrate metabolism and BMI and demonstrates the power of integratedgenomic approaches beyond genome-wide association studies.", "metadata": {}}
+{"_id": "6296189", "title": "", "text": "Loss, trauma, and human resilience: have we underestimated the human capacity to thrive afterextremely aversive events?Many people are exposed to loss or potentially traumatic events at some pointin their lives, and yet they continue to have positive emotional experiences and show only minor andtransient disruptions in their ability to function. Unfortunately, because much of psychology's knowledgeabout how adults cope with loss or trauma has come from individuals who sought treatment or exhibitedgreat distress, loss and trauma theorists have often viewed this type of resilience as either rare orpathological. The author challenges these assumptions by reviewing evidence that resilience represents adistinct trajectory from the process of recovery, that resilience in the face of loss or potential trauma ismore common than is often believed, and that there are multiple and sometimes unexpected pathways toresilience.", "metadata": {}}
+{"_id": "6308416", "title": "", "text": "Role of boundary conditions in an experimental model of epithelial wound healing.Coordinated cellmovements in epithelial layers are essential for proper tissue morphogenesis and homeostasis, but ourunderstanding of the mechanisms that coordinate the behavior of multiple cells in these processes is farfrom complete. Recent experiments with Madin-Darby canine kidney epithelial monolayers revealed awave-like pattern of injury-induced MAPK activation and showed that it is essential for collective cellmigration after wounding. To investigate the effects of the different aspects of wounding on cell sheetmigration, we engineered a system that allowed us to dissect the classic wound healing assay. Westudied Madin-Darby canine kidney sheet migration under three different conditions: 1) the classic woundhealing assay, 2) empty space induction, where a confluent monolayer is grown adjacent to a slab ofpolydimethylsiloxane and the monolayer is not injured but allowed to migrate upon removal of the slab,and 3) injury via polydimethylsiloxane membrane peel-off, where an injured monolayer migrates ontoplain tissue culture surface, as in the case of empty space induction allowing for direct comparison. Bytracking the motion of individual cells within the sheet under these three conditions, we show how thedynamics of the individual cells' motion is responsible for the coordinated migration of the sheet and iscoordinated with the activation of ERK1/2 MAPK. In addition, we demonstrate that the propagation of thewaves of MAPK activation depends on the generation of reactive oxygen species at the wound edge.", "metadata": {}}
+{"_id": "6309659", "title": "", "text": "Reproductive period and risk of dementia in postmenopausal women.CONTEXT Exogenous estrogen usemay lower risk of dementia in postmenopausal women. A relationship between long-term exposure toendogenous estrogens and incident dementia has been hypothesized but not studied. OBJECTIVE Todetermine whether a longer reproductive period, as an indicator of longer exposure to endogenousestrogens, is associated with lower risk of dementia and Alzheimer disease (AD) in women who havenatural menopause. DESIGN AND SETTING The Rotterdam Study, a population-based prospective cohortstudy conducted in the Netherlands. PARTICIPANTS A total of 3601 women aged 55 years or older whodid not have dementia at baseline (1990-1993) and had information on age at menarche, age atmenopause, and type of menopause. Participants were reexamined in 1993-1994 and 1997-1999 andwere continuously monitored for development of dementia. MAIN OUTCOME MEASURES Incidence ofdementia, based on Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition criteria,and AD, based on National Institute of Neurological Disorders and Stroke/Alzheimer's Disease andRelated Disorders Association criteria, compared by quartiles of reproductive period among women withnatural menopause. RESULTS During 21 046 person-years of follow-up (median follow-up, 6.3 years),199 women developed dementia, including 159 who developed AD. After adjusting for age, dementia wasnot clearly associated with length of reproductive period. However, after adjusting for multiple covariates,women with natural menopause and more reproductive years had an increased risk of dementia(adjusted rate ratio [RR] for women with >39 reproductive years [highest quartile] compared with <34reproductive years [lowest quartile], 1.78; 95% confidence interval [CI], 1.12-2.84). The adjusted RR peryear of increase was 1.04 (95% CI, 1.01-1.08). For risk of AD, the adjusted RRs were 1.51 (95% CI,0.91-2.50) and 1.03 (95% CI, 1.00-1.07), respectively. Risk of dementia associated with a longerreproductive period was most pronounced in APOE epsilon4 carriers (adjusted RR for >39 reproductiveyears compared with <34 reproductive years, 4.20 [95% CI, 1.97-8.92] for dementia and 3.42 [95% CI,1.51-7.75] for AD), whereas in noncarriers, no clear association with dementia or AD was observed.CONCLUSION Our findings do not support the hypothesis that a longer reproductive period reduces risk ofdementia in women who have natural menopause.", "metadata": {}}
+{"_id": "6313547", "title": "", "text": "Effects of growth hormone and insulin-like growth factor 1 deficiency on ageing and longevity.Presentknowledge on the effects of growth hormone (GH)/insulin-like growth hormone (IGF)1 deficiency onageing and lifespan are reviewed. Evidence is presented that isolated GH deficiency (IGHD), multiplepituitary hormone deficiencies (MPHD) including GH, as well as primary IGE1 deficiency (GH resistance,Laron syndrome) present signs of early ageing such as thin and wrinkled skin, obesity, hyperglycemiaand osteoporosis. These changes do not seem to affect the lifespan, as patients reach old age. Animalmodels of genetic MPHD (Ames and Snell mice) and GH receptor knockout mice (primary IGF1 deficiency)also have a statistically significant higher longevity compared to normal controls. On the contrary, micetransgenic for GH and acromegalic patients secreting large amounts of GH have premature death. Inconclusion longstanding GH/IGF1 deficiency affects several parameters of the ageing process withoutimpairing lifespan, and as shown in animal models prolongs longevity. In contrast high GH/IGF1 levelsaccelerate death.", "metadata": {}}
+{"_id": "6315132", "title": "", "text": "KLF1-null neonates display hydrops fetalis and a deranged erythroid transcriptome.We describe a case ofsevere neonatal anemia with kernicterus caused by compound heterozygosity for null mutations in KLF1,each inherited from asymptomatic parents. One of the mutations is novel. This is the first described caseof a KLF1-null human. The phenotype of severe nonspherocytic hemolytic anemia, jaundice,hepatosplenomegaly, and marked erythroblastosis is more severe than that present in congenitaldyserythropoietic anemia type IV as a result of dominant mutations in the second zinc-finger of KLF1.There was a very high level of HbF expression into childhood (>70%), consistent with a key role for KLF1in human hemoglobin switching. We performed RNA-seq on circulating erythroblasts and found thathuman KLF1 acts like mouse Klf1 to coordinate expression of many genes required to build a red cellincluding those encoding globins, cytoskeletal components, AHSP, heme synthesis enzymes, cell-cycleregulators, and blood group antigens. We identify novel KLF1 target genes including KIF23 and KIF11which are required for proper cytokinesis. We also identify new roles for KLF1 in autophagy, globaltranscriptional control, and RNA splicing. We suggest loss of KLF1 should be considered in otherwiseunexplained cases of severe neonatal NSHA or hydrops fetalis.", "metadata": {}}
+{"_id": "6319826", "title": "", "text": "Quantifying heterogeneity in a meta-analysis.The extent of heterogeneity in a meta-analysis partlydetermines the difficulty in drawing overall conclusions. This extent may be measured by estimating abetween-study variance, but interpretation is then specific to a particular treatment effect metric. A testfor the existence of heterogeneity exists, but depends on the number of studies in the meta-analysis. Wedevelop measures of the impact of heterogeneity on a meta-analysis, from mathematical criteria, that areindependent of the number of studies and the treatment effect metric. We derive and propose threesuitable statistics: H is the square root of the chi2 heterogeneity statistic divided by its degrees offreedom; R is the ratio of the standard error of the underlying mean from a random effects meta-analysisto the standard error of a fixed effect meta-analytic estimate, and I2 is a transformation of (H) thatdescribes the proportion of total variation in study estimates that is due to heterogeneity. We discussinterpretation, interval estimates and other properties of these measures and examine them in fiveexample data sets showing different amounts of heterogeneity. We conclude that H and I2, which canusually be calculated for published meta-analyses, are particularly useful summaries of the impact ofheterogeneity. One or both should be presented in published meta-analyses in preference to the test forheterogeneity.", "metadata": {}}
+{"_id": "6323196", "title": "", "text": "Neurocognitive Development in Children Experiencing Intrauterine Growth Retardation and Born Small forGestational Age: Pathological, Constitutional and Therapeutic PathwaysInterest in the neurocognitive andpsychosocial outcomes in children who are born small for gestational age (SGA) has increased since therecent approval of growth hormone (GH) therapy in this indication. The objective of GH treatment in SGAchildren is to provide a symptomatic treatment for growth retardation. From a patient perspective, theultimate goals of GH therapy are the reduction in the present or future risk of neurocognitive,psychological, social or occupational impairment, not the accompanying improvements in growth velocityand final height per se. Therefore, from a scientific perspective, neurocognitive and psychosocialendpoints become relevant domains of assessment to determine the final treatment benefit experiencedby the patient born SGA. This article reviews recent available studies on developmental risks in SGA, andthen transforms the empirical findings into an integrated conceptual framework on the sources andmediators of neurocognitive and psychosocial outcomes in intrauterine growth retardation and SGA. Thisframework depicts two distinct therapeutic pathways by which GH therapy may improve neurocognitiveand behavioural outcomes. The first (‘traditional’) pathway is the prevention of exposure toshort-stature-related stressors via an improvement in growth velocity and final height. The secondpathway refers to potential metabolic, and thus neurotropic and psychotropic, effects of GH binding atreceptors in the central nervous system, thus changing neuronal activity. To date, the existence andpotential mechanisms of such physiologically and not psychologically mediated effects of GH onneurocognitive functioning in SGA patients remain hypothetical.", "metadata": {}}
+{"_id": "6325527", "title": "", "text": "Gpr124 is essential for blood–brain barrier integrity in central nervous system diseaseAlthoughblood–brain barrier (BBB) compromise is central to the etiology of diverse central nervous system (CNS)disorders, endothelial receptor proteins that control BBB function are poorly defined. The endothelialG-protein-coupled receptor (GPCR) Gpr124 has been reported to be required for normal forebrainangiogenesis and BBB function in mouse embryos, but the role of this receptor in adult animals isunknown. Here Gpr124 conditional knockout (CKO) in the endothelia of adult mice did not affecthomeostatic BBB integrity, but resulted in BBB disruption and microvascular hemorrhage in mousemodels of both ischemic stroke and glioblastoma, accompanied by reduced cerebrovascular canonicalWnt–β-catenin signaling. Constitutive activation of Wnt–β-catenin signaling fully corrected the BBBdisruption and hemorrhage defects of Gpr124-CKO mice, with rescue of the endothelial gene tightjunction, pericyte coverage and extracellular-matrix deficits. We thus identify Gpr124 as an endothelialGPCR specifically required for endothelial Wnt signaling and BBB integrity under pathological conditions inadult mice. This finding implicates Gpr124 as a potential therapeutic target for human CNS disorderscharacterized by BBB disruption.", "metadata": {}}
+{"_id": "6327940", "title": "", "text": "Vegan proteins may reduce risk of cancer, obesity, and cardiovascular disease by promoting increasedglucagon activity.Amino acids modulate the secretion of both insulin and glucagon; the composition ofdietary protein therefore has the potential to influence the balance of glucagon and insulin activity. Soyprotein, as well as many other vegan proteins, are higher in non-essential amino acids than mostanimal-derived food proteins, and as a result should preferentially favor glucagon production. Acting onhepatocytes, glucagon promotes (and insulin inhibits) cAMP-dependent mechanisms that down-regulatelipogenic enzymes and cholesterol synthesis, while up-regulating hepatic LDL receptors and production ofthe IGF-I antagonist IGFBP-1. The insulin-sensitizing properties of many vegan diets--high in fiber, low insaturated fat--should amplify these effects by down-regulating insulin secretion. Additionally, therelatively low essential amino acid content of some vegan diets may decrease hepatic IGF-I synthesis.Thus, diets featuring vegan proteins can be expected to lower elevated serum lipid levels, promoteweight loss, and decrease circulating IGF-I activity. The latter effect should impede cancer induction (asis seen in animal studies with soy protein), lessen neutrophil-mediated inflammatory damage, and slowgrowth and maturation in children. In fact, vegans tend to have low serum lipids, lean physiques, shorterstature, later puberty, and decreased risk for certain prominent 'Western' cancers; a vegan diet hasdocumented clinical efficacy in rheumatoid arthritis. Low-fat vegan diets may be especially protective inregard to cancers linked to insulin resistance--namely, breast and colon cancer--as well as prostatecancer; conversely, the high IGF-I activity associated with heavy ingestion of animal products may belargely responsible for the epidemic of 'Western' cancers in wealthy societies. Increased phytochemicalintake is also likely to contribute to the reduction of cancer risk in vegans. Regression of coronarystenoses has been documented during low-fat vegan diets coupled with exercise training; such regimensalso tend to markedly improve diabetic control and lower elevated blood pressure. Risk of many otherdegenerative disorders may be decreased in vegans, although reduced growth factor activity may beresponsible for an increased risk of hemorrhagic stroke. By altering the glucagon/insulin balance, it isconceivable that supplemental intakes of key non-essential amino acids could enable omnivores to enjoysome of the health advantages of a vegan diet. An unnecessarily high intake of essential aminoacids--either in the absolute sense or relative to total dietary protein--may prove to be as grave a riskfactor for 'Western' degenerative diseases as is excessive fat intake.", "metadata": {}}
+{"_id": "6333347", "title": "", "text": "AIR-2: An Aurora/Ipl1-related Protein Kinase Associated with Chromosomes and Midbody MicrotubulesIs  Required for Polar Body Extrusion and Cytokinesis  in Caenorhabditis elegans EmbryosAn emergingfamily of kinases related to the Drosophila Aurora and budding yeast Ipl1 proteins has been implicated inchromosome segregation and mitotic spindle formation in a number of organisms. Unlike otherAurora/Ipl1-related kinases, the Caenorhabditis elegans orthologue, AIR-2, is associated with meiotic andmitotic chromosomes. AIR-2 is initially localized to the chromosomes of the most mature prophaseI–arrested oocyte residing next to the spermatheca. This localization is dependent on the presence ofsperm in the spermatheca. After fertilization, AIR-2 remains associated with chromosomes during eachmeiotic division. However, during both meiotic anaphases, AIR-2 is present between the separatingchromosomes. AIR-2 also remains associated with both extruded polar bodies. In the embryo, AIR-2 isfound on metaphase chromosomes, moves to midbody microtubules at anaphase, and then persists atthe cytokinesis remnant. Disruption of AIR-2 expression by RNA- mediated interference produces entirebroods of one-cell embryos that have executed multiple cell cycles in the complete absence ofcytokinesis. The embryos accumulate large amounts of DNA and microtubule asters. Polar bodies are notextruded, but remain in the embryo where they continue to replicate. The cytokinesis defect appears tobe late in the cell cycle because transient cleavage furrows initiate at the proper location, but regressbefore the division is complete. Additionally, staining with a marker of midbody microtubules revealedthat at least some of the components of the midbody are not well localized in the absence of AIR-2activity. Our results suggest that during each meiotic and mitotic division, AIR-2 may coordinate thecongression of metaphase chromosomes with the subsequent events of polar body extrusion andcytokinesis.", "metadata": {}}
+{"_id": "6334188", "title": "", "text": "History of chronic comorbidity and risk of chemotherapy-induced febrile neutropenia in cancer patientsnot receiving G-CSF prophylaxis.BACKGROUND Chemotherapy-induced febrile neutropenia (FN) is aclinically important complication that affects patient outcome by delaying chemotherapy doses orreducing dose intensity. Risk of FN depends on chemotherapy- and patient-level factors. We sought todetermine the effects of chronic comorbidities on risk of FN. DESIGN We conducted a cohort study toexamine the association between a variety of chronic comorbidities and risk of FN in patients diagnosedwith six types of cancer (non-Hodgkin lymphoma and breast, colorectal, lung, ovary, and gastric cancer)from 2000 to 2009 who were treated with chemotherapy at Kaiser Permanente Southern California, alarge managed care organization. We excluded those patients who received primary prophylacticgranulocyte colony-stimulating factor. History of comorbidities and FN events were identified usingelectronic medical records. Cox models adjusting for propensity score, stratified by cancer type, wereused to determine the association between comorbid conditions and FN. Models that additionally adjustedfor cancer stage, baseline neutrophil count, chemotherapy regimen, and dose reduction were alsoevaluated. RESULTS A total of 19 160 patients with mean age of 60 years were included; 963 (5.0%)developed FN in the first chemotherapy cycle. Chronic obstructive pulmonary disease [hazard ratio (HR)= 1.30 (1.07-1.57)], congestive heart failure [HR = 1.43 (1.00-1.98)], HIV infection [HR = 3.40(1.90-5.63)], autoimmune disease [HR = 2.01 (1.10-3.33)], peptic ulcer disease [HR = 1.57(1.05-2.26)], renal disease [HR = 1.60 (1.21-2.09)], and thyroid disorder [HR = 1.32 (1.06-1.64)] wereall associated with a significantly increased FN risk. CONCLUSIONS These results provide evidence thathistory of several chronic comorbidities increases risk of FN, which should be considered when managingpatients during chemotherapy.", "metadata": {}}
+{"_id": "6363093", "title": "", "text": "Glioblastoma Subclasses Can Be Defined by Activity among Signal Transduction Pathways and AssociatedGenomic AlterationsBACKGROUND Glioblastoma multiforme (GBM) is an umbrella designation thatincludes a heterogeneous group of primary brain tumors. Several classification strategies of GBM havebeen reported, some by clinical course and others by resemblance to cell types either in the adult orduring development. From a practical and therapeutic standpoint, classifying GBMs by signal transductionpathway activation and by mutation in pathway member genes may be particularly valuable for thedevelopment of targeted therapies. METHODOLOGY/PRINCIPAL FINDINGS We performed targetedproteomic analysis of 27 surgical glioma samples to identify patterns of coordinate activation amongglioma-relevant signal transduction pathways, then compared these results with integrated analysis ofgenomic and expression data of 243 GBM samples from The Cancer Genome Atlas (TCGA). In the patternof signaling, three subclasses of GBM emerge which appear to be associated with predominance of EGFRactivation, PDGFR activation, or loss of the RAS regulator NF1. The EGFR signaling class has prominentNotch pathway activation measured by elevated expression of Notch ligands, cleaved Notch receptor, anddownstream target Hes1. The PDGF class showed high levels of PDGFB ligand and phosphorylation ofPDGFRbeta and NFKB. NF1-loss was associated with lower overall MAPK and PI3K activation and relativeoverexpression of the mesenchymal marker YKL40. These three signaling classes appear to correspondwith distinct transcriptomal subclasses of primary GBM samples from TCGA for which copy numberaberration and mutation of EGFR, PDGFRA, and NF1 are signature events. CONCLUSIONS/SIGNIFICANCEProteomic analysis of GBM samples revealed three patterns of expression and activation of proteins inglioma-relevant signaling pathways. These three classes are comprised of roughly equal numbersshowing either EGFR activation associated with amplification and mutation of the receptor, PDGF-pathwayactivation that is primarily ligand-driven, or loss of NF1 expression. The associated signaling activitiescorrelating with these sentinel alterations provide insight into glioma biology and therapeutic strategies.", "metadata": {}}
+{"_id": "6368017", "title": "", "text": "Loss of sex discrimination and male-male aggression in mice deficient for TRP2.The mouse vomeronasalorgan (VNO) is thought to mediate social behaviors and neuroendocrine changes elicited by pheromonalcues. The molecular mechanisms underlying the sensory response to pheromones and the behavioralrepertoire induced through the VNO are not fully characterized. Using the tools of mouse genetics andmultielectrode recording, we demonstrate that the sensory activation of VNO neurons requires TRP2, aputative ion channel of the transient receptor potential family that is expressed exclusively in theseneurons. Moreover, we show that male mice deficient in TRP2 expression fail to display male-maleaggression, and they initiate sexual and courtship behaviors toward both males and females. Our studysuggests that, in the mouse, sensory activation of the VNO is essential for sex discrimination ofconspecifics and thus ensures gender-specific behavior.", "metadata": {}}
+{"_id": "6372244", "title": "", "text": "Antibiotic-induced shifts in the mouse gut microbiome and metabolome increase susceptibility toClostridium difficile infectionAntibiotics can have significant and long-lasting effects on thegastrointestinal tract microbiota, reducing colonization resistance against pathogens including Clostridiumdifficile. Here we show that antibiotic treatment induces substantial changes in the gut microbialcommunity and in the metabolome of mice susceptible to C. difficile infection. Levels of secondary bileacids, glucose, free fatty acids and dipeptides decrease, whereas those of primary bile acids and sugaralcohols increase, reflecting the modified metabolic activity of the altered gut microbiome. In vitro and exvivo analyses demonstrate that C. difficile can exploit specific metabolites that become more abundant inthe mouse gut after antibiotics, including the primary bile acid taurocholate for germination, and carbonsources such as mannitol, fructose, sorbitol, raffinose and stachyose for growth. Our results indicate thatantibiotic-mediated alteration of the gut microbiome converts the global metabolic profile to one thatfavours C. difficile germination and growth.", "metadata": {}}
+{"_id": "6374918", "title": "", "text": "Chemosensitization of acute myeloid leukemia (AML) following mobilization by the CXCR4 antagonistAMD3100.The CXCR4-SDF-1 axis plays a central role in the trafficking and retention of normal andmalignant stem cells in the bone marrow (BM) microenvironment. Here, we used a mouse model of acutepromyelocytic leukemia (APL) and a small molecule competitive antagonist of CXCR4, AMD3100, toexamine the interaction of mouse APL cells with the BM microenvironment. APL cells from a murinecathepsin G-PML-RARalpha knockin mouse were genetically modified with firefly luciferase (APL(luc)) toallow tracking by bioluminescence imaging. Coculture of APL(luc) cells with M2-10B4 stromal cellsprotected the leukemia cells from chemotherapy-induced apoptosis in vitro. Upon injection into syngeneicrecipients, APL(luc) cells rapidly migrated to the BM followed by egress to the spleen then to theperipheral blood with death due to leukostasis by day 15. Administration of AMD3100 to leukemic miceinduced a 1.6-fold increase in total leukocytes and a 9-fold increase of circulating APL blast counts, whichpeak at 3 hours and return to baseline by 12 hours. Treatment of leukemic mice with chemotherapy plusAMD3100 resulted in decreased tumor burden and improved overall survival compared with mice treatedwith chemotherapy alone. These studies provide a proof-of-principle for directing therapy to the criticaltethers that promote AML-niche interactions.", "metadata": {}}
+{"_id": "6386930", "title": "", "text": "Insights into G-quadruplex specific recognition by the DEAH-box helicase RHAU: Solution structure of apeptide-quadruplex complex.Four-stranded nucleic acid structures called G-quadruplexes have beenassociated with important cellular processes, which should require G-quadruplex-protein interaction.However, the structural basis for specific G-quadruplex recognition by proteins has not been understood.The DEAH (Asp-Glu-Ala-His) box RNA helicase associated with AU-rich element (RHAU) (also namedDHX36 or G4R1) specifically binds to and resolves parallel-stranded G-quadruplexes. Here we identifiedan 18-amino acid G-quadruplex-binding domain of RHAU and determined the structure of this peptidebound to a parallel DNA G-quadruplex. Our structure explains how RHAU specifically recognizes parallelG-quadruplexes. The peptide covers a terminal guanine base tetrad (G-tetrad), and clamps theG-quadruplex using three-anchor-point electrostatic interactions between three positively charged aminoacids and negatively charged phosphate groups. This binding mode is strikingly similar to that of mostligands selected for specific G-quadruplex targeting. Binding to an exposed G-tetrad represents a simpleand efficient way to specifically target G-quadruplex structures.", "metadata": {}}
+{"_id": "6387956", "title": "", "text": "IQ and non-clinical psychotic symptoms in 12-year-olds: results  from the ALSPAC birthcohortBACKGROUND Non-clinical psychotic symptoms appear common in children, but it is possible that aproportion of reported symptoms result from misinterpretation. There is a well-established associationbetween pre-morbid low IQ score and schizophrenia. Psychosis-like symptoms in children may also be arisk factor for psychotic disorder but their relationship with IQ is unclear. AIMS To investigate theprevalence, nature and frequency of psychosis-like symptoms in 12-year-old children and study theirrelationship with IQ. METHOD Longitudinal study using the Avon Longitudinal Study of Parents andChildren (ALSPAC) birth cohort. A total of 6455 children completed screening questions for 12 psychoticsymptoms followed by a semi-structured clinical assessment. IQ was assessed at 8 years of age using theWechsler Intelligence Scale for Children (3rd UK edition). RESULTS The 6-month period prevalence forone or more symptoms was 13.7% (95% CI 12.8-14.5). After adjustment for confounding variables,there was a non-linear association between IQ score and psychosis-like symptoms, such that only thosewith below average IQ score had an increased risk of reporting such symptoms. CONCLUSIONSNon-clinical psychotic symptoms occur in a significant proportion of 12-year-olds. Symptoms areassociated with low IQ and also less strongly with a high IQ score. The pattern of association with IQdiffers from that observed in schizophrenia.", "metadata": {}}
+{"_id": "6397191", "title": "", "text": "Endothelin-1 is induced by cytokines in human vascular smooth muscle cells: evidence for intracellularendothelin-converting enzyme.Endothelin-1 (ET-1) is the predominant endothelin isopeptide generatedby the vascular wall and therefore appears to be the most important peptide involved in regulation ofcardiovascular events. Many pathologic conditions are associated with elevations of ET-1 in the bloodvessel wall. Because these conditions are often cytokine driven, we examined the effects of a mixture ofcytokines on ET-1 production in human vascular smooth muscle cells (VSMCs) derived from internalmammary artery and saphenous vein (SV). Incubation of IMA and SV VSMCs with tumor necrosisfactor-alpha (10 ng/ml) and interferon-gamma (1000 U/ml) in combination for up to 48 h markedlyelevated the expression of mRNA for prepro-ET-1 and the release of ET-1 into the culture medium. Thiscytokine-stimulated release of ET-1 was inhibited by a series of dual endothelin-converting enzyme(ECE)/neutral endopeptidase inhibitors, phosphoramidon, CGS 26303, and CGS 26393, with anaccompanying increase in big ET-1 release but with no effect on expression of mRNA for prepro-ET-1.These same compounds were 10 times more potent at inhibiting the conversion of exogenously appliedbig ET-1 to ET-1. ECE-1b/c mRNA is present in SV VSMCs, however no ECE-1a is present in these cells.Thus VSMCs most probably contain, like endothelial cells, an intracellular ECE responsible for theendogenous synthesis of ET-1. Under the influence of pro-inflammatory mediators the vascular smoothmuscle can therefore become an important site of ET-1 production, as has already been established forthe dilator mediators nitric oxide, prostaglandin I2, and prostaglandin E2.", "metadata": {}}
+{"_id": "6401675", "title": "", "text": "Transposable elements have rewired the core regulatory network of human embryonic stemcellsDetection of new genomic control elements is critical in understanding transcriptional regulatorynetworks in their entirety. We studied the genome-wide binding locations of three key regulatory proteins(POU5F1, also known as OCT4; NANOG; and CTCF) in human and mouse embryonic stem cells. Incontrast to CTCF, we found that the binding profiles of OCT4 and NANOG are markedly different, withonly \u00005% of the regions being homologously occupied. We show that transposable elements contributedup to 25% of the bound sites in humans and mice and have wired new genes into the core regulatorynetwork of embryonic stem cells. These data indicate that species-specific transposable elements havesubstantially altered the transcriptional circuitry of pluripotent stem cells.", "metadata": {}}
+{"_id": "6404801", "title": "", "text": "Cytomegalovirus microRNAs Facilitate Persistent Virus Infection in Salivary GlandsMicro (mi)RNAs aresmall non-coding RNAs that regulate the expression of their targets' messenger RNAs through bothtranslational inhibition and regulation of target RNA stability. Recently, a number of viruses, particularlyof the herpesvirus family, have been shown to express their own miRNAs to control both viral and cellulartranscripts. Although some targets of viral miRNAs are known, their function in a physiologically relevantinfection remains to be elucidated. As such, no in vivo phenotype of a viral miRNA knock-out mutant hasbeen described so far. Here, we report on the first functional phenotype of a miRNA knock-out virus invivo. During subacute infection of a mutant mouse cytomegalovirus lacking two viral miRNAs, virusproduction is selectively reduced in salivary glands, an organ essential for virus persistence andhorizontal transmission. This phenotype depends on several parameters including viral load and mousegenetic background, and is abolished by combined but not single depletion of natural killer (NK) andCD4+ T cells. Together, our results point towards a miRNA-based immunoevasion mechanism importantfor long-term virus persistence.", "metadata": {}}
+{"_id": "6407356", "title": "", "text": "Coxibs and other nonsteroidal anti-inflammatory drugs in animal models of cancerchemoprevention.Coxibs, including celecoxib, and other nonsteroidal anti-inflammatory drugs (NSAID),including aspirin, are among the most promising cancer chemopreventive agents in development today.This article examines the data on the efficacy of these agents in animal model studies of cancerprevention carried out by the authors. The studies evaluated here are restricted to our rodent models ofcolon/intestinal, bladder, and nonmelanoma skin cancer, in which celecoxib and other NSAIDs wereadministered as either cancer preventive or therapeutic agents. These studies may shed light on severalquestions. Is celecoxib unique compared with other NSAIDs, and if so, what implications would this havefor human use? Are standard NSAIDs (which inhibit both COX-1 and COX-2) as effective as celecoxib inanimal studies? Is the efficacy of celecoxib in particular or NSAIDs in general due to their off-targeteffects or to their effects on COX-1 and COX-2? What is the likely efficacy of low-dose aspirin? Somequestions raised by human trials and epidemiology are discussed and related to our observations inanimal model studies. We also discuss the problem of cardiovascular (CV) events associated with coxibsand certain other NSAIDs and whether results in animal models are predictive of efficacy in humans. Onthe basis of epidemiologic studies and its CV profile, aspirin seems to be the most promising NSAID forpreventing human colorectal, bladder, and skin cancer, although the animal data for aspirin are lessclear. A comprehensive understanding of the results of coxibs and other NSAIDs in animal studies mayhelp inform and shape human trials of these commonly employed, relatively inexpensive, and highlyeffective compounds.", "metadata": {}}
+{"_id": "6415816", "title": "", "text": "The porphyrias: advances in diagnosis and treatment.The inborn errors of heme biosynthesis, theporphyrias, are 8 genetically distinct metabolic disorders that can be classified as \"acute hepatic,\"\"hepatic cutaneous,\" and \"erythropoietic cutaneous\" diseases. Recent advances in understanding theirpathogenesis and molecular genetic heterogeneity have led to improved diagnosis and treatment. Theseadvances include DNA-based diagnoses for all the porphyrias, new understanding of the pathogenesis ofthe acute hepatic porphyrias, identification of the iron overload-induced inhibitor of hepatic uroporphyrindecarboxylase activity that causes the most common porphyria, porphyria cutanea tarda, theidentification of an X-linked form of erythropoietic protoporphyria due to gain-of-function mutations inerythroid-specific 5-aminolevulinate synthase (ALAS2), and new and experimental treatments for theerythropoietic porphyrias. Knowledge of these advances is relevant for hematologists because theyadminister the hematin infusions to treat the acute attacks in patients with the acute hepatic porphyrias,perform the chronic phlebotomies to reduce the iron overload and clear the dermatologic lesions inporphyria cutanea tarda, and diagnose and treat the erythropoietic porphyrias, including chronicerythrocyte transfusions, bone marrow or hematopoietic stem cell transplants, and experimentalpharmacologic chaperone and stem cell gene therapies for congenital erythropoietic protoporphyria.These developments are reviewed to update hematologists on the latest advances in these diversedisorders.", "metadata": {}}
+{"_id": "6417632", "title": "", "text": "Neutrophilic infiltration within the airway smooth muscle in patients with COPD.BACKGROUND COPD is aninflammatory disorder characterised by chronic airflow limitation, but the extent to which airwayinflammation is related to functional abnormalities is still uncertain. The interaction betweeninflammatory cells and airway smooth muscle may have a crucial role. METHODS To investigate themicrolocalisation of inflammatory cells within the airway smooth muscle in COPD, surgical specimensobtained from 26 subjects undergoing thoracotomy (eight smokers with COPD, 10 smokers with normallung function, and eight non-smoking controls) were examined. Immunohistochemical analysis was usedto quantify the number of neutrophils, macrophages, mast cells, CD4+ and CD8+ cells localised withinthe smooth muscle of peripheral airways. RESULTS Smokers with COPD had an increased number ofneutrophils and CD8+ cells in the airway smooth muscle compared with non-smokers. Smokers withnormal lung function also had a neutrophilic infiltration in the airway smooth muscle, but to a lesserextent. When all the subjects were analysed as one group, neutrophilic infiltration was inversely relatedto forced expiratory volume in 1 second (% predicted). CONCLUSIONS Microlocalisation of neutrophilsand CD8+ cells in the airway smooth muscle in smokers with COPD suggests a possible role for thesecells in the pathogenesis of smoking induced airflow limitation.", "metadata": {}}
+{"_id": "6421734", "title": "", "text": "Characteristics of service users and provider organisations associated with experience of out of hoursgeneral practitioner care in England: population based cross sectional postal questionnairesurvey.OBJECTIVE To investigate the experience of users of out of hours general practitioner services inEngland, UK. DESIGN Population based cross sectional postal questionnaire survey. SETTING GeneralPractice Patient Survey 2012-13. MAIN OUTCOME MEASURES Potential associations betweensociodemographic factors (including ethnicity and ability to take time away from work during workinghours to attend a healthcare consultation) and provider organisation type (not for profit, NHS, orcommercial) and service users' experience of out of hours care (timeliness, confidence and trust in theout of hours clinician, and overall experience of the service), rated on a scale of 0-100. Whichsociodemographic/provider characteristics were associated with service users' experience, the extent towhich any observed differences could be because of clustering of service users of a particularsociodemographic group within poorer scoring providers, and the extent to which observed differences inexperience varied across types of provider. RESULTS The overall response rate was 35%;971,232/2,750,000 patients returned surveys. Data from 902,170 individual service users were mappedthrough their registered practice to one of 86 providers of out of hours GP care with known organisationtype. Commercial providers of out of hours GP care were associated with poorer reports of overallexperience of care, with a mean difference of -3.13 (95% confidence interval -4.96 to -1.30) comparedwith not for profit providers. Asian service users reported lower scores for all three experience outcomesthan white service users (mean difference for overall experience of care -3.62, -4.36 to -2.89), as didservice users who were unable to take time away from work compared with service users who did notwork (mean difference for overall experience of care -4.73, -5.29 to -4.17). CONCLUSIONS Commercialproviders of out of hours GP care were associated with poorer experience of care. Targeted interventionsaimed at improving experience for patients from ethnic minorities and patients who are unable to taketime away from work might be warranted.", "metadata": {}}
+{"_id": "6421792", "title": "", "text": "Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALLAcutelymphoblastic leukemia (ALL) is an aggressive hematological tumor resulting from the malignanttransformation of lymphoid progenitors. Despite intensive chemotherapy, 20% of pediatric patients andover 50% of adult patients with ALL do not achieve a complete remission or relapse after intensifiedchemotherapy, making disease relapse and resistance to therapy the most substantial challenge in thetreatment of this disease. Using whole-exome sequencing, we identify mutations in the cytosolic5'-nucleotidase II gene (NT5C2), which encodes a 5'-nucleotidase enzyme that is responsible for theinactivation of nucleoside-analog chemotherapy drugs, in 20/103 (19%) relapse T cell ALLs and 1/35(3%) relapse B-precursor ALLs. NT5C2 mutant proteins show increased nucleotidase activity in vitro andconferred resistance to chemotherapy with 6-mercaptopurine and 6-thioguanine when expressed in ALLlymphoblasts. These results support a prominent role for activating mutations in NT5C2 and increasednucleoside-analog metabolism in disease progression and chemotherapy resistance in ALL.", "metadata": {}}
+{"_id": "6422576", "title": "", "text": "Ubiquitin-dependent protein degradation.A growing number of cellular regulatory mechanisms are beinglinked to protein modification by the polypeptide ubiquitin. These include key transitions in the cell cycle,class I antigen processing, signal transduction pathways, and receptor-mediated endocytosis. In most,but not all, of these examples, ubiquitination of a protein leads to its degradation by the 26S proteasome.Following attachment of ubiquitin to a substrate and binding of the ubiquitinated protein to theproteasome, the bound substrate must be unfolded (and eventually deubiquitinated) and translocatedthrough a narrow set of channels that leads to the proteasome interior, where the polypeptide is cleavedinto short peptides. Protein ubiquitination and deubiquitination are both mediated by large enzymefamilies, and the proteasome itself comprises a family of related but functionally distinct particles. Thisdiversity underlies both the high substrate specificity of the ubiquitin system and the variety of regulatorymechanisms that it serves.", "metadata": {}}
+{"_id": "6426919", "title": "", "text": "A novel molecular mechanism of dual resistance to nucleoside and nonnucleoside reverse transcriptaseinhibitors.Recently, mutations in the connection subdomain (CN) and RNase H domain of HIV-1 reversetranscriptase (RT) were observed to exhibit dual resistance to nucleoside and nonnucleoside reversetranscriptase inhibitors (NRTIs and NNRTIs). To elucidate the mechanism by which CN and RH mutationsconfer resistance to NNRTIs, we hypothesized that these mutations reduce RNase H cleavage and providemore time for the NNRTI to dissociate from the RT, resulting in the resumption of DNA synthesis andenhanced NNRTI resistance. We observed that the effect of the reduction in RNase H cleavage on NNRTIresistance is dependent upon the affinity of each NNRTI to the RT and further influenced by the presenceof NNRTI-binding pocket (BP) mutants. D549N, Q475A, and Y501A mutants, which reduce RNase Hcleavage, enhance resistance to nevirapine (NVP) and delavirdine (DLV), but not to efavirenz (EFV) andetravirine (ETR), consistent with their increase in affinity for RT. Combining the D549N mutant withNNRTI BP mutants further increases NNRTI resistance from 3- to 30-fold, supporting the role ofNNRTI-RT affinity in our NNRTI resistance model. We also demonstrated that CNs fromtreatment-experienced patients, previously reported to enhance NRTI resistance, also reduce RNase Hcleavage and enhance NNRTI resistance in the context of the patient RT pol domain or a wild-type poldomain. Together, these results confirm key predictions of our NNRTI resistance model and providesupport for a unifying mechanism by which CN and RH mutations can exhibit dual NRTI and NNRTIresistance.", "metadata": {}}
+{"_id": "6431384", "title": "", "text": "Location Coding by Opponent Neural Populations in the Auditory CortexAlthough the auditory cortex playsa necessary role in sound localization, physiological investigations in the cortex reveal inhomogeneoussampling of auditory space that is difficult to reconcile with localization behavior under the assumption oflocal spatial coding. Most neurons respond maximally to sounds located far to the left or right side, withfew neurons tuned to the frontal midline. Paradoxically, psychophysical studies show optimal spatialacuity across the frontal midline. In this paper, we revisit the problem of inhomogeneous spatial samplingin three fields of cat auditory cortex. In each field, we confirm that neural responses tend to be greatestfor lateral positions, but show the greatest modulation for near-midline source locations. Moreover,identification of source locations based on cortical responses shows sharp discrimination of left from rightbut relatively inaccurate discrimination of locations within each half of space. Motivated by these findings,we explore an opponent-process theory in which sound-source locations are represented by differences inthe activity of two broadly tuned channels formed by contra- and ipsilaterally preferring neurons. Finally,we demonstrate a simple model, based on spike-count differences across cortical populations, thatprovides bias-free, level-invariant localization—and thus also a solution to the “binding problem” ofassociating spatial information with other nonspatial attributes of sounds.", "metadata": {}}
+{"_id": "6441369", "title": "", "text": "MLL1 Inhibition Reprograms Epiblast Stem Cells to Naive Pluripotency.The interconversion between naiveand primed pluripotent states is accompanied by drastic epigenetic rearrangements. However, it isunclear whether intrinsic epigenetic events can drive reprogramming to naive pluripotency or if distinctchromatin states are instead simply a reflection of discrete pluripotent states. Here, we show thatblocking histone H3K4 methyltransferase MLL1 activity with the small-molecule inhibitor MM-401reprograms mouse epiblast stem cells (EpiSCs) to naive pluripotency. This reversion is highly efficientand synchronized, with more than 50% of treated EpiSCs exhibiting features of naive embryonic stemcells (ESCs) within 3 days. Reverted ESCs reactivate the silenced X chromosome and contribute toembryos following blastocyst injection, generating germline-competent chimeras. Importantly, blockingMLL1 leads to global redistribution of H3K4me1 at enhancers and represses lineage determinant factorsand EpiSC markers, which indirectly regulate ESC transcription circuitry. These findings show thatdiscrete perturbation of H3K4 methylation is sufficient to drive reprogramming to naive pluripotency.", "metadata": {}}
+{"_id": "6446747", "title": "", "text": "MafB/c-Maf deficiency enables self-renewal of differentiated functional macrophages.In metazoanorganisms, terminal differentiation is generally tightly linked to cell cycle exit, whereas theundifferentiated state of pluripotent stem cells is associated with unlimited self-renewal. Here, we reportthat combined deficiency for the transcription factors MafB and c-Maf enables extended expansion ofmature monocytes and macrophages in culture without loss of differentiated phenotype and function.Upon transplantation, the expanded cells are nontumorigenic and contribute to functional macrophagepopulations in vivo. Small hairpin RNA inactivation shows that continuous proliferation of MafB/c-Mafdeficient macrophages requires concomitant up-regulation of two pluripotent stem cell-inducing factors,KLF4 and c-Myc. Our results indicate that MafB/c-MafB deficiency renders self-renewal compatible withterminal differentiation. It thus appears possible to amplify functional differentiated cells withoutmalignant transformation or stem cell intermediates.", "metadata": {}}
+{"_id": "6454371", "title": "", "text": "Macropinocytosis: an endocytic pathway for internalising large gulps.Macropinocytosis is a regulated formof endocytosis that mediates the non-selective uptake of solute molecules, nutrients and antigens. It isan actin-dependent process initiated from surface membrane ruffles that give rise to large endocyticvacuoles called macropinosomes. Macropinocytosis is important in a range of physiological processes; it ishighly active in macrophages and dendritic cells where it is a major pathway for the capture of antigens,it is relevant to cell migration and tumour metastasis and it represents a portal of cell entry exploited bya range of pathogens. The molecular basis for the formation and maturation of macropinosomes has onlyrecently begun to be defined. Here, we review the general characteristics of macropinocytosis, describesome of the regulators of this pathway, which have been identified to date and highlight strategies toexplore the relevance of this endocytosis pathway in vivo.", "metadata": {}}
+{"_id": "6455142", "title": "", "text": "KDM5B regulates embryonic stem cell self-renewal and represses cryptic intragenictranscription.Although regulation of histone methylation is believed to contribute to embryonic stem cell(ESC) self-renewal, the mechanisms remain obscure. We show here that the histone H3 trimethyl lysine 4(H3K4me3) demethylase, KDM5B, is a downstream Nanog target and critical for ESC self-renewal.Although KDM5B is believed to function as a promoter-bound repressor, we find that it paradoxicallyfunctions as an activator of a gene network associated with self-renewal. ChIP-Seq reveals that KDM5B ispredominantly targeted to intragenic regions and that it is recruited to H3K36me3 via an interaction withthe chromodomain protein MRG15. Depletion of KDM5B or MRG15 increases intragenic H3K4me3,increases cryptic intragenic transcription, and inhibits transcriptional elongation of KDM5B target genes.We propose that KDM5B activates self-renewal-associated gene expression by repressing cryptic initiationand maintaining an H3K4me3 gradient important for productive transcriptional elongation.", "metadata": {}}
+{"_id": "6472746", "title": "", "text": "Increased CDK1 activity determines the timing of kinetochore-microtubule attachments in meiosisIChromosome segregation during cell division depends on stable attachment of kinetochores to spindlemicrotubules. Mitotic spindle formation and kinetochore-microtubule (K-MT) capture typically occur withinminutes of nuclear envelope breakdown. In contrast, during meiosis I in mouse oocytes, formation of theacentrosomal bipolar spindle takes 3-4 h, and stabilization of K-MT attachments is delayed an additional3-4 h. The mechanism responsible for this delay, which likely prevents stabilization of erroneousattachments during spindle formation, is unknown. Here we show that during meiosis I, attachments areregulated by CDK1 activity, which gradually increases through prometaphase and metaphase I. Partialreduction of CDK1 activity delayed formation of stable attachments, whereas a premature increase inCDK1 activity led to precocious formation of stable attachments and eventually lagging chromosomes atanaphase I. These results indicate that the slow increase in CDK1 activity in meiosis I acts as a timingmechanism to allow stable K-MT attachments only after bipolar spindle formation, thus preventingattachment errors.", "metadata": {}}
+{"_id": "6477536", "title": "", "text": "Discontinuation and non-publication of surgical randomised controlled trials: observationalstudyOBJECTIVE To determine the rate of early discontinuation and non-publication of randomisedcontrolled trials involving patients undergoing surgery. DESIGN Cross sectional observational study ofregistered and published trials. SETTING Randomised controlled trials of interventions in patientsundergoing a surgical procedure. DATA SOURCES The ClinicalTrials.gov database was searched forinterventional trials registered between January 2008 and December 2009 using the keyword \"surgery\".Recruitment status was extracted from the ClinicalTrials.gov database. A systematic search for studiespublished in peer reviewed journals was performed; if they were not found, results posted on theClinicalTrials.gov results database were sought. Email queries were sent to trial investigators ofdiscontinued and unpublished completed trials if no reason for the respective status was disclosed. MAINOUTCOME MEASURES Trial discontinuation before completion and non-publication after completion.Logistic regression was used to determine the effect of funding source on publication status, withadjustment for intervention type and trial size. RESULTS Of 818 registered trials found using the keyword\"surgery\", 395 met the inclusion criteria. Of these, 21% (81/395) were discontinued early, mostcommonly owing to poor recruitment (44%, 36/81). The remaining 314 (79%) trials proceeded tocompletion, with a publication rate of 66% (208/314) at a median time of 4.9 (interquartile range4.0-6.0) years from study completion to publication search. A further 6% (20/314) of studies presentedresults on ClinicalTrials.gov without a corresponding peer reviewed publication. Industry funding did notaffect the rate of discontinuation (adjusted odds ratio 0.91, 95% confidence interval 0.54 to 1.55) butwas associated with a lower odds of publication for completed trials (0.43, 0.26 to 0.72). Investigators'email addresses for trials with an uncertain fate were identified for 71.4% (10/14) of discontinued trialsand 83% (101/122) of unpublished studies. Only 43% (6/14) and 20% (25/122) replies were received.Email responses for completed trials indicated 11 trials in press, five published studies (four innon-indexed peer reviewed journals), and nine trials remaining unpublished. CONCLUSIONS One in fivesurgical randomised controlled trials are discontinued early, one in three completed trials remainunpublished, and investigators of unpublished studies are frequently not contactable. This represents awaste of research resources and raises ethical concerns regarding hidden clinical data and futileparticipation by patients with its attendant risks. To promote future efficiency and transparency, changesare proposed to research governance frameworks to overcome these concerns.", "metadata": {}}
+{"_id": "6477740", "title": "", "text": "Efficient Generation of Fully Reprogrammed Human iPS Cells via Polycistronic Retroviral Vector and a NewCocktail of Chemical CompoundsDirect reprogramming of human somatic cells into induced pluripotentstem (iPS) cells by defined transcription factors (TFs) provides great potential for regenerative medicineand biomedical research. This procedure has many challenges, including low reprogramming efficiency,many partially reprogrammed colonies, somatic coding mutations in the genome, etc. Here, we describea simple approach for generating fully reprogrammed human iPS cells by using a single polycistronicretroviral vector expressing four human TFs in a single open reading frame (ORF), combined with acocktail containing three small molecules (Sodium butyrate, SB431542, and PD0325901). Our resultsdemonstrate that human iPS cells generated by this approach express human ES cells markers andexhibit pluripotency demonstrated by their abilities to differentiate into the three germ layers in vitro andin vivo. Notably, this approach not only provides a much faster reprogramming process but alsosignificantly diminishes partially reprogrammed iPS cell colonies, thus facilitating efficient isolation ofdesired fully reprogrammed iPS cell colonies.", "metadata": {}}
+{"_id": "6490571", "title": "", "text": "Prevalence, severity, and unmet need for treatment of mental disorders in the World Health OrganizationWorld Mental Health Surveys.CONTEXT Little is known about the extent or severity of untreated mentaldisorders, especially in less-developed countries. OBJECTIVE To estimate prevalence, severity, andtreatment of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) mentaldisorders in 14 countries (6 less developed, 8 developed) in the World Health Organization (WHO) WorldMental Health (WMH) Survey Initiative. DESIGN, SETTING, AND PARTICIPANTS Face-to-face householdsurveys of 60 463 community adults conducted from 2001-2003 in 14 countries in the Americas, Europe,the Middle East, Africa, and Asia. MAIN OUTCOME MEASURES The DSM-IV disorders, severity, andtreatment were assessed with the WMH version of the WHO Composite International Diagnostic Interview(WMH-CIDI), a fully structured, lay-administered psychiatric diagnostic interview. RESULTS Theprevalence of having any WMH-CIDI/DSM-IV disorder in the prior year varied widely, from 4.3% inShanghai to 26.4% in the United States, with an interquartile range (IQR) of 9.1%-16.9%. Between33.1% (Colombia) and 80.9% (Nigeria) of 12-month cases were mild (IQR, 40.2%-53.3%). Seriousdisorders were associated with substantial role disability. Although disorder severity was correlated withprobability of treatment in almost all countries, 35.5% to 50.3% of serious cases in developed countriesand 76.3% to 85.4% in less-developed countries received no treatment in the 12 months before theinterview. Due to the high prevalence of mild and subthreshold cases, the number of those who receivedtreatment far exceeds the number of untreated serious cases in every country. CONCLUSIONSReallocation of treatment resources could substantially decrease the problem of unmet need fortreatment of mental disorders among serious cases. Structural barriers exist to this reallocation. Carefulconsideration needs to be given to the value of treating some mild cases, especially those at risk forprogressing to more serious disorders.", "metadata": {}}
+{"_id": "6491532", "title": "", "text": "Successful '9-month Bangladesh regimen' for multidrug-resistant tuberculosis among over 500consecutive patients.SETTING Tuberculosis (TB) program, Damien Foundation Projects, Bangladesh.OBJECTIVE To summarize the outcome and its determinants of the first treatment for multidrug-resistantTB using a standardized regimen consisting of a minimum 9 months. DESIGN This was a prospective,observational study of a gatifloxacin (GFX) based directly observed regimen, mainly with initialhospitalization. The 4-month intensive phase was extended until sputum smear conversion. Patients weremonitored using culture for up to 2 years after treatment completion. RESULTS Of the 515 patients whomet the study inclusion criteria and were successively enrolled from 2005 to 2011, 84.4% had abacteriologically favorable outcome. Due to extensive disease with delayed sputum conversion, only halfof the patients completed treatment within 9 months; however, 95% were able to complete treatmentwithin 12 months. Eleven patients failed or relapsed, and 93.1% of the 435 patients who weresuccessfully treated completed at least 12 months post-treatment follow-up. The strongest risk factor fora bacteriologically unfavorable outcome was high-level fluoroquinolone (FQ) resistance, particularly whencompounded by initial pyrazinamide (PZA) resistance. Low-level FQ resistance had no unfavorable effecton treatment outcome. Amplification of drug resistance occurred only once, in a patient strain that wasinitially only susceptible to kanamycin and clofazimine. CONCLUSION The excellent outcome of theBangladesh regimen was largely maintained. Bacteriological treatment failures and relapses were rare,except among patients with high-level GFX resistance, notably in the presence of PZA resistance.", "metadata": {}}
+{"_id": "6492658", "title": "", "text": "A Null Mutation in Inositol Polyphosphate 4-Phosphatase Type I Causes Selective Neuronal Loss in WeebleMutant MiceWeeble mutant mice have severe locomotor instability and significant neuronal loss in thecerebellum and in the hippocampal CA1 field. Genetic mapping was used to localize the mutation to thegene encoding inositol polyphosphate 4-phosphatase type I (Inpp4a), where a single nucleotide deletionresults in a likely null allele. The substrates of INPP4A are intermediates in a pathway affectingintracellular Ca(2+) release but are also involved in cell cycle regulation through binding the Aktprotooncogene; dysfunction in either may account for the neuronal loss of weeble mice. Although othermutations in phosphoinositide enzymes are associated with synaptic defects without neuronal loss,weeble shows that Inpp4a is critical for the survival of a subset of neurons during postnatal developmentin mice.", "metadata": {}}
+{"_id": "6493422", "title": "", "text": "The myeloid transcription factor KLF2 regulates the host response to polymicrobial infection andendotoxic shock.Precise control of myeloid cell activation is required for optimal host defense. However,this activation process must be under exquisite control to prevent uncontrolled inflammation. Herein, weidentify the Kruppel-like transcription factor 2 (KLF2) as a potent regulator of myeloid cell activation invivo. Exposure of myeloid cells to hypoxia and/or bacterial products reduced KLF2 expression whileinducing hypoxia inducible factor-1α (HIF-1α), findings that were recapitulated in human septic patients.Myeloid KLF2 was found to be a potent inhibitor of nuclear factor-kappaB (NF-κB)-dependent HIF-1αtranscription and, consequently, a critical determinant of outcome in models of polymicrobial infectionand endotoxemia. Collectively, these observations identify KLF2 as a tonic repressor of myeloid cellactivation in vivo and an essential regulator of the innate immune system.", "metadata": {}}
+{"_id": "6501747", "title": "", "text": "PQBP1 Is a Proximal Sensor of the cGAS-Dependent Innate Response to HIV-1Dendritic cells (DCs) play acritical role in the immune response to viral infection through the facilitation of cell-intrinsic antiviralactivity and the activation of adaptive immunity. HIV-1 infection of DCs triggers an IRF3-dependentinnate immune response, which requires the activity of cyclic GAMP synthase (cGAS). We report theresults of a targeted RNAi screen utilizing primary human monocyte-derived DCs (MDDCs) to identifyimmune regulators that directly interface with HIV-1-encoded features to initiate this innate response.Polyglutamine binding protein 1 (PQBP1) emerged as a strong candidate through this analysis. We foundthat PQBP1 directly binds to reverse-transcribed HIV-1 DNA and interacts with cGAS to initiate anIRF3-dependent innate response. MDDCs derived from Renpenning syndrome patients, who harbormutations in the PQBP1 locus, possess a severely attenuated innate immune response to HIV-1challenge, underscoring the role of PQBP1 as a proximal innate sensor of a HIV-1 infection.", "metadata": {}}
+{"_id": "6503185", "title": "", "text": "Malaria biology and disease pathogenesis: insights for new treatmentsPlasmodium falciparum malaria, aninfectious disease caused by a parasitic protozoan, claims the lives of nearly a million children each yearin Africa alone and is a top public health concern. Evidence is accumulating that resistance to artemisininderivatives, the frontline therapy for the asexual blood stage of the infection, is developing in southeastAsia. Renewed initiatives to eliminate malaria will benefit from an expanded repertoire of antimalarials,including new drugs that kill circulating P. falciparum gametocytes, thereby preventing transmission. Ourcurrent understanding of the biology of asexual blood-stage parasites and gametocytes and the ability toculture them in vitro lends optimism that high-throughput screenings of large chemical libraries willproduce a new generation of antimalarial drugs. There is also a need for new therapies to reduce the highmortality of severe malaria. An understanding of the pathophysiology of severe disease may identifyrational targets for drugs that improve survival.", "metadata": {}}
+{"_id": "6503534", "title": "", "text": "Mutations among Italian mucopolysaccharidosis type I patientsA group of 27 Italian patients wasscreened for α-L-iduronidase mucopolysaccharidosis type I mutations. Mutations were found in 18patients, with 28 alleles identified. The two most common mutations in northern Europeans (W402X andQ70X) accounted for 11% and 13% of the alleles, respectively. The R89Q mutation, uncommon inEuropeans, was found only in one patient, accounting for 1 of 54 alleles (1.9%). The other mutations,P533R, A327P and G51D, accounted for 11%, 5.6% and 9.3% of the total alleles, respectively.Interestingly, the high frequency of the P533R mutation seems to be confined to Sicily and is higher thanthe 3% reported in a British/Australian study.", "metadata": {}}
+{"_id": "6504953", "title": "", "text": "Radiation-Related Cancer Risks at Low Doses among Atomic Bomb SurvivorsAbstract Pierce, D. A. andPreston, D. L. Radiation-Related Cancer Risks at Low Doses among Atomic Bomb Survivors. To clarify theinformation in the Radiation Effects Research Foundation data regarding cancer risks of low radiationdoses, we focus on survivors with doses less than 0.5 Sv. For reasons indicated, we also restrict attentionmainly to survivors within 3,000 m of the hypocenter of the bombs. Analysis is of solid cancer incidencefrom 1958–1994, involving 7,000 cancer cases among 50,000 survivors in that dose and distance range.The results provide useful risk estimates for doses as low as 0.05–0.1 Sv, which are not overestimated bylinear risk estimates computed from the wider dose ranges 0–2 Sv or 0–4 Sv. There is a statisticallysignificant risk in the range 0–0.1 Sv, and an upper confidence limit on any possible threshold iscomputed as 0.06 Sv. It is indicated that modification of the neutron dose estimates currently underconsideration would not markedly change the conclusions.", "metadata": {}}
+{"_id": "6517267", "title": "", "text": "Barriers and facilitators to implement shared decision making in multidisciplinary sciatica care: aqualitative studyBACKGROUND The Dutch multidisciplinary sciatica guideline recommends that the teamof professionals involved in sciatica care and the patient together decide on surgical or prolongedconservative treatment (shared decision making [SDM]). Despite this recommendation, SDM is not yetintegrated in sciatica care. Existing literature concerning barriers and facilitators to SDM implementationmainly focuses on one discipline only, whereas multidisciplinary care may involve other barriers andfacilitators, or make these more complex for both professionals and patients. Therefore, this qualitativestudy aims to identify barriers and facilitators perceived by patients and professionals for SDMimplementation in multidisciplinary sciatica care. METHODS We conducted 40 semi-structured interviewswith professionals involved in sciatica care (general practitioners, physical therapists, neurologists,neurosurgeons, and orthopedic surgeons) and three focus groups among patients (six to eight pergroup). The interviews and focus groups were audiotaped and transcribed in full. Reported barriers andfacilitators were classified according to the framework of Grol and Wensing. The software package Atlas.ti7.0 was used for analysis. RESULTS Professionals reported 53 barriers and 5 facilitators, and patients 35barriers and 18 facilitators for SDM in sciatica care. Professionals perceived most barriers at the level ofthe organizational context, and facilitators at the level of the individual professional. Patients reportedmost barriers and facilitators at the level of the individual professional. Several barriers and facilitatorscorrespond with barriers and facilitators found in the literature (e.g., lack of time, motivation) but alsonew barriers and facilitators were identified. Many of these new barriers mentioned by both professionalsand patients were related to the multidisciplinary setting, such as lack of visibility, lack of trust inexpertise of other disciplines, and lack of communication between disciplines. CONCLUSIONS This studyidentified barriers and facilitators for SDM in the multidisciplinary sciatica setting, by both professionalsand patients. It is clear that more barriers than facilitators are perceived for implementation of SDM insciatica care. Newly identified barriers and facilitators are related to the multidisciplinary care setting.Therefore, an effective implementation strategy of SDM in a multidisciplinary setting such as in sciaticacare should focus on these barriers and facilitators.", "metadata": {}}
+{"_id": "6517763", "title": "", "text": "Molecular characterization of long-term survivors of glioblastoma using genome- and transcriptome-wideprofiling.The prognosis of glioblastoma, the most malignant type of glioma, is still poor, with only aminority of patients showing long-term survival of more than three years after diagnosis. To elucidate themolecular aberrations in glioblastomas of long-term survivors, we performed genome- and/ortranscriptome-wide molecular profiling of glioblastoma samples from 94 patients, including 28 long-termsurvivors with >36 months overall survival (OS), 20 short-term survivors with <12 months OS and 46patients with intermediate OS. Integrative bioinformatic analyses were used to characterize molecularaberrations in the distinct survival groups considering established molecular markers such as isocitratedehydrogenase 1 or 2 (IDH1/2) mutations, and O(6) -methylguanine DNA methyltransferase (MGMT)promoter methylation. Patients with long-term survival were younger and more often had IDH1/2-mutantand MGMT-methylated tumors. Gene expression profiling revealed over-representation of a distinct(proneural-like) expression signature in long-term survivors that was linked to IDH1/2 mutation.However, IDH1/2-wildtype glioblastomas from long-term survivors did not show distinct gene expressionprofiles and included proneural, classical and mesenchymal glioblastoma subtypes. Genomic imbalancesalso differed between IDH1/2-mutant and IDH1/2-wildtype tumors, but not between survival groups ofIDH1/2-wildtype patients. Thus, our data support an important role for MGMT promoter methylation andIDH1/2 mutation in glioblastoma long-term survival and corroborate the association of IDH1/2 mutationwith distinct genomic and transcriptional profiles. Importantly, however, IDH1/2-wildtype glioblastomasin our cohort of long-term survivors lacked distinctive DNA copy number changes and gene expressionsignatures, indicating that other factors might have been responsible for long survival in this particularsubgroup of patients.", "metadata": {}}
+{"_id": "6525844", "title": "", "text": "Impact of aortic stiffness on survival in end-stage renal disease.BACKGROUND Damage to large arteriesis a major factor in the high cardiovascular morbidity and mortality of patients with end-stage renaldisease (ESRD). Increased arterial stiffness and intima-media thickness, together with increased pulsepressure, are the principal arterial alterations. Whether increased aortic pulse-wave velocity (PWV), aclassic marker of increased arterial stiffness, may predict all-cause and/or cardiovascular mortality hasnever been investigated. METHODS AND RESULTS A cohort of 241 patients with ESRD undergoinghemodialysis was studied between April 1987 and April 1998. The mean duration of follow-up was72+/-41 months (mean+/-SD). Mean age at entry was 51.5+/-16.3 years. Seventy-three deathsoccurred, including 48 cardiovascular and 25 noncardiovascular fatal events. At entry, together withstandard clinical and biochemical analyses, patients underwent echocardiography and aortic PWVmeasured by Doppler ultrasonography. On the basis of Cox analyses, 2 factors emerged as predictors ofall-cause and cardiovascular mortality: age and aortic PWV. Hemoglobin and low diastolic pressureinterfered to a smaller extent. After adjustment for all the confounding factors, an OR for PWV >12. 0versus <9.4 m/s was 5.4 (95% CI, 2.4 to 11.9) for all-cause mortality and 5.9 (95% CI, 2.3 to 15.5) forcardiovascular mortality. For each PWV increase of 1 m/s in our study population, all-causemortality-adjusted OR was 1.39 (95% CI, 1.19 to 1.62). CONCLUSIONS These results provide the firstdirect evidence that in patients with ESRD, increased aortic stiffness determined by measurement ofaortic PWV is a strong independent predictor of all-cause and mainly cardiovascular mortality.", "metadata": {}}
+{"_id": "6532806", "title": "", "text": "An integrated database of genes responsive to the Myc oncogenic transcription factor: identification ofdirect genomic targetsWe report a database of genes responsive to the Myc oncogenic transcriptionfactor. The database Myc Target Gene prioritizes candidate target genes according to experimentalevidence and clusters responsive genes into functional groups. We coupled the prioritization of targetgenes with phylogenetic sequence comparisons to predict c-Myc target binding sites, which are in turnvalidated by chromatin immunoprecipitation assays. This database is essential for the understanding ofthe genetic regulatory networks underlying the genesis of cancers.", "metadata": {}}
+{"_id": "6535392", "title": "", "text": "siRNA specificity searching incorporating mismatch tolerance data.UNLABELLED Artificially synthesizedshort interfering RNAs (siRNAs) are widely used in functional genomics to knock down specific targetgenes. One ongoing challenge is to guarantee that the siRNA does not elicit off-target effects. Initialreports suggested that siRNAs were highly sequence-specific; however, subsequent data indicates thatthis is not necessarily the case. It is still uncertain what level of similarity and other rules are required foran off-target effect to be observed, and scoring schemes have not been developed to look beyond simplemeasures such as the number of mismatches or the number of consecutive matching bases present. Wecreated design rules for predicting the likelihood of a non-specific effect and present a web server thatallows the user to check the specificity of a given siRNA in a flexible manner using a combination ofmethods. The server finds potential off-target matches in the corresponding RefSeq database and ranksthem according to a scoring system based on experimental studies of specificity. AVAILABILITY Theserver is available at http://informatics-eskitis.griffith.edu.au/SpecificityServer.", "metadata": {}}
+{"_id": "6536598", "title": "", "text": "The Ino80 chromatin-remodeling complex restores chromatin structure during UV DNA damagerepairChromatin structure is modulated during deoxyribonucleic acid excision repair, but how this isachieved is unclear. Loss of the yeast Ino80 chromatin-remodeling complex (Ino80-C) moderatelysensitizes cells to ultraviolet (UV) light. In this paper, we show that INO80 acts in the same geneticpathway as nucleotide excision repair (NER) and that the Ino80-C contributes to efficient UVphotoproduct removal in a region of high nucleosome occupancy. Moreover, Ino80 interacts with theearly NER damage recognition complex Rad4-Rad23 and is recruited to chromatin by Rad4 in a UVdamage-dependent manner. Using a modified chromatin immunoprecipitation assay, we find thatchromatin disruption during UV lesion repair is normal, whereas the restoration of nucleosome structureis defective in ino80 mutant cells. Collectively, our work suggests that Ino80 is recruited to sites of UVlesion repair through interactions with the NER apparatus and is required for the restoration of chromatinstructure after repair.", "metadata": {}}
+{"_id": "6540064", "title": "", "text": "Effects of PCSK9 Inhibition With Alirocumab on Lipoprotein Metabolism in Healthy HumansBACKGROUNDAlirocumab, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), lowersplasma low-density lipoprotein (LDL) cholesterol and apolipoprotein B100 (apoB). Although studies inmice and cells have identified increased hepatic LDL receptors as the basis for LDL lowering by PCSK9inhibitors, there have been no human studies characterizing the effects of PCSK9 inhibitors on lipoproteinmetabolism. In particular, it is not known whether inhibition of PCSK9 has any effects on very low-densitylipoprotein or intermediate-density lipoprotein (IDL) metabolism. Inhibition of PCSK9 also results inreductions of plasma lipoprotein (a) levels. The regulation of plasma Lp(a) levels, including the role ofLDL receptors in the clearance of Lp(a), is poorly defined, and no mechanistic studies of the Lp(a)lowering by alirocumab in humans have been published to date. METHODS Eighteen (10 F, 8 mol/L)participants completed a placebo-controlled, 2-period study. They received 2 doses of placebo, 2 weeksapart, followed by 5 doses of 150 mg of alirocumab, 2 weeks apart. At the end of each period, fractionalclearance rates (FCRs) and production rates (PRs) of apoB and apo(a) were determined. In 10participants, postprandial triglycerides and apoB48 levels were measured. RESULTS Alirocumab reducedultracentrifugally isolated LDL-C by 55.1%, LDL-apoB by 56.3%, and plasma Lp(a) by 18.7%. The fall inLDL-apoB was caused by an 80.4% increase in LDL-apoB FCR and a 23.9% reduction in LDL-apoB PR.The latter was due to a 46.1% increase in IDL-apoB FCR coupled with a 27.2% decrease in conversion ofIDL to LDL. The FCR of apo(a) tended to increase (24.6%) without any change in apo(a) PR. Alirocumabhad no effects on FCRs or PRs of very low-density lipoproteins-apoB and very low-density lipoproteinstriglycerides or on postprandial plasma triglycerides or apoB48 concentrations. CONCLUSIONSAlirocumab decreased LDL-C and LDL-apoB by increasing IDL- and LDL-apoB FCRs and decreasingLDL-apoB PR. These results are consistent with increases in LDL receptors available to clear IDL and LDLfrom blood during PCSK9 inhibition. The increase in apo(a) FCR during alirocumab treatment suggeststhat increased LDL receptors may also play a role in the reduction of plasma Lp(a). CLINICAL TRIALREGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01959971.", "metadata": {}}
+{"_id": "6544701", "title": "", "text": "A more efficient method to generate integration-free human iPS cellsWe report a simple method, usingp53 suppression and nontransforming L-Myc, to generate human induced pluripotent stem cells (iPSCs)with episomal plasmid vectors. We generated human iPSCs from multiple donors, including two putativehuman leukocyte antigen (HLA)-homozygous donors who match \u000020% of the Japanese population atmajor HLA loci; most iPSCs are integrated transgene-free. This method may provide iPSCs suitable forautologous and allologous stem-cell therapy in the future.", "metadata": {}}
+{"_id": "6549091", "title": "", "text": "Permanent cardiac pacing versus medical treatment for the prevention of recurrent vasovagal syncope: amulticenter, randomized, controlled trial.BACKGROUND This clinical investigation was performed tocompare the effects of permanent dual-chamber cardiac pacing with pharmacological therapy in patientswith recurrent vasovagal syncope. METHODS AND RESULTS Patients from 14 centers were randomized toreceive either a DDD pacemaker provided with rate-drop response function or the beta-blocker atenololat the dosage of 100 mg once a day. Inclusion criteria were age >35 years, >/=3 syncopal spells in thepreceding 2 years, and positive response to tilt table testing with syncope occurring in association withrelative bradycardia. The primary outcome was the first recurrence of syncope after randomization.Enrollment was started in December 1997, and the first formal interim analysis was performed on July30, 2000. By that time, 93 patients (38 men and 55 women; mean age, 58.1+/-14.3 years) had beenenrolled and randomized, although follow-up data were available for all patients (46 patients in thepacemaker arm, 47 patients in the pharmacological arm). The interim analysis showed a significant effectin favor of permanent cardiac pacing (recurrence of syncope in 2 patients [4.3%] after a median of 390days) compared with medical treatment (recurrence of syncope in 12 patients [25.5%] after a median of135 days; OR, 0.133; 95% CI, 0.028 to 0.632; P=0.004). Consequently, enrollment and follow-up wereterminated. CONCLUSIONS DDD pacing with rate-drop response function is more effective thanbeta-blockade for the prevention of syncopal recurrences in highly symptomatic vasovagal fainters withrelative bradycardia during tilt-induced syncope.", "metadata": {}}
+{"_id": "6550579", "title": "", "text": "A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy.Epidermalgrowth factor receptor (EGFR) and HER3 each form heterodimers with HER2 and have independentlybeen implicated as key coreceptors that drive HER2-amplified breast cancer. Some studies suggest adominant role for EGFR, a notion of renewed interest given the development of dual HER2/EGFRsmall-molecule inhibitors. Other studies point to HER3 as the primary coreceptor. To clarify the relativecontributions of EGFR and HER3 to HER2 signaling, we studied receptor knockdown via small interferingRNA technology across a panel of six HER2-overexpressing cell lines. Interestingly, HER3 was as criticalas HER2 for maintaining cell proliferation in most cell lines, whereas EGFR was dispensable. Induction ofHER3 knockdown in the HER2-overexpressing BT474M1 cell line was found to inhibit growth inthree-dimensional culture and induce rapid tumor regression of in vivo xenografts. Furthermore,preferential phosphorylation of HER3, but not EGFR, was observed in HER2-amplified breast cancertissues. Given these data suggesting HER3 as an important therapeutic target, we examined the activityof pertuzumab, a HER2 antibody that inhibits HER3 signaling by blocking ligand-induced HER2/HER3heterodimerization. Pertuzumab inhibited ligand-dependent morphogenesis in three-dimensional cultureand induced tumor regression in the heregulin-dependent MDA-MB-175 xenograft model. Importantly,these activities of pertuzumab were distinct from those of trastuzumab, a monoclonal antibody currentlyused for treatment of HER2-amplified breast cancer patients. Our data suggest that inhibition of HER3may be more clinically relevant than inhibition of EGFR in HER2-amplified breast cancer and also suggestthat adding pertuzumab to trastuzumab may augment therapeutic benefit by blocking HER2/HER3signaling.", "metadata": {}}
+{"_id": "6559201", "title": "", "text": "Mechanisms of astrocytogenesis in the mammalian brain.In the mammalian central nervous system,astrocytes are the most abundant cell type and play crucial roles in brain development and function.Astrocytes are known to be produced from multipotent neural stem cells (NSCs) at the late gestationalstage during brain development, and accumulating evidence indicates that this stage-dependentgeneration of astrocytes from NSCs is achieved by systematic cooperation between environmental cuesand cell-intrinsic programs. Exemplifying the former is cytokine signaling through the gp130-Januskinase/signal transducer and activator of transcription 3 pathway, and exemplifying the latter isepigenetic modification of astrocyte-specific genes. Here, we introduce recent advances in ourunderstanding of the mechanisms that coordinate astrocytogenesis from NSCs by modulating signalingpathways and epigenetic programs, with a particular focus on the developing mammalian forebrain.", "metadata": {}}
+{"_id": "6559701", "title": "", "text": "Regulation of the latent-lytic switch in Epstein-Barr virus.Epstein-Barr virus (EBV) infection contributes tothe development of several different types of human malignancy, including Burkitt lymphoma, Hodgkinlymphoma, and nasopharyngeal carcinoma. As a herpesvirus, EBV can establish latent or lytic infection incells. EBV-positive tumors are composed almost exclusively of cells with latent EBV infection. Strategiesfor inducing the lytic form of EBV infection in tumor cells are being investigated as a potential therapy forEBV-positive tumors. In this article, we review how cellular and viral proteins regulate the latent-lytic EBVswitch in infected B cells and epithelial cells, and discuss how harnessing lytic viral reactivation might beused therapeutically.", "metadata": {}}
+{"_id": "6561200", "title": "", "text": "Efficacy of HPV DNA testing with cytology triage and/or repeat HPV DNA testing in primary cervical cancerscreening.BACKGROUND Primary cervical screening with both human papillomavirus (HPV) DNA testingand cytological examination of cervical cells with a Pap test (cytology) has been evaluated in randomizedclinical trials. Because the vast majority of women with positive cytology are also HPV DNA positive,screening strategies that use HPV DNA testing as the primary screening test may be more effective.METHODS We used the database from the intervention arm (n = 6,257 women) of a population-basedrandomized trial of double screening with cytology and HPV DNA testing to evaluate the efficacy of 11possible cervical screening strategies that are based on HPV DNA testing alone, cytology alone, and HPVDNA testing combined with cytology among women aged 32-38 years. The main outcome measures weresensitivity for detection of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) within 6 months ofenrollment or at colposcopy for women with a persistent type-specific HPV infection and the number ofscreening tests and positive predictive value (PPV) for each screening strategy. All statistical tests weretwo-sided. RESULTS Compared with screening by cytology alone, double testing with cytology and fortype-specific HPV persistence resulted in a 35% (95% confidence interval [CI] = 15% to 60%) increasein sensitivity to detect CIN3+, without a statistically significant reduction in the PPV (relative PPV = 0.76,95% CI = 0.52 to 1.10), but with more than twice as many screening tests needed. Several strategiesthat incorporated screening for high-risk HPV subtypes were explored, but they resulted in reduced PPVcompared with cytology. Compared with cytology, primary screening with HPV DNA testing followed bycytological triage and repeat HPV DNA testing of HPV DNA-positive women with normal cytologyincreased the CIN3+ sensitivity by 30% (95% CI = 9% to 54%), maintained a high PPV (relative PPV =0.87, 95% CI = 0.60 to 1.26), and resulted in a mere 12% increase in the number of screening tests(from 6,257 to 7,019 tests). CONCLUSIONS Primary HPV DNA-based screening with cytology triage andrepeat HPV DNA testing of cytology-negative women appears to be the most feasible cervical screeningstrategy.", "metadata": {}}
+{"_id": "6565037", "title": "", "text": "Extrasynaptic Glutamate Spillover in the Hippocampus: Dependence on Temperature and the Role ofActive Glutamate UptakeAt excitatory synapses on CA1 pyramidal cells of the hippocampus, a largerquantal content is sensed by N-methyl-D-aspartic acid receptors (NMDARs) than byalpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). A novel explanation forthis discrepancy is that glutamate released from terminals presynaptic to one cell can diffuse to andactivate NMDARs, but not AMPARs, on a neighboring cell. If this occurs in the living brain, it couldinvalidate the view that glutamatergic synapses function as private communication channels betweenneurons. Here, we show that the discrepancy in quantal content mediated by the two receptors is greatlydecreased at physiological temperature, compared with conventional recording conditions. This effect oftemperature is not due to changes in release probability or uncovering of latent AMPARs. It is, however,partially reversed by the glutamate uptake inhibitor dihydrokainate. The results suggest that glutamatetransporters play a critical role in limiting the extrasynaptic diffusion of glutamate, thereby minimizingcross-talk between neighboring excitatory synapses.", "metadata": {}}
+{"_id": "6580081", "title": "", "text": "Molecular mechanisms of hepatic ischemia-reperfusion injury and preconditioning.Ischemia-reperfusioninjury is, at least in part, responsible for the morbidity associated with liver surgery under total vascularexclusion or after liver transplantation. The pathophysiology of hepatic ischemia-reperfusion includes anumber of mechanisms that contribute to various degrees in the overall injury. Some of the topicsdiscussed in this review include cellular mechanisms of injury, formation of pro- and anti-inflammatorymediators, expression of adhesion molecules, and the role of oxidant stress during the inflammatoryresponse. Furthermore, the roles of nitric oxide in preventing microcirculatory disturbances and as asubstrate for peroxynitrite formation are reviewed. In addition, emerging mechanisms of protection byischemic preconditioning are discussed. On the basis of current knowledge, preconditioning orpharmacological interventions that mimic these effects have the greatest potential to improve clinicaloutcome in liver surgery involving ischemic stress and reperfusion.", "metadata": {}}
+{"_id": "6588614", "title": "", "text": "Characterization of a FGF19 Variant with Altered Receptor Specificity Revealed a Central Role for FGFR1cin the Regulation of Glucose MetabolismDiabetes and associated metabolic conditions have reachedpandemic proportions worldwide, and there is a clear unmet medical need for new therapies that are botheffective and safe. FGF19 and FGF21 are distinctive members of the FGF family that function as endocrinehormones. Both have potent effects on normalizing glucose, lipid, and energy homeostasis, andtherefore, represent attractive potential next generation therapies for combating the growing epidemicsof type 2 diabetes and obesity. The mechanism responsible for these impressive metabolic effectsremains unknown. While both FGF19 and FGF21 can activate FGFRs 1c, 2c, and 3c in the presence ofco-receptor βKlotho in vitro, which receptor is responsible for the metabolic activities observed in vivoremains unknown. Here we have generated a variant of FGF19, FGF19-7, that has altered receptorspecificity with a strong bias toward FGFR1c. We show that FGF19-7 is equally efficacious as wild typeFGF19 in regulating glucose, lipid, and energy metabolism in both diet-induced obesity andleptin-deficient mouse models. These results are the first direct demonstration of the central role of theβKlotho/FGFR1c receptor complex in glucose and lipid regulation, and also strongly suggest thatactivation of this receptor complex alone might be sufficient to achieve all the metabolic functions ofendocrine FGF molecules.", "metadata": {}}
+{"_id": "6599693", "title": "", "text": "Empirical verification of evolutionary theories of agingWe recently selected 3 long-lived mutant strains ofSaccharomyces cerevisiae by a lasting exposure to exogenous lithocholic acid. Each mutant strain canmaintain the extended chronological lifespan after numerous passages in medium without lithocholic acid.In this study, we used these long-lived yeast mutants for empirical verification of evolutionary theories ofaging. We provide evidence that the dominant polygenic trait extending longevity of each of thesemutants 1) does not affect such key features of early-life fitness as the exponential growth rate, efficacyof post-exponential growth and fecundity; and 2) enhances such features of early-life fitness assusceptibility to chronic exogenous stresses, and the resistance to apoptotic and liponecrotic forms ofprogrammed cell death. These findings validate evolutionary theories of programmed aging. We alsodemonstrate that under laboratory conditions that imitate the process of natural selection within anecosystem, each of these long-lived mutant strains is forced out of the ecosystem by the parentalwild-type strain exhibiting shorter lifespan. We therefore concluded that yeast cells have evolved somemechanisms for limiting their lifespan upon reaching a certain chronological age. These mechanisms drivethe evolution of yeast longevity towards maintaining a finite yeast chronological lifespan withinecosystems.", "metadata": {}}
+{"_id": "6609935", "title": "", "text": "Differential regulation of actin microfilaments by human MICAL proteins.The Drosophila melanogasterMICAL protein is essential for the neuronal growth cone machinery that functions through plexin- andsemaphorin-mediated axonal signaling. Drosophila MICAL is also involved in regulating myofilamentorganization and synaptic structures, and serves as an actin disassembly factor downstream ofplexin-mediated axonal repulsion. In mammalian cells there are three known isoforms, MICAL1, MICAL2and MICAL3, as well as the MICAL-like proteins MICAL-L1 and MICAL-L2, but little is known of theirfunction, and information comes almost exclusively from neural cells. In this study we show that innon-neural cells human MICALs are required for normal actin organization, and all three MICALs regulateactin stress fibers. Moreover, we provide evidence that the generation of reactive oxygen species byMICAL proteins is crucial for their actin-regulatory function. However, although MICAL1 is auto-inhibitedby its C-terminal coiled-coil region, MICAL2 remains constitutively active and affects stress fibers. Thesedata suggest differential but complementary roles for MICAL1 and MICAL2 in actin microfilamentregulation.", "metadata": {}}
+{"_id": "6625693", "title": "", "text": "Suppression of inflammatory and neuropathic pain by uncoupling CRMP-2 from the presynaptic Ca2+channel complexThe use of N-type voltage-gated calcium channel (CaV2.2) blockers to treat pain islimited by many physiological side effects. Here we report that inflammatory and neuropathichypersensitivity can be suppressed by inhibiting the binding of collapsin response mediator protein 2(CRMP-2) to CaV2.2 and thereby reducing channel function. A peptide of CRMP-2 fused to the HIVtransactivator of transcription (TAT) protein (TAT-CBD3) decreased neuropeptide release from sensoryneurons and excitatory synaptic transmission in dorsal horn neurons, reduced meningeal blood flow,reduced nocifensive behavior induced by formalin injection or corneal capsaicin application and reversedneuropathic hypersensitivity produced by an antiretroviral drug. TAT-CBD3 was mildly anxiolytic withoutaffecting memory retrieval, sensorimotor function or depression. At doses tenfold higher than thatrequired to reduce hypersensitivity in vivo, TAT-CBD3 caused a transient episode of tail kinking and bodycontortion. By preventing CRMP-2–mediated enhancement of CaV2.2 function, TAT-CBD3 alleviatedinflammatory and neuropathic hypersensitivity, an approach that may prove useful in managing chronicpain.", "metadata": {}}
+{"_id": "6636088", "title": "", "text": "Identification and characterization of a common set of complex I assembly intermediates in mitochondriafrom patients with complex I deficiency.Deficiencies in the activity of complex I (NADH: ubiquinoneoxidoreductase) are an important cause of human mitochondrial disease. Complex I is composed of atleast 46 structural subunits that are encoded in both nuclear and mitochondrial DNA. Enzyme deficiencycan result from either impaired catalytic efficiency or an inability to assemble the holoenzyme complex;however, the assembly process remains poorly understood. We have used two-dimensionalBlue-Native/SDS gel electrophoresis and a panel of 11 antibodies directed against structural subunits ofthe enzyme to investigate complex I assembly in the muscle mitochondria from four patients withcomplex I deficiency caused by either mitochondrial or nuclear gene defects. Immunoblot analyses ofsecond dimension denaturing gels identified seven distinct complex I subcomplexes in the patientsstudied, five of which could also be detected in nondenaturing gels in the first dimension. Although theabundance of these intermediates varied among the different patients, a common constellation ofsubcomplexes was observed in all cases. A similar profile of subcomplexes was present in ahuman/mouse hybrid fibroblast cell line with a severe complex I deficiency due to an almost completelack of assembly of the holoenzyme complex. The finding that diverse causes of complex I deficiencyproduce a similar pattern of complex I subcomplexes suggests that these are intermediates in theassembly of the holoenzyme complex. We propose a possible assembly pathway for the complex, whichdiffers significantly from that proposed for Neurospora, the current model for complex I assembly.", "metadata": {}}
+{"_id": "6647414", "title": "", "text": "Leisure time physical activity and mortality: a detailed pooled analysis of the dose-responserelationship.IMPORTANCE The 2008 Physical Activity Guidelines for Americans recommended a minimumof 75 vigorous-intensity or 150 moderate-intensity minutes per week (7.5 metabolic-equivalent hours perweek) of aerobic activity for substantial health benefit and suggested additional benefits by doing morethan double this amount. However, the upper limit of longevity benefit or possible harm with morephysical activity is unclear. OBJECTIVE To quantify the dose-response association between leisure timephysical activity and mortality and define the upper limit of benefit or harm associated with increasedlevels of physical activity. DESIGN, SETTING, AND PARTICIPANTS We pooled data from 6 studies in theNational Cancer Institute Cohort Consortium (baseline 1992-2003). Population-based prospective cohortsin the United States and Europe with self-reported physical activity were analyzed in 2014. A total of661,137 men and women (median age, 62 years; range, 21-98 years) and 116,686 deaths wereincluded. We used Cox proportional hazards regression with cohort stratification to generatemultivariable-adjusted hazard ratios (HRs) and 95% CIs. Median follow-up time was 14.2 years.EXPOSURES Leisure time moderate- to vigorous-intensity physical activity. MAIN OUTCOMES ANDMEASURES The upper limit of mortality benefit from high levels of leisure time physical activity. RESULTSCompared with individuals reporting no leisure time physical activity, we observed a 20% lower mortalityrisk among those performing less than the recommended minimum of 7.5 metabolic-equivalent hours perweek (HR, 0.80 [95% CI, 0.78-0.82]), a 31% lower risk at 1 to 2 times the recommended minimum (HR,0.69 [95% CI, 0.67-0.70]), and a 37% lower risk at 2 to 3 times the minimum (HR, 0.63 [95% CI,0.62-0.65]). An upper threshold for mortality benefit occurred at 3 to 5 times the physical activityrecommendation (HR, 0.61 [95% CI, 0.59-0.62]); however, compared with the recommended minimum,the additional benefit was modest (31% vs 39%). There was no evidence of harm at 10 or more timesthe recommended minimum (HR, 0.69 [95% CI, 0.59-0.78]). A similar dose-response relationship wasobserved for mortality due to cardiovascular disease and to cancer. CONCLUSIONS AND RELEVANCEMeeting the 2008 Physical Activity Guidelines for Americans minimum by either moderate- orvigorous-intensity activities was associated with nearly the maximum longevity benefit. We observed abenefit threshold at approximately 3 to 5 times the recommended leisure time physical activity minimumand no excess risk at 10 or more times the minimum. In regard to mortality, health care professionalsshould encourage inactive adults to perform leisure time physical activity and do not need to discourageadults who already participate in high-activity levels.", "metadata": {}}
+{"_id": "6650933", "title": "", "text": "Green tea polyphenol causes differential oxidative environments in tumor versus normal epithelialcells.Green tea polyphenols (GTPPs) are considered beneficial to human health, especially aschemopreventive agents. Recently, cytotoxic reactive oxygen species (ROS) were identified in tumor andcertain normal cell cultures incubated with high concentrations of the most abundant GTPP,(-)-epigallocatechin-3-gallate (EGCG). If EGCG also provokes the production of ROS in normal epithelialcells, it may preclude the topical use of EGCG at higher doses. The current study examined the oxidativestatus of normal epithelial, normal salivary gland, and oral carcinoma cells treated with EGCG, using ROSmeasurement and catalase and superoxide dismutase activity assays. The results demonstrated that highconcentrations of EGCG induced oxidative stress only in tumor cells. In contrast, EGCG reduced ROS innormal cells to background levels. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assayand 5-bromodeoxyuridine incorporation data were also compared between the two oral carcinoma celllines treated by EGCG, which suggest that a difference in the levels of endogenous catalase activity mayplay an important role in reducing oxidative stress provoked by EGCG in tumor cells. It is concluded thatpathways activated by GTPPs or EGCG in normal epithelial versus tumor cells create different oxidativeenvironments, favoring either normal cell survival or tumor cell destruction. This finding may lead toapplications of naturally occurring polyphenols to enhance the effectiveness of chemo/radiation therapyto promote cancer cell death while protecting normal cells.", "metadata": {}}
+{"_id": "6669242", "title": "", "text": "Protein acetylation affects acetate metabolism, motility and acid stress response in EscherichiacoliAlthough protein acetylation is widely observed, it has been associated with few specific regulatoryfunctions making it poorly understood. To interrogate its functionality, we analyzed the acetylome inEscherichia coli knockout mutants of cobB, the only known sirtuin-like deacetylase, and patZ, thebest-known protein acetyltransferase. For four growth conditions, more than 2,000 unique acetylatedpeptides, belonging to 809 proteins, were identified and differentially quantified. Nearly 65% of theseproteins are related to metabolism. The global activity of CobB contributes to the deacetylation of a largenumber of substrates and has a major impact on physiology. Apart from the regulation of acetyl-CoAsynthetase, we found that CobB-controlled acetylation of isocitrate lyase contributes to the fine-tuning ofthe glyoxylate shunt. Acetylation of the transcription factor RcsB prevents DNA binding, activating flagellabiosynthesis and motility, and increases acid stress susceptibility. Surprisingly, deletion of patZ increasedacetylation in acetate cultures, which suggests that it regulates the levels of acetylating agents. Theresults presented offer new insights into functional roles of protein acetylation in metabolic fitness andglobal cell regulation.", "metadata": {}}
+{"_id": "6670101", "title": "", "text": "Ribosome biogenesis: Achilles heel of cancer?It is long been known that cancer and non-cancer cells canbe distinguished on the basis of their nucleolar morphologies. As early as the 19th century, it wasreported that cancer cells have larger and more irregularly shaped nucleoli. Since then, pathologists haveused nucleolar morphology to predict the clinical outcome [1]. Nucleolar morphology is altered due to theup-regulation of ribosomal gene transcription. Within nucleoli, ribosomal genes (rDNA) are transcribed byRNA polymerase I (pol I). The pre-ribosomal RNA (pre-rRNA) transcripts are subsequently modified andprocessed into the mature 18S, 5.8S and 28S rRNAs. 5S rRNA is transcribed by RNA polymerase III inthe nucleoplasm. Together with the ribosomal proteins, the 5S rRNA is imported into the nucleolus where40S and 60S ribosomal subunits are assembled prior to export to the cytoplasm [1, 2]. Oncogenes suchas c-Myc can both directly and indirectly upregulate rDNA transcription, while tumour suppressors likep53 and Rb suppress ribosome biogenesis. Mutations in these genes not only result in deregulated cellcycle control, but also upregulated ribosome biogenesis. In addition to ribosome biogenesis, the nucleolusis a key cellular stress sensor and plays a central role in p53 activation [1, 2]. The increased translationalcapacity of cancer cells enables them to maintain higher proliferation rates. As stated by Ruggero,“compared with normal cells, cancer cells may be addicted to increases in ribosome biogenesis andnumber” [1]. This provides new therapeutic opportunities. As it turns out many chemotherapeutic drugsused in cancer treatment already inhibit ribosome biogenesis. In one recent survey it was shown that 20out of 36 drugs in clinical use inhibit ribosome biogenesis [3]. Most of these drugs were originallydesigned to target highly proliferating cells by damaging DNA, interfering with DNA synthesis or withmitosis. These targeting modalities of these drugs also lead to toxicity in normal highly proliferatingtissues. An example is ActinomycinD (AMD), a DNA intercalator which has a preference for GC-rich DNAsequences. As rDNA has above average GC-richness and because of its open chromatin conformation, lowconcentrations of AMD preferentially inhibit RNA polymerase I transcription and upon prolonged exposurecauses genome wide DNA damage. Alkylating drugs like cisplatin and oxaliplatin or topoisomerasespoisons like camptothecin inhibit pol I transcription. The degree to which inhibition of ribosomebiogenesis contributes to the efficacy of these drugs is difficult to establish [3]. This raises an importantquestion. Can targeting ribosome biogenesis without DNA damage offer any therapeutic potential? Tworecently described drugs CX-5461 and BMH-21 are now providing evidence that inhibition of ribosomebiogenesis by targeting transcription of rDNA by pol I has promising therapeutic potential. CX-5461 wasdesigned to specifically inhibit pol I transcription by disrupting pre-initiation complex formation at therDNA promoter. CX-5461 has been shown to activate p53 via nucleolar stress. It induces autophagy aswell as senescence in a multiple types of cancer cells in a p53-dependent manner. Especially in leukaemiaand lymphoma cells, treatment with CX-5461 induces p53-dependent apoptosis, while normal cellstolerate it [4, 5]. Whether the drug also induces DNA damage was not fully addressed, but it wasdemonstrated that it could induce cell death in cells lacking ATM - a key mediator of DNA double strandbreak responses. However, more recently Laiho and colleagues have shown that at high concentrations,CX-5461 does induce a γH2AX response, raising concerns about DNA damage [6]. BMH-21 was identifiedin a screen performed by Laiho and colleagues aimed at identifying novel p53 activators. Like AMD,BMH-21 is a DNA intercalator with preference for GC rich sequences [7]. Continuing the parallel withAMD, BMH-21 is a potent and specific inhibitor rDNA transcription and induces nucleolar reorganisationoften referred to as nucleolar capping. Interestingly, transcription inhibition was followed by thedegradation of the main pol I subunit, RPA194, by the proteasome [6]. In contrast with AMD, initialindications were that BMH-21 did not appear to induce DNA damage as evidenced by the lack of a γH2AXresponse [7]. Inhibition of transcription by BMH-21 causes nucleolar stress, resulting in decreasedproliferation and cell death. P53 is activated in BMH-21 treated cells but is not required for itsanti-proliferative effects. Intriguingly, it appears that cancer cells with high demands for ribosomebiogenesis are selectively targeted [6]. The current publication in Oncotarget now rules out any role forDNA damage signalling and repair pathways in the BMH-21 response. Moreover, BMH-21 derivatives that", "metadata": {}}
+{"_id": "6673421", "title": "", "text": "Cell and molecular mechanisms of insulin-induced angiogenesisAngiogenesis, the development of newblood vessel from pre-existing vessels, is a key process in the formation of the granulation tissue duringwound healing. The appropriate development of new blood vessels, along with their subsequentmaturation and differentiation, establishes the foundation for functional wound neovasculature. Weperformed studies in vivo and used a variety of cellular and molecular approaches in vitro to show thatinsulin stimulates angiogenesis and to elucidate the signalling mechanisms by which this proteinstimulates microvessel development. Mice skin injected with insulin shows longer vessels with morebranches, along with increased numbers of associated alpha-smooth muscle actin-expressing cells,suggesting the appropriate differentiation and maturation of the new vessels. We also found that insulinstimulates human microvascular endothelial cell migration and tube formation, and that these effectsoccur independently of VEGF/VEGFR signalling, but are dependent upon the insulin receptor itself.Downstream signalling pathways involve PI3K, Akt, sterol regulatory element-binding protein 1(SREBP-1) and Rac1; inhibition of these pathways results in elimination of endothelial cell migration andtube formation and significantly decreases the development of microvessels. Our findings stronglysuggest that insulin is a good candidate for the treatment of ischaemic wounds and other conditions inwhich blood vessel development is impaired.", "metadata": {}}
+{"_id": "6690087", "title": "", "text": "Inhibition of mammalian target of rapamycin potentiates thrombin-induced intercellular adhesionmolecule-1 expression by accelerating and stabilizing NF-kappa B activation in endothelial cells.Weaddressed the regulatory function of mammalian target of rapamycin (mTOR) in the mechanism ofthrombin-induced ICAM-1 gene expression in endothelial cells. Pretreatment of HUVECs with rapamycin,an inhibitor of mTOR, augmented thrombin-induced ICAM-1 expression. Inhibition of mTOR by thisapproach promoted whereas over-expression of mTOR inhibited thrombin-induced transcriptional activityof NF-kappaB, an essential regulator of ICAM-1 transcription. Analysis of the NF-kappaB signalingpathway revealed that inhibition of mTOR potentiated IkappaB kinase activation resulting in a rapid andpersistent phosphorylation of IkappaBalpha on Ser32 and Ser36, a requirement for IkappaBalphadegradation. Consistent with these data, we observed a more efficient and stable nuclear localization ofRelA/p65 and, subsequently, the DNA binding activity of NF-kappaB by thrombin following mTORinhibition. These data define a novel role of mTOR in down-regulating thrombin-induced ICAM-1expression in endothelial cells by controlling a delayed and transient activation of NF-kappaB.", "metadata": {}}
+{"_id": "6710699", "title": "", "text": "Homologous recombination resolution defect in werner syndrome.Werner syndrome (WRN) is anuncommon autosomal recessive disease whose phenotype includes features of premature aging, geneticinstability, and an elevated risk of cancer. We used three different experimental strategies to show thatWRN cellular phenotypes of limited cell division potential, DNA damage hypersensitivity, and defectivehomologous recombination (HR) are interrelated. WRN cell survival and the generation of viable mitoticrecombinant progeny could be rescued by expressing wild-type WRN protein or by expressing thebacterial resolvase protein RusA. The dependence of WRN cellular phenotypes on RAD51-dependent HRpathways was demonstrated by using a dominant-negative RAD51 protein to suppress mitoticrecombination in WRN and control cells: the suppression of RAD51-dependent recombination led tosignificantly improved survival of WRN cells following DNA damage. These results define a physiologicalrole for the WRN RecQ helicase protein in RAD51-dependent HR and identify a mechanistic link betweendefective recombination resolution and limited cell division potential, DNA damage hypersensitivity, andgenetic instability in human somatic cells.", "metadata": {}}
+{"_id": "6710713", "title": "", "text": "Risk factors at medical school for subsequent professional misconduct: multicentre retrospectivecase-control studyOBJECTIVE To determine whether there are risk factors in a doctor's time at medicalschool that are associated with subsequent professional misconduct. DESIGN Matched case-control study.Setting Records from medical schools and the General Medical Council (GMC). PARTICIPANTS 59 doctorswho had graduated from any one of eight medical schools in the United Kingdom in 1958-97 and had aproved finding of serious professional misconduct in GMC proceedings in 1999-2004 (cases); 236 controls(four for each case) were selected by systematic sampling from matching graduation cohorts.Case-control status was revealed by the GMC after completion of data entry. MAIN OUTCOME MEASUREOdds ratios for being a \"case,\" with multivariable conditional logistic regression of potential risk factorsincluding pre-admission characteristics and progress during the course. These data were obtained fromanonymised copies of the students' progress files held by their original medical schools. RESULTSUnivariate conditional logistic regression analysis found that cases were more likely to be men, to be oflower estimated social class, and to have had academic difficulties during their medical course, especiallyin the early years. Multivariable analysis showed that male sex (odds ratio 9.80, 95% confidence interval2.43 to 39.44, P=0.001), lower social class (4.28, 1.52 to 12.09, P=0.006), and failure of early orpreclinical examinations (5.47, 2.17 to 13.79, P<0.001) were independently associated with being a case.CONCLUSIONS This small study suggests that male sex, a lower socioeconomic background, and earlyacademic difficulties at medical school could be risk factors for subsequent professional misconduct. Thefindings are preliminary and should be interpreted with caution. Most doctors with risk factors will notcome before the GMC's disciplinary panels.", "metadata": {}}
+{"_id": "6712836", "title": "", "text": "MiD49 and MiD51, new components of the mitochondrial fission machinery.Mitochondria form intricatenetworks through fission and fusion events. Here, we identify mitochondrial dynamics proteins of 49 and51 kDa (MiD49 and MiD51, respectively) anchored in the mitochondrial outer membrane. MiD49/51 formfoci and rings around mitochondria similar to the fission mediator dynamin-related protein 1 (Drp1).MiD49/51 directly recruit Drp1 to the mitochondrial surface, whereas their knockdown reduces Drp1association, leading to unopposed fusion. Overexpression of MiD49/51 seems to sequester Drp1 fromfunctioning at mitochondria and cause fused tubules to associate with actin. Thus, MiD49/51 are newmediators of mitochondrial division affecting Drp1 action at mitochondria.", "metadata": {}}
+{"_id": "6717533", "title": "", "text": "Maximal activation of transcription by statl and stat3 requires both tyrosine and serinephosphorylationStat1 and Stat3 are latent transcriptional factors activated initially throughphosphorylation on single tyrosine residues induced by cytokine and growth factor occupation of cellsurface receptors. Here we show that phosphorylation on a single serine (residue 727) in each protein isalso required for maximal transcriptional activity. Both cytokines and growth factors are capable ofinducing the serine phosphorylation of Stat1 and Stat3. These experiments show that gene activation byStat1 and Stat3, which obligatorily require tyrosine phosphorylation to become active, also depends formaximal activation on one or more of the many serine kinases.", "metadata": {}}
+{"_id": "6718824", "title": "", "text": "Protein restriction during pregnancy affects maternal liver lipid metabolism and fetal brain lipidcomposition in the rat.Suboptimal developmental environments program offspring to lifelong metabolicproblems. The aim of this study was to determine the impact of protein restriction in pregnancy onmaternal liver lipid metabolism at 19 days of gestation (dG) and its effect on fetal brain development.Control (C) and restricted (R) mothers were fed with isocaloric diets containing 20 and 10% of casein. At19 dG, maternal blood and livers and fetal livers and brains were collected. Serum insulin and leptinlevels were determinate in mothers. Maternal and fetal liver lipid and fetal brain lipid quantification wereperformed. Maternal liver and fetal brain fatty acids were quantified by gas chromatography. In mothers,liver desaturase and elongase mRNAs were measured by RT-PCR. Maternal body and liver weights weresimilar in both groups. However, fat body composition, including liver lipids, was lower in R mothers. Ahigher fasting insulin at 19 dG in the R group was observed (C = 0.2 +/- 0.04 vs. R = 0.9 +/- 0.16ng/ml, P < 0.01) and was inversely related to early growth retardation. Serum leptin in R mothers wassignificantly higher than that observed in C rats (C = 5 +/- 0.1 vs. R = 7 +/- 0.7 ng/ml, P < 0.05). Inaddition, protein restriction significantly reduced gene expression in maternal liver of desaturases andelongases and the concentration of arachidonic (AA) and docosahexanoic (DHA) acids. In fetus from Rmothers, a low body weight (C = 3 +/- 0.3 vs. R = 2 +/- 0.1 g, P < 0.05), as well as liver and brainlipids, including the content of DHA in the brain, was reduced. This study showed that protein restrictionduring pregnancy may negatively impact normal fetal brain development by changes in maternal lipidmetabolism.", "metadata": {}}
+{"_id": "6722522", "title": "", "text": "Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathicseeds.Recent experimental evidence suggests that transcellular propagation of fibrillar protein aggregatesdrives the progression of neurodegenerative diseases in a prion-like manner. This phenomenon is nowwell described in cell and animal models and involves the release of protein aggregates into theextracellular space. Free aggregates then enter neighboring cells to seed further fibrillization. Themechanism by which aggregated extracellular proteins such as tau and α-synuclein bind and enter cells totrigger intracellular fibril formation is unknown. Prior work indicates that prion protein aggregates bindheparan sulfate proteoglycans (HSPGs) on the cell surface to transmit pathologic processes. Here, we findthat tau fibril uptake also occurs via HSPG binding. This is blocked in cultured cells and primary neuronsby heparin, chlorate, heparinase, and genetic knockdown of a key HSPG synthetic enzyme, Ext1.Interference with tau binding to HSPGs prevents recombinant tau fibrils from inducing intracellularaggregation and blocks transcellular aggregate propagation. In vivo, a heparin mimetic, F6, blocksneuronal uptake of stereotactically injected tau fibrils. Finally, uptake and seeding by α-synuclein fibrils,but not huntingtin fibrils, occurs by the same mechanism as tau. This work suggests a unifyingmechanism of cell uptake and propagation for tauopathy and synucleinopathy.", "metadata": {}}
+{"_id": "6723450", "title": "", "text": "Effects of Bifidobacterium animalis administered during lactation on allergic and autoimmune responsesin rodents.Probiotics are promoted as being beneficial to health and positive effects on the immunesystem have been reported. Beneficial immune effects have been attributed to several mechanisms,including stimulating T helper 1 (Th1) immunity. To explore the effects of the probiotic Bifidobacteriumanimalis on Th1- and Th2-mediated immune responses, two different animal models representing eitherTh1- or Th2-mediated immune responses were used: a rat model for experimental autoimmuneencephalomyelitis (EAE) (Th1) and a mouse model for respiratory allergy induced by ovalbumin (OVA)(Th2). B. animalis administration started when the mice or rats were 2 weeks old. Respiratory allergy orEAE were induced when the animals were 6-7 weeks old. In the allergy model, B. animalis modestlyreduced the number of infiltrating eosinophils and lymphocytes in the lungs, but no effects onallergen-specific serum immunoglobulin E levels were found. Cytokine profiles assessed after culturingspleen cells with the mitogen concanvalin A (ConA) showed that B. animalis skewed the Th1/Th2 balancetowards Th1 in females. However, allergen-induced cytokine production in females was not affected by B.animalis. In males, B. animalis significantly decreased ConA-induced interleukin-13 and a trend towardslower levels of OVA-induced Th2 cytokines. In the EAE model, B. animalis significantly reduced theduration of clinical symptoms by almost 2 days in males and improved the body weight gain during theexperimental period compared with the control group. Our data show that B. animalis reduced severalimmune parameters in the allergy as well as in the autoimmunity model.", "metadata": {}}
+{"_id": "6729465", "title": "", "text": "Planar Cell Polarity Signaling Pathway in Congenital Heart DiseasesCongenital heart disease (CHD) is acommon cardiac disorder in humans. Despite many advances in the understanding of CHD and theidentification of many associated genes, the fundamental etiology for the majority of cases remainsunclear. The planar cell polarity (PCP) signaling pathway, responsible for tissue polarity in Drosophila andgastrulation movements and cardiogenesis in vertebrates, has been shown to play multiple roles duringcardiac differentiation and development. The disrupted function of PCP signaling is connected to someCHDs. Here, we summarize our current understanding of how PCP factors affect the pathogenesis of CHD.", "metadata": {}}
+{"_id": "6748318", "title": "", "text": "Cost-effectiveness of human papillomavirus vaccination and screening in Spain.BACKGROUND In Spain,prophylactic vaccination against human papillomavirus (HPV) types 16 and 18 is being offeredfree-of-charge to one birth cohort of girls aged 11-14. Screening is opportunistic (annual/biannual)contributing to social and geographical disparities. METHODS A multi-HPV-type microsimulation modelwas calibrated to epidemiologic data from Spain utilising likelihood-based methods to assess the healthand economic impact of adding HPV vaccination to cervical cancer screening. Strategies included (1)screening alone of women over age 25, varying frequency (every 1-5 years) and test (cytology, HPV DNAtesting); (2) HPV vaccination of 11-year-old girls combined with screening. Outcomes included lifetimecancer risk, life expectancy, lifetime costs, number of clinical procedures and incrementalcost-effectiveness ratios. RESULTS After the introduction of HPV vaccination, screening will need tocontinue, and strategies that incorporated HPV testing are more effective and cost-effective than thosewith cytology alone. For vaccinated girls, 5-year organised cytology with HPV testing as triage from ages30 to 65 costs 24,350€ per year of life saved (YLS), assuming life-long vaccine immunity againstHPV-16/18 by 3 doses with 90% coverage. Unvaccinated girls would benefit from organised cytologyscreening with HPV testing as triage; 5-year screening from ages 30 to 65 costs 16,060€/YLS and 4-yearscreening from ages 30 to 85 costs 38,250€/YLS. Interventions would be cost-effective depending on thecost-effectiveness threshold and the vaccine price. CONCLUSIONS In Spain, inequitable coverage andoveruse of cytology make screening programmes inefficient. If high vaccination coverage amongpre-adolescent girls is achieved, organised cytology screening with HPV triage starting at ages 30 to atleast 65 every 4-5 years represents the best balance between costs and benefits.", "metadata": {}}
+{"_id": "6751418", "title": "", "text": "Dosimetry and risk estimates of radioiodine therapy for large, multinodular goiters.UNLABELLED Inpatients with a large, multinodular goiter (> 100 g), radiation absorbed doses in the thyroid, surroundingtissues and remainder of the body were estimated after therapeutic administration of 131I(3.7 MBq or100 microCi/g of thyroid tissue retained at 24 hr). METHODS Thermoluminescent dosimeter (TLD)measurements were performed on 23 patients (12 euthyroid and 1I hyperthyroid; thyroid weight 222 +/-72 g; 2.1 +/- 0.9 GBq 131I) on the skin over the thyroid, over the submandibular gland and over theparotid gland. Thyroid radioactivity measurements were done daily in 6 euthyroid and 6 hyperthyroidpatients (thyroid weight 204 +/- 69 g; 1.9 +/- 0.9 GBq 131I). An iodine biokinetic model and the MIRDmethodology were used to estimate absorbed doses in organs. Cancer risks were calculated using ICRPPublication 60. RESULTS Cumulated absorbed doses on the skin (TLD measurements) were 4.2 +/- 1.4Gy (thyroid), 1.2 +/- 0.6 Gy (submandibular) and 0.4 +/- 0.2 Gy (parotid). All these values weresignificantly correlated with the amount of radioiodine retained in the thyroid at 24 hr (euthyroid versushyperthyroid not significant). Absorbed doses in the thyroid of 94 +/- 25 Gy for euthyroid and 93 +/- 17Gy for hyperthyroid patients were calculated (thyroid radioactivity measurements). Extrathyroidalabsorbed doses (means of 12 patients) were 0.88 Gy in the urinary bladder, 0.57 Gy in the smallintestine, 0.38 Gy in the stomach, and ranged from 0.05 to 0.30 Gy in other organs (euthyroid versushyperthyroid not significant). A 1.6% life-time risk of development of cancer outside the thyroid glandwas calculated. When applied to people of 65 yr and older the estimated risk is approximately 0.5%.CONCLUSION These data may help in choosing the treatment regimen for individual patients with a large,multinodular goiter, who have to be treated for hyperthyroidism or compressive problems. In youngerpatients, surgery may be preferred. However, for elderly patients and patients with cardiopulmonarydisease, the advantages of noninvasive radioiodine treatment will outweight the life-time risk of thismode of therapy.", "metadata": {}}
+{"_id": "6766459", "title": "", "text": "RBM3 regulates temperature sensitive miR-142–5p and miR-143 (thermomiRs), which target immunegenes and control feverFever is commonly used to diagnose disease and is consistently associated withincreased mortality in critically ill patients. However, the molecular controls of elevated body temperatureare poorly understood. We discovered that the expression of RNA-binding motif protein 3 (RBM3), knownto respond to cold stress and to modulate microRNA (miRNA) expression, was reduced in 30 patients withfever, and in THP-1-derived macrophages maintained at a fever-like temperature (40 °C). Notably, RBM3expression is reduced during fever whether or not infection is demonstrable. Reduced RBM3 expressionresulted in increased expression of RBM3-targeted temperature-sensitive miRNAs, we termedthermomiRs. ThermomiRs such as miR-142-5p and miR-143 in turn target endogenous pyrogensincluding IL-6, IL6ST, TLR2, PGE2 and TNF to complete a negative feedback mechanism, which may becrucial to prevent pathological hyperthermia. Using normal PBMCs that were exogenously exposed tofever-like temperature (40 °C), we further demonstrate the trend by which decreased levels of RBM3were associated with increased levels of miR-142-5p and miR-143 and vice versa over a 24 h timecourse. Collectively, our results indicate the existence of a negative feedback loop that regulates fever viareduced RBM3 levels and increased expression of miR-142-5p and miR-143.", "metadata": {}}
+{"_id": "6767133", "title": "", "text": "Patient preferences and expectations for care: determinants in patients with lumbar intervertebral discherniation.STUDY DESIGN Prospective observational cohort. OBJECTIVE To describe the baselinecharacteristics of patients with a diagnosis of intervertebral disc herniation who had different treatmentpreferences and the relationship of specific expectations with those preferences. SUMMARY OFBACKGROUND DATA Data were gathered from the observational cohort of the Spine Patient OutcomesResearch Trial (SPORT). Patients in the observational cohort met eligibility requirements identical to thoseof the randomized cohort, but declined randomization, receiving instead the treatment of their choice.METHODS Baseline preference and expectation data were acquired at the time of enrollment of thepatient, before exposure to the informed consent process. Univariate analyses were performed using a ttest for continuous variables and chi for categorical variables. Multivariate analyses were also performedwith ANCOVA for continuous variables and logistic regression for categorical variables. Multiple logisticregression models were developed in a forward stepwise fashion using blocks of variables. RESULTS Morepatients preferred operative care: 67% preferred surgery, 28% preferred nonoperative treatment, and6% were unsure; 53% of those preferring surgery stated a definite preference, whereas only 18% ofthose preferring nonoperative care had a definite preference. Patients preferring surgery were younger,had lower levels of education, and higher levels of unemployment/disability. This group also reportedhigher pain, worse physical and mental functioning, more back pain related disability, a longer duration ofsymptoms, and more opiate use. Gender, race, comorbidities, and use of other therapies did not differsignificantly across preference groups. Patients' expectations regarding improvement with nonoperativecare was the strongest predictor of preference. CONCLUSION Patient expectations, particularly regardingthe benefit of nonoperative treatment, are the primary determinant of surgery preference among patientswith lumbar intervertebral disc herniation. Demographic, functional status, and prior treatmentexperience had significant associations with patients' expectations and preferences.", "metadata": {}}
+{"_id": "6767271", "title": "", "text": "Cord factor and peptidoglycan recapitulate the Th17-promoting adjuvant activity of mycobacteria throughmincle/CARD9 signaling and the inflammasome.Although adjuvants are critical vaccine components, theirmodes of action are poorly understood. In this study, we investigated the mechanisms by which theheat-killed mycobacteria in CFA promote Th17 CD4(+) T cell responses. We found that IL-17 secretion byCD4(+) T cells following CFA immunization requires MyD88 and IL-1β/IL-1R signaling. Throughmeasurement of Ag-specific responses after adoptive transfer of OTII cells, we confirmed thatMyD88-dependent signaling controls Th17 differentiation rather than simply production of IL-17.Additional experiments showed that CFA-induced Th17 differentiation involves IL-1β processing by theinflammasome, as mice lacking caspase-1, ASC, or NLRP3 exhibit partially defective responses afterimmunization. Biochemical fractionation studies further revealed that peptidoglycan is the majorcomponent of heat-killed mycobacteria responsible for inflammasome activation. By assaying Il1btranscripts in the injection site skin of CFA-immunized mice, we found that signaling through the adaptormolecule caspase activation and recruitment domain 9 (CARD9) plays a major role in triggering pro-IL-1βexpression. Moreover, we demonstrated that recognition of the mycobacterial glycolipid trehalosedimycolate (cord factor) by the C-type lectin receptor mincle partially explains this CARD9 requirement.Importantly, purified peptidoglycan and cord factor administered in mineral oil synergized to recapitulatethe Th17-promoting activity of CFA, and, as expected, this response was diminished in caspase-1- andCARD9-deficient mice. Taken together, these findings suggest a general strategy for the rational designof Th17-skewing adjuvants by combining agonists of the CARD9 pathway with inflammasome activators.", "metadata": {}}
+{"_id": "6776834", "title": "", "text": "OPA1 gene therapy prevents retinal ganglion cell loss in a Dominant Optic Atrophy mousemodelDominant optic atrophy (DOA) is a rare progressive and irreversible blinding disease which is one ofthe most frequent forms of hereditary optic neuropathy. DOA is mainly caused by dominant mutation inthe OPA1 gene encoding a large mitochondrial GTPase with crucial roles in membrane dynamics and cellsurvival. Hereditary optic neuropathies are commonly characterized by the degeneration of retinalganglion cells, leading to the optic nerve atrophy and the progressive loss of visual acuity. Up to now,despite increasing advances in the understanding of the pathological mechanisms, DOA remainsintractable. Here, we tested the efficiency of gene therapy on a genetically-modified mouse modelreproducing DOA vision loss. We performed intravitreal injections of an Adeno-Associated Virus carryingthe human OPA1 cDNA under the control of the cytomegalovirus promotor. Our results provide the firstevidence that gene therapy is efficient on a mouse model of DOA as the wild-type OPA1 expression isable to alleviate the OPA1-induced retinal ganglion cell degeneration, the hallmark of the disease. Theseresults displayed encouraging effects of gene therapy for Dominant Optic Atrophy, fostering futureinvestigations aiming at clinical trials in patients.", "metadata": {}}
+{"_id": "6784372", "title": "", "text": "Multiple degradation pathways regulate versatile CIP/KIP CDK inhibitors.The mammalian CIP/KIP familyof cyclin-dependent kinase (CDK) inhibitors (CKIs) comprises three proteins--p21(Cip1/WAF1),p27(Kip1), and p57(Kip2)--that bind and inhibit cyclin-CDK complexes, which are key regulators of thecell cycle. CIP/KIP CKIs have additional independent functions in regulating transcription, apoptosis andactin cytoskeletal dynamics. These divergent functions are performed in distinct cellular compartmentsand contribute to the seemingly contradictory observation that the CKIs can both suppress and promotecancer. Multiple ubiquitin ligases (E3s) direct the proteasome-mediated degradation of p21, p27 and p57.This review analyzes recent data highlighting our current understanding of how distinct E3 pathwaysregulate subpopulations of the CKIs to control their diverse functions.", "metadata": {}}
+{"_id": "6788835", "title": "", "text": "Dislocation of a type I membrane protein requires interactions between membrane-spanning segmentswithin the lipid bilayer.The human cytomegalovirus gene product US11 causes rapid degradation of classI major histocompatibility complex (MHCI) heavy chains by inducing their dislocation from theendoplasmic reticulum (ER) and subsequent degradation by the proteasome. This set of reactionsresembles the endogenous cellular quality control pathway that removes misfolded or unassembledproteins from the ER. We show that the transmembrane domain (TMD) of US11 is essential for MHCIheavy chain dislocation, but dispensable for MHCI binding. A Gln residue at position 192 in the US11 TMDis crucial for the ubiquitination and degradation of MHCI heavy chains. Cells that express US11 TMDmutants allow formation of MHCI-beta2m complexes, but their rate of egress from the ER is significantlyimpaired. Further mutagenesis data are consistent with the presence of an alpha-helical structure in theUS11 TMD essential for MHCI heavy chain dislocation. The failure of US11 TMD mutants to catalyzedislocation is a unique instance in which a polar residue in the TMD of a type I membrane protein isrequired for that protein's function. Targeting of MHCI heavy chains for dislocation by US11 thus requiresthe formation of interhelical hydrogen bonds within the ER membrane.", "metadata": {}}
+{"_id": "6790197", "title": "", "text": "Prostate cancer-associated gene expression alterations determined from needle biopsies.PURPOSE Toaccurately identify gene expression alterations that differentiate neoplastic from normal prostateepithelium using an approach that avoids contamination by unwanted cellular components and is notcompromised by acute gene expression changes associated with tumor devascularization and resultingischemia. EXPERIMENTAL DESIGN Approximately 3,000 neoplastic and benign prostate epithelial cellswere isolated using laser capture microdissection from snap-frozen prostate biopsy specimens providedby 31 patients who subsequently participated in a clinical trial of preoperative chemotherapy. cDNAsynthesized from amplified total RNA was hybridized to custom-made microarrays composed of 6,200clones derived from the Prostate Expression Database. Expression differences for selected genes wereverified using quantitative reverse transcription-PCR. RESULTS Comparative analyses identified 954transcript alterations associated with cancer (q < 0.01%), including 149 differentially expressed geneswith no known functional roles. Gene expression changes associated with ischemia and surgical removalof the prostate gland were absent. Genes up-regulated in prostate cancer were statistically enriched incategories related to cellular metabolism, energy use, signal transduction, and molecular transport.Genes down-regulated in prostate cancers were enriched in categories related to immune response,cellular responses to pathogens, and apoptosis. A heterogeneous pattern of androgen receptor expressionchanges was noted. In exploratory analyses, androgen receptor down-regulation was associated with alower probability of cancer relapse after neoadjuvant chemotherapy followed by radical prostatectomy.CONCLUSIONS Assessments of tumor phenotypes based on gene expression for treatment stratificationand drug targeting of oncogenic alterations may best be ascertained using biopsy-based analyses wherethe effects of ischemia do not complicate interpretation.", "metadata": {}}
+{"_id": "6793674", "title": "", "text": "Circulating trimethylamine N\u0000oxide and the risk of cardiovascular diseases: a systematic review andmeta\u0000analysis of 11 prospective cohort studiesCirculating trimethylamine N-oxide (TMAO), a canonicalmetabolite from gut flora, has been related to the risk of cardiovascular disorders. However, theassociation between circulating TMAO and the risk of cardiovascular events has not been quantitativelyevaluated. We performed a systematic review and meta-analysis of all available cohort studies regardingthe association between baseline circulating TMAO and subsequent cardiovascular events. Embase andPubMed databases were searched for relevant cohort studies. The overall hazard ratios for the developingof cardiovascular events (CVEs) and mortality were extracted. Heterogeneity among the included studieswas evaluated with Cochran's Q Test and I2 statistics. A random-effect model or a fixed-effect model wasapplied depending on the heterogeneity. Subgroup analysis and meta-regression were used to evaluatethe source of heterogeneity. Among the 11 eligible studies, three reported both CVE and mortalityoutcome, one reported only CVEs and the other seven provided mortality data only. Higher circulatingTMAO was associated with a 23% higher risk of CVEs (HR = 1.23, 95% CI: 1.07-1.42, I2 = 31.4%) and a55% higher risk of all-cause mortality (HR = 1.55, 95% CI: 1.19-2.02, I2 = 80.8%). Notably, the latterassociation may be blunted by potential publication bias, although sensitivity analysis by omitting onestudy at a time did not significantly change the results. Further subgroup analysis and meta-regressiondid not support that the location of the study, follow-up duration, publication year, populationcharacteristics or the samples of TMAO affect the results significantly. Higher circulating TMAO mayindependently predict the risk of subsequent cardiovascular events and mortality.", "metadata": {}}
+{"_id": "6796297", "title": "", "text": "PDGF-BB secreted by preosteoclasts induces angiogenesis during coupling with osteogenesisOsteogenesisduring bone modeling and remodeling is coupled with angiogenesis. A recent study showed that a specificvessel subtype, strongly positive for CD31 and endomucin (CD31hiEmcnhi), couples angiogenesis andosteogenesis. Here, we found that platelet-derived growth factor-BB (PDGF-BB) secreted bypreosteoclasts induces CD31hiEmcnhi vessel formation during bone modeling and remodeling. Mice withdepletion of PDGF-BB in the tartrate-resistant acid phosphatase–positive cell lineage show significantlylower trabecular and cortical bone mass, serum and bone marrow PDGF-BB concentrations, and fewerCD31hiEmcnhi vessels compared to wild-type mice. In the ovariectomy (OVX)-induced osteoporoticmouse model, serum and bone marrow levels of PDGF-BB and numbers of CD31hiEmcnhi vessels aresignificantly lower compared to sham-operated controls. Treatment with exogenous PDGF-BB or inhibitionof cathepsin K to increase the number of preosteoclasts, and thus the endogenous levels of PDGF-BB,increases CD31hiEmcnhi vessel number and stimulates bone formation in OVX mice. Thus,pharmacotherapies that increase PDGF-BB secretion from preosteoclasts offer a new therapeutic targetfor treating osteoporosis by promoting angiogenesis and thus bone formation.", "metadata": {}}
+{"_id": "6807122", "title": "", "text": "Discovery of endothelial to mesenchymal transition as a source for carcinoma-associatedfibroblasts.Activated fibroblasts are associated with many different tumors. Myofibroblasts, activatedfibroblasts, and perivascular mesenchymal cells such as pericytes play a role in cancer progression. Manystudies suggest that myofibroblasts facilitate tumor growth and cancer progression. The source formyofibroblasts and other activated fibroblasts within the tumors is still debated. Although de novoactivation of quiescent fibroblasts into alpha-smooth muscle actin (alpha SMA)-positive myofibroblasts isone likely source, epithelial to mesenchymal transition and bone marrow recruitment are also evolving aspossible mechanisms for the emergence of a heterogeneous population of carcinoma-associatedfibroblasts. Here, we show that transforming growth factor-beta1 could induce proliferating endothelialcells to undergo a phenotypic conversion into fibroblast-like cells. Such endothelial to mesenchymaltransition (EndMT) is associated with the emergence of mesenchymal marker fibroblast-specific protein-1(FSP1) and down-regulation of CD31/PECAM. Additionally, we show EndMT in tumors using the B16F10melanoma model and the Rip-Tag2 spontaneous pancreatic carcinoma model. Crossing Tie2-Cre micewith R26Rosa-lox-Stop-lox-LacZ mice allows for irreversible tagging of endothelial cells. We provideunequivocal evidence for EndMT at the invasive front of the tumors in these transgenic mice. Collectively,our results show that EndMT is a unique mechanism for the accumulation of carcinoma-associatedfibroblasts and suggest that antiangiogenic treatment of tumors may have a direct effect in decreasingactivated fibroblasts that likely facilitate cancer progression.", "metadata": {}}
+{"_id": "6812319", "title": "", "text": "ERCC1 and MUS81–EME1 promote sister chromatid separation by processing late replicationintermediates at common fragile sites during mitosisChromosomal instability (CIN) is a hallmark oftumour initiation and progression. Some genomic regions are particularly unstable under replicationstress, notably common fragile sites (CFSs) whose rearrangements in tumour cells contribute to cancerdevelopment. Recent work has shown that the Fanconi anaemia (FANC) pathway plays a role inpreventing defective chromosome segregation and CIN under conditions of replication stress. Strikingly,FANCD2 is recruited to regions hosting CFSs on metaphase chromosomes. To decipher the mechanismsprotecting CFSs in G2/M, we searched for proteins that co-localize with FANCD2 on mitotic chromosomes,and identified XPF–ERCC1 and MUS81–EME1, two structure-specific endonucleases. We show thatdepletion of either ERCC1 or MUS81–EME1 affects accurate processing of replication intermediates orunder-replicated DNA that persist at CFSs until mitosis. Depletion of these endonucleases also leads to anincrease in the frequency of chromosome bridges during anaphase that, in turn, favours accumulation ofDNA damage in the following G1 phase.", "metadata": {}}
+{"_id": "6820680", "title": "", "text": "Engineered RNA viral synthesis of microRNAs.MicroRNAs (miRNAs) are short noncoding RNAs that exertposttranscriptional gene silencing and regulate gene expression. In addition to the hundreds of conservedcellular miRNAs that have been identified, miRNAs of viral origin have been isolated and found tomodulate both the viral life cycle and the cellular transcriptome. Thus far, detection of virus-derivedmiRNAs has been largely limited to DNA viruses, suggesting that RNA viruses may be unable to exploitthis aspect of transcriptional regulation. Lack of RNA virus-produced miRNAs has been attributed to thereplicative constraints that would incur following RNase III processing of a genomic hairpin. To ascertainwhether the generation of viral miRNAs is limited to DNA viruses, we investigated whether influenza viruscould be designed to deliver functional miRNAs without affecting replication. Here, we describe a modifiedinfluenza A virus that expresses cellular microRNA-124 (miR-124). Insertion of the miR-124 hairpin intoan intron of the nuclear export protein transcript resulted in endogenous processing and functionalmiR-124. We demonstrate that a viral RNA genome incorporating a hairpin does not result in segmentinstability or miRNA-mediated genomic targeting, thereby permitting the virus to produce a miRNAwithout having a negative impact on viral replication. This work demonstrates that RNA viruses canproduce functional miRNAs and suggests that this level of transcriptional regulation may extend beyondDNA viruses.", "metadata": {}}
+{"_id": "6826100", "title": "", "text": "The developmental potential of iPSCs is greatly influenced by reprogramming factor selection.Inducedpluripotent stem cells (iPSCs) are commonly generated by transduction of Oct4, Sox2, Klf4, and Myc(OSKM) into cells. Although iPSCs are pluripotent, they frequently exhibit high variation in terms ofquality, as measured in mice by chimera contribution and tetraploid complementation. Reliablyhigh-quality iPSCs will be needed for future therapeutic applications. Here, we show that one majordeterminant of iPSC quality is the combination of reprogramming factors used. Based on tetraploidcomplementation, we found that ectopic expression of Sall4, Nanog, Esrrb, and Lin28 (SNEL) in mouseembryonic fibroblasts (MEFs) generated high-quality iPSCs more efficiently than other combinations offactors including OSKM. Although differentially methylated regions, transcript number of masterregulators, establishment of specific superenhancers, and global aneuploidy were comparable betweenhigh- and low-quality lines, aberrant gene expression, trisomy of chromosome 8, and abnormal H2A.Xdeposition were distinguishing features that could potentially also be applicable to human.", "metadata": {}}
+{"_id": "6826636", "title": "", "text": "GiardiaDB and TrichDB: integrated genomic resources for the eukaryotic protist pathogens Giardialamblia and Trichomonas vaginalisGiardiaDB (http://GiardiaDB.org) and TrichDB (http://TrichDB.org)house the genome databases for Giardia lamblia and Trichomonas vaginalis, respectively, and representthe latest additions to the EuPathDB (http://EuPathDB.org) family of functional genomic databases.GiardiaDB and TrichDB employ the same framework as other EuPathDB sites (CryptoDB, PlasmoDB andToxoDB), supporting fully integrated and searchable databases. Genomic-scale data available via theseresources may be queried based on BLAST searches, annotation keywords and gene ID searches, GOterms, sequence motifs and other protein characteristics. Functional queries may also be formulated,based on transcript and protein expression data from a variety of platforms. Phylogenetic relationshipsmay also be interrogated. The ability to combine the results from independent queries, and to storequeries and query results for future use facilitates complex, genome-wide mining of functional genomicdata.", "metadata": {}}
+{"_id": "6828370", "title": "", "text": "A coding-independent function of gene and pseudogene mRNAs regulates tumour biologyThe canonicalrole of messenger RNA (mRNA) is to deliver protein-coding information to sites of protein synthesis.However, given that microRNAs bind to RNAs, we hypothesized that RNAs could possess a regulatory rolethat relies on their ability to compete for microRNA binding, independently of their protein-codingfunction. As a model for the protein-coding-independent role of RNAs, we describe the functionalrelationship between the mRNAs produced by the PTEN tumour suppressor gene and its pseudogenePTENP1 and the critical consequences of this interaction. We find that PTENP1 is biologically active as itcan regulate cellular levels of PTEN and exert a growth-suppressive role. We also show that the PTENP1locus is selectively lost in human cancer. We extended our analysis to other cancer-related genes thatpossess pseudogenes, such as oncogenic KRAS. We also demonstrate that the transcripts ofprotein-coding genes such as PTEN are biologically active. These findings attribute a novel biological roleto expressed pseudogenes, as they can regulate coding gene expression, and reveal a non-codingfunction for mRNAs.", "metadata": {}}
+{"_id": "6836086", "title": "", "text": "Identification of a Multicomponent Complex Required for Outer Membrane Biogenesis in EscherichiacoliGram-negative bacteria have an outer membrane (OM) that functions as a barrier to protect the cellfrom toxic compounds such as antibiotics and detergents. The OM is a highly asymmetric bilayercomposed of phospholipids, glycolipids, and proteins. Assembly of this essential organelle occurs outsidethe cytoplasm in an environment that lacks obvious energy sources such as ATP, and the mechanismsinvolved are poorly understood. We describe the identification of a multiprotein complex required for theassembly of proteins in the OM of Escherichia coli. We also demonstrate genetic interactions betweengenes encoding components of this protein assembly complex and imp, which encodes a protein involvedin the assembly of lipopolysaccharides (LPS) in the OM. These genetic interactions suggest a role for YfgL,one of the lipoprotein components of the protein assembly complex, in a homeostatic control mechanismthat coordinates the overall OM assembly process.", "metadata": {}}
+{"_id": "6841927", "title": "", "text": "Transtheoretical model-based multiple behavior intervention for weight management: effectiveness on apopulation basis.BACKGROUND The increasing prevalence of overweight and obesity underscores theneed for evidence-based, easily disseminable interventions for weight management that can be deliveredon a population basis. The Transtheoretical Model (TTM) offers a promising theoretical framework formultiple behavior weight management interventions. METHODS Overweight or obese adults (BMI25-39.9; n=1277) were randomized to no-treatment control or home-based, stage-matched multiplebehavior interventions for up to three behaviors related to weight management at 0, 3, 6, and 9 months.All participants were re-assessed at 6, 12, and 24 months. RESULTS Significant treatment effects werefound for healthy eating (47.5% versus 34.3%), exercise (44.90% versus 38.10%), managing emotionaldistress (49.7% versus 30.30%), and untreated fruit and vegetable intake (48.5% versus 39.0%)progressing to Action/Maintenance at 24 months. The groups differed on weight lost at 24 months.Co-variation of behavior change occurred and was much more pronounced in the treatment group, whereindividuals progressing to Action/Maintenance for a single behavior were 2.5-5 times more likely to makeprogress on another behavior. The impact of the multiple behavior intervention was more than threetimes that of single behavior interventions. CONCLUSIONS This study demonstrates the ability ofTTM-based tailored feedback to improve healthy eating, exercise, managing emotional distress, andweight on a population basis. The treatment produced a high level of population impact that futuremultiple behavior interventions can seek to surpass.", "metadata": {}}
+{"_id": "6847208", "title": "", "text": "Autoinduction and signal transduction in the regulation of staphylococcal virulence.The accessory genesof Staphylococcus aureus, including those involved in pathogenesis, are controlled by a complexregulatory network that includes at least four two-component systems, one of which, agr, is a quorumsensor, an alternative sigma factor and a large set of transcription factors, including at least two of thesuperantigen genes, tst and seb. These regulatory genes are hypothesized to act in a time- andpopulation density-dependent manner to integrate signals received from the external environment withthe internal metabolic machinery of the cell, in order to achieve the production of particular subsets ofaccessory/virulence factors at the time and in quantities that are appropriate to the needs of theorganism at any given location. From the standpoint of pathogenesis, the regulatory agenda ispresumably tuned to particular sites in the host organism. To address this hypothesis, it will be necessaryto understand in considerable detail the regulatory interactions among the organism's numerouscontrolling systems. This review is an attempt to integrate a large body of data into the beginnings of amodel that will hopefully help to guide research towards a full-scale test.", "metadata": {}}
+{"_id": "6853699", "title": "", "text": "Macrophages in the Pathogenesis of AtherosclerosisIn atherosclerosis, the accumulation of apolipoproteinB-lipoproteins in the matrix beneath the endothelial cell layer of blood vessels leads to the recruitment ofmonocytes, the cells of the immune system that give rise to macrophages and dendritic cells.Macrophages derived from these recruited monocytes participate in a maladaptive, nonresolvinginflammatory response that expands the subendothelial layer due to the accumulation of cells, lipid, andmatrix. Some lesions subsequently form a necrotic core, triggering acute thrombotic vascular disease,including myocardial infarction, stroke, and sudden cardiac death. This Review discusses the central rolesof macrophages in each of these stages of disease pathogenesis.", "metadata": {}}
+{"_id": "6863070", "title": "", "text": "Three-dimensional superresolution colocalization of intracellular protein superstructures and the cellsurface in live Caulobacter crescentus.Recently, single-molecule imaging and photocontrol have enabledsuperresolution optical microscopy of cellular structures beyond Abbe's diffraction limit, extending thefrontier of noninvasive imaging of structures within living cells. However, live-cell superresolution imaginghas been challenged by the need to image three-dimensional (3D) structures relative to their biologicalcontext, such as the cellular membrane. We have developed a technique, termed superresolution bypower-dependent active intermittency and points accumulation for imaging in nanoscale topography(SPRAIPAINT) that combines imaging of intracellular enhanced YFP (eYFP) fusions (SPRAI) with stochasticlocalization of the cell surface (PAINT) to image two different fluorophores sequentially with only onelaser. Simple light-induced blinking of eYFP and collisional flux onto the cell surface by Nile red are usedto achieve single-molecule localizations, without any antibody labeling, cell membrane permeabilization,or thiol-oxygen scavenger systems required. Here we demonstrate live-cell 3D superresolution imaging ofCrescentin-eYFP, a cytoskeletal fluorescent protein fusion, colocalized with the surface of the bacteriumCaulobacter crescentus using a double-helix point spread function microscope. Three-dimensionalcolocalization of intracellular protein structures and the cell surface with superresolution opticalmicroscopy opens the door for the analysis of protein interactions in living cells with excellent precision(20-40 nm in 3D) over a large field of view (12 12 μm).", "metadata": {}}
+{"_id": "6876224", "title": "", "text": "Overweight prevalence among youth in the United States: Why so many different numbers?Severalrecent publications have presented different estimates for the prevalence of overweight among youth inthe United States. Prevalence estimates range from 11–24%, despite describing the same results fromthe third National Health and Nutrition Examination Survey (NHANES III). This paper discusses thevariety and evolution of different overweight prevalence estimates. Issues of definition, measurements,criteria selection and comparison groups are considered and implications for estimates of the prevalenceof overweight among youth are explored. Reference percentiles for body mass index (BMI) from severalpublications are compared. The differences in published estimates from NHANES III are noted andexplained.", "metadata": {}}
+{"_id": "6896063", "title": "", "text": "Senescence and aging: the critical roles of p53p53 functions as a transcription factor involved in cell-cyclecontrol, DNA repair, apoptosis and cellular stress responses. However, besides inducing cell growth arrestand apoptosis, p53 activation also modulates cellular senescence and organismal aging. Senescence is anirreversible cell-cycle arrest that has a crucial role both in aging and as a robust physiological antitumorresponse, which counteracts oncogenic insults. Therefore, via the regulation of senescence, p53contributes to tumor growth suppression, in a manner strictly dependent by its expression and cellularcontext. In this review, we focus on the recent advances on the contribution of p53 to cellular senescenceand its implication for cancer therapy, and we will discuss p53’s impact on animal lifespan. Moreover, wedescribe p53-mediated regulation of several physiological pathways that could mediate its role in bothsenescence and aging.", "metadata": {}}
+{"_id": "6903077", "title": "", "text": "Asymmetric cryo-EM reconstruction of phage MS2 reveals genome structure in situIn single-strandedribonucleic acid (RNA) viruses, virus capsid assembly and genome packaging are intertwined processes.Using cryo-electron microscopy and single particle analysis we determined the asymmetric virionstructure of bacteriophage MS2, which includes 178 copies of the coat protein, a single copy of theA-protein and the RNA genome. This reveals that in situ, the viral RNA genome can adopt a definedconformation. The RNA forms a branched network of stem-loops that almost all allocate near the capsidinner surface, while predominantly binding to coat protein dimers that are located in one-half of thecapsid. This suggests that genomic RNA is highly involved in genome packaging and virion assembly.", "metadata": {}}
+{"_id": "6910577", "title": "", "text": "Harnessing transposons for cancer gene discoveryRecently, it has become possible to mobilize theTc1/mariner transposon, Sleeping Beauty (SB), in mouse somatic cells at frequencies high enough toinduce cancer. Tumours result from SB insertional mutagenesis of cancer genes, thus facilitating theidentification of the genes and signalling pathways that drive tumour formation. A conditional SBtransposition system has also been developed that makes it possible to limit where SB mutagenesisoccurs, providing a means to selectively model many types of human cancer. SB mutagenesis has alreadyidentified a large collection of known cancer genes in addition to a plethora of new candidate cancergenes and potential drug targets.", "metadata": {}}
+{"_id": "6913227", "title": "", "text": "MicroRNA-Containing T-Regulatory-Cell-Derived Exosomes Suppress Pathogenic T Helper 1 CellsFoxp3(+)T regulatory (Treg) cells prevent inflammatory disease but the mechanistic basis of suppression is notunderstood completely. Gene silencing by RNA interference can act in a cell-autonomous andnon-cell-autonomous manner, providing mechanisms of intercellular regulation. Here, we demonstratethat non-cell-autonomous gene silencing, mediated by miRNA-containing exosomes, is a mechanismemployed by Treg cells to suppress T-cell-mediated disease. Treg cells transferred microRNAs (miRNA) tovarious immune cells, including T helper 1 (Th1) cells, suppressing Th1 cell proliferation and cytokinesecretion. Use of Dicer-deficient or Rab27a and Rab27b double-deficient Treg cells to disrupt miRNAbiogenesis or the exosomal pathway, respectively, established a requirement for miRNAs and exosomesfor Treg-cell-mediated suppression. Transcriptional analysis and miRNA inhibitor studies showed thatexosome-mediated transfer of Let-7d from Treg cell to Th1 cells contributed to suppression andprevention of systemic disease. These studies reveal a mechanism of Treg-cell-mediated suppressionmediated by miRNA-containing exosomes.", "metadata": {}}
+{"_id": "6917133", "title": "", "text": "Estimating risk curves for first-degree relatives of patients with Alzheimer’s disease: The REVEALstudyPurpose: The REVEAL study is a randomized, controlled study of the psychological and behavioralimpact of APOE disclosure in a risk assessment protocol provided to first degree relatives of patients withAlzheimer’s disease. The protocol presents risk information as cumulative incidence curves. This articledescribes how these curves were estimated. Methods: Curves were calculated using Bayes’ rule tocompute the posterior survival curves incorporating APOE information. Results: A combination of survivaldata from the MIRAGE study and gender- and age-specific APOE odds ratios were used to create riskcurves for males and females within each of the 6 APOE genotypes. Conclusion: Utilizing comparativegenotype relative risk information and survival data from family studies, estimates of gender-, age-, andgenotype-specific risk can be generated for use in a risk assessment research study that featuresgenotype disclosure.", "metadata": {}}
+{"_id": "6923795", "title": "", "text": "Up-regulation of endothelial nitric-oxide synthase by endothelium-derived hyperpolarizing factor involvesmitogen-activated protein kinase and protein kinase C signaling pathways.Cytochrome P450(P450)-dependent metabolites of arachidonic acid, the epoxyeicosatrienoic acids (EETs), are proposed tobe endothelium-derived hyperpolarizing factors (EDHF) that affect vascular tone; however, the effects ofEDHF on endothelial-derived nitric oxide biosynthesis remain unknown. We examined the regulation ofendothelial nitric-oxide synthase (eNOS) by EDHF and investigated the relevant signaling pathwaysinvolved. The P450 epoxygenases CYP102 F87V mutant, CYP2C11-CYPOR, and CYP2J2 were transfectedinto cultured bovine aortic endothelial cells, and the effects of endogenously formed or exogenouslyapplied EETs on eNOS expression and activity were assessed. Transfection with the P450 epoxygenasesled to increased eNOS protein expression, an effect that was attenuated by cotreatment with the P450inhibitor 17-ODYA. Northern analysis demonstrated that P450 transfection led to increased eNOS mRNAlevels consistent with an effect at the pretranslational level. P450 epoxygenase transfection resulted inincreased eNOS activity as measured by the conversion of L-arginine to L-citrulline. Addition of syntheticEETs (50-200 nM) to the culture media also increased eNOS expression and activity. Treatment withmitogen-activated protein kinase (MAPK), MAPK kinase, and protein kinase C inhibitors apigenin,2'-amino-3'-methoxyflavone (PD98059), and 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7),respectively, significantly inhibited the effects of P450 transfection on eNOS expression. Overexpressionof P450 epoxygenases or addition of synthetic EETs increased Thr495 phosphorylation of eNOS, an effectthat was inhibited by both apigenin and PD98059. Overexpression of P450 epoxygenases in rats resultedin increased aortic eNOS expression, providing direct evidence that EDHF can influence vascular eNOSlevels in vivo. Based on this data, we conclude that EDHF up-regulates eNOS via activation of MAPK andprotein kinase C signaling pathways.", "metadata": {}}
+{"_id": "6923961", "title": "", "text": "Prostaglandin E2 promotes intestinal tumor growth via DNA methylationAlthough aberrant DNAmethylation is considered to be one of the key ways by which tumor-suppressor and DNA-repair genesare silenced during tumor initiation and progression, the mechanisms underlying DNA methylationalterations in cancer remain unclear. Here we show that prostaglandin E(2) (PGE(2)) silences certaintumor-suppressor and DNA-repair genes through DNA methylation to promote tumor growth. Thesefindings uncover a previously unrecognized role for PGE(2) in the promotion of tumor progression.", "metadata": {}}
+{"_id": "6936141", "title": "", "text": "Nef is physically recruited into the immunological synapse and potentiates T cell activation early after TCRengagement.The HIV-1 protein Nef enhances viral pathogenicity and accelerates disease progression invivo. Nef potentiates T cell activation by an unknown mechanism, probably by optimizing the intracellularenvironment for HIV replication. Using a new T cell reporter system, we have found that Nef more thandoubles the number of cells expressing the transcription factors NF-kappaB and NFAT after TCRstimulation. This Nef-induced priming of TCR signaling pathways occurred independently of calciumsignaling and involved a very proximal step before protein kinase C activation. Engagement of the TCR byMHC-bound Ag triggers the formation of the immunological synapse by recruiting detergent-resistantmembrane microdomains, termed lipid rafts. Approximately 5-10% of the total cellular pool of Nef islocalized within lipid rafts. Using confocal and real-time microscopy, we found that Nef in lipid rafts wasrecruited into the immunological synapse within minutes after Ab engagement of the TCR/CD3 and CD28receptors. This recruitment was dependent on the N-terminal domain of Nef encompassing itsmyristoylation. Nef did not increase the number of cell surface lipid rafts or immunological synapses.Recently, studies have shown a specific interaction of Nef with an active subpopulation of p21-activatedkinase-2 found only in the lipid rafts. Thus, the corecruitment of Nef and key cellular partners (e.g.,activated p21-activated kinase-2) into the immunological synapse may underlie the increased frequencyof cells expressing transcriptionally active forms of NF-kappaB and NFAT and the resultant changes in Tcell activation.", "metadata": {}}
+{"_id": "6944800", "title": "", "text": "Microenvironmental regulation of tumor progression and metastasisCancers develop in complex tissueenvironments, which they depend on for sustained growth, invasion and metastasis. Unlike tumor cells,stromal cell types within the tumor microenvironment (TME) are genetically stable and thus represent anattractive therapeutic target with reduced risk of resistance and tumor recurrence. However, specificallydisrupting the pro-tumorigenic TME is a challenging undertaking, as the TME has diverse capacities toinduce both beneficial and adverse consequences for tumorigenesis. Furthermore, many studies haveshown that the microenvironment is capable of normalizing tumor cells, suggesting that re-education ofstromal cells, rather than targeted ablation per se, may be an effective strategy for treating cancer. Herewe discuss the paradoxical roles of the TME during specific stages of cancer progression and metastasis,as well as recent therapeutic attempts to re-educate stromal cells within the TME to haveanti-tumorigenic effects.", "metadata": {}}
+{"_id": "6945285", "title": "", "text": "Bezafibrate in men with lower extremity arterial disease: randomised controlled trial.OBJECTIVE Toassess the effect of bezafibrate on the risk of coronary heart disease and stroke in men with lowerextremity arterial disease. DESIGN Double blind placebo controlled randomised trial. SETTING 85 generalpractices and nine hospital vascular clinics. PARTICIPANTS 1568 men, mean age 68.2 years (range 35 to92) at recruitment. INTERVENTIONS Bezafibrate 400 mg daily (783 men) or placebo (785 men). MAINOUTCOME MEASURES Combination of coronary heart disease and of stroke. All coronary events, fatal andnon-fatal coronary events separately, and strokes alone (secondary end points). RESULTS Bezafibrate didnot reduce the incidence of coronary heart disease and stroke. There were 150 and 160 events in theactive and placebo groups respectively (relative risk 0.96, 95% confidence interval 0.76 to 1.21). Therewere 90 and 111 major coronary events in the active and placebo groups respectively (0.81, 0.60 to1.08), of which 64 and 65 were fatal (0.95, 0.66 to 1.37) and 26 and 46 non-fatal (0.60, 0.36 to 0.99).Beneficial effects on non-fatal events were greatest in men aged <65 years at entry, in whom benefit wasalso seen for all coronary events (0.38, 0.20 to 0.72). There were no significant effects in older men.There were 60 strokes in those on active treatment and 49 in those on placebo (1.34, 0.80 to 2.01).There were 204 and 195 deaths from all causes in the two groups respectively (1.03, 0.83 to 1.26).Bezafibrate reduced the severity of intermittent claudication for up to three years. CONCLUSIONSBezafibrate has no effect on the incidence of coronary heart disease and of stroke combined but mayreduce the incidence of non-fatal coronary events, particularly in those aged <65 years at entry, in whomall coronary events may also be reduced.", "metadata": {}}
+{"_id": "6945691", "title": "", "text": "The modulation of human natural killer cell activity by prostaglandins.Prostaglandins (PGs) have beenimplicated as a regulator of tumor growth in mice and humans. Since natural killer cell (NK) cytotoxicitymay be an important component of immune surveillance against cancer, it is appropriate to studywhether the amount of PGs produced by tumors may be sufficient to suppress NK activity. Accordingly,the effect of various PGs on the NK activity of human peripheral mononuclear cells was investigated. Thepercentage cytotoxicity was measured by the release of Cr51 from labeled K562 and other target cells. Atvery high concentrations of PG (10(-6) M), suppression was seen with PGE2, PGD2, PGA2, and PGF2alpha. However, at concentrations of PG in the physiologic range (10(-8) M), significant suppression wasseen with PGE2 and PGD2 only. The percentage suppression with PGE2 ranged from 77% to 9.5% over arange of concentrations from 10(-5) to 10(-9) M (45% at 10(-8) M). Significant suppression wasobserved at 10(-8) M PGE2 with 4 different targets and at effector:target ratios varying from 50:1 to12.5:1. To assess whether the suppressive effect of PGE2 was directed at the effector and/or target cell,K562 cells or effector cells were pretreated with PGE2. Significant suppression was seen with effector cellpretreatment but not with target cell pretreatment. Finally, the suppressive effects of supernatantsobtained from tumor cell lines (polyoma virus-transformed murine fibroblast cell line, PY3T3) wasdetermined. The marked suppressive effect of the supernatant could be attributed to its content of PGE.Thus, it appears that the production of PGE by tumor cells may be an important modulator of human NKactivity.", "metadata": {}}
+{"_id": "6947286", "title": "", "text": "Association analysis between anterior-pharynx defective-1 genes polymorphisms and Alzheimer'sdisease.Recent biological studies indicate the importance of anterior-pharynx defective-1 (APH-1)proteins in Alzheimer's disease (AD) pathogenesis. We scanned APH-1 genes for the presence ofsequence variations by denaturing high performance liquid chromatography and analyzed theirdistribution in an Italian sample of 113 AD patients and 132 controls. We found six differentpolymorphisms: three of them, all in APH-1b, predict an aminoacid substitution (T27I, V199L and F217L);the others are either silent or in non-coding regions. None of them is significantly associated with thedisease; data stratification by the apolipoprotein E epsilon4 carrier status show a trend for coexistence ofthe transversion c+651T>G (F217L) with the epsilon4 allele. Our data suggest that polymorphisms inAPH-1a/b coding regions are not linked with higher risk for sporadic AD in our Italian population sample.", "metadata": {}}
+{"_id": "6948886", "title": "", "text": "Dynamic epigenetic regulation of glioblastoma tumorigenicity through LSD1 modulation of MYCexpression.The available evidence suggests that the lethality of glioblastoma is driven by smallsubpopulations of cells that self-renew and exhibit tumorigenicity. It remains unclear whethertumorigenicity exists as a static property of a few cells or as a dynamically acquired property. We usedtumor-sphere and xenograft formation as assays for tumorigenicity and examined subclones isolatedfrom established and primary glioblastoma lines. Our results indicate that glioblastoma tumorigenicity islargely deterministic, yet the property can be acquired spontaneously at low frequencies. Further, thesedynamic transitions are governed by epigenetic reprogramming through the lysine-specific demethylase 1(LSD1). LSD depletion increases trimethylation of histone 3 lysine 4 at the avian myelocytomatosis viraloncogene homolog (MYC) locus, which elevates MYC expression. MYC, in turn, regulates oligodendrocytelineage transcription factor 2 (OLIG2), SRY (sex determining region Y)-box 2 (SOX2), and POU class 3homeobox 2 (POU3F2), a core set of transcription factors required for reprogramming glioblastoma cellsinto stem-like states. Our model suggests epigenetic regulation of key transcription factors governstransitions between tumorigenic states and provides a framework for glioblastoma therapeuticdevelopment.", "metadata": {}}
+{"_id": "6955746", "title": "", "text": "Auditory Cortex Tracks Both Auditory and Visual Stimulus Dynamics Using Low-Frequency NeuronalPhase ModulationIntegrating information across sensory domains to construct a unified representation ofmulti-sensory signals is a fundamental characteristic of perception in ecological contexts. One provocativehypothesis deriving from neurophysiology suggests that there exists early and direct cross-modal phasemodulation. We provide evidence, based on magnetoencephalography (MEG) recordings from participantsviewing audiovisual movies, that low-frequency neuronal information lies at the basis of the synergisticcoordination of information across auditory and visual streams. In particular, the phase of the 2-7 Hzdelta and theta band responses carries robust (in single trials) and usable information (for parsing thetemporal structure) about stimulus dynamics in both sensory modalities concurrently. These experimentsare the first to show in humans that a particular cortical mechanism, delta-theta phase modulation acrossearly sensory areas, plays an important \"active\" role in continuously tracking naturalistic audio-visualstreams, carrying dynamic multi-sensory information, and reflecting cross-sensory interaction in realtime.", "metadata": {}}
+{"_id": "6957332", "title": "", "text": "The diagnosis and management of gastro-oesophageal reflux in infants.Gastro-oesophageal reflux (GOR)and gastro-oesophageal reflux disease (GORD) occur frequently during the first months of life.Gastro-oesophageal reflux may be a primary gastro-intestinal motility disorder, but it may also besecondary to other conditions such as cow's milk protein allergy. Objective diagnosis can be difficultbecause there may be absence of correlation between history, results of pH monitoring and histology.Severe GORD may cause minor symptoms, and minor GOR may cause severe symptoms. Severaldifferent therapeutic interventions exist. Simply stated, thickened formula reduces regurgitation andalginates and proton pump inhibitors can be used to decrease acid GOR, depending on the severity of theGORD. Efficacy data of prokinetic drugs are either lacking or disappointing. Regarding side-effects,interest has been focused on cisapride, although other molecules have similar effects. Long-termside-effects such as the nutritional consequence of therapeutic management have been insufficientlystudied, especially for the acid-reducing molecules.", "metadata": {}}
+{"_id": "6961811", "title": "", "text": "Increased sensitivity of antigen-experienced T cells through the enrichment of oligomeric T cell receptorcomplexes.Although memory T cells respond more vigorously to stimulation and they are more sensitiveto low doses of antigen than naive T cells, the molecular basis of this increased sensitivity remainsunclear. We have previously shown that the T cell receptor (TCR) exists as different-sized oligomers onthe surface of resting T cells and that large oligomers are preferentially activated in response to lowantigen doses. Through biochemistry and electron microscopy, we now showed that previously stimulatedand memory T cells have more and larger TCR oligomers at the cell surface than their naive counterparts.Reconstitution of cells and mice with a point mutant of the CD3ζ subunit, which impairs TCR oligomerformation, demonstrated that the increased size of TCR oligomers was directly responsible for theincreased sensitivity of antigen-experienced T cells. Thus, we propose that an \"avidity maturation\"mechanism underlies T cell antigenic memory.", "metadata": {}}
+{"_id": "6962472", "title": "", "text": "G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedicalsciences.G*Power (Erdfelder, Faul, & Buchner, 1996) was designed as a general stand-alone poweranalysis program for statistical tests commonly used in social and behavioral research. G*Power 3 is amajor extension of, and improvement over, the previous versions. It runs on widely used computerplatforms (i.e., Windows XP, Windows Vista, and Mac OS X 10.4) and covers many different statisticaltests of the t, F, and chi2 test families. In addition, it includes power analyses for z tests and some exacttests. G*Power 3 provides improved effect size calculators and graphic options, supports bothdistribution-based and design-based input modes, and offers all types of power analyses in which usersmight be interested. Like its predecessors, G*Power 3 is free.", "metadata": {}}
+{"_id": "6969753", "title": "", "text": "Dynamic interactions of cortactin and membrane type 1 matrix metalloproteinase at invadopodia:defining the stages of invadopodia formation and function.Metastatic tumor cells that actively migrateand invade surrounding tissues rely on invadopodia to degrade extracellular matrix (ECM) barriers.Invadopodia are membrane protrusions that localize enzymes required for ECM degradation. Little isknown about the formation, function, and regulation of invadopodia. Here, we show that invadopodiahave two distinct aspects: (a) structural for organizing the cellular actin cytoskeleton to form membraneprotrusions and (b) functional for using proteolytic enzyme(s) for ECM degradation. Small interfering RNA(siRNA) inhibition established that organization of invadopodia structure requires cortactin, whereasprotease inhibitor studies identified membrane type 1 matrix metalloproteinase (MT1-MMP) as the keyinvadopodial enzyme responsible for gelatin matrix degradation in the breast carcinoma cell lineMDA-MB-231. The inhibition of invadopodial structure assembly by cortactin depletion resulted in a blockof matrix degradation due to failure of invadopodia formation. Either protease inhibition or MT1-MMPsiRNA depletion moderately decreased the formation of invadopodial structures that were identified asactin-cortactin accumulations at the ventral cell membrane adherent to matrix. The invadopodia thatwere able to form upon MT1-MMP inhibition or depletion retained actin-cortactin accumulations but wereunable to degrade matrix. Examination of cells at different time points as well as live-cell imagingrevealed four distinct invadopodial stages: membrane cortactin aggregation at membranes adherent tomatrix, MT1-MMP accumulation at the region of cortactin accumulation, matrix degradation at theinvadopodia region, and subsequent cortactin dissociation from the area of continued MT1-MMPaccumulation associated with foci of degraded matrix. Based on these results, we propose a stepwisemodel of invadopodia formation and function.", "metadata": {}}
+{"_id": "6974477", "title": "", "text": "PEP-FOLD: an updated de novo structure prediction server for both linear and disulfide bonded cyclicpeptidesIn the context of the renewed interest of peptides as therapeutics, it is important to have anon-line resource for 3D structure prediction of peptides with well-defined structures in aqueous solution.We present an updated version of PEP-FOLD allowing the treatment of both linear and disulphide bondedcyclic peptides with 9-36 amino acids. The server makes possible to define disulphide bonds and anyresidue-residue proximity under the guidance of the biologists. Using a benchmark of 34 cyclic peptideswith one, two and three disulphide bonds, the best PEP-FOLD models deviate by an average RMS of 2.75Å from the full NMR structures. Using a benchmark of 37 linear peptides, PEP-FOLD locates lowest-energyconformations deviating by 3 Å RMS from the NMR rigid cores. The evolution of PEP-FOLD comes as anew on-line service to supersede the previous server. The server is available at:http://bioserv.rpbs.univ-paris-diderot.fr/PEP-FOLD.", "metadata": {}}
+{"_id": "6985854", "title": "", "text": "Discrimination of speech stimuli based on neuronal response phase patterns depends on acoustics but notcomprehension.Speech stimuli give rise to neural activity in the listener that can be observed aswaveforms using magnetoencephalography. Although waveforms vary greatly from trial to trial due toactivity unrelated to the stimulus, it has been demonstrated that spoken sentences can be discriminatedbased on theta-band (3-7 Hz) phase patterns in single-trial response waveforms. Furthermore,manipulations of the speech signal envelope and fine structure that reduced intelligibility were found toproduce correlated reductions in discrimination performance, suggesting a relationship betweentheta-band phase patterns and speech comprehension. This study investigates the nature of thisrelationship, hypothesizing that theta-band phase patterns primarily reflect cortical processing oflow-frequency (<40 Hz) modulations present in the acoustic signal and required for intelligibility, ratherthan processing exclusively related to comprehension (e.g., lexical, syntactic, semantic). Using stimulithat are quite similar to normal spoken sentences in terms of low-frequency modulation characteristicsbut are unintelligible (i.e., their time-inverted counterparts), we find that discrimination performancebased on theta-band phase patterns is equal for both types of stimuli. Consistent with earlier findings, wealso observe that whereas theta-band phase patterns differ across stimuli, power patterns do not. We usea simulation model of the single-trial response to spoken sentence stimuli to demonstrate thatphase-locked responses to low-frequency modulations of the acoustic signal can account not only for thephase but also for the power results. The simulation offers insight into the interpretation of the empiricalresults with respect to phase-resetting and power-enhancement models of the evoked response.", "metadata": {}}
+{"_id": "6993046", "title": "", "text": "Breathing more with weaker respiratory muscles in pulmonary arterial hypertension.Exertional fatigueand dyspnoea limit the daily activities of patients with pulmonary arterial hypertension 1. Thesesymptoms are usually explained by the inability of the overloaded right ventricle to perfuse the lungs andto adapt systemic oxygen delivery to oxygen demand. Accordingly, pulmonary hypertension patientspresent with reductions in peak oxygen uptake, anaerobic threshold, oxygen pulse, ventilatory efficiencyand 6-min walk distance 2–8. This ergospirometric profile is strikingly similar to that of congestive heartfailure 8–12, further supporting the notion of impaired cardiac output adaptation to peripheral oxygenrequirements as the main cause of decreased exercise capacity. However, in both pulmonaryhypertension and heart failure, ergospirometric variables and walk distances are better correlated tofunctional class and prognosis than to haemodynamic function 3, 6, 7, 10–12. In addition, impairedskeletal muscle function has been repeatedly reported in heart failure, fuelling a “muscle hypothesis”relating dyspnoea and fatigue symptoms to skeletal muscle metaboreceptor and/or ergoreceptor reflexes13. The muscle hypothesis implies a persistent sympathetic nervous system activation, which has indeedbeen shown to occur in heart failure 14 and also, more recently, in pulmonary hypertension 15. Untilnow, there have been no studies on skeletal muscle function in pulmonary arterial hypertension. In thepresent issue of the European Respiratory Journal , Meyer et al. 16 report data suggesting thatrespiratory muscle strength is decreased in pulmonary arterial hypertension. In a prospective study on 37patients with idiopathic pulmonary hypertension, significant decreases in maximal inspiratory (MIP) andexpiratory pressures (MEP) were measured, together with an increased mouth occlusion pressure withinfirst 0.1 s of inspiration ( P 0.1), suggesting inadequate muscle …", "metadata": {}}
+{"_id": "7005276", "title": "", "text": "Acetic Acid Activates the AMP-Activated Protein Kinase Signaling Pathway to Regulate Lipid Metabolism inBovine HepatocytesThe effect of acetic acid on hepatic lipid metabolism in ruminants differs significantlyfrom that in monogastric animals. Therefore, the aim of this study was to investigate the regulationmechanism of acetic acid on the hepatic lipid metabolism in dairy cows. The AMP-activated protein kinase(AMPK) signaling pathway plays a key role in regulating hepatic lipid metabolism. In vitro, bovinehepatocytes were cultured and treated with different concentrations of sodium acetate (neutralized aceticacid) and BML-275 (an AMPKα inhibitor). Acetic acid consumed a large amount of ATP, resulting in anincrease in AMPKα phosphorylation. The increase in AMPKα phosphorylation increased the expression andtranscriptional activity of peroxisome proliferator-activated receptor α, which upregulated the expressionof lipid oxidation genes, thereby increasing lipid oxidation in bovine hepatocytes. Furthermore, elevatedAMPKα phosphorylation reduced the expression and transcriptional activity of the sterol regulatoryelement-binding protein 1c and the carbohydrate responsive element-binding protein, which reduced theexpression of lipogenic genes, thereby decreasing lipid biosynthesis in bovine hepatocytes. In addition,activated AMPKα inhibited the activity of acetyl-CoA carboxylase. Consequently, the triglyceride contentin the acetate-treated hepatocytes was significantly decreased. These results indicate that acetic acidactivates the AMPKα signaling pathway to increase lipid oxidation and decrease lipid synthesis in bovinehepatocytes, thereby reducing liver fat accumulation in dairy cows.", "metadata": {}}
+{"_id": "7011850", "title": "", "text": "Unawareness of hypoglycaemia and inadequate hypoglycaemic counterregulation: no causal relation withdiabetic autonomic neuropathy.OBJECTIVE To examine the traditional view that unawareness ofhypoglycaemia and inadequate hypoglycaemic counterregulation in insulin dependent diabetes mellitusare manifestations of autonomic neuropathy. DESIGN Perspective assessment of unawareness ofhypoglycaemia and detailed assessment of autonomic neuropathy in patients with insulin dependentdiabetes according to the adequacy of their hypoglycaemic counterregulation. SETTING One routinediabetic unit in a university teaching hospital. PATIENTS 23 Patients aged 21-52 with insulin dependentdiabetes mellitus (seven with symptoms suggesting autonomic neuropathy, nine with a serious clinicalproblem with hypoglycaemia, and seven without symptoms of autonomic neuropathy and withoutproblems with hypoglycaemia) and 10 controls with a similar age distribution, without a personal orfamily history of diabetes. MAIN OUTCOME MEASURES Presence of autonomic neuropathy as assessedwith a test of the longest sympathetic fibres (acetylcholine sweatspot test), a pupil test, and a battery ofseven cardiovascular autonomic function tests; adequacy of hypoglycaemic glucose counterregulationduring a 40 mU/kg/h insulin infusion test; history of unawareness of hypoglycaemia; and response ofplasma pancreatic polypeptide during hypoglycaemia, which depends on an intact and respondingautonomic innervation of the pancreas. RESULTS There was little evidence of autonomic neuropathy ineither the 12 diabetic patients with a history of unawareness of hypoglycaemia or the seven patients withinadequate hypoglycaemic counterregulation. By contrast, in all seven patients with clear evidence ofautonomic neuropathy there was no history of unawareness of hypoglycaemia and in six out of seventhere was adequate hypoglycaemic counterregulation. Unawareness of hypoglycaemia and inadequatehypoglycaemic counterregulation were significantly associated (p less than 0.01). The response of plasmapancreatic polypeptide in the diabetic patients with adequate counterregulation but without autonomicneuropathy was not significantly different from that of the controls (change in plasma pancreaticpolypeptide 226.8 v 414 pmol/l). The patients with autonomic neuropathy had a negligible plasmapancreatic polypeptide response (3.7 pmol/l), but this response was also blunted in the patients withinadequate hypoglycaemic counterregulation (72.4 pmol/l) compared with that of the controls (p lessthan 0.05). CONCLUSIONS Unawareness of hypoglycaemia and inadequate glucose counterregulationduring hypoglycaemia are related to each other but are not due to autonomic neuropathy. The bluntedplasma pancreatic polypeptide responses of the patients with inadequate hypoglycaemiccounterregulation may reflect diminished autonomic activity consequent upon reduced responsiveness ofa central glucoregulatory centre, rather than classical autonomic neuropathy.", "metadata": {}}
+{"_id": "7020505", "title": "", "text": "Genetic Abnormalities in Chronic Lymphocytic Leukemia: Where We Are and Where We GoChromosomalabnormalities in chronic lymphocytic leukemia (CLL) are detected in up to 80% of patients. Among them,deletions of 11q, 13q, 17p, and trisomy 12 have a known prognostic value and play an important role inCLL pathogenesis and evolution, determining patients outcome and therapeutic strategies. Standardmethods used to identify these genomic aberrations include both conventional G-banding cytogenetics(CGC) and fluorescence in situ hybridization (FISH). Although FISH analyses have been implemented asthe gold standard, CGC allows the identification of chromosomal translocations and complex karyotypes,the latest associated with poor outcome. Genomic arrays have a higher resolution that allows thedetection of cryptic abnormalities, although these have not been fully implemented in routinelaboratories. In the last years, next generation sequencing (NGS) methods have identified a wide rangeof gene mutations (e.g., TP53, NOTCH1, SF3B1, and BIRC3) which have improved our knowledge aboutCLL development, allowing us to refine both the prognostic subgroups and better therapeutic strategies.Clonal evolution has also recently arisen as a key point in CLL, integrating cytogenetic alterations andmutations in a dynamic model that improve our understanding about its clinical course and relapse.", "metadata": {}}
+{"_id": "7028976", "title": "", "text": "Epidermal growth factor receptor expression identifies functionally and molecularly distincttumor-initiating cells in human glioblastoma multiforme and is required for gliomagenesis.Epidermalgrowth factor receptor (EGFR) is a known diagnostic and, although controversial, prognostic marker ofhuman glioblastoma multiforme (GBM). However, its functional role and biological significance in GBMremain elusive. Here, we show that multiple GBM cell subpopulations could be purified from thespecimens of patients with GBM and from cancer stem cell (CSC) lines based on the expression of EGFRand of other putative CSC markers. All these subpopulations are molecularly and functionally distinct, aretumorigenic, and need to express EGFR to promote experimental tumorigenesis. Among them,EGFR-expressing tumor-initiating cells (TIC) display the most malignant functional and molecularphenotype. Accordingly, modulation of EGFR expression by gain-of-function and loss-of-functionstrategies in GBM CSC lines enhances and reduces their tumorigenic ability, respectively, suggesting thatEGFR plays a fundamental role in gliomagenesis. These findings open up the possibility of newtherapeutically relevant scenarios, as the presence of functionally heterogeneous EGFR(pos) andEGFR(neg) TIC subpopulations within the same tumor might affect clinical response to treatment.", "metadata": {}}
+{"_id": "7029990", "title": "", "text": "Stress-induced apoptosis associated with null mutation of ADAR1 RNA editing deaminase gene.One typeof RNA editing involves the conversion of adenosine residues into inosine in double-stranded RNA throughthe action of adenosine deaminases acting on RNA (ADAR). A-to-I RNA editing of the coding sequencecould result in synthesis of proteins not directly encoded in the genome. ADAR edits also non-codingsequences of target RNAs, such as introns and 3'-untranslated regions, which may affect splicing,translation, and mRNA stability. Three mammalian ADAR gene family members (ADAR1-3) have beenidentified. Here we investigated phenotypes of mice homozygous for ADAR1 null mutation. Although liveADAR1-/- embryos with normal gross appearance could be recovered up to E11.5, widespread apoptosiswas detected in many tissues. Fibroblasts derived from ADAR1-/- embryos were also prone to apoptosisinduced by serum deprivation. Our results demonstrate an essential requirement for ADAR1 inembryogenesis and suggest that it functions to promote survival of numerous tissues by editing one ormore double-stranded RNAs required for protection against stress-induced apoptosis.", "metadata": {}}
+{"_id": "7034001", "title": "", "text": "Outcome of multipair donor kidney exchange by a web-based algorithm.Donor kidney exchange is anestablished method to overcome incompatibility of donor-recipient pairs (DRP). A computerized algorithmwas devised to exchange donor kidney and was tested in a multicenter setting. The algorithm was madeaccording to the consensus of participating centers. It makes all possible exchange combinations not onlybetween two incompatible DRP but also circularly among three DRP and selects an optimum set ofexchange combinations, considering several factors that can affect the outcome of the exchangedtransplant. The algorithm was implemented as a web-based program, and matching was performed fivetimes. Fifty-three DRP were enrolled from five transplant centers. The numbers of DRP that were enrolledin each matching were 38 (25:13), 39 (34:5), 33 (31:2), 32 (28:4), and 34 (30:4)(carryover:newcomer). The numbers of generated exchange combinations were 4:11, 3:17, 2:12, 2:3,and 2:3 (two-pair exchange:three-pair exchange), and the numbers of DRP in selected exchangecombinations were six, 12, six, five, and four in each matching. The numbers of DRP with blood type Orecipient or AB donor were five and one, respectively, in selected exchange combinations. Six DRP oftwo-pair exchange combinations and six DRP of three-pair exchange combinations underwenttransplantation successfully. Computerized algorithm of donor kidney exchange was tried not onlybetween two incompatible DRP but also circularly among three DRP. It showed that the algorithm haspotential to improve the outcome of donor kidney exchange, especially for disadvantaged DRP with bloodtype O recipients or AB donors.", "metadata": {}}
+{"_id": "7036529", "title": "", "text": "Light Activation of Channelrhodopsin-2 in Excitable Cells of Caenorhabditis elegans Triggers RapidBehavioral ResponsesFor studying the function of specific neurons in their native circuitry, it is desired toprecisely control their activity. This often requires dissection to allow accurate electrical stimulation orneurotransmitter application , and it is thus inherently difficult in live animals, especially in small modelorganisms. Here, we employed channelrhodopsin-2 (ChR2), a directly light-gated cation channel from thegreen alga Chlamydomonas reinhardtii, in excitable cells of the nematode Caenorhabditis elegans, totrigger specific behaviors, simply by illumination. Channelrhodopsins are 7-transmembrane-helix proteinsthat resemble the light-driven proton pump bacteriorhodopsin , and they also utilize the chromophoreall-trans retinal, but to open an intrinsic cation pore. In muscle cells, light-activated ChR2 evoked strong,simultaneous contractions, which were reduced in the background of mutated L-type, voltage-gatedCa2+-channels (VGCCs) and ryanodine receptors (RyRs). Electrophysiological analysis demonstratedrapid inward currents that persisted as long as the illumination. When ChR2 was expressed inmechanosensory neurons, light evoked withdrawal behaviors that are normally elicited by mechanicalstimulation. Furthermore, ChR2 enabled activity of these neurons in mutants lacking the MEC-4/MEC-10mechanosensory ion channel . Thus, specific neurons or muscles expressing ChR2 can be quickly andreversibly activated by light in live and behaving, as well as dissected, animals.", "metadata": {}}
+{"_id": "7039855", "title": "", "text": "Neuronal activity regulates remyelination via glutamate signalling to oligodendrocyte progenitorsMyelinregeneration can occur spontaneously in demyelinating diseases such as multiple sclerosis (MS).However, the underlying mechanisms and causes of its frequent failure remain incompletely understood.Here we show, using an in-vivo remyelination model, that demyelinated axons are electrically active andgenerate de novo synapses with recruited oligodendrocyte progenitor cells (OPCs), which, early afterlesion induction, sense neuronal activity by expressing AMPA(α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)/kainate receptors. Blocking neuronal activity,axonal vesicular release or AMPA receptors in demyelinated lesions results in reduced remyelination. Inthe absence of neuronal activity there is a \u00006-fold increase in OPC number within the lesions and areduced proportion of differentiated oligodendrocytes. These findings reveal that neuronal activity andrelease of glutamate instruct OPCs to differentiate into new myelinating oligodendrocytes that recoverlost function. Co-localization of OPCs with the presynaptic protein VGluT2 in MS lesions implies that thismechanism may provide novel targets to therapeutically enhance remyelination.", "metadata": {}}
+{"_id": "7042304", "title": "", "text": "The threshold for polyglutamine-expansion protein aggregation and cellular toxicity is dynamic andinfluenced by aging in Caenorhabditis elegans.Studies of the mutant gene in Huntington's disease, andfor eight related neurodegenerative disorders, have identified polyglutamine (polyQ) expansions as abasis for cellular toxicity. This finding has led to a disease hypothesis that protein aggregation andcellular dysfunction can occur at a threshold of approximately 40 glutamine residues. Here, we test thishypothesis by expression of fluorescently tagged polyQ proteins (Q29, Q33, Q35, Q40, and Q44) in thebody wall muscle cells of Caenorhabditis elegans and show that young adults exhibit a sharp boundary at35-40 glutamines associated with the appearance of protein aggregates and loss of motility. Surprisingly,genetically identical animals expressing near-threshold polyQ repeats exhibited a high degree of variationin the appearance of protein aggregates and cellular toxicity that was dependent on repeat length andexacerbated during aging. The role of genetically determined aging pathways in the progression ofage-dependent polyQ-mediated aggregation and cellular toxicity was tested by expressing Q82 in thebackground of age-1 mutant animals that exhibit an extended lifespan. We observed a dramatic delay ofpolyQ toxicity and appearance of protein aggregates. These data provide experimental support for thethreshold hypothesis of polyQ-mediated toxicity in an experimental organism and emphasize theimportance of the threshold as a point at which genetic modifiers and aging influence biochemicalenvironment and protein homeostasis in the cell.", "metadata": {}}
+{"_id": "7046487", "title": "", "text": "Inflammation meets cancer, with NF-κB as the matchmakerInflammation is a fundamental protectiveresponse that sometimes goes awry and becomes a major cofactor in the pathogenesis of many chronichuman diseases, including cancer. Here we review the evolutionary relationship and opposing functions ofthe transcription factor NF-κB in inflammation and cancer. Although it seems to fulfill a distinctlytumor-promoting role in many types of cancer, NF-κB has a confounding role in certain tumors.Understanding the activity and function of NF-κB in the context of tumorigenesis is critical for itssuccessful taming, an important challenge for modern cancer biology.", "metadata": {}}
+{"_id": "7059897", "title": "", "text": "IgBLAST: an immunoglobulin variable domain sequence analysis toolThe variable domain of animmunoglobulin (IG) sequence is encoded by multiple genes, including the variable (V) gene, thediversity (D) gene and the joining (J) gene. Analysis of IG sequences typically requires identification ofeach gene, as well as a comparison of sequence variations in the context of defined regions. Generalpurpose tools, such as the BLAST program, have only limited use for such tasks, as the rearrangednature of an IG sequence and the variable length of each gene requires multiple rounds of BLASTsearches for a single IG sequence. Additionally, manual assembly of different genes is difficult anderror-prone. To address these issues and to facilitate other common tasks in analysing IG sequences, wehave developed the sequence analysis tool IgBLAST (http://www.ncbi.nlm.nih.gov/igblast/). With thistool, users can view the matches to the germline V, D and J genes, details at rearrangement junctions,the delineation of IG V domain framework regions and complementarity determining regions. IgBLASThas the capability to analyse nucleotide and protein sequences and can process sequences in batches.Furthermore, IgBLAST allows searches against the germline gene databases and other sequencedatabases simultaneously to minimize the chance of missing possibly the best matching germline V gene.", "metadata": {}}
+{"_id": "7074001", "title": "", "text": "Evidence into practice. Application of psychological models of change in evidence-basedimplementation.Psychiatrists have long recognised that routine clinical practice needs to be shaped andinformed by external evidence (Lewis, 1958). Psychiatric researchers were among the first to utilisemulti-centre randomised controlled trials (demonstrating the effectiveness of antipsychotics), andpsychologists were among the first in the health field to develop techniques of meta-analysis. Socialworkers, too, point to their tradition with the publication of one of the earliest controlled trials (Lehrman,1949).", "metadata": {}}
+{"_id": "7093809", "title": "", "text": "Wnt signaling establishes anteroposterior neuronal polarity and requires retromer in C. elegans.SecretedWnt proteins influence neural connectivity by regulating axon guidance, dendritic morphogenesis andsynapse formation. We report a new role for Wnt and Frizzled proteins in establishing the anteroposteriorpolarity of the mechanosensory neurons ALM and PLM in C. elegans. Disruption of Wnt signaling leads toa complete inversion of ALM and PLM polarity: the anterior process adopts the length, branching patternand synaptic properties of the wild-type posterior process, and vice versa. Different but overlapping setsof Wnt proteins regulate neuronal polarity in different body regions. Wnts act directly on PLM via theFrizzled LIN-17. In addition, we show that they are needed for axon branching and anteriorly directedaxon growth. We also find that the retromer, a conserved protein complex that mediates transcytosis andendosome-to-Golgi protein trafficking, plays a key role in Wnt signaling. Deletion mutations of retromersubunits cause ALM and PLM polarity, and other Wnt-related defects. We show that retromer proteinVPS-35 is required in Wnt-expressing cells and propose that retromer activity is needed to generate afully active Wnt signal.", "metadata": {}}
+{"_id": "7098463", "title": "", "text": "Adjustable gastric banding and conventional therapy for type 2 diabetes: a randomized controlledtrial.CONTEXT Observational studies suggest that surgically induced loss of weight may be effectivetherapy for type 2 diabetes. OBJECTIVE To determine if surgically induced weight loss results in betterglycemic control and less need for diabetes medications than conventional approaches to weight loss anddiabetes control. DESIGN, SETTING, AND PARTICIPANTS Unblinded randomized controlled trial conductedfrom December 2002 through December 2006 at the University Obesity Research Center in Australia,with general community recruitment to established treatment programs. Participants were 60 obesepatients (BMI >30 and <40) with recently diagnosed (<2 years) type 2 diabetes. INTERVENTIONSConventional diabetes therapy with a focus on weight loss by lifestyle change vs laparoscopic adjustablegastric banding with conventional diabetes care. MAIN OUTCOME MEASURES Remission of type 2diabetes (fasting glucose level <126 mg/dL [7.0 mmol/L] and glycated hemoglobin [HbA1c] value <6.2%while taking no glycemic therapy). Secondary measures included weight and components of themetabolic syndrome. Analysis was by intention-to-treat. RESULTS Of the 60 patients enrolled, 55 (92%)completed the 2-year follow-up. Remission of type 2 diabetes was achieved by 22 (73%) in the surgicalgroup and 4 (13%) in the conventional-therapy group. Relative risk of remission for the surgical groupwas 5.5 (95% confidence interval, 2.2-14.0). Surgical and conventional-therapy groups lost a mean (SD)of 20.7% (8.6%) and 1.7% (5.2%) of weight, respectively, at 2 years (P < .001). Remission of type 2diabetes was related to weight loss (R2 = 0.46, P < .001) and lower baseline HbA1c levels (combined R2= 0.52, P < .001). There were no serious complications in either group. CONCLUSIONS Participantsrandomized to surgical therapy were more likely to achieve remission of type 2 diabetes through greaterweight loss. These results need to be confirmed in a larger, more diverse population and have long-termefficacy assessed. TRIAL REGISTRATION actr.org Identifier: ACTRN012605000159651.", "metadata": {}}
+{"_id": "7111021", "title": "", "text": "Integration of antiretroviral therapy with tuberculosis treatment.BACKGROUND We previously reportedthat integrating antiretroviral therapy (ART) with tuberculosis treatment reduces mortality. However, thetiming for the initiation of ART during tuberculosis treatment remains unresolved. METHODS Weconducted a three-group, open-label, randomized, controlled trial in South Africa involving 642ambulatory patients, all with tuberculosis (confirmed by a positive sputum smear for acid-fast bacilli),human immunodeficiency virus infection, and a CD4+ T-cell count of less than 500 per cubic millimeter.Findings in the earlier-ART group (ART initiated within 4 weeks after the start of tuberculosis treatment,214 patients) and later-ART group (ART initiated during the first 4 weeks of the continuation phase oftuberculosis treatment, 215 patients) are presented here. RESULTS At baseline, the median CD4+ T-cellcount was 150 per cubic millimeter, and the median viral load was 161,000 copies per milliliter, with nosignificant differences between the two groups. The incidence rate of the acquired immunodeficiencysyndrome (AIDS) or death was 6.9 cases per 100 person-years in the earlier-ART group (18 cases) ascompared with 7.8 per 100 person-years in the later-ART group (19 cases) (incidence-rate ratio, 0.89;95% confidence interval [CI], 0.44 to 1.79; P=0.73). However, among patients with CD4+ T-cell countsof less than 50 per cubic millimeter, the incidence rates of AIDS or death were 8.5 and 26.3 cases per100 person-years, respectively (incidence-rate ratio, 0.32; 95% CI, 0.07 to 1.13; P=0.06). The incidencerates of the immune reconstitution inflammatory syndrome (IRIS) were 20.1 and 7.7 cases per 100person-years, respectively (incidence-rate ratio, 2.62; 95% CI, 1.48 to 4.82; P<0.001). Adverse eventsrequiring a switching of antiretroviral drugs occurred in 10 patients in the earlier-ART group and 1 patientin the later-ART group (P=0.006). CONCLUSIONS Early initiation of ART in patients with CD4+ T-cellcounts of less than 50 per cubic millimeter increased AIDS-free survival. Deferral of the initiation of ARTto the first 4 weeks of the continuation phase of tuberculosis therapy in those with higher CD4+ T-cellcounts reduced the risks of IRIS and other adverse events related to ART without increasing the risk ofAIDS or death. (Funded by the U.S. President's Emergency Plan for AIDS Relief and others; SAPITClinicalTrials.gov number, NCT00398996.).", "metadata": {}}
+{"_id": "7114092", "title": "", "text": "From bloodjournal.hematologylibrary.org at PENN STATE UNIVERSITY on February 23, 2013. Forpersonal use only.Megakaryocyte (MK) is the naturally polyploid cell that gives rise to platelets.Polyploidization occurs by endomitosis, which was a process considered to be an incomplete mitosisaborted in anaphase. Here, we used time-lapse confocal video microscopy to visualize the endomitoticprocess of primary human megakaryocytes. Our results show that the switch from mitosis to endomitosiscorresponds to a late failure of cytokinesis accompanied by a backward movement of the 2 daughtercells. No abnormality was observed in the central spindle of endomitotic MKs. A furrow formation waspresent, but the contractile ring was abnormal because accumulation of nonmuscle myosin IIA waslacking. In addition, a defect in cell elongation was observed in dipolar endomitotic MKs during telophase.RhoA and F-actin were partially concentrated at the site of furrowing. Inhibition of the Rho/Rock pathwaycaused the disappearance of F-actin at midzone and increased MK ploidy level. This inhibition wasassociated with a more pronounced defect in furrow formation as well as in spindle elongation. Ourresults suggest that the late failure of cytokinesis responsible for the endomitotic process is related to apartial defect in the Rho/Rock pathway activation.", "metadata": {}}
+{"_id": "7115651", "title": "", "text": "Key role for IL-21 in experimental autoimmune uveitis.IL-21 is a pleiotropic type 1 cytokine that sharesthe common cytokine receptor γ-chain, γ(c), with IL-2, IL-4, IL-7, IL-9, and IL-15. IL-21 is mosthomologous to IL-2. These cytokines are encoded by adjacent genes, but they are functionally distinct.Whereas IL-2 promotes development of regulatory T cells and confers protection from autoimmunedisease, IL-21 promotes differentiation of Th17 cells and is implicated in several autoimmune diseases,including type 1 diabetes and systemic lupus erythematosus. However, the roles of IL-21 and IL-2 in CNSautoimmune diseases such as multiple sclerosis and uveitis have been controversial. Here, we generatedIl21-mCherry/Il2-emGFP dual-reporter transgenic mice and showed that development of experimentalautoimmune uveitis (EAU) correlated with the presence of T cells coexpressing IL-21 and IL-2 into theretina. Furthermore, Il21r(-/-) mice were more resistant to EAU development than wild-type mice, andadoptive transfer of Il21r(-/-) T cells induced much less severe EAU, underscoring the need for IL-21 inthe development of this disease and suggesting that blocking IL-21/γ(c)-signaling pathways may providea means for controlling CNS auto-inflammatory diseases.", "metadata": {}}
+{"_id": "7116734", "title": "", "text": "Nicotinamide Phosphoribosyltransferase/Visfatin Does Not Catalyze Nicotinamide MononucleotideFormation in Blood PlasmaNicotinamide (Nam) phosphoribosyltransferase (NAMPT) is the rate-limitingenzyme in mammalian NAD synthesis, catalyzing nicotinamide mononucleotide (NMN) formation fromNam and 5-phosphoribosyl 1-pyrophosphate (PRPP). NAMPT has also been described as an adipocytokinevisfatin with a variety of actions, although physiological significance of this protein remains unclear. Ithas been proposed that possible actions of visfatin are mediated through the extracellular formation ofNMN. However, we did not detect NMN in mouse blood plasma, even with a highly specific and sensitiveliquid chromatography/tandem mass spectrometry. Furthermore, there is no or little ATP, the activator ofNAMPT, in extracellular spaces. We thus questioned whether visfatin catalyzes the in situ formation ofNMN under such extracellular milieus. To address this question, we here determined K(m) values for thesubstrates Nam and PRPP in the NAMPT reaction without or with ATP using a recombinant human enzymeand found that 1 mM ATP dramatically decreases K(m) values for the substrates, in particular PRPP to itsintracellular concentration. Consistent with the kinetic data, only when ATP is present at millimolar levels,NAMPT efficiently catalyzed the NMN formation at the intracellular concentrations of the substrates. Muchlower concentrations of Nam and almost the absence of PRPP and ATP in the blood plasma suggest thatNAMPT should not efficiently catalyze its reaction under the extracellular milieu. Indeed, NAMPT did notform NMN in the blood plasma. From these kinetic analyses of the enzyme and quantitative determinationof its substrates, activator, and product, we conclude that visfatin does not participate in NMN formationunder the extracellular milieus. Together with the absence of NMN in the blood plasma, our conclusiondoes not support the concept of \"NAMPT-mediated systemic NAD biosynthesis. \" Our study wouldadvance current understanding of visfatin physiology.", "metadata": {}}
+{"_id": "7137057", "title": "", "text": "Hepatitis B virus replication is regulated by the acetylation status of hepatitis B virus cccDNA-bound H3and H4 histones.BACKGROUND & AIMS HBV covalently closed circular DNA (cccDNA), the replicativeintermediate responsible for persistent HBV infection of hepatocytes, is the template for transcription ofall viral mRNAs. Nuclear cccDNA accumulates as a stable episome organized into minichromosomes byhistone and nonhistone proteins. In this study we investigated, by a newly developed sensitive andspecific assay, the relationship between viral replication and HBV chromatin assembly, transcription, andinteraction with viral and cellular regulatory proteins. METHODS To achieve this aim we coupled aquantitative chromatin immunoprecipitation (ChIP) technique to an established method that allows theamplification of virion-encapsidated HBV genomes after transfection of linear HBV DNA into humanhepatoma HuH7 cells. The cccDNA-ChIP technique was also applied to study HBV minichromosometranscriptional regulation in liver tissue from HBV-infected patients. RESULTS The use ofanti-acetyl-H4/-H3 specific antibodies to immunoprecipitate transcriptionally active chromatin revealedthat HBV replication is regulated by the acetylation status of the cccDNA-bound H3/H4 histones. Class Ihistone deacetylases inhibitors induced an evident increase of both cccDNA-bound acetylated H4 and HBVreplication. Finally, histones hypoacetylation and histone deacetylase 1 recruitment onto the cccDNA inliver tissue correlated with low HBV viremia in hepatitis B patients. CONCLUSIONS We developed aChIP-based assay to analyze, in vitro and ex vivo, the transcriptional regulation of HBV cccDNAminichromosome. Our results provide new insights on the regulation of HBV replication and identify theenzymatic activities that modulate the acetylation of cccDNA-bound histones as new therapeutic targetsfor anti-HBV drugs.", "metadata": {}}
+{"_id": "7142113", "title": "", "text": "Visualization of cell cycle in mouse embryos with Fucci2 reporter directed by Rosa26 promoter.Fuccitechnology makes possible the distinction between live cells in the G(1) and S/G(2)/M phases bydual-color imaging. This technology relies upon ubiquitylation-mediated proteolysis, and transgenic miceexpressing Fucci provide a powerful model system with which to study the coordination of the cell cycleand development. The mice were initially generated using the CAG promoter; lines expressing the G(1)and S/G(2)/M phase probes that emitted orange (mKO2) and green (mAG) fluorescence, respectively,were separately constructed. Owing to cell type-biased strength of the CAG promoter as well as thepositional effects of random transgenesis, however, we noticed some variability in Fucci expressionlevels. To control more reliably the expression of cell cycle probes, we used different genetic approachesto create two types of reporter mouse lines with Fucci2 and Rosa26 transcriptional machinery. Fucci2 is arecently developed Fucci derivative, which emits red (mCherry) and green (mVenus) fluorescence andprovides better color contrast than Fucci. A new transgenic line, R26p-Fucci2, utilizes the Rosa26promoter and harbors the G(1) and S/G(2)/M phase probes in a single transgene to preserve theirco-inheritance. In the other R26R-Fucci2 approach, the two probes are incorporated into Rosa26 locusconditionally. The Cre-mediated loxP recombination technique thus allows researchers to designcell-type-specific Fucci2 expression. By performing time-lapse imaging experiments using R26p-Fucci2and R26-Fucci2 in which R26R-Fucci2 had undergone germline loxP recombination, we demonstrated thegreat promise of these mouse reporters for studying cell cycle behavior in vivo.", "metadata": {}}
+{"_id": "7145763", "title": "", "text": "Tit-for-Tat: Type VI Secretion System Counterattack during Bacterial Cell-Cell InteractionsThe bacterialtype VI secretion system (T6SS) is a dynamic organelle that bacteria use to target prey cells for inhibitionvia translocation of effector proteins. Time-lapse fluorescence microscopy has documented strikingdynamics of opposed T6SS organelles in adjacent sister cells of Pseudomonas aeruginosa. Such cell-cellinteractions have been termed \"T6SS dueling\" and likely reflect a biological process that is driven byT6SS antibacterial attack. Here, we show that T6SS dueling behavior strongly influences the ability of P.aeruginosa to prey upon heterologous bacterial species. We show that, in the case of P. aeruginosa,T6SS-dependent killing of either Vibrio cholerae or Acinetobacter baylyi is greatly stimulated by T6SSactivity occurring in those prey species. Our data suggest that, in P. aeruginosa, T6SS organelle assemblyand lethal counterattack are regulated by a signal that corresponds to the point of attack of the T6SSapparatus elaborated by a second aggressive T6SS(+) bacterial cell. PAPERFLICK:", "metadata": {}}
+{"_id": "7150238", "title": "", "text": "The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes.Fibroblastgrowth factor 21 (FGF21) is a recently discovered metabolic regulator. Exogenous FGF21 producesbeneficial metabolic effects in animal models; however, the translation of these observations to humanshas not been tested. Here, we studied the effects of LY2405319 (LY), a variant of FGF21, in arandomized, placebo-controlled, double-blind proof-of-concept trial in patients with obesity and type 2diabetes. Patients received placebo or 3, 10, or 20 mg of LY daily for 28 days. LY treatment producedsignificant improvements in dyslipidemia, including decreases in low-density lipoprotein cholesterol andtriglycerides and increases in high-density lipoprotein cholesterol and a shift to a potentially lessatherogenic apolipoprotein concentration profile. Favorable effects on body weight, fasting insulin, andadiponectin were also detected. However, only a trend toward glucose lowering was observed. Theseresults indicate that FGF21 is bioactive in humans and suggest that FGF21-based therapies may beeffective for the treatment of selected metabolic disorders.", "metadata": {}}
+{"_id": "7151961", "title": "", "text": "Visualization of recombination intermediates produced by RAD52-mediated single-strandannealing.Double-strand breaks (DSBs) occur frequently during DNA replication. They are also caused byionizing radiation, chemical damage or as part of the series of programmed events that occur duringmeiosis. In yeast, DSB repair requires RAD52, a protein that plays a critical role in homologousrecombination. Here we describe the actions of human RAD52 protein in a model system for single-strandannealing (SSA) using tailed (i.e. exonuclease resected) duplex DNA molecules. Purified human RAD52protein binds resected DSBs and promotes associations between complementary DNA termini.Heteroduplex intermediates of these recombination reactions have been visualized by electronmicroscopy, revealing the specific binding of multiple rings of RAD52 to the resected termini and theformation of large protein complexes at heteroduplex joints formed by RAD52-mediated annealing.", "metadata": {}}
+{"_id": "7155555", "title": "", "text": "Crucial Role of Interferon Consensus Sequence Binding Protein, but neither of Interferon RegulatoryFactor 1 nor of Nitric Oxide Synthesis for Protection Against Murine ListeriosisListeria monocytogenes iswidely used as a model to study immune responses against intracellular bacteria. It has been shown thatneutrophils and macrophages play an important role to restrict bacterial replication in the early phase ofprimary infection in mice, and that the cytokines interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α)are essential for protection. However, the involved signaling pathways and effector mechanisms are stillpoorly understood. This study investigated mouse strains deficient for the IFN-dependent transcriptionfactors interferon consensus sequence binding protein (ICSBP), interferon regulatory factor (IRF)1 or 2for their capacity to eliminate Listeria in vivo and in vitro and for production of inducible reactive nitrogenintermediates (RNI) or reactive oxygen intermediates (ROI) in macrophages. ICSBP−/− and to a lesserdegree also IRF2−/− mice were highly susceptible to Listeria infection. This correlated with impairedelimination of Listeria from infected peritoneal macrophage (PEM) cultures stimulated with IFN-γ in vitro;in addition these cultures showed reduced and delayed oxidative burst upon IFN-γ stimulation, whereasnitric oxide production was normal. In contrast, mice deficient for IRF1 were not able to produce nitricoxide, but they efficiently controlled Listeria in vivo and in vitro. These results indicate that (a) theICSBP/IRF2 complex is essential for IFN-γ–mediated protection against Listeria and that (b) ROI togetherwith additional still unknown effector mechanisms may be responsible for the anti-Listeria activity ofmacrophages, whereas IRF1-induced RNI are not limiting.", "metadata": {}}
+{"_id": "7157436", "title": "", "text": "Neuronal replacement from endogenous precursors in the adult brain after strokeIn the adult brain, newneurons are continuously generated in the subventricular zone and dentate gyrus, but it is unknownwhether these neurons can replace those lost following damage or disease. Here we show that stroke,caused by transient middle cerebral artery occlusion in adult rats, leads to a marked increase of cellproliferation in the subventricular zone. Stroke-generated new neurons, as well as neuroblasts probablyalready formed before the insult, migrate into the severely damaged area of the striatum, where theyexpress markers of developing and mature, striatal medium-sized spiny neurons. Thus, stroke inducesdifferentiation of new neurons into the phenotype of most of the neurons destroyed by the ischemiclesion. Here we show that the adult brain has the capacity for self-repair after insults causing extensiveneuronal death. If the new neurons are functional and their formation can be stimulated, a noveltherapeutic strategy might be developed for stroke in humans.", "metadata": {}}
+{"_id": "7165938", "title": "", "text": "Overexpression of the circadian clock gene Bmal1 increases sensitivity to oxaliplatin in colorectalcancer.PURPOSE The circadian clock gene Bmal1 is involved in cancer cell proliferation and DNA damagesensitivity. The aim of this study was to explore the effect of Bmal1 on oxaliplatin sensitivity and todetermine its clinical significance in colorectal cancer. EXPERIMENTAL DESIGN Three colorectal cancer celllines, HCT116, THC8307 and HT29, were used. The Bmal1-mediated control of colorectal cancer cellproliferation was tested in vitro and in vivo. MTT and colony formation assays were performed todetermine the sensitivity of colorectal cancer cells to oxaliplatin. Flow cytometry was used to examinechanges in the cell-cycle distribution and apoptosis rate. Proteins expressed downstream of Bmal1 uponits overexpression were determined by Western blotting. Immunohistochemistry was used to analyzeBmal1 expression in 82 archived colorectal cancer tumors from patients treated with oxaliplatin-basedregimens. RESULTS Bmal1 overexpression inhibited colorectal cancer cell proliferation and increasedcolorectal cancer sensitivity to oxaliplatin in three colorectal cancer cell lines and HCT116 cells model invivo. Furthermore, the overall survival of patients with colorectal cancer with high Bmal1 levels in theirprimary tumors was significantly longer than that of patients with low Bmal1 levels (27 vs. 19 months; P= 0.043). The progression-free survival of patients with high Bmal1 expression was also significantlylonger than that of patients with low Bmal1 expression (11 vs. 5 months; P = 0.015). Mechanistically, theeffect of Bmal1 was associated with its ability to regulate G2-M arrest by activating the ATM pathway.CONCLUSION Bmal1 shows the potential as a novel prognostic biomarker and may represent a newtherapeutic target in colorectal cancer.", "metadata": {}}
+{"_id": "7177329", "title": "", "text": "Evolution of an HIV glycan–dependent broadly neutralizing antibody epitope through immuneescapeNeutralizing antibodies are likely to play a crucial part in a preventative HIV-1 vaccine. Althoughefforts to elicit broadly cross-neutralizing (BCN) antibodies by vaccination have been unsuccessful, aminority of individuals naturally develop these antibodies after many years of infection. How suchantibodies arise, and the role of viral evolution in shaping these responses, is unknown. Here we show, intwo HIV-1–infected individuals who developed BCN antibodies targeting the glycan at Asn332 on thegp120 envelope, that this glycan was absent on the initial infecting virus. However, this BCN epitopeevolved within 6 months, through immune escape from earlier strain-specific antibodies that resulted in ashift of a glycan to position 332. Both viruses that lacked the glycan at amino acid 332 were resistant tothe Asn332-dependent BCN monoclonal antibody PGT128 (ref. 8), whereas escaped variants thatacquired this glycan were sensitive. Analysis of large sequence and neutralization data sets showed the332 glycan to be significantly under-represented in transmitted subtype C viruses compared to chronicviruses, with the absence of this glycan corresponding with resistance to PGT128. These findings highlightthe dynamic interplay between early antibodies and viral escape in driving the evolution of conservedBCN antibody epitopes.", "metadata": {}}
+{"_id": "7185591", "title": "", "text": "Sir2-Independent Life Span Extension by Calorie Restriction in YeastCalorie restriction slows aging andincreases life span in many organisms. In yeast, a mechanistic explanation has been proposed wherebycalorie restriction slows aging by activating Sir2. Here we report the identification of a Sir2-independentpathway responsible for a majority of the longevity benefit associated with calorie restriction. Deletion ofFOB1 and overexpression of SIR2 have been previously found to increase life span by reducing the levelsof toxic rDNA circles in aged mother cells. We find that combining calorie restriction with either of thesegenetic interventions dramatically enhances longevity, resulting in the longest-lived yeast strain reportedthus far. Further, calorie restriction results in a greater life span extension in cells lacking both Sir2 andFob1 than in cells where Sir2 is present. These findings indicate that Sir2 and calorie restriction act inparallel pathways to promote longevity in yeast and, perhaps, higher eukaryotes.", "metadata": {}}
+{"_id": "7198295", "title": "", "text": "The Effect of Submaximal Exercise Preceded by Single Whole-Body Cryotherapy on the Markers ofOxidative Stress and Inflammation in Blood of Volleyball PlayersThe aim of the study was to determinethe effect of single whole-body cryotherapy (WBC) session applied prior to submaximal exercise on theactivity of antioxidant enzymes, the concentration of lipid peroxidation products, total oxidative status,and the level of cytokines in blood of volleyball players. The study group consisted of 18 maleprofessional volleyball players, who were subjected to extremely cold air (-130°C) prior to exerciseperformed on cycloergometer. Blood samples were taken five times: before WBC, after WBC procedure,after exercise preceded by cryotherapy (WBC exercise), and before and after exercise without WBC(control exercise). The activity of catalase statistically significantly increased after control exercise.Moreover, the activity of catalase and superoxide dismutase was lower after WBC exercise than aftercontrol exercise (P < 0.001). After WBC exercise, the level of IL-6 and IL-1β was also lower (P < 0.001)than after control exercise. The obtained results may suggest that cryotherapy prior to exercise may havesome antioxidant and anti-inflammatory properties. The relations between the level of studied oxidativestress and inflammatory markers may testify to the contribution of reactive oxygen species in cytokinesrelease into the blood system in response to exercise and WBC.", "metadata": {}}
+{"_id": "7209559", "title": "", "text": "Incidence of childhood distal forearm fractures over 30 years: a population-based study.CONTEXT Theincidence of distal forearm fractures in children peaks around the time of the pubertal growth spurt,possibly because physical activity increases at the time of a transient deficit in cortical bone mass due tothe increased calcium demand during maximal skeletal growth. Changes in physical activity or diet maytherefore influence risk of forearm fracture. OBJECTIVE To determine whether there has been a change inthe incidence of distal forearm fractures in children in recent years. DESIGN, SETTING, AND PATIENTSPopulation-based study among Rochester, Minn, residents younger than 35 years with distal forearmfractures in 1969-1971, 1979-1981, 1989-1991, and 1999-2001. MAIN OUTCOME MEASURE Estimatedincidence of distal forearm fractures in 4 time periods. RESULTS Comparably age- and sex-adjustedannual incidence rates per 100 000 increased from 263.3 (95% confidence interval [CI], 231.1-295.4) in1969-1971 to 322.3 (95% CI, 285.3-359.4) in 1979-1981 and to 399.8 (95% CI, 361.0-438.6) in1989-1991 before leveling off at 372.9 (95% CI, 339.1-406.7) in 1999-2001. Age-adjusted incidencerates per 100 000 were 32% greater among male residents in 1999-2001 compared with 1969-1971(409.4 [95% CI, 359.9-459.0] vs 309.4 [95% CI, 259.3-359.5]; P =.01) and 56% greater among femaleresidents in the same time periods (334.3 [95% CI, 288.6-380.1] vs 214.6 [95% CI, 174.9-254.4];P<.001). The peak incidence and greatest increase occurred between ages 11 and 14 years in boys and 8and 11 years in girls. CONCLUSIONS There has been a statistically significant increase in the incidence ofdistal forearm fractures in children and adolescents, but whether this is due to changing patterns ofphysical activity, decreased bone acquisition due to poor calcium intake, or both is unclear at present.Given the large number of childhood fractures, however, studies are needed to define the cause(s) of thisincrease.", "metadata": {}}
+{"_id": "7211056", "title": "", "text": "Tolerance of whole-genome doubling propagates chromosomal instability and accelerates cancer genomeevolution.UNLABELLED The contribution of whole-genome doubling to chromosomal instability (CIN) andtumor evolution is unclear. We use long-term culture of isogenic tetraploid cells from a stable diploidcolon cancer progenitor to investigate how a genome-doubling event affects genome stability over time.Rare cells that survive genome doubling demonstrate increased tolerance to chromosome aberrations.Tetraploid cells do not exhibit increased frequencies of structural or numerical CIN per chromosome.However, the tolerant phenotype in tetraploid cells, coupled with a doubling of chromosome aberrationsper cell, allows chromosome abnormalities to evolve specifically in tetraploids, recapitulatingchromosomal changes in genomically complex colorectal tumors. Finally, a genome-doubling event isindependently predictive of poor relapse-free survival in early-stage disease in two independent cohortsin multivariate analyses [discovery data: hazard ratio (HR), 4.70, 95% confidence interval (CI),1.04-21.37; validation data: HR, 1.59, 95% CI, 1.05-2.42]. These data highlight an important role forthe tolerance of genome doubling in driving cancer genome evolution. SIGNIFICANCE Our work shedslight on the importance of whole-genome–doubling events in colorectal cancer evolution. We show thattetraploid cells undergo rapid genomic changes and recapitulate the genetic alterations seen inchromosomally unstable tumors. Furthermore, we demonstrate that a genome-doubling event isprognostic of poor relapse-free survival in this disease type.", "metadata": {}}
+{"_id": "7221410", "title": "", "text": "Alzheimer’s Disease Risk Gene CD33 Inhibits Microglial Uptake of Amyloid BetaThe transmembraneprotein CD33 is a sialic acid-binding immunoglobulin-like lectin that regulates innate immunity but has noknown functions in the brain. We have previously shown that the CD33 gene is a risk factor forAlzheimer's disease (AD). Here, we observed increased expression of CD33 in microglial cells in AD brain.The minor allele of the CD33 SNP rs3865444, which confers protection against AD, was associated withreductions in both CD33 expression and insoluble amyloid beta 42 (Aβ42) levels in AD brain.Furthermore, the numbers of CD33-immunoreactive microglia were positively correlated with insolubleAβ42 levels and plaque burden in AD brain. CD33 inhibited uptake and clearance of Aβ42 in microglial cellcultures. Finally, brain levels of insoluble Aβ42 as well as amyloid plaque burden were markedly reducedin APP(Swe)/PS1(ΔE9)/CD33(-/-) mice. Therefore, CD33 inactivation mitigates Aβ pathology and CD33inhibition could represent a novel therapy for AD.", "metadata": {}}
+{"_id": "7223604", "title": "", "text": "Aluminum fluoride stimulates surface protrusions in cells overexpressing the ARF6 GTPaseTo study theeffector function of the ADP- ribosylation factor (ARF) 6 GTP-binding protein, we transfected HeLa cellswith wild-type, epitope-tagged ARF6. Previously shown to indirectly activate the ARF1 GTPase, aluminumfluoride (AIF) treatment of ARF6-transfected cells resulted in a redistribution of both ARF6 and actin todiscrete sites on the plasma membrane, which became increasingly protrusive over time. The effects ofAIF were reversible, specific to cells transfected with wild-type ARF6, and resembled the cellularprotrusions observed in cells expressing the GTPase defective mutant of ARF6. Importantly, theprotrusions observed in cells transfected with ARF6 were distinct from the enhanced stress fibers andmembrane ruffles observed in cells transfected with RhoA and Rac1, respectively. In cells formingprotrusions, there was an apparent stimulation of macropinocytosis and membrane recycling within theprotrusive structures. In contrast, no block in transferrin uptake or alteration of the distribution ofclathrin AP-2 complexes was detected in these cells. The AIF-induced, ARF6- dependent formation ofprotrusive structures was blocked by cytochalasin D and inhibitors of the lipoxygenase pathway. Theseobservations support a novel role for the ARF6 GTPase in modeling the plasma membrane and underlyingcytoskeleton.", "metadata": {}}
+{"_id": "7224632", "title": "", "text": "A longitudinal diffusion tensor imaging study assessing white matter fiber tracts after sports-relatedconcussion.The extent of structural injury in sports-related concussion (SRC) is central to the course ofrecovery, long-term effects, and the decision to return to play. In the present longitudinal study, we useddiffusion tensor imaging (DTI) to assess white matter (WM) fiber tract integrity within 2 days, 2 weeks,and 2 months of concussive injury. Participants were right-handed male varsity contact-sport athletes(20.2±1.0 years of age) with a medically diagnosed SRC (no loss of consciousness). They were comparedto right-handed male varsity non-contact-sport athletes serving as controls (19.9±1.7 years). We foundsignificantly increased radial diffusivity (RD) in concussed athletes (n=12; paired t-test, tract-basedspatial statistics; p<0.025) at 2 days, when compared to the 2-week postinjury time point. The increasewas found in a cluster of right hemisphere voxels, spanning the posterior limb of the internal capsule(IC), the retrolenticular part of the IC, the inferior longitudinal fasciculus, the inferior fronto-occipitalfasciculus (sagittal stratum), and the anterior thalamic radiation. Post-hoc, univariate, between-group(controls vs. concussed), mixed-effects analysis of the cluster showed significantly higher RD at 2 days(p=0.002), as compared to the controls, with a trend in the same direction at 2 months (p=0.11). Resultsfor fractional anisotropy (FA) in the same cluster showed a similar, but inverted, pattern; FA wasdecreased at 2 days and at 2 months postinjury, when compared to healthy controls. At 2 weekspostinjury, no statistical differences between concussed and control athletes were found with regard toeither RD or FA. These results support the hypothesis of increased RD and reduced FA within 72 hpostinjury, followed by recovery that may extend beyond 2 weeks. RD appears to be a sensitive measureof concussive injury.", "metadata": {}}
+{"_id": "7224723", "title": "", "text": "HIV–1 Infects Multipotent Progenitor Cells Causing Cell Death and Establishing Latent CellularReservoirsHIV causes a chronic infection characterized by depletion of CD4(+) T lymphocytes and thedevelopment of opportunistic infections. Despite drugs that inhibit viral spread, HIV infection has beendifficult to cure because of uncharacterized reservoirs of infected cells that are resistant to highly activeantiretroviral therapy (HAART) and the immune response. Here we used CD34(+) cells from infectedpeople as well as in vitro studies of wild-type HIV to show infection and killing of CD34(+) multipotenthematopoietic progenitor cells (HPCs). In some HPCs, we detected latent infection that stably persisted incell culture until viral gene expression was activated by differentiation factors. A unique reporter HIV thatdirectly detects latently infected cells in vitro confirmed the presence of distinct populations of active andlatently infected HPCs. These findings have major implications for understanding HIV bone marrowpathology and the mechanisms by which HIV causes persistent infection.", "metadata": {}}
+{"_id": "7225911", "title": "", "text": "The human long non-coding RNA-RoR is a p53 repressor in response to DNA damageIt is well known thatupon stress, the level of the tumor suppressor p53 is remarkably elevated. However, despite extensivestudies, the underlying mechanism involving important inter-players for stress-induced p53 regulation isstill not fully understood. We present evidence that the human lincRNA-RoR (RoR) is a strong negativeregulator of p53. Unlike MDM2 that causes p53 degradation through the ubiquitin-proteasome pathway,RoR suppresses p53 translation through direct interaction with the heterogeneous nuclearribonucleoprotein I (hnRNP I). Importantly, a 28-base RoR sequence carrying hnRNP I binding motifs isessential and sufficient for p53 repression. We further show that RoR inhibits p53-mediated cell cyclearrest and apoptosis. Finally, we demonstrate a RoR-p53 autoregulatory feedback loop where p53transcriptionally induces RoR expression. Together, these results suggest that the RoR-hnRNP I-p53 axismay constitute an additional surveillance network for the cell to better respond to various stresses.", "metadata": {}}
+{"_id": "7227763", "title": "", "text": "Experimental and clinical studies on lactate and pyruvate as indicators of the severity of acute circulatoryfailure (shock).The increase in lactate (L) and pyruvate (P) content of arterial blood during experimentaland clinical shock states and the extent to which such increases serve as measures of oxygen deficit andirreversible injury were investigated on an empirical basis. A standardized method for production ofhemorrhagic shock in the Wistar rat was employed. During a 4-hour bleeding period, oxygenconsumption of the rat was reduced to approximately 40% of control value, pH was reduced from 7.39 to7.08, and a concurrent increase in L from 0.80 to 6.06 mm and in P from 0.07 to 0.18 mm wereobserved. Cumulative oxygen debt correlated with log L (r = 0.50; P < 0.0005) and both weresignificantly related to survival. Correlation of cumulative oxygen debt and survival, both with P and withcomputed values of the lactate pyruvate ratio (L/P) and excess lactate (XL), were of no highermagnitude. Partial correlation analysis demonstrated that neither the measurement of P nor thecomputation of L/P or XL improved predictability...", "metadata": {}}
+{"_id": "7228140", "title": "", "text": "Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductaladenocarcinomaPancreatic ductal adenocarcinoma (PDAC) remains a lethal disease with a 5-year survivalrate of 4%. A key hallmark of PDAC is extensive stromal involvement, which makes capturing precisetumor-specific molecular information difficult. Here we have overcome this problem by applying blindsource separation to a diverse collection of PDAC gene expression microarray data, including data fromprimary tumor, metastatic and normal samples. By digitally separating tumor, stromal and normal geneexpression, we have identified and validated two tumor subtypes, including a 'basal-like' subtype that hasworse outcome and is molecularly similar to basal tumors in bladder and breast cancers. Furthermore, wedefine 'normal' and 'activated' stromal subtypes, which are independently prognostic. Our results providenew insights into the molecular composition of PDAC, which may be used to tailor therapies or providedecision support in a clinical setting where the choice and timing of therapies are critical.", "metadata": {}}
+{"_id": "7230315", "title": "", "text": "Inducible nitric oxide synthase in pulmonary alveolar macrophages from patients with tuberculosisThehigh-output pathway of nitric oxide production helps protect mice from infection by several pathogens,including Mycobacterium tuberculosis. However, based on studies of cells cultured from blood, it iscontroversial whether human mononuclear phagocytes can express the corresponding inducible nitricoxide synthase (iNOS;NOS2). The present study examined alveolar macrophages fixed directly afterbronchopulmonary lavage. An average of 65% of the macrophages from 11 of 11 patients with untreated,culture-positive pulmonary tuberculosis reacted with an antibody documented herein to be monospecificfor human NOS2. In contrast, a mean of 10% of bronchoalveolar lavage cells were positive from each offive clinically normal subjects. Tuberculosis patients' macrophages displayed diaphorase activity in thesame proportion that they stained for NOS2, under assay conditions wherein the diaphorase reaction wasstrictly dependent on NOS2 expression. Bronchoalveolar lavage specimens also contained NOS2 mRNA.Thus, macrophages in the lungs of people with clinically active Mycobacterium tuberculosis infection oftenexpress catalytically competent NOS2.", "metadata": {}}
+{"_id": "7239105", "title": "", "text": "The use of mouse models to understand and improve cognitive deficits in Down syndromeRemarkableadvances have been made in recent years towards therapeutics for cognitive impairment in individualswith Down syndrome (DS) by using mouse models. In this review, we briefly describe the phenotypes ofmouse models that represent outcome targets for drug testing, the behavioral tests used to assessimpairments in cognition and the known mechanisms of action of several drugs that are being used inpreclinical studies or are likely to be tested in clinical trials. Overlaps in the distribution of targets and inthe pathways that are affected by these diverse drugs in the trisomic brain suggest new avenues for DSresearch and drug development.", "metadata": {}}
+{"_id": "7260461", "title": "", "text": "position-specific gap penaltiesThe sensitivity of the commonly used progressive multiple sequencealignment method has been greatly improved for the alignment of divergent protein sequences. Firstly,individual weights are assigned to each sequence in a partial alignment in order to down-weightnear-duplicate sequences and up-weight the most divergent ones. Secondly, amino acid substitutionmatrices are varied at different alignment stages according to the divergence of the sequences to bealigned. Thirdly, residue-specific gap penalties and locally reduced gap penalties in hydrophilic regionsencourage new gaps in potential loop regions rather than regular secondary structure. Fourthly, positionsin early alignments where gaps have been opened receive locally reduced gap penalties to encourage theopening up of new gaps at these positions. These modifications are incorporated into a new program,CLUSTAL W which is freely available.", "metadata": {}}
+{"_id": "7261402", "title": "", "text": "Pedestrian Detection via Periodic Motion AnalysisWe describe algorithms for detecting pedestrians invideos acquired by infrared (and color) sensors. Two approaches are proposed based on gait. The firstemploys computationally efficient periodicity measurements. Unlike other methods, it estimates aperiodic motion frequency using two cascading hypothesis testing steps to filter out non-cyclic pixels sothat it works well for both radial and lateral walking directions. The extraction of the period is efficientand robust with respect to sensor noise and cluttered background. In order to integrate shape andmotion, we convert the cyclic pattern into a binary sequence by Maximal Principal Gait Angle (MPGA)fitting in the second method. It does not require alignment and continuously estimates the period using aPhase-locked Loop. Both methods are evaluated by experimental results that measure performance as afunction of size, movement direction, frame rate and sequence length.", "metadata": {}}
+{"_id": "7264949", "title": "", "text": "Seroepidemiological survey of feline retrovirus infections in cats in Taiwan in 1993 and 1994.In order toinvestigate the prevalence of infections with three feline retroviruses feline immunodeficiency virus (FIV),feline leukemia virus (FeLV) and feline syncytial virus (FSV) in Taiwan, we collected a total of 75 bloodsamples from cats from veterinary hospitals, a breeding cattery and a homeless shelter in 1993 and1994. We examined the presences of anti-FIV and FSV antibodies and FeLV-p27 antigen in these samplesby the indirect immunofluorescence and/or enzyme-linked immunosorbent assays. All of the serumsamples positive for FIV were obtained from homeless cats and the overall FIV positive rate was 4%. Theoverall positive rates of FSV and FeLV were 28% and 1.3%, respectively. From these results, togetherwith previous seroepidemiological surveys by others, it was revealed that the prevalence of FIV and FeLVinfections appeared to be lower in Taiwan than in the United States or Japan. In contrast, the prevalenceof FSV infection in Taiwan was as high as that in Japan.", "metadata": {}}
+{"_id": "7268522", "title": "", "text": "Notch targets and their regulation.The proteolytic cleavages elicited by activation of the Notch receptorrelease an intracellular fragment, Notch intracellular domain, which enters the nucleus to activate thetranscription of targets. Changes in transcription are therefore a major output of this pathway. However,the Notch outputs clearly differ from cell type to cell type. In this review we discuss currentunderstanding of Notch targets, the mechanisms involved in their transcriptional regulation, and whatmight underlie the activation of different sets of targets in different cell types.", "metadata": {}}
+{"_id": "7277084", "title": "", "text": "Extraction and Analysis of Multiple Periodic Motions in Video SequencesThe analysis of periodic orrepetitive motions is useful in many applications, such as the recognition and classification of human andanimal activities. Existing methods for the analysis of periodic motions first extract motion trajectoriesusing spatial information and then determine if they are periodic. These approaches are mostly based onfeature matching or spatial correlation, which are often infeasible, unreliable, or computationallydemanding. In this paper, we present a new approach, based on the time- frequency analysis of thevideo sequence as a whole. Multiple periodic trajectories are extracted and their periods are estimatedsimultaneously. The objects that are moving in a periodic manner are extracted using the spatial domaininformation. Experiments with synthetic and real sequences display the capabilities of this approach.", "metadata": {}}
+{"_id": "7281161", "title": "", "text": "MicroRNA-21 is up-regulated in allergic airway inflammation and regulates IL-12p35 expression.Allergicairway inflammation is characterized by marked in situ changes in gene and protein expression, yet therole of microRNAs (miRNAs), a new family of key mRNA regulatory molecules, in this process has not yetbeen reported. Using a highly sensitive microarray-based approach, we identified 21 miRNAs withdifferential expression between doxycycline-induced lung-specific IL-13 transgenic mice (with allergicairway inflammation) and control mice. In particular, we observed overexpression of miR-21 andunderexpression of miR-1 in the induced IL-13 transgenic mice compared with control mice. Thesefindings were validated in two independent models of allergen-induced allergic airway inflammation andin IL-4 lung transgenic mice. Although IL-13-induced miR-21 expression was IL-13Ralpha1 dependent,allergen-induced miR-21 expression was mediated mainly independent of IL-13Ralpha1 and STAT6.Notably, predictive algorithms identified potential direct miR-21 targets among IL-13-regulated lungtranscripts, such as IL-12p35 mRNA, which was decreased in IL-13 transgenic mice. Introduction ofpre-miR-21 dose dependently inhibited cellular expression of a reporter vector harboring the3'-untranslated region of IL-12p35. Moreover, mutating miR-21 binding sites in IL-12p35 3'-untranslatedregion abrogated miR-21-mediated repression. In summary, we have identified a miRNA signature inallergic airway inflammation, which includes miR-21 that modulates IL-12, a molecule germane to Th cellpolarization.", "metadata": {}}
+{"_id": "7285256", "title": "", "text": "COPD: epidemiology, prevalence, morbidity and mortality, and disease heterogeneity.COPD continues tocause a heavy health and economic burden both in the United States and around the world. Some of therisk factors for COPD are well-known and include smoking, occupational exposures, air pollution, airwayhyperresponsiveness, asthma, and certain genetic variations, although many questions, such as why <20% of smokers develop significant airway obstruction, remain. Precise definitions of COPD vary and arefrequently dependent on an accurate diagnosis of the problem by a physician. These differences in thedefinition of COPD can have large effects on the estimates of COPD in the population. Furthermore,evidence that COPD represents several different disease processes with potentially different interventionscontinues to emerge. In most of the world, COPD prevalence and mortality are still increasing and likelywill continue to rise in response to increases in smoking, particularly by women and adolescents.Resources aimed at smoking cessation and prevention, COPD education and early detection, and bettertreatment will be of the most benefit in our continuing efforts against this important cause of morbidityand mortality.", "metadata": {}}
+{"_id": "7299977", "title": "", "text": "Changing geographic ranges of ticks and tick-borne pathogens: drivers, mechanisms and consequencesfor pathogen diversityThe geographic ranges of ticks and tick-borne pathogens are changing due to globaland local environmental (including climatic) changes. In this review we explore current knowledge of thedrivers for changes in the ranges of ticks and tick-borne pathogen species and strains via effects on theirbasic reproduction number (R 0), and the mechanisms of dispersal that allow ticks and tick-bornepathogens to invade suitable environments. Using the expanding geographic distribution of the vectorsand agent of Lyme disease as an example we then investigate what could be expected of the diversity oftick-borne pathogens during the process of range expansion, and compare this with what is currentlybeing observed. Lastly we explore how historic population and range expansions and contractions couldbe reflected in the phylogeography of ticks and tick-borne pathogens seen in recent years, and concludethat combined study of currently changing tick and tick-borne pathogen ranges and diversity, withphylogeographic analysis, may help us better predict future patterns of invasion and diversity.", "metadata": {}}
+{"_id": "7317051", "title": "", "text": "Mutant KRAS is a druggable target for pancreatic cancer.Pancreatic ductal adenocarcinoma (PDA)represents an unmet therapeutic challenge. PDA is addicted to the activity of the mutated KRASoncogene which is considered so far an undruggable therapeutic target. We propose an approach totarget KRAS effectively in patients using RNA interference. To meet this challenge, we have developed alocal prolonged siRNA delivery system (Local Drug EluteR, LODER) shedding siRNA against the mutatedKRAS (siG12D LODER). The siG12D LODER was assessed for its structural, release, and deliveryproperties in vitro and in vivo. The effect of the siG12D LODER on tumor growth was assessed in s.c. andorthotopic mouse models. KRAS silencing effect was further assessed on the KRAS downstream signalingpathway. The LODER-encapsulated siRNA was stable and active in vivo for 155 d. Treatment of PDA cellswith siG12D LODER resulted in a significant decrease in KRAS levels, leading to inhibition of proliferationand epithelial-mesenchymal transition. In vivo, siG12D LODER impeded the growth of human pancreatictumor cells and prolonged mouse survival. We report a reproducible and safe delivery platform based ona miniature biodegradable polymeric matrix, for the controlled and prolonged delivery of siRNA. Thistechnology provides the following advantages: (i) siRNA is protected from degradation; (ii) the siRNA isslowly released locally within the tumor for prolonged periods; and (iii) the siG12D LODER elicits atherapeutic effect, thereby demonstrating that mutated KRAS is indeed a druggable target.", "metadata": {}}
+{"_id": "7324039", "title": "", "text": "Trimmomatic: a flexible trimmer for Illumina sequence dataMOTIVATION Although many next-generationsequencing (NGS) read preprocessing tools already existed, we could not find any tool or combination oftools that met our requirements in terms of flexibility, correct handling of paired-end data and highperformance. We have developed Trimmomatic as a more flexible and efficient preprocessing tool, whichcould correctly handle paired-end data. RESULTS The value of NGS read preprocessing is demonstratedfor both reference-based and reference-free tasks. Trimmomatic is shown to produce output that is atleast competitive with, and in many cases superior to, that produced by other tools, in all scenariostested. AVAILABILITY AND IMPLEMENTATION Trimmomatic is licensed under GPL V3. It is cross-platform(Java 1.5+ required) and available athttp://www.usadellab.org/cms/index.php?page=trimmomatic   CONTACTusadel@bio1.rwth-aachen.de   SUPPLEMENTARY INFORMATION Supplementary data are available atBioinformatics online.", "metadata": {}}
+{"_id": "7343711", "title": "", "text": "Basics of PD-1 in self-tolerance, infection, and cancer immunitySuccessful cancer treatment requiresunderstanding host immune response against tumor cells. PD-1 belongs to the CD28 superfamily ofreceptors that work as “checkpoints” of immune activation. PD-1 maintains immune self-tolerance toprevent autoimmunity and controls T-cell reaction during infection to prevent excessive tissue damage.Tumor cells that arise from normal tissue acquire mutations that can be targeted by lymphocytes.Accumulating lines of evidence suggest that tumor cells evade host immune attack by expressingphysiological PD-1 ligands and stimulating PD-1 on the lymphocytes. Based on this idea, researchershave successfully demonstrated that systemic administration of monoclonal antibodies that inhibit thebinding of PD-1 to the ligands reactivated T cells and augmented the anti-cancer immune response. Inthis review, I summarize the basics of T-cell biology and its regulation by PD-1 and discuss the currentunderstanding and questions about this multifaceted molecule.", "metadata": {}}
+{"_id": "7357135", "title": "", "text": "Dissociation of β1- and β2-adrenergic receptor subtypes in the retrieval of cocaine-associatedmemory.Drug seeking is maintained by encounters with drug-associated cues, and disrupting retrieval ofthese drug-cue associations would reduce the risk of relapse. Retrieval of cocaine-associated memories isdependent on β-adrenergic receptor (β-AR) activation, and blockade of these receptors induces apersistent retrieval deficit. Whether retrieval of cocaine-associated memory is mediated by a specificβ-AR subtype, however, remains unclear. Using a cocaine conditioned place preference (CPP) procedure,we examined whether retrieval of a cocaine CPP memory is mediated collectively by β1- and β2-ARs, orby one of these β-AR subtypes alone. We show that co-blockade of β1- and β2-ARs abolished CPPexpression on that and subsequent drug-free CPP tests, resulting in a long-lasting retrieval deficit thatprevented subsequent cocaine-induced reinstatement. To dissociate the necessity of either β1- or β2-ARsalone, we administered subtype-specific antagonists prior to retrieval. Administration of a β1-ARantagonist before the initial CPP trial dose-dependently reduced expression of a CPP on that andsubsequent drug-free trials as compared to vehicle administration. In contrast, administration of a β2-ARantagonist had no effect on initial CPP expression, although the highest dose reduced subsequent CPPexpression. Importantly, either β1- or β2-AR blockade prior to an initial retrieval trial preventedsubsequent cocaine-induced reinstatement. Our findings indicate that the β1-AR subtype mediatesretrieval of a cocaine CPP, and that acutely blocking either β1- or β2-ARs can prevent subsequentcocaine-induced reinstatement. Thus, β-AR antagonists, particularly β1-ARs antagonists, could serve asadjuncts for addiction therapies to prevent retrieval of drug-associated memories and provide protectionagainst relapse.", "metadata": {}}
+{"_id": "7370282", "title": "", "text": "Podoplanin-Rich Stromal Networks Induce Dendritic Cell Motility via Activation of the C-type LectinReceptor CLEC-2To initiate adaptive immunity, dendritic cells (DCs) move from parenchymal tissues tolymphoid organs by migrating along stromal scaffolds that display the glycoprotein podoplanin (PDPN).PDPN is expressed by lymphatic endothelial and fibroblastic reticular cells and promotes blood-lymphseparation during development by activating the C-type lectin receptor, CLEC-2, on platelets. Here, wedescribe a role for CLEC-2 in the morphodynamic behavior and motility of DCs. CLEC-2 deficiency in DCsimpaired their entry into lymphatics and trafficking to and within lymph nodes, thereby reducing T cellpriming. CLEC-2 engagement of PDPN was necessary for DCs to spread and migrate along stromalsurfaces and sufficient to induce membrane protrusions. CLEC-2 activation triggered cell spreading viadownregulation of RhoA activity and myosin light-chain phosphorylation and triggered F-actin-richprotrusions via Vav signaling and Rac1 activation. Thus, activation of CLEC-2 by PDPN rearranges theactin cytoskeleton in DCs to promote efficient motility along stromal surfaces.", "metadata": {}}
+{"_id": "7373120", "title": "", "text": "The Public Health Responsibility Deal: brokering a deal for public health, but on whoseterms?UNLABELLED Coalitions of multinational food and drink businesses have pledged to reformulatetheir products and to market them responsibly. Largely business-led and self-regulated, the integrity ofthese voluntary initiatives has been questioned. The Public Health Responsibility Deal in England is anexample of a voluntary initiative that is government-led. Does this approach provide evidence that withpublic leadership there is potential for voluntary actions to deliver meaningful results for public health?METHODS The subject of the research is the calorie reduction initiative of the Responsibility Deal. Sourcematerial was obtained primarily through a series of UK Freedom of Information requests and comprisespreviously unpublished Department of Health documentation relating to relevant meetings held during2011 and 2012. RESULTS The Responsibility Deal approach to calorie reduction deliberately involves thefood industry in the specification of the measures it is to implement (reformulation and portion control).Finding the common ground between private and public interests has resulted in the deflection of publichealth objectives and the preclusion of adequate monitoring and evaluation. CONCLUSIONS TheResponsibility Deal approach is fundamentally flawed in its expectation that industry will take voluntaryactions that prioritise public health interests above its own. Being government-led counts for little in theabsence of sanctions to drive compliance. Instead the initiative affords private interests the opportunityto influence in their favour the public health policies and strategies that affect their products.", "metadata": {}}
+{"_id": "7373453", "title": "", "text": "Role of endothelial shear stress in the natural history of coronary atherosclerosis and vascularremodeling: molecular, cellular, and vascular behavior.Although the entire coronary tree is exposed tothe atherogenic effect of the systemic risk factors, atherosclerotic lesions form at specific arterial regions,where low and oscillatory endothelial shear stress (ESS) occur. Low ESS modulates endothelial geneexpression through complex mechanoreception and mechanotransduction processes, inducing anatherogenic endothelial phenotype and formation of an early atherosclerotic plaque. Each early plaqueexhibits an individual natural history of progression, regression, or stabilization, which is dependent notonly on the formation and progression of atherosclerosis but also on the vascular remodeling response.Although the pathophysiologic mechanisms involved in the remodeling of the atherosclerotic wall areincompletely understood, the dynamic interplay between local hemodynamic milieu, low ESS inparticular, and the biology of the wall is likely to be important. In this review, we explore the molecular,cellular, and vascular processes supporting the role of low ESS in the natural history of coronaryatherosclerosis and vascular remodeling and indicate likely mechanisms concerning the different naturalhistory trajectories of individual coronary lesions. Atherosclerotic plaques associated with excessiveexpansive remodeling evolve to high-risk plaques, because low ESS conditions persist, thereby promotingcontinued local lipid accumulation, inflammation, oxidative stress, matrix breakdown, and eventuallyfurther plaque progression and excessive expansive remodeling. An enhanced understanding of thepathobiologic processes responsible for atherosclerosis and vascular remodeling might allow for earlyidentification of a high-risk coronary plaque and thereby provide a rationale for innovative diagnosticand/or therapeutic strategies for the management of coronary patients and prevention of acute coronarysyndromes.", "metadata": {}}
+{"_id": "7386360", "title": "", "text": "Schistosoma mansoni worms induce anergy of T cells via selective up-regulation of programmed deathligand 1 on macrophages.Infectious pathogens can selectively stimulate activation or suppression of Tcells to facilitate their survival within humans. In this study we demonstrate that the trematode parasiteSchistosoma mansoni has evolved with two distinct mechanisms to suppress T cell activation. During theinitial 4- to 12-wk acute stages of a worm infection both CD4(+) and CD8(+) T cells are anergized. Incontrast, infection with male and female worms induced T cell anergy at 4 wk, which was replaced afteregg laying by T cell suppression via a known NO-dependent mechanism, that was detected for up to 40wk after infection. Worm-induced anergy was mediated by splenic F4/80(+) macrophages (Mphi) via anIL-4-, IL-13-, IL-10-, TGF-beta-, and NO-independent, but cell contact-dependent, mechanism. F4/80(+)Mphi isolated from worm-infected mice were shown to induce anergy of naive T cells in vitro.Furthermore, naive Mphi exposed to live worms in vitro also induced anergy in naive T cells. Flowcytometry on in vivo and in vitro worm-modulated Mphi revealed that of the family of B7 costimulatorymolecules, only programmed death ligand 1 (PD-L1) was selectively up-regulated. The addition ofinhibitory mAb against PD-L1, but not PD-L2, to worm-modulated Mphi completely blocked the ability ofthese cells to anergize T cells. These data highlight a novel mechanism through which S. mansoni wormshave usurped the natural function of PD-L1 to reduce T cell activation during early acute stages ofinfection before the subsequent emergence of egg-induced T cell suppression in the chronic stages ofinfection.", "metadata": {}}
+{"_id": "7396492", "title": "", "text": "Thawing Frozen Robust Multi-array Analysis (fRMA)BACKGROUND A novel method of microarraypreprocessing--Frozen Robust Multi-array Analysis (fRMA)--has recently been developed. This algorithmallows the user to preprocess arrays individually while retaining the advantages of multi-arraypreprocessing methods. The frozen parameter estimates required by this algorithm are generated using alarge database of publicly available arrays. Curation of such a database and creation of the frozenparameter estimates is time-consuming; therefore, fRMA has only been implemented on the most widelyused Affymetrix platforms. RESULTS We present an R package, frmaTools, that allows the user to quicklycreate his or her own frozen parameter vectors. We describe how this package fits into a preprocessingworkflow and explore the size of the training dataset needed to generate reliable frozen parameterestimates. This is followed by a discussion of specific situations in which one might wish to create one'sown fRMA implementation. For a few specific scenarios, we demonstrate that fRMA performs well evenwhen a large database of arrays in unavailable. CONCLUSIONS By allowing the user to easily create his orher own fRMA implementation, the frmaTools package greatly increases the applicability of the fRMAalgorithm. The frmaTools package is freely available as part of the Bioconductor project.", "metadata": {}}
+{"_id": "7399084", "title": "", "text": "Transcriptional repressor Blimp-1 is essential for T cell homeostasis and self-toleranceT cell homeostasisis crucial for a functional immune system, as the accumulation of T cells resulting from lack of regulatoryT cells or an inability to shut down immune responses can lead to inflammation and autoimmunepathology. Here we show that Blimp-1, a transcriptional repressor that is a 'master regulator' of terminalB cell differentiation, was expressed in a subset of antigen-experienced CD4+ and CD8+ T cells. Micereconstituted with fetal liver stem cells expressing a mutant Blimp-1 lacking the DNA-binding domaindeveloped a lethal multiorgan inflammatory disease caused by an accumulation of effector and memory Tcells. These data identify Blimp-1 as an essential regulator of T cell homeostasis and suggest that Blimp-1regulates both B cell and T cell differentiation.", "metadata": {}}
+{"_id": "7416873", "title": "", "text": "Nuclear repositioning of the VSG promoter during developmental silencing in TrypanosomabruceiInterphase nuclear repositioning of chromosomes has been implicated in the epigenetic regulationof RNA polymerase (pol) II transcription. However, little is known about the nuclear position–dependentregulation of RNA pol I–transcribed loci. Trypanosoma brucei is an excellent model system to address thisquestion because its two main surface protein genes, procyclin and variant surface glycoprotein (VSG),are transcribed by pol I and undergo distinct transcriptional activation or downregulation events duringdevelopmental differentiation. Although the monoallelically expressed VSG locus is exclusively localized toan extranucleolar body in the bloodstream form, in this study, we report that nonmutually exclusiveprocyclin genes are located at the nucleolar periphery. Interestingly, ribosomal DNA loci and pol Itranscription activity are restricted to similar perinucleolar positions. Upon developmental transcriptionaldownregulation, however, the active VSG promoter selectively undergoes a rapid and dramaticrepositioning to the nuclear envelope. Subsequently, the VSG promoter region was subjected tochromatin condensation. We propose a model whereby the VSG expression site pol I promoter isselectively targeted by temporal nuclear repositioning during developmental silencing.", "metadata": {}}
+{"_id": "7419612", "title": "", "text": "An administrative claims measure suitable for profiling hospital performance on the basis of 30-dayall-cause readmission rates among patients with heart failure.BACKGROUND Readmission soon afterhospital discharge is an expensive and often preventable event for patients with heart failure. We presenta model approved by the National Quality Forum for the purpose of public reporting of hospital-levelreadmission rates by the Centers for Medicare & Medicaid Services. METHODS AND RESULTS Wedeveloped a hierarchical logistic regression model to calculate hospital risk-standardized 30-day all-causereadmission rates for patients hospitalized with heart failure. The model was derived with the use ofMedicare claims data for a 2004 cohort and validated with the use of claims and medical record data. Theunadjusted readmission rate was 23.6%. The final model included 37 variables, had discriminationranging from 15% observed 30-day readmission rate in the lowest predictive decile to 37% in the upperdecile, and had a c statistic of 0.60. The 25th and 75th percentiles of the risk-standardized readmissionrates across 4669 hospitals were 23.1% and 24.0%, with 5th and 95th percentiles of 22.2% and 25.1%,respectively. The odds of all-cause readmission for a hospital 1 standard deviation above average was1.30 times that of a hospital 1 standard deviation below average. State-level adjusted readmission ratesdeveloped with the use of the claims model are similar to rates produced for the same cohort with the useof a medical record model (correlation, 0.97; median difference, 0.06 percentage points). CONCLUSIONSThis claims-based model of hospital risk-standardized readmission rates for heart failure patientsproduces estimates that may serve as surrogates for those derived from a medical record model.", "metadata": {}}
+{"_id": "7421677", "title": "", "text": "Queueing up for enzymatic processing: correlated signaling through coupled degradationHigh-throughputtechnologies have led to the generation of complex wiring diagrams as a post-sequencing paradigm fordepicting the interactions between vast and diverse cellular species. While these diagrams are useful foranalyzing biological systems on a large scale, a detailed understanding of the molecular mechanisms thatunderlie the observed network connections is critical for the further development of systems andsynthetic biology. Here, we use queueing theory to investigate how 'waiting lines' can lead to correlationsbetween protein 'customers' that are coupled solely through a downstream set of enzymatic 'servers'.Using the E. coli ClpXP degradation machine as a model processing system, we observe significantcross-talk between two networks that are indirectly coupled through a common set of processors. Wefurther illustrate the implications of enzymatic queueing using a synthetic biology application, in whichtwo independent synthetic networks demonstrate synchronized behavior when common ClpXP machineryis overburdened. Our results demonstrate that such post-translational processes can lead to dynamicconnections in cellular networks and may provide a mechanistic understanding of existing but currentlyinexplicable links.", "metadata": {}}
+{"_id": "7426741", "title": "", "text": "The histone demethylases Jhdm1a/1b enhance somatic cell reprogramming in a vitamin-C-dependentmanner.Reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) resets the epigenometo an embryonic-like state. Vitamin C enhances the reprogramming process, but the underlyingmechanisms are unclear. Here we show that the histone demethylases Jhdm1a/1b are key effectors ofsomatic cell reprogramming downstream of vitamin C. We first observed that vitamin C inducesH3K36me2/3 demethylation in mouse embryonic fibroblasts in culture and during reprogramming. Wethen identified Jhdm1a/1b, two known vitamin-C-dependent H3K36 demethylases, as potent regulatorsof reprogramming through gain- and loss-of-function approaches. Furthermore, we found that Jhdm1baccelerates cell cycle progression and suppresses cell senescence during reprogramming by repressingthe Ink4/Arf locus. Jhdm1b also cooperates with Oct4 to activate the microRNA cluster 302/367, anintegral component of the pluripotency machinery. Our results therefore reveal a role for H3K36me2/3 incell fate determination and establish a link between histone demethylases and vitamin-C-inducedreprogramming.", "metadata": {}}
+{"_id": "7433668", "title": "", "text": "Preexisting helminth infection induces inhibition of innate pulmonary anti-tuberculosis defense byengaging the IL-4 receptor pathwayTuberculosis and helminthic infections coexist in many parts of theworld, yet the impact of helminth-elicited Th2 responses on the ability of the host to controlMycobacterium tuberculosis (Mtb) infection has not been fully explored. We show that mice infected withthe intestinal helminth Nippostrongylus brasiliensis (Nb) exhibit a transitory impairment of resistance toairborne Mtb infection. Furthermore, a second dose of Nb infection substantially increases the bacterialburden in the lungs of co-infected mice. Interestingly, the Th2 response in the co-infected animals did notimpair the onset and development of the protective Mtb-specific Th1 cellular immune responses.However, the helminth-induced Th2 environment resulted in the accumulation of alternatively activatedmacrophages (AAMs) in the lung. Co-infected mice lacking interleukin (IL) 4Rα exhibited improved abilityto control Mtb infection, which was accompanied by significantly reduced accumulation of AAMs.Moreover, IL-4Rα(-/-) mice adoptively transferred with wild-type macrophages had a significantly higherMtb load in their lungs compared with those that received IL-4Rα(-/-) macrophages, suggesting a directcontribution for the IL-4R pathway to the heightened susceptibility of co-infected animals. The Th2response can thus enhance the intracellular persistence of Mtb, in part by mediating the alternativeactivation of macrophages via the IL-4Rα signaling pathway.", "metadata": {}}
+{"_id": "7438803", "title": "", "text": "Archaea in biogeochemical cycles.Archaea constitute a considerable fraction of the microbial biomass onEarth. Like Bacteria they have evolved a variety of energy metabolisms using organic and/or inorganicelectron donors and acceptors, and many of them are able to fix carbon from inorganic sources. Archaeathus play crucial roles in the Earth's global geochemical cycles and influence greenhouse gas emissions.Methanogenesis and anaerobic methane oxidation are important steps in the carbon cycle; both areperformed exclusively by anaerobic archaea. Oxidation of ammonia to nitrite is performed byThaumarchaeota. They represent the only archaeal group that resides in large numbers in the globalaerobic terrestrial and marine environments on Earth. Sulfur-dependent archaea are confined mostly tohot environments, but metal leaching by acidophiles and reduction of sulfate by anaerobic,nonthermophilic methane oxidizers have a potential impact on the environment. The metabolisms of alarge number of archaea, in particular those dominating the subsurface, remain to be explored.", "metadata": {}}
+{"_id": "7447120", "title": "", "text": "Novel proteinaceous infectious particles cause scrapie.After infection and a prolonged incubation period,the scrapie agent causes a degenerative disease of the central nervous system in sheep and goats. Sixlines of evidence including sensitivity to proteases demonstrate that this agent contains a protein that isrequired for infectivity. Although the scrapie agent is irreversibly inactivated by alkali, five procedureswith more specificity for modifying nucleic acids failed to cause inactivation. The agent showsheterogeneity with respect to size, apparently a result of its hydrophobicity; the smallest form may havea molecular weight of 50,000 or less. Because the novel properties of the scrapie agent distinguish it fromviruses, plasmids, and viroids, a new term \"prion\" is proposed to denote a small proteinaceous infectiousparticle which is resistant to inactivation by most procedures that modify nucleic acids. Knowledge of thescrapie agent structure may have significance for understanding the causes of several degenerativediseases.", "metadata": {}}
+{"_id": "7451018", "title": "", "text": "Viral Carcinogenesis.Cancer has been recognized for thousands of years. Egyptians believed that canceroccurred at the will of the gods. Hippocrates believed human disease resulted from an imbalance of thefour humors: blood, phlegm, yellow bile, and black bile with cancer being caused by excess black bile.The lymph theory of cancer replaced the humoral theory and the blastema theory replaced the lymphtheory. Rudolph Virchow was the first to recognize that cancer cells like all cells came from other cellsand believed chronic irritation caused cancer. At the same time there was a belief that trauma causedcancer, though it never evolved after many experiments inducing trauma. The birth of virology occurredin 1892 when Dimitri Ivanofsky demonstrated that diseased tobacco plants remained infective afterfiltering their sap through a filter that trapped bacteria. Martinus Beijerinck would call the tiny infectiveagent a virus and both Dimitri Ivanofsky and Marinus Beijerinck would become the fathers of virology.Not to long thereafter, Payton Rous founded the field of tumor virology in 1911 with his discovery of atransmittable sarcoma of chickens by what would come to be called Rous sarcoma virus or RSV for short.The first identified human tumor virus was the Epstein-Barr virus (EBV), named after Tony Epstein andYvonne Barr who visualized the virus particles in Burkitt's lymphoma cells by electron microscopy in1965. Since that time, many viruses have been associated with carcinogenesis including the moststudied, human papilloma virus associated with cervical carcinoma, many other anogenital carcinomas,and oropharyngeal carcinoma. The World Health Organization currently estimates that approximately22% of worldwide cancers are attributable to infectious etiologies, of which viral etiologies is estimated at15-20%. The field of tumor virology/viral carcinogenesis has not only identified viruses as etiologicagents of human cancers, but has also given molecular insights to all human cancers including theoncogene activation and tumor suppressor gene inactivation.", "metadata": {}}
+{"_id": "7451607", "title": "", "text": "Monitoring spatiotemporal biogenesis of macromolecular assemblies by pulse-chase epitopelabeling.Many cellular proteins perform their roles within macromolecular assemblies. Hence, anunderstanding of how these multiprotein complexes form is a fundamental question in cell biology. Wedeveloped a translation-controlled pulse-chase system that allows time-resolved isolation of newlyforming multiprotein complexes in chemical quantities suitable for biochemical and cell biological analysis.The \"pulse\" is triggered by an unnatural amino acid, which induces immediate translation of an amberstop codon repressed mRNA encoding the protein of interest with a built-in tag for detection andpurification. The \"chase\" is elicited by stopping translation of this bait via a riboswitch in the respectivemRNA. Over the course of validating our method, we discovered a distinct time-resolved assembly stepduring NPC biogenesis and could directly monitor the spatiotemporal maturation of preribosomes viaimmunofluorescence detection and purification of a pulse-labeled ribosomal protein. Thus, we provide aninnovative strategy to study dynamic protein assembly within cellular networks.", "metadata": {}}
+{"_id": "7454794", "title": "", "text": "Statins in the primary prevention of cardiovascular diseaseStatins are widely used in the evidence-basedlowering of cardiovascular disease (CVD) risk. The use of these drugs for secondary prevention of CVD iswell founded, but their expanding use in primary prevention—in individuals without documentedCVD—has raised some concerns. Firstly, evidence suggests that, in primary prevention, statinssubstantially decrease CVD morbidity, but only moderately reduce CVD mortality. Secondly, long-termstatin use might cause adverse effects, such as incident diabetes mellitus. Thirdly, the cost-effectivenessof such a strategy is unclear, and has to be balanced against the risk of 'overmedicating' the generalpopulation. Data clearly support the use of statins for primary prevention in high-risk individuals, inwhom the strategy is cost-effective and the benefits exceed the risks. Whether primary prevention isbeneficial in individuals at low or moderate risk is not certain. Therefore, the prescription of statins forprimary prevention should be individualized on the basis of clinical judgment, particularly for low-riskindividuals. In appropriately selected individuals, statins should also be used for primary prevention ofischaemic stroke and transient ischaemic attack.", "metadata": {}}
+{"_id": "7465900", "title": "", "text": "Acetylation of apurinic/apyrimidinic endonuclease-1 regulates Helicobacter pylori-mediated gastricepithelial cell apoptosis.BACKGROUND & AIMS Helicobacter pylori-induced gastric epithelial cell (GEC)apoptosis is a complex process that includes activation of the tumor suppressor p53. p53-mediatedapoptosis involves p53 activation, bax transcription, and cytochrome c release from mitochondria.Apurinic/apyrimidinic endonuclease-1 (APE-1) regulates transcriptional activity of p53, and H pyloriinduce APE-1 expression in human GECs. H pylori infection increases intracellular calcium ionconcentration [Ca2+]i of GECs, which induces APE-1 acetylation. We investigated the effects of H pyloriinfection and APE-1 acetylation on GEC apoptosis. METHODS AGS cells (wild-type or with suppressedAPE-1), KATO III cells, and cells isolated from gastric biopsy specimens were infected with H pylori.Effects were examined by immunoblotting, real-time reverse-transcription polymerase chain reaction,immunoprecipitation, immunofluorescence microscopy, chromatin immunoprecipitation, mobility shift,DNA binding, and luciferase assays. RESULTS H pylori infection increased [Ca2+]i and acetylation ofAPE-1 in GECs, but the acetylation status of APE-1 did not affect the transcriptional activity of p53. InGECs, expression of a form of APE-1 that could not be acetylated increased total and mitochondrial levelsof Bax and induced release of cytochrome c and fragmentation of DNA; expression of wild-type APE-1reduced these apoptotic events. We identified a negative calcium response element in the human baxpromoter and found that poly (adenosine diphosphate-ribose) polymerase 1 recruited the acetylatedAPE-1/histone deacetylase-1 repressor complex to bax nCaRE. CONCLUSIONS H pylori-mediatedacetylation of APE-1 suppresses Bax expression; this prevents p53-mediated apoptosis when H pyloriinfect GECs.", "metadata": {}}
+{"_id": "7468449", "title": "", "text": "A beginning of the end: new insights into the functional organization of telomeresEver since the firstdemonstration of their repetitive sequence and unique replication pathway, telomeres have beguiledresearchers with how they function in protecting chromosome ends. Of course much has been learnedover the years, and we now appreciate that telomeres are comprised of the multimeric protein/DNAshelterin complex and that the formation of t-loops provides protection from DNA damage machinery.Deriving their name from D-loops, t-loops are generated by the insertion of the 3' overhang intotelomeric repeats facilitated by the binding of TRF2. Recent studies have uncovered novel forms ofchromosome end-structure that may implicate telomere organization in cellular processes beyond itsessential role in telomere protection and homeostasis. In particular, we have recently described thatt-loops form in a TRF2-dependent manner at interstitial telomere repeat sequences, which we termedinterstitial telomere loops (ITLs). These structures are also dependent on association of lamin A/C, acanonical component of the nucleoskeleton that is mutated in myriad human diseases, including humansegmental progeroid syndromes. Since ITLs are associated with telomere stability and require functionallamin A/C, our study suggests a mechanistic link between cellular aging (replicative senescence inducedby telomere shortening) and organismal aging (modeled by Hutchinson Gilford Progeria Syndrome). Herewe speculate on other potential ramifications of ITL formation, from gene expression to genome stabilityto chromosome structure.", "metadata": {}}
+{"_id": "7481159", "title": "", "text": "Biochemical analysis of TssK, a core component of the bacterial Type VI secretion system, reveals distinctoligomeric states of TssK and identifies a TssK–TssFG subcomplexGram-negative bacteria use the Type VIsecretion system (T6SS) to inject toxic proteins into rival bacteria or eukaryotic cells. However, themechanism of the T6SS is incompletely understood. In the present study, we investigated a conservedcomponent of the T6SS, TssK, using the antibacterial T6SS of Serratia marcescens as a model system.TssK was confirmed to be essential for effector secretion by the T6SS. The native protein, although notan integral membrane protein, appeared to localize to the inner membrane, consistent with its presencewithin a membrane-anchored assembly. Recombinant TssK purified from S. marcescens was found toexist in several stable oligomeric forms, namely trimer, hexamer and higher-order species. Native-levelpurification of TssK identified TssF and TssG as interacting proteins. TssF and TssG, conserved T6SScomponents of unknown function, were required for T6SS activity, but not for correct localization of TssK.A complex containing TssK, TssF and TssG was subsequently purified in vitro, confirming that these threeproteins form a new subcomplex within the T6SS. Our findings provide new insight into the T6SSassembly, allowing us to propose a model whereby TssK recruits TssFG into the membrane-associatedT6SS complex and different oligomeric states of TssK may contribute to the dynamic mechanism of thesystem.", "metadata": {}}
+{"_id": "7482674", "title": "", "text": "Involvement of ER Stress in Dysmyelination of Pelizaeus-Merzbacher Disease with PLP1 MissenseMutations Shown by iPSC-Derived OligodendrocytesPelizaeus-Merzbacher disease (PMD) is a form ofX-linked leukodystrophy caused by mutations in the proteolipid protein 1 (PLP1) gene. Although PLP1proteins with missense mutations have been shown to accumulate in the rough endoplasmic reticulum(ER) in disease model animals and cell lines transfected with mutant PLP1 genes, the exact pathogeneticmechanism of PMD has not previously been clarified. In this study, we established induced pluripotentstem cells (iPSCs) from two PMD patients carrying missense mutation and differentiated them intooligodendrocytes in vitro. In the PMD iPSC-derived oligodendrocytes, mislocalization of mutant PLP1proteins to the ER and an association between increased susceptibility to ER stress and increasednumbers of apoptotic oligodendrocytes were observed. Moreover, electron microscopic analysisdemonstrated drastically reduced myelin formation accompanied by abnormal ER morphology. Thus, thisstudy demonstrates the involvement of ER stress in pathogenic dysmyelination in the oligodendrocytes ofPMD patients with the PLP1 missense mutation.", "metadata": {}}
+{"_id": "7485455", "title": "", "text": "Using Routine Surveillance Data to Estimate the Epidemic Potential of Emerging Zoonoses: Application tothe Emergence of US Swine Origin Influenza A H3N2v VirusBACKGROUND Prior to emergence in humanpopulations, zoonoses such as SARS cause occasional infections in human populations exposed toreservoir species. The risk of widespread epidemics in humans can be assessed by monitoring thereproduction number R (average number of persons infected by a human case). However, until now,estimating R required detailed outbreak investigations of human clusters, for which resources andexpertise are not always available. Additionally, existing methods do not correct for important selectionand under-ascertainment biases. Here, we present simple estimation methods that overcome many ofthese limitations. METHODS AND FINDINGS Our approach is based on a parsimonious mathematicalmodel of disease transmission and only requires data collected through routine surveillance and standardcase investigations. We apply it to assess the transmissibility of swine-origin influenza A H3N2v-M virus inthe US, Nipah virus in Malaysia and Bangladesh, and also present a non-zoonotic example (cholera in theDominican Republic). Estimation is based on two simple summary statistics, the proportion infected bythe natural reservoir among detected cases (G) and among the subset of the first detected cases in eachcluster (F). If detection of a case does not affect detection of other cases from the same cluster, we findthat R can be estimated by 1-G; otherwise R can be estimated by 1-F when the case detection rate is low.In more general cases, bounds on R can still be derived. CONCLUSIONS We have developed a simpleapproach with limited data requirements that enables robust assessment of the risks posed by emergingzoonoses. We illustrate this by deriving transmissibility estimates for the H3N2v-M virus, an importantstep in evaluating the possible pandemic threat posed by this virus. Please see later in the article for theEditors' Summary.", "metadata": {}}
+{"_id": "7486516", "title": "", "text": "Independently Evolving Species in Asexual Bdelloid RotifersAsexuals are an important test case fortheories of why species exist. If asexual clades displayed the same pattern of discrete variation as sexualclades, this would challenge the traditional view that sex is necessary for diversification into species.However, critical evidence has been lacking: all putative examples have involved organisms with recentor ongoing histories of recombination and have relied on visual interpretation of patterns of genetic andphenotypic variation rather than on formal tests of alternative evolutionary scenarios. Here we show thata classic asexual clade, the bdelloid rotifers, has diversified into distinct evolutionary species. Intensivesampling of the genus Rotaria reveals the presence of well-separated genetic clusters indicative ofindependent evolution. Moreover, combined genetic and morphological analyses reveal divergentselection in feeding morphology, indicative of niche divergence. Some of the morphologically coherentgroups experiencing divergent selection contain several genetic clusters, in common with findings ofcryptic species in sexual organisms. Our results show that the main causes of speciation in sexualorganisms, population isolation and divergent selection, have the same qualitative effects in an asexualclade. The study also demonstrates how combined molecular and morphological analyses can shed newlight on the evolutionary nature of species.", "metadata": {}}
+{"_id": "7487927", "title": "", "text": "The Ribosome Biogenesis Factor Nol11 Is Required for Optimal rDNA Transcription and CraniofacialDevelopment in XenopusThe production of ribosomes is ubiquitous and fundamental to life. As such, it issurprising that defects in ribosome biogenesis underlie a growing number of symptomatically distinctinherited disorders, collectively called ribosomopathies. We previously determined that the nucleolarprotein, NOL11, is essential for optimal pre-rRNA transcription and processing in human tissue culturecells. However, the role of NOL11 in the development of a multicellular organism remains unknown. Here,we reveal a critical function for NOL11 in vertebrate ribosome biogenesis and craniofacial development.Nol11 is strongly expressed in the developing cranial neural crest (CNC) of both amphibians andmammals, and knockdown of Xenopus nol11 results in impaired pre-rRNA transcription and processing,increased apoptosis, and abnormal development of the craniofacial cartilages. Inhibition of p53 rescuesthis skeletal phenotype, but not the underlying ribosome biogenesis defect, demonstrating anevolutionarily conserved control mechanism through which ribosome-impaired craniofacial cells areremoved. Excessive activation of this mechanism impairs craniofacial development. Together, ourfindings reveal a novel requirement for Nol11 in craniofacial development, present the first frog model ofa ribosomopathy, and provide further insight into the clinically important relationship between specificribosome biogenesis proteins and craniofacial cell survival.", "metadata": {}}
+{"_id": "7488455", "title": "", "text": "Genomic Nucleosome Organization Reconstituted with Pure ProteinsChromatin remodelers regulate genesby organizing nucleosomes around promoters, but their individual contributions are obfuscated by thecomplex in vivo milieu of factor redundancy and indirect effects. Genome-wide reconstitution of promoternucleosome organization with purified proteins resolves this problem and is therefore a critical goal. Here,we reconstitute four stages of nucleosome architecture using purified components: yeast genomic DNA,histones, sequence-specific Abf1/Reb1, and remodelers RSC, ISW2, INO80, and ISW1a. We identifydirect, specific, and sufficient contributions that in vivo observations validate. First, RSC clears promotersby translating poly(dA:dT) into directional nucleosome removal. Second, partial redundancy isrecapitulated where INO80 alone, or ISW2 at Abf1/Reb1sites, positions +1 nucleosomes. Third, INO80and ISW2 each align downstream nucleosomal arrays. Fourth, ISW1a tightens the spacing to canonicalrepeat lengths. Such a minimal set of rules and proteins establishes core mechanisms by which promoterchromatin architecture arises through a blend of redundancy and specialization.", "metadata": {}}
+{"_id": "7489663", "title": "", "text": "Identification of splenic reservoir monocytes and their deployment to inflammatory sites.A currentparadigm states that monocytes circulate freely and patrol blood vessels but differentiate irreversibly intodendritic cells (DCs) or macrophages upon tissue entry. Here we show that bona fide undifferentiatedmonocytes reside in the spleen and outnumber their equivalents in circulation. The reservoir monocytesassemble in clusters in the cords of the subcapsular red pulp and are distinct from macrophages and DCs.In response to ischemic myocardial injury, splenic monocytes increase their motility, exit the spleen enmasse, accumulate in injured tissue, and participate in wound healing. These observations uncover a rolefor the spleen as a site for storage and rapid deployment of monocytes and identify splenic monocytes asa resource that the body exploits to regulate inflammation.", "metadata": {}}
+{"_id": "7492250", "title": "", "text": "Prox1 Is Required for Granule Cell Maturation and Intermediate Progenitor Maintenance During BrainNeurogenesisThe dentate gyrus has an important role in learning and memory, and adult neurogenesis inthe subgranular zone of the dentate gyrus may play a role in the acquisition of new memories. Thehomeobox gene Prox1 is expressed in the dentate gyrus during embryonic development and adultneurogenesis. Here we show that Prox1 is necessary for the maturation of granule cells in the dentategyrus during development and for the maintenance of intermediate progenitors during adultneurogenesis. We also demonstrate that Prox1-expressing intermediate progenitors are required for adultneural stem cell self-maintenance in the subgranular zone; thus, we have identified a previously unknownnon-cell autonomous regulatory feedback mechanism that controls adult neurogenesis in this region ofthe mammalian brain. Finally, we show that the ectopic expression of Prox1 induces prematuredifferentiation of neural stem cells.", "metadata": {}}
+{"_id": "7492420", "title": "", "text": "The abbreviated pluripotent cell cycle.Human embryonic stem cells (hESCs) and induced pluripotent stemcells proliferate rapidly and divide symmetrically producing equivalent progeny cells. In contrast, lineagecommitted cells acquire an extended symmetrical cell cycle. Self-renewal of tissue-specific stem cells issustained by asymmetric cell division where one progeny cell remains a progenitor while the partnerprogeny cell exits the cell cycle and differentiates. There are three principal contexts for considering theoperation and regulation of the pluripotent cell cycle: temporal, regulatory, and structural. The primarytemporal context that the pluripotent self-renewal cell cycle of hESCs is a short G1 period withoutreducing periods of time allocated to S phase, G2, and mitosis. The rules that govern proliferation inhESCs remain to be comprehensively established. However, several lines of evidence suggest a key rolefor the naïve transcriptome of hESCs, which is competent to stringently regulate the embryonic stem cell(ESC) cell cycle. This supports the requirements of pluripotent cells to self-propagate while suppressingexpression of genes that confer lineage commitment and/or tissue specificity. However, for the first time,we consider unique dimensions to the architectural organization and assembly of regulatory machineryfor gene expression in nuclear microenviornments that define parameters of pluripotency. From bothfundamental biological and clinical perspectives, understanding control of the abbreviated ESC cycle canprovide options to coordinate control of proliferation versus differentiation. Wound healing, tissueengineering, and cell-based therapy to mitigate developmental aberrations illustrate applications thatbenefit from knowledge of the biology of the pluripotent cell cycle.", "metadata": {}}
+{"_id": "7506409", "title": "", "text": "Senescent growth arrest in mesenchymal stem cells is bypassed by Wip1-mediated downregulation ofintrinsic stress signaling pathways.Human mesenchymal stem cells (hMSCs) have been widely studied asa source of primary adult stem cells for cell therapy because of their multidifferentiation potential;however, the growth arrest (also known as \"premature senescence\") often found in hMSCs cultured invitro has been a major obstacle to the in-depth characterization of these cells. In addition, the inability tomaintain constant cell growth hampers the development of additional genetic modifications aimed atachieving desired levels of differentiation to specific tissues; however, the molecular mechanisms thatgovern this phenomenon remain unclear, with the exception of a few studies demonstrating thatinduction of p16INK4a is responsible for this senescence-like event. Here, we observed that thepremature growth arrest in hMSCs occurs in parallel with the induction of p16INK4a, following abrogationof inhibitory phosphorylation of retinoblastoma protein. These stress responses were concurrent withincreased formation of reactive oxygen species (ROSs) from mitochondria and increased p38mitogen-activated protein kinase (MAPK) activity. The introduction of Wip1 (wild-type p53 induciblephosphatase-1), a well-studied stress modulator, significantly lowered p16INK4a expression and led top38 MAPK inactivation, although it failed to affect the levels of ROSs. Moreover, the suppression of stressresponses by Wip1 apparently extended the life span of hMSCs, compared with control conditions, whilemaintaining their multilineage differentiation potential. Based on these results, we suggest that senescentgrowth arrest in hMSCs may result from activation of stress signaling pathways and consequent onset ofstress responses, due in part to ROS production during prolonged in vitro culture.", "metadata": {}}
+{"_id": "7514614", "title": "", "text": "Understanding the Odd Science of AgingEvolutionary considerations suggest aging is caused not by activegene programming but by evolved limitations in somatic maintenance, resulting in a build-up of damage.Ecological factors such as hazard rates and food availability influence the trade-offs between investing ingrowth, reproduction, and somatic survival, explaining why species evolved different life spans and whyaging rate can sometimes be altered, for example, by dietary restriction. To understand the cell andmolecular basis of aging is to unravel the multiplicity of mechanisms causing damage to accumulate andthe complex array of systems working to keep damage at bay.", "metadata": {}}
+{"_id": "7521113", "title": "", "text": "Fate mapping reveals origins and dynamics of monocytes and tissue macrophages underhomeostasis.Mononuclear phagocytes, including monocytes, macrophages, and dendritic cells, contributeto tissue integrity as well as to innate and adaptive immune defense. Emerging evidence for labor divisionindicates that manipulation of these cells could bear therapeutic potential. However, specific ontogeniesof individual populations and the overall functional organization of this cellular network are not welldefined. Here we report a fate-mapping study of the murine monocyte and macrophage compartmenttaking advantage of constitutive and conditional CX(3)CR1 promoter-driven Cre recombinase expression.We have demonstrated that major tissue-resident macrophage populations, including liver Kupffer cellsand lung alveolar, splenic, and peritoneal macrophages, are established prior to birth and maintainthemselves subsequently during adulthood independent of replenishment by blood monocytes.Furthermore, we have established that short-lived Ly6C(+) monocytes constitute obligatory steady-stateprecursors of blood-resident Ly6C(-) cells and that the abundance of Ly6C(+) blood monocytesdynamically controls the circulation lifespan of their progeny.", "metadata": {}}
+{"_id": "7547329", "title": "", "text": "Dealing with substantial heterogeneity in Cochrane reviews. Cross-sectional studyBACKGROUND Dealingwith heterogeneity in meta-analyses is often tricky, and there is only limited advice for authors on whatto do. We investigated how authors addressed different degrees of heterogeneity, in particular whetherthey used a fixed effect model, which assumes that all the included studies are estimating the same trueeffect, or a random effects model where this is not assumed. METHODS We sampled randomly 60Cochrane reviews from 2008, which presented a result in its first meta-analysis with substantialheterogeneity (I2 greater than 50%, i.e. more than 50% of the variation is due to heterogeneity ratherthan chance). We extracted information on choice of statistical model, how the authors had handled theheterogeneity, and assessed the methodological quality of the reviews in relation to this. RESULTS Thedistribution of heterogeneity was rather uniform in the whole I2 interval, 50-100%. A fixed effect modelwas used in 33 reviews (55%), but there was no correlation between I2 and choice of model (P = 0.79).We considered that 20 reviews (33%), 16 of which had used a fixed effect model, had major problems.The most common problems were: use of a fixed effect model and lack of rationale for choice of thatmodel, lack of comment on even severe heterogeneity and of reservations and explanations of its likelycauses. The problematic reviews had significantly fewer included trials than other reviews (4.3 vs. 8.0, P= 0.024). The problems became less pronounced with time, as those reviews that were most recentlyupdated more often used a random effects model. CONCLUSION One-third of Cochrane reviews withsubstantial heterogeneity had major problems in relation to their handling of heterogeneity. Moreattention is needed to this issue, as the problems we identified can be essential for the conclusions of thereviews.", "metadata": {}}
+{"_id": "7548577", "title": "", "text": "Antagonistic Controls of Autophagy and Glycogen Accumulation by Snf1p, the Yeast Homolog ofAMP-Activated Protein Kinase, and the Cyclin-DependentIn the yeast Saccharomyces cerevisiae, glycogenis accumulated as a carbohydrate reserve when cells are deprived of nutrients. Yeast mutated in SNF1, agene encoding a protein kinase required for glucose derepression, has diminished glycogen accumulationand concomitant inactivation of glycogen synthase. Restoration of synthesis in an snf1 strain results onlyin transient glycogen accumulation, implying the existence of other SNF1-dependent controls of glycogenstorage. A genetic screen revealed that two genes involved in autophagy, APG1 and APG13, may beregulated by SNF1. Increased autophagic activity was observed in wild-type cells entering the stationaryphase, but this induction was impaired in an snf1 strain. Mutants defective for autophagy were able tosynthesize glycogen upon approaching the stationary phase, but were unable to maintain their glycogenstores, because subsequent synthesis was impaired and degradation by phosphorylase, Gph1p, wasenhanced. Thus, deletion of GPH1 partially reversed the loss of glycogen accumulation in autophagymutants. Loss of the vacuolar glucosidase, SGA1, also protected glycogen stores, but only very late in thestationary phase. Gph1p and Sga1p may therefore degrade physically distinct pools of glycogen. Pho85pis a cyclin-dependent protein kinase that antagonizes SNF1 control of glycogen synthesis. Induction ofautophagy in pho85 mutants entering the stationary phase was exaggerated compared to the level inwild-type cells, but was blocked in apg1 pho85 mutants. We propose that Snf1p and Pho85p are,respectively, positive and negative regulators of autophagy, probably via Apg1 and/or Apg13. Defectiveglycogen storage in snf1 cells can be attributed to both defective synthesis upon entry into stationaryphase and impaired maintenance of glycogen levels caused by the lack of autophagy.", "metadata": {}}
+{"_id": "7549811", "title": "", "text": "Preferential binding of a kinesin-1 motor to GTP-tubulin–rich microtubules underlies polarized vesicletransportPolarized transport in neurons is fundamental for the formation of neuronal circuitry. A motordomain-containing truncated KIF5 (a kinesin-1) recognizes axonal microtubules, which are enriched inEB1 binding sites, and selectively accumulates at the tips of axons. However, it remains unknown whatcue KIF5 recognizes to result in this selective accumulation. We found that axonal microtubules werepreferentially stained by the anti-GTP-tubulin antibody hMB11. Super-resolution microscopy combinedwith EM immunocytochemistry revealed that hMB11 was localized at KIF5 attachment sites. In addition,EB1, which binds preferentially to guanylyl-methylene-diphosphate (GMPCPP) microtubules in vitro,recognized hMB11 binding sites on axonal microtubules. Further, expression of hMB11 antibody inneurons disrupted the selective accumulation of truncated KIF5 in the axon tips. In vitro studies revealedapproximately threefold stronger binding of KIF5 motor head to GMPCPP microtubules than to GDPmicrotubules. Collectively, these data suggest that the abundance of GTP-tubulin in axonal microtubulesmay underlie selective KIF5 localization and polarized axonal vesicular transport.", "metadata": {}}
+{"_id": "7552147", "title": "", "text": "Developmental biology of the pancreas.The pancreas is an organ containing two distinct populations ofcells, the exocrine cells that secrete enzymes into the digestive tract, and the endocrine cells that secretehormones into the bloodstream. It arises from the endoderm as a dorsal and a ventral bud which fusetogether to form the single organ. Mammals, birds, reptiles and amphibians have a pancreas with similarhistology and mode of development, while in some fish, the islet cells are segregated as Brockmannbodies. Invertebrates do not have a pancreas, but comparable endocrine cells may be found in the gut orthe brain. The early pancreatic bud shows uniform expression of the homeobox gene IPF-1 (also knownas IDX-1, STF-1 or PDX), which when mutated to inactivity leads to total absence of the organ. Theoccurrence of heterotopic pancreas in the embryo, and also the metaplasias that can be displayed by aregenerating pancreas in the adult, both suggest that only a few gene products distinguish the pancreaticcell state from that of the surrounding tissues of duodenum, gall bladder and liver. In the developingpancreatic buds, the endocrine cells start to differentiate before the exocrine cells, and co-expression ofdifferent hormones by the same cell is often observed at early stages. Although pancreatic endocrine cellsproduce many gene products also characteristic of neurons, evidence from in vitro cultures and fromquailchick grafts shows that they are of endogenous and not of neural crest origin. Observational studiessuggest strongly that both endocrine and exocrine cells arise from the same endodermal rudiment.Development of the pancreas in embryonic life requires a trophic stimulus from the associatedmesenchyme. In postnatal life, all cell types in the pancreas continue to grow. Destruction of acinartissue by duct ligation or ethionine treatment is followed by rapid regeneration. Surgical removal of partsof the pancreas is followed by moderate but incomplete regeneration of both acini and islets. Poisoningwith alloxan or streptozotocin can lead to permanent depletion of beta cells. Although the cell kinetics ofthe pancreas are not understood, it seems likely that there is a continuous slow turnover of cells, fedfrom a stem cells population in the ducts, and that the controls on the production rate of each cell typeare local rather than systemic.", "metadata": {}}
+{"_id": "7552215", "title": "", "text": "Long term pharmacotherapy for obesity and overweight: updated meta-analysis.OBJECTIVE Tosummarise the long term efficacy of anti-obesity drugs in reducing weight and improving health status.DESIGN Updated meta-analysis of randomised trials. DATA SOURCES Medline, Embase, the Cochranecontrolled trials register, the Current Science meta-register of controlled trials, and reference lists ofidentified articles. All data sources were searched from December 2002 (end date of last search) toDecember 2006. STUDIES REVIEWED Double blind randomised placebo controlled trials of approvedanti-obesity drugs used in adults (age over 18) for one year or longer. RESULTS 30 trials of one to fouryears' duration met the inclusion criteria: 16 orlistat (n=10 631 participants), 10 sibutramine (n=2623),and four rimonabant (n=6365). Of these, 14 trials were new and 16 had previously been identified.Attrition rates averaged 30-40%. Compared with placebo, orlistat reduced weight by 2.9 kg (95%confidence interval 2.5 kg to 3.2 kg), sibutramine by 4.2 kg (3.6 kg to 4.7 kg), and rimonabant by 4.7 kg(4.1 kg to 5.3 kg). Patients receiving active drug treatment were significantly more likely to achieve 5%and 10% weight loss thresholds. Orlistat reduced the incidence of diabetes and improved concentrationsof total cholesterol and low density lipoprotein cholesterol, blood pressure, and glycaemic control inpatients with diabetes but increased rates of gastrointestinal side effects and slightly loweredconcentrations of high density lipoprotein. Sibutramine improved [corrected] concentrations of highdensity lipoprotein cholesterol and triglycerides [corrected] Rimonabant improved concentrations of highdensity lipoprotein cholesterol and triglycerides, blood pressure, and glycaemic control in patients withdiabetes but increased the risk of mood disorders. CONCLUSIONS Orlistat, sibutramine, and rimonabantmodestly reduce weight, have differing effects on cardiovascular risk profiles, and have specific adverseeffects.", "metadata": {}}
+{"_id": "7560876", "title": "", "text": "The centrosome cycle: Centriole biogenesis, duplication and inherent asymmetriesCentrosomes aremicrotubule-organizing centres of animal cells. They influence the morphology of the microtubulecytoskeleton, function as the base for the primary cilium and serve as a nexus for important signallingpathways. At the core of a typical centrosome are two cylindrical microtubule-based structures termedcentrioles, which recruit a matrix of associated pericentriolar material. Cells begin the cell cycle withexactly one centrosome, and the duplication of centrioles is constrained such that it occurs only once percell cycle and at a specific site in the cell. As a result of this duplication mechanism, the two centriolesdiffer in age and maturity, and thus have different functions; for example, the older of the two centriolescan initiate the formation of a ciliary axoneme. We discuss spatial aspects of the centrosome duplicationcycle, the mechanism of centriole assembly and the possible consequences of the inherent asymmetry ofcentrioles and centrosomes.", "metadata": {}}
+{"_id": "7568596", "title": "", "text": "Osteoclasts control reactivation of dormant myeloma cells by remodelling the endosteal nicheMultiplemyeloma is largely incurable, despite development of therapies that target myeloma cell-intrinsicpathways. Disease relapse is thought to originate from dormant myeloma cells, localized in specializedniches, which resist therapy and repopulate the tumour. However, little is known about the niche, andhow it exerts cell-extrinsic control over myeloma cell dormancy and reactivation. In this study, we trackindividual myeloma cells by intravital imaging as they colonize the endosteal niche, enter a dormant stateand subsequently become activated to form colonies. We demonstrate that dormancy is a reversible statethat is switched 'on' by engagement with bone-lining cells or osteoblasts, and switched 'off' by osteoclastsremodelling the endosteal niche. Dormant myeloma cells are resistant to chemotherapy that targetsdividing cells. The demonstration that the endosteal niche is pivotal in controlling myeloma cell dormancyhighlights the potential for targeting cell-extrinsic mechanisms to overcome cell-intrinsic drug resistanceand prevent disease relapse.", "metadata": {}}
+{"_id": "7581911", "title": "", "text": "Human embryonic stem cells with biological and epigenetic characteristics similar to those of mouseESCs.Human and mouse embryonic stem cells (ESCs) are derived from blastocyst-stage embryos buthave very different biological properties, and molecular analyses suggest that the pluripotent state ofhuman ESCs isolated so far corresponds to that of mouse-derived epiblast stem cells (EpiSCs). Here werewire the identity of conventional human ESCs into a more immature state that extensively sharesdefining features with pluripotent mouse ESCs. This was achieved by ectopic induction of Oct4, Klf4, andKlf2 factors combined with LIF and inhibitors of glycogen synthase kinase 3beta (GSK3beta) andmitogen-activated protein kinase (ERK1/2) pathway. Forskolin, a protein kinase A pathway agonist whichcan induce Klf4 and Klf2 expression, transiently substitutes for the requirement for ectopic transgeneexpression. In contrast to conventional human ESCs, these epigenetically converted cells have growthproperties, an X-chromosome activation state (XaXa), a gene expression profile, and a signaling pathwaydependence that are highly similar to those of mouse ESCs. Finally, the same growth conditions allow thederivation of human induced pluripotent stem (iPS) cells with similar properties as mouse iPS cells. Thegeneration of validated \"naïve\" human ESCs will allow the molecular dissection of a previously undefinedpluripotent state in humans and may open up new opportunities for patient-specific, disease-relevantresearch.", "metadata": {}}
+{"_id": "7583104", "title": "", "text": "IDEAL in meshes for prolapse, urinary incontinence, and hernia repair.PURPOSE Mesh surgeries arecounted among the most frequently applied surgical procedures. Despite global spread of mesh applyingsurgeries, there is no current systematic analysis of incidence and possible prevention of adverse eventsafter mesh implantation. MATERIALS AND METHODS Based on the recommendations of IDEAL an in vitrotest system for biocompatibility of surgical meshes has been generated (Innovation). Coating strategiesfor biocompatibility optimization have been developed (Development). The native and modified alloplasticmaterials have been tested in an animal model over 2 years (Exploration and Assessment and Long-termstudy). RESULTS In 3 meshes, implanted in sheep and explanted at 4 different time points (a, 3 months;b, 6 months; c, 12 months; and d, 24 months) over 24 months, thickness of inflammatory tissue (TVT a,35 µm; b, 32 µm; c, 33 µm; d, 28 µm; UltraPro, a, 25 µm; b, 24 µm; c, 21 µm; d, 22 µm; PVDF a, 20µm; b, 21 µm; c, 14 µm; d, 15µm), connective tissue (TVT a, 37 µm; b, 36 µm; c, 43 µm; d, 41 µm;UltraPro a, 33 µm; b, 32 µm; c, 40 µm; d, 38 µm; PVDF a, 25 µm; b, 22 µm; c, 22 µm; d, 24 µm), andmacrophage infiltration (TVT a, 36%; b, 33%; c, 23%; d, 20%; UltraPro a, 34%; b, 28%; c, 25%; d,22%; PVDF a, 24%; b, 18%; c, 18%; d, 16%) revealed comparable ranking characteristics at every timepoint after explantation. The in vivo performance of these meshes in a sheep model was predictable witha previously developed in vitro test system. Coating of meshes with autologous plasma prior toimplantation seems to have a positive effect on the meshes biocompatibility. CONCLUSION We haveapplied IDEAL criteria on a new innovation for surgical meshes. The results permit the generation of aranking of currently available meshes with potential to optimize future meshes.", "metadata": {}}
+{"_id": "7583161", "title": "", "text": "Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues.Insemisyngeneic heterotopic bone marrow transplants the donor or recipient origin of cells of osteogenicand hematopoietic tissues was identified by chromosome markers (T6) and by reverse transplantationinto the initial donor line. In syngeneic and semisyngeneic grafts of bone marrow under the renal capsulebone and bone marrow are formed. In allogeneic grafts only bone is formed; this bone is subsequentlyresorbed. In 14-month semisyngeneic transplants the bone marrow consists of recipient cells. This is truefor both the proliferating pool and the stem cells of hematopoietic tissue. At the same time, osteogenicprecursor cells and bone tissue in these transplants are of donor origin. A discussion is presented of theinterrelationship between determinated osteogenic precursor cells (preosteoblasts) and hematopoieticstem cells (or their descendants) in which osteogenesis is inducible.", "metadata": {}}
+{"_id": "7583725", "title": "", "text": "TRPM7 is required for breast tumor cell metastasis.TRPM7 encodes a Ca2+-permeable nonselective cationchannel with kinase activity. TRPM7 has been implicated in control of cell adhesion and migration, butwhether TRPM7 activity contributes to cancer progression has not been established. Here we report thathigh levels of TRPM7 expression independently predict poor outcome in breast cancer patients and that itis functionally required for metastasis formation in a mouse xenograft model of human breast cancer.Mechanistic investigation revealed that TRPM7 regulated myosin II-based cellular tension, therebymodifying focal adhesion number, cell-cell adhesion and polarized cell movement. Our findings thereforesuggest that TRPM7 is part of a mechanosensory complex adopted by cancer cells to drive metastasisformation.", "metadata": {}}
+{"_id": "7595742", "title": "", "text": "Frailty Syndrome: A Transitional State in a Dynamic ProcessFrailty has long been considered synonymouswith disability and comorbidity, to be highly prevalent in old age and to confer a high risk for falls,hospitalization and mortality. However, it is becoming recognized that frailty may be a distinct clinicalsyndrome with a biological basis. The frailty process appears to be a transitional state in the dynamicprogression from robustness to functional decline. During this process, total physiological reservesdecrease and become less likely to be sufficient for the maintenance and repair of the ageing body.Central to the clinical concept of frailty is that no single altered system alone defines it, but that multiplesystems are involved. Clinical consensus regarding the phenotype which constitutes frailty, drawing uponthe opinions of numerous authors, shows the characteristics to include wasting (loss of both muscle massand strength and weight loss), loss of endurance, decreased balance and mobility, slowed performance,relative inactivity and, potentially, decreased cognitive function. Frailty is a distinct entity easilyrecognized by clinicians, with multiple manifestations and with no single symptom being sufficient oressential in its presentation. Manifestations include appearance (consistent or not with age), nutritionalstatus (thin, weight loss), subjective health rating (health perception), performance (cognition, fatigue),sensory/physical impairments (vision, hearing, strength) and current care (medication, hospital).Although the early stages of the frailty process may be clinically silent, when depleted reserves reach anaggregate threshold leading to serious vulnerability, the syndrome may become detectable by looking atclinical, functional, behavioral and biological markers. Thus, a better understanding of these clinicalchanges and their underlying mechanisms, beginning in the pre-frail state, may confirm the impressionheld by many geriatricians that increasing frailty is distinguishable from ageing and in consequence ispotentially reversible. We therefore provide an update of the physiopathology and clinical and biologicalcharacteristics of the frailty process and speculate on possible preventative approaches.", "metadata": {}}
+{"_id": "7602348", "title": "", "text": "Progression of preclinical diastolic dysfunction to the development of symptoms.BACKGROUND Preclinicaldiastolic dysfunction (PDD) has been defined as subjects with normal systolic function, diastolicdysfunction but no symptoms of heart failure (HF). The clinical phenotype and natural history of thesyndrome remains poorly defined. This study's objective was to determine the clinical phenotype andprogression to HF in a group of patients with normal systolic function and moderate or severe diastolicdysfunction as determinate by Doppler criteria without any clinical diagnosis of HF according to theFramingham criteria or any symptoms of HF, specifically dyspnoea, oedema or fatigue at the time ofechocardiography. METHODS The authors used resources of the Mayo Clinic echocardiography databaseto consecutively select among patients who had an echocardiogram in 2005, a cohort with moderate orsevere diastolic dysfunction by Doppler criteria and EF >or=50%. Patients could not have a diagnosis ofHF, or any HF symptoms-specifically dyspnoea, oedema or fatigue-at the time of echocardiography; norgrade 3 or greater valvular dysfunction (except tricuspid valve). A total of 82 patients had their medicalchart reviewed. Primary endpoint was the time to the development of (1) HF according to theFramingham criteria or (2) any symptoms of dyspnoea, oedema or fatigue. RESULTS The mean age ofthe cohort of PDD subjects was 69+/-10 years with a female (67%) preponderance. Presence ofhypertension was 76%, coronary artery disease was 29%, paroxysmal atrial fibrillation was 26%,estimated creatinine clearance <60 ml/min was 51%. The 2-year cumulative probability of developmentof HF according to the Framingham criteria was 1.9%; however, the 2-year cumulative probability ofdevelopment of any symptoms was 31.1%. The 2-year cumulative probability for cardiac hospitalisationwas 21.2%. Peripheral vascular disease and hypertension were independently associated with increasedlikelihood for the development of symptoms. CONCLUSION The study demonstrates that hypertension,hyperlipidaemia, CAD and renal dysfunction are prevalent in patients with PDD. More importantly,although the progression to the development of clinical HF over 2 years was low, there was a moderatedegree of progression to development of symptoms and cardiac hospitalisations over 2 years. Based onthe finding that only PVD and hypertension were independently associated with the progression to thedevelopment of symptoms in subject with PDD, the authors speculate that ventricular-arterial interactionmay be important to the progression of diastolic dysfunction to the development of symptoms.", "metadata": {}}
+{"_id": "7613033", "title": "", "text": "Aspirin in the chemoprevention of colorectal neoplasia: an overview.Considerable evidence supports theeffectiveness of aspirin for chemoprevention of colorectal cancer (CRC) in addition to its well-establishedbenefits in the prevention of vascular disease. Epidemiologic studies have consistently observed aninverse association between aspirin use and risk of CRC. A recent pooled analysis of a long-term posttrialfollow-up of nearly 14,000 patients from four randomized, cardiovascular disease prevention trialsshowed that daily aspirin treatment for about five years was associated with a 34% reduction in 20-yearCRC mortality. A separate metaanalysis of nearly 3,000 patients with a history of colorectal adenoma orcancer in four randomized adenoma prevention trials showed that aspirin reduced the occurrence ofadvanced adenomas by 28% and any adenoma by 17%. Aspirin has also been shown to be beneficial in aclinical trial of patients with Lynch syndrome, a hereditary CRC syndrome; in those treated with aspirinfor at least two years, there was a 50% or more reduction in the risk of CRC commencing five years afterrandomization and after aspirin had been discontinued. A few observational studies have shown anincrease in survival among patients with CRC who use aspirin. Taken together, these findings strengthenthe case for consideration of long-term aspirin use in CRC prevention. Despite these compelling data,there is a lack of consensus about the balance of risks and benefits associated with long-term aspirin use,particularly in low-risk populations. The optimal dose to use for cancer prevention and the precisemechanism underlying aspirin's anticancer effect require further investigation.", "metadata": {}}
+{"_id": "7621534", "title": "", "text": "Chemokine receptor trio: CXCR3, CXCR4 and CXCR7 crosstalk via CXCL11 and CXCL12.Althoughchemokines are well established to function in immunity and endothelial cell activation and proliferation,a rapidly growing literature suggests that CXC Chemokine receptors CXCR3, CXCR4 and CXCR7 arecritical in the development and progression of solid tumors. The effect of these chemokine receptors intumorigenesis is mediated via interactions with shared ligands I-TAC (CXCL11) and SDF-1 (CXCL12).Over the last decade, CXCR4 has been extensively reported to be overexpressed in most human solidtumors and has earned considerable attention toward elucidating its role in cancer metastasis. To enrichthe existing armamentarium of anti-cancerous agents, many inhibitors of CXCL12-CXCR4 axis haveemerged as additional or alternative agents for neo-adjuvant treatments and even many of them are inpreclinical and clinical stages of their development. However, the discovery of CXCR7 as another receptorfor CXCL12 with rather high binding affinity and recent reports about its involvement in cancerprogression, has questioned the potential of \"selective blockade\" of CXCR4 as cancer chemotherapeutics.Interestingly, CXCR7 can also bind another chemokine CXCL11, which is an established ligand for CXCR3.Recent reports have documented that CXCR3 and their ligands are overexpressed in different solidtumors and regulate tumor growth and metastasis. Therefore, it is important to consider the interactionsand crosstalk between these three chemokine receptors and their ligand mediated signaling cascades forthe development of effective anti-cancer therapies. Emerging evidence also indicates that these receptorsare differentially expressed in tumor endothelial cells as well as in cancer stem cells, suggesting theirdirect role in regulating tumor angiogenesis and metastasis. In this review, we will focus on the signalsmediated by this receptor trio via their shared ligands and their role in tumor growth and progression.", "metadata": {}}
+{"_id": "7622767", "title": "", "text": "Human Cyclin a Is Required for Mitosis until Mid ProphaseWe have used microinjection and time-lapsevideo microscopy to study the role of cyclin A in mitosis. We have injected purified, active cyclinA/cyclin-dependent kinase 2 (CDK2) into synchronized cells at specific points in the cell cycle and assayedits effect on cell division. We find that cyclin A/CDK2 will drive G2 phase cells into mitosis within 30 min ofmicroinjection, up to 4 h before control cells enter mitosis. Often this premature mitosis is abnormal; thechromosomes do not completely condense and daughter cells fuse. Remarkably, microinjecting cyclinA/CDK2 into S phase cells has no effect on progress through the following G2 phase or mitosis. Incomplementary experiments we have microinjected the amino terminus of p21Cip1/Waf1/Sdi1 (p21N)into cells to inhibit cyclin A/CDK2 activity. We find that p21N will prevent S phase or G2 phase cells fromentering mitosis, and will cause early prophase cells to return to interphase. These results suggest thatcyclin A/CDK2 is a rate-limiting component required for entry into mitosis, and for progress throughmitosis until late prophase. They also suggest that cyclin A/CDK2 may be the target of the recentlydescribed prophase checkpoint.", "metadata": {}}
+{"_id": "7627167", "title": "", "text": "Brief, four-session group CBT reduces binge eating behaviors among bariatric surgerycandidates.BACKGROUND The objective of this study was to evaluate the effectiveness of a brief,4-session cognitive behavioral, group psychotherapy for binge eating among bariatric surgery candidatesat an academic medical center. Binge eating behaviors have been linked to poorer outcomes amongbariatric surgery patients, and binge eating disorder have be considered a contraindication in surgeryprograms, some of which have mandated preoperative binge eating treatment. However, no previousstudies have examined whether a preoperative binge eating intervention could successfully reduce bingeeating behaviors among severely obese bariatric surgery candidates. METHODS A total of 243 bariatricsurgery candidates completed a brief cognitive behavioral group treatment for binge eating behaviors andwere administered the Binge Eating Scale and reported the number of weekly binge eating episodes atthe initial psychological evaluation and again after the group sessions. The study used a pre-postintervention design. RESULTS The results suggested significant reductions in both binge eating behaviorsand cognitions and binge eating episodes after the group intervention. The intervention's effectivenessdid not differ according to gender or ethnicity (black versus white). CONCLUSION A brief cognitivebehavioral intervention can reduce binge eating behaviors among bariatric surgery candidates. Given thepotential influence of binge eating on outcomes, bariatric surgery programs could benefit by treatingbinge eating before surgery.", "metadata": {}}
+{"_id": "7639744", "title": "", "text": "Influence of smoking cessation after diagnosis of early stage lung cancer on prognosis: systematic reviewof observational studies with meta-analysisOBJECTIVE To systematically review the evidence thatsmoking cessation after diagnosis of a primary lung tumour affects prognosis. DESIGN Systematic reviewwith meta-analysis. DATA SOURCES CINAHL (from 1981), Embase (from 1980), Medline (from 1966),Web of Science (from 1966), CENTRAL (from 1977) to December 2008, and reference lists of includedstudies. STUDY SELECTION Randomised controlled trials or observational longitudinal studies thatmeasured the effect of quitting smoking after diagnosis of lung cancer on prognostic outcomes,regardless of stage at presentation or tumour histology, were included. DATA EXTRACTION Tworesearchers independently identified studies for inclusion and extracted data. Estimates were combinedby using a random effects model, and the I(2) statistic was used to examine heterogeneity. Life tableswere used to model five year survival for early stage non-small cell lung cancer and limited stage smallcell lung cancer, using death rates for continuing smokers and quitters obtained from this review.RESULTS In 9/10 included studies, most patients studied were diagnosed as having an early stage lungtumour. Continued smoking was associated with a significantly increased risk of all cause mortality(hazard ratio 2.94, 95% confidence interval 1.15 to 7.54) and recurrence (1.86, 1.01 to 3.41) in earlystage non-small cell lung cancer and of all cause mortality (1.86, 1.33 to 2.59), development of a secondprimary tumour (4.31, 1.09 to 16.98), and recurrence (1.26, 1.06 to 1.50) in limited stage small cell lungcancer. No study contained data on the effect of quitting smoking on cancer specific mortality or ondevelopment of a second primary tumour in non-small cell lung cancer. Life table modelling on the basisof these data estimated 33% five year survival in 65 year old patients with early stage non-small cell lungcancer who continued to smoke compared with 70% in those who quit smoking. In limited stage smallcell lung cancer, an estimated 29% of continuing smokers would survive for five years compared with63% of quitters on the basis of the data from this review. CONCLUSIONS This review providespreliminary evidence that smoking cessation after diagnosis of early stage lung cancer improvesprognostic outcomes. From life table modelling, the estimated number of deaths prevented is larger thanwould be expected from reduction of cardiorespiratory deaths after smoking cessation, so most of themortality gain is likely to be due to reduced cancer progression. These findings indicate that offeringsmoking cessation treatment to patients presenting with early stage lung cancer may be beneficial.", "metadata": {}}
+{"_id": "7640058", "title": "", "text": "Epigenetic reprogramming and induced pluripotency.The cloning of animals from adult cells hasdemonstrated that the developmental state of adult cells can be reprogrammed into that of embryoniccells by uncharacterized factors within the oocyte. More recently, transcription factors have beenidentified that can induce pluripotency in somatic cells without the use of oocytes, generating inducedpluripotent stem (iPS) cells. iPS cells provide a unique platform to dissect the molecular mechanisms thatunderlie epigenetic reprogramming. Moreover, iPS cells can teach us about principles of normaldevelopment and disease, and might ultimately facilitate the treatment of patients by custom-tailored celltherapy.", "metadata": {}}
+{"_id": "7640792", "title": "", "text": "Sex differences in mortality following acute coronary syndromes.CONTEXT Conflicting information existsabout whether sex differences modulate short-term mortality following acute coronary syndromes (ACS).OBJECTIVES To investigate the relationship between sex and 30-day mortality in ACS, and to determinewhether this relationship was modified by clinical syndrome or coronary anatomy using a large databaseacross the spectrum of ACS and adjusting for potentially confounding clinical covariates. DESIGN,SETTING, AND PARTICIPANTS A convenience sample of patients pooled from 11 independent,international, randomized ACS clinical trials between 1993 and 2006 whose databases are maintained atthe Duke Clinical Research Institute, Durham, North Carolina. Of 136 247 patients, 38 048 (28%) werewomen; 102 004 (26% women) with ST-segment elevation myocardial infarction (STEMI), 14 466 (29%women) with non-STEMI (NSTEMI), and 19 777 (40% women) with unstable angina. MAIN OUTCOMEMEASURE Thirty-day mortality following ACS. RESULTS Thirty-day mortality was 9.6% in women and5.3% in men (odds ratio [OR], 1.91; 95% confidence interval [CI], 1.83-2.00). After multivariableadjustment, mortality was not significantly different between women and men (adjusted OR, 1.06; 95%CI, 0.99-1.15). A significant sex by type of ACS interaction was demonstrated (P < .001). In STEMI,30-day mortality was higher among women (adjusted OR, 1.15; 95% CI, 1.06-1.24), whereas in NSTEMI(adjusted OR, 0.77; 95% CI, 0.63-0.95) and unstable angina, mortality was lower among women(adjusted OR, 0.55; 95% CI, 0.43-0.70). In a cohort of 35 128 patients with angiographic data, womenmore often had nonobstructive (15% vs 8%) and less often had 2-vessel (25% vs 28%) and 3-vessel(23% vs 26%) coronary disease, regardless of ACS type. After additional adjustment for angiographicdisease severity, 30-day mortality among women was not significantly different than men, regardless ofACS type. The relationship between sex and 30-day mortality was similar across the levels ofangiographic disease severity (P for interaction = .70). CONCLUSIONS Sex-based differences existed in30-day mortality among patients with ACS and vary depending on clinical presentation. However, thesedifferences appear to be largely explained by clinical differences at presentation and severity ofangiographically documented disease.", "metadata": {}}
+{"_id": "7643848", "title": "", "text": "Membrane topology of the 60-kDa Oxa1p homologue from Escherichia coli.We have characterized themembrane topology of a 60-kDa inner membrane protein from Escherichia coli that is homologous to therecently identified Oxa1p protein in Saccharomyces cerevisiae mitochondria implicated in the assembly ofmitochondrial inner membrane proteins. Hydrophobicity and alkaline phosphatase fusion analysessuggest a membrane topology with six transmembrane segments, including an N-terminal signal-anchorsequence not present in mitochondrial Oxa1p. In contrast to partial N-terminal fusion protein constructs,the full-length protein folds into a protease-resistant conformation, suggesting that important foldingdeterminants are present in the C-terminal part of the molecule.", "metadata": {}}
+{"_id": "7645565", "title": "", "text": "Identifying and Characterizing Interplay between Hepatitis B Virus X Protein and Smc5/6Hepatitis B Xprotein (HBx) plays an essential role in the hepatitis B virus (HBV) replication cycle, but the function ofHBx has been elusive until recently. It was recently shown that transcription from the HBV genome(covalently-closed circular DNA, cccDNA) is inhibited by the structural maintenance of chromosome 5/6complex (Smc5/6), and that a key function of HBx is to redirect the DNA-damage binding protein 1(DDB1) E3 ubiquitin ligase to target this complex for degradation. By doing so, HBx alleviatestranscriptional repression by Smc5/6 and stimulates HBV gene expression. In this review, we discuss indetail how the interplay between HBx and Smc5/6 was identified and characterized. We also discuss whatis known regarding the repression of cccDNA transcription by Smc5/6, the timing of HBx expression, andthe potential role of HBx in promoting hepatocellular carcinoma (HCC).", "metadata": {}}
+{"_id": "7647224", "title": "", "text": "Hepatitis C Virus (HCV) Vertical Transmission in 12-Month-Old Infants Born to HCV-Infected Women andAssessment of Maternal Risk FactorsBackground. Hepatitis C virus (HCV) is an underappreciated cause ofpediatric liver disease, most frequently acquired by vertical transmission (VT). Current guidelines thatinclude the option of screening infants for HCV RNA at 1-2 months are based on data prior to currentreal-time polymerase chain reaction (PCR)-based testing. Previous studies have demonstrated VT rates of4%-15% and an association with high maternal viral load. We evaluated HCV RNA in infants with HCV VTand assessed maternal risk factors in a prospective cohort in Cairo, Egypt. Methods. Pregnant womenwere screened for HCV from December 2012 to March 2014. For those with HCV viremia, their infantswere tested at 12 months for HCV RNA using real-time PCR. Maternal risk factors assessed for HCV VTassociation included HCV RNA levels, mode of delivery, and maternal IL28B genotype. Results. Of 2514women screened, a total of 54 women were viremic (2.1%) and delivered 56 infants. Of those, 51 infantsof 49 women were tested at 12 months of age. Only 7 infants were viremic, with an HCV VT rate of14.3% (7 of 49). Median HCV RNA in the infants was 2100 IU/mL. None of the maternal risk factorsanalyzed were associated with transmission. Conclusions. In Egypt where HCV is highly endemic, weobserved an overall 12-month HCV VT rate of 14.3%. Further studies should focus on better identificationof pregnant women more likely to vertically transmit HCV and earlier testing of infants to identify thoselikely to develop chronicity.", "metadata": {}}
+{"_id": "7650066", "title": "", "text": "Long-term follow-up of cervical disease in women screened by cytology and HPV testing: results from theHART studyBACKGROUND Several studies have shown that testing for high-risk human papillomavirus(HPV) types results in an improved sensitivity for CIN2+, compared with cytology, although with asomewhat lower specificity. METHODS We obtained follow-up results, with at least one smear afterparticipation in the HART study, which compared HPV testing (HC-II) with cytology as a primaryscreening modality. RESULTS With a median follow-up of 6 years, 42 additional cases of CIN2+ wereidentified; women who were HPV positive at baseline were more likely to develop CIN2+ than those whowere HPV negative (hazard ratio (HR) 17.2; 95% confidence interval (CI) (9.3-31.6)) and the riskincreased with increasing viral load. Compared with HPV-negative women (relative light unit (RLU) <1),the HR (95% CI) was 5.4 (1.6, 18.2) for 1-10 RLU and 25.5 (13.6, 47.9) for RLU > or = 10. Positivecytology (borderline or worse compared with negative) was also predictive of developing CIN2, althoughto a lesser extent (HR 8.7; 95% CI (4.5-17.1)). Only one case of CIN3 and three cases of CIN2 werefound in women who showed a positive cytology result but were HPV negative at baseline. CONCLUSIONAfter 5 years of follow-up, CIN2+ occurred in 0.23% of women who were HPV negative at baselinecompared with 0.48% of women who showed a negative cytology result, indicating a much longerlow-risk interval for CIN2+ after HPV testing.", "metadata": {}}
+{"_id": "7655029", "title": "", "text": "The Burden of Trachoma in Ayod County of Southern SudanBACKGROUND Blindness due to trachoma isavoidable through Surgery, Antibiotics, Facial hygiene and Environmental improvements (SAFE). Recentsurveys have shown trachoma to be a serious cause of blindness in Southern Sudan. We conducted thissurvey in Ayod County of Jonglei State to estimate the need for intervention activities to eliminateblinding trachoma. METHODOLOGY AND FINDINGS A cross-sectional two-stage cluster random surveywas conducted in November 2006. All residents of selected households were clinically assessed fortrachoma using the World Health Organization (WHO) simplified grading scheme. A total of 2,335 peoplefrom 392 households were examined, of whom 1,107 were over 14 years of age. Prevalence of signs ofactive trachoma in children 1-9 years of age was: trachomatous inflammation follicular (TF) = 80.1%(95% confidence interval [CI], 73.9-86.3); trachomatous inflammation intense (TI) = 60.7% (95% CI,54.6-66.8); and TF and/or TI (active trachoma) = 88.3% (95% CI, 83.7-92.9). Prevalence oftrachomatous trichiasis (TT) was 14.6% (95% CI, 10.9-18.3) in adults over 14 years of age; 2.9% (95%CI, 0.4-5.3) in children 1-14 years of age; and 8.4% (95% CI, 5.5-11.3) overall. The prevalence ofcorneal opacity in persons over 14 years of age with TT was 6.4% (95% CI, 4.5-8.3). No statisticallysignificant difference was observed in the prevalence of trachoma signs between genders. Trachomaaffected almost all households surveyed: 384/392 (98.0%) had at least one person with active trachomaand 130 (33.2%) had at least one person with trichiasis. CONCLUSIONS Trachoma is an unnecessarypublic health problem in Ayod. The high prevalence of active trachoma and trichiasis confirms the severeburden of blinding trachoma found in other post-conflict areas of Southern Sudan. Based on WHOrecommended thresholds, all aspects of the SAFE strategy are indicated to eliminate blinding trachoma inAyod.", "metadata": {}}
+{"_id": "7662206", "title": "", "text": "A Century of Cholesterol and Coronaries: From Plaques to Genes to StatinsOne-fourth of all deaths inindustrialized countries result from coronary heart disease. A century of research has revealed theessential causative agent: cholesterol-carrying low-density lipoprotein (LDL). LDL is controlled by specificreceptors (LDLRs) in liver that remove it from blood. Mutations that eliminate LDLRs raise LDL and causeheart attacks in childhood, whereas mutations that raise LDLRs reduce LDL and diminish heart attacks. Ifwe are to eliminate coronary disease, lowering LDL should be the primary goal. Effective means toachieve this goal are currently available. The key questions are: who to treat, when to treat, and howlong to treat.", "metadata": {}}
+{"_id": "7662395", "title": "", "text": "Perinatal mortality in rural China: retrospective cohort study.OBJECTIVES To explore the use of local civilregistration data to assess the perinatal mortality in a typical rural county in a less developed province inChina, 1999-2000. DESIGN Retrospective cohort study. Pregnancies in a cohort of women followed fromregistration of pregnancy to outcome of infant seven days after birth. SETTING Routine family planningrecords in 20 rural townships in eastern China. SUBJECTS 3697 pregnancies registered by the local familyplanning system during 1999. MAIN OUTCOME MEASURES Abortions, stillbirths, early neonatal mortality,perinatal mortality. RESULTS Only three cases were lost to follow up. The average age of the women atpregnancy was 25.9 years. Three hundred and twelve pregnancies were aborted and 240 ended inmiscarriage (total 552, 15%). The perinatal mortality rate was 69 per 1000 births, the rate of stillbirthwas 24 per 1000 births, and the early neonatal mortality was 46 per 1000 live births. The early neonatalmortality was 29 in boys and 69 in girls per 1000 live births. The perinatal mortality rate increasednotably with parity and was higher in townships having lower income per capita. CONCLUSIONS Thefamily planning system at the most local level is a useful data source for studying perinatal mortality inrural China. The perinatal mortality rate in the study county was higher than previously reported for bothrural and urban areas in China. The results by parity and sex of the infant raise concern over the impactof the one child policy.", "metadata": {}}
+{"_id": "7666498", "title": "", "text": "Genetic disruption of aurora B uncovers an essential role for aurora C during early mammaliandevelopment.Mitosis is controlled by multiple kinases that drive cell cycle progression and preventchromosome mis-segregation. Aurora kinase B interacts with survivin, borealin and incenp to form thechromosomal passenger complex (CPC), which is involved in the regulation of microtubule-kinetochoreattachments and cytokinesis. Whereas genetic ablation of survivin, borealin or incenp results in earlylethality at the morula stage, we show here that aurora B is dispensable for CPC function during early celldivisions and aurora B-null embryos are normally implanted. This is due to a crucial function of aurora Cduring these early embryonic cycles. Expression of aurora C decreases during late blastocyst stagesresulting in post-implantation defects in aurora B-null embryos. These defects correlate with abundantprometaphase figures and apoptotic cell death of the aurora B-deficient inner cell mass. Conditionaldeletion of aurora B in somatic cells that do not express aurora C results in chromosomal misalignmentand lack of chromosome segregation. Re-expression of wild-type, but not kinase-dead, aurora C rescuesthis defect, suggesting functional overlap between these two kinases. Finally, aurora B-null cells partiallyarrest in the presence of nocodazole, suggesting that this kinase is not essential for the spindle assemblycheckpoint.", "metadata": {}}
+{"_id": "7681810", "title": "", "text": "NuSAP is essential for chromatin-induced spindle formation during early embryogenesis.Mitotic spindleassembly is mediated by two processes: a centrosomal and a chromosomal pathway. RanGTP regulatesthe latter process by releasing microtubule-associated proteins from inhibitory complexes. NuSAP, amicrotubule- and DNA-binding protein, is a target of RanGTP and promotes the formation of microtubulesnear chromosomes. However, the contribution of NuSAP to cell proliferation in vivo is unknown. Here, wedemonstrate that the expression of NuSAP highly correlates with cell proliferation during embryogenesisand adult life, making it a reliable marker of proliferating cells. Additionally, we show that NuSAPdeficiency in mice leads to early embryonic lethality. Spindle assembly in NuSAP-deficient cells is highlyinefficient and chromosomes remain dispersed in the mitotic cytoplasm. As a result of sustained spindlecheckpoint activity, the cells are unable to progress through mitosis, eventually leading to caspaseactivation and apoptotic cell death. Together, our findings demonstrate that NuSAP is essential forproliferation of embryonic cells and, simultaneously, they underscore the importance ofchromatin-induced spindle assembly.", "metadata": {}}
+{"_id": "7688110", "title": "", "text": "E2F-6: a novel member of the E2F family is an inhibitor of E2F-dependent transcriptionThe E2F family oftranscription factors are essential for the regulation of genes required for appropriate progression throughthe cell cycle. Five members of the E2F family have been previously reported, namely E2F1-5. All five arekey elements in transcriptional regulation of essential genes, and they can be divided into two functionalgroups, those that induce S-phase progression when overexpressed in quiescent cells (E2Fs 1–3), andthose that do not (E2Fs 4–5). Here, we describe the identification of a novel member of this family, whichwe refer to as E2F-6. E2F-6 shares significant homology with E2Fs 1–5, especially within the DNAbinding, heterodimerization and marked box domains. Unlike E2Fs 1–5, E2F-6 lacks a transactivation anda pocket protein binding domain, hence, forms a unique third group within the E2F family. E2F-6 is anuclear protein that can form heterodimers with the DP proteins (both DP-1 and DP-2) in vitro and invivo. Our results show that the complex formed between E2F-6 and the DP proteins, possesses high DNAbinding activity, displaying a preference for a TTTCCCGC E2F recognition site, which is slightly different tothe E2F consensus site derived from the E2 promoter (TTTCGCGC). In contrast to the other members ofthe E2F family, ectopic expression of E2F-6 inhibits transcription from promoters possessing E2Frecognition sites rather than activating transcription. In addition, overexpression of E2F-6 suppresses thetransactivational effects of co-expression of E2F-1 and DP-1. The inhibitory effect of E2F-6 is dependenton its DNA binding activity and its ability to form heterodimers with the DPs. Interestingly, ectopicexpression of E2F-6 leads to accumulation of cells in S-phase. Our data suggest that E2F-6 expressiondelays the exit from S-phase rather than inducing S-phase, which further emphasizes the functionaldifference between E2F-6 and the previously known E2F family members.", "metadata": {}}
+{"_id": "7708803", "title": "", "text": "Enhancement of hippocampal pyramidal cell excitability by the novel selective slow-afterhyperpolarizationchannel blocker 3-(triphenylmethylaminomethyl)pyridine (UCL2077).The slow afterhyperpolarization(sAHP) in hippocampal neurons has been implicated in learning and memory. However, its precise role incell excitability and central nervous system function has not been explicitly tested for 2 reasons: 1) thereare, at present, no selective inhibitors that effectively reduce the underlying current in vivo or in intact invitro tissue preparations, and 2) although it is known that a small conductance K(+) channel thatactivates after a rise in [Ca(2+)](i) underlies the sAHP, the exact molecular identity remains unknown.We show that 3-(triphenylmethylaminomethyl)pyridine (UCL2077), a novel compound, suppressed thesAHP present in hippocampal neurons in culture (IC(50) = 0.5 microM) and in the slice preparation(IC(50) approximately 10 microM). UCL2077 was selective, having minimal effects on Ca(2+) channels,action potentials, input resistance and the medium afterhyperpolarization. UCL2077 also had little effecton heterologously expressed small conductance Ca(2+)-activated K(+) (SK) channels. Moreover,UCL2077 and apamin, a selective SK channel blocker, affected spike firing in hippocampal neurons indifferent ways. These results provide further evidence that SK channels are unlikely to underlie the sAHP.This study also demonstrates that UCL2077, the most potent, selective sAHP blocker described so far, is auseful pharmacological tool for exploring the role of sAHP channels in the regulation of cell excitability inintact tissue preparations and, potentially, in vivo.", "metadata": {}}
+{"_id": "7711685", "title": "", "text": "Lessons from sudden coronary death: a comprehensive morphological classification scheme foratherosclerotic lesions.This review will reconsider the current paradigm for understanding the critical,final steps in the progression of atherosclerotic lesions. That scheme, largely an outgrowth ofobservations of autopsy tissues by Davies and colleagues,1 2 asserts that the cause of death inatherosclerotic coronary artery disease is rupture of an advanced atherosclerotic lesion. Although thisassumption may be partially true, recent autopsy studies suggest that it is incomplete. To reconsider thisparadigm, we reexamined the morphological classification scheme for lesions proposed by the AmericanHeart Association (AHA).3 4 This scheme is difficult to use for 2 reasons. First, it uses a very long list ofroman numerals modified by letter codes that are difficult to remember. Second, it implies an orderly,linear pattern of lesion progression. This tends to be ambiguous, because it is not clear whether there is asingle sequence of events during the progression of all lesions. We have therefore tried to devise asimpler classification scheme that is consistent with the AHA categories but is easier to use, able to dealwith a wide array of morphological variations, and not overly burdened by mechanistic implications. Thecurrent paradigm is based on the belief that type IV lesions, or “atheromas,” described by the AHA arestable because the fatty, necrotic core is contained by a smooth muscle cell–rich fibrous cap. Virchow’sanalysis5 in 1858 pointed out that historically, the term “atheroma” refers to a dermal cyst (“Grutzbalg”),a fatty …", "metadata": {}}
+{"_id": "7717468", "title": "", "text": "Loss of allergen 1 confers a hypervirulent phenotype that resembles mucoid switch variants ofCryptococcus neoformans.Microbial survival in a host is usually dependent on the ability of a pathogen toundergo changes that promote escape from host defense mechanisms. The human-pathogenic fungusCryptococcus neoformans undergoes phenotypic switching in vivo that promotes persistence in tissue. Bymicroarray and real-time PCR analyses, the allergen 1 gene (ALL1) was found to be downregulated in thehypervirulent mucoid switch variant, both during logarithmic growth and during intracellular growth inmacrophages. The ALL1 gene encodes a small cytoplasmic protein that is involved in capsule formation.Growth of an all1Delta gene deletion mutant was normal. Similar to cells of the mucoid switch variant,all1Delta cells produced a larger polysaccharide capsule than cells of the smooth parent and thecomplemented strain produced, and the enlarged capsule inhibited macrophage phagocytosis. Themutant exhibited a modest defect in capsule induction compared to all of the other variants. In animalmodels the phenotype of the all1Delta mutant mimicked the hypervirulent phenotype of the mucoidswitch variant, which is characterized by decreased host survival and elevated intracranial pressure.Decreased survival is likely the result of both an ineffective cell-mediated immune response and impairedphagocytosis by macrophages. Consequently, we concluded that, unlike loss of most virulence-associatedgenes, where loss of gene function results in attenuated virulence, loss of the ALL1 gene enhancesvirulence by altering the host-pathogen interaction and thereby impairing clearance. Our data identifiedthe first cryptococcal gene associated with elevated intracranial pressure and support the hypothesis thatan environmental opportunistic pathogen has modified its virulence in vivo by epigenetic downregulationof gene function.", "metadata": {}}
+{"_id": "7729656", "title": "", "text": "Lessons from more than 80 structures of the GluA2 ligand-binding domain in complex with agonists,antagonists and allosteric modulators.Ionotropic glutamate receptors (iGluRs) constitute a family ofligand-gated ion channels that are essential for mediating fast synaptic transmission in the centralnervous system. These receptors play an important role for the development and function of the nervoussystem, and are essential in learning and memory. However, iGluRs are also implicated in or have causalroles for several brain disorders, e.g. epilepsy, Alzheimer's disease, Parkinson's disease andschizophrenia. Their involvement in neurological diseases has stimulated widespread interest in theirstructure and function. Since the first publication in 1998 of the structure of a recombinant solubleprotein comprising the ligand-binding domain of GluA2 extensive studies have afforded numerous crystalstructures of wildtype and mutant proteins including different ligands. The structural information obtainedcombined with functional data have led to models for receptor activation and desensitization by agonists,inhibition by antagonists and block of desensitization by positive allosteric modulators. Furthermore, thestructural and functional studies have formed a powerful platform for the design of new selectivecompounds.", "metadata": {}}
+{"_id": "7734150", "title": "", "text": "Diaphragm Atrophy and Contractile Dysfunction in a Murine Model of Pulmonary HypertensionPulmonaryhypertension (PH) causes loss of body weight and inspiratory (diaphragm) muscle dysfunction. A modelof PH induced by drug (monocrotaline, MCT) has been extensively used in mice to examine the etiology ofPH. However, it is unclear if PH induced by MCT in mice reproduces the loss of body weight anddiaphragm muscle dysfunction seen in patients. This is a pre-requisite for widespread use of mice toexamine mechanisms of cachexia and diaphragm abnormalities in PH. Thus, we measured body andsoleus muscle weight, food intake, and diaphragm contractile properties in mice after 6-8 weeks of saline(control) or MCT (600 mg/kg) injections. Body weight progressively decreased in PH mice, while foodintake was similar in both groups. PH decreased (P<0.05) diaphragm maximal isometric specific force,maximal shortening velocity, and peak power. Protein carbonyls in whole-diaphragm lysates and theabundance of select myofibrillar proteins were unchanged by PH. Our findings show diaphragm isometricand isotonic contractile abnormalities in a murine model of PH induced by MCT. Overall, the murine modelof PH elicited by MCT mimics loss of body weight and diaphragm muscle weakness reported in PHpatients.", "metadata": {}}
+{"_id": "7735859", "title": "", "text": "Identification of an anti-inflammatory protein from Faecalibacterium prausnitzii, a commensal bacteriumdeficient in Crohn's disease.BACKGROUND Crohn's disease (CD)-associated dysbiosis is characterised bya loss of Faecalibacterium prausnitzii, whose culture supernatant exerts an anti-inflammatory effect bothin vitro and in vivo. However, the chemical nature of the anti-inflammatory compounds has not yet beendetermined. METHODS Peptidomic analysis using mass spectrometry was applied to F. prausnitziisupernatant. Anti-inflammatory effects of identified peptides were tested in vitro directly on intestinalepithelial cell lines and on cell lines transfected with a plasmid construction coding for the candidateprotein encompassing these peptides. In vivo, the cDNA of the candidate protein was delivered to the gutby recombinant lactic acid bacteria to prevent dinitrobenzene sulfonic acid (DNBS)-colitis in mice.RESULTS The seven peptides, identified in the F. prausnitzii culture supernatants, derived from a singlemicrobial anti-inflammatory molecule (MAM), a protein of 15 kDa, and comprising 53% of non-polarresidues. This last feature prevented the direct characterisation of the putative anti-inflammatory activityof MAM-derived peptides. Transfection of MAM cDNA in epithelial cells led to a significant decrease in theactivation of the nuclear factor (NF)-κB pathway with a dose-dependent effect. Finally, the use of afood-grade bacterium, Lactococcus lactis, delivering a plasmid encoding MAM was able to alleviateDNBS-induced colitis in mice. CONCLUSIONS A 15 kDa protein with anti-inflammatory properties isproduced by F. prausnitzii, a commensal bacterium involved in CD pathogenesis. This protein is able toinhibit the NF-κB pathway in intestinal epithelial cells and to prevent colitis in an animal model.", "metadata": {}}
+{"_id": "7736860", "title": "", "text": "Calcium store sensor stromal-interaction molecule 1-dependent signaling plays an important role incervical cancer growth, migration, and angiogenesis.Store-operated Ca(2+) entry (SOCE) is the principalCa(2+) entry mechanism in nonexcitable cells. Stromal-interaction molecule 1 (STIM1) is an endoplasmicreticulum Ca(2+) sensor that triggers SOCE activation. However, the role of STIM1 in regulating cancerprogression remains controversial and its clinical relevance is unclear. Here we show thatSTIM1-dependent signaling is important for cervical cancer cell proliferation, migration, and angiogenesis.STIM1 overexpression in tumor tissue is noted in 71% cases of early-stage cervical cancer. In tumortissues, the level of STIM1 expression is significantly associated with the risk of metastasis and survival.EGF-stimulated cancer cell migration requires STIM1 expression and EGF increases the interactionbetween STIM1 and Orai1 in juxta-membrane areas, and thus induces Ca(2+) influx. STIM1 involves theactivation of Ca(2+)-regulated protease calpain, as well as Ca(2+)-regulated cytoplasmic kinase Pyk2,which regulate the focal-adhesion dynamics of migratory cervical cancer cells. Because of an increase ofp21 protein levels and a decrease of Cdc25C protein levels, STIM1-silencing in cervical cancer cellssignificantly inhibits cell proliferation by arresting the cell cycle at the S and G2/M phases. STIM1 alsoregulates the production of VEGF in cervical cancer cells. Interference with STIM1 expression or blockadeof SOCE activity inhibits tumor angiogenesis and growth in animal models, confirming the crucial role ofSTIM1-mediated Ca(2+) influx in aggravating tumor development in vivo. These results makeSTIM1-dependent signaling an attractive target for therapeutic intervention.", "metadata": {}}
+{"_id": "7751726", "title": "", "text": "A feasibility study for a randomised controlled trial of the Positive Reappraisal Coping Intervention, anovel supportive technique for recurrent miscarriageINTRODUCTION Recurrent miscarriage (RM) isdiagnosed when a woman has had three or more miscarriages. Increased levels of distress and anxietyare common during the waiting period of any subsequent pregnancies, posing a significant threat topsychological well-being. However, only limited support and therapy are available for these women, andmany are left to cope alone. The Positive Reappraisal Coping Intervention (PRCI) is a novelself-administered supportive technique which has been shown to be effective in patients awaiting theoutcome of in vitro fertilisation treatment. The primary objective of this study is to assess the feasibilityand effectiveness of the PRCI in improving quality of life in the difficult waiting period which women withprevious RM endure before an ongoing pregnancy can be confirmed. METHODS AND ANALYSIS Arandomised controlled trial (RCT) feasibility study will establish the viability of conducting a multicentreRCT to definitively test the effects of the PRCI on the psychological well-being of women who haveexperienced RM during the initial waiting period of a subsequent pregnancy. A second component consistsof a qualitative process evaluation exploring the initial experience of pregnancy following repeatedmiscarriages. Participants (n=50) will be randomised into one of two groups. The PRCI intervention groupwill receive the PRCI card and weekly questionnaires to assess their psychological well-being during thewaiting period of their new pregnancy. The non-intervention group will be asked to complete the sameweekly questionnaires. The qualitative process analysis will employ semistructured interviews (n=20) toaddress relevant aspects of the study objectives. ETHICS AND DISSEMINATION Ethics approval has beenobtained from the National Research Ethics Service Committee South Central-Hampshire A. Participatingcentres have given National Health Service R&D approval. Study findings will be disseminated throughpeer reviewed journals, national and international conferences and lay user groups. TRIALREGISTRATION NUMBER ISRCTN43571276. This study was registered with the ISRCTN 18/02/2014following adoption onto the United Kingdom Clinical Research Network (UKCRN) portfolio. Recruitment ofthe first participant occurred 04/02/2014.", "metadata": {}}
+{"_id": "7757997", "title": "", "text": "Report of the National Heart, Lung, and Blood Institute Workshop on Lipoprotein(a) and CardiovascularDisease: recent advances and future directions.It has been estimated that approximately 37% of the USpopulation judged to be at high risk for developing coronary artery disease (CAD), based on the NationalCholesterol Education Program guidelines, have increased plasma lipoprotein(a) [Lp(a)], whereas Lp(a) isincreased in only 14% of those judged to be at low risk. Therefore, the importance of establishing abetter understanding of the relative contribution of Lp(a) to the risk burden for CAD and other forms ofvascular disease, as well as the underlying mechanisms, is clearly evident. However, the structuralcomplexity and size heterogeneity of Lp(a) have hindered the development of immunoassays toaccurately measure Lp(a) concentrations in plasma. The large intermethod variation in Lp(a) values hasmade it difficult to compare data from different clinical studies and to achieve a uniform interpretation ofclinical data. A workshop was recently convened by the National Heart, Lung, and Blood Institute (NHLBI)to evaluate our current understanding of Lp(a) as a risk factor for atherosclerotic disorders; to determinehow future studies could be designed to more clearly define the extent to which, and mechanisms bywhich, Lp(a) participates in these processes; and to present the results of the NHLBI-supported programfor the evaluation and standardization of Lp(a) immunoassays. This report includes the most recent datapresented by the workshop participants and the resulting practical and research recommendations.", "metadata": {}}
+{"_id": "7764903", "title": "", "text": "Classification, functions, and clinical relevance of extracellular vesicles.Both eukaryotic and prokaryoticcells release small, phospholipid-enclosed vesicles into their environment. Why do cells release vesicles?Initial studies showed that eukaryotic vesicles are used to remove obsolete cellular molecules. Althoughthis release of vesicles is beneficial to the cell, the vesicles can also be a danger to their environment, forinstance in blood, where vesicles can provide a surface supporting coagulation. Evidence is accumulatingthat vesicles are cargo containers used by eukaryotic cells to exchange biomolecules as transmembranereceptors and genetic information. Because also bacteria communicate to each other via extracellularvesicles, the intercellular communication via extracellular cargo carriers seems to be conservedthroughout evolution, and therefore vesicles are likely to be a highly efficient, robust, and economicmanner of exchanging information between cells. Furthermore, vesicles protect cells from accumulationof waste or drugs, they contribute to physiology and pathology, and they have a myriad of potentialclinical applications, ranging from biomarkers to anticancer therapy. Because vesicles may pass theblood-brain barrier, they can perhaps even be considered naturally occurring liposomes. Unfortunately,pathways of vesicle release and vesicles themselves are also being used by tumors and infectiousdiseases to facilitate spreading, and to escape from immune surveillance. In this review, the differenttypes, nomenclature, functions, and clinical relevance of vesicles will be discussed.", "metadata": {}}
+{"_id": "7766808", "title": "", "text": "Estimating the sample mean and standard deviation from the sample size, median, range and/orinterquartile rangeIn systematic reviews and meta-analysis, researchers often pool the results of thesample mean and standard deviation from a set of similar clinical trials. A number of the trials, however,reported the study using the median, the minimum and maximum values, and/or the first and thirdquartiles. Hence, in order to combine results, one may have to estimate the sample mean and standarddeviation for such trials. In this paper, we propose to improve the existing literature in several directions.First, we show that the sample standard deviation estimation in Hozo et al. (2005) has some seriouslimitations and is always less satisfactory in practice. Inspired by this, we propose a new estimationmethod by incorporating the sample size. Second, we systematically study the sample mean andstandard deviation estimation problem under more general settings where the first and third quartiles arealso available for the trials. Through simulation studies, we demonstrate that the proposed methodsgreatly improve the existing methods and enrich the literature. We conclude our work with a summarytable that serves as a comprehensive guidance for performing meta-analysis in different situations.", "metadata": {}}
+{"_id": "7795952", "title": "", "text": "Fascin protein is critical for transforming growth factor β protein-induced invasion and filopodia formationin spindle-shaped tumor cells.Fascin, an actin-bundling protein overexpressed in all carcinomas, has beenassociated with poor prognosis, shorter survival, and more metastatic diseases. It is believed that fascinfacilitates tumor metastasis by promoting the formation of invasive membrane protrusions. However, themechanisms by which fascin is overexpressed in tumors are not clear. TGFβ is a cytokine secreted bytumor and mesenchymal cells and promotes metastasis in many late stage tumors. The pro-metastasismechanisms of TGFβ remain to be fully elucidated. Here we demonstrated that TGFβ induced fascinexpression in spindle-shaped tumor cells through the canonical Smad-dependent pathway. Fascin wascritical for TGFβ-promoted filopodia formation, migration, and invasion in spindle tumor cells. Moreimportantly, fascin expression significantly correlates with TGFβ1 and TGFβ receptor I levels in a cohort ofprimary breast tumor samples. Our results indicate that elevated TGFβ level in the tumormicroenvironment may be responsible for fascin overexpression in some of the metastatic tumors. Ourdata also suggest that fascin could play a central role in TGFβ-promoted tumor metastasis.", "metadata": {}}
+{"_id": "7808055", "title": "", "text": "DNA methylation age of human tissues and cell typesBACKGROUND It is not yet known whether DNAmethylation levels can be used to accurately predict age across a broad spectrum of human tissues andcell types, nor whether the resulting age prediction is a biologically meaningful measure. RESULTS Ideveloped a multi-tissue predictor of age that allows one to estimate the DNA methylation age of mosttissues and cell types. The predictor, which is freely available, was developed using 8,000 samples from82 Illumina DNA methylation array datasets, encompassing 51 healthy tissues and cell types. I found thatDNA methylation age has the following properties: first, it is close to zero for embryonic and inducedpluripotent stem cells; second, it correlates with cell passage number; third, it gives rise to a highlyheritable measure of age acceleration; and, fourth, it is applicable to chimpanzee tissues. Analysis of6,000 cancer samples from 32 datasets showed that all of the considered 20 cancer types exhibitsignificant age acceleration, with an average of 36 years. Low age-acceleration of cancer tissue isassociated with a high number of somatic mutations and TP53 mutations, while mutations in steroidreceptors greatly accelerate DNA methylation age in breast cancer. Finally, I characterize the 353 CpGsites that together form an aging clock in terms of chromatin states and tissue variance. CONCLUSIONS Ipropose that DNA methylation age measures the cumulative effect of an epigenetic maintenance system.This novel epigenetic clock can be used to address a host of questions in developmental biology, cancerand aging research.", "metadata": {}}
+{"_id": "7813993", "title": "", "text": "Whole-body MR vascular screening detects unsuspected concomitant vascular disease in coronary heartdisease patientsCoronary heart disease (CHD) patients often show atherosclerotic vascular disease inother vascular territories. We evaluated how often whole-body MR imaging detects concomitant arterialpathologies in CHD patients, and how often these pathologies were not known to the patients previously.Of 4,814 participants in the population-based Heinz Nixdorf Recall Study, 327 reported CHD (i.e.,previous coronary bypass surgery, angioplasty); of those, 160 patients (mean age 66.4 years) wereexamined using MR of the brain, the heart (excluding the coronary arteries), and whole-body MRangiography. The prevalence of each vascular pathology was assessed, correlated to the others andcompared to patients’ histories. Of the 160 CHD patients, 16 (10%) showed MR signs of stroke, and 77(48.1%) had a stenosis >50% in at least one extracerebral peripheral artery (other than the coronaries),including 28 (17.5%) with relevant renal artery stenoses, and 20 (12.5%) with relevant extracerebralinternal carotid artery stenoses. False negative histories were reported in 12 of 81 cases with myocardialinfarctions, and in 11 of 16 cases with cerebrovascular infarctions. This whole-body atherosclerosis MRscreening program allows previously unknown concomitant vascular disease to be detected in coronaryheart disease patients. Its prospective value should be assessed in further studies.", "metadata": {}}
+{"_id": "7820043", "title": "", "text": "Key role of Ubc5 and lysine-63 polyubiquitination in viral activation of IRF3.The mitochondrial antiviralsignaling protein (MAVS; also known as IPS-1, VISA, and CARDIF) is essential for innate immuneresponse against RNA viruses. MAVS transduces signals from the cytosolic RIG-I-like receptors, whichbind to viral RNAs. But how MAVS activates downstream transcription factors such as IRF3 to inducetype-I interferons is not well understood. We have established a cell-free system in which mitochondriaderived from virus-infected cells activate IRF3 in the cytosol. Fractionation of the cytosol led to theidentification of Ubc5 as a ubiquitin-conjugating enzyme (E2) required for IRF3 activation. Using aninducible RNAi strategy, we demonstrate that catalytically active Ubc5 is required for IRF3 activation byviral infection. The activation of IRF3 also requires two ubiquitin-binding domains of NEMO. Furthermore,we show that replacement of endogenous ubiquitin with its K63R mutant abolishes viral activation ofIRF3, demonstrating that K63 polyubiquitination plays a key role in IRF3 activation.", "metadata": {}}
+{"_id": "7821634", "title": "", "text": "Profiling of residual breast cancers after neoadjuvant chemotherapy identifies DUSP4 deficiency as amechanism of drug resistanceNeoadjuvant chemotherapy (NAC) induces a pathological completeresponse (pCR) in \u000030% of patients with breast cancer. However, many patients have residual cancerafter chemotherapy, which correlates with a higher risk of metastatic recurrence and poorer outcomethan those who achieve a pCR. We hypothesized that molecular profiling of tumors after NAC wouldidentify genes associated with drug resistance. Digital transcript counting was used to profile surgicallyresected breast cancers after NAC. Low concentrations of dual specificity protein phosphatase 4 (DUSP4),an ERK phosphatase, correlated with high post-NAC tumor cell proliferation and with basal-like breastcancer (BLBC) status. BLBC had higher DUSP4 promoter methylation and gene expression patterns ofRas-ERK pathway activation relative to other breast cancer subtypes. DUSP4 overexpression increasedchemotherapy-induced apoptosis, whereas DUSP4 depletion dampened the response to chemotherapy.Reduced DUSP4 expression in primary tumors after NAC was associated with treatment-refractory highKi-67 scores and shorter recurrence-free survival. Finally, inhibition of mitogen-activated protein kinasekinase (MEK) synergized with docetaxel treatment in BLBC xenografts. Thus, DUSP4 downregulationactivates the Ras-ERK pathway in BLBC, resulting in an attenuated response to anti-cancerchemotherapy.", "metadata": {}}
+{"_id": "7834603", "title": "", "text": "Age-related behaviors have distinct transcriptional profiles in Caenorhabditis elegans.There has been agreat deal of interest in identifying potential biomarkers of aging. Biomarkers of aging would be useful topredict potential vulnerabilities in an individual that may arise well before they are chronologicallyexpected, due to idiosyncratic aging rates that occur between individuals. Prior attempts to identifybiomarkers of aging have often relied on the comparisons of long-lived animals to a wild-type control.However, the effect of interventions in model systems that prolong lifespan (such as single genemutations or caloric restriction) can sometimes be difficult to interpret due to the manipulation itselfhaving multiple unforeseen consequences on physiology, unrelated to aging itself. The search forpredictive biomarkers of aging therefore is problematic, and the identification of metrics that can be usedto predict either physiological or chronological age would be of great value. One methodology that hasbeen used to identify biomarkers for numerous pathologies is gene expression profiling. Here, we reportwhole-genome expression profiles of individual wild-type Caenorhabditis elegans covering the entirewild-type nematode lifespan. Individual nematodes were scored for either age-related behavioralphenotypes, or survival, and then subsequently associated with their respective gene expression profiles.This facilitated the identification of transcriptional profiles that were highly associated with eitherphysiological or chronological age. Overall, our approach serves as a paradigm for identifying potentialbiomarkers of aging in higher organisms that can be repeatedly sampled throughout their lifespan.", "metadata": {}}
+{"_id": "7837879", "title": "", "text": "Synchronization of Diffusively-Connected Nonlinear Systems: Results Based on Contractions with Respectto General NormsContraction theory provides an elegant way to analyze the behavior of certain nonlineardynamical systems. In this paper, we discuss the application of contraction to synchronization ofdiffusively interconnected components described by nonlinear differential equations. We provideestimates of convergence of the difference in states between components, in the cases of line, complete,and star graphs, and Cartesian products of such graphs. We base our approach on contraction theory,using matrix measures derived from norms that are not induced by inner products. Such norms are themost appropriate in many applications, but proofs cannot rely upon Lyapunov-like linear matrixinequalities, and different techniques, such as the use of the Perron-Frobenious Theorem in the cases ofL1 or L∞ norms, must be introduced.", "metadata": {}}
+{"_id": "7838799", "title": "", "text": "GeneTrack--a genomic data processing and visualization framework.MOTIVATION High-throughput'ChIP-chip' and 'ChIP-seq' methodologies generate sufficiently large data sets that analysis posessignificant informatics challenges, particularly for research groups with modest computational support. Toaddress this challenge, we devised a software platform for storing, analyzing and visualizing highresolution genome-wide binding data. GeneTrack automates several steps of a typical data processingpipeline, including smoothing and peak detection, and facilitates dissemination of the results via the web.Our software is freely available via the Google Project Hosting environment athttp://genetrack.googlecode.com", "metadata": {}}
+{"_id": "7840442", "title": "", "text": "Multisite optical recording of excitability in the enteric nervous system.A multisite optical recordingtechnique consisting of an array of 464 photodiodes was used to measure dynamic changes intransmembrane potentials (Vm) of guinea-pig and mouse enteric neurones stained with thevoltage-sensitive dye Di-8-ANEPPS. Optical recordings of Vm changes in enteric neurones which wereevoked by depolarizing current pulses or synaptic activation mirrored the Vm changes measuredintracellularly in the same neurone. Action potentials had fractional change in fluorescence of -0.09 +/-0.06% and their peak to peak noise level was 20 +/- 14% of the action potential amplitude. Opticalrecordings after electrical stimulation of interganglionic nerve strands revealed slow EPSPs, nicotinergicsupra- and subthreshold fast EPSPs as well as propagation of action potentials along interganglionicstrands. Local application of acetylcholine onto a single ganglion induced reproducibly and dosedependently action potential discharge demonstrating the feasibility of neuropharmacological studies. Theoptical mapping made it possible to record action potentials simultaneously in a large number ofneurones with high spatiotemporal resolution that is unattainable by conventional techniques. Thistechnique presents a powerful tool to study excitability spread within enteric circuits and to assessdifferential activation of enteric populations in response to a number of stimuli which modulate neuronalactivity directly or through synaptic mechanisms.", "metadata": {}}
+{"_id": "7848113", "title": "", "text": "Telomere-bound TRF1 and TRF2 stall the replication fork at telomeric repeats.Vertebrate telomeresconsist of tandem repeats of T2AG3 and associated proteins including the telomeric DNA-bindingproteins, TRF1 and TRF2. It has been proposed that telomeres assume two interswitchable states, theopen state that is accessible to various trans-acting factors and the closed state that excludes thosefactors. TRF1 and TRF2 are believed to promote the formation of the closed state. However, little isknown about how those two states influence DNA replication. We analyzed the effects of TRF1 and TRF2on telomeric replication both in vitro and in vivo. By exploiting the in vitro replication system of linearSV40 DNA, we found that telomeric repeats are a poor replication template. Moreover, the addition ofrecombinant TRF1 and TRF2 significantly stalled the replication fork progression at telomeric repeats.When TRF1 was overexpressed in HeLa cells, cells with 4N DNA content were accumulated. Furthermore,cytological analyses revealed that the replication focus overlapped with telomere signals at a significantlyhigher frequency in TRF1-overexpressing cells than in control cells. The results suggest that TRF1 andTRF2 exert inhibitory effects on replication fork progression.", "metadata": {}}
+{"_id": "7850867", "title": "", "text": "Margination of white blood cells in microcapillary flow.Margination of white blood cells (WBCs) towardsvessel walls is an essential precondition for their efficient adhesion to the vascular endothelium. Weperform numerical simulations with a two-dimensional blood flow model to investigate the dependence ofWBC margination on hydrodynamic interactions of blood cells with the vessel walls, as well as on theircollective behavior and deformability. We find WBC margination to be optimal in intermediate ranges ofred blood cell (RBC) volume fractions and flow rates, while, beyond these ranges, it is substantiallyattenuated. RBC aggregation enhances WBC margination, while WBC deformability reduces it. Theseresults are combined in state diagrams, which identify WBC margination for a wide range of flow and cellsuspension conditions.", "metadata": {}}
+{"_id": "7852582", "title": "", "text": "Lung cancer treatment waiting times and tumour growth.We report a single-centre prospective audit of29 lung cancer patients who were awaiting radical (potentially curative) radiotherapy. This was the totalnumber assessed as suitable for radical treatment by one consultant during 1999. At the time ofassessment they had been newly diagnosed and staged with a computed tomographic (CT) scan of chest.They had a subsequent CT scan prior to starting treatment for the purpose of planning the radiationfields. We have now measured tumour size on the diagnostic scans and compared this with the size onthe planning scans. We have documented the delay between diagnostic and planning CT scanning and thetotal time between first hospital visit and starting treatment. Two patients had progression of symptomswhile on the waiting list, making them unfit for radical treatment, and another four had tumourprogression on planning CT such that the tumour volume was too large for radical treatment. Therefore,21% of potentially curable patients became incurable on the waiting list. The delay between diagnosticand planning CT scans ranged from 18 to 131 days (median 54), with increases in the cross-sectionaltumour size over that period ranging zero to 373%. The delay between the first hospital visit and startingtreatment was 35-187 days (median 94); between the date of the radiotherapy request and the startingdate for treatment it was 23-61 days (median 44). Limited access to specialists is the reason most oftenadvanced for the poor performance of the UK in treating lung cancer. This study demonstrates that, evenfor the select minority of patients who have specialist referral and are deemed suitable for potentiallycurative treatment, the outcome is prejudiced by waiting times that allow tumour progression.", "metadata": {}}
+{"_id": "7860396", "title": "", "text": "Functional coupling of RNAP II transcription to spliceosome assembly.The pathway of gene expression inhigher eukaryotes involves a highly complex network of physical and functional interactions among thedifferent machines involved in each step of the pathway. Here we established an efficient in vitro systemto determine how RNA polymerase II (RNAP II) transcription is functionally coupled to pre-mRNA splicing.Strikingly, our data show that nascent pre-messenger RNA (pre-mRNA) synthesized by RNAP II isimmediately and quantitatively directed into the spliceosome assembly pathway. In contrast, nascentpre-mRNA synthesized by T7 RNA polymerase is quantitatively assembled into the nonspecific H complex,which consists of heterogeneous nuclear ribonucleoprotein (hnRNP) proteins and is inhibitory forspliceosome assembly. Consequently, RNAP II transcription results in a dramatic increase in both thekinetics of splicing and overall yield of spliced mRNA relative to that observed for T7 transcription. Weconclude that RNAP II mediates the functional coupling of transcription to splicing by directing thenascent pre-mRNA into spliceosome assembly, thereby bypassing interaction of the pre-mRNA with theinhibitory hnRNP proteins.", "metadata": {}}
+{"_id": "7869794", "title": "", "text": "Calicum microdomains form within neutrophils at the neutrophil–tumor cell synapse: role inantibody-dependent target cell apoptosisCa2+ messages are broadly important in cellular signaltransduction. In immune cells, Ca2+ signaling is an essential step in many forms of activation.Neutrophil-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) is one form of leukocyteactivation that plays an important role in tumor cell killing in vitro and in patient care. Using fluorescencemethodologies, we found that neutrophils exhibit Ca2+ signals during ADCC directed against breastfibrosarcoma cells. Importantly, these signals were localized to Ca2+ microdomains at theneutrophil-to-tumor cell interface where they display dynamic features such as movement, fusion, andfission. These signals were blocked by the intracellular Ca2+ buffer BAPTA. At the neutrophil–tumor cellsynapse, the neutrophil’s cytoplasm was enriched in STIM1, a crucial mediator of Ca2+ signaling,whereas the Ca2+-binding proteins calbindin and parvalbumin were not affected. Our findings suggestthat Ca2+ microdomains are due to an active signaling process. As Ca2+ signals within neutrophils werenecessary for specific tumor cell apoptosis, a central role of microdomains in leukocyte-mediated tumorcell destruction is indicated.", "metadata": {}}
+{"_id": "7873737", "title": "", "text": "Platelet glycoprotein IIb/IIIa inhibitors reduce mortality in diabetic patients withnon-ST-segment-elevation acute coronary syndromes.BACKGROUND Diabetes mellitus is a major riskfactor for adverse outcomes after acute coronary syndromes (ACS). Because this disease may beassociated with increased platelet aggregation, we investigated whether diabetic patients with ACS deriveparticular benefit from platelet glycoprotein (GP) IIb/IIIa receptor inhibition. METHODS AND RESULTS Weperformed a meta-analysis of the diabetic populations enrolled in the 6 large-scale platelet GP IIb/IIIainhibitor ACS trials: PRISM, PRISM-PLUS, PARAGON A, PARAGON B, PURSUIT, and GUSTO IV. Among6458 diabetic patients, platelet GP IIb/IIIa inhibition was associated with a significant mortality reductionat 30 days, from 6.2% to 4.6% (OR 0.74; 95% CI 0.59 to 0.92; P=0.007). Conversely, 23 072nondiabetic patients had no survival benefit (3.0% versus 3.0%). The interaction between platelet GPIIb/IIIa inhibition and diabetic status was statistically significant (P=0.036). Among 1279 diabeticpatients undergoing percutaneous coronary intervention (PCI) during index hospitalization, the use ofthese agents was associated with a mortality reduction at 30 days from 4.0% to 1.2% (OR 0.30; 95% CI0.14 to 0.69; P=0.002). CONCLUSIONS This meta-analysis, including the entire large-scale trialexperience of intravenous platelet GP IIb/IIIa inhibitors for the medical management ofnon-ST-segment-elevation ACS, shows that these agents may significantly reduce mortality at 30 days indiabetic patients. Although not based on a randomized assessment, the survival benefit appears to be ofgreater magnitude in patients undergoing PCI. Therefore, the use of platelet GP IIb/IIIa inhibitors shouldbe strongly considered in diabetic patients with ACS.", "metadata": {}}
+{"_id": "7875158", "title": "", "text": "Glucose deprivation-induced cytotoxicity and alterations in mitogen-activated protein kinase activationare mediated by oxidative stress in multidrug-resistant human breast carcinoma cells.We previouslyobserved that glucose deprivation induces cell death in multidrug-resistant human breast carcinoma cells(MCF-7/ADR). As a follow up we wished to test the hypothesis that metabolic oxidative stress was thecausative process or at least the link between causative processes behind the cytotoxicity. In the studiesdescribed here, we demonstrate that mitogen-activated protein kinase (MAPK) was activated within 3 minof being in glucose-free medium and remained activated for 3 h. Glucose deprivation for 2-4 h alsocaused oxidative stress as evidenced by a 3-fold greater steady state concentration of oxidizedglutathione and a 3-fold increase in pro-oxidant production. Glucose and glutamate treatment rapidlysuppressed MAPK activation and rescued cells from cytotoxicity. Glutamate and the peroxide scavenger,pyruvate, rescued the cells from cell killing as well as suppressed pro-oxidant production. In addition thethiol antioxidant, N-acetyl-L-cysteine, rescued cells from glucose deprivation-induced cytotoxicity andsuppressed MAPK activation. These results suggest that glucose deprivation-induced cytotoxicity andalterations in MAPK signal transduction are mediated by oxidative stress in MCF-7/ADR. These resultsalso support the speculation that a common mechanism of glucose deprivation-induced cytotoxicity inmammalian cells may involve metabolic oxidative stress.", "metadata": {}}
+{"_id": "7878807", "title": "", "text": "A structural basis for kinetochore recruitment of the Ndc80 complex via two distinct centromerereceptors.The Ndc80 complex is the key microtubule-binding element of the kinetochore. In contrast tothe well-characterized interaction of Ndc80-Nuf2 heads with microtubules, little is known about how theSpc24-25 heterodimer connects to centromeric chromatin. Here, we present molecular details ofSpc24-25 in complex with the histone-fold protein Cnn1/CENP-T illustrating how this connectionultimately links microtubules to chromosomes. The conserved Ndc80 receptor motif of Cnn1 is bound asan α helix in a hydrophobic cleft at the interface between Spc24 and Spc25. Point mutations that disruptthe Ndc80-Cnn1 interaction also abrogate binding to the Mtw1 complex and are lethal in yeast. Weidentify a Cnn1-related motif in the Dsn1 subunit of the Mtw1 complex, necessary for Ndc80 binding andessential for yeast growth. Replacing this region with the Cnn1 peptide restores viability demonstratingfunctionality of the Ndc80-binding module in different molecular contexts. Finally, phosphorylation of theCnn1 N-terminus coordinates the binding of the two competing Ndc80 interaction partners. Together, ourdata provide structural insights into the modular binding mechanism of the Ndc80 complex to itscentromere recruiters.", "metadata": {}}
+{"_id": "7898952", "title": "", "text": "Feedback Circuit among INK4 Tumor Suppressors Constrains Human Glioblastoma DevelopmentWe havedeveloped a nonheuristic genome topography scan (GTS) algorithm to characterize the patterns ofgenomic alterations in human glioblastoma (GBM), identifying frequent p18(INK4C) and p16(INK4A)codeletion. Functional reconstitution of p18(INK4C) in GBM cells null for both p16(INK4A) andp18(INK4C) resulted in impaired cell-cycle progression and tumorigenic potential. Conversely,RNAi-mediated depletion of p18(INK4C) in p16(INK4A)-deficient primary astrocytes or established GBMcells enhanced tumorigenicity in vitro and in vivo. Furthermore, acute suppression of p16(INK4A) inprimary astrocytes induced a concomitant increase in p18(INK4C). Together, these findings uncover afeedback regulatory circuit in the astrocytic lineage and demonstrate a bona fide tumor suppressor rolefor p18(INK4C) in human GBM wherein it functions cooperatively with other INK4 family members toconstrain inappropriate proliferation.", "metadata": {}}
+{"_id": "7915836", "title": "", "text": "The SMC5/6 complex maintains telomere length in ALT cancer cells through SUMOylation oftelomere-binding proteinsMost cancer cells activate telomerase to elongate telomeres and achieveunlimited replicative potential. Some cancer cells cannot activate telomerase and use telomerehomologous recombination (HR) to elongate telomeres, a mechanism termed alternative lengthening oftelomeres (ALT). A hallmark of ALT cells is the recruitment of telomeres to PML bodies (termed APBs).Here, we show that the SMC5/6 complex localizes to APBs in ALT cells and is required for targetingtelomeres to APBs. The MMS21 SUMO ligase of the SMC5/6 complex SUMOylates multipletelomere-binding proteins, including TRF1 and TRF2. Inhibition of TRF1 or TRF2 SUMOylation preventsAPB formation. Depletion of SMC5/6 subunits by RNA interference inhibits telomere HR, causing telomereshortening and senescence in ALT cells. Thus, the SMC5/6 complex facilitates telomere HR and elongationin ALT cells by promoting APB formation through SUMOylation of telomere-binding proteins.", "metadata": {}}
+{"_id": "7925817", "title": "", "text": "Dynein pulls microtubules without rotating its stalk.Dynein is a microtubule motor that powers motility ofcilia and flagella. There is evidence that the relative sliding of the doublet microtubules is due to aconformational change in the motor domain that moves a microtubule bound to the end of an extensionknown as the stalk. A predominant model for the movement involves a rotation of the head domain, withits stalk, toward the microtubule plus end. However, stalks bound to microtubules have been difficult toobserve. Here, we present the clearest views so far of stalks in action, by observing sea urchin, outer armdynein molecules bound to microtubules, with a new method, \"cryo-positive stain\" electron microscopy.The dynein molecules in the complex were shown to be active in in vitro motility assays. Analysis of theelectron micrographs shows that the stalk angles relative to microtubules do not change significantlybetween the ADP.vanadate and no-nucleotide states, but the heads, together with their stalks, shift withrespect to their A-tubule attachments. Our results disagree with models in which the stalk acts as a leverarm to amplify structural changes. The observed movement of the head and stalk relative to the tailindicates a new plausible mechanism, in which dynein uses its stalk as a grappling hook, catching atubulin subunit 8 nm ahead and pulling on it by retracting a part of the tail (linker).", "metadata": {}}
+{"_id": "7929932", "title": "", "text": "The INO80 chromatin remodeling complex in transcription, replication and repair.The Ino80 ATPase is amember of the SNF2 family of ATPases and functions as an integral component of a multisubunitATP-dependent chromatin remodeling complex. Although INO80 complexes from yeast and highereukaryotes share a common core of conserved subunits, the complexes have diverged substantiallyduring evolution and have acquired new subunits with apparently species-specific functions. Recentstudies have shown that the INO80 complex contributes to a wide variety of chromatin-dependentnuclear transactions, including transcription, DNA repair and DNA replication.", "metadata": {}}
+{"_id": "7944381", "title": "", "text": "VEX1 controls the allelic exclusion required for antigenic variation in trypanosomes.Allelic exclusionunderpins antigenic variation and immune evasion in African trypanosomes. These bloodstream parasitesuse RNA polymerase-I (pol-I) to transcribe just one telomeric variant surface glycoprotein (VSG) gene ata time, producing superabundant and switchable VSG coats. We identified trypanosome VSG exclusion-1(VEX1) using a genetic screen for defects in telomere-exclusive expression. VEX1 was sequestered by theactive VSG and silencing of other VSGs failed when VEX1 was either ectopically expressed or depleted,indicating positive and negative regulation, respectively. Positive regulation affected VSGs andnontelomeric pol-I-transcribed genes, whereas negative regulation primarily affected VSGs. Negativeregulation by VEX1 also affected telomeric pol-I-transcribed reporter constructs, but only when theycontained blocks of sequence sharing homology with a pol-I-transcribed locus. We conclude thatrestricted positive regulation due to VEX1 sequestration, combined with VEX1-dependent, possiblyhomology-dependent silencing, drives a \"winner-takes-all\" mechanism of allelic exclusion.", "metadata": {}}
+{"_id": "7948486", "title": "", "text": "Kruppel-like factor 2 (KLF2) regulates monocyte differentiation and functions in mBSA and IL-1β-inducedarthritis.Kruppel-like factor 2 (KLF2) plays an important role in the regulation of a variety of immunecells, including monocytes. We have previously shown that KLF2 inhibits proinflammatory activation ofmonocytes. However, the role of KLF2 in arthritis is yet to be investigated. In the current study, we showthat recruitment of significantly greater numbers of inflammatory subset of CD11b(+)F4/80(+)Ly6C+monocytes to the inflammatory sites in KLF2 hemizygous mice compared to the wild type littermatecontrols. In parallel, inflammatory mediators, MCP-1, Cox-2 and PAI-1 were significantly up-regulated inbone marrow-derived monocytes isolated from KLF2 hemizygous mice, in comparison to wild-typecontrols. Methylated-BSA and IL-1β-induced arthritis was more severe in KLF2 hemizygous mice ascompared to the littermate wild type controls. Consistent with this observation, monocytes isolated fromKLF2 hemizygous mice showed an increased number of cells matured and differentiated towardsosteoclastic lineage, potentially contributing to the severity of cartilage and bone damage in inducedarthritic mice. The severity of arthritis was associated with the higher expression of proteins such asHSP60, HSP90 and MMP13 and attenuated levels of pPTEN, p21, p38 and HSP25/27 molecules in bonemarrow cells of arthritic KLF2 hemizygous mice compared to littermate wild type controls. The dataprovide new insights and evidences of KLF2-mediated transcriptional regulation of arthritis via modulationof monocyte differentiation and function.", "metadata": {}}
+{"_id": "7965928", "title": "", "text": "Relationship of collegiate football experience and concussion with hippocampal volume and cognitiveoutcomes.IMPORTANCE Concussion and subconcussive impacts have been associated with short-termdisrupted cognitive performance in collegiate athletes, but there are limited data on their long-termneuroanatomic and cognitive consequences. OBJECTIVE To assess the relationships of concussion historyand years of football experience with hippocampal volume and cognitive performance in collegiatefootball athletes. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional study conducted between June2011 and August 2013 at a US psychiatric research institute specializing in neuroimaging amongcollegiate football players with a history of clinician-diagnosed concussion (n = 25), collegiate footballplayers without a history of concussion (n = 25), and non-football-playing, age-, sex-, andeducation-matched healthy controls (n = 25). EXPOSURES History of clinician-diagnosed concussion andyears of football experience. MAIN OUTCOMES AND MEASURES High-resolution anatomical magneticresonance imaging was used to quantify brain volumes. Baseline scores on a computerizedconcussion-related cognitive battery were used for cognitive assessment in athletes. RESULTS Playerswith and without a history of concussion had smaller hippocampal volumes relative to healthy controlparticipants (with concussion: t48 = 7.58; P < .001; mean difference, 1788 μL; 95% CI, 1317-2258 μL;without concussion: t48 = 4.35; P < .001, mean difference, 1027 μL; 95% CI, 556-1498 μL). Playerswith a history of concussion had smaller hippocampal volumes than players without concussion (t48 =3.15; P < .001; mean difference, 761 μL; 95% CI, 280-1242 μL). In both athlete groups, there was astatistically significant inverse relationship between left hippocampal volume and number of years offootball played (t46 = -3.62; P < .001; coefficient = -43.54; 95% CI, -67.66 to -19.41). Behavioraltesting demonstrated no differences between athletes with and without a concussion history on 5cognitive measures but did show an inverse correlation between years of playing football and reactiontime (ρ42 = -0.43; 95% CI, -0.46 to -0.40; P = .005). CONCLUSIONS AND RELEVANCE Among a groupof collegiate football athletes, there was a significant inverse relationship of concussion and years offootball played with hippocampal volume. Years of football experience also correlated with slower reactiontime. Further research is needed to determine the temporal relationships of these findings.", "metadata": {}}
+{"_id": "7968532", "title": "", "text": "STING and the innate immune response to nucleic acids in the cytosolCytosolic detection ofpathogen-derived nucleic acids is critical for the initiation of innate immune defense against diversebacterial, viral and eukaryotic pathogens. Conversely, inappropriate responses to cytosolic nucleic acidscan produce severe autoimmune pathology. The host protein STING has been identified as a centralsignaling molecule in the innate immune response to cytosolic nucleic acids. STING seems to beespecially critical for responses to cytosolic DNA and the unique bacterial nucleic acids called 'cyclicdinucleotides'. Here we discuss advances in the understanding of STING and highlight the manyunresolved issues in the field.", "metadata": {}}
+{"_id": "7970974", "title": "", "text": "Global Assessment of Genomic Regions Required for Growth in Mycobacterium tuberculosisIdentifyinggenomic elements required for viability is central to our understanding of the basic physiology of bacterialpathogens. Recently, the combination of high-density mutagenesis and deep sequencing has allowed forthe identification of required and conditionally required genes in many bacteria. Genes, however, makeup only a part of the complex genomes of important bacterial pathogens. Here, we use an unbiasedanalysis to comprehensively identify genomic regions, including genes, domains, and intergenicelements, required for the optimal growth of Mycobacterium tuberculosis, a major global healthpathogen. We found that several proteins jointly contain both domains required for optimal growth anddomains that are dispensable. In addition, many non-coding regions, including regulatory elements andnon-coding RNAs, are critical for mycobacterial growth. Our analysis shows that the genetic requirementsfor growth are more complex than can be appreciated using gene-centric analysis.", "metadata": {}}
+{"_id": "7975937", "title": "", "text": "Cyclooxygenase-Dependent Tumor Growth through Evasion of ImmunityThe mechanisms by whichmelanoma and other cancer cells evade anti-tumor immunity remain incompletely understood. Here, weshow that the growth of tumors formed by mutant Braf(V600E) mouse melanoma cells in animmunocompetent host requires their production of prostaglandin E2, which suppresses immunity andfuels tumor-promoting inflammation. Genetic ablation of cyclooxygenases (COX) or prostaglandin Esynthases in Braf(V600E) mouse melanoma cells, as well as in Nras(G12D) melanoma or in breast orcolorectal cancer cells, renders them susceptible to immune control and provokes a shift in the tumorinflammatory profile toward classic anti-cancer immune pathways. This mouse COX-dependentinflammatory signature is remarkably conserved in human cutaneous melanoma biopsies, arguing forCOX activity as a driver of immune suppression across species. Pre-clinical data demonstrate thatinhibition of COX synergizes with anti-PD-1 blockade in inducing eradication of tumors, implying that COXinhibitors could be useful adjuvants for immune-based therapies in cancer patients.", "metadata": {}}
+{"_id": "7986878", "title": "", "text": "Anti-alphav integrin monoclonal antibody intetumumab enhances the efficacy of radiation therapy andreduces metastasis of human cancer xenografts in nude rats.We previously reported that intetumumab(CNTO 95), a fully human anti-αv integrin monoclonal antibody, is a radiosensitizer in mice withxenograft tumors. Because intetumumab does not cross-react with mouse integrins, but hascross-reactivity with rat integrins, we next studied the potential combined use of radiation therapy andintetumumab in human cancer xenograft models in nude rats to assess effects on both tumor cells andthe tumor microenvironment. Nude rats bearing human head and neck cancer and non-small cell lungcancer (NSCLC) xenografts were treated with intetumumab and fractionated local tumor radiotherapy.Effects on tumor growth and metastasis, blood perfusion, oxygenation, and gastrointestinal toxicity werestudied. Intetumumab alone had a moderate effect on tumor growth. When combined with fractionatedradiation therapy, intetumumab significantly inhibited tumor growth and produced a tumor response ratethat was significantly better than with radiation therapy alone. Treatment with intetumumab alsosignificantly reduced lung metastasis in the A549 NSCLC xenograft model. The oxygenation and bloodperfusion in xenograft tumors measured by microbubble-enhanced ultrasound imaging were substantiallyincreased after treatment with intetumumab. The combined use of intetumumab and radiation therapyreduced the microvessel density and increased apoptosis in tumor cells and the tumor microenvironment.Toxicity studies showed that treatment with intetumumab did not cause the histopathologic changes inthe lungs and did not sensitize the sensitive gastrointestinal epithelium to the effect of radiation therapy.Intetumumab can potentiate the efficacy of fractionated radiation therapy in human cancer xenografttumors in nude rats without increased toxicity.", "metadata": {}}
+{"_id": "7988832", "title": "", "text": "Methylomic trajectories across human fetal brain development.Epigenetic processes play a key role inorchestrating transcriptional regulation during development. The importance of DNA methylation in fetalbrain development is highlighted by the dynamic expression of de novo DNA methyltransferases duringthe perinatal period and neurodevelopmental deficits associated with mutations in the methyl-CpGbinding protein 2 (MECP2) gene. However, our knowledge about the temporal changes to the epigenomeduring fetal brain development has, to date, been limited. We quantified genome-wide patterns of DNAmethylation at \u0000 400,000 sites in 179 human fetal brain samples (100 male, 79 female) spanning 23 to184 d post-conception. We identified highly significant changes in DNA methylation across fetal braindevelopment at >7% of sites, with an enrichment of loci becoming hypomethylated with fetal age. Sitesassociated with developmental changes in DNA methylation during fetal brain development weresignificantly underrepresented in promoter regulatory regions but significantly overrepresented in regionsflanking CpG islands (shores and shelves) and gene bodies. Highly significant differences in DNAmethylation were observed between males and females at a number of autosomal sites, with a smallnumber of regions showing sex-specific DNA methylation trajectories across brain development.Weighted gene comethylation network analysis (WGCNA) revealed discrete modules of comethylated lociassociated with fetal age that are significantly enriched for genes involved in neurodevelopmentalprocesses. This is, to our knowledge, the most extensive study of DNA methylation across human fetalbrain development to date, confirming the prenatal period as a time of considerable epigenomic plasticity.", "metadata": {}}
+{"_id": "7997337", "title": "", "text": "Synaptic Determinants of Rett SyndromeThere is mounting evidence showing that the structural andmolecular organization of synaptic connections is affected both in human patients and in animal modelsof neurological and psychiatric diseases. As a consequence of these experimental observations, it hasbeen introduced the concept of synapsopathies, a notion describing brain disorders of synaptic functionand plasticity. A close correlation between neurological diseases and synaptic abnormalities is especiallyrelevant for those syndromes including also mental retardation in their symptomatology, such as Rettsyndrome (RS). RS (MIM312750) is an X-linked dominant neurological disorder that is caused in themajority of cases by mutations in methyl-CpG-binding protein 2 (MeCP2). This review will focus on thecurrent knowledge of the synaptic alterations produced by mutations of the gene MeCP2 in mouse modelsof RS and will highlight prospects experimental therapies currently in use. Different experimentalapproaches have revealed that RS could be the consequence of an impairment in the homeostasis ofsynaptic transmission in specific brain regions. Indeed, several forms of experience-induced neuronalplasticity are impaired in the absence of MeCP2. Based on the results presented in this review, it isreasonable to propose that understanding how the brain is affected by diseases such as RS is at reach.This effort will bring us closer to identify the neurobiological bases of human cognition.", "metadata": {}}
+{"_id": "8002529", "title": "", "text": "Depressive symptoms and physical decline in community-dwelling older persons.CONTEXT Significantsymptoms of depression are common in the older community-dwelling population. Although depressivesymptoms and disability may commonly occur in the same person, whether depressive symptomscontribute to subsequent functional decline has not been elucidated. OBJECTIVE To determine whetherdepressive symptoms in older persons increase the risk of subsequent decline in physical function asmeasured by objective performance-based tests. DESIGN A 4-year prospective cohort study. SETTINGThe communities of Iowa and Washington counties, Iowa. PARTICIPANTS A total of 1286 persons aged71 years and older who completed a short battery of physical performance tests in 1988 and again 4years later. MAIN OUTCOME MEASURES Baseline depressive symptoms were assessed by the Center forEpidemiological Studies Depression Scale. Physical performance tests included an assessment of standingbalance, a timed 2.4-m (8-ft) walk, and a timed test of 5 repetitions of rising from a chair and sittingdown. RESULTS After adjustment for baseline performance score, health status, and sociodemographicfactors, increasing levels of depressive symptoms were predictive of greater decline in physicalperformance over 4 years (odds ratio for decline in those with depressed mood vs those without, 1.55;95% confidence interval [CI], 1.02-2.34). Even among those at the high end of the functional spectrum,who reported no disability, the severity of depressive symptoms predicted subsequent decline in physicalperformance (odds ratio for decline, 1.03; 95% CI, 1.00-1.08). CONCLUSIONS This study providesevidence that older persons who report depressive symptoms are at higher risk of subsequent physicaldecline. These results suggest that prevention or reduction of depressed mood could play a role inreducing functional decline in older persons.", "metadata": {}}
+{"_id": "8002887", "title": "", "text": "Foxk proteins repress the initiation of starvation-induced atrophy and autophagy programsAutophagy isthe primary catabolic process triggered in response to starvation. Although autophagic regulation withinthe cytosolic compartment is well established, it is becoming clear that nuclear events also regulate theinduction or repression of autophagy. Nevertheless, a thorough understanding of the mechanisms bywhich sequence-specific transcription factors modulate expression of genes required for autophagy islacking. Here, we identify Foxk proteins (Foxk1 and Foxk2) as transcriptional repressors of autophagy inmuscle cells and fibroblasts. Interestingly, Foxk1/2 serve to counter-balance another forkheadtranscription factor, Foxo3, which induces an overlapping set of autophagic and atrophic targets inmuscle. Foxk1/2 specifically recruits Sin3A-HDAC complexes to restrict acetylation of histone H4 andexpression of critical autophagy genes. Remarkably, mTOR promotes the transcriptional activity of Foxk1by facilitating nuclear entry to specifically limit basal levels of autophagy in nutrient-rich conditions. Ourstudy highlights an ancient, conserved mechanism whereby nutritional status is interpreted by mTOR torestrict autophagy by repressing essential autophagy genes through Foxk-Sin3-mediated transcriptionalcontrol.", "metadata": {}}
+{"_id": "8005007", "title": "", "text": "PRRSV receptors and their roles in virus infectionPorcine reproductive and respiratory syndrome virus(PRRSV) has a restricted cell tropism and prefers to invade well-differentiated cells of themonocyte/macrophage lineage, such as pulmonary alveolar macrophages and African green monkeykidney cell line MA-104 and its derivatives, such as Marc-145, Vero and CL-2621. PRRSV infection of thehost cells actually is a receptor-mediated endocytosis and replication process. The presence and absenceof the cellular receptors decide whether the cell lines are permissive or non-permissive to PRRSVinfection. Several PRRSV non-permissive cell lines, such as BHK-21, PK-15 and CHO-K1, have beenshown to become sensitive to the virus infection upon expression of the recombinant receptor proteins.Up to now, heparin sulfate, sialoadhesin, CD163, CD151 and vimentin have been identified as theimportant PRRSV receptors via their involvement in virus attachment, internalization or uncoating. Eachreceptor is characterized by the distribution in different cells, the function in virus different infectionstages and the interaction model with the viral proteins or genes. Joint forces of the receptors recentlyattract attentions due to the specific function. PRRSV receptors have become the targets for designingthe new anti-viral reagents or the recombinant cell lines used for isolating the viruses or developing moreeffective vaccines due to their more conserved sequences compared with the genetic variation of thevirus. In this paper, the role of PRRSV receptors and the molecular mechanism of the interaction betweenthe virus and the receptors are reviewed.", "metadata": {}}
+{"_id": "8006440", "title": "", "text": "Kinetic Analysis Reveals the Fate of a MicroRNA following Target Regulation in MammalianCellsConsiderable details about microRNA (miRNA) biogenesis and regulation have been uncovered, butlittle is known about the fate of the miRNA subsequent to target regulation. To gain insight into thisprocess, we carried out kinetic analysis of a miRNA's turnover following termination of its biogenesis andduring regulation of a target that is not subject to Ago2-mediated catalytic cleavage. By quantitating thenumber of molecules of the miRNA and its target in steady state and in the course of its decay, we foundthat each miRNA molecule was able to regulate at least two target transcripts, providing in vivo evidencethat the miRNA is not irreversibly sequestered with its target and that the nonslicing pathway of miRNAregulation is multiple-turnover. Using deep sequencing, we further show that miRNA recycling is limitedby target regulation, which promotes posttranscriptional modifications to the 3' end of the miRNA andaccelerates the miRNA's rate of decay. These studies provide new insight into the efficiency of miRNAregulation that help to explain how a miRNA can regulate a vast number of transcripts and that identifyone of the mechanisms that impart specificity to miRNA decay in mammalian cells.", "metadata": {}}
+{"_id": "8025177", "title": "", "text": "Estimation of nuclear DNA content in plants using flow cytometryFlow cytometry (FCM) usingDNA-selective fluorochromes is now the prevailing method for the measurement of nuclear DNA contentin plants. Ease of sample preparation and high sample throughput make it generally better suited thanother methods such as Feulgen densitometry to estimate genome size, level of generative polyploidy,nuclear replication state and endopolyploidy (polysomaty). Here we present four protocols for samplepreparation (suspensions of intact cell nuclei) and describe the analysis of nuclear DNA amounts usingFCM. We consider the chemicals and equipment necessary, the measurement process, data analysis, anddescribe the most frequent problems encountered with plant material such as the interference ofsecondary metabolites. The purpose and requirement of internal and external standardization arediscussed. The importance of using a correct terminology for DNA amounts and genome size isunderlined, and its basic principles are explained.", "metadata": {}}
+{"_id": "8037453", "title": "", "text": "Predictive value of bone resorption and formation markers in cancer patients with bone metastasesreceiving the bisphosphonate zoledronic acid.PURPOSE Three large, randomized trials of patients withbone metastases recently demonstrated that zoledronic acid reduces the risk of skeletal-related events.These trials provide an opportunity for investigating the correlation between bone metabolism and clinicaloutcome during bisphosphonate therapy. PATIENTS AND METHODS Urinary measurements ofN-telopeptide (Ntx) and serum bone alkaline phosphatase (BAP) were obtained in 1,824bisphosphonate-treated patients-1,462 with zoledronic acid (breast, 490; prostate, 411; myeloma, 210;non-small-cell lung, 183; other, 168) and 362 with pamidronate (breast, 254; myeloma, 108). Thisexploratory cohort analysis grouped patients by baseline and most recent levels of Ntx as low (< 50nmol/mmol creatinine), moderate (50 to 99 nmol/mmol creatinine), or high (> or = 100 nmol/mmolcreatinine), and BAP as low (< 146 U/L) or high (> or = 146 U/L). The relative risks for negative clinicaloutcomes were estimated for each group using multiple-event and Cox regression models withtime-varying covariates. RESULTS Patients with high and moderate Ntx levels had 2-fold increases intheir risk of skeletal complications and disease progression compared with patients with low Ntx levels (P< .001 for all). High Ntx levels in each solid tumor category were associated with a 4- to 6-fold increasedrisk of death on study, and moderate Ntx levels a 2- to 4-fold increased risk compared with low Ntx levels(P < .001 for all). Bone alkaline phosphatase also showed some correlation with risk of negative clinicaloutcomes. CONCLUSION The bone resorption marker Ntx provides valuable prognostic information inpatients with bone metastases receiving bisphosphonates.", "metadata": {}}
+{"_id": "8038329", "title": "", "text": "Role of CD28-B7 interactions in generation and maintenance of CD8 T cell memory.Although the role ofCD28-B7 interaction in the activation of naive T cells is well established, its importance in the generationand maintenance of T cell memory is not well understood. In this study, we examined the requirement forCD28-B7 interactions in primary T cell activation and immune memory. Ag-specific CD8 T cell responseswere compared between wild-type (+/+) and CD28-deficient (CD28(-/-)) mice following an acuteinfection with lymphocytic choriomeningitis virus (LCMV). During the primary response, there was asubstantial activation and expansion of LCMV-specific CD8 T cells in both +/+ and CD28(-/-) mice.However, the magnitude of the primary CD8 T cell response to both dominant and subdominant LCMVCTL epitopes was approximately 2- to 3-fold lower in CD28(-/-) mice compared with +/+ mice; the lackof CD28-mediated costimulation did not lead to preferential suppression of CD8 T cell responses to theweaker subdominant epitopes. As seen in CD28(-/-) mice, blockade of B7-mediated costimulation byCTLA4-Ig treatment of +/+ mice also resulted in a 2-fold reduction in the anti-LCMV CD8 T cellresponses. Loss of CD28/B7 interactions did not significantly affect the generation and maintenance ofCD8 T cell memory; the magnitude of CD8 T cell memory was approximately 2-fold lower in CD28(-/-)mice as compared with +/+ mice. Further, in CD28(-/-) mice, LCMV-specific memory CD8 T cells showednormal homeostatic proliferation in vivo and also conferred protective immunity. Therefore, CD28signaling is not necessary for the proliferative renewal and maintenance of memory CD8 T cells.", "metadata": {}}
+{"_id": "8042158", "title": "", "text": "Systematic reviews from astronomy to zoology: myths and misconceptions.Systematic literature reviewsare widely used as an aid to evidence based decision making. For example, reviews of randomisedcontrolled trials are regularly used to answer questions about the effectiveness of healthcareinterventions. The high profile of systematic reviews as a cornerstone of evidence based medicine,however, has led to several misconceptions about their purpose and methods. Among these is the beliefthat systematic reviews are applicable only to randomised controlled trials and that they are incapable ofdealing with other forms of evidence, such as from non-randomised studies or qualitative research. Thesystematic literature review is a method of locating, appraising, and synthesising evidence. The value ofregularly updated systematic reviews in the assessment of effectiveness of healthcare interventions wasdramatically illustrated by Antman and colleagues, who showed that review articles failed to mentionadvances in treatment identified by an updated systematic review.1  It is nearly a quarter of a centurysince Gene Glass coined the term “meta-analysis” to refer to the quantitative synthesis of the results ofprimary studies.2 The importance of making explicit efforts to limit bias in the review of literature,however, has been emphasised by social scientists at least since the 1960s.3 In recent years systematicreviews have found an important role in health services research, and the growing interest in evidencebased approaches to decision making makes it likely that their use will increase. Not everybody acceptsthat systematic reviews are necessary or desirable, and as one moves further away from the clinicalapplications of systematic reviews cynicism about their utility grows. Several arguments are commonlyused to reject a wider role for systematic reviews, and these arguments are often based on majormisconceptions about the history, purpose, methods, and uses of systematic reviews. I have examinedeight common myths about …", "metadata": {}}
+{"_id": "8063697", "title": "", "text": "Acellular pertussis vaccines protect against disease but fail to prevent infection and transmission in anonhuman primate model.Pertussis is a highly contagious respiratory illness caused by the bacterialpathogen Bordetella pertussis. Pertussis rates in the United States have been rising and reached a 50-yhigh of 42,000 cases in 2012. Although pertussis resurgence is not completely understood, wehypothesize that current acellular pertussis (aP) vaccines fail to prevent colonization and transmission. Totest our hypothesis, infant baboons were vaccinated at 2, 4, and 6 mo of age with aP or whole-cellpertussis (wP) vaccines and challenged with B. pertussis at 7 mo. Infection was followed by quantifyingcolonization in nasopharyngeal washes and monitoring leukocytosis and symptoms. Baboons vaccinatedwith aP were protected from severe pertussis-associated symptoms but not from colonization, did notclear the infection faster than naïve animals, and readily transmitted B. pertussis to unvaccinatedcontacts. Vaccination with wP induced a more rapid clearance compared with naïve and aP-vaccinatedanimals. By comparison, previously infected animals were not colonized upon secondary infection.Although all vaccinated and previously infected animals had robust serum antibody responses, we foundkey differences in T-cell immunity. Previously infected animals and wP-vaccinated animals possess strongB. pertussis-specific T helper 17 (Th17) memory and Th1 memory, whereas aP vaccination induced aTh1/Th2 response instead. The observation that aP, which induces an immune response mismatched tothat induced by natural infection, fails to prevent colonization or transmission provides a plausibleexplanation for the resurgence of pertussis and suggests that optimal control of pertussis will require thedevelopment of improved vaccines.", "metadata": {}}
+{"_id": "8065561", "title": "", "text": "Specific and cooperative binding of E. coli single-stranded DNA binding protein to mRNA.Fluorometrictitration of E. coli single-stranded DNA binding protein with various RNAs showed that the proteinspecifically and cooperatively binds to its own mRNA. The binding inhibited in vitro expression of ssb andbla but not nusA. This inhibition takes place at a physiological concentration of SSB. The function of theprotein in gene regulation is discussed.", "metadata": {}}
+{"_id": "8069939", "title": "", "text": "ACAM2000™: The new smallpox vaccine for United States Strategic National StockpileSmallpox waseradicated more than 30 years ago, but heightened concerns over bioterrorism have brought smallpoxand smallpox vaccination back to the forefront. The previously licensed smallpox vaccine in the UnitedStates, Dryvax (Wyeth Laboratories, Inc.), was highly effective, but the supply was insufficient tovaccinate the entire current US population. Additionally, Dryvax had a questionable safety profile since itconsisted of a pool of vaccinia virus strains with varying degrees of virulence, and was grown on the skinof calves, an outdated technique that poses an unnecessary risk of contamination. The US governmenthas therefore recently supported development of an improved live vaccinia virus smallpox vaccine. Thisinitiative has resulted in the development of ACAM2000 (Acambis, Inc.), a single plaque-purified vacciniavirus derivative of Dryvax, aseptically propagated in cell culture. Preclinical and clinical trials reported in2008 demonstrated that ACAM2000 has comparable immunogenicity to that of Dryvax, and causes asimilar frequency of adverse events. Furthermore, like Dryvax, ACAM2000 vaccination has been shown bycareful cardiac screening to result in an unexpectedly high rate of myocarditis and pericarditis. ACAM2000received US Food and Drug Administration (FDA) approval in August 2007, and replaced Dryvax for allsmallpox vaccinations in February 2008. Currently, over 200 million doses of ACAM2000 have beenproduced for the US Strategic National Stockpile. This review of ACAM2000 addresses the production,characterization, clinical trials, and adverse events associated with this new smallpox vaccine.", "metadata": {}}
+{"_id": "8082528", "title": "", "text": "Risk of malignant neoplasms in patients with pulmonary sarcoidosis.BACKGROUND For over 20 years theassociation between sarcoidosis and malignancy, particularly lymphoma and lung cancer, has beendisputed with misclassification being the major concern. The aim of the present study was to analyse theincidence of malignancies in a cohort of patients with sarcoidosis by linkage to a nationwide populationbased cancer register. METHODS The cohort comprised 254 patients followed for a median of 25 yearsuntil death, emigration, or 31 December 1992, whichever came first. The expected number of cancercases was calculated using the annual age and sex specific cancer rates from the Danish Cancer Registry.RESULTS Thirty six cancers were registered, three of which were misclassified as sarcoidosis, leaving 33cancers compared with 23 expected (standardised incidence ratio (SIR) = 1.4; 95% CI 0.99 to 2.0). Fivelung cancers were observed compared with 2.5 expected, yielding an SIR of 2.0 (95% CI 0.7 to 4.7).There was no incidence of lymphoma and only one case of leukaemia. There was a significant excessnumber of pharyngeal cancers based on two cases (SIR = 15.4; 95% CI 1.7 to 56). CONCLUSIONS Thisstudy does not support the theory of an association between sarcoidosis and malignancy, and the mainreason other studies have shown such an association is most likely to have been due to selection bias andmisclassification.", "metadata": {}}
+{"_id": "8083310", "title": "", "text": "Rps14 haploinsufficiency causes a block in erythroid differentiation mediated by S100A8 andS100A9Impaired erythropoiesis in the deletion 5q (del(5q)) subtype of myelodysplastic syndrome (MDS)has been linked to heterozygous deletion of RPS14, which encodes the ribosomal protein small subunit14. We generated mice with conditional inactivation of Rps14 and demonstrated an erythroiddifferentiation defect that is dependent on the tumor suppressor protein p53 (encoded by Trp53 in mice)and is characterized by apoptosis at the transition from polychromatic to orthochromatic erythroblasts.This defect resulted in age-dependent progressive anemia, megakaryocyte dysplasia and loss ofhematopoietic stem cell (HSC) quiescence. As assessed by quantitative proteomics, mutant erythroblastsexpressed higher levels of proteins involved in innate immune signaling, notably the heterodimeric S100calcium-binding proteins S100a8 and S100a9. S100a8—whose expression was increased in mutanterythroblasts, monocytes and macrophages—is functionally involved in the erythroid defect caused by theRps14 deletion, as addition of recombinant S100a8 was sufficient to induce a differentiation defect inwild-type erythroid cells, and genetic inactivation of S100a8 expression rescued the erythroiddifferentiation defect of Rps14-haploinsufficient HSCs. Our data link Rps14 haploinsufficiency in del(5q)MDS to activation of the innate immune system and induction of S100A8-S100A9 expression, leading to ap53-dependent erythroid differentiation defect.", "metadata": {}}
+{"_id": "8087082", "title": "", "text": "A Microtubule Interactome: Complexes with Roles in Cell Cycle and MitosisThe microtubule (MT)cytoskeleton is required for many aspects of cell function, including the transport of intracellularmaterials, the maintenance of cell polarity, and the regulation of mitosis. These functions are coordinatedby MT-associated proteins (MAPs), which work in concert with each other, binding MTs and altering theirproperties. We have used a MT cosedimentation assay, combined with 1D and 2D PAGE and massspectrometry, to identify over 250 MAPs from early Drosophila embryos. We have taken twocomplementary approaches to analyse the cellular function of novel MAPs isolated using this approach.First, we have carried out an RNA interference (RNAi) screen, identifying 21 previously uncharacterisedgenes involved in MT organisation. Second, we have undertaken a bioinformatics analysis based onbinary protein interaction data to produce putative interaction networks of MAPs. By combining bothapproaches, we have identified and validated MAP complexes with potentially important roles in cell cycleregulation and mitosis. This study therefore demonstrates that biologically relevant data can beharvested using such a multidisciplinary approach, and identifies new MAPs, many of which appear to beimportant in cell division.", "metadata": {}}
+{"_id": "8093935", "title": "", "text": "Structure of the Guanine Nucleotide Exchange Factor Sec7 Domain of Human Arno and Analysis of theInteraction with ARF GTPaseSec7-related guanine nucleotide exchange factors (GEFs) initiate vesiclebudding from the Golgi membrane surface by converting the GTPase ARF to a GTP-bound,membrane-associated form. Here we report the crystal structure of the catalytic Sec7 homology domainof Arno, a human GEF for ARF1, determined at 2.2 angstroms resolution. The Sec7 domain is anelongated, all-helical protein with a distinctive hydrophobic groove that is phylogenetically conserved.Structure-based mutagenesis identifies the groove and an adjacent conserved loop as the ARF-interactingsurface. The sites of Sec7 domain interaction on ARF1 have subsequently been mapped, by proteinfootprinting experiments, to the switch 1 and switch 2 GTPase regions, leading to a model for theinteraction between ARF GTPases and Sec7 domain exchange factors.", "metadata": {}}
+{"_id": "8122346", "title": "", "text": "Brief Communication Repeated Cocaine Administration Increases Voltage-Sensitive Calcium Currents inResponse to Membrane Depolarization in Medial Prefrontal Cortex Pyramidal NeuronsThe medialprefrontal cortex (mPFC) plays a critical role in cocaine addiction. However, evidence to elucidate how themPFC is functionally involved in cocaine addiction remains incomplete. Recent studies have revealed thatrepeated cocaine administration induces various neuroadaptations in pyramidal mPFC neurons, includinga reduction in voltage-gated K+ currents (VGKCs) and a possible increase in voltage-sensitive Ca2+currents (I(Ca)). Here, we performed both current-clamp recordings in brain slices and voltage-clamprecordings in freshly dissociated cells to determine whether I(Ca) is altered in mPFC pyramidal neuronsafter chronic cocaine treatment with a short-term or long-term withdrawal. In addition, a critical role ofVGKCs in regulating the generation of Ca2+ plateau potential was also studied in mPFC neurons.Repeated cocaine administration significantly prolonged the duration of evoked Ca2+ plateau potentialsand increased the whole-cell I(Ca) in mPFC neurons after a 3 d withdrawal. Selective blockade of L-typeCa2+ channels by nifedipine not only significantly increased the threshold but also reduced the durationand amplitude of Ca2+ plateau potentials in both saline- and cocaine-withdrawn mPFC neurons.However, there was no significant difference in the increased threshold, reduced duration, and decreasedamplitude of Ca2+ potentials between saline- and cocaine-withdrawn neurons after blockade of L-typeCa2+ channels. Moreover, an increase in amplitude was also observed, whereas the prolonged durationpersisted, in Ca2+ potentials after 2-3 weeks of withdrawal. These findings indicate that chronic exposureto cocaine facilitates the responsiveness of I(Ca), particularly via the activated L-type Ca2+ channels, toexcitatory stimuli in rat mPFC pyramidal neurons.", "metadata": {}}
+{"_id": "8126244", "title": "", "text": "Rational Extension of the Ribosome Biogenesis Pathway Using Network-Guided GeneticsBiogenesis ofribosomes is an essential cellular process conserved across all eukaryotes and is known to require >170genes for the assembly, modification, and trafficking of ribosome components through multiple cellularcompartments. Despite intensive study, this pathway likely involves many additional genes. Here, weemploy network-guided genetics-an approach for associating candidate genes with biological processesthat capitalizes on recent advances in functional genomic and proteomic studies-to computationallyidentify additional ribosomal biogenesis genes. We experimentally evaluated >100 candidate yeast genesin a battery of assays, confirming involvement of at least 15 new genes, including previouslyuncharacterized genes (YDL063C, YIL091C, YOR287C, YOR006C/TSR3, YOL022C/TSR4). We associatethe new genes with specific aspects of ribosomal subunit maturation, ribosomal particle association, andribosomal subunit nuclear export, and we identify genes specifically required for the processing of 5S, 7S,20S, 27S, and 35S rRNAs. These results reveal new connections between ribosome biogenesis and mRNAsplicing and add >10% new genes-most with human orthologs-to the biogenesis pathway, significantlyextending our understanding of a universally conserved eukaryotic process.", "metadata": {}}
+{"_id": "8133050", "title": "", "text": "Quantifying Transmission Investment in Malaria ParasitesMany microparasites infect new hosts withspecialized life stages, requiring a subset of the parasite population to forgo proliferation and develop intotransmission forms. Transmission stage production influences infectivity, host exploitation, and theimpact of medical interventions like drug treatment. Predicting how parasites will respond to public healthefforts on both epidemiological and evolutionary timescales requires understanding transmissionstrategies. These strategies can rarely be observed directly and must typically be inferred from infectiondynamics. Using malaria as a case study, we test previously described methods for inferring transmissionstage investment against simulated data generated with a model of within-host infection dynamics,where the true transmission investment is known. We show that existing methods are inadequate andpotentially very misleading. The key difficulty lies in separating transmission stages produced by differentgenerations of parasites. We develop a new approach that performs much better on simulated data.Applying this approach to real data from mice infected with a single Plasmodium chabaudi strain, weestimate that transmission investment varies from zero to 20%, with evidence for variable investmentover time in some hosts, but not others. These patterns suggest that, even in experimental infectionswhere host genetics and other environmental factors are controlled, parasites may exhibit remarkablydifferent patterns of transmission investment.", "metadata": {}}
+{"_id": "8133180", "title": "", "text": "Roles of induced expression of MAPK phosphatase-2 in tumor development in RET-MEN2A transgenicmiceGermline mutations in the RET tyrosine kinase gene are responsible for the development of multipleendocrine neoplasia 2A and 2B (MEN2A and MEN2B). However, knowledge of the fundamental principlesthat determine the mutant RET-mediated signaling remains elusive. Here, we report increased expressionof mitogen-activated protein kinase phosphatase-2 (MKP-2) in carcinomas developed in transgenic micecarrying RET with the MEN2A mutation (RET-MEN2A). The expression of MKP-2 was not only induced byRET-MEN2A or RET-MEN2B mutant proteins but also by the activation of endogenous RET by its ligand,glial cell line-derived neurotrophic factor (GDNF). MKP-2 expression was also evident in the MKK-f cellline, which was established from a mammary tumor developed in a RET-MEN2A transgenic mouse.Inhibition of MKP-2 attenuated the in vitro and in vivo proliferation of MKK-f cells, which was mediated bythe suppression of cyclin B1 expression. Furthermore, we found that MKP-2 is highly expressed inmedullary thyroid carcinomas derived from MEN2A patients. These findings suggest that the increasedexpression of MKP-2 may play a crucial role in oncogenic signaling downstream of mutant RET, leading toderegulation of cell cycle.", "metadata": {}}
+{"_id": "8137081", "title": "", "text": "Effects of repeated social stress on leukocyte distribution in bone marrow, peripheral blood andspleenLeukocyte trafficking between the various body compartments has an important surveillancefunction that ensures the detection of antigen and enables the immune system to initiate a rapid andeffective response. Repeated social defeat of group-housed male mice induced by daily, acute encounterswith an aggressive conspecific substantially altered leukocyte trafficking and led to a gradualredistribution of immune cells in bone marrow, peripheral blood and spleen. Recurrent exposure to thestressor over a period of 2, 4 or 6 consecutive days was associated with cell mobilization and increasedmyelopoiesis in the bone marrow that was paralleled by an accumulation of neutrophils and monocytes incirculation and spleen. Substantial depletion of B cells in bone marrow and blood was associated with anincrease in splenic B cells indicating a redirection of this cell type to the spleen. In contrast, T cells weremarkedly reduced in these immune compartments. The recruitment of CD11b+ leukocytes (i.e.,monocytes/macrophages and neutrophils) from the bone marrow to the spleen might play a critical rolein the development of functional glucocorticoid resistance in the murine spleen that was reported incontext with repeated social defeat.", "metadata": {}}
+{"_id": "8144920", "title": "", "text": "Lentivirally transduced dendritic cells as a tool for cancer immunotherapy.BACKGROUND Dendritic cells(DC) are the professional antigen-presenting cells of the immune system, fully equipped to prime naive Tcells and thus essential components for cancer immunotherapy. METHODS We tested the influence ofseveral elements (cPPT, trip, WPRE, SIN) on the transduction efficiency of human DC. Human and murineDC were transduced with tNGFR-encoding lentiviruses to assess the effect of transduction on phenotypeand function. Human DC were transduced with lentiviruses encoding huIi80MAGE-A3 and murine DC withhuIi80tOVA to test antigen presentation. RESULTS A self-inactivating (SIN) lentiviral vector containingthe trip element was most efficient in transducing human DC. The transduction of DC with trip/SIN tNGFRencoding lentiviral vectors at MOI 15 resulted in stable gene expression in up to 94.6% (murine) and88.2% (human) of the mature DC, without perturbing viability, phenotype and function. HumanhuIi80MAGE-A3-transduced DC were able to stimulate MAGE-A3-specific CD4(+) and CD8(+) T cellclones and could prime both MAGE-A3-specific CD4(+) and CD8(+) T cells in vitro. MurinehuIi80tOVA-transduced DC were able to present OVA peptides in the context of MHC class I and class IIin vitro and induced a strong OVA-specific cytotoxic T lymphocyte response in vivo, that was protectiveagainst subsequent challenge with OVA-expressing tumor cells. CONCLUSIONS We show that, usinglentiviral vectors, efficient gene transfer in human and murine DC can be obtained and that these DC canelicit antigen-specific immune responses in vitro and in vivo. The composition of the transfer vector has amajor impact on the transduction efficiency.", "metadata": {}}
+{"_id": "8148122", "title": "", "text": "Global Reorganization of Replication Domains During Embryonic Stem Cell DifferentiationDNA replicationin mammals is regulated via the coordinate firing of clusters of replicons that duplicate megabase-sizedchromosome segments at specific times during S-phase. Cytogenetic studies show that these \"repliconclusters\" coalesce as subchromosomal units that persist through multiple cell generations, but themolecular boundaries of such units have remained elusive. Moreover, the extent to which changes inreplication timing occur during differentiation and their relationship to transcription changes has not beenrigorously investigated. We have constructed high-resolution replication-timing profiles in mouseembryonic stem cells (mESCs) before and after differentiation to neural precursor cells. We demonstratethat chromosomes can be segmented into multimegabase domains of coordinate replication, which wecall \"replication domains,\" separated by transition regions whose replication kinetics are consistent withlarge originless segments. The molecular boundaries of replication domains are remarkably wellconserved between distantly related ESC lines and induced pluripotent stem cells. Unexpectedly, ESCdifferentiation was accompanied by the consolidation of smaller differentially replicating domains intolarger coordinately replicated units whose replication time was more aligned to isochore GC content andthe density of LINE-1 transposable elements, but not gene density. Replication-timing changes werecoordinated with transcription changes for weak promoters more than strong promoters, and wereaccompanied by rearrangements in subnuclear position. We conclude that replication profiles arecell-type specific, and changes in these profiles reveal chromosome segments that undergo large changesin organization during differentiation. Moreover, smaller replication domains and a higher density oftiming transition regions that interrupt isochore replication timing define a novel characteristic of thepluripotent state.", "metadata": {}}
+{"_id": "8148304", "title": "", "text": "Molecular characterization of the yeast meiotic regulatory gene RIM1.In the yeast Saccharomycescerevisiae, genetic studies suggest that the RIM1 gene encodes a positive regulator of meiosis. rim1mutations cause reduced expression of IME1, which is required for expression of many meiotic genes,and thus lead to a partial defect in meiosis and spore formation. We report the sequence of RIM1 andfunctional analysis of its coding region. The RIM1 gene product (RIM1) contains three regions similar toC2H2 zinc fingers. Serine substitutions for cysteine in each of the putative zinc fingers abolish RIM1function. The carboxyl-terminus of RIM1 is enriched in acidic amino acids and is required for full RIM1activity. RIM1 also contains two putative cAMP-dependent protein kinase (cAPK) phosphorylation sites. Atone site, substitution of alanine for serine does not affect RIM1 activity; at the other site, this substitutionimpairs activity. This analysis of RIM1 suggests that the protein may function as a transcriptionalactivator. We have used the cloned RIM1 gene to create a complete rim1 deletion. This null allele, likepreviously isolated rim1 mutations, causes a partial meiotic defect. In addition to RIM1, maximum IME1expression requires the MCK1 and IME4 gene products. Defects associated with rim1, mck1, and ime4mutations in expression of a meiotic reporter gene (ime2-lacZ) and in sporulation are additive. Thesefindings suggest that RIM1 acts independently of MCK1 and IME4 to stimulate IME1 expression.", "metadata": {}}
+{"_id": "8150638", "title": "", "text": "Butyrate greatly enhances derivation of human induced pluripotent stem cells by promoting epigeneticremodeling and the expression of pluripotency-associated genes.We report here that butyrate, a naturallyoccurring fatty acid commonly used as a nutritional supplement and differentiation agent, greatlyenhances the efficiency of induced pluripotent stem (iPS) cell derivation from human adult or fetalfibroblasts. After transient butyrate treatment, the iPS cell derivation efficiency is enhanced by 15- to51-fold using either retroviral or piggyBac transposon vectors expressing 4 to 5 reprogramming genes.Butyrate stimulation is more remarkable (>100- to 200-fold) on reprogramming in the absence of eitherKLF4 or MYC transgene. Butyrate treatment did not negatively affect properties of iPS cell linesestablished by either 3 or 4 retroviral vectors or a single piggyBac DNA transposon vector. Thesecharacterized iPS cell lines, including those derived from an adult patient with sickle cell disease by eitherthe piggyBac or retroviral vectors, show normal karyotypes and pluripotency. To gain insights into theunderlying mechanisms of butyrate stimulation, we conducted genome-wide gene expression andpromoter DNA methylation microarrays and other epigenetic analyses on established iPS cells and cellsfrom intermediate stages of the reprogramming process. By days 6 to 12 during reprogramming,butyrate treatment enhanced histone H3 acetylation, promoter DNA demethylation, and the expression ofendogenous pluripotency-associated genes, including DPPA2, whose overexpression partially substitutesfor butyrate stimulation. Thus, butyrate as a cell permeable small molecule provides a simple tool tofurther investigate molecular mechanisms of cellular reprogramming. Moreover, butyrate stimulationprovides an efficient method for reprogramming various human adult somatic cells, including cells frompatients that are more refractory to reprogramming.", "metadata": {}}
+{"_id": "8182950", "title": "", "text": "Nanoparticle conjugation of CpG enhances adjuvancy for cellular immunity and memory recall at lowdose.In subunit vaccines, strong CD8(+) T-cell responses are desired, yet they are elusive at reasonableadjuvant doses. We show that targeting adjuvant to the lymph node (LN) via ultrasmall polymericnanoparticles (NPs), which rapidly drain to the LN after intradermal injection, greatly enhances adjuvantefficacy at low doses. Coupling CpG-B or CpG-C oligonucleotides to NPs led to better dual-targeting ofadjuvant and antigen (codelivered on separate NPs) in cross-presenting dendritic cells compared withfree adjuvant. This led to enhanced dendritic cell maturation and T helper 1 (Th1)-cytokine secretion, inturn driving stronger effector CD8(+) T-cell activation with enhanced cytolytic profiles and, importantly,more powerful memory recall. With only 4 μg CpG, NP-CpG-B could substantially protect mice fromsyngeneic tumor challenge, even after 4 mo of vaccination, compared with free CpG-B. Together, theseresults show that nanocarriers can enhance vaccine efficacy at a low adjuvant dose for inducing potentand long-lived cellular immunity.", "metadata": {}}
+{"_id": "8185080", "title": "", "text": "Induction of pluripotent stem cells by defined factors is greatly improved by small-moleculecompoundsReprogramming of mouse and human somatic cells can be achieved by ectopic expression oftranscription factors, but with low efficiencies. We report that DNA methyltransferase and histonedeacetylase (HDAC) inhibitors improve reprogramming efficiency. In particular, valproic acid (VPA), anHDAC inhibitor, improves reprogramming efficiency by more than 100-fold, using Oct4-GFP as a reporter.VPA also enables efficient induction of pluripotent stem cells without introduction of the oncogene c-Myc.", "metadata": {}}
+{"_id": "8190282", "title": "", "text": "Noninvasive ventilation for treatment of acute respiratory failure in patients undergoing solid organtransplantation: a randomized trial.CONTEXT Noninvasive ventilation (NIV) has been associated withlower rates of endotracheal intubation in populations of patients with acute respiratory failure. OBJECTIVETo compare NIV with standard treatment using supplemental oxygen administration to avoidendotracheal intubation in recipients of solid organ transplantation with acute hypoxemic respiratoryfailure. DESIGN AND SETTING Prospective randomized study conducted at a 14-bed, general intensivecare unit of a university hospital. PATIENTS Of 238 patients who underwent solid organ transplantationfrom December 1995 to October 1997, 51 were treated for acute respiratory failure. Of these, 40 wereeligible and 20 were randomized to each group. INTERVENTION Noninvasive ventilation vs standardtreatment with supplemental oxygen administration. MAIN OUTCOME MEASURES The need forendotracheal intubation and mechanical ventilation at any time during the study, complications notpresent on admission, duration of ventilatory assistance, length of hospital stay, and intensive care unitmortality. RESULTS The 2 groups were similar at study entry. Within the first hour of treatment, 14patients (70%) in the NIV group, and 5 patients (25%) in the standard treatment group improved theirratio of the PaO2 to the fraction of inspired oxygen (FIO2). Over time, a sustained improvement in PaO2to FIO2 was noted in 12 patients (60%) in the NIV group, and in 5 patients (25%) randomized tostandard treatment (P = .03). The use of NIV was associated with a significant reduction in the rate ofendotracheal intubation (20% vs 70%; P = .002), rate of fatal complications (20% vs 50%; P = .05),length of stay in the intensive care unit by survivors (mean [SD] days, 5.5 [3] vs 9 [4]; P = .03), andintensive care unit mortality (20% vs 50%; P = .05). Hospital mortality did not differ. CONCLUSIONSThese results indicate that transplantation programs should consider NIV in the treatment of selectedrecipients of transplantation with acute respiratory failure.", "metadata": {}}
+{"_id": "8202880", "title": "", "text": "BIOINFORMATICS APPLICATIONS NOTESUMMARY MADE4, microarray ade4, is a software package thatfacilitates multivariate analysis of microarray gene-expression data. MADE4 accepts a wide variety ofgene-expression data formats. MADE4 takes advantage of the extensive multivariate statistical andgraphical functions in the R package ade4, extending these for application to microarray data. Inaddition, MADE4 provides new graphical and visualization tools that aid in interpretation of multivariateanalysis of microarray data.", "metadata": {}}
+{"_id": "8208212", "title": "", "text": "Dual and opposing roles of primary cilia in medulloblastoma developmentRecent work has shown thatprimary cilia are essential for Hedgehog (Hh) signaling during mammalian development. It is also knownthat aberrant Hh signaling can lead to cancer, but the role of primary cilia in oncogenesis is not known.Cerebellar granule neuron precursors (GNPs) can give rise to medulloblastomas, the most commonmalignant brain tumor in children. The primary cilium and Hh signaling are required for GNP proliferation.We asked whether primary cilia in GNPs have a role in medulloblastoma growth in mice. Genetic ablationof primary cilia blocked medulloblastoma formation when this tumor was driven by a constitutively activeSmoothened protein (Smo), an upstream activator of Hh signaling. In contrast, removal of cilia wasrequired for medulloblastoma growth by a constitutively active glioma-associated oncogene family zincfinger-2 (GLI2), a downstream transcription factor. Thus, primary cilia are either required for or inhibitmedulloblastoma formation, depending on the initiating oncogenic event. Remarkably, the presence orabsence of cilia was associated with specific variants of human medulloblastomas; primary cilia werefound in medulloblastomas with activation in HH or WNT signaling but not in most medulloblastomas inother distinct molecular subgroups. Primary cilia could serve as a diagnostic tool and provide new insightsinto the mechanism of tumorigenesis.", "metadata": {}}
+{"_id": "8210189", "title": "", "text": "RAS genes in Saccharomyces cerevisiae: signal transduction in search of a pathway.Ras proteins inbudding yeasts initially appeared to regulate initiation of the cell cycle in response to nutrient availability.More recent work, while clarifying the mechanism of Ras-mediated signal transduction, has underminedour notion of the signal Ras transmits. We now suspect that Ras helps to coordinate cellular metabolismand mass accumulation, but what Ras responds to is not clear.", "metadata": {}}
+{"_id": "8219248", "title": "", "text": "Use of synthetic peptides to locate novel integrin alpha2beta1-binding motifs in human collagen III.A setof 57 synthetic peptides encompassing the entire triplehelical domain of human collagen III was used tolocate binding sites for the collagen-binding integrin alpha(2)beta(1). The capacity of the peptides tosupport Mg(2+)-dependent binding of several integrin preparations was examined. Wild-type integrins(recombinant alpha(2) I-domain, alpha(2)beta(1) purified from platelet membranes, and recombinantsoluble alpha(2)beta(1) expressed as an alpha(2)-Fos/beta(1)-Jun heterodimer) bound well to only threepeptides, two containing GXX'GER motifs (GROGER and GMOGER, where O is hydroxyproline) and onecontaining two adjacent GXX'GEN motifs (GLKGEN and GLOGEN). Two mutant alpha(2) I-domains weretested: the inactive T221A mutant, which recognized no peptides, and the constitutively active E318Wmutant, which bound a larger subset of peptides. Adhesion of activated human platelets toGER-containing peptides was greater than that of resting platelets, and HT1080 cells bound well to moreof the peptides compared with platelets. Binding of cells and recombinant proteins was abolished byanti-alpha(2) monoclonal antibody 6F1 and by chelation of Mg(2+). We describe two novel high affinityintegrin-binding motifs in human collagen III (GROGER and GLOGEN) and a third motif (GLKGEN) thatdisplays intermediate activity. Each motif was verified using shorter synthetic peptides.", "metadata": {}}
+{"_id": "8227227", "title": "", "text": "Locations of cerebral infarctions in tuberculous meningitisThe locations of cerebral infarctions werestudied in 14 patients with tuberculous meningitis (TBM) and 173 patients with noninflammatory ischemicstroke (IS). In patients with TBM, 75% of infarctions occurred in the “TB zone” supplied by medial striateand thalamoperforating arteries; only 11% occurred in the “IS zone” supplied by lateral striate, anteriorchoroidal and thalamogeniculate arteries. In patients with IS 29% of infarctions occurred in the IS zone,29% in the subcortical white matter, and 24% in (or involving) the cerebral cortex. Only 11% occurred inthe TB zone. Bilaterally symmetrical infarctions of the TB zone were common with TMB (71%) but rarewith IS (5%).", "metadata": {}}
+{"_id": "8246090", "title": "", "text": "TRP channels of intracellular membranes.Ion channels are classically understood to regulate the flux ofions across the plasma membrane in response to a variety of environmental and intracellular cues. Ionchannels serve a number of functions in intracellular membranes as well. These channels may betemporarily localized to intracellular membranes as a function of their biosynthetic or secretory pathways,i.e., en route to their destination location. Intracellular membrane ion channels may also be located in theendocytic pathways, either being recycled back to the plasma membrane or targeted to the lysosome fordegradation. Several channels do participate in intracellular signal transduction; the most well knownexample is the inositol 1,4,5-trisphosphate receptor (IP(3)R) in the endoplasmic reticulum. Someorganellar intracellular membrane channels are required for the ionic homeostasis of their residingorganelles. Several newly-discovered intracellular membrane Ca(2+) channels actually play active rolesin membrane trafficking. Transient receptor potential (TRP) proteins are a superfamily (28 members inmammal) of Ca(2+)-permeable channels with diverse tissue distribution, subcellular localization, andphysiological functions. Almost all mammalian TRP channels studied thus far, like their ancestor yeastTRP channel (TRPY1) that localizes to the vacuole compartment, are also (in addition to their plasmamembrane localization) found to be localized to intracellular membranes. Accumulated evidence suggeststhat intracellularly-localized TRP channels actively participate in regulating membrane traffic, signaltransduction, and vesicular ion homeostasis. This review aims to provide a summary of these recentworks. The discussion will also be extended to the basic membrane and electrical properties of theTRP-residing compartments.", "metadata": {}}
+{"_id": "8246922", "title": "", "text": "the Development of Autoimmune Myocarditis in Mice by anBACKGROUND Interleukin (IL)-12 exerts apotent proinflammatory effect by stimulating T-helper (Th) 1 responses. This effect is believed to bemediated primarily through the activation of STAT4 and subsequent production of interferon(IFN)-gamma. Methods and Results- We examined the role of IL-12 receptor (IL-12R) signaling in thedevelopment of murine experimental autoimmune myocarditis (EAM) induced by cardiac myosinimmunization. Both IL-12Rbeta1-deficient mice and STAT4-deficient mice were resistant to the inductionof myocarditis. Treatment with exogenous IL-12 exacerbated disease. We questioned whetherIFN-gamma is required for the disease-promoting activity of IL-12. On the contrary, we found thatIFN-gamma suppresses EAM. Lack of IFN-gamma due to either depletion with an antibody or a geneticdeficiency exacerbated myocarditis. Spleens from IFN-gamma-deficient mice immunized with cardiacmyosin showed increased cellularity; greater numbers of CD3+, CD4+, CD8+, and IL-2-producing cells;and heightened ability to produce cytokines on stimulation in vitro. Treatment of mice with recombinantIFN-gamma suppressed the development of myocarditis. CONCLUSIONS IL-12/IL-12R/STAT4 signalingpromotes the development of EAM. In contrast, IFN-gamma plays a protective role. The disease-limitingeffects of IFN-gamma might be explained by its ability to control the expansion of activated Tlymphocytes.", "metadata": {}}
+{"_id": "8247469", "title": "", "text": "The Viral and Cellular MicroRNA Targetome in Lymphoblastoid Cell LinesEpstein-Barr virus (EBV) is aubiquitous human herpesvirus linked to a number of B cell cancers and lymphoproliferative disorders.During latent infection, EBV expresses 25 viral pre-microRNAs (miRNAs) and induces the expression ofspecific host miRNAs, such as miR-155 and miR-21, which potentially play a role in viral oncogenesis. Todate, only a limited number of EBV miRNA targets have been identified; thus, the role of EBV miRNAs inviral pathogenesis and/or lymphomagenesis is not well defined. Here, we used photoactivatableribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) combined with deepsequencing and computational analysis to comprehensively examine the viral and cellular miRNAtargetome in EBV strain B95-8-infected lymphoblastoid cell lines (LCLs). We identified 7,827miRNA-interaction sites in 3,492 cellular 3'UTRs. 531 of these sites contained seed matches to viralmiRNAs. 24 PAR-CLIP-identified miRNA:3'UTR interactions were confirmed by reporter assays. Ourresults reveal that EBV miRNAs predominantly target cellular transcripts during latent infection, therebymanipulating the host environment. Furthermore, targets of EBV miRNAs are involved in multiple cellularprocesses that are directly relevant to viral infection, including innate immunity, cell survival, and cellproliferation. Finally, we present evidence that myc-regulated host miRNAs from the miR-17/92 clustercan regulate latent viral gene expression. This comprehensive survey of the miRNA targetome inEBV-infected B cells represents a key step towards defining the functions of EBV-encoded miRNAs, andpotentially, identifying novel therapeutic targets for EBV-associated malignancies.", "metadata": {}}
+{"_id": "8247597", "title": "", "text": "Mitochondrial Dysfunction Leads to Nuclear Genome Instability via an Iron-Sulfur Cluster DefectMutationsand deletions in the mitochondrial genome (mtDNA), as well as instability of the nuclear genome, areinvolved in multiple human diseases. Here, we report that in Saccharomyces cerevisiae, loss of mtDNAleads to nuclear genome instability, through a process of cell-cycle arrest and selection we define as acellular crisis. This crisis is not mediated by the absence of respiration, but instead correlates with areduction in the mitochondrial membrane potential. Analysis of cells undergoing this crisis identified adefect in iron-sulfur cluster (ISC) biogenesis, which requires normal mitochondrial function. We foundthat downregulation of nonmitochondrial ISC protein biogenesis was sufficient to cause increasedgenomic instability in cells with intact mitochondrial function. These results suggest mitochondrialdysfunction stimulates nuclear genome instability by inhibiting the production of ISC-containingprotein(s), which are required for maintenance of nuclear genome integrity. For a video summary of thisarticle, see the PaperFlick file available with the online Supplemental Data.", "metadata": {}}
+{"_id": "8250852", "title": "", "text": "Replisome stall events have shaped the distribution of replication origins in the genomes of yeastsDuringS phase, the entire genome must be precisely duplicated, with no sections of DNA left unreplicated. Here,we develop a simple mathematical model to describe the probability of replication failing due to theirreversible stalling of replication forks. We show that the probability of complete genome replication ismaximized if replication origins are evenly spaced, the largest inter-origin distances are minimized, andthe end-most origins are positioned close to chromosome ends. We show that origin positions in the yeastSaccharomyces cerevisiae genome conform to all three predictions thereby maximizing the probability ofcomplete replication if replication forks stall. Origin positions in four other yeasts-Kluyveromyces lactis,Lachancea kluyveri, Lachancea waltii and Schizosaccharomyces pombe-also conform to these predictions.Equating failure rates at chromosome ends with those in chromosome interiors gives a mean pernucleotide fork stall rate of \u00005 × 10(-8), which is consistent with experimental estimates. Using thisvalue in our theoretical predictions gives replication failure rates that are consistent with data fromreplication origin knockout experiments. Our theory also predicts that significantly larger genomes, suchas those of mammals, will experience a much greater probability of replication failure genome-wide, andtherefore will likely require additional compensatory mechanisms.", "metadata": {}}
+{"_id": "8267678", "title": "", "text": "Regulation of chromatin by histone modificationsChromatin is not an inert structure, but rather aninstructive DNA scaffold that can respond to external cues to regulate the many uses of DNA. A principlecomponent of chromatin that plays a key role in this regulation is the modification of histones. There is anever-growing list of these modifications and the complexity of their action is only just beginning to beunderstood. However, it is clear that histone modifications play fundamental roles in most biologicalprocesses that are involved in the manipulation and expression of DNA. Here, we describe the knownhistone modifications, define where they are found genomically and discuss some of their functionalconsequences, concentrating mostly on transcription where the majority of characterisation has takenplace.", "metadata": {}}
+{"_id": "8290760", "title": "", "text": "Single-Cell Expression Analyses during Cellular Reprogramming Reveal an Early Stochastic and a LateHierarchic PhaseDuring cellular reprogramming, only a small fraction of cells become induced pluripotentstem cells (iPSCs). Previous analyses of gene expression during reprogramming were based onpopulations of cells, impeding single-cell level identification of reprogramming events. We utilized twogene expression technologies to profile 48 genes in single cells at various stages during thereprogramming process. Analysis of early stages revealed considerable variation in gene expressionbetween cells in contrast to late stages. Expression of Esrrb, Utf1, Lin28, and Dppa2 is a better predictorfor cells to progress into iPSCs than expression of the previously suggested reprogramming markersFbxo15, Fgf4, and Oct4. Stochastic gene expression early in reprogramming is followed by a latehierarchical phase with Sox2 being the upstream factor in a gene expression hierarchy. Finally,downstream factors derived from the late phase, which do not include Oct4, Sox2, Klf4, c-Myc, andNanog, can activate the pluripotency circuitry.", "metadata": {}}
+{"_id": "8290953", "title": "", "text": "Scaffold-based three-dimensional human fibroblast culture provides a structural matrix that supportsangiogenesis in infarcted heart tissue.BACKGROUND We have developed techniques to implantangiogenic patches onto the epicardium over regions of infarcted cardiac tissue to stimulaterevascularization of the damaged tissue. These experiments used a scaffold-based 3D human dermalfibroblast culture (3DFC) as an epicardial patch. The 3DFC contains viable cells that secrete angiogenicgrowth factors and has previously been shown to stimulate angiogenic activity. The hypothesis testedwas that a viable 3DFC cardiac patch would stimulate an angiogenic response within an area of infarctedcardiac tissue. METHODS AND RESULTS A coronary occlusion of a branch of the left anterior descendingcoronary artery was performed by thermal ligation in severe combined immunodeficient mice. 3DFCs withor without viable cells were sized to the damaged area, implanted in replicate mice onto the epicardiumat the site of tissue injury, and compared with animals that received infarct surgery but no implant.Fourteen and 30 days after surgery, hearts were exposed and photographed, and tissue samples wereprepared for histology and cytochemistry. Fourteen and 30 days after surgery, the damaged myocardiumreceiving viable 3DFC exhibited a significantly greater angiogenic response (including arterioles, venules,and capillaries) than nonviable and untreated control groups. CONCLUSIONS In this animal model, viable3DFC stimulates angiogenesis within a region of cardiac infarction and can augment a repair response indamaged tissue. Therefore, a potential use for 3DFC is the repair of myocardial tissue damaged byinfarction.", "metadata": {}}
+{"_id": "8294009", "title": "", "text": "Global tuberculosis control: lessons learnt and future prospectsTuberculosis (TB) is an ancient disease,but not a disease of the past. After disappearing from the world public health agenda in the 1960s and1970s, TB returned in the early 1990s for several reasons, including the emergence of the HIV/AIDSpandemic and increases in drug resistance. More than 100 years after the discovery of the tuberclebacillus by Robert Koch, what is the status of TB control worldwide? Here, we review the evolution ofglobal TB control policies, including DOTS (directly observed therapy, short course) and the Stop TBStrategy, and assess whether the challenges and obstacles faced by the public health communityworldwide in developing and implementing this strategy can aid future action towards the elimination ofTB.", "metadata": {}}
+{"_id": "8298120", "title": "", "text": "Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic reviewand meta-analysis.PURPOSE Glaucoma is the leading cause of global irreversible blindness. Presentestimates of global glaucoma prevalence are not up-to-date and focused mainly on European ancestrypopulations. We systematically examined the global prevalence of primary open-angle glaucoma (POAG)and primary angle-closure glaucoma (PACG), and projected the number of affected people in 2020 and2040. DESIGN Systematic review and meta-analysis. PARTICIPANTS Data from 50 population-basedstudies (3770 POAG cases among 140,496 examined individuals and 786 PACG cases among 112 398examined individuals). METHODS We searched PubMed, Medline, and Web of Science forpopulation-based studies of glaucoma prevalence published up to March 25, 2013. Hierarchical Bayesianapproach was used to estimate the pooled glaucoma prevalence of the population aged 40-80 years alongwith 95% credible intervals (CrIs). Projections of glaucoma were estimated based on the United NationsWorld Population Prospects. Bayesian meta-regression models were performed to assess the associationbetween the prevalence of POAG and the relevant factors. MAIN OUTCOME MEASURES Prevalence andprojection numbers of glaucoma cases. RESULTS The global prevalence of glaucoma for population aged40-80 years is 3.54% (95% CrI, 2.09-5.82). The prevalence of POAG is highest in Africa (4.20%; 95%CrI, 2.08-7.35), and the prevalence of PACG is highest in Asia (1.09%; 95% CrI, 0.43-2.32). In 2013,the number of people (aged 40-80 years) with glaucoma worldwide was estimated to be 64.3 million,increasing to 76.0 million in 2020 and 111.8 million in 2040. In the Bayesian meta-regression model,men were more likely to have POAG than women (odds ratio [OR], 1.36; 95% CrI, 1.23-1.52), and afteradjusting for age, gender, habitation type, response rate, and year of study, people of African ancestrywere more likely to have POAG than people of European ancestry (OR, 2.80; 95% CrI, 1.83-4.06), andpeople living in urban areas were more likely to have POAG than those in rural areas (OR, 1.58; 95% CrI,1.19-2.04). CONCLUSIONS The number of people with glaucoma worldwide will increase to 111.8 millionin 2040, disproportionally affecting people residing in Asia and Africa. These estimates are important inguiding the designs of glaucoma screening, treatment, and related public health strategies.", "metadata": {}}
+{"_id": "8300657", "title": "", "text": "Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection.Humanand simian immunodeficiency virus (HIV and SIV) replicate optimally in activated memory CD4(+) T cells,a cell type that is abundant in the intestine. SIV infection of rhesus monkeys resulted in profound andselective depletion of CD4+ T cells in the intestine within days of infection, before any such changes inperipheral lymphoid tissues. The loss of CD4+ T cells in the intestine occurred coincident with productiveinfection of large numbers of mononuclear cells at this site. The intestine appears to be a major target forSIV replication and the major site of CD4+ T cell loss in early SIV infection.", "metadata": {}}
+{"_id": "8305686", "title": "", "text": "Interaction of streptavidin-based peptide-MHC oligomers (tetramers) with cell-surface TCRs.The bindingof oligomeric peptide-MHC (pMHC) complexes to cell surface TCR can be considered to approximateTCR-pMHC interactions at cell-cell interfaces. In this study, we analyzed the equilibrium binding ofstreptavidin-based pMHC oligomers (tetramers) and their dissociation kinetics from CD8(pos) T cells from2C-TCR transgenic mice and from T cell hybridomas that expressed the 2C TCR or a high-affinity mutant(m33) of this TCR. Our results show that the tetramers did not come close to saturating cell-surface TCR(binding only 10-30% of cell-surface receptors), as is generally assumed in deriving affinity values(K(D)), in part because of dissociative losses from tetramer-stained cells. Guided by a kinetic model, theoligomer dissociation rate and equilibrium constants were seen to depend not only on monovalentassociation and dissociation rates (k(off) and k(on)), but also on a multivalent association rate (μ) andTCR cell-surface density. Our results suggest that dissociation rates could account for the recentlydescribed surprisingly high frequency of tetramer-negative, functionally competent T cells in some T cellresponses.", "metadata": {}}
+{"_id": "8317408", "title": "", "text": "Human monocyte characteristics are altered in hypercholesterolaemia.Peripheral blood monocytes areinvolved during atherogenesis in adhering to endothelium, migrating into the subendothelial space andtaking-up lipoproteins to become macrophage/foam cells. We have assessed whether peripheral bloodmonocyte characteristics are altered in human hyperlipidaemia in age/sex/smoking status matched pairsof patients and controls. Monocytes from the hypercholesterolaemic patients, as opposed to the controls,were more sensitive to stimulation by the agonist, N-formyl-methionyl-leucyl-phenylalanine, with respectto chemokinesis (stimulation index 1.48 +/- 0.17 vs. 1.10 +/- 0.14), chemotaxis (4.05 +/- 0.55 vs. 2.72+/- 0.24) and adhesion to porcine aortic endothelial monolayers (1.26 +/- 0.05 vs. 1.17 +/- 0.06). Thepatients' monocyte total surface expression of the adhesion glycoprotein CD11b/CD18 (37.5 +/- 7.1 vs.36.0 +/- 7.1), but not CD11c/CD18 (31.6 +/- 7.2 vs. 31.4 +/- 6.8), was increased; however, themonocytes in hyperlipidaemia were larger (9.15 +/- 0.11 microns vs. 8.98 +/- 0.11 microns) such thatthe surface density of CD11b/CD18 was not altered (0.144 +/- 0.029 vs. 0.142 +/- 0.029). The datasuggest that circulating monocytes are functionally different in hypercholesterolaemia. This may explainthe increased involvement by monocytes in hypercholesterolaemia-related atherogenesis.", "metadata": {}}
+{"_id": "8318286", "title": "", "text": "Adult Mammalian Neural Stem Cells and Neurogenesis: Five Decades Later.Adult somatic stem cells invarious organs maintain homeostatic tissue regeneration and enhance plasticity. Since its initial discoveryfive decades ago, investigations of adult neurogenesis and neural stem cells have led to an establishedand expanding field that has significantly influenced many facets of neuroscience, developmental biology,and regenerative medicine. Here we review recent progress and focus on questions related to adultmammalian neural stem cells that also apply to other somatic stem cells. We further discuss emergingtopics that are guiding the field toward better understanding adult neural stem cells and ultimatelyapplying these principles to improve human health.", "metadata": {}}
+{"_id": "8318922", "title": "", "text": "Relationship of ambulatory blood pressure and the heart rate profile with renal function parameters inhypertensive patients with chronic kidney disease.Strict blood pressure (BP) control is reportedlyimportant for the management of hypertensive patients with chronic kidney disease (CKD). The purposeof this cross-sectional study was to examine whether the variables of ambulatory BP and the heart rate(HR) profile, central hemodynamics, and arterial stiffness were closely related to the renal functionparameters (urine albumin excretion rate [UACR] and estimated glomerular filtration rate [eGFR])observed in 25 consecutive hospitalized hypertensive patients with CKD. There were significant positiverelationships between UACR and 24-hour, daytime, and nighttime ambulatory systolic BP. In addition,there were significant negative relationships between UACR and 24-hour and daytime HR variability. Thecirculating B-type natriuretic peptide level and hemoglobin A1c were also positively related to UACR. Withrespect to eGFR, although the 24-hour and nighttime HR variability were positively associated with eGFR,the circulating pentosidine and nighttime HR had a negative relationship with eGFR. On the other hand,central hemodynamics and arterial stiffness did not exhibit any significant association with renal functionparameters. These results indicate that ambulatory BP and the HR profile are closely modulated by renalfunction deterioration. Further studies are needed to investigate the causal relationship betweenambulatory BP and the HR profile and renal function parameters in hypertensive patients with CKD.", "metadata": {}}
+{"_id": "8325952", "title": "", "text": "The frequency and immunodominance of islet-specific CD8+ T-cell responses change after type 1diabetes diagnosis and treatment.OBJECTIVE Islet-reactive CD8(+) T-cells play a key role in thepathogenesis of type 1 diabetes in the NOD mouse. The predominant T-cell specificities change over time,but whether similar shifts also occur after clinical diagnosis and insulin treatment in type 1 diabeticpatients is unknown. RESEARCH DESIGN AND METHODS We took advantage of a recently validatedislet-specific CD8(+) T-cell gamma-interferon enzyme-linked immunospot (ISL8Spot) assay to followresponses against preproinsulin (PPI), GAD, insulinoma-associated protein 2 (IA-2), and islet-specificglucose-6-phosphatase catalytic subunit-related protein (IGRP) epitopes in 15 HLA-A2(+) adult type 1diabetic patients close to diagnosis and at a second time point 7-16 months later. RESULTS CD8(+) T-cellreactivities were less frequent at follow-up, as 28.6% of responses tested positive at type 1 diabetesdiagnosis vs. 13.2% after a median of 11 months (P = 0.003). While GAD and IA-2 autoantibody (aAb)titers were unchanged in 75% of cases, the fraction of patients responding to PPI and/or GAD epitopes byISL8Spot decreased from 60-67 to 20% (P < 0.02). The previously subdominant IA-2(206-214) andIGRP(265-273) peptides were newly targeted, thus becoming the immunodominant epitopes.CONCLUSIONS Shifts both in frequency and in immunodominance of CD8(+) T-cell responses occur morerapidly than do changes in aAb titers. These different kinetics may suggest complementary clinicalapplications for T-cell and aAb measurements.", "metadata": {}}
+{"_id": "8327914", "title": "", "text": "A Protein Inventory of Human Ribosome Biogenesis Reveals an Essential Function of Exportin 5 in 60SSubunit ExportThe assembly of ribosomal subunits in eukaryotes is a complex, multistep process so farmostly studied in yeast. In S. cerevisiae, more than 200 factors including ribosomal proteins andtrans-acting factors are required for the ordered assembly of 40S and 60S ribosomal subunits. To date,only few human homologs of these yeast ribosome synthesis factors have been characterized. Here, weused a systematic RNA interference (RNAi) approach to analyze the contribution of 464 candidate factorsto ribosomal subunit biogenesis in human cells. The screen was based on visual readouts, using inducible,fluorescent ribosomal proteins as reporters. By performing computer-based image analysis utilizingsupervised machine-learning techniques, we obtained evidence for a functional link of 153 humanproteins to ribosome synthesis. Our data show that core features of ribosome assembly are conservedfrom yeast to human, but differences exist for instance with respect to 60S subunit export. Unexpectedly,our RNAi screen uncovered a requirement for the export receptor Exportin 5 (Exp5) in nuclear export of60S subunits in human cells. We show that Exp5, like the known 60S exportin Crm1, binds to pre-60Sparticles in a RanGTP-dependent manner. Interference with either Exp5 or Crm1 function blocks 60Sexport in both human cells and frog oocytes, whereas 40S export is compromised only upon inhibition ofCrm1. Thus, 60S subunit export is dependent on at least two RanGTP-binding exportins in vertebratecells.", "metadata": {}}
+{"_id": "8331432", "title": "", "text": "Binding of the winged-helix transcription factor HNF3 to a linker histone site on the nucleosome.Thetranscription factor HNF3 and linker histones H1 and H5 possess winged-helix DNA-binding domains, yetHNF3 and other fork head-related proteins activate genes during development whereas linker histonescompact DNA in chromatin and repress gene expression. We compared how the two classes of factorsinteract with chromatin templates and found that HNF3 binds DNA at the side of nucleosome cores,similarly to what has been reported for linker histone. A nucleosome structural binding site for HNF3 isoccupied at the albumin transcriptional enhancer in active and potentially active chromatin, but not ininactive chromatin in vivo. While wild-type HNF3 protein does not compact DNA extending from thenucleosome, as does linker histone, site-directed mutants of HNF3 can compact nucleosomal DNA if theycontain basic amino acids at positions previously shown to be essential for nucleosomal DNA compactionby linker histones. The results illustrate how transcription factors can possess special nucleosome-bindingactivities that are not predicted from studies of factor interactions with free DNA.", "metadata": {}}
+{"_id": "8352137", "title": "", "text": "Rapid recent growth and divergence of rice nuclear genomes.By employing the nuclear DNA of the Africanrice Oryza glaberrima as a reference genome, the timing, natures, mechanisms, and specificities ofrecent sequence evolution in the indica and japonica subspecies of Oryza sativa were identified. The dataindicate that the genome sizes of both indica and japonica have increased substantially, >2% and >6%,respectively, since their divergence from a common ancestor, mainly because of the amplification ofLTR-retrotransposons. However, losses of all classes of DNA sequence through unequal homologousrecombination and illegitimate recombination have attenuated the growth of the rice genome. Smalldeletions have been particularly frequent throughout the genome. In >1 Mb of orthologous regions thatwe analyzed, no cases of complete gene acquisition or loss from either indica or japonica were found, norwas any example of precise transposon excision detected. The sequences between genes were observedto have a very high rate of divergence, indicating a molecular clock for transposable elements that is atleast 2-fold more rapid than synonymous base substitutions within genes. We found that regions prone tofrequent insertions and deletions also exhibit higher levels of point mutation. These results indicate ahighly dynamic rice genome with competing processes for the generation and removal of geneticvariation.", "metadata": {}}
+{"_id": "8354687", "title": "", "text": "Detection of an autoreactive T-cell population within the polyclonal repertoire that undergoes distinctautoimmune regulator (Aire)-mediated selection.The autoimmune regulator (Aire) plays a critical role incentral tolerance by promoting the display of tissue-specific antigens in the thymus. To study theinfluence of Aire on thymic selection in a physiological setting, we used tetramer reagents to detectautoreactive T cells specific for the Aire-dependent tissue-specific antigen interphotoreceptorretinoid-binding protein (IRBP), in the polyclonal repertoire. Two class II tetramer reagents weredesigned to identify T cells specific for two different peptide epitopes of IRBP. Analyses of the polyclonalT-cell repertoire showed a high frequency of activated T cells specific for both IRBP tetramers in Aire(-/-)mice, but not in Aire(+/+) mice. Surprisingly, although one tetramer-binding T-cell population wasefficiently deleted in the thymus in an Aire-dependent manner, the second tetramer-binding populationwas not deleted and could be detected in both the Aire(-/-) and Aire(+/+) T-cell repertoires. We foundthat Aire-dependent thymic deletion of IRBP-specific T cells relies on intercellular transfer of IRBPbetween thymic stroma and bone marrow-derived antigen-presenting cells. Furthermore, our datasuggest that Aire-mediated deletion relies not only on thymic expression of IRBP, but also on properantigen processing and presentation of IRBP by thymic antigen-presenting cells.", "metadata": {}}
+{"_id": "8373753", "title": "", "text": "Spatial and temporal heterogeneity of Anopheles mosquitoes and Plasmodium falciparum transmissionalong the Kenyan coast.The seasonal dynamics and spatial distributions of Anopheles mosquitoes andPlasmodium falciparum parasites were studied for one year at 30 villages in Malindi, Kilifi, and KwaleDistricts along the coast of Kenya. Anopheline mosquitoes were sampled inside houses at each site onceevery two months and malaria parasite prevalence in local school children was determined at the end ofthe entomologic survey. A total of 5,476 Anopheles gambiae s.l. and 3,461 An. funestus were collected.Species in the An. gambiae complex, identified by a polymerase chain reaction, included 81.9% An.gambiae s.s., 12.8% An. arabiensis, and 5.3% An. merus. Anopheles gambiae s.s. contributed most tothe transmission of P. falciparum along the coast as a whole, while An. funestus accounted for more than50% of all transmission in Kwale District. Large spatial heterogeneity of transmission intensity (< 1 up to120 infective bites per person per year) resulted in correspondingly large and significantly relatedvariations in parasite prevalence (range = 38-83%). Thirty-two percent of the sites (7 of 22 sites) withmalaria prevalences ranging from 38% to 70% had annual entomologic inoculation rates (EIR) less thanfive infective bites per person per year. Anopheles gambiae s.l. and An. funestus densities in Kwale werenot significantly influenced by rainfall. However, both were positively correlated with rainfall one andthree months previously in Malindi and Kilifi Districts, respectively. These unexpected variations in therelationship between mosquito populations and rainfall suggest environmental heterogeneity in thepredominant aquatic habitats in each district. One important conclusion is that the highly non-linearrelationship between EIRs and prevalence indicates that the consistent pattern of high prevalence mightbe governed by substantial variation in transmission intensity measured by entomologic surveys. Thefield-based estimate of entomologic parameters on a district level does not provide a sensitive indicatorof transmission intensity in this study.", "metadata": {}}
+{"_id": "8385277", "title": "", "text": "Myelodysplasia and leukemia of Fanconi anemia are associated with a specific pattern of genomicabnormalities that includes cryptic RUNX1/AML1 lesions.Fanconi anemia (FA) is a genetic conditionassociated with bone marrow (BM) failure, myelodysplasia (MDS), and acute myeloid leukemia (AML). Westudied 57 FA patients with hypoplastic or aplastic anemia (n = 20), MDS (n = 18), AML (n = 11), or noBM abnormality (n = 8). BM samples were analyzed by karyotype, high-density DNA arrays with respectto paired fibroblasts, and by selected oncogene sequencing. A specific pattern of chromosomalabnormalities was found in MDS/AML, which included 1q+ (44.8%), 3q+ (41.4%), -7/7q (17.2%), and11q- (13.8%). Moreover, cryptic RUNX1/AML1 lesions (translocations, deletions, or mutations) wereobserved for the first time in FA (20.7%). Rare mutations of NRAS, FLT3-ITD, MLL-PTD, ERGamplification, and ZFP36L2-PRDM16 translocation, but no TP53, TET2, CBL, NPM1, and CEBPα mutationswere found. Frequent homozygosity regions were related not to somatic copy-neutral loss ofheterozygosity but to consanguinity, suggesting that homologous recombination is not a commonprogression mechanism in FA. Importantly, the RUNX1 and other chromosomal/genomic lesions werefound at the MDS/AML stages, except for 1q+, which was found at all stages. These data haveimplications for staging and therapeutic managing in FA patients, and also to analyze the mechanisms ofclonal evolution and oncogenesis in a background of genomic instability and BM failure.", "metadata": {}}
+{"_id": "8386609", "title": "", "text": "Molecular and Cellular Approaches for Diversifying and Extending OptogeneticsOptogenetic technologiesemploy light to control biological processes within targeted cells in vivo with high temporal precision.Here, we show that application of molecular trafficking principles can expand the optogenetic repertoirealong several long-sought dimensions. Subcellular and transcellular trafficking strategies now permit (1)optical regulation at the far-red/infrared border and extension of optogenetic control across the entirevisible spectrum, (2) increased potency of optical inhibition without increased light power requirement(nanoampere-scale chloride-mediated photocurrents that maintain the light sensitivity and reversible,step-like kinetic stability of earlier tools), and (3) generalizable strategies for targeting cells based notonly on genetic identity, but also on morphology and tissue topology, to allow versatile targeting whenpromoters are not known or in genetically intractable organisms. Together, these results illustrate use ofcell-biological principles to enable expansion of the versatile fast optogenetic technologies suitable forintact-systems biology and behavior.", "metadata": {}}
+{"_id": "8396189", "title": "", "text": "An analysis of the Caenorhabditis elegans lipid raft proteome using geLC-MS/MS.Lipid rafts aremicrodomains of the phospholipid bilayer, proposed to form semi-stable \"islands\" that act as a platformfor several important cellular processes; major classes of raft-resident proteins include signalling proteinsand glycosylphosphatidylinositol (GPI)-anchored proteins. Proteomic studies into lipid rafts have beenmainly carried out in mammalian cell lines and single cell organisms. The nematode Caenorhabditiselegans, the model organism with a well-defined developmental profile, is ideally suited for the study ofthis subcellular locale in a complex developmental context. A study of the lipid raft proteome of C.elegans is presented here. A total of 44 proteins were identified from the lipid raft fraction usinggeLC-MS/MS, of which 40 have been determined to be likely raft proteins after analysis of predictedfunctions. Prediction of GPI-anchoring of the proteins found 21 to be potentially modified in this way, twoof which were experimentally confirmed to be GPI-anchored. This work is the first reported study of thelipid raft proteome in C. elegans. The results show that raft proteins, including numerous GPI-anchoredproteins, may have a variety of potentially important roles within the nematode, and will hopefully lead toC. elegans becoming a useful model for the study of lipid rafts.", "metadata": {}}
+{"_id": "8398627", "title": "", "text": "Geographic distribution of community-acquired methicillin-resistant Staphylococcus aureus soft tissueinfections.PURPOSE The goal of this study is to look at the geographic growth patterns ofcommunity-acquired methicillin-resistant Staphylococcus aureus (MRSA) infections in our local region andto determine if specific geographic areas are at increased risk. METHODS After Institution Review Boardapproval (132603-3), a retrospective chart review was conducted of 614 patients who underwent incisionand drainage of an abscess by a single pediatric surgical practice from January 2004 to December 2008.In addition, previously published data from 195 patients who underwent incision and drainage of anabscess from January 2000 to December 2003 were reviewed. RESULTS The most commonly culturedorganism found in the pediatric population undergoing incision and drainage was S aureus (n = 388), ofwhich 258 (66%) were methicillin resistant. This is a 21% increase from the rate of MRSA culturesidentified from 2000 to 2003. Geographic information system space-time analysis showed that a clusterof 14 MRSA cases was located within a 1.44-km radius between 2000 and 2003, and 5 separate clustersof more than 20 MRSA infection cases each were identified in 3 separate cities over the 8-year time spanusing geographic information system spatial analysis (P value = .001). CONCLUSION Methicillin-resistantS aureus has now become the most prevalent organism isolated from cultures of community-acquiredabscesses requiring incision and drainage in the pediatric population in our local region. Significantclustering of MRSA infections has appeared in several different cities within our geographic region.", "metadata": {}}
+{"_id": "8411251", "title": "", "text": "The right place at the right time: chaperoning core histone variants.Histone proteins dynamically regulatechromatin structure and epigenetic signaling to maintain cell homeostasis. These processes requirecontrolled spatial and temporal deposition and eviction of histones by their dedicated chaperones. Withthe evolution of histone variants, a network of functionally specific histone chaperones has emerged.Molecular details of the determinants of chaperone specificity for different histone variants are only slowlybeing resolved. A complete understanding of these processes is essential to shed light on the genuinebiological roles of histone variants, their chaperones, and their impact on chromatin dynamics.", "metadata": {}}
+{"_id": "8417211", "title": "", "text": "Phosphorylation site mutations in heterochromatin protein 1 (HP1) reduce or eliminate silencingactivity.HP1 is an essential heterochromatin-associated protein in Drosophila. HP1 has dosage-dependenteffects on the silencing of euchromatic genes that are mislocalized to heterochromatin and is required forthe normal expression of at least two heterochromatic genes. HP1 is multiply phosphorylated in vivo, andHP1 hyperphosphorylation is correlated with heterochromatin assembly during development. The purposeof this study was to test whether HP1 phosphorylation modifies biological activity and biochemicalproperties of HP1. To determine sites of HP1 phosphorylation in vivo and whether phosphorylation affectsany biochemical properties of HP1, we expressed Drosophila HP1 in lepidopteran cultured cells using arecombinant baculovirus vector. Phosphopeptides were identified by matrix-assisted laser desorptionionization/time of flight mass spectroscopy; these peptides contain target sites for casein kinase II,protein tyrosine kinase, and PIM-1 kinase. Purified HP1 from bacterial (unphosphorylated) andlepidopteran (phosphorylated) cells has similar secondary structure. Phosphorylation has no effect on HP1self-association but alters the DNA binding properties of HP1, suggesting that phosphorylation coulddifferentially regulate HP1-dependent interactions. Serine-to-alanine and serine-to-glutamatesubstitutions at consensus protein kinase motifs resulted in reduction or loss of silencing activity ofmutant HP1 in transgenic flies. These results suggest that dynamic phosphorylation/dephosphorylationregulates HP1 activity in heterochromatic silencing.", "metadata": {}}
+{"_id": "8425533", "title": "", "text": "Elimination of paternal mitochondria in mouse embryos occurs through autophagic degradationdependent on PARKIN and MUL1A defining feature of mitochondria is their maternal mode of inheritance.However, little is understood about the cellular mechanism through which paternal mitochondria,delivered from sperm, are eliminated from early mammalian embryos. Autophagy has been implicated innematodes, but whether this mechanism is conserved in mammals has been disputed. Here, we showthat cultured mouse fibroblasts and pre-implantation embryos use a common pathway for elimination ofmitochondria. Both situations utilize mitophagy, in which mitochondria are sequestered byautophagosomes and delivered to lysosomes for degradation. The E3 ubiquitin ligases PARKIN and MUL1play redundant roles in elimination of paternal mitochondria. The process is associated withdepolarization of paternal mitochondria and additionally requires the mitochondrial outer membraneprotein FIS1, the autophagy adaptor P62, and PINK1 kinase. Our results indicate that strict maternaltransmission of mitochondria relies on mitophagy and uncover a collaboration between MUL1 and PARKINin this process.", "metadata": {}}
+{"_id": "8426046", "title": "", "text": "Ribosome Profiling Provides Evidence that Large Noncoding RNAs Do Not Encode ProteinsLarge noncodingRNAs are emerging as an important component in cellular regulation. Considerable evidence indicatesthat these transcripts act directly as functional RNAs rather than through an encoded protein product.However, a recent study of ribosome occupancy reported that many large intergenic ncRNAs (lincRNAs)are bound by ribosomes, raising the possibility that they are translated into proteins. Here, we show thatclassical noncoding RNAs and 5' UTRs show the same ribosome occupancy as lincRNAs, demonstratingthat ribosome occupancy alone is not sufficient to classify transcripts as coding or noncoding. Instead, wedefine a metric based on the known property of translation whereby translating ribosomes are releasedupon encountering a bona fide stop codon. We show that this metric accurately discriminates betweenprotein-coding transcripts and all classes of known noncoding transcripts, including lincRNAs. Takentogether, these results argue that the large majority of lincRNAs do not function through encodedproteins.", "metadata": {}}
+{"_id": "8427306", "title": "", "text": "Isolation of a Fusion Transcript, AMLl IETO, With Similarity toWe have developed a restriction map of thechromosome 21 breakpoint region involved in t(8;21)(q22;q22.3) acute myelogenous leukemia (AML)and have isolated a genomic junction clone containing chromosome 8 and 21 material. Using probes fromthese regions, rearrangements have been identified in each of nine cases of t(8;21) AML examined. Inaddition, we have isolated cDNA clones from a t(8;21) AML cDNA library that contain fused sequencesfrom chromosome 8 and 21. The chromosome 8 component, referred to as ETO (for eight twenty-one), isencoded over a large genomic region, as suggested by the analysis of corresponding yeast artificialchromosomes (YACs). The DNA sequence of the chromosome 21 portion of the fusion transcript isderived from the normal AML1 gene. A striking similarity (67% identity over 387 bp, with a corresponding69% amino acid identity) was detected between AML1 and the Drosophila segmentation gene, runt. Thecritical consequence of the translocation is the juxtaposition of 5' sequences of AML1 to 3' sequences ofETO, oriented telomere to centromere on the der(8) chromosome.", "metadata": {}}
+{"_id": "8428837", "title": "", "text": "Treatment of spondyloarthropathy with 5-aminosalicylic acid (mesalazine): an open trial.OBJECTIVEAnkylosing spondylitis (AS) and spondyloarthropathy (SpA) are inflammatory diseases of unknownetiology. Various exogenous and endogenous (inherited) factors play a role in their development.Sulfasalazine (SSZ) is generally accepted as a disease modifying drug in the treatment of AS and SpA.Which part of SSZ, 5-acetylsalicylic acid (5-ASA, mesalazine) or sulfapyridine (SP), is the effective moietyis unknown. As the bowel, colon, and the ileum play an important role in the development of AS and SpA,it may be possible that 5-ASA is the effective moiety, with a similar mode of action as in the treatment ofinflammatory bowel disease. To determine the efficacy of 5-ASA an open pilot study was done in 2 groupsof patients with SpA.   METHODS Twenty patients with SpA, who were taking SSZ, were switched to5-ASA (Pentasa), and 19 patients with active SpA were treated with 5-ASA without previousadministration of SSZ. RESULTS In the first group, 17 (85%) patients responded with respect to thephysician global clinical assessment compared to the previous SSZ treatment period; whereas in thesecond patient group a statistically significant improvement was obtained in erythrocyte sedimentationrate. CONCLUSION The results support our hypothesis that 5-ASA might be the active moiety of SSZ inthe treatment of SpA.", "metadata": {}}
+{"_id": "8428935", "title": "", "text": "Relationship of physical activity and television watching with body weight and level of fatness amongchildren: results from the Third National Health and Nutrition Examination Survey.CONTEXT Physicalinactivity contributes to weight gain in adults, but whether this relationship is true for children of differentethnic groups is not well established. OBJECTIVE To assess participation in vigorous activity andtelevision watching habits and their relationship to body weight and fatness in US children. DESIGNNationally representative cross-sectional survey with an in-person interview and medical examination.SETTING AND PARTICIPANTS Between 1988 and 1994, 4063 children aged 8 through 16 years wereexamined as part of the National Health and Nutrition Examination Survey III. Mexican Americans andnon-Hispanic blacks were oversampled to produce reliable estimates for these groups. MAIN OUTCOMEMEASURES Episodes of weekly vigorous activity and daily hours of television watched, and theirrelationship to body mass index and body fatness. RESULTS Eighty percent of US children reportedperforming 3 or more bouts of vigorous activity each week. This rate was lower in non-Hispanic black andMexican American girls (69% and 73%, respectively). Twenty percent of US children participated in 2 orfewer bouts of vigorous activity perweek, and the rate was higher in girls (26%) than in boys (17%).Overall, 26% of US children watched 4 or more hours of television per day and 67% watched at least 2hours per day. Non-Hispanic black children had the highest rates of watching 4 or more hours oftelevision per day (42%). Boys and girls who watch 4 or more hours of television each day had greaterbody fat (P<.001) and had a greater body mass index (P<.001) than those who watched less than 2hours per day. CONCLUSIONS Many US children watch a great deal of television and are inadequatelyvigorously active. Vigorous activity levels are lowest among girls, non-Hispanic blacks, and MexicanAmericans. Intervention strategies to promote lifelong physical activity among US children are needed tostem the adverse health consequences of inactivity.", "metadata": {}}
+{"_id": "8446259", "title": "", "text": "Vascular Calcification in Chronic Kidney Disease is Induced by Bone Morphogenetic Protein-2 via aMechanism Involving the Wnt/β-Catenin PathwayBackground: Vascular calcification (VC), in whichvascular smooth muscle cells (VSMCs) undergo a phenotypic transformation into osteoblast-like cells, isone of the emergent risk factors for the accelerated atherosclerosis process characteristic of chronickidney disease (CKD). Phosphate is an important regulator of VC. Methods: The expression of differentsmooth muscle cell or osteogenesis markers in response to high concentrations of phosphate orexogenous bone morphogenetic protein 2 (BMP-2) was examined by qRT-PCR and western blotting in ratVSMCs. Osteocalcin secretion was measured by radioimmunoassay. Differentiation and calcification ofVSMCs were examined by alkaline phosphatase (ALP) activity assay and Alizarin staining. Short hairpinRNA-mediated silencing of β-catenin was performed to examine the involvement of Wnt/β-cateninsignaling in VSMC calcification and osteoblastic differentiation induced by high phosphate or BMP-2.Apoptosis was determined by TUNEL assay and immunofluorescence imaging. Results: BMP-2 serumlevels were significantly higher in CKD patients than in controls. High phosphate concentrations andBMP-2 induced VSMC apoptosis and upregulated the expression of β-catenin, Msx2, Runx2 and thephosphate cotransporter Pit1, whereas a BMP-2 neutralization antibody reversed these effects.Knockdown of β-catenin abolished the effect of high phosphate and BMP-2 on VSMC apoptosis andcalcification. Conclusions: BMP-2 plays a crucial role in calcium deposition in VSMCs and VC in CKDpatients via a mechanism involving the Wnt/β-catenin pathway.", "metadata": {}}
+{"_id": "8446324", "title": "", "text": "Advances in brain tumor surgery.Advances in the fields of molecular and translational research, oncology,and surgery have emboldened the medical community to believe that intrinsic brain tumors may betreatable. Intraoperative imaging and brain mapping allow operations adjacent to eloquent cortex andmore radical resection of tumors with increased confidence and safety. Despite these advances, theinfiltrating edge of a neoplasm and distant microscopic satellite lesions will never be amendable to asurgical cure. Indeed, it is continued research into the delivery of an efficacious chemobiologic agent thatwill eventually allows us to manage this primary cause of treatment failure.", "metadata": {}}
+{"_id": "8447873", "title": "", "text": "Systematic review of controlled clinical trials of gastric lavage in acute organophosphorus pesticidepoisoning.BACKGROUND Organophosphorus pesticide (OP) self-poisoning is a major problem in thedeveloping rural world. There is little clinical trial data to guide therapy, hindering the identification ofbest therapy. Despite the recognition of adverse effects, gastric lavage is commonly done in Asia. Weaimed to identify studies assessing its effectiveness. METHOD We systematically searched the literaturefor controlled clinical studies that assessed the effect of gastric lavage in OP pesticide self-poisoning.RESULTS All 56 studies identified were Chinese and reported benefit from the intervention studied,including multiple gastric lavages, use of norepinephrine or pralidoxime in the lavage fluid, concurrenttreatment with naloxone or scopolamine, insertion of the gastric tube via a laparotomy incision, andlavage later than 12 h post-ingestion. However, only 23 were RCTs and none presented adequatemethodology for their quality to be assessed. The patient population and study treatment protocol werenot defined - large variation in case fatality in the control arm of the studies (from 4.5 to 93%) suggestsmarked variation between studies and likely between study arms. No study compared an interventionagainst a control group receiving no gastric lavage or provided any data to indicate whether a significantquantity of poison was removed. CONCLUSION Despite widespread use of multiple gastric lavages for OPpesticide poisoning across Asia, there is currently no high-quality evidence to support its clinicaleffectiveness. There is a need for studies to identify in which patients and for what duration gastric lavageis able to remove significant quantities of poison. Following these studies, large clinical trials will berequired to address the effectiveness and safety of gastric lavage (either single or multiple) in acute OPpesticide poisoning.", "metadata": {}}
+{"_id": "8453819", "title": "", "text": "Integrin activation by Fam38A uses a novel mechanism of R-Ras targeting to the endoplasmicreticulum.The integrin family of heterodimeric cell-surface receptors are fundamental in cell-cell andcell-matrix adhesion. Changes to either integrin-ligand affinity or integrin gene expression are central to avariety of disease processes, including inflammation, cardiovascular disease and cancer. In screening fornovel activators of integrin-ligand affinity we identified the previously uncharacterisedmulti-transmembrane domain protein Fam38A, located at the endoplasmic reticulum (ER). siRNAknockdown of Fam38A in epithelial cells inactivates endogenous beta1 integrin, reducing cell adhesion.Fam38A mediates integrin activation by recruiting the small GTPase R-Ras to the ER, which activates thecalcium-activated protease calpain by increasing Ca(2+) release from cytoplasmic stores.Fam38A-induced integrin activation is blocked by inhibition of either R-Ras or calpain activity, or by siRNAknockdown of talin, a well-described calpain substrate. This highlights a novel mechanism for integrinactivation by Fam38A, utilising calpain and R-Ras signalling from the ER. These data represent the firstdescription of a novel spatial regulator of R-Ras, of an alternative integrin activation-suppression pathwaybased on direct relocalisation of R-Ras to the ER, and of a mechanism linking R-Ras and calpain signallingfrom the ER with modulation of integrin-ligand affinity.", "metadata": {}}
+{"_id": "8458567", "title": "", "text": "Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimerformation of their receptorsPEROXISOMES are cytoplasmic organelles which are important in mammals inmodulation of lipid homeostasis, including the metabolism of long-chain fatty acids and conversion ofcholesterol to bile salts (reviewed in refs 1 and 2). Amphipathic carboxylates such as clofibric acid havebeen used in man as hypolipidaemic agents and in rodents they stimulate the proliferation ofperoxisomes. These agents, termed peroxisome proliferators, and all-trans retinoic acid activate genesinvolved in peroxisomal-mediated β-oxidation of fatty acids1–4. Here we show that the receptor activatedby peroxisome proliferators5 and the retinoid X receptor-α (ref. 6) form a heterodimer that activatesacyl-CoA oxidase gene expression in response to either clofibric acid or the retinoid X receptor-α ligand,9-cis retinoic acid, an all-trans retinoic acid metabolite7,8; simultaneous exposure to both activatorsresults in a synergistic induction of gene expression. These data demonstrate the coupling of theperoxisome proliferator and retinoid signalling pathways and provide evidence for a physiological role for9-cis retinoic acid in modulating lipid metabolism.", "metadata": {}}
+{"_id": "8460275", "title": "", "text": "The Utilization of Extracellular Proteins as Nutrients Is Suppressed by mTORC1Despite being surroundedby diverse nutrients, mammalian cells preferentially metabolize glucose and free amino acids. Recently,Ras-induced macropinocytosis of extracellular proteins was shown to reduce a transformed cell'sdependence on extracellular glutamine. Here, we demonstrate that protein macropinocytosis can alsoserve as an essential amino acid source. Lysosomal degradation of extracellular proteins can sustain cellsurvival and induce activation of mTORC1 but fails to elicit significant cell accumulation. Unlike itsgrowth-promoting activity under amino-acid-replete conditions, we discovered that mTORC1 activationsuppresses proliferation when cells rely on extracellular proteins as an amino acid source. InhibitingmTORC1 results in increased catabolism of endocytosed proteins and enhances cell proliferation duringnutrient-depleted conditions in vitro and within vascularly compromised tumors in vivo. Thus, bypreventing nutritional consumption of extracellular proteins, mTORC1 couples growth to availability offree amino acids. These results may have important implications for the use of mTOR inhibitors astherapeutics.", "metadata": {}}
+{"_id": "8476213", "title": "", "text": "A general model to explore complex dominance patterns in plant sporophytic self-incompatibilitysystems.We developed a general model of sporophytic self-incompatibility under negativefrequency-dependent selection allowing complex patterns of dominance among alleles. We used thismodel deterministically to investigate the effects on equilibrium allelic frequencies of the number ofdominance classes, the number of alleles per dominance class, the asymmetry in dominance expressionbetween pollen and pistil, and whether selection acts on male fitness only or both on male and on femalefitnesses. We show that the so-called \"recessive effect\" occurs under a wide variety of situations. Wefound emerging properties of finite population models with several alleles per dominance class such asthat higher numbers of alleles are maintained in more dominant classes and that the number ofdominance classes can evolve. We also investigated the occurrence of homozygous genotypes and foundthat substantial proportions of those can occur for the most recessive alleles. We used the model for twospecies with complex dominance patterns to test whether allelic frequencies in natural populations are inagreement with the distribution predicted by our model. We suggest that the model can be used to testexplicitly for additional, allele-specific, selective forces.", "metadata": {}}
+{"_id": "8477699", "title": "", "text": "Metabolic Reprograming in Macrophage PolarizationStudying the metabolism of immune cells in recentyears has emphasized the tight link existing between the metabolic state and the phenotype of thesecells. Macrophages in particular are a good example of this phenomenon. Whether the macrophageobtains its energy through glycolysis or through oxidative metabolism can give rise to differentphenotypes. Classically activated or M1 macrophages are key players of the first line of defense againstbacterial infections and are known to obtain energy through glycolysis. Alternatively activated or M2macrophages on the other hand are involved in tissue repair and wound healing and use oxidativemetabolism to fuel their longer-term functions. Metabolic intermediates, however, are not just a source ofenergy but can be directly implicated in a particular macrophage phenotype. In M1 macrophages, theKrebs cycle intermediate succinate regulates HIF1α, which is responsible for driving the sustainedproduction of the pro-inflammatory cytokine IL1β. In M2 macrophages, the sedoheptulose kinasecarbohydrate kinase-like protein is critical for regulating the pentose phosphate pathway. The potential totarget these events and impact on disease is an exciting prospect.", "metadata": {}}
+{"_id": "8494570", "title": "", "text": "Characterization of constitutive CTCF/cohesin loci: a possible role in establishing topological domains inmammalian genomesBACKGROUND Recent studies suggested that human/mammalian genomes aredivided into large, discrete domains that are units of chromosome organization. CTCF, a CCCTC bindingfactor, has a diverse role in genome regulation including transcriptional regulation,chromosome-boundary insulation, DNA replication, and chromatin packaging. It remains unclear whethera subset of CTCF binding sites plays a functional role in establishing/maintaining chromatin topologicaldomains. RESULTS We systematically analysed the genomic, transcriptomic and epigenetic profiles of theCTCF binding sites in 56 human cell lines from ENCODE. We identified ~24,000 CTCF sites (referred to asconstitutive sites) that were bound in more than 90% of the cell lines. Our analysis revealed: 1)constitutive CTCF loci were located in constitutive open chromatin and often co-localized with constitutivecohesin loci; 2) most constitutive CTCF loci were distant from transcription start sites and lacked CpGislands but were enriched with the full-spectrum CTCF motifs: a recently reported 33/34-mer and twoother potentially novel (22/26-mer); 3) more importantly, most constitutive CTCF loci were present inCTCF-mediated chromatin interactions detected by ChIA-PET and these pair-wise interactions occurredpredominantly within, but not between, topological domains identified by Hi-C.   CONCLUSIONS Ourresults suggest that the constitutive CTCF sites may play a role in organizing/maintaining the recentlyidentified topological domains that are common across most human cells.", "metadata": {}}
+{"_id": "8496132", "title": "", "text": "Regulation of Bcl-2 expression by HuR in HL60 leukemia cells and A431 carcinoma cells.Overexpressionof the proto-oncogene bcl-2 promotes abnormal cell survival by inhibiting apoptosis. Expression of bcl-2is determined, in part, by regulatory mechanisms that control the stability of bcl-2 mRNA. Elements in the3'-untranslated region of bcl-2 mRNA have been shown to play a role in regulating the stability of themessage. Previously, it was found that the RNA binding proteins nucleolin and Ebp1 have a role instabilizing bcl-2 mRNA in HL60 cells. Here, we have identified HuR as a component of bcl-2 messengerribonucleoprotein (mRNP) complexes. RNA coimmunoprecipitation assays showed that HuR binds to bcl-2mRNA in vivo. We also observed an RNA-dependent coprecipitation of HuR and nucleolin, suggesting thatthe two proteins are present in common mRNP complexes. Moreover, nucleolin and HuR bindconcurrently to bcl-2 AU-rich element (ARE) RNA in vitro, suggesting separate binding sites for theseproteins on bcl-2 mRNA. Knockdown of HuR in A431 cells leads to down-regulation of bcl-2 mRNA andprotein levels. Observation of a decreased ratio of bcl-2 mRNA to heterogeneous nuclear RNA in HuRknockdown cells confirmed a positive role for HuR in regulating bcl-2 stability. Recombinant HuR retardsexosome-mediated decay of bcl-2 ARE RNA in extracts of HL60 cells. This supports a role for HuR in theregulation of bcl-2 mRNA stability in HL60 cells, as well as in A431 cells. Addition of nucleolin and HuR toHL60 cell extracts produced a synergistic protective effect on decay of bcl-2 ARE RNA. HuR knockdownalso leads to redistribution of bcl-2 mRNA from polysomes to monosomes. Thus, HuR seems to play apositive role in both regulation of bcl-2 mRNA translation and mRNA stability.", "metadata": {}}
+{"_id": "8502193", "title": "", "text": "The Worldwide Variation in Avian Clutch Size across Species and SpaceTraits such as clutch size varymarkedly across species and environmental gradients but have usually been investigated from either acomparative or a geographic perspective, respectively. We analyzed the global variation in clutch sizeacross 5,290 bird species, excluding brood parasites and pelagic species. We integrated intrinsic(morphological, behavioural), extrinsic (environmental), and phylogenetic effects in a combined modelthat predicts up to 68% of the interspecific variation in clutch size. We then applied the samespecies-level model to predict mean clutch size across 2,521 assemblages worldwide and found that itexplains the observed eco-geographic pattern very well. Clutches are consistently largest in cavitynesters and in species occupying seasonal environments, highlighting the importance of offspring andadult mortality that is jointly expressed in intrinsic and extrinsic correlates. The findings offer aconceptual bridge between macroecology and comparative biology and provide a global and integrativeunderstanding of the eco-geographic and cross-species variation in a core life-history trait.", "metadata": {}}
+{"_id": "8509018", "title": "", "text": "Diastolic heart failure--abnormalities in active relaxation and passive stiffness of the leftventricle.BACKGROUND Patients with signs and symptoms of heart failure and a normal left ventricularejection fraction are said to have diastolic heart failure. It has traditionally been thought that thepathophysiological cause of heart failure in these patients is an abnormality in the diastolic properties ofthe left ventricle; however, this hypothesis remains largely unproven. METHODS We prospectivelyidentified 47 patients who met the diagnostic criteria for definite diastolic heart failure; all the patientshad signs and symptoms of heart failure, a normal ejection fraction, and an increased left ventricularend-diastolic pressure. Ten patients who had no evidence of cardiovascular disease served as controls.Left ventricular diastolic function was assessed by means of cardiac catheterization andechocardiography. RESULTS The patients with diastolic heart failure had abnormal left ventricularrelaxation and increased left ventricular chamber stiffness. The mean (+/-SD) time constant for theisovolumic-pressure decline (tau) was longer in the group with diastolic heart failure than in the controlgroup (59+/-14 msec vs. 35+/-10 msec, P=0.01). The diastolic pressure-volume relation was shifted upand to the left in the patients with diastolic heart failure as compared with the controls. The corrected leftventricular passive-stiffness constant was significantly higher in the group with diastolic heart failure thanin the control group (0.03+/-0.01 vs. 0.01+/-0.01, P<0.001). CONCLUSIONS Patients with heart failureand a normal ejection fraction have significant abnormalities in active relaxation and passive stiffness. Inthese patients, the pathophysiological cause of elevated diastolic pressures and heart failure is abnormaldiastolic function.", "metadata": {}}
+{"_id": "8512633", "title": "", "text": "The lncRNAs PCGEM1 and PRNCR1 are not implicated in castration resistant prostate cancerLongnoncoding RNAs (IncRNAs) are increasingly implicated in cancer biology, contributing to essential cancercell functions such as proliferation, invasion, and metastasis. In prostate cancer, several lncRNAs havebeen nominated as critical actors in disease pathogenesis. Among these, expression of PCGEM1 andPRNCR1 has been identified as a possible component in disease progression through the coordination ofandrogen receptor (AR) signaling (Yang et al., Nature 2013, see ref. [1]). However, concerns regardingthe robustness of these findings have been suggested. Here, we sought to evaluate whether PCGEM1 andPRNCR1 are associated with prostate cancer. Through a comprehensive analysis of RNA-sequencing data(RNA-seq), we find evidence that PCGEM1 but not PRNCR1 is associated with prostate cancer. We employa large cohort of >230 high-risk prostate cancer patients with long-term outcomes data to show that, incontrast to prior reports, neither gene is associated with poor patient outcomes. We further observe noevidence that PCGEM1 nor PRNCR1 interact with AR, and neither gene is a component of AR signaling.Thus, we conclusively demonstrate that PCGEM1 and PRNCR1 are not prognostic lncRNAs in prostatecancer and we refute suggestions that these lncRNAs interact in AR signaling.", "metadata": {}}
+{"_id": "8519911", "title": "", "text": "p38MAPK controls expression of multiple cell cycle inhibitors and islet proliferation with advancingage.Aging is a complex organismal process that is controlled by genetic, environmental, and behavioralfactors. Accumulating evidence supports a role for different cell cycle inhibitors in mammalian aging.Little is known, however, about the upstream signals that induce their expression. Here, we explore therole of p38MAPK by generating a dominant-negative allele (p38(AF)) in which activating phosphorylationsites Thr180 and Tyr182 are mutated. Heterozygous p38(AF) mice show a marked attenuation ofp38-dependent signaling and age-induced expression of multiple cell cycle inhibitors in different organs,including pancreatic islets. As a result, aged p38(AF/+) mice show enhanced proliferation andregeneration of islets when compared to wild-type littermates. We further find an age-related reduction inexpression of the p38-specific phosphatase Wip1. Wip1-deficient mice demonstrate decreased isletproliferation, while Wip1 overexpression rescues aging-related decline in proliferation and regenerativecapacity. We propose that modulation of p38MAPK activity may provide new avenues for treating certainage-related degenerative diseases.", "metadata": {}}
+{"_id": "8520041", "title": "", "text": "ACTA PSYCHIATRICAOBJECTIVE We explored the subjective effects associated with olanzapine,risperidone and older antipsychotics. METHOD We conducted a content analysis of an Internet databaseof comments about prescribed medications. RESULTS We analysed 223 comments on risperidone, 170 onolanzapine and 46 relating to three older antipsychotics. The predominant subjective effects produced byall drugs consisted of sedation, cognitive impairment and emotional flattening or indifference.Connections appeared between these effects and Parkinsonian-like symptoms with the older drugs,sexual impairment with risperidone and metabolic effects with olanzapine. The experience of akathisiawas frequently linked to suicidal thoughts. Some respondents described how the drugs' subjective effectshelped to reduce symptoms of mania, psychosis and anxiety. CONCLUSION The generalisability ofInternet data is uncertain. However, the data suggest that adverse subjective effects play a central rolein the experience of taking antipsychotic drugs and may be related to the drugs' desired benefits.", "metadata": {}}
+{"_id": "8524891", "title": "", "text": "White matter hyperintensities are a core feature of Alzheimer's disease: Evidence from the dominantlyinherited Alzheimer network.OBJECTIVE White matter hyperintensities (WMHs) are areas of increasedsignal on T2-weighted magnetic resonance imaging (MRI) scans that most commonly reflect small vesselcerebrovascular disease. Increased WMH volume is associated with risk and progression of Alzheimer'sdisease (AD). These observations are typically interpreted as evidence that vascular abnormalities playan additive, independent role contributing to symptom presentation, but not core features of AD. Weexamined the severity and distribution of WMH in presymptomatic PSEN1, PSEN2, and APP mutationcarriers to determine the extent to which WMH manifest in individuals genetically determined to developAD. METHODS The study comprised participants (n = 299; age = 39.03 ± 10.13) from the DominantlyInherited Alzheimer Network, including 184 (61.5%) with a mutation that results in AD and 115 (38.5%)first-degree relatives who were noncarrier controls. We calculated the estimated years from expectedsymptom onset (EYO) by subtracting the affected parent's symptom onset age from the participant's age.Baseline MRI data were analyzed for total and regional WMH. Mixed-effects piece-wise linear regressionwas used to examine WMH differences between carriers and noncarriers with respect to EYO. RESULTSMutation carriers had greater total WMH volumes, which appeared to increase approximately 6 yearsbefore expected symptom onset. Effects were most prominent for the parietal and occipital lobe, whichshowed divergent effects as early as 22 years before estimated onset. INTERPRETATIONAutosomal-dominant AD is associated with increased WMH well before expected symptom onset. Thefindings suggest the possibility that WMHs are a core feature of AD, a potential therapeutic target, and afactor that should be integrated into pathogenic models of the disease. Ann Neurol 2016;79:929-939.", "metadata": {}}
+{"_id": "8529693", "title": "", "text": "Maternal and child undernutrition: consequences for adult health and human capitalIn this paper wereview the associations between maternal and child undernutrition with human capital and risk of adultdiseases in low-income and middle-income countries. We analysed data from five long-standingprospective cohort studies from Brazil, Guatemala, India, the Philippines, and South Africa and noted thatindices of maternal and child undernutrition (maternal height, birthweight, intrauterine growth restriction,and weight, height, and body-mass index at 2 years according to the new WHO growth standards) wererelated to adult outcomes (height, schooling, income or assets, offspring birthweight, body-mass index,glucose concentrations, blood pressure). We undertook systematic reviews of studies from low-incomeand middle-income countries for these outcomes and for indicators related to blood lipids, cardiovasculardisease, lung and immune function, cancers, osteoporosis, and mental illness. Undernutrition wasstrongly associated, both in the review of published work and in new analyses, with shorter adult height,less schooling, reduced economic productivity, and--for women--lower offspring birthweight. Associationswith adult disease indicators were not so clear-cut. Increased size at birth and in childhood werepositively associated with adult body-mass index and to a lesser extent with blood pressure values, butnot with blood glucose concentrations. In our new analyses and in published work, lower birthweight andundernutrition in childhood were risk factors for high glucose concentrations, blood pressure, and harmfullipid profiles once adult body-mass index and height were adjusted for, suggesting that rapid postnatalweight gain--especially after infancy--is linked to these conditions. The review of published worksindicates that there is insufficient information about long-term changes in immune function, blood lipids,or osteoporosis indicators. Birthweight is positively associated with lung function and with the incidenceof some cancers, and undernutrition could be associated with mental illness. We noted thatheight-for-age at 2 years was the best predictor of human capital and that undernutrition is associatedwith lower human capital. We conclude that damage suffered in early life leads to permanent impairment,and might also affect future generations. Its prevention will probably bring about important health,educational, and economic benefits. Chronic diseases are especially common in undernourished childrenwho experience rapid weight gain after infancy.", "metadata": {}}
+{"_id": "8533245", "title": "", "text": "Ubiquitin-dependent intramembrane rhomboid protease promotes ERAD of membrane proteins.TheER-associated degradation (ERAD) pathway serves as an important cellular safeguard by directingincorrectly folded and unassembled proteins from the ER to the proteasome. Still, however, little is knownabout the components mediating ERAD of membrane proteins. Here we show that the evolutionaryconserved rhomboid family protein RHBDL4 is a ubiquitin-dependent ER-resident intramembraneprotease that is upregulated upon ER stress. RHBDL4 cleaves single-spanning and polytopic membraneproteins with unstable transmembrane helices, leading to their degradation by the canonical ERADmachinery. RHBDL4 specifically binds the AAA+-ATPase p97, suggesting that proteolytic processing anddislocation into the cytosol are functionally linked. The phylogenetic relationship between rhomboids andthe ERAD factor derlin suggests that substrates for intramembrane proteolysis and protein dislocation arerecruited by a shared mechanism.", "metadata": {}}
+{"_id": "8536018", "title": "", "text": "Detection and function of nitric oxide during the hypersensitive response in Arabidopsis thaliana: wherethere's a will there's a way.Nitric oxide (NO) was identified as a key player in plant defence responsesapproximately 20 years ago and a large body of evidence has accumulated since then supporting its roleas a signalling molecule. However, there are many discrepancies in current NO detection assays and theenzymatic pathways responsible for its synthesis have yet to be determined. This has provoked strongdebates concerning the function of NO in plants, even questioning its existence in planta. Here we gatherdata obtained using the model pathosystem Arabidopsis/Pseudomonas, which confirms the production ofNO during the hypersensitive response and supports is role as a trigger of hypersensitive cell death and amediator of defence gene expression. Finally, we discuss potential sources of NO synthesis, focusing onthe role of nitrite as major substrate for NO production during incompatible interactions.", "metadata": {}}
+{"_id": "8538916", "title": "", "text": "The Cytosolic Chaperonin CCT/TRiC and Cancer Cell ProliferationThe molecular chaperone CCT/TRiC playsa central role in maintaining cellular proteostasis as it mediates the folding of the major cytoskeletalproteins tubulins and actins. CCT/TRiC is also involved in the oncoprotein cyclin E, the Von Hippel-Lindautumour suppressor protein, cyclin B and p21(ras) folding which strongly suggests that it is involved in cellproliferation and tumor genesis. To assess the involvement of CCT/TRiC in tumor genesis, we quantifiedits expression levels and activity in 18 cancer, one non-cancer human cell lines and a non-cancer humanliver. We show that the expression levels of CCT/TRiC in cancer cell lines are higher than that in normalcells. However, CCT/TRiC activity does not always correlate with its expression levels. We thereforedocumented the expression levels of CCT/TRiC modulators and partners PhLP3, Hop/P60, prefoldin andHsc/Hsp70. Our analysis reveals a functional interplay between molecular chaperones that might accountfor a precise modulation of CCT/TRiC activity in cell proliferation through changes in the cellular levels ofprefoldin and/or Hsc/p70 and CCT/TRiC client protein availability. Our observation and approaches bringnovel insights in the role of CCT/TRiC-mediated protein folding machinery in cancer cell development.", "metadata": {}}
+{"_id": "8548635", "title": "", "text": "RBP2 Belongs to a Family of Demethylases, Specific for Tri-and Dimethylated Lysine 4 on Histone3Methylation of histones has been regarded as a stable modification defining the epigenetic program ofthe cell, which regulates chromatin structure and transcription. However, the recent discovery of histonedemethylases has challenged the stable nature of histone methylation. Here we demonstrate that theJARID1 proteins RBP2, PLU1, and SMCX are histone demethylases specific for di- and trimethylatedhistone 3 lysine 4 (H3K4). Consistent with a role for the JARID1 Drosophila homolog Lid in regulatingexpression of homeotic genes during development, we show that RBP2 is displaced from Hox genesduring embryonic stem (ES) cell differentiation correlating with an increase of their H3K4me3 levels andexpression. Furthermore, we show that mutation or RNAi depletion of the C. elegans JARID1 homologrbr-2 leads to increased levels of H3K4me3 during larval development and defects in vulva formation.Taken together, these results suggest that H3K4me3/me2 demethylation regulated by the JARID1 familyplays an important role during development.", "metadata": {}}
+{"_id": "8551160", "title": "", "text": "Mitochondria: Dynamic Organelles in Disease, Aging, and DevelopmentMitochondria are the primaryenergy-generating system in most eukaryotic cells. Additionally, they participate in intermediarymetabolism, calcium signaling, and apoptosis. Given these well-established functions, it might beexpected that mitochondrial dysfunction would give rise to a simple and predictable set of defects in alltissues. However, mitochondrial dysfunction has pleiotropic effects in multicellular organisms. Clearly,much about the basic biology of mitochondria remains to be understood. Here we discuss recent workthat suggests that the dynamics (fusion and fission) of these organelles is important in development anddisease.", "metadata": {}}
+{"_id": "8563659", "title": "", "text": "Persistence of HIV-1 Receptor-Positive Cells after HSV-2 Reactivation: A Potential Mechanism forIncreased HIV-1 AcquisitionTo explore the mechanism by which herpes simplex virus (HSV)-2 infection isrelated to HIV-1 acquisition, we conducted in situ analysis of the cellular infiltrate from sequentialbiopsies of HSV-2 lesions from patients on and off antiviral therapy. CD4(+) and CD8(+) T cells and amixed population of plasmacytoid and myeloid dendritic cells (DCs), including cells expressing the C-typelectin receptor DC-SIGN, persisted at sites of HSV-2 reactivation for months after healing, even with dailyantiviral therapy. The CD4(+) T cells that persisted reacted to HSV-2 antigen, were enriched forexpression of the chemokine receptor CCR5, and were contiguous to DCs expressing the interleukin-3receptor CD123 or DC-SIGN. Ex vivo infection with a CCR5-tropic strain of HIV-1 revealed greaterconcentrations of integrated HIV-1 DNA in cells derived from healed genital lesion biopsies than in cellsfrom control skin biopsies. The persistence and enrichment of HIV receptor-positive inflammatory cells inthe genitalia help explain the inability of anti-HSV-2 therapy to reduce HIV acquisition.", "metadata": {}}
+{"_id": "8570317", "title": "", "text": "Chronic daily headache in Taipei, Taiwan: prevalence, follow-up and outcome predictors.We conducted atwo-stage population-based headache survey among subjects aged > or = 15 in Taipei, Taiwan. Subjectswith chronic daily headache (CDH) in the past year were identified, interviewed and followed-up. CDHwas defined as a headache frequency > 15 days/month, with a duration > 4 h/day. Of the 3377participants, 108 (3.2%) fulfilled the criteria for CDH, with a higher prevalence in women (4.3%) thanmen (1.9%). TM was the most common subtype (55%), followed by CTTH (44%). Thirty-four per cent ofthe CDH subjects overused analgesics. At the 2-year follow-up, 35% of the CDH subjects still had CDH.The significant predictors for persistent CDH at follow-up included: older age ( > or = 40 years) (RR =2.4), CDH onset after 32 years (RR = 1.8), CDH duration > or = 6 years (RR = 2.0), medication overuse(RR = 1.8), and \"daily\" headache (RR = 2.1). We found that CDH is not uncommon in the community andits prevalence is similar among different populations. Older subjects and those with medication overusemay have a more protracted course of illness.", "metadata": {}}
+{"_id": "8570478", "title": "", "text": "In vivo microtubules are copolymers of available beta-tubulin isotypes: localization of each of sixvertebrate beta-tubulin isotypes using polyclonal antibodies elicited by synthetic peptideantigensbeta-Tubulin is encoded in the genomes of higher animals by a small multigene familycomprising approximately seven functional genes. These genes produce a family of closely related, butdistinct polypeptide isotypes that are distinguished principally by sequences within the approximately 15carboxy-terminal amino acid residues. By immunizing rabbits with chemically synthesized peptidescorresponding to these variable domain sequences, we have now prepared polyclonal antibodies specificfor each of six distinct isotypes. Specificity of each antiserum has been demonstrated unambiguously byantibody binding to bacterially produced, cloned proteins representing each isotype and by the inhibitionof such binding by preincubation of each antiserum only with the immunizing peptide and not withheterologous peptides. Protein blotting of known amounts of cloned, isotypically pure polypeptides haspermitted accurate quantitative measurement of the amount of each beta-tubulin isotype present in thesoluble and polymer forms in various cells, but has not revealed a bias for preferential assembly of anyisotype. Localization of each isotype in three different cell types using indirect immunofluorescence hasdemonstrated that in vivo each class of microtubules distinguishable by light microscopy is assembled ascopolymers of all isotypes expressed in a single cell.", "metadata": {}}
+{"_id": "8570690", "title": "", "text": "Topiramate for smoking cessation: a randomized, placebo-controlled pilot study.INTRODUCTIONTopiramate (TOP) blocks glutamate receptors and facilitates GABA (γ-aminobutyric acid)neurotransmission, effects that may facilitate smoking cessation. We compared the effects of behavioralcounseling combined with (a) TOP, (b) TOP/nicotine patch (TOP/NIC), or (c) placebo (PLC) for smokingcessation. METHODS We conducted a 10-week randomized trial in which subjects and research personnelwere blinded to TOP versus PLC but not to the TOP/NIC patch condition. In groups receiving TOP, themedication dosage was titrated gradually up to 200 mg/day. The smoking quit date (QD) was scheduledafter 2 weeks of medication treatment. NIC (21 mg) was started on the QD in subjects randomized to theTOP/NIC condition. The main outcome measure was the end-of-treatment, 4-week continuous abstinencerate (CAR; biochemically confirmed). RESULTS Fifty-seven subjects were randomized to treatment. The4-week CAR was 1 of 19 (5%) in the PLC group, 5 of 19 (26%) in the TOP group, and 7 of 19 (37%) inthe TOP/NIC group (p = .056). Pairwise comparisons showed a difference between TOP/NIC and PLC (p =.042) and a nonsignificant difference between TOP and PLC (p = .18). The PLC group gained 0.37lb/week, the TOP group lost 0.41 lb/week, and the TOP/NIC group lost 0.07 lb/week (p = .004). Pairwisecomparisons showed a difference between TOP and PLC (p < .001) and between TOP/NIC and PLC groups(p = .035). Paresthesia was more frequent in subjects on TOP than PLC (p = .011). CONCLUSIONS TOP,alone or in combination with the NIC, resulted in a numerically higher quit rate than PLC and decreasedweight. A larger, PLC-controlled trial is needed to confirm these findings.", "metadata": {}}
+{"_id": "8577229", "title": "", "text": "Break-induced DNA replication.Recombination-dependent DNA replication, often called break-inducedreplication (BIR), was initially invoked to explain recombination events in bacteriophage but it hasrecently been recognized as a fundamentally important mechanism to repair double-strand chromosomebreaks in eukaryotes. This mechanism appears to be critically important in the restarting of stalled andbroken replication forks and in maintaining the integrity of eroded telomeres. Although BIR helpspreserve genome integrity during replication, it also promotes genome instability by the production ofloss of heterozygosity and the formation of nonreciprocal translocations, as well as in the generation ofcomplex chromosomal rearrangements.", "metadata": {}}
+{"_id": "8582337", "title": "", "text": "The state of US health, 1990-2010: burden of diseases, injuries, and risk factors.IMPORTANCEUnderstanding the major health problems in the United States and how they are changing over time iscritical for informing national health policy. OBJECTIVES To measure the burden of diseases, injuries, andleading risk factors in the United States from 1990 to 2010 and to compare these measurements withthose of the 34 countries in the Organisation for Economic Co-operation and Development (OECD)countries. DESIGN We used the systematic analysis of descriptive epidemiology of 291 diseases andinjuries, 1160 sequelae of these diseases and injuries, and 67 risk factors or clusters of risk factors from1990 to 2010 for 187 countries developed for the Global Burden of Disease 2010 Study to describe thehealth status of the United States and to compare US health outcomes with those of 34 OECD countries.Years of life lost due to premature mortality (YLLs) were computed by multiplying the number of deathsat each age by a reference life expectancy at that age. Years lived with disability (YLDs) were calculatedby multiplying prevalence (based on systematic reviews) by the disability weight (based onpopulation-based surveys) for each sequela; disability in this study refers to any short- or long-term lossof health. Disability-adjusted life-years (DALYs) were estimated as the sum of YLDs and YLLs. Deaths andDALYs related to risk factors were based on systematic reviews and meta-analyses of exposure data andrelative risks for risk-outcome pairs. Healthy life expectancy (HALE) was used to summarize overallpopulation health, accounting for both length of life and levels of ill health experienced at different ages.RESULTS US life expectancy for both sexes combined increased from 75.2 years in 1990 to 78.2 years in2010; during the same period, HALE increased from 65.8 years to 68.1 years. The diseases and injurieswith the largest number of YLLs in 2010 were ischemic heart disease, lung cancer, stroke, chronicobstructive pulmonary disease, and road injury. Age-standardized YLL rates increased for Alzheimerdisease, drug use disorders, chronic kidney disease, kidney cancer, and falls. The diseases with thelargest number of YLDs in 2010 were low back pain, major depressive disorder, other musculoskeletaldisorders, neck pain, and anxiety disorders. As the US population has aged, YLDs have comprised alarger share of DALYs than have YLLs. The leading risk factors related to DALYs were dietary risks,tobacco smoking, high body mass index, high blood pressure, high fasting plasma glucose, physicalinactivity, and alcohol use. Among 34 OECD countries between 1990 and 2010, the US rank for theage-standardized death rate changed from 18th to 27th, for the age-standardized YLL rate from 23rd to28th, for the age-standardized YLD rate from 5th to 6th, for life expectancy at birth from 20th to 27th,and for HALE from 14th to 26th. CONCLUSIONS AND RELEVANCE From 1990 to 2010, the United Statesmade substantial progress in improving health. Life expectancy at birth and HALE increased, all-causedeath rates at all ages decreased, and age-specific rates of years lived with disability remained stable.However, morbidity and chronic disability now account for nearly half of the US health burden, andimprovements in population health in the United States have not kept pace with advances in populationhealth in other wealthy nations.", "metadata": {}}
+{"_id": "8593263", "title": "", "text": "Malaria risk perception, knowledge and prophylaxis practices among travellers of African ethnicity livingin Paris and visiting their country of origin in sub-Saharan Africa.An observational prospective cohortstudy assessed malaria risk perception, knowledge and prophylaxis practices among individuals of Africanethnicity living in Paris and travelling to their country of origin to visit friends or relatives (VFR). Thestudy compared two groups of VFR who had visited a travel clinic (TC; n=122) or a travel agency (TA;n=69) before departure. Of the 47% of VFR citing malaria as a health concern, 75% knew that malaria ismosquito-borne and that bed nets are an effective preventive measure. Perception of high malaria riskwas greater in the TA group (33%) than in the TC group (7%). The availability of a malaria vaccine wasmentioned by 35% of VFR, with frequent confusion between yellow fever vaccine and malaria prevention.Twenty-nine percent took adequate chemoprophylaxis with complete adherence, which was higheramong the TC group (41%) than the TA group (12%). Effective antivector protection measures usedwere bed nets (16%), wearing long clothes at night (14%) and air conditioning (8%), with no differencesbetween the study groups except in the use of impregnated bed nets (11% of the TC group and none ofthe TA group). Media coverage, malaria chemoprophylaxis repayment and cultural adaptation ofpreventive messages should be improved to reduce the high rate of inadequate malaria prophylaxis inVFR.", "metadata": {}}
+{"_id": "8595678", "title": "", "text": "Effect modification by population dietary folate on the association between MTHFR genotype,homocysteine, and stroke risk: a meta-analysis of genetic studies and randomised trialsBACKGROUNDThe MTHFR 677C\u0000T polymorphism has been associated with raised homocysteine concentration andincreased risk of stroke. A previous overview showed that the effects were greatest in regions with lowdietary folate consumption, but differentiation between the effect of folate and small-study bias wasdifficult. A meta-analysis of randomised trials of homocysteine-lowering interventions showed noreduction in coronary heart disease events or stroke, but the trials were generally set in populations withhigh folate consumption. We aimed to reduce the effect of small-study bias and investigate whetherfolate status modifies the association between MTHFR 677C\u0000T and stroke in a genetic analysis andmeta-analysis of randomised controlled trials. METHODS We established a collaboration of genetic studiesconsisting of 237 datasets including 59,995 individuals with data for homocysteine and 20,885 strokeevents. We compared the genetic findings with a meta-analysis of 13 randomised trials ofhomocysteine-lowering treatments and stroke risk (45,549 individuals, 2314 stroke events, 269 transientischaemic attacks). FINDINGS The effect of the MTHFR 677C\u0000T variant on homocysteine concentrationwas larger in low folate regions (Asia; difference between individuals with TT versus CC genotype, 3·12μmol/L, 95% CI 2·23 to 4·01) than in areas with folate fortification (America, Australia, and New Zealand,high; 0·13 μmol/L, -0·85 to 1·11). The odds ratio (OR) for stroke was also higher in Asia (1·68, 95% CI1·44 to 1·97) than in America, Australia, and New Zealand, high (1·03, 0·84 to 1·25). Most randomisedtrials took place in regions with high or increasing population folate concentrations. The summary relativerisk (RR) of stroke in trials of homocysteine-lowering interventions (0·94, 95% CI 0·85 to 1·04) wassimilar to that predicted for the same extent of homocysteine reduction in large genetic studies inpopulations with similar folate status (predicted RR 1·00, 95% CI 0·90 to 1·11). Although the predictedeffect of homocysteine reduction from large genetic studies in low folate regions (Asia) was larger (RR0·78, 95% CI 0·68 to 0·90), no trial has evaluated the effect of lowering of homocysteine on stroke riskexclusively in a low folate region. INTERPRETATION In regions with increasing levels or establishedpolicies of population folate supplementation, evidence from genetic studies and randomised trials isconcordant in suggesting an absence of benefit from lowering of homocysteine for prevention of stroke.Further large-scale genetic studies of the association between MTHFR 677C\u0000T and stroke in low folatesettings are needed to distinguish effect modification by folate from small-study bias. If futurerandomised trials of homocysteine-lowering interventions for stroke prevention are undertaken, theyshould take place in regions with low folate consumption. FUNDING Full funding sources listed at end ofpaper (see Acknowledgments).", "metadata": {}}
+{"_id": "8596357", "title": "", "text": "Porcine circovirus type 2 DNA influences cytoskeleton rearrangements in plasmacytoid andmonocyte-derived dendritic cells.Functional disruption of dendritic cells (DC) is an important strategy forviral pathogens to evade host defences. In this context, porcine circovirus type 2 (PCV2), asingle-stranded DNA virus, impairs plasmacytoid DC (pDC) and conventional DC activation by certainviruses or Toll-like receptor (TLR) ligands. This inhibitory capacity is associated with the viral DNA, butthe impairment does not affect all signalling cascades; TLR7 ligation by small chemical molecules will stillinduce interleukin-6 (IL-6) and tumour necrosis factor-α secretion, but not interferon-α or IL-12. In thisstudy, the molecular mechanisms by which silencing occurs were investigated. PP2, a potent inhibitor ofthe Lyn and Hck kinases, produced a similar profile to the PCV2 DNA interference with cytokine secretionby pDC, efficiently inhibiting cell activation induced through TLR9, but not TLR7, ligation. Confocalmicroscopy and cytometry analysis strongly suggested that PCV2 DNA impairs actin polymerization andendocytosis in pDC and monocyte-derived DC, respectively. Altogether, this study delineates for the firsttime particular molecular mechanisms involved in PCV2 interference with DC danger recognition, whichmay be responsible for the virus-induced immunosuppression observed in infected pigs.", "metadata": {}}
+{"_id": "8596837", "title": "", "text": "Sympathetic neural and cardiovascular responses during static handgrip exercise in women with a historyof hypertensive pregnancyWomen with a history of hypertensive pregnancy are at greater risk for futurecardiovascular events; however, the mechanisms for this increased risk are unknown. Evidence suggeststhat an exercise stimulus unmasks latent hypertensive tendencies, identifying individuals at the greatestrisk for developing cardiovascular disease. The current study examined the hypothesis that women with ahypertensive pregnancy history exhibit an augmented exercise pressor response. Normotensive womenwith a history of healthy pregnancy (CON; n = 9) and hypertensive pregnancy (HP+; n = 12) werestudied during the mid-luteal phase of the menstrual cycle. Heart rate (HR), systolic and diastolic bloodpressure (SBP, DBP), and muscle sympathetic nerve activity (MSNA) were measured during a coldpressor test (CPT), and, following a sufficient period of recovery, during static handgrip to fatigue (SHG)and post-exercise circulatory arrest (PECA). The BP, HR, and MSNA responses to the CPT were similarbetween groups. The SBP response to SHG and PECA was similar between groups, but DBP and HR weresignificantly greater in HP+ women (both p < 0.05). MSNA burst frequency, but not burst incidence ortotal activity, tended to be elevated in HP+ women during the stressor (peak Δ from baseline 31 ± 13 vs.23 ± 13 bursts/min; p for group = 0.06). Despite no clinical signs of cardiovascular disease orhypertension, women with a history of hypertensive pregnancy display an enhanced cardiovascularreactivity to an exercise stimulus compared to women with a healthy pregnancy history. This responsemay be indicative of impaired cardiovascular control that precedes the clinical manifestation ofhypertension or cardiovascular events.", "metadata": {}}
+{"_id": "8604837", "title": "", "text": "Exercise and the immune system: regulation, integration, and adaptation.Stress-induced immunologicalreactions to exercise have stimulated much research into stress immunology and neuroimmunology. It issuggested that exercise can be employed as a model of temporary immunosuppression that occurs aftersevere physical stress. The exercise-stress model can be easily manipulated experimentally and allowsfor the study of interactions between the nervous, the endocrine, and the immune systems. This reviewfocuses on mechanisms underlying exercise-induced immune changes such as neuroendocrinologicalfactors including catecholamines, growth hormone, cortisol, beta-endorphin, and sex steroids. Thecontribution of a metabolic link between skeletal muscles and the lymphoid system is also reviewed. Themechanisms of exercise-associated muscle damage and the initiation of the inflammatory cytokinecascade are discussed. Given that exercise modulates the immune system in healthy individuals,considerations of the clinical ramifications of exercise in the prevention of diseases for which the immunesystem has a role is of importance. Accordingly, drawing on the experimental, clinical, andepidemiological literature, we address the interactions between exercise and infectious diseases as wellas exercise and neoplasia within the context of both aging and nutrition.", "metadata": {}}
+{"_id": "8610932", "title": "", "text": "Positive feedback between PU.1 and the cell cycle controls myeloid differentiation.Regulatory genecircuits with positive-feedback loops control stem cell differentiation, but several mechanisms cancontribute to positive feedback. Here, we dissect feedback mechanisms through which the transcriptionfactor PU.1 controls lymphoid and myeloid differentiation. Quantitative live-cell imaging revealed thatdeveloping B cells decrease PU.1 levels by reducing PU.1 transcription, whereas developing macrophagesincrease PU.1 levels by lengthening their cell cycles, which causes stable PU.1 accumulation. ExogenousPU.1 expression in progenitors increases endogenous PU.1 levels by inducing cell cycle lengthening,implying positive feedback between a regulatory factor and the cell cycle. Mathematical modeling showedthat this cell cycle-coupled feedback architecture effectively stabilizes a slow-dividing differentiated state.These results show that cell cycle duration functions as an integral part of a positive autoregulatory circuitto control cell fate.", "metadata": {}}
+{"_id": "8629328", "title": "", "text": "Peripheral B cell subsets.Our understanding of the origins and the biological functions of differentperipheral B cell subsets continues to evolve. Some understanding has been obtained regarding thesynergy between BCR-derived signals and other receptors and signaling pathways that drive thedevelopment of follicular, marginal zone, and B-1 B cells, but this remains a complex and poorlyunderstood issue. More recent information regarding the origins of B-1 and B-2 B cells, the ability offollicular B cells to mature both in the bone marrow and the spleen, the existence of a definable precursorfor MZ B cells, and the ability of follicular B cells to occupy two distinct niches are all highlighted in thisreview.", "metadata": {}}
+{"_id": "8639034", "title": "", "text": "Human IL-10 is produced by both type 1 helper (Th1) and type 2 helper (Th2) T cell clones and inhibitstheir antigen-specific proliferation and cytokine production.IL-10 gene transcription and IL-10 proteinproduction was assessed in both type 1 (Th1) and type 2 (Th2) CD4+ human T cell clones by polymerasechain reaction and ELISA, respectively. Although Th2 clones apparently showed higher IL-10 mRNAlevels, IL-10 mRNA expression was consistently found in Th1 clones, as well. Likewise, measurable IL-10levels were found in the supernatants of both Th1 and Th2 clones. The effect of human IL-10 (h-IL-10)and viral IL-10 (v-IL-10) on the proliferative response and cytokine production by Th1 and Th2 humanclones was also investigated. Addition in culture of h-IL-10 and v-IL-10 significantly reduced theproliferation of both Th1 and Th2 clones in response to the specific Ag and to PHA, but it had no inhibitoryeffect on the proliferative response of Th1 and Th2 clones to IL-2. h-IL-10 and v-IL-10 also inhibited theAg-induced production of gamma-interferon (IFN-gamma) by Th1 clones and the production of IL-4 andIL-5 by Th2 clones, whereas they had no effect on the cytokine synthesis by the same clones stimulatedwith PMA plus anti-CD3 antibody. Preincubation of APC, but not of clonal T blasts, with h-IL-10 resulted inthe inhibition of Ag-induced proliferation of both Th1 and Th2 clones, supporting the view that h-IL-10primarily affects APC. These data demonstrate that, unlike the murine system where IL-10 is a product ofTh2 (but not Th1) cells and seems to mainly down-regulate the Th1 response, in the human system,IL-10 is produced by, and down-regulates the function of, both Th1 and Th2 cells.", "metadata": {}}
+{"_id": "8642784", "title": "", "text": "Evaluating strategies for improving ovarian response of the poor responder undergoing assistedreproductive techniques.OBJECTIVE To assess the efficacy of various controlled ovarian hyperstimulation(COH) regimens in the prior poor-responder patient preparing for assisted reproductive techniques.DESIGN English-language literature review. PATIENT(S) Candidates for assisted reproductive techniqueswho had been defined as having a prior suboptimal response to standard COH regimens.INTERVENTION(S) A variety of regimes are reviewed, including increased gonadotropin doses, change ofgonadotropins, adjunctive growth hormone (GH), luteal phase (long) GnRH agonist (GnRH-a) initiation,early follicular phase (flare) GnRH-a initiation, low-dose luteal phase (ultrashort) GnRH-a initiation,progestin pretreatment, and microdose flare GnRH-a initiation. MAIN OUTCOME MEASURE(S) Maximalserum E(2) levels, follicular development, dose, and duration of gonadotropin therapy, cycle cancellationrates, oocytes retrieved, embryos transferred, and clinical and ongoing pregnancy rates. RESULT(S) Alack of uniformity in definition of the poor responder and of prospective randomized trials make datainterpretation somewhat difficult. Of the varied strategies proposed, those that seem to be moreuniformly beneficial are microdose GnRH-a flare and late luteal phase initiation of a short course oflow-dose GnRH-a discontinued before COH. CONCLUSION(S) No single regimen will benefit all poorresponders. General acceptance of uniform definitions and performance of large-scale prospectiverandomized trials are critical. Development of a reliable precycle screen will allow effective differentiationamong normal responders, poor responders, and those who will not conceive with their own oocytes.", "metadata": {}}
+{"_id": "8646760", "title": "", "text": "Identification and Functional Characterization of N-Terminally Acetylated Proteins in DrosophilamelanogasterProtein modifications play a major role for most biological processes in living organisms.Amino-terminal acetylation of proteins is a common modification found throughout the tree of life: theN-terminus of a nascent polypeptide chain becomes co-translationally acetylated, often after the removalof the initiating methionine residue. While the enzymes and protein complexes involved in theseprocesses have been extensively studied, only little is known about the biological function of suchN-terminal modification events. To identify common principles of N-terminal acetylation, we analyzed theamino-terminal peptides from proteins extracted from Drosophila Kc167 cells. We detected more than1,200 mature protein N-termini and could show that N-terminal acetylation occurs in insects with asimilar frequency as in humans. As the sole true determinant for N-terminal acetylation we could extractthe (X)PX rule that indicates the prevention of acetylation under all circumstances. We could show thatthis rule can be used to genetically engineer a protein to study the biological relevance of the presence orabsence of an acetyl group, thereby generating a generic assay to probe the functional importance ofN-terminal acetylation. We applied the assay by expressing mutated proteins as transgenes in cell linesand in flies. Here, we present a straightforward strategy to systematically study the functional relevanceof N-terminal acetylations in cells and whole organisms. Since the (X)PX rule seems to be of generalvalidity in lower as well as higher eukaryotes, we propose that it can be used to study the function ofN-terminal acetylation in all species.", "metadata": {}}
+{"_id": "8654183", "title": "", "text": "Bax translocation and mitochondrial fragmentation induced by Helicobacter pylori.BACKGROUND ANDAIMS Previous in vitro and in vivo studies have revealed an association between Helicobacter pyloriinfection and apoptosis in gastric epithelial cells. Although involvement of the Bcl-2 family of proteins aswell as cytochrome c release has been demonstrated in H pylori induced cell death, the exact role of themitochondria during this type of programmed cell death has not been fully elucidated. Therefore, wesought to determine whether or not Bax translocation and mitochondrial fragmentation occur onexposure of gastric epithelial cells to H pylori, resulting in cell death. METHODS Experiments wereperformed with human gastric adenocarcinoma (AGS) cells, AGS cells transfected with the HPV-E6 gene(which inactivates p53 function), AGS-neo cells (transfected with the backbone construct), mouseembryonic fibroblasts (MEFs), and p19(ARF) null (ARF(-/-)) MEFs. Cells were incubated with a cagpositive H pylori strain for up to 24 hours, lysed, and cytoplasmic and mitochondrial membrane fractionswere analysed by western blot for Bax translocation. RESULTS Bax translocation was detected in AGS,AGS-neo, and normal MEF cells after exposure to H pylori for three hours, but not in ARF(-/-) MEFs cells.Translocation of Bax after H pylori incubation was also detected in AGS-E6 cells (inactive p53 gene) butto a lesser degree than in AGS-neo cells. In parallel studies, the mitochondrial morphology of living cellsinfected with H pylori was assessed by confocal microscopy. Mitochondrial fragmentation was detectableafter 10 hours of H pylori incubation with AGS cells and after seven hours with MEF cells. In wild-typeMEFs, mitochondrial fragmentation was significantly increased in comparison with ARF null MEFs (43% v10.4%, respectively). Furthermore, mitochondrial depolarisation and caspase-3 activity were initiatedwithin four hours in cells incubated with H pylori, and these events were inhibited by forced expression ofBcl-2. CONCLUSIONS These data suggest that during H pylori induced apoptosis, Bax translocates to themitochondria which subsequently undergo depolarisation and profound fragmentation. Functional ARFand p53 proteins may play an important role in H pylori induced mitochondrial modification.", "metadata": {}}
+{"_id": "8659426", "title": "", "text": "Cancer chemoprevention: a rapidly evolving fieldCancer chemoprevention involves the chronicadministration of a synthetic, natural or biological agent to reduce or delay the occurrence of malignancy.The potential value of this approach has been demonstrated with trials in breast, prostate and coloncancer. The paradigm for developing new chemopreventive agents has changed markedly in the lastdecade and now involves extensive preclinical mechanistic evaluation of agents before clinical trials areinstituted and a focus on defining biomarkers of activity that can be used as early predictors of efficacy.This review will summarise the current status of the field of chemoprevention and highlight potential newdevelopments.", "metadata": {}}
+{"_id": "8665891", "title": "", "text": "Dengue is still an imported disease in China: a case study in Guangzhou.Dengue virus and its fourserotypes (DENV 1-4) infect approximately 390 million people worldwide each year, with most cases intropical and subtropical regions. Because of repeated introduction of DENV from epidemic regions andsuitable weather conditions, many regions have shifted from hypo-endemicity to hyper-endemicity overrecent decades. Since the first dengue outbreak in 1978, it is crucial to understand the current situationin China over nearly 40 years. The purpose of the study was to examine whether dengue in China wasendemic or not, which is essential for relevant dengue control and prevention strategy implementation inChina. The study, combining epidemiological characteristics of dengue from the disease notificationsystem, phylogenetic and phylogeographic analyses, showed that all four serotypes had been detected inGuangzhou, China, which was dominated by DENV 1-2. The Maximum Likelihood tree analytic resultsshowed that the virus detected in Guangzhou localized in different clades, except of virus of 2002 and2003 clustered together. There existed the mutual introductions between Guangzhou and Southeast Asia.Most of the viruses were imported from Southeast Asia and the sources of outbreaks in Guangzhoumainly originated from Thailand, Indonesia, and the Philippines. The study indicates that dengue in Chinastill remains as an imported disease, with the possibility of localization.", "metadata": {}}
+{"_id": "8670178", "title": "", "text": "The UNAIDS Estimation and Projection Package: a software package to estimate and project national HIVepidemics.This paper describes the Estimation and Projection Package (EPP) for estimating and projectingHIV prevalence levels in countries with generalised epidemics. The paper gives an overall summary of thesoftware and interface. It describes the process of defining and modelling a national epidemic in terms oflocally relevant sub-epidemics and the four epidemiological parameters used to fit a curve to produce theprevalence trends in the epidemic. It also provides an example of using the EPP in a country with ageneralised epidemic. The paper discusses the strengths and weaknesses of the software and itsenvisaged future developments.", "metadata": {}}
+{"_id": "8671456", "title": "", "text": "Oncolytic adenovirus armed with IL-24 Inhibits the growth of breast cancer in vitro and invivoBACKGROUND Interleukin-24 (IL-24) is a cytokine that belongs to the IL-10 family. It can selectivelyinduce cancer cell apoptosis which has been utilized as a cancer gene therapy strategy. METHODS Arecombinant type five adenovirus containing IL-24 gene (designated CNHK600-IL24) was constructed,whose replication is activated only in tumor cells. The replication of CNHK600-IL24 in breast tumor cellsand fibroblasts were assessed by TCID50 and MTT assay; the secretion of IL-24 was measured by ELISAand western blotting. The in vivo anti-tumor effect of CNHK600-IL24 was investigated in nude micecarrying orthotopic or metastatic breast tumor. RESULTS We observed that CNHK600-IL24 could replicateefficiently and resulted in high level IL-24 expression and massive cell death in human breast cancer cellMDA-MB-231 but not in normal fibroblast cell MRC-5. In addition, orthotopic breast tumor growth in thenude mice model was significantly suppressed when CNHK600-IL24 was administered. In the metastaticmodel generated by tail vein injection, CNHK600-IL24 virotherapy significantly improved survivalcompared with the same virus expressing EGFP (median survival CNHK600-IL24, 55 days vs.CNHK600-EGFP, 41 day, p < 0.05 Mantal-Cox test). A similar phenomenon was observed in themetastatic model achieved by left ventricular injection as suggested by in vivo luminescence imaging oftumor growth. CONCLUSION The oncolytic adenovirus armed with IL-24, which exhibited enhancedanti-tumor activity and improved survival, is a promising candidate for virotherapy of breast cancer.", "metadata": {}}
+{"_id": "8672737", "title": "", "text": "Brain stem and cerebellar hyperintense lesions in migraine.BACKGROUND AND PURPOSE Migraineurs areat increased risk of cerebellar infarcts and supratentorial white matter lesions. The prevalence, frequency,and distribution of infratentorial hyperintense lesions in migraine are unknown. METHODS Migraineurswith aura (n=161), without aura (n=134), and controls (n=140) from a population-based sample ofadults (30 to 60 years of age) were evaluated with MRI. RESULTS Infratentorial hyperintensities wereidentified in 13 of 295 (4.4%) migraineurs and in 1 of 140 (0.7%) controls (P=0.04). Twelve cases hadhyperintensities, mostly bilaterally, in the dorsal basis pontis. Those with infratentorial hyperintensitiesalso had supratentorial white matter lesions more often. CONCLUSIONS We found an increasedprevalence of infratentorial (mostly pontine) hyperintensities in migraineurs from the general population.This extends the knowledge about vulnerable brain regions and type of lesions in migraine brains. Ahemodynamic ischemic pathogenesis is likely, but further research is needed.", "metadata": {}}
+{"_id": "8677721", "title": "", "text": "NDRG1 promotes growth of hepatocellular carcinoma cells by directly interacting with GSK-3β and Nur77to prevent β-catenin degradationThe N-myc downstream regulated gene 1 (NDRG1) is significantlyassociated with advanced tumor stages and poor survival of hepatocellular carcinoma (HCC), therebyimplicating it as a potential target for HCC treatment. We aim to further understand its biological roles inhepatocarcinogenesis, as a means to exploit it for therapeutic purposes. By screening using theProtoArray® Human Protein Microarrays, we identified glycogen synthase kinase 3β (GSK-3β) and theorphan nuclear receptor (Nur77) as potential interaction partners of NDRG1. These interactions wereconfirmed in HCC cell lines in vitro by co-immunoprecipitation; and co-localizations of NDRG1 withGSK-3β and Nur77 were observed by immunofluorescence staining. Additionally, high levels of NDRG1competitively bind to GSK-3β and Nur77 to allow β-catenin to escape degradation, with consequentelevated levels of downstream oncogenic genes. In vivo, we consistently observed that NDRG1suppression in HCC xenografts decreased β-catenin levels and its downstream target Cyclin D1, withconcomitant tumor growth inhibition. Clinically, the over-expression of NDRG1 in HCC patient samples ispositively correlated with GSK-3β-9ser (|\u0000\u0000 R | = 0.28, p = 0.01), Nur77 (|\u0000\u0000 R | = 0.42, p < 0.001),and β-catenin (| R |= 0.32, p = 0.003) expressions. In conclusion, we identified GSK-3β and Nur77 asnovel interaction partners of NDRG1. These protein-protein interactions regulate the turnover ofβ-catenin and subsequent downstream signaling mediated by β-catenin in HCC cells, and providespotential targets for future therapeutic interventions.", "metadata": {}}
+{"_id": "8690595", "title": "", "text": "A tutorial on statistical methods for population association studiesAlthough genetic association studieshave been with us for many years, even for the simplest analyses there is little consensus on the mostappropriate statistical procedures. Here I give an overview of statistical approaches to populationassociation studies, including preliminary analyses (Hardy–Weinberg equilibrium testing, inference ofphase and missing data, and SNP tagging), and single-SNP and multipoint tests for association. My goal isto outline the key methods with a brief discussion of problems (population structure and multiple testing),avenues for solutions and some ongoing developments.", "metadata": {}}
+{"_id": "8692744", "title": "", "text": "Identification and Characterization of Multiple TRIM Proteins That Inhibit Hepatitis B VirusTranscriptionTripartite motif (TRIM) proteins constitute a family of over 100 members that shareconserved tripartite motifs and exhibit diverse biological functions. Several TRIM proteins have beenshown to restrict viral infections and regulate host cellular innate immune responses. In order to identifyTRIM proteins that modulate the infection of hepatitis B virus (HBV), we tested 38 human TRIMs for theireffects on HBV gene expression, capsid assembly and DNA synthesis in human hepatoma cells (HepG2).The study revealed that ectopic expression of 8 TRIM proteins in HepG2 cells potently reduced theamounts of secreted HBV surface and e antigens as well as intracellular capsid and capsid DNA.Mechanistic analyses further demonstrated that the 8 TRIMs not only reduced the expression of HBVmRNAs, but also inhibited HBV enhancer I and enhancer II activities. Studies focused on TRIM41 revealedthat a HBV DNA segment spanning nucleotide 1638 to nucleotide 1763 was essential forTRIM41-mediated inhibition of HBV enhancer II activity and the inhibitory effect depended on the E3ubiquitin ligase activity of TRIM41 as well as the integrity of TRIM41 C-terminal domain. Moreover,knockdown of endogenous TRIM41 in a HepG2-derived stable cell line significantly increased the level ofHBV preC/C RNA, leading to an increase in viral core protein, capsid and capsid DNA. Our studies havethus identified eight TRIM proteins that are able to inhibit HBV transcription and provided strongevidences suggesting the endogenous role of TRIM41 in regulating HBV transcription in human hepatomacells.", "metadata": {}}
+{"_id": "8698208", "title": "", "text": "A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndromeRett syndrome(RTT) is an inherited neurodevelopmental disorder of females that occurs once in 10,000–15,000 births.Affected females develop normally for 6–18 months, but then lose voluntary movements, includingspeech and hand skills. Most RTT patients are heterozygous for mutations in the X-linked gene MECP2(refs. 3–12), encoding a protein that binds to methylated sites in genomic DNA and facilitates genesilencing. Previous work with Mecp2-null embryonic stem cells indicated that MeCP2 is essential formouse embryogenesis. Here we generate mice lacking Mecp2 using Cre-loxP technology. Both Mecp2-nullmice and mice in which Mecp2 was deleted in brain showed severe neurological symptoms atapproximately six weeks of age. Compensation for absence of MeCP2 in other tissues by MeCP1 (refs.19,20) was not apparent in genetic or biochemical tests. After several months, heterozygous female micealso showed behavioral symptoms. The overlapping delay before symptom onset in humans and mice,despite their profoundly different rates of development, raises the possibility that stability of brainfunction, not brain development per se, is compromised by the absence of MeCP2.", "metadata": {}}
+{"_id": "8698857", "title": "", "text": "The p38/MK2-Driven Exchange between Tristetraprolin and HuR Regulates AU–Rich Element–DependentTranslationTNF expression of macrophages is under stringent translational control that depends on thep38 MAPK/MK2 pathway and the AU-rich element (ARE) in the TNF mRNA. Here, we elucidate themolecular mechanism of phosphorylation-regulated translation of TNF. We demonstrate that translationof the TNF-precursor at the ER requires expression of the ARE-binding and -stabilizing factor humanantigen R (HuR) together with either activity of the p38 MAPK/MK2 pathway or the absence of theARE-binding and -destabilizing factor tristetraprolin (TTP). We show that phosphorylation of TTP by MK2decreases its affinity to the ARE, inhibits its ability to replace HuR, and permits HuR-mediated initiation oftranslation of TNF mRNA. Since translation of TTP's own mRNA is also regulated by this mechanism, anintrinsic feedback control of the inflammatory response is ensured. The phosphorylation-regulatedTTP/HuR exchange at target mRNAs provides a reversible switch between unstable/non-translatable andstable/efficiently translated mRNAs.", "metadata": {}}
+{"_id": "8702697", "title": "", "text": "miR-205 hinders the malignant interplay between prostate cancer cells and associated fibroblasts.AIMSTumor microenvironment is a strong determinant for the acquisition of metastatic potential of cancercells. We have recently demonstrated that cancer-associated fibroblasts (CAFs) elicit a redox-dependentepithelial-mesenchymal transition (EMT) in prostate cancer (PCa) cells, driven bycycloxygenase-2/hypoxia-inducible factor-1 (HIF-1)/nuclear factor-κB pathway and enhancing tumoraggressiveness. Here, we investigated the involvement of microRNAs (miRNAs) in tumor-stroma interplayto identify possible tools to counteract oxidative stress and metastasis dissemination. RESULTS We foundthat miR-205 is the most downmodulated miRNA in PCa cells upon CAF stimulation, due to directtranscriptional repression by HIF-1, a known redox-sensitive transcription factor. Rescue experimentsdemonstrated that ectopic miR-205 overexpression in PCa cells counteracts CAF-induced EMT, thusimpairing enhancement of cell invasion, acquisition of stem cell traits, tumorigenicity, and metastaticdissemination. In addition, miR-205 blocks tumor-driven activation of surrounding fibroblasts by reducingpro-inflammatory cytokine secretion. INNOVATION Overall, such findings suggest miR-205 as a brakeagainst PCa metastasis by blocking both the afferent and efferent arms of the circuit between tumor cellsand associated fibroblasts, thus interrupting the pro-oxidant and pro-inflammatory circuitries engaged byreactive stroma. CONCLUSION The evidence that miR-205 replacement in PCa cells is able not only toprevent but also to revert the oxidative/pro-inflammatory axis leading to EMT induced by CAFs sets therationale for developing miRNA-based approaches to prevent and treat metastatic disease.", "metadata": {}}
+{"_id": "8708082", "title": "", "text": "The prevention of type 2 diabetesType 2 diabetes mellitus (T2DM) affects more than 7% of adults in theUS and leads to substantial personal and economic burden. In prediabetic states insulin secretion andaction—potential targets of preventive interventions—are impaired. In trials lifestyle modification (i.e.weight loss and exercise) has proven effective in preventing incident T2DM in high-risk groups, althoughweight loss has the greatest effect. Various medications (e.g. metformin, thiazolidinediones andacarbose) can also prevent or delay T2DM. Whether diabetes-prevention strategies also ultimatelyprevent the development of diabetic vascular complications is unknown, but cardiovascular risk factorsare favorably affected. Preventive strategies that can be implemented in routine clinical settings havebeen developed and evaluated. Widespread application has, however, been limited by local financialconsiderations, even though cost-effectiveness might be achieved at the population level.", "metadata": {}}
+{"_id": "8712839", "title": "", "text": "The transcriptional landscape of the mammalian genome.This study describes comprehensive polling oftranscription start and termination sites and analysis of previously unidentified full-length complementaryDNAs derived from the mouse genome. We identify the 5' and 3' boundaries of 181,047 transcripts withextensive variation in transcripts arising from alternative promoter usage, splicing, and polyadenylation.There are 16,247 new mouse protein-coding transcripts, including 5154 encoding previously unidentifiedproteins. Genomic mapping of the transcriptome reveals transcriptional forests, with overlappingtranscription on both strands, separated by deserts in which few transcripts are observed. The dataprovide a comprehensive platform for the comparative analysis of mammalian transcriptional regulationin differentiation and development.", "metadata": {}}
+{"_id": "8721150", "title": "", "text": "The Protein Data BankThe Protein Data Bank [PDB; Berman, Westbrook et al. (2000), Nucleic Acids Res.28, 235-242; http://www.pdb.org/] is the single worldwide archive of primary structural data of biologicalmacromolecules. Many secondary sources of information are derived from PDB data. It is the startingpoint for studies in structural bioinformatics. This article describes the goals of the PDB, the systems inplace for data deposition and access, how to obtain further information and plans for the futuredevelopment of the resource. The reader should come away with an understanding of the scope of thePDB and what is provided by the resource.", "metadata": {}}
+{"_id": "8724666", "title": "", "text": "Cell-State-Specific Metabolic Dependency in Hematopoiesis and LeukemogenesisThe balance betweenoxidative and nonoxidative glucose metabolism is essential for a number of pathophysiological processes.By deleting enzymes that affect aerobic glycolysis with different potencies, we examine how modulatingglucose metabolism specifically affects hematopoietic and leukemic cell populations. We find that adeficiency in the M2 pyruvate kinase isoform (PKM2) reduces the levels of metabolic intermediatesimportant for biosynthesis and impairs progenitor function without perturbing hematopoietic stem cells(HSCs), whereas lactate dehydrogenase A (LDHA) deletion significantly inhibits the function of both HSCsand progenitors during hematopoiesis. In contrast, leukemia initiation by transforming alleles putativelyaffecting either HSCs or progenitors is inhibited in the absence of either PKM2 or LDHA, indicating thatthe cell-state-specific responses to metabolic manipulation in hematopoiesis do not apply to the setting ofleukemia. This finding suggests that fine-tuning the level of glycolysis may be explored therapeutically fortreating leukemia while preserving HSC function.", "metadata": {}}
+{"_id": "8734695", "title": "", "text": "A transition in brain state during propofol-induced unconsciousness.Rhythmic oscillations shape corticaldynamics during active behavior, sleep, and general anesthesia. Cross-frequency phase-amplitudecoupling is a prominent feature of cortical oscillations, but its role in organizing conscious andunconscious brain states is poorly understood. Using high-density EEG and intracranialelectrocorticography during gradual induction of propofol general anesthesia in humans, we discovered arapid drug-induced transition between distinct states with opposite phase-amplitude coupling anddifferent cortical source distributions. One state occurs during unconsciousness and may be similar tosleep slow oscillations. A second state occurs at the loss or recovery of consciousness and resembles anenhanced slow cortical potential. These results provide objective electrophysiological landmarks ofdistinct unconscious brain states, and could be used to help improve EEG-based monitoring for generalanesthesia.", "metadata": {}}
+{"_id": "8747771", "title": "", "text": "Cohesins and condensins orchestrate the 4D dynamics of yeast chromosomes during the cellcycleDuplication and segregation of chromosomes involves dynamic reorganization of their internalstructure by conserved architectural proteins, including the structural maintenance of chromosomes(SMC) complexes cohesin and condensin. Despite active investigation of the roles of these factors, agenome-wide view of dynamic chromosome architecture at both small and large scale during cell divisionis still missing. Here, we report the first comprehensive 4D analysis of the higher-order organization ofthe Saccharomyces cerevisiae genome throughout the cell cycle and investigate the roles of SMCcomplexes in controlling structural transitions. During replication, cohesion establishment promotesnumerous long-range intra-chromosomal contacts and correlates with the individualization ofchromosomes, which culminates at metaphase. In anaphase, mitotic chromosomes are abruptlyreorganized depending on mechanical forces exerted by the mitotic spindle. Formation of acondensin-dependent loop bridging the centromere cluster with the rDNA loci suggests thatcondensin-mediated forces may also directly facilitate segregation. This work therefore comprehensivelyrecapitulates cell cycle-dependent chromosome dynamics in a unicellular eukaryote, but also unveils newfeatures of chromosome structural reorganization during highly conserved stages of cell division.", "metadata": {}}
+{"_id": "8748720", "title": "", "text": "Genome-wide patterns of divergence and gene flow across a butterfly radiation.The Heliconius butterfliesare a diverse recent radiation comprising multiple levels of divergence with ongoing gene flow betweenspecies. The recently sequenced genome of Heliconius melpomene allowed us to investigate the genomicevolution of this group using dense RAD marker sequencing. Phylogenetic analysis of 54 individualsrobustly supported reciprocal monophyly of H. melpomene and Heliconius cydno and refuted previousphylogenetic hypotheses that H. melpomene may be paraphylectic with respect to H. cydno. Heliconiustimareta also formed a monophyletic clade closely related but distinct from H. cydno with Heliconiusheurippa falling within this clade. We find evidence for genetic admixture between sympatric populationsof the sister clades H. melpomene and H. cydno/timareta, particularly between H. cydno and H.melpomene from Central America and between H. timareta and H. melpomene from the eastern slopes ofthe Andes. Between races, divergence is primarily explained by isolation by distance and there is nodetectable genetic population structure between parapatric races, suggesting that hybrid zones betweenraces are not zones of secondary contact. Our results also support previous findings that colour patternloci are shared between populations and species with similar colour pattern elements. Furthermore, thispattern is almost unique to these genomic regions, with only a very small number of other loci showingsignificant similarity between populations and species with similar colour patterns.", "metadata": {}}
+{"_id": "8756719", "title": "", "text": "Randomized, double-blind study of the safety, tolerability, and efficacy of tafenoquine versus mefloquinefor malaria prophylaxis in nonimmune subjects.This study represents the first phase III trial of the safety,tolerability, and effectiveness of tafenoquine for malaria prophylaxis. In a randomized (3:1),double-blinded study, Australian soldiers received weekly malaria prophylaxis with 200 mg tafenoquine(492 subjects) or 250 mg mefloquine (162 subjects) for 6 months on a peacekeeping deployment to EastTimor. After returning to Australia, tafenoquine-receiving subjects received a placebo andmefloquine-receiving subjects received 30 mg primaquine daily for 14 days. There were no clinicallysignificant differences between hematological and biochemical parameters of the treatment groups.Treatment-related adverse events for the two groups were similar (tafenoquine, 13.4%; mefloquine,11.7%). Three subjects on tafenoquine (0.6%) and none on mefloquine discontinued prophylaxis becauseof possible drug-related adverse events. No diagnoses of malaria occurred for either group duringdeployment, but 4 cases (0.9%) and 1 case (0.7%) of Plasmodium vivax infection occurred among thetafenoquine and mefloquine groups, respectively, up to 20 weeks after discontinuation of medication. In asubset of subjects recruited for detailed safety assessments, treatment-related mild vortex keratopathywas detected in 93% (69 of 74) of tafenoquine subjects but none of the 21 mefloquine subjects. Thevortex keratopathy was not associated with any effect on visual acuity and was fully resolved in allsubjects by 1 year. Tafenoquine appears to be safe and well tolerated as malaria prophylaxis. Althoughthe volunteers' precise exposure to malaria could not be proven in this study, tafenoquine appears to bea highly efficacious drug for malaria prophylaxis.", "metadata": {}}
+{"_id": "8759633", "title": "", "text": "Domain-wide regulation of DNA replication timing during mammalian developmentStudies of replicationtiming provide a handle into previously impenetrable higher-order levels of chromosome organization andtheir plasticity during development. Although mechanisms regulating replication timing are not clear,novel genome-wide studies provide a thorough survey of the extent to which replication timing isregulated during most of the early cell fate transitions in mammals, revealing coordinated changes of adefined set of 400–800 kb chromosomal segments that involve at least half the genome. Furthermore,changes in replication time are linked to changes in sub-nuclear organization and domain-widetranscriptional potential, and tissue-specific replication timing profiles are conserved from mouse tohuman, suggesting that the program has developmental significance. Hence, these studies have provideda solid foundation for linking megabase level chromosome structure to function, and suggest a centralrole for replication in domain-level genome organization.", "metadata": {}}
+{"_id": "8764879", "title": "", "text": "PU.1-mediated upregulation of CSF1R is crucial for leukemia stem cell potential induced byMOZ-TIF2Leukemias and other cancers possess self-renewing stem cells that help to maintain the cancer.Cancer stem cell eradication is thought to be crucial for successful anticancer therapy. Using an acutemyeloid leukemia (AML) model induced by the leukemia-associated monocytic leukemia zinc finger(MOZ)-TIF2 fusion protein, we show here that AML can be cured by the ablation of leukemia stem cells.The MOZ fusion proteins MOZ-TIF2 and MOZ-CBP interacted with the transcription factor PU.1 tostimulate the expression of macrophage colony–stimulating factor receptor (CSF1R, also known asM-CSFR, c-FMS or CD115). Studies using PU.1-deficient mice showed that PU.1 is essential for the abilityof MOZ-TIF2 to establish and maintain AML stem cells. Cells expressing high amounts of CSF1R(CSF1Rhigh cells), but not those expressing low amounts of CSF1R (CSF1Rlow cells), showed potentleukemia-initiating activity. Using transgenic mice expressing a drug-inducible suicide gene controlled bythe CSF1R promoter, we cured AML by ablation of CSF1Rhigh cells. Moreover, induction of AML wassuppressed in CSF1R-deficient mice and CSF1R inhibitors slowed the progression of MOZ-TIF2–inducedleukemia. Thus, in this subtype of AML, leukemia stem cells are contained within the CSF1Rhigh cellpopulation, and we suggest that targeting of PU.1-mediated upregulation of CSF1R expression might be auseful therapeutic approach.", "metadata": {}}
+{"_id": "8771704", "title": "", "text": "Pharmacological blockage of fibro/adipogenic progenitor expansion and suppression of regenerativefibrogenesis is associated with impaired skeletal muscle regeneration.Acute skeletal muscle injurytriggers an expansion of fibro/adipogenic progenitors (FAPs) and a transient stage of fibrogenesischaracterized by extracellular matrix deposition. While the perpetuation of such phase can lead topermanent tissue scarring, the consequences of its suppression remain to be studied. Using a model ofacute muscle damage we were able to determine that pharmacological inhibition of FAP expansion byNilotinib, a tyrosine kinase inhibitor with potent antifibrotic activity, exerts a detrimental effect onmyogenesis during regeneration. We found that Nilotinib inhibits the damage-induced expansion ofsatellite cells in vivo, but it does not affect in vitro proliferation, suggesting a non cell-autonomous effect.Nilotinib impairs regenerative fibrogenesis by preventing the injury-triggered expansion anddifferentiation of resident CD45(-):CD31(-):α7integrin(-):Sca1(+) mesenchymal FAPs. Our data supportthe notion that the expansion of FAPs and transient fibrogenesis observed during regeneration play animportant trophic role toward tissue-specific stem cells.", "metadata": {}}
+{"_id": "8774475", "title": "", "text": "Deregulation of Scribble Promotes Mammary Tumorigenesis and Reveals a Role for Cell Polarity inCarcinomaLoss of cell polarity proteins such as Scribble induces neoplasia in Drosophila by promotinguncontrolled proliferation. In mammals, the role that polarity proteins play during tumorigenesis is notwell understood. Here, we demonstrate that depletion of Scribble in mammary epithelia disrupts cellpolarity, blocks three-dimensional morphogenesis, inhibits apoptosis, and induces dysplasia in vivo thatprogress to tumors after long latency. Loss of Scribble cooperates with oncogenes such as c-myc totransform epithelial cells and induce tumors in vivo by blocking activation of an apoptosis pathway. Likedepletion, mislocalization of Scribble from cell-cell junction was sufficient to promote cell transformation.Interestingly, spontaneous mammary tumors in mice and humans possess both downregulated andmislocalized Scribble. Thus, we demonstrate that scribble inhibits breast cancer formation and thatderegulation of polarity pathways promotes dysplastic and neoplastic growth in mammals by disruptingmorphogenesis and inhibiting cell death.", "metadata": {}}
+{"_id": "8780599", "title": "", "text": "The Polymeal: a more natural, safer, and probably tastier (than the Polypill) strategy to reducecardiovascular disease by more than 75%.OBJECTIVE Although the Polypill concept (proposed in 2003) ispromising in terms of benefits for cardiovascular risk management, the potential costs and adverseeffects are its main pitfalls. The objective of this study was to identify a tastier and safer alternative tothe Polypill: the Polymeal. METHODS Data on the ingredients of the Polymeal were taken from theliterature. The evidence based recipe included wine, fish, dark chocolate, fruits, vegetables, garlic, andalmonds. Data from the Framingham heart study and the Framingham offspring study were used to buildlife tables to model the benefits of the Polymeal in the general population from age 50, assumingmultiplicative correlations. RESULTS Combining the ingredients of the Polymeal would reducecardiovascular disease events by 76%. For men, taking the Polymeal daily represented an increase intotal life expectancy of 6.6 years, an increase in life expectancy free from cardiovascular disease of 9.0years, and a decrease in life expectancy with cardiovascular disease of 2.4 years. The correspondingdifferences for women were 4.8, 8.1, and 3.3 years. CONCLUSION The Polymeal promises to be aneffective, non-pharmacological, safe, cheap, and tasty alternative to reduce cardiovascular morbidity andincrease life expectancy in the general population.", "metadata": {}}
+{"_id": "8790729", "title": "", "text": "Islet-Like Clusters Derived from Mesenchymal Stem Cells in Wharton's Jelly of the Human Umbilical Cordfor Transplantation to Control Type 1 DiabetesBACKGROUND There is a widespread interest in developingrenewable sources of islet-replacement tissue for type I diabetes mellitus. Human mesenchymal cellsisolated from the Wharton's jelly of the umbilical cord (HUMSCs), which can be easily obtained andprocessed compared with embryonic and bone marrow stem cells, possess stem cell properties. HUMSCsmay be a valuable source for the generation of islets. METHODOLOGY AND PRINCIPAL FINDINGSHUMSCs were induced to transform into islet-like cell clusters in vitro through stepwise culturing inneuron-conditioned medium. To assess the functional stability of the islet-like cell clusters in vivo, thesecell clusters were transplanted into the liver of streptozotocin-induced diabetic rats via laparotomy.Glucose tolerance was measured on week 12 after transplantation accompanied withimmunohistochemistry and electron microscopy analysis. These islet-like cell clusters were shown tocontain human C-peptide and release human insulin in response to physiological glucose levels. Real-timeRT-PCR detected the expressions of insulin and other pancreatic beta-cell-related genes (Pdx1, Hlxb9,Nkx2.2, Nkx6.1, and Glut-2) in these islet-like cell clusters. The hyperglycemia and glucose intolerance instreptozotocin-induced diabetic rats was significantly alleviated after xenotransplantation of islet-like cellclusters, without the use of immunosuppressants. In addition to the existence of islet-like cell clusters inthe liver, some special fused liver cells were also found, which characterized by human insulin andnuclei-positive staining and possessing secretory granules. CONCLUSIONS AND SIGNIFICANCE In thisstudy, we successfully differentiate HUMSCs into mature islet-like cell clusters, and these islet-like cellclusters possess insulin-producing ability in vitro and in vivo. HUMSCs in Wharton's Jelly of the umbilicalcord seem to be the preferential source of stem cells to convert into insulin-producing cells, because ofthe large potential donor pool, its rapid availability, no risk of discomfort for the donor, and low risk ofrejection.", "metadata": {}}
+{"_id": "8814634", "title": "", "text": "Use of perioperative hydroxyethyl starch 6% and albumin 5% in elective joint arthroplasty andassociation with adverse outcomes: a retrospective population based analysisOBJECTIVE To determinewhether the perioperative use of hydroxyethyl starch 6% and albumin 5% in elective joint arthroplastiesare associated with an increased risk for perioperative complications. DESIGN Retrospective cohort studyof population based data between 2006 and 2013. SETTING Data from 510 different hospitals across theUnited States participating in the Premier Perspective database. PARTICIPANTS 1,051,441 patientsundergoing elective total hip and knee arthroplasties. EXPOSURES Perioperative fluid resuscitation withhydroxyethyl starch 6% or albumin 5%, or neither. MAIN OUTCOME MEASURES Acute renal failure andthromboembolic, cardiac, and pulmonary complications. RESULTS Compared with patients who receivedneither colloid, perioperative fluid resuscitation with hydroxyethyl starch 6% or albumin 5% wasassociated with an increased risk of acute renal failure (odds ratios 1.23 (95% confidence interval 1.13 to1.34) and 1.56 (1.36 to 1.78), respectively) and most other complications. A recent decrease inhydroxyethyl starch 6% use was noted, whereas that of albumin 5% increased. CONCLUSIONS Similar tostudies in critically ill patients, we showed that use of hydroxyethyl starch 6% was associated with anincreased risk of acute renal failure and other complications in the elective perioperative orthopedicsetting. This increased risk also applied to albumin 5%. These findings raise questions regarding thewidespread use of these colloids in elective joint arthroplasty procedures.", "metadata": {}}
+{"_id": "8816869", "title": "", "text": "BMAL1 and CLOCK, Two Essential Components of the Circadian Clock, Are Involved in GlucoseHomeostasisCircadian timing is generated through a unique series of autoregulatory interactions termedthe molecular clock. Behavioral rhythms subject to the molecular clock are well characterized. Wedemonstrate a role for Bmal1 and Clock in the regulation of glucose homeostasis. Inactivation of theknown clock components Bmal1 (Mop3) and Clock suppress the diurnal variation in glucose andtriglycerides. Gluconeogenesis is abolished by deletion of Bmal1 and is depressed in Clock mutants, butthe counterregulatory response of corticosterone and glucagon to insulin-induced hypoglycaemia isretained. Furthermore, a high-fat diet modulates carbohydrate metabolism by amplifying circadianvariation in glucose tolerance and insulin sensitivity, and mutation of Clock restores the chow-fedphenotype. Bmal1 and Clock, genes that function in the core molecular clock, exert profound control overrecovery from insulin-induced hypoglycaemia. Furthermore, asynchronous dietary cues may modifyglucose homeostasis via their interactions with peripheral molecular clocks.", "metadata": {}}
+{"_id": "8839502", "title": "", "text": "Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes.Theincidence of chronic kidney diseases is increasing worldwide, and these conditions are emerging as amajor public health problem. While genetic factors contribute to susceptibility and progression of renaldisease, proteinuria has been claimed as an independent predictor of outcome. Reduction of urinaryprotein levels by various medications and a low-protein diet limits renal function decline in individualswith nondiabetic and diabetic nephropathies to the point that remission of the disease and regression ofrenal lesions have been observed in experimental animals and even in humans. In animal models,regression of glomerular structural changes is associated with remodeling of the glomerular architecture.Instrumental to this discovery were 3D reconstruction studies of the glomerular capillary tuft, whichallowed the quantification of sclerosis volume reduction and capillary regeneration upon treatment.Regeneration of capillary segments might result from the contribution of resident cells, but progenitorcells of renal or extrarenal origin may also have a role. This review describes recent advances in ourunderstanding of the mechanisms and mediators underlying renal tissue repair ultimately responsible forregression of renal injury.", "metadata": {}}
+{"_id": "8842332", "title": "", "text": "Contemporary type 1 diabetes pregnancy outcomes: impact of obesity and glycaemic control.OBJECTIVETo compare contemporary pregnancy outcomes in women with and without type 1 diabetes, and toexamine the effects of obesity and glycaemic control on these outcomes. DESIGN AND SETTING Historicalcohort study in a specialist diabetes and maternity network in Victoria. PARTICIPANTS All singleton births(at least 20 weeks' gestation), 2010-2013, were analysed: 107 pregnancies to women with type 1diabetes and 27 075 pregnancies to women without diabetes. Women with type 2 diabetes or gestationaldiabetes were excluded. METHODS Data were extracted from the Birthing Outcomes System database;associations between type 1 diabetes and pregnancy outcomes were analysed by multivariableregression. MAIN OUTCOME MEASURES Mode of birth; maternal and neonatal outcomes. RESULTS Themean body mass index was higher for women with type 1 diabetes than for women without diabetes(mean, 27.3 kg/m(2) [SD, 5.0] v 25.7 kg/m(2) [SD, 5.9]; P = 0.01); the median gestation period fortheir babies was shorter (median, 37.3 weeks [IQR, 34.6-38.1] v 39.4 weeks [IQR, 38.4-40.4]; P <0.001) and they were more likely to be large for gestational age (LGA) (adjusted odds ratio [aOR], 7.9;95% CI, 5.3-11.8). Women with type 1 diabetes were more likely to have had labour induced (aOR, 3.0;95% CI, 2.0-4.5), a caesarean delivery (aOR, 4.6; 95% CI, 3.1-7.0), or a pre-term birth (aOR, 6.7; 95%CI, 4.5-10.0); their babies were more likely to have shoulder dystocia (aOR, 8.2; 95% CI, 3.6-18.7),hypoglycaemia (aOR, 10.3; 95% CI, 6.8-15.6), jaundice (aOR, 5.1; 95% CI, 3.3-7.7), respiratorydistress (aOR, 2.5; 95% CI, 1.4-4.4) or to suffer perinatal death (aOR, 4.3; 95% CI, 1.9-9.9). In womenwith type 1 diabetes, greater obesity was associated with increased odds for an LGA baby or congenitalmalformation, and increased HbA1c levels were associated with pre-term birth and perinatal death.CONCLUSION Women with type 1 diabetes, even when managed in a specialist setting, still experienceadverse obstetric and neonatal outcomes. Poor glycaemic control is not wholly responsible for adverseoutcomes, reinforcing the importance of other risk factors, such as obesity and weight gain.", "metadata": {}}
+{"_id": "8856690", "title": "", "text": "Molecular Mechanisms of Vitamin D ActionThe hormonal metabolite of vitamin D, 1α,25-dihydroxyvitaminD3 (1,25D), initiates biological responses via binding to the vitamin D receptor (VDR). When occupied by1,25D, VDR interacts with the retinoid X receptor (RXR) to form a heterodimer that binds to vitamin Dresponsive elements in the region of genes directly controlled by 1,25D. By recruiting complexes of eithercoactivators or corepressors, ligand-activated VDR-RXR modulates the transcription of genes encodingproteins that promulgate the traditional functions of vitamin D, including signaling intestinal calcium andphosphate absorption to effect skeletal and calcium homeostasis. Thus, vitamin D action in a particularcell depends upon the metabolic production or delivery of sufficient concentrations of the 1,25D ligand,expression of adequate VDR and RXR coreceptor proteins, and cell-specific programming oftranscriptional responses to regulate select genes that encode proteins that function in mediating theeffects of vitamin D. For example, 1,25D induces RANKL, SPP1 (osteopontin), and BGP (osteocalcin) togovern bone mineral remodeling; TRPV6, CaBP9k, and claudin 2 to promote intestinal calciumabsorption; and TRPV5, klotho, and Npt2c to regulate renal calcium and phosphate reabsorption. VDRappears to function unliganded by 1,25D in keratinocytes to drive mammalian hair cycling via regulationof genes such as CASP14, S100A8, SOSTDC1, and others affecting Wnt signaling. Finally, alternative,low-affinity, non-vitamin D VDR ligands, e.g., lithocholic acid, docosahexaenoic acid, and curcumin, havebeen reported. Combined alternative VDR ligand(s) and 1,25D/VDR control of gene expression may delaychronic disorders of aging such as osteoporosis, type 2 diabetes, cardiovascular disease, and cancer.", "metadata": {}}
+{"_id": "8858602", "title": "", "text": "Quantitative Temporal Viromics: An Approach to Investigate Host-Pathogen InteractionA systematicquantitative analysis of temporal changes in host and viral proteins throughout the course of a productiveinfection could provide dynamic insights into virus-host interaction. We developed a proteomic techniquecalled \"quantitative temporal viromics\" (QTV), which employs multiplexed tandem-mass-tag-based massspectrometry. Human cytomegalovirus (HCMV) is not only an important pathogen but a paradigm of viralimmune evasion. QTV detailed how HCMV orchestrates the expression of >8,000 cellular proteins,including 1,200 cell-surface proteins to manipulate signaling pathways and counterintrinsic, innate, andadaptive immune defenses. QTV predicted natural killer and T cell ligands, as well as 29 viral proteinspresent at the cell surface, potential therapeutic targets. Temporal profiles of >80% of HCMV canonicalgenes and 14 noncanonical HCMV open reading frames were defined. QTV is a powerful method that canyield important insights into viral infection and is applicable to any virus with a robust in vitro model.", "metadata": {}}
+{"_id": "8868863", "title": "", "text": "Interactions between sleep, circadian function, and glucose metabolism: implications for risk and severityof diabetes.Sleep disturbances, including sleep insufficiency and sleep fragmentation, have been linked toabnormal glucose metabolism and increased diabetes risk. Well-controlled laboratory studies haveprovided insights regarding the underlying mechanisms. Several large prospective studies suggest thatthese sleep disturbances are associated with an increased risk of incident diabetes. Obstructive sleepapnea, which combines sleep fragmentation and hypoxemia, is a major risk factor for insulin resistanceand possibly diabetes. Whether glycemic control in type 2 diabetes patients can be improved by treatingsleep apnea remains controversial. Recently, sleep disturbances during pregnancy and their relationshipto gestational diabetes and hyperglycemia have received considerable attention owing to potentialadverse effects on maternal and fetal health. Additionally, evidence from animal models has identifieddisruption of the circadian system as a putative risk factor for adverse metabolic outcomes. The purposeof this review is to provide an update on the current state of knowledge linking sleep disturbances,circadian dysfunction, and glucose metabolism. Experimental, prospective, and interventional studies arediscussed.", "metadata": {}}
+{"_id": "8883846", "title": "", "text": "Antibody-Based HIV-1 Vaccines: Recent Developments and Future DirectionsThe Global HIV VaccineEnterprise convened a two-day workshop in May of 2007 to discuss humoral immune responses to HIVand approaches to design vaccines that induce viral neutralizing and other potentially protective antibodyresponses. The goals of this workshop were to identify key scientific issues, gaps, and opportunities thathave emerged since the Enterprise Strategic Plan was first published in 2005 [1], and to makerecommendations that Enterprise stakeholders can use to plan new activities. Most effective viralvaccines work, at least in part, by generating antibodies that inactivate or neutralize the invading virus,and the existing data strongly suggest that an optimally effective HIV-1 vaccine should elicit potentantiviral neutralizing antibodies. However, unlike acute viral pathogens, HIV-1 chronically replicates inthe host and evades the antibody response. This immune evasion, along with the large genetic variationamong HIV-1 strains worldwide, has posed major obstacles to vaccine development. Current HIV vaccinecandidates do not elicit neutralizing antibodies against most circulating virus strains, and thus theinduction of a protective antibody response remains a major priority for HIV-1 vaccine development. Foran antibody-based HIV-1 vaccine, progress in vaccine design is generally gauged by in vitro assays thatmeasure the ability of vaccine-induced antibodies to neutralize a broad spectrum of viral isolatesrepresenting the major genetic subtypes (clades) of HIV-1 [2]. Although it is not known what magnitudeand breadth of neutralization will predict protection in vaccine recipients, it is clear that current vaccineimmunogens elicit antibodies that neutralize only a minority of circulating isolates. Thus, much progressneeds to be made in this area. Also, though virus neutralization is considered a critical benchmark for avaccine, this may not be the only benchmark for predicting success with antibody-based HIV-1 vaccineimmunogens. The main targets for neutralizing antibodies to HIV-1 are the surface gp120 andtrans-membrane gp41 envelope glycoproteins (Env) that mediate receptor and coreceptor binding andthe subsequent membrane fusion events that allow the virus to gain entry into cells [3]. Antibodiesneutralize the virus by binding these viral spikes and blocking virus entry into susceptible cells, such asCD4+ T cells [4,5]. In order to chronically replicate in the host, the virus exploits several mechanisms toshield itself against antibody recognition, including a dense outer coating of sugar molecules (N-linkedglycans) and the strategic positioning of cysteine–cysteine loop structures on the gp120 molecule [6–8].These shielding mechanisms, although highly effective, have vulnerabilities imposed by fitnessconstraints. Information on the precise location and molecular structure of these vulnerable regions couldbe valuable for the rational design of improved vaccine immunogens. Participants in the workshopidentified four areas that, if given proper attention, could provide key information that would bring thefield closer to an effective antibody-based HIV-1 vaccine: (1) structure-assisted immunogen design, (2)role of Fc receptors and complement, (3) assay standardization and validation, and (4) immunoregulationof B cell responses.", "metadata": {}}
+{"_id": "8891333", "title": "", "text": "Targeted therapy for cancer stem cells: the patched pathway and ABC transportersData from certainleukemias as well as brain and breast cancer indicate that there is a small population of tumor cells with‘stem cell’ characteristics and the capacity for self-renewal. The self-renewing cells have many of theproperties of normal stem cells and have been termed ‘cancer stem cells’. These cancer stem cells makeup as few as 1% of the cells in a tumor, making them difficult to detect and study. Like normal stem cells,cancer stem cells have a number of properties permitting them to survive traditional cancerchemotherapy and radiation therapy. These cells express high levels of ATP-binding cassette (ABC) drugtransporters, providing for a level of resistance; are relatively quiescent; have higher levels of DNA repairand a lowered ability to enter apoptosis. Combined cancer therapy approaches targeting the cancer stemcells and the non-stem cells may be developed with increased efficacy. Efforts to target theHedgehog/Patched pathway, critical to embryonic growth and differentiation, and the ABCG2 drug effluxtransporter will be presented.", "metadata": {}}
+{"_id": "8892905", "title": "", "text": "Increased in vivo amyloid-β42 production, exchange, and loss in presenilin mutation carriers.Alzheimer'sdisease (AD) is hypothesized to be caused by an overproduction or reduced clearance of amyloid-β (Aβ)peptide. Autosomal dominant AD (ADAD) caused by mutations in the presenilin (PSEN) gene have beenpostulated to result from increased production of Aβ42 compared to Aβ40 in the central nervous system(CNS). This has been demonstrated in rodent models of ADAD but not in human mutation carriers. Weused compartmental modeling of stable isotope labeling kinetic (SILK) studies in human carriers of PSENmutations and related noncarriers to evaluate the pathophysiological effects of PSEN1 and PSEN2mutations on the production and turnover of Aβ isoforms. We compared these findings by mutation statusand amount of fibrillar amyloid deposition as measured by positron emission tomography (PET) using theamyloid tracer Pittsburgh compound B (PIB). CNS Aβ42 to Aβ40 production rates were 24% higher inmutation carriers compared to noncarriers, and this was independent of fibrillar amyloid depositsquantified by PET PIB imaging. The fractional turnover rate of soluble Aβ42 relative to Aβ40 was 65%faster in mutation carriers and correlated with amyloid deposition, consistent with increased deposition ofAβ42 into plaques, leading to reduced recovery of Aβ42 in cerebrospinal fluid (CSF). Reversible exchangeof Aβ42 peptides with preexisting unlabeled peptide was observed in the presence of plaques. Thesefindings support the hypothesis that Aβ42 is overproduced in the CNS of humans with PSEN mutationsthat cause AD, and demonstrate that soluble Aβ42 turnover and exchange processes are altered in thepresence of amyloid plaques, causing a reduction in Aβ42 concentrations in the CSF.", "metadata": {}}
+{"_id": "8903143", "title": "", "text": "Basic residues in the T-cell receptor ζ cytoplasmic domain mediate membrane association and modulatesignaling.The T-cell receptor (TCR) consists of a TCRαβ heterodimer, a TCRζ homodimer, and CD3γε andCD3δε heterodimers. The precise mechanism of T-cell triggering following TCR ligand engagementremains elusive. Previous studies reported that the cytoplasmic tail of CD3ε binds to the plasmamembrane through a basic residue-rich stretch (BRS) and proposed that dissociation from the membraneis required for phosphorylation thereof. In this report we show that BRS motifs within the cytoplasmic tailof TCRζ mediate association with the plasma membrane and that TCR engagement results in TCRζdissociation from the membrane. This dissociation requires phosphorylation of the TCRζ immunoreceptortyrosine-based activation motifs by lymphocyte cell-specificprotein tyrosine kinase (Lck) but notζ-chain-associated protein kinase 70 binding. Mutations of the TCRζ BRS motifs that disrupt thismembrane association attenuate proximal and distal responses induced by TCR engagement. Thesemutations appear to alter the localization of TCRζ with respect to Lck as well as the mobility of the TCRcomplex. This study reveals that tyrosine phosphorylation of the TCRζ cytoplasmic domain regulates itsassociation with the plasma membrane and highlights the functional importance of TCRζ BRS motifs.", "metadata": {}}
+{"_id": "8906858", "title": "", "text": "Policies for alcohol restriction and their association with interpersonal violence: a time-series analysis ofhomicides in Cali, Colombia.BACKGROUND Cali, Colombia, has a high incidence of interpersonal violencedeaths. Various alcohol control policies have been implemented to reduce alcohol-related problems. Theobjective of this study was to determine whether different alcohol control policies were associated withchanges in the incidence rate of homicides. METHODS Ecologic study conducted during 2004-08 using atime-series design. Policies were implemented with variations in hours of restriction of sales andconsumption of alcohol. Most restrictive policies prohibited alcohol between 2 a.m. and 10 a.m. for 446non-consecutive days. Moderately restrictive policies prohibited alcohol between 3 a.m. and 10 a.m. for1277 non-consecutive days. Lax policies prohibited alcohol between 4 a.m. and 10 a.m. for 104non-consecutive days. In conditional autoregressive negative binomial regressions, rates of homicidesand unintentional injury deaths (excluding traffic events) were compared between different periods ofdays when different policies were in effect. RESULTS There was an increased risk of homicides in periodswhen the moderately restrictive policies were in effect compared with periods when the most restrictivepolicies were in effect [incidence rate ratio (IRR) 1.15, 90% confidence interval (CI) 1.05-1.26, P =0.012], and there was an even higher risk of homicides in periods when the lax policies were in effectcompared with periods when the most restrictive policies were in effect (IRR 1.42, 90% CI 1.26-1.61, P <0.001). Less restrictive policies were not associated with increased risk of unintentional injury deaths.CONCLUSION Extended hours of sales and consumption of alcohol were associated with increased risk ofhomicides. Strong restrictions on alcohol availability could reduce the incidence of interpersonal violenceevents in communities where homicides are high.", "metadata": {}}
+{"_id": "8909176", "title": "", "text": "Effects of SNF1 on Maltose Metabolism and Leavening Ability of Baker's Yeast in Lean Dough.Maltosemetabolism of baker's yeast (Saccharomyces cerevisiae) in lean dough is negatively influenced byglucose repression, thereby delaying the dough fermentation. To improve maltose metabolism andleavening ability, it is necessary to alleviate glucose repression. The Snf1 protein kinase is well known tobe essential for the response to glucose repression and required for transcription of glucose-repressedgenes including the maltose-utilization genes (MAL). In this study, the SNF1 overexpression and deletionindustrial baker's yeast strains were constructed and characterized in terms of maltose utilization, growthand fermentation characteristics, mRNA levels of MAL genes (MAL62 encoding the maltase and MAL61encoding the maltose permease) and maltase and maltose permease activities. Our results suggest thatoverexpression of SNF1 was effective to glucose derepression for enhancing MAL expression levels andenzymes (maltase and maltose permease) activities. These enhancements could result in an 18%increase in maltose metabolism of industrial baker's yeast in LSMLD medium (the low sugar model liquiddough fermentation medium) containing glucose and maltose and a 15% increase in leavening ability inlean dough. These findings provide a valuable insight of breeding industrial baker's yeast for rapidfermentation.", "metadata": {}}
+{"_id": "8925851", "title": "", "text": "Review articleRibosomopathies compose a collection of disorders in which genetic abnormalities causeimpaired ribosome biogenesis and function, resulting in specific clinical phenotypes. Congenital mutationsin RPS19 and other genes encoding ribosomal proteins cause Diamond-Blackfan anemia, a disordercharacterized by hypoplastic, macrocytic anemia. Mutations in other genes required for normal ribosomebiogenesis have been implicated in other rare congenital syndromes, Schwachman-Diamond syndrome,dyskeratosis congenita, cartilage hair hypoplasia, and Treacher Collins syndrome. In addition, the 5q-syndrome, a subtype of myelodysplastic syndrome, is caused by a somatically acquired deletion ofchromosome 5q, which leads to haploinsufficiency of the ribosomal protein RPS14 and an erythroidphenotype highly similar to Diamond-Blackfan anemia. Acquired abnormalities in ribosome function havebeen implicated more broadly in human malignancies. The p53 pathway provides a surveillancemechanism for protein translation as well as genome integrity and is activated by defects in ribosomebiogenesis; this pathway appears to be a critical mediator of many of the clinical features ofribosomopathies. Elucidation of the mechanisms whereby selective abnormalities in ribosome biogenesiscause specific clinical syndromes will hopefully lead to novel therapeutic strategies for these diseases.", "metadata": {}}
+{"_id": "8963413", "title": "", "text": "PD-L1 expression in human cancers and its association with clinical outcomesPD-L1 is animmunoinhibitory molecule that suppresses the activation of T cells, leading to the progression of tumors.Overexpression of PD-L1 in cancers such as gastric cancer, hepatocellular carcinoma, renal cellcarcinoma, esophageal cancer, pancreatic cancer, ovarian cancer, and bladder cancer is associated withpoor clinical outcomes. In contrast, PD-L1 expression correlates with better clinical outcomes in breastcancer and merkel cell carcinoma. The prognostic value of PD-L1 expression in lung cancer, colorectalcancer, and melanoma is controversial. Blocking antibodies that target PD-1 and PD-L1 have achievedremarkable response rates in cancer patients who have PD-L1-overexpressing tumors. However, usingPD-L1 as an exclusive predictive biomarker for cancer immunotherapy is questionable due to the lowaccuracy of PD-L1 immunohistochemistry staining. Factors that affect the accuracy of PD-L1immunohistochemistry staining are as follows. First, antibodies used in different studies have differentsensitivity. Second, in different studies, the cut-off value of PD-L1 staining positivity is different. Third,PD-L1 expression in tumors is not uniform, and sampling time and location may affect the results ofPD-L1 staining. Therefore, better understanding of tumor microenvironment and use of other biomarkerssuch as gene marker and combined index are necessary to better identify patients who will benefit fromPD-1/PD-L1 checkpoint blockade therapy.", "metadata": {}}
+{"_id": "8979167", "title": "", "text": "Primate cytomegaloviruses encode and express an IL-10-like protein.An open reading frame (ORF) withhomology to interleukin-10 (IL-10) has been identified in rhesus cytomegalovirus (RhCMV). TheIL-10-like protein is generated from a multispliced, polyadenylated early gene transcript encompassingpart of the corresponding UL111A ORF of human CMV (HCMV). Immunological analyses confirmexpression of the IL-10-like protein both in tissue culture and in RhCMV-infected rhesus macaques.Conserved ORFs were subsequently identified in human, baboon, and African green monkey CMV, and afully processed transcript has been mapped in fibroblasts infected with the Towne strain of HCMV. Theconservation of this previously unrecognized ORF suggests that the protein may play an essential role inprimate CMV persistence and pathogenesis.", "metadata": {}}
+{"_id": "8989616", "title": "", "text": "Genome Sequencing and Analysis of the Tasmanian Devil and Its Transmissible CancerThe Tasmaniandevil (Sarcophilus harrisii), the largest marsupial carnivore, is endangered due to a transmissible facialcancer spread by direct transfer of living cancer cells through biting. Here we describe the sequencing,assembly, and annotation of the Tasmanian devil genome and whole-genome sequences for twogeographically distant subclones of the cancer. Genomic analysis suggests that the cancer first arosefrom a female Tasmanian devil and that the clone has subsequently genetically diverged during its spreadacross Tasmania. The devil cancer genome contains more than 17,000 somatic base substitutionmutations and bears the imprint of a distinct mutational process. Genotyping of somatic mutations in 104geographically and temporally distributed Tasmanian devil tumors reveals the pattern of evolution andspread of this parasitic clonal lineage, with evidence of a selective sweep in one geographical area andpersistence of parallel lineages in other populations.", "metadata": {}}
+{"_id": "8994465", "title": "", "text": "A Temporarily Distinct Subpopulation of Slow-Cycling Melanoma Cells Is Required for Continuous TumorGrowthMelanomas are highly heterogeneous tumors, but the biological significance of their differentsubpopulations is not clear. Using the H3K4 demethylase JARID1B (KDM5B/PLU-1/RBP2-H1) as abiomarker, we have characterized a small subpopulation of slow-cycling melanoma cells that cycle withdoubling times of >4 weeks within the rapidly proliferating main population. Isolated JARID1B-positivemelanoma cells give rise to a highly proliferative progeny. Knockdown of JARID1B leads to an initialacceleration of tumor growth followed by exhaustion which suggests that the JARID1B-positivesubpopulation is essential for continuous tumor growth. Expression of JARID1B is dynamically regulatedand does not follow a hierarchical cancer stem cell model because JARID1B-negative cells can becomepositive and even single melanoma cells irrespective of selection are tumorigenic. These results suggest anew understanding of melanoma heterogeneity with tumor maintenance as a dynamic process mediatedby a temporarily distinct subpopulation.", "metadata": {}}
+{"_id": "8995263", "title": "", "text": "A map of human circular RNAs in clinically relevant tissuesCellular circular RNAs (circRNAs) are generatedby head-to-tail splicing and are present in all multicellular organisms studied so far. Recently, circRNAshave emerged as a large class of RNA which can function as post-transcriptional regulators. It has alsobeen shown that many circRNAs are tissue- and stage-specifically expressed. Moreover, the unusualstability and expression specificity make circRNAs important candidates for clinical biomarker research.Here, we present a circRNA expression resource of 20 human tissues highly relevant to disease-relatedresearch: vascular smooth muscle cells (VSMCs), human umbilical vein cells (HUVECs), artery endothelialcells (HUAECs), atrium, vena cava, neutrophils, platelets, cerebral cortex, placenta, and samples frommesenchymal stem cell differentiation. In eight different samples from a single donor, we found highlytissue-specific circRNA expression. Circular-to-linear RNA ratios revealed that many circRNAs wereexpressed higher than their linear host transcripts. Among the 71 validated circRNAs, we noticedpotential biomarkers. In adenosine deaminase-deficient, severe combined immunodeficiency (ADA-SCID)patients and in Wiskott-Aldrich-Syndrome (WAS) patients' samples, we found evidence for differentialcircRNA expression of genes that are involved in the molecular pathogenesis of both phenotypes. Ourfindings underscore the need to assess circRNAs in mechanisms of human disease. KEY MESSAGES:circRNA resource catalog of 20 clinically relevant tissues. circRNA expression is highly tissue-specific.circRNA transcripts are often more abundant than their linear host RNAs. circRNAs can be differentiallyexpressed in disease-associated genes.", "metadata": {}}
+{"_id": "8997410", "title": "", "text": "Arp2/3 complex inhibition radically alters lamellipodial actin architecture, suspended cell shape, and thecell spreading processRecent studies have investigated the dendritic actin cytoskeleton of the cell edge'slamellipodial (LP) region by experimentally decreasing the activity of the actin filament nucleator andbranch former, the Arp2/3 complex. Here we extend these studies via pharmacological inhibition of theArp2/3 complex in sea urchin coelomocytes, cells that possess an unusually broad LP region and displaycorrespondingly exaggerated centripetal flow. Using light and electron microscopy, we demonstrate thatArp2/3 complex inhibition via the drug CK666 dramatically altered LP actin architecture, slowedcentripetal flow, drove a lamellipodial-to-filopodial shape change in suspended cells, and induced a novelactin structural organization during cell spreading. A general feature of the CK666 phenotype incoelomocytes was transverse actin arcs, and arc generation was arrested by a formin inhibitor. We alsodemonstrate that CK666 treatment produces actin arcs in other cells with broad LP regions, namely fishkeratocytes and Drosophila S2 cells. We hypothesize that the actin arcs made visible by Arp2/3 complexinhibition in coelomocytes may represent an exaggerated manifestation of the elongate mother filamentsthat could possibly serve as the scaffold for the production of the dendritic actin network.", "metadata": {}}
+{"_id": "9021186", "title": "", "text": "Synergistic Activation of HIV-1 Expression by Deacetylase Inhibitors and Prostratin: Implications forTreatment of Latent InfectionThe persistence of transcriptionally silent but replication-competent HIV-1reservoirs in Highly Active Anti-Retroviral Therapy (HAART)-treated infected individuals, represents amajor hurdle to virus eradication. Activation of HIV-1 gene expression in these cells together with anefficient HAART has been proposed as an adjuvant therapy aimed at decreasing the pool of latent viralreservoirs. Using the latently-infected U1 monocytic cell line and latently-infected J-Lat T-cell clones, wehere demonstrated a strong synergistic activation of HIV-1 production by clinically used histonedeacetylase inhibitors (HDACIs) combined with prostratin, a non-tumor-promoting nuclear factor (NF)-kappaB inducer. In J-Lat cells, we showed that this synergism was due, at least partially, to thesynergistic recruitment of unresponsive cells into the expressing cell population. A combination ofprostratin+HDACI synergistically activated the 5' Long Terminal Repeat (5'LTR) from HIV-1 Major groupsubtypes representing the most prevalent viral genetic forms, as shown by transient transfection reporterassays. Mechanistically, HDACIs increased prostratin-induced DNA-binding activity of nuclear NF-kappaBand degradation of cytoplasmic NF-kappaB inhibitor, IkappaBalpha . Moreover, the combined treatmentprostratin+HDACI caused a more pronounced nucleosomal remodeling in the U1 viral promoter regionthan the treatments with the compounds alone. This more pronounced remodeling correlated with asynergistic reactivation of HIV-1 transcription following the combined treatment prostratin+HDACI, asdemonstrated by measuring recruitment of RNA polymerase II to the 5'LTR and both initiated andelongated transcripts. The physiological relevance of the prostratin+HDACI synergism was shown inCD8(+)-depleted peripheral blood mononuclear cells from HAART-treated patients with undetectable viralload. Moreover, this combined treatment reactivated viral replication in resting CD4(+) T cells isolatedfrom similar patients. Our results suggest that combinations of different kinds of proviral activators mayhave important implications for reducing the size of latent HIV-1 reservoirs in HAART-treated patients.", "metadata": {}}
+{"_id": "9038803", "title": "", "text": "Centrosome aberrations: cause or consequence of cancer progression?Many human tumours showcentrosome aberrations, indicating an underlying deregulation of centrosome structure, duplication orsegregation. Centrosomes organize microtubule arrays throughout the cell cycle, thereby influencing bothtissue architecture and the accuracy of chromosome segregation. But what are the origins of centrosomalabnormalities in tumours, and what impact do they have on the generation of invasive, geneticallyunbalanced cells during cancer progression?", "metadata": {}}
+{"_id": "9047718", "title": "", "text": "Autonomic neuropathy, QT interval lengthening, and unexpected deaths in male diabetic patientsQTintervals were measured over RR intervals ranging from 500 ms to 1000 ms in 13 normal male subjects,13 male diabetic subjects without and 13 with autonomic neuropathy. There was a close linearrelationship between QT and RR in all subjects. The slope of the regression line was significantly greaterin the autonomic neuropathy group than the normal group. Thirty-two male diabetic subjects withvarying degrees of autonomic dysfunction had repeat QT measurements 3 (range 2–6) years later. QTand QTC lengthened significantly at the second visit, unrelated to age or time between recordings, butwhich corresponded with changes in autonomic function. Of 71 male diabetic subjects under 60 yearsfollowed for 3 years, 13 had died, 8 unexpectedly. Of those with autonomic neuropathy, QT and QTCwere significantly longer in those who subsequently died, despite similar ages and duration of diabetes.We conclude that QT/RR interval relationships are altered in diabetic autonomic neuropathy, and thatchanges in QT length with time parallel changese in autonomic function. There may be an associationbetween QT interval prolongation and the risk of dying unexpectedly in diabetic autonomic neuropathy.", "metadata": {}}
+{"_id": "9056874", "title": "", "text": "Incidence of cancer after immunosuppressive treatment for heart transplantation.Prolonged or intensiveimmunosuppressive therapy used after organ transplantation is complicated by an increased incidence ofcancer. Striking differences in incidence are observed in heart and heart-lung transplant recipients whencompared with renal transplant patients. The most significant increase was in the incidence of lymphomasin cardiac versus renal patients. Moreover, a two-fold greater increase of all neoplasms was found incardiac recipients, with nearly a six-fold increase in visceral tumors. Several factors may account forthese differences. In cardiac allograft recipients, intensive immunosuppression is frequently used toreverse acute rejection and the highest number of cardiac transplants was performed in the era ofpolypharmacy, usually consisting of triple therapy.", "metadata": {}}
+{"_id": "9063688", "title": "", "text": "Nucleating actin for invasionThe invasion of cancer cells into the surrounding tissue is a prerequisite andinitial step in metastasis, which is the leading cause of death from cancer. Invasive cell migration requiresthe formation of various structures, such as invadopodia and pseudopodia, which require actin assemblythat is regulated by specialized actin nucleation factors. There is a large variety of different actinnucleators in human cells, such as formins, spire and Arp2/3-regulating proteins, and the list is likely togrow. Studies of the mechanisms of various actin nucleation factors that are involved in cancer cellfunction may ultimately provide new treatments for invasive and metastatic disease.", "metadata": {}}
+{"_id": "9076196", "title": "", "text": "GFI1 and GFI1B control the loss of endothelial identity of hemogenic endothelium during hematopoieticcommitment.Recent studies have established that during embryonic development, hematopoieticprogenitors and stem cells are generated from hemogenic endothelium precursors through a processtermed endothelial to hematopoietic transition (EHT). The transcription factor RUNX1 is essential for thisprocess, but its main downstream effectors remain largely unknown. Here, we report the identification ofGfi1 and Gfi1b as direct targets of RUNX1 and critical regulators of EHT. GFI1 and GFI1B are able totrigger, in the absence of RUNX1, the down-regulation of endothelial markers and the formation of roundcells, a morphologic change characteristic of EHT. Conversely, blood progenitors in Gfi1- andGfi1b-deficient embryos maintain the expression of endothelial genes. Moreover, those cells are notreleased from the yolk sac and disseminated into embryonic tissues. Taken together, our findingsdemonstrate a critical and specific role of the GFI1 transcription factors in the first steps of the processleading to the generation of hematopoietic progenitors from hemogenic endothelium.", "metadata": {}}
+{"_id": "9091863", "title": "", "text": "An RNA-directed nuclease mediates post-transcriptional gene silencing in Drosophila cells.In a diversegroup of organisms that includes Caenorhabditis elegans, Drosophila, planaria, hydra, trypanosomes,fungi and plants, the introduction of double-stranded RNAs inhibits gene expression in asequence-specific manner. These responses, called RNA interference or post-transcriptional genesilencing, may provide anti-viral defence, modulate transposition or regulate gene expression. We havetaken a biochemical approach towards elucidating the mechanisms underlying this genetic phenomenon.Here we show that 'loss-of-function' phenotypes can be created in cultured Drosophila cells bytransfection with specific double-stranded RNAs. This coincides with a marked reduction in the level ofcognate cellular messenger RNAs. Extracts of transfected cells contain a nuclease activity that specificallydegrades exogenous transcripts homologous to transfected double-stranded RNA. This enzyme containsan essential RNA component. After partial purification, the sequence-specific nuclease co-fractionateswith a discrete, approximately 25-nucleotide RNA species which may confer specificity to the enzymethrough homology to the substrate mRNAs.", "metadata": {}}
+{"_id": "9095394", "title": "", "text": "Expression of basal cell keratin 15 and keratin 19 in oral squamous neoplasms represents diversepathophysiologies.Human epithelium contains keratin, which is expressed during differentiation.Depending on the target cell type, different types of keratin are expressed, and their alterations seem torepresent changes in cell properties. The basal cells of oral epithelium express keratin 5 (K5), K14, K15and K19, but their alterations in tumors are unclear. To address this issue and to seek possible diagnosticapplication, we examined the expression of these keratins in oral squamous cell carcinoma (OSCC) andsquamous intraepithelial neoplasm (SIN). cDNA microarray analysis of 43 OSCC revealed slightupregulation of KRT14, downregulation of KRT15 and KRT19, and unaltered KRT5 expression. There weregreat variations in KRT15 and KRT19 expression across each cancer. Well-differentiated OSCC tended toexpress more KRT15 and less KRT19 compared to moderately- or poorly-differentiated OSCC. KRT15 waspositively correlated with differentiation-related keratin, KRT13. These observations were furtherinvestigated by immunohistochemical examination. K5 and K14 were ubiquitously expressed in all 50OSCC and 50 SIN examined. K15 and K19 were generally downregulated, but were considerably retainedin about half of the cases and showed diverse expression patterns. K15-positive cancers tended to show awell-differentiated phenotype, and K19-positive cancers tended to show more invasive tumor fronts. MostK19-positive cancers appeared to develop with little associating SIN. K19 was consistently downregulatedin SIN, while K15 was downregulated mainly in high grade SIN. In summary, K15 and K19, unlike K5 orK14, are expressed variably in both SIN and OSCC, which reflects the differences in their pathogenesisand biological behaviors, suggesting their prospective applications as markers for subclassifying OSCCand SIN.", "metadata": {}}
+{"_id": "9095943", "title": "", "text": "Exosomes in Plasma of Patients with Ovarian Carcinoma: Potential Biomarkers of Tumor Progression andResponse to Therapy.BACKGROUND In patients with Ovarian Cancer (OvCa) exosomes released by tumorcells are present in the plasma and could be involved in tumor progression. This study examines theassociation between the exosome presence/protein content in plasma of OvCa patients and diseaseoutcome, response to standard therapy and/or tumorresistance to therapies in patients studied atdiagnosis and also serially during and after therapy. DESIGN AND METHODS Exosomes were purifiedfrom OvCa patients' plasma (n=22), patients with benign tumors (n=10) or (n=10) healthy controls (NC)using ultracentrifugation. Exosomes were visualized by scanning electron microscopy. Their proteincontent was measured. The presence of MAGE 3/6 and TGF-β1 in exosomes was evaluated in Westernblots. RESULTS The OvCa patients' plasma contained higher levels of exosomal proteins (p<0.05)compared to those isolated from plasma of patients with benign tumors or NC. Exosomes isolated fromOvCa patients's plasma carried TGF-β1 and MAGE3/6, which distinguished OvCa patients from those withbenign tumors and NC. High protein levels of exosomes were seen in newly diagnosed patients; howeverin advanced stages of OvCa patients the protein content of isolated exosomes was significantly higherthan that of early stages. The exosome levels variably changed during/after chemotherapy, andcorrelations between the changes in exosomal protein levels and clinical data suggested that the proteincontent of exosomes might be useful in predicting responses to therapy and prognosis in OvCa patients.CONCLUSION Analysis of plasma exosomes levels offers a novel approach to diagnosis and monitoringresponse to therapies in OvCa patients.", "metadata": {}}
+{"_id": "9110810", "title": "", "text": "Insecticide impregnated curtains to control domestic transmission of cutaneous leishmaniasis inVenezuela: cluster randomised trial.OBJECTIVE To measure the impact on transmission of leishmaniasisof curtains impregnated with insecticide. DESIGN Cluster randomised controlled trial: household interviewsurvey, observational study of people's behaviour, entomological study with light trap captures ofsandflies inside houses. SETTING 14 urban sectors in Trujillo, Venezuela. PARTICIPANTS 2913 inhabitantsof 569 houses. INTERVENTION Sectors were paired according to their 12 month cumulative incidence ofcutaneous leishmaniasis, one sector in each pair was randomly allocated to receive polyester curtainsimpregnated with lambdacyhalothrin (intervention group) while the other sector received curtains withoutinsecticide or no curtains (control groups). After 12 months a follow up household survey was conducted.MAIN OUTCOME MEASURES Reduction in abundance of sandflies indoors and 12 month incidence ofclinical cases of cutaneous leishmaniasis. RESULTS Transmission of cutaneous leishmaniasis occurredmainly in the domestic setting, with the incidence over 12 months of 4%. The mean number of sandfliesper trap per night was 16. After follow up the 12 month incidence of cutaneous leishmaniasis was 0% inthe intervention group and 8% in the six pairs in the control group that received unimpregnated curtains(mean difference 8, 95% confidence interval 4.22 to 11.78; P=0.001). There were significantly fewersandflies in the intervention group (2 v 15, mean difference 13 sandflies per trap; 9 to 17; P<0.001).CONCLUSION Curtains impregnated with insecticide provide a high degree of protection against indoortransmission of cutaneous leishmaniasis.", "metadata": {}}
+{"_id": "9113824", "title": "", "text": "Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes inadult mice.Pancreatic ductal adenocarcinoma (PDA), one of the deadliest human cancers, often involvessomatic activation of K-Ras oncogenes. We report that selective expression of an endogenousK-Ras(G12V) oncogene in embryonic cells of acinar/centroacinar lineage results in pancreaticintraepithelial neoplasias (PanINs) and invasive PDA, suggesting that PDA originates by differentiation ofacinar/centroacinar cells or their precursors into ductal-like cells. Surprisingly, adult mice becomerefractory to K-Ras(G12V)-induced PanINs and PDA. However, if these mice are challenged with a mildform of chronic pancreatitis, they develop the full spectrum of PanINs and invasive PDA. Theseobservations suggest that, during adulthood, PDA stems from a combination of genetic (e.g., somaticK-Ras mutations) and nongenetic (e.g., tissue damage) events.", "metadata": {}}
+{"_id": "9122283", "title": "", "text": "Relative roles of direct regeneration versus paracrine effects of human cardiosphere-derived cellstransplanted into infarcted mice.RATIONALE Multiple biological mechanisms contribute to the efficacy ofcardiac cell therapy. Most prominent among these are direct heart muscle and blood vessel regenerationfrom transplanted cells, as opposed to paracrine enhancement of tissue preservation and/or recruitmentof endogenous repair. OBJECTIVE Human cardiac progenitor cells, cultured as cardiospheres (CSps) or asCSp-derived cells (CDCs), have been shown to be capable of direct cardiac regeneration in vivo. Here wecharacterized paracrine effects in CDC transplantation and investigated their relative importance versusdirect differentiation of surviving transplanted cells. METHODS AND RESULTS In vitro, many growthfactors were found in media conditioned by human adult CSps and CDCs; CDC-conditioned media exertedantiapoptotic effects on neonatal rat ventricular myocytes, and proangiogenic effects on human umbilicalvein endothelial cells. In vivo, human CDCs secreted vascular endothelial growth factor, hepatocytegrowth factor, and insulin-like growth factor 1 when transplanted into the same SCID mouse model ofacute myocardial infarction where they were previously shown to improve function and to produce tissueregeneration. Injection of CDCs in the peri-infarct zone increased the expression of Akt, decreasedapoptotic rate and caspase 3 level, and increased capillary density, indicating overall higher tissueresilience. Based on the number of human-specific cells relative to overall increases in capillary densityand myocardial viability, direct differentiation quantitatively accounted for 20% to 50% of the observedeffects. CONCLUSIONS Together with their spontaneous commitment to cardiac and angiogenicdifferentiation, transplanted CDCs serve as \"role models,\" recruiting endogenous regeneration andimproving tissue resistance to ischemic stress. The contribution of the role model effect rivals or exceedsthat of direct regeneration.", "metadata": {}}
+{"_id": "9142761", "title": "", "text": "The IC(50) of anti-Pfs25 antibody in membrane-feeding assay varies among species.Plasmodiumfalciparum surface protein 25 (Pfs25) is a candidate for transmission-blocking vaccines (TBVs). Anti-Pfs25antibodies block the development of oocysts in membrane-feeding assays and we have shown the activitycorrelates with antibody titer. In this study, we purified Pfs25-specific IgGs to convert antibody titer tomicrog/mL and determined the amount of antibody required to inhibit 50% of oocyst development(IC(50)). The IC(50) were, 15.9, 4.2, 41.2, and 85.6microg/mL for mouse, rabbit, monkey and human,respectively, and the differences among species were significant. Anti-Pfs25 sera from rabbit, monkeyand human showed different patterns of competition against 6 mouse monoclonal antibodies, and theavidity of antibodies among four species were also different. These data suggests that informationobtained from animal studies which assess efficacy of TBV candidates may be difficult to translate tohuman immunization.", "metadata": {}}
+{"_id": "9154703", "title": "", "text": "Single-Cell RNA-Seq Reveals Dynamic, Random Monoallelic Gene Expression in MammalianCellsExpression from both alleles is generally observed in analyses of diploid cell populations, but studiesaddressing allelic expression patterns genome-wide in single cells are lacking. Here, we present globalanalyses of allelic expression across individual cells of mouse preimplantation embryos of mixedbackground (CAST/EiJ × C57BL/6J). We discovered abundant (12 to 24%) monoallelic expression ofautosomal genes and that expression of the two alleles occurs independently. The monoallelic expressionappeared random and dynamic because there was considerable variation among closely relatedembryonic cells. Similar patterns of monoallelic expression were observed in mature cells. Our allelicexpression analysis also demonstrates the de novo inactivation of the paternal X chromosome. Weconclude that independent and stochastic allelic transcription generates abundant random monoallelicexpression in the mammalian cell.", "metadata": {}}
+{"_id": "9159125", "title": "", "text": "Lipopolysaccharide-dependent prostaglandin E(2) production is regulated by the glutathione-dependentprostaglandin E(2) synthase gene induced by the Toll-like receptor 4/MyD88/NF-IL6pathway.Macrophages produce a large amount of PGE(2) during inflammation. This lipid mediatormodulates various immune responses. PGE(2) acts on macrophages and inhibits production of cytokinessuch as TNF-alpha and IL-12. Membrane-bound glutathione-dependent PGE(2) synthase (mPGES) hasbeen shown to be a terminal enzyme of the cyclooxygenase-2-mediated PGE(2) biosynthesis. Here weidentified mPGES as a molecule that is induced by LPS in macrophages. The expression of mPGES wasnot induced by LPS in mice lacking Toll-like receptor 4 or MyD88. Furthermore, mice deficient in NF-IL6showed neither induction of mPGES nor biosynthesis of PGE(2) in response to LPS, indicating that mPGESexpression in response to LPS is regulated by a Toll-like receptor 4/MyD88/NF-IL6-dependent signalingpathway. We generated mPGES-deficient mice and investigated the role of mPGES in vivo. The miceshowed no augmentation of the PGE(2) production in response to LPS. However, they were not impairedin the LPS-induced production of inflammatory cytokines and showed normal response to the LPS-inducedshock. Thus, mPGES is critically involved in the biosynthesis of PGE(2) induced by LPS, but is dispensablefor the modulation of inflammatory responses.", "metadata": {}}
+{"_id": "9159495", "title": "", "text": "A microRNA feedback loop regulates global microRNA abundance during aging.Expression levels of manymicroRNAs (miRNAs) change during aging, notably declining globally in a number of organisms andtissues across taxa. However, little is known about the mechanisms or the biological relevance for thischange. We investigated the network of genes that controls miRNA transcription and processing during C.elegans aging. We found that miRNA biogenesis genes are highly networked with transcription factorsand aging-associated miRNAs. In particular, miR-71, known to influence life span and itself up-regulatedduring aging, represses alg-1/Argonaute expression post-transcriptionally during aging. Increased ALG-1abundance in mir-71 loss-of-function mutants led to globally increased miRNA expression. Interestingly,these mutants demonstrated widespread mRNA expression dysregulation and diminished levels ofvariability both in gene expression and in overall life span. Thus, the progressive molecular decline oftenthought to be the result of accumulated damage over an organism's life may be partially explained by amiRNA-directed mechanism of age-associated decline.", "metadata": {}}
+{"_id": "9160947", "title": "", "text": "Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient miceInterleukin 7(IL-7) stimulates the proliferation of B cell progenitors, thymocytes, and mature T cells through aninteraction with a high affinity receptor (IL-7R) belonging to the hematopoietin receptor superfamily. Wehave further addressed the role of IL-7 and its receptor during B and T cell development by generatingmice genetically deficient in IL-7R. Mutant mice display a profound reduction in thymic and peripherallymphoid cellularity. Analyses of lymphoid progenitor populations in IL-7R-deficient mice define preciselythose developmental stages affected by the mutation and reveal a critical role for IL-7R during earlylymphoid development. Significantly, these studies indicate that the phase of thymocyte expansionoccurring before the onset of T cell receptor gene rearrangement is critically dependent upon, andmediated by the high affinity receptor for IL-7.", "metadata": {}}
+{"_id": "9161988", "title": "", "text": "Immune Activation with HIV VaccinesThe development of a safe and effective HIV vaccine is perhaps themost important and challenging goal remaining in HIV-AIDS research. Recent progress using a poxvirusvector prime and envelope protein boost strategy demonstrated a modest but statistically significant levelof efficacy and established the concept that a vaccine could prevent HIV infection (1), and approaches toboost durability and efficacy are currently in the planning stages (2). But the results of two vaccineconcepts based on recombinant adenovirus serotype-5 (rAd5) (3–5) pointed to a potential majorproblem—that such vaccines might increase susceptibility to HIV infection. This also raised the questionof whether the problem extends to some or all of the other recombinant adenovirus vectors currently indevelopment or to other vector-based vaccines.", "metadata": {}}
+{"_id": "9164724", "title": "", "text": "Distribution of dystrophin- and utrophin-associated protein complexes during activation of humanneutrophils.OBJECTIVE Dystrophins, utrophins, and their associated proteins are involved in structuraland signaling roles in nonmuscle tissues; however, description of these proteins in neutrophils remainedunexplored. Therefore we characterize the pattern expression, and the cellular distribution of dystrophinand utrophin gene products and dystrophin-associated proteins (i.e., beta-dystroglycan,alpha-syntrophin, and alpha-dystrobrevins) in relation to actin filaments in resting and activated withformyl-methionyl-leucyl-phenylalanine human neutrophils. MATERIALS AND METHODS Resting andfMLP-activated human neutrophils were analyzed by immunoblot and by confocal microscopy analysis.Immunoprecipitation assays were performed to corroborate the presence of protein complexes. RESULTSImmunoprecipitation assays and confocal analysis demonstrated the presence of twodystrophin-associated protein complexes in resting and activated neutrophils: the former formed byDp71d/Dp71Delta(110)(m) and dystrophin-associated proteins (beta-dystroglycan, alpha-syntrophin,alpha-dystrobrevin-1, and -2), while the latter contains Up400, instead of Dp71d/Dp71Delta(110)(m), asa central component of the dystrophin-associated protein complexes (DAPC). Confocal analysis alsoshowed the subcellular redistribution of Dp71d/Dp71Delta(110)(m) approximately DAPC and Up400approximately DAPC in F-actin-based structures displayed during activation process with fMLP.CONCLUSIONS Our study showed the existence of two protein complexes formed byDp71d/Dp71Delta(110)(m) or Up400 associated with DAPs in resting and fMLP-treated humanpolymorphonuclears. The interaction of these complexes with the actin cytoskeleton is indicative of theirdynamic participation in the chemotaxis process.", "metadata": {}}
+{"_id": "9167230", "title": "", "text": "Global and regional burden of hospital admissions for severe acute lower respiratory infections in youngchildren in 2010: a systematic analysisBACKGROUND The annual number of hospital admissions andin-hospital deaths due to severe acute lower respiratory infections (ALRI) in young children worldwide isunknown. We aimed to estimate the incidence of admissions and deaths for such infections in childrenyounger than 5 years in 2010. METHODS We estimated the incidence of admissions for severe and verysevere ALRI in children younger than 5 years, stratified by age and region, with data from a systematicreview of studies published between Jan 1, 1990, and March 31, 2012, and from 28 unpublishedpopulation-based studies. We applied these incidence estimates to population estimates for 2010, tocalculate the global and regional burden in children admitted with severe ALRI in that year. We estimatedin-hospital mortality due to severe and very severe ALRI by combining incidence estimates with casefatality ratios from hospital-based studies. FINDINGS We identified 89 eligible studies and estimated thatin 2010, 11·9 million (95% CI 10·3-13·9 million) episodes of severe and 3·0 million (2·1-4·2 million)episodes of very severe ALRI resulted in hospital admissions in young children worldwide. Incidence washigher in boys than in girls, the sex disparity being greatest in South Asian studies. On the basis of datafrom 37 hospital studies reporting case fatality ratios for severe ALRI, we estimated that roughly 265,000(95% CI 160,000-450,000) in-hospital deaths took place in young children, with 99% of these deaths indeveloping countries. Therefore, the data suggest that although 62% of children with severe ALRI aretreated in hospitals, 81% of deaths happen outside hospitals. INTERPRETATION Severe ALRI is asubstantial burden on health services worldwide and a major cause of hospital referral and admission inyoung children. Improved hospital access and reduced inequities, such as those related to sex and ruralstatus, could substantially decrease mortality related to such infection. Community-based managementof severe disease could be an important complementary strategy to reduce pneumonia mortality andhealth inequities. FUNDING WHO.", "metadata": {}}
+{"_id": "9169645", "title": "", "text": "Identification of a novel p53 functional domain that is necessary for mediating apoptosis.The ability ofp53 to induce apoptosis requires its sequence-specific DNA binding activity; however, thetransactivation-deficient p53(Gln22-Ser23) can still induce apoptosis. Previously, we have shown that theregion between residues 23 and 97 in p53 is necessary for such activity. In an effort to more preciselymap a domain necessary for apoptosis within the N terminus, we found that deletion of the N-terminal 23amino acids compromises, but does not abolish, p53 induction of apoptosis. Surprisingly, p53(Delta1-42),which lacks the N-terminal 42 amino acids and the previously defined activation domain, retains theability to induce apoptosis to an even higher level than wild-type p53. A more extensive deletion, whicheliminates the N-terminal 63 amino acids, renders p53 completely inert in mediating apoptosis. Inaddition, we found that both p53(Delta1-42) and p53(Gln22-Ser23) can activate a subset of cellular p53targets. Furthermore, we showed that residues 53 and 54 are critical for the apoptotic and transcriptionalactivities of both p53(Delta1-42) and p53(Gln22-Ser23). Taken together, these data suggest that withinresidues 43-63 lie an apoptotic domain as well as another transcriptional activation domain. We thereforepostulate that the apoptotic activity in p53(Gln22-Ser23) and p53(Delta1-42) is stilltranscription-dependent.", "metadata": {}}
+{"_id": "9171913", "title": "", "text": "Risk of breast cancer in relation to blood lipids: a prospective study of 31,209 Norwegian womenIn thisprospective study, the relationship between blood lipids and breast cancer risk was examined. Between1977 and 1983, 31,209 Norwegian women, 20 to 54 years of age, attended a health screening carriedout by the Norwegian National Health Screening Services. The screening consisted of a questionnaire,anthropometric measurements, and nonfasting blood drawn for analysis of total serum cholesterol (TC),triglyceride (TG), and high density lipoprotein (HDL) cholesterol. Low density lipoprotein (LDL) cholesterolwas calculated by the Friedewald's formula. During the seven to 13 years of follow-up, 302 breast cancercases were identified by linkage to the Norwegian Cancer Registry. After adjustment for some of theknown risk factors of breast cancer, the relative risk of women in the highest quartile of TC comparedwith women in the lowest quartile was 0.87 (95 percent confidence interval [CI]=0.61–1.23). Thecorresponding relative risks and CIs were 0.82 (CI=0.58–1.16) for TG, 1.02 (CI=0.73–1.42) for HDL, and0.93 (CI=0.67–1.29) for LDL. No association between breast cancer risk and blood lipids was found in thetotal population, nor when the data were divided into those diagnosed before or after the age of 50 as adividing line between pre- and postmenopausal diagnosis.", "metadata": {}}
+{"_id": "9178310", "title": "", "text": "Involvement of lysosomal dysfunction in autophagosome accumulation and early pathologies in adiposetissue of obese miceWhether obesity accelerates or suppresses autophagy in adipose tissue is stilldebatable. To clarify dysregulation of autophagy and its role in pathologies of obese adipose tissue, wefocused on lysosomal function, protease maturation and activity, both in vivo and in vitro. First, weshowed that autophagosome formation was accelerated, but autophagic clearance was impaired in obeseadipose tissue. We also found protein and activity levels of CTSL (cathepsin L) were suppressed in obeseadipose tissue, while the activity of CTSB (cathepsin B) was significantly enhanced. Moreover, cellularsenescence and inflammasomes were activated in obese adipose tissue. In 3T3L1 adipocytes,downregulation of CTSL deteriorated autophagic clearance, upregulated expression of CTSB, promotedcellular senescence and activated inflammasomes. Upregulation of CTSB promoted additional activationof inflammasomes. Therefore, we suggest lysosomal dysfunction observed in obese adipose tissue leadsto lower autophagic clearance, resulting in autophagosome accumulation. Simultaneously, lysosomalabnormalities, including deteriorated CTSL function and compensatory activation of CTSB, caused cellularsenescence and inflammasome activation. Our findings strongly suggest lysosomal dysfunction isinvolved in early pathologies of obese adipose tissue.", "metadata": {}}
+{"_id": "9185195", "title": "", "text": "ARNO regulates VEGF-dependent tissue responses by stabilizing endothelial VEGFR-2 surfaceexpression.AIMS The vascular endothelial growth factor (VEGF) stimulates angiogenesis by induction ofvessel permeability, proliferation, and migration of endothelial cells, an important process in ischaemicdiseases. ADP-ribosylation factor (ARF) nucleotide-binding site opener (ARNO) (cytohesin-2) is a guanineexchange factor important for cellular signalling through ARF GTPases. However, a role for ARNO inVEGF-dependent endothelial processes has so far not been documented. Therefore, we investigatedwhether ARNO has a role in VEGF-dependent activation of endothelial cells and thus vessel permeability.METHODS AND RESULTS ARNO expression was observed in endothelial cells in vitro by RT-PCR, westernblotting, and immunofluorescence as well as ex vivo by immunohistochemical staining of mouse aorta.Treatment with the cytohesin inhibitor SecinH3 or with an ARNO siRNA prevented VEGF-dependent Aktactivation, assessed by detection of phosphorylated Akt, and proliferation of endothelial cells in vitro,measured by methylthiazoletetrazolium (MTT) reduction. In addition, ARNO suppression reducedVEGF-induced permeability in vessels of the mouse (C57BL/6) cremaster muscle in vivo, as measured byextravasation of fluorescein isothiocyanate (FITC)-dextran. Moreover, ARNO knock-down acceleratedligand-induced reduction in vascular endothelial growth factor receptor-2 (VEGFR-2) surface expression,internalization, and degradation, as assessed by flow cytometry and western blotting, respectively.CONCLUSION Our findings indicate an important and novel role for endothelial ARNO in VEGF-dependentinitiation of angiogenesis by regulation of VEGFR-2 internalization in endothelial cells, resulting in theactivation of the Akt pathway, vessel permeability, and ultimately endothelial proliferation. Thus, ARNOmay be a new essential player in endothelial signalling and angiogenesis.", "metadata": {}}
+{"_id": "9194077", "title": "", "text": "Effects of Hypoxia and Oxidative Stress on Expression of Neprilysin in Human Neuroblastoma Cells andRat Cortical Neurones and AstrocytesPathogenesis of Alzheimer’s disease (AD), which is characterised byaccumulation of extracellular deposits of β-amyloid peptide (Aβ) in the brain, has recently been linked tovascular disorders such as ischemia and stroke. Aβ is constantly produced in the brain from amyloidprecursor protein (APP) through its cleavage by β- and γ-secretases and certain Aβ species are toxic forneurones. The brain has an endogenous mechanism of Aβ removal via proteolytic degradation and thezinc metalloproteinase neprilysin (NEP) is a critical regulator of Aβ concentration. Down-regulation of NEPcould predispose to AD. By comparing the effects of hypoxia and oxidative stress on expression andactivity of the Aβ-degrading enzyme NEP in human neuroblastoma NB7 cells and rat primary corticalneurones we have demonstrated that hypoxia reduced NEP expression at the protein and mRNA levels aswell as its activity. On contrary in astrocytes hypoxia increased NEP mRNA expression.", "metadata": {}}
+{"_id": "9196472", "title": "", "text": "Genetics and Beyond – The Transcriptome of Human Monocytes and Disease SusceptibilityBACKGROUNDVariability of gene expression in human may link gene sequence variability and phenotypes; however,non-genetic variations, alone or in combination with genetics, may also influence expression traits andhave a critical role in physiological and disease processes. METHODOLOGY/PRINCIPAL FINDINGS To getbetter insight into the overall variability of gene expression, we assessed the transcriptome of circulatingmonocytes, a key cell involved in immunity-related diseases and atherosclerosis, in 1,490 unrelatedindividuals and investigated its association with >675,000 SNPs and 10 common cardiovascular riskfactors. Out of 12,808 expressed genes, 2,745 expression quantitative trait loci were detected(P<5.78x10(-12)), most of them (90%) being cis-modulated. Extensive analyses showed thatassociations identified by genome-wide association studies of lipids, body mass index or blood pressurewere rarely compatible with a mediation by monocyte expression level at the locus. At a study-wide level(P<3.9x10(-7)), 1,662 expression traits (13.0%) were significantly associated with at least one riskfactor. Genome-wide interaction analyses suggested that genetic variability and risk factors mostly actedadditively on gene expression. Because of the structure of correlation among expression traits, thevariability of risk factors could be characterized by a limited set of independent gene expressions whichmay have biological and clinical relevance. For example expression traits associated with cigarettesmoking were more strongly associated with carotid atherosclerosis than smoking itself.CONCLUSIONS/SIGNIFICANCE This study demonstrates that the monocyte transcriptome is a potentintegrator of genetic and non-genetic influences of relevance for disease pathophysiology and riskassessment.", "metadata": {}}
+{"_id": "9197092", "title": "", "text": "Molecular mechanisms of (-)-epicatechin and chlorogenic acid on the regulation of the apoptotic andsurvival/proliferation pathways in a human hepatoma cell line.Dietary polyphenols have been associatedwith reduced risk of chronic diseases, but the precise molecular mechanisms of protection remainunclear. This work was aimed at studying the effect of (-)-epicatechin (EC) and chlorogenic acid (CGA) onthe regulation of apoptotic and survival/proliferation pathways in a human hepatoma cell line (HepG2).EC or CGA treatment for 18 h had a slight effect on cell viability and decreased reactive oxygen speciesformation, and EC alone promoted cell proliferation, whereas CGA increased glutathione levels. Phenolsneither induced the caspase cascade for apoptosis nor affected expression levels of Bcl-xL or Bax. Asustained activation of the major survival signals AKT/PI-3-kinase and ERK was shown in EC-treatedcells, rather than in CGA-exposed cells. These data suggest that EC and CGA have no effect on apoptosisand enhance the intrinsic cellular tolerance against oxidative insults either by activatingsurvival/proliferation pathways or by increasing antioxidant potential in HepG2.", "metadata": {}}
+{"_id": "9197786", "title": "", "text": "Wnt5a mediates nerve growth factor-dependent axonal branching and growth in developing sympatheticneurons.Nerve growth factor (NGF) is a potent survival and axon growth factor for neuronal populationsin the peripheral nervous system. Although the mechanisms by which target-derived NGF influencessurvival of innervating neurons have been extensively investigated, its regulation of axonal growth andtarget innervation are just being elucidated. Here, we identify Wnt5a, a member of the Wnt family ofsecreted growth factors, as a key downstream effector of NGF in mediating axonal branching and growthin developing sympathetic neurons. Wnt5a is robustly expressed in sympathetic neurons when theiraxons are innervating NGF-expressing targets. NGF:TrkA signaling enhances neuronal expression ofWnt5a. Wnt5a rapidly induces axon branching while it has a long-term effect on promoting axonextension. Loss of Wnt5a function revealed that it is necessary for NGF-dependent axonal branching andgrowth, but not survival, in vitro. Furthermore, Wnt5a(-/-) mice display reduced innervation ofNGF-expressing target tissues, and a subsequent increase in neuronal apoptosis, in vivo. Wnt5a functionsin developing sympathetic neurons by locally activating protein kinase C in axons. Together, our findingsdefine a novel regulatory pathway in which Wnt5a, expressed in sympathetic neurons in response totarget-derived NGF, regulates innervation of peripheral targets.", "metadata": {}}
+{"_id": "9199796", "title": "", "text": "The Snf1 kinase controls glucose repression in yeast by modulating interactions between the Mig1repressor and the Cyc8-Tup1 co-repressor.Among lower eukaryotes, glucose repression is a conserved,widely spread mechanism regulating carbon catabolism. The yeast Snf1 kinase, the Mig1 DNA-bindingrepressor and the Mig1-interacting co-repressor complex Cyc8(Ssn6)-Tup1 are central components ofthis pathway. Previous experiments suggested that cytoplasmic translocation of Mig1, upon itsphosphorylation by Snf1 in the nucleus, is the key regulatory step for releasing glucose repression. In thisreport we re-evaluate this model. We establish the coordinated repressive action of Mig1 and Cyc8-Tup1on GAL1 transcription, but we find that Cyc8-Tup1 is not tethered by Mig1 to the promoter DNA. Wedemonstrate that both negative regulators occupy GAL1 continuously under either repression oractivation conditions, although the majority of the Mig1 is redistributed to the cytoplasm upon activation.We show that Snf1-dependent phosphorylation of Mig1 abolishes interaction with Cyc8-Tup1, and wepropose that regulation of this interaction, not the Mig1 cytoplasmic localization, is the molecular switchthat controls transcriptional repression/de-repression.", "metadata": {}}
+{"_id": "9211173", "title": "", "text": "ARID1A mutations in endometriosis-associated ovarian carcinomas.BACKGROUND Ovarian clear-cell andendometrioid carcinomas may arise from endometriosis, but the molecular events involved in thistransformation have not been described. METHODS We sequenced the whole transcriptomes of 18ovarian clear-cell carcinomas and 1 ovarian clear-cell carcinoma cell line and found somatic mutations inARID1A (the AT-rich interactive domain 1A [SWI-like] gene) in 6 of the samples. ARID1A encodesBAF250a, a key component of the SWI–SNF chromatin remodeling complex. We sequenced ARID1A in anadditional 210 ovarian carcinomas and a second ovarian clear-cell carcinoma cell line and measuredBAF250a expression by means of immunohistochemical analysis in an additional 455 ovarian carcinomas.RESULTS ARID1A mutations were seen in 55 of 119 ovarian clear-cell carcinomas (46%), 10 of 33endometrioid carcinomas (30%), and none of the 76 high-grade serous ovarian carcinomas. Seventeencarcinomas had two somatic mutations each. Loss of the BAF250a protein correlated strongly with theovarian clear-cell carcinoma and endometrioid carcinoma subtypes and the presence of ARID1Amutations. In two patients, ARID1A mutations and loss of BAF250a expression were evident in the tumorand contiguous atypical endometriosis but not in distant endometriotic lesions. CONCLUSIONS These dataimplicate ARID1A as a tumor-suppressor gene frequently disrupted in ovarian clear-cell and endometrioidcarcinomas. Since ARID1A mutation and loss of BAF250a can be seen in the preneoplastic lesions, wespeculate that this is an early event in the transformation of endometriosis into cancer. (Funded by theBritish Columbia Cancer Foundation and the Vancouver General Hospital–University of British ColumbiaHospital Foundation.).", "metadata": {}}
+{"_id": "9217800", "title": "", "text": "The ALS-associated proteins FUS and TDP-43 function together to affect Drosophila locomotion and lifespan.The fatal adult motor neuron disease amyotrophic lateral sclerosis (ALS) shares some clinical andpathological overlap with frontotemporal dementia (FTD), an early-onset neurodegenerative disorder. TheRNA/DNA-binding proteins fused in sarcoma (FUS; also known as TLS) and TAR DNA binding protein-43(TDP-43) have recently been shown to be genetically and pathologically associated with familial forms ofALS and FTD. It is currently unknown whether perturbation of these proteins results in disease throughmechanisms that are independent of normal protein function or via the pathophysiological disruption ofmolecular processes in which they are both critical. Here, we report that Drosophila mutants in which thehomolog of FUS is disrupted exhibit decreased adult viability, diminished locomotor speed, and reducedlife span compared with controls. These phenotypes were fully rescued by wild-type human FUS, but notALS-associated mutant FUS proteins. A mutant of the Drosophila homolog of TDP-43 had similar, butmore severe, deficits. Through cross-rescue analysis, we demonstrated that FUS acted together with anddownstream of TDP-43 in a common genetic pathway in neurons. Furthermore, we found that theseproteins associated with each other in an RNA-dependent complex. Our results establish that FUS andTDP-43 function together in vivo and suggest that molecular pathways requiring the combined activitiesof both of these proteins may be disrupted in ALS and FTD.", "metadata": {}}
+{"_id": "9225850", "title": "", "text": "Non-canonical PI3K-Cdc42-Pak-Mek-Erk Signaling Promotes Immune-Complex-Induced Apoptosis inHuman NeutrophilsNeutrophils are peripheral blood leukocytes that represent the first line of immune celldefense against bacterial and fungal infections but are also crucial players in the generation of theinflammatory response. Many neutrophil cell surface receptors regulate important cellular processes viaactivation of agonist-activated PI3Ks. We show here that activation of human neutrophils with insolubleimmune complexes drives a previously uncharacterized, PI3K-dependent, non-canonical, pro-apoptoticsignaling pathway, FcγR-PI3Kβ/δ-Cdc42-Pak-Mek-Erk. This is a rare demonstration ofRas/Raf-independent activation of Erk and of PI3K-mediated activation of Cdc42. In addition,comparative analysis of immune-complex- and fMLF-induced signaling uncovers key differences inpathways used by human and murine neutrophils. The non-canonical pathway we identify in this studymay be important for the resolution of inflammation in chronic inflammatory diseases that rely onimmune-complex-driven neutrophil activation.", "metadata": {}}
+{"_id": "9226649", "title": "", "text": "Inflammation-induced tumorigenesis in the colon is regulated by caspase-1 and NLRC4.Chronicinflammation is a known risk factor for tumorigenesis, yet the precise mechanism of this association iscurrently unknown. The inflammasome, a multiprotein complex formed by NOD-like receptor (NLR)family members, has recently been shown to orchestrate multiple innate and adaptive immuneresponses, yet its potential role in inflammation-induced cancer has been little studied. Using theazoxymethane and dextran sodium sulfate colitis-associated colorectal cancer model, we show thatcaspase-1-deficient (Casp1(-/-)) mice have enhanced tumor formation. Surprisingly, the role ofcaspase-1 in tumorigenesis was not through regulation of colonic inflammation, but rather throughregulation of colonic epithelial cell proliferation and apoptosis. Consequently, caspase-1-deficient micedemonstrate increased colonic epithelial cell proliferation in early stages of injury-induced tumorformation and reduced apoptosis in advanced tumors. We suggest a model in which the NLRC4inflammasome is central to colonic inflammation-induced tumor formation through regulation of epithelialcell response to injury.", "metadata": {}}
+{"_id": "9239963", "title": "", "text": "The nuclear receptors SF1 and LRH1 are expressed in endometrial cancer cells and regulate steroidogenicgene transcription by cooperating with AP-1 factors.Excessive exposure to estradiol represents the mainrisk factor for endometrial cancer. The abnormally high estradiol levels in the endometrium of womenwith endometrial cancer are most likely due to overproduction by the tumour itself. Endometrial cancercells express the genes encoding the steroidogenic enzymes involved in estradiol synthesis. Here we usedRT-PCR and Western blot to show that the nuclear receptors SF1 and LRH1, two well-known regulators ofsteroidogenic gene expression in gonadal and adrenal cells, are also expressed in endometrial cancer celllines. By transient transfections, we found that SF1 and LRH1, but not the related nuclear receptorNUR77, can activate the promoters of three human steroidogenic genes: STAR, HSD3B2, and CYP19A1PII. Similarly, forskolin but not PMA, could activate all three promoters. In addition, we found that bothSF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known tobe associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation ofthe STAR, HSD3B2, and CYP19A1 PII promoters. All together, our data provide novel insights into themechanisms of steroidogenic gene expression in endometrial cancer cells and thus in the regulation ofestradiol biosynthesis by tumour cells.", "metadata": {}}
+{"_id": "9244474", "title": "", "text": "Dietary factors in chronic inflammation: food tolerances and intolerances of a New Zealand CaucasianCrohn's disease population.Diet is known to play a major role in the symptoms of the inflammatory boweldisease, Crohn's disease (CD). Although no single diet is appropriate to all individuals, most CD patientsare aware of foods that provide adverse or beneficial effects. This study seeks to categorise foods inrelation to their effects on symptoms of CD, in a New Zealand Caucasian population. Four hundred andforty-six subjects from two different centres in New Zealand were recruited into the study. An extensivedietary questionnaire (257 food items in 15 groups) recorded self-reported dietary tolerances andintolerances. Across each of the food groups, there were statistically significant differences amongresponses to foods. A two-dimensional graphical summary enabled stratification of foods according to theprobability that they will be either beneficial or detrimental. A small number of foods are frequentlyconsidered to be beneficial, including white fish, salmon and tuna, gluten-free products, oatmeal,bananas, boiled potatoes, sweet potatoes (kumara), pumpkin, soya milk, goat's milk and yoghurt. Foodsthat are typically considered detrimental include grapefruit, chilli or chilli sauce, corn and corn products,peanuts, cream, salami, curried foods, cola drinks, high energy drinks, beer, and red wine. For a numberof the food items, the same item that was beneficial for one group of subjects was detrimental to others;in particular soya milk, goat's milk, yoghurt, oatmeal, kiwifruit, prunes, apple, broccoli, cauliflower,linseed, pumpkin seed, sunflower seed, ginger and ginger products, beef, lamb, liver, and oily fish. It wasnot possible to identify a specific group of food items that should be avoided by all CD patients. The widerange of detrimental items suggests that dietary maintenance of remission is likely to be difficult, and toexclude a substantial number of foods. Personalised diets may be especially important to theseindividuals.", "metadata": {}}
+{"_id": "9254550", "title": "", "text": "Age as a risk factor for thrombocytopenia and anaemia in children treated for acute uncomplicatedfalciparum malaria.BACKGROUND & OBJECTIVES Anaemia is commonly observed in children withmalaria, but reports on leucocyte and platelet count abnormalities associated with malaria areinconsistent. This study examined the effect of age, gender, parasite density and temperature onhaematological parameters in children with acute uncomplicated malaria. METHODS Haematologicalparameters were determined in children with acute uncomplicated malaria, and these were correlatedwith age, sex, temperature and parasite density. Statistical analysis was done using SAS 9.1. RESULTSSix hundred and ninety five children with acute uncomplicated malaria participated in the study. Themean age was 51.7 months +/- 33.8. At presentation, anaemia occurred in 43.8% of the patients andchildren <5 yr had a significantly lower haematocrit (28.4% +/- 4.8) than that of older children (32.8%+/- 4.8) (p <0.001), but the haematocrit was not significantly different by days 14 and 28. There was nodifference between both sexes. Leucocytosis was more frequently seen than leucopenia (9.5% vs 3%).Thrombocytopenia was found in 59.3% of enrolled patients. More than half of the patients withthrombocytopenia had recovered by Day 28. Baseline platelet count was related to Day 14 (r = 0.6, p <0.0001) and Day 28 (r = 0.2, p = 0.0015) and the haematocrit on Day 28 (r = 0.12, p = 0.00197).Platelet count showed no correlation with temperature, parasite density and leucocyte count. Haematocritcorrelated with age (r = 0.4, p < 0.0001); but not with parasite density or temperature. Leucocyte countshowed no correlation with age or parasite density. CONCLUSION While thrombocytopenia was the mostcommon haematological finding and may be of diagnostic importance, anaemia and leucocytosis weremore common in the under fives.", "metadata": {}}
+{"_id": "9257019", "title": "", "text": "Discovery of endogenous catecholamines in lymphocytes and evidence for catecholamine regulation oflymphocyte function via an autocrine loop.Evidence has been obtained that catecholamines and theirmetabolites are present in single lymphocytes and extracts of T- and B-cell clones by use of capillaryelectrophoresis with electrochemical detection. Pharmacological inhibition of tyrosine hydroxylase reducesobserved catecholamine levels, suggesting catecholamine synthesis by lymphocytes. Intracellulardopamine levels are shown to be increased by extra-cellular dopamine, suggesting a cellular-uptakemechanism. Furthermore, incubation with either dopamine or L-dihydroxyphenylalanine, a precursor ofdopamine, results in a dose-dependent inhibition of lymphocyte proliferation and differentiation.Together, these results suggest the presence of an autocrine loop whereby lymphocytes down-regulatetheir own activity.", "metadata": {}}
+{"_id": "9272598", "title": "", "text": "Structure-based drug design identifies polythiophenes as antiprion compoundsPrions cause transmissiblespongiform encephalopathies for which no treatment exists. Prions consist of PrPSc, a misfolded andaggregated form of the cellular prion protein (PrPC). We explore the antiprion properties of luminescentconjugated polythiophenes (LCPs) that bind and stabilize ordered protein aggregates. By administering alibrary of structurally diverse LCPs to the brains of prion-infected mice via osmotic minipumps, we foundthat antiprion activity required a minimum of five thiophene rings bearing regularly spaced carboxyl sidegroups. Solid-state nuclear magnetic resonance analyses and molecular dynamics simulations revealedthat anionic side chains interacted with complementary, regularly spaced cationic amyloid residues ofmodel prions. These findings allowed us to extract structural rules governing the interaction betweenLCPs and protein aggregates, which we then used to design a new set of LCPs with optimized binding.The new set of LCPs showed robust prophylactic and therapeutic potency in prion-infected mice, with thelead compound extending survival by >80% and showing activity against both mouse and hamster prionsas well as efficacy upon intraperitoneal administration into mice. These results demonstrate the feasibilityof targeted chemical design of compounds that may be useful for treating diseases of aberrant proteinaggregation such as prion disease.", "metadata": {}}
+{"_id": "9274291", "title": "", "text": "Comparisons of patient and physician expectations for cancer survivorship care.PURPOSE To compareexpectations for cancer survivorship care between patients and their physicians and between primarycare providers (PCPs) and oncologists. METHODS Survivors and their physicians were surveyed toevaluate for expectations regarding physician participation in primary cancer follow-up, screening forother cancers, general preventive health, and management of comorbidities. RESULTS Of 992 eligiblesurvivors and 607 physicians surveyed, 535 (54%) and 378 (62%) were assessable, respectively. Amongphysician respondents, 255 (67%) were PCPs and 123 (33%) were oncologists. Comparing patients withtheir oncologists, expectations were highly discrepant for screening for cancers other than the index one(agreement rate, 29%), with patients anticipating significantly more oncologist involvement. Betweenpatients and their PCPs, expectations were most incongruent for primary cancer follow-up (agreementrate, 35%), with PCPs indicating they should contribute a much greater part to this aspect of care.Expectations between patients and their PCPs were generally more concordant than between patients andtheir oncologists. PCPs and oncologists showed high discordances in perceptions of their own roles forprimary cancer follow-up, cancer screening, and general preventive health (agreement rates of 3%, 44%,and 51%, respectively). In the case of primary cancer follow-up, both PCPs and oncologists indicatedthey should carry substantial responsibility for this task. CONCLUSION Patients and physicians havediscordant expectations with respect to the roles of PCPs and oncologists in cancer survivorship care.Uncertainties around physician roles and responsibilities can lead to deficiencies in care, supporting theneed to make survivorship care planning a standard component in cancer management.", "metadata": {}}
+{"_id": "9278263", "title": "", "text": "MHC class I antigen presentation: learning from viral evasion strategiesThe cell surface display ofpeptides by MHC class I molecules to lymphocytes provides the host with an important surveillancemechanism to protect against invading pathogens. However, in turn, viruses have evolved elegantstrategies to inhibit various stages of the MHC class I antigen presentation pathway and prevent thedisplay of viral peptides. This Review highlights how the elucidation of mechanisms of viral immuneevasion is important for advancing our understanding of virus–host interactions and can further ourknowledge of the MHC class I presentation pathway as well as other cellular pathways.", "metadata": {}}
+{"_id": "9283422", "title": "", "text": "T cell receptor-proximal signals are sustained in peripheral microclusters and terminated in the centralsupramolecular activation cluster.T cell receptor (TCR) signaling is initiated and sustained inmicroclusters; however, it's not known whether signaling also occurs in the TCR-rich centralsupramolecular activation cluster (cSMAC). We showed that the cSMAC formed by fusion of microclusterscontained more CD45 than microclusters and is a site enriched in lysobisphosphatidic acid, a lipidinvolved in sorting ubiquitinated membrane proteins for degradation. Calcium signaling via TCR wasblocked within 2 min by anti-MHCp treatment and 1 min by latrunculin-A treatment. TCR-MHCpinteractions in the cSMAC survived these perturbations for 10 min and hence were not sufficient tosustain signaling. TCR microclusters were also resistant to disruption by anti-MHCp and latrunculin-Atreatments. We propose that TCR signaling is sustained by stabilized microclusters and is terminated inthe cSMAC, a structure from which TCR are sorted for degradation. Our studies reveal a role for F-actin inTCR signaling beyond microcluster formation.", "metadata": {}}
+{"_id": "9285396", "title": "", "text": "The role of red cell distribution width in the prognosis of patients with gastric cancer.BACKGROUNDAlthough the red cell distribution width (RDW) has been reported as a reliable predictor of prognosis inseveral types of cancer, to our knowledge the prognostic value of RDW in gastric carcinoma has not beenstudied, so far. OBJECTIVE We aimed to investigate the role of red cell distribution width (RDW) inpredicting prognosis in gastric cancer patients. METHODS All gastric cancer patients who underwentcurative surgery (n= 172, 110M/62F) over a five-year study period were evaluated. Data ondemographics, preoperative RDW levels, tumor characteristics (early stage: I and II, advanced stage:IIIA-B-C), disease-free (DFS) and overall survival (OS) were retrospectively reviewed. Patients wereclassified as high RDW group (RDW ≥ 16, n= 62) or low RDW group (RDW < 16, n= 110). RESULTSOverall mortality and postoperative 60-day mortality in both groups were 55% and 14%, respectively. Aborderline significant association between RDW (0.063) and mortality was noted. Preoperative RDWlevels were significantly higher in patients with short-term mortality (17.9 ± 4.3 vs. 16 ± 3.2, p= 0.015).In high RDW group, the incidence of advanced gastric cancer was significantly higher (75 vs. 51%, p=0.002), whereas DFS (0.035) and OS (p= 0.04) were lower. CONCLUSION The frequency of advancedcancer was high in patients with high RDWvalues. High RDW values were strongly associated withshort-term mortality although only a borderline relationship with overall survival was observed.", "metadata": {}}
+{"_id": "9288638", "title": "", "text": "Vascular responsiveness in isolated perfused kidneys of diabetic hypertensive rats.OBJECTIVE The aim ofthis study was to investigate whether diabetes and hypertension cause additive effects in the responsesto various vasoconstrictor and vasodilator agents, in isolated perfused kidneys obtained fromstreptozotocin (STZ)-diabetic Wistar-Kyoto (WKY) rats and from diabetic spontaneously hypertensive rats(SHR). METHODS SHR and WKY rats were administered STZ 55 mg/kg by intravenous injection into alateral tail vein at age 12 weeks. Eight weeks later the kidneys were isolated and perfused via the leftrenal artery with a physiological salt solution. Renal perfusion pressure was measured continuously.Concentration response curves were plotted for various vasoconstrictor and vasodilator agents. RESULTSBoth the diabetic and the hypertensive state were associated with an increased wet kidney weight. Thecontractile responses of the renal arterial system to phenylephrine (PhE), serotonin (5-HT) andangiotensin II (Ang II) in terms both of the maximal rise in perfusion pressure (mmHg) and of thesensitivity (log EC50) were the same in preparations from diabetic WKY rats and in those fromnormoglycaemic WKY rats. The maximal contractile responses both to PhE and to Ang II were enhancedin kidneys from SHR compared with those in kidneys from their normotensive controls, whereassimultaneously occurring diabetes impaired this sensitization. After precontraction with 3 x 10(-6) mol/lPhE both endothelium-dependent (methacholine) and endothelium-independent (sodium nitroprusside)vasodilator drugs caused the same vasodilator response in the preparations taken from the four groups ofanimals. CONCLUSION In isolated perfused kidneys obtained from STZ-diabetic WKY rats and SHR, theisolated diabetic state did not influence the vasoconstriction caused by various agonists. However, theenhanced vascular reactivity in the hypertensive state was blunted by simultaneously occurring diabetesmellitus. Endothelium-dependent and -independent vasorelaxation in this model was not affected neitherby the hypertensive nor by the diabetic state.", "metadata": {}}
+{"_id": "9291596", "title": "", "text": "DNA replication is required To elicit cellular responses to psoralen-induced DNA interstrandcross-links.Following introduction of DNA interstrand cross-links (ICLs), mammalian cells displaychromosome breakage or cell cycle delay with a 4N DNA content. To further understand the nature of thedelay, previously described as a G(2)/M arrest, we developed a protocol to generate ICLs during specificintervals of the cell cycle. Synchronous populations of G(1), S, and G(2) cells were treated withphotoactivated 4'-hydroxymethyl-4,5',8-trimethylpsoralen (HMT) and scored for normal passage intomitosis. In contrast to what was found for ionizing radiation, ICLs introduced during G(2) did not result ina G(2)/M arrest, mitotic arrest, or chromosome breakage. Rather, subsequent passage through S phasewas required to trigger both chromosome breakage and arrest in the next cell cycle. Similarly, ICLsintroduced during G(1) did not cause a G(1)/S arrest. We conclude that DNA replication is required toelicit the cellular responses of cell cycle arrest and genomic instability after psoralen-induced ICLs. Inprimary human fibroblasts, the 4N DNA content cell cycle arrest triggered by ICLs was long lasting butreversible. Kinetic analysis suggested that these cells could remove up to approximately 2,500ICLs/genome at an average rate of 11 ICLs/genome/h.", "metadata": {}}
+{"_id": "9291668", "title": "", "text": "DNA methylation and healthy human agingThe process of aging results in a host of changes at thecellular and molecular levels, which include senescence, telomere shortening, and changes in geneexpression. Epigenetic patterns also change over the lifespan, suggesting that epigenetic changes mayconstitute an important component of the aging process. The epigenetic mark that has been most highlystudied is DNA methylation, the presence of methyl groups at CpG dinucleotides. These dinucleotides areoften located near gene promoters and associate with gene expression levels. Early studies indicated thatglobal levels of DNA methylation increase over the first few years of life and then decrease beginning inlate adulthood. Recently, with the advent of microarray and next-generation sequencing technologies,increases in variability of DNA methylation with age have been observed, and a number of site-specificpatterns have been identified. It has also been shown that certain CpG sites are highly associated withage, to the extent that prediction models using a small number of these sites can accurately predict thechronological age of the donor. Together, these observations point to the existence of two phenomenathat both contribute to age-related DNA methylation changes: epigenetic drift and the epigenetic clock.In this review, we focus on healthy human aging throughout the lifetime and discuss the dynamics ofDNA methylation as well as how interactions between the genome, environment, and the epigenomeinfluence aging rates. We also discuss the impact of determining 'epigenetic age' for human health andoutline some important caveats to existing and future studies.", "metadata": {}}
+{"_id": "9301606", "title": "", "text": "Parathyroid hormone-induced E4BP4/NFIL3 down-regulates transcription in osteoblasts.Parathyroidhormone (PTH), a major regulator of bone metabolism, activates the PTHR1 receptor on the osteoblastplasma membrane to initiate signaling and induce transcription of primary response genes. Subsequently,primary genes with transcriptional activity regulate expression of downstream PTH targets. We haveidentified the adenovirus E4 promoter-binding protein/nuclear factor regulated by IL-3 (E4bp4) as aPTH-induced primary gene in osteoblasts. E4BP4 is a basic leucine zipper (bZIP) transcription factor thatrepresses or activates transcription in non-osteoblastic cells. We report here that PTH rapidly andtransiently induced E4bp4 mRNA in osteoblastic cells and that this induction did not require proteinsynthesis. PTH also induced E4BP4 protein synthesis and E4BP4 binding to a consensus but not to amutant E4BP4 response element (EBPRE). E4BP4 overexpression inhibited an EBPRE-containingpromoter-reporter construct, whereas PTH treatment attenuated activity of the same construct in primarymouse osteoblasts. Finally, E4BP4 overexpression inhibited PTH-induced activity of a cyclooxygenase-2promoter-reporter construct. Our data suggest a role for E4BP4 in attenuation of PTH target genetranscription in osteoblasts.", "metadata": {}}
+{"_id": "9304312", "title": "", "text": "Molecular basis of synaptic vesicle cargo recognition by the endocytic sorting adaptor stonin 2Synaptictransmission depends on clathrin-mediated recycling of synaptic vesicles (SVs). How select SV proteinsare targeted for internalization has remained elusive. Stonins are evolutionarily conserved adaptorsdedicated to endocytic sorting of the SV protein synaptotagmin. Our data identify the moleculardeterminants for recognition of synaptotagmin by stonin 2 or its Caenorhabditis elegans orthologueUNC-41B. The interaction involves the direct association of clusters of basic residues on the surface of thecytoplasmic domain of synaptotagmin 1 and a beta strand within the mu-homology domain of stonin 2.Mutation of K783, Y784, and E785 to alanine within this stonin 2 beta strand results in failure of themutant stonin protein to associate with synaptotagmin, to accumulate at synapses, and to facilitatesynaptotagmin internalization. Synaptotagmin-binding-defective UNC-41B is unable to rescue paralysis inC. elegans stonin mutant animals, suggesting that the mechanism of stonin-mediated SV cargorecognition is conserved from worms to mammals.", "metadata": {}}
+{"_id": "9306247", "title": "", "text": "Size separation of circulatory DNA in maternal plasma permits ready detection of fetal DNApolymorphisms.BACKGROUND Analysis of fetal DNA in maternal plasma has recently been introduced asa new method for noninvasive prenatal diagnosis, particularly for the analysis of fetal genetic traits,which are absent from the maternal genome, e.g., RHD or Y-chromosome-specific sequences. To date,the analysis of other fetal genetic traits has been more problematic because of the overwhelmingpresence of maternal DNA sequences in the circulation. We examined whether different biochemicalproperties can be discerned between fetal and maternal circulatory DNA. METHODS Plasma DNA wasexamined by agarose gel electrophoresis. The fractions of fetal and maternal DNA in size-fractionatedfragments were assayed by real-time PCR. The determination of paternally and maternally inherited fetalgenetic traits was examined by use of highly polymorphic chromosome-21-specific microsatellitemarkers. RESULTS Size fractionation of circulatory DNA indicated that the major portion of cell-free fetalDNA had an approximate molecular size of <0.3 kb, whereas maternally derived sequences were, onaverage, considerably larger than 1 kb. Analysis of size-fractionated DNA (</=0.3 kb) from maternalplasma samples facilitated the ready detection of paternally and maternally inherited microsatellitemarkers. CONCLUSIONS Circulatory fetal DNA can be enriched by size selection of fragment sizes lessthan approximately 0.3 kb. Such selection permits easier analysis of both paternally and maternallyinherited DNA polymorphisms.", "metadata": {}}
+{"_id": "9310407", "title": "", "text": "The intravascular volume effect of Ringer's lactate is below 20%: a prospective study inhumansINTRODUCTION Isotonic crystalloids play a central role in perioperative fluid management.Isooncotic preparations of colloids (for example, human albumin or hydroxyethyl starch) remain nearlycompletely intravascular when infused to compensate for acute blood losses. Recent data wereinterpreted to indicate a comparable intravascular volume effect for crystalloids, challenging theoccasionally suggested advantage of using colloids to treat hypovolemia. General physiological knowledgeand clinical experience, however, suggest otherwise. METHODS In a prospective study, double-tracerblood volume measurements were performed before and after intended normovolemic hemodilution inten female adults, simultaneously substituting the three-fold amount of withdrawn blood with Ringer'slactate. Any originated deficits were substituted with half the volume of 20% human albumin, followed bya further assessment of blood volume. To assess significance between the measurements, repeatedmeasures analysis of variance (ANOVA) according to Fisher were performed. If significant results wereshown, paired t tests (according to Student) for the singular measurements were taken. P < 0.05 wasconsidered to be significant. RESULTS A total of 1,097 ± 285 ml of whole blood were withdrawn (641 ±155 ml/m(2) body surface area) and simultaneously replaced by 3,430 ± 806 ml of Ringer's lactate. Allpatients showed a significant decrease in blood volume after hemodilution (-459 ± 185 ml; P < 0.05) thatdid not involve relevant hemodynamical changes, and a significant increase in interstitial water content(+2,157 ± 606 ml; P < 0.05). The volume effect of Ringer's lactate was 17 ± 10%. The infusion of 245 ±64 ml of 20% human albumin in this situation restored blood volume back to baseline values, the volumeeffect being 184 ± 63%. CONCLUSIONS Substitution of isolated intravascular deficits in cardiopulmonaryhealthy adults with the three-fold amount of Ringer's lactate impedes maintenance of intravascularnormovolemia. The main side effect was an impressive interstitial fluid accumulation, which was partlyrestored by the intravenous infusion of 20% human albumin. We recommend to substitute the five-foldamount of crystalloids or to use an isooncotic preparation in the face of acute bleeding in patients whereedema prevention might be advantageous.", "metadata": {}}
+{"_id": "9315213", "title": "", "text": "Fibroblast Growth Factor 21 Prevents Atherosclerosis by Suppression of Hepatic Sterol RegulatoryElement-Binding Protein-2 and Induction of Adiponectin in MiceBACKGROUND Fibroblast growth factor 21(FGF21) is a metabolic hormone with pleiotropic effects on glucose and lipid metabolism and insulinsensitivity. It acts as a key downstream target of both peroxisome proliferator-activated receptor α and γ,the agonists of which have been used for lipid lowering and insulin sensitization, respectively. However,the role of FGF21 in the cardiovascular system remains elusive. METHODS AND RESULTS The roles ofFGF21 in atherosclerosis were investigated by evaluating the impact of FGF21 deficiency andreplenishment with recombinant FGF21 in apolipoprotein E(-/-) mice. FGF21 deficiency causes a markedexacerbation of atherosclerotic plaque formation and premature death in apolipoprotein E(-/-) mice,which is accompanied by hypoadiponectinemia and severe hypercholesterolemia. Replenishment ofFGF21 protects against atherosclerosis in apolipoprotein E(-/-)mice via 2 independent mechanisms,inducing the adipocyte production of adiponectin, which in turn acts on the blood vessels to inhibitneointima formation and macrophage inflammation, and suppressing the hepatic expression of thetranscription factor sterol regulatory element-binding protein-2, thereby leading to reduced cholesterolsynthesis and attenuation of hypercholesterolemia. Chronic treatment with adiponectin partially reversesatherosclerosis without obvious effects on hypercholesterolemia in FGF21-deficient apolipoprotein E(-/-)mice. By contrast, the cholesterol-lowering effects of FGF21 are abrogated by hepatic expression of sterolregulatory element-binding protein-2. CONCLUSIONS FGF21 protects against atherosclerosis via finetuning the multiorgan crosstalk among liver, adipose tissue, and blood vessels.", "metadata": {}}
+{"_id": "9317504", "title": "", "text": "VARNA: Interactive drawing and editing of the RNA secondary structureDESCRIPTION VARNA is a tool forthe automated drawing, visualization and annotation of the secondary structure of RNA, designed as acompanion software for web servers and databases. FEATURES VARNA implements four drawingalgorithms, supports input/output using the classic formats dbn, ct, bpseq and RNAML and exports thedrawing as five picture formats, either pixel-based (JPEG, PNG) or vector-based (SVG, EPS and XFIG). Italso allows manual modification and structural annotation of the resulting drawing using either aninteractive point and click approach, within a web server or through command-line arguments.AVAILABILITY VARNA is a free software, released under the terms of the GPLv3.0 license and available athttp://varna.lri.fr. SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformaticsonline.", "metadata": {}}
+{"_id": "9334631", "title": "", "text": "C-reactive protein decreases interleukin-10 secretion in activated human monocyte-derived macrophagesvia inhibition of cyclic AMP production.OBJECTIVE C-Reactive protein (CRP), a cardiovascular risk marker,could also participate in atherosclerosis. Atherosclerotic plaques express CRP and interleukin (IL)-10, amajor antiinflammatory cytokine. IL-10 deficiency results in increased lesion formation, whereas IL-10delivery attenuates lesions. We tested the effect of CRP on lipopolysaccharide (LPS)-induced IL-10secretion in human monocyte-derived macrophages (HMDMs). METHODS AND RESULTS Incubation ofHMDMs with CRP significantly decreased LPS-induced IL-10 mRNA and intracellular and secreted IL-10protein and destabilized IL-10 mRNA. Also, CRP alone increased secretion of IL-8, IL-6, and tumornecrosis factor from HMDMs and did not inhibit LPS-induced secretion of these cytokines. Fc gammareceptor I antibodies significantly reversed CRP-mediated IL-10 inhibition. CRP significantly decreasedintracellular cAMP, phospho-cAMP response element binding protein (pCREB), and adenyl cyclase activity.cAMP agonists reversed CRP-mediated IL-10 inhibition. Overexpression of wild-type and constitutivelyactive CREB in THP-1 cells revealed attenuation of the inhibitory effect of CRP on LPS-induced IL-10levels. CRP also inhibited hemoglobin:haptoglobin-induced IL-10 and heme oxygenase-1. Furthermore,administration of human CRP to rats significantly decreased IL-10 levels. CONCLUSIONS This studyprovides novel evidence that CRP, by decreasing IL-10 alters the antiinflammatory/proinflammatorybalance, accentuating inflammation, which is pivotal in atherothrombosis.", "metadata": {}}
+{"_id": "9379687", "title": "", "text": "The DNA polymerase activity of Pol ε holoenzyme is required for rapid and efficient chromosomal DNAreplication in Xenopus egg extractsDNA polymerase ε (Pol ε) is involved in DNA replication, repair, andcell-cycle checkpoint control in eukaryotic cells. Although the roles of replicative Pol α and Pol δ inchromosomal DNA replication are relatively well understood and well documented, the precise role of Polε in chromosomal DNA replication is not well understood. This study uses a Xenopus egg extract DNAreplication system to further elucidate the replicative role(s) played by Pol ε. Previous studies show thatthe initiation timing and elongation of chromosomal DNA replication are markedly impaired in Polε-depleted Xenopus egg extracts, with reduced accumulation of replicative intermediates and products.This study shows that normal replication is restored by addition of Pol ε holoenzyme to Pol ε-depletedextracts, but not by addition of polymerase-deficient forms of Pol ε, including polymerase point ordeletion mutants or incomplete enzyme complexes. Evidence is also provided that Pol ε holoenzymeinteracts directly with GINS, Cdc45p and Cut5p, each of which plays an important role in initiation ofchromosomal DNA replication in eukaryotic cells. These results indicate that the DNA polymerase activityof Pol ε holoenzyme plays an essential role in normal chromosomal DNA replication in Xenopus eggextracts. These are the first biochemical data to show the DNA polymerase activity of Pol ε holoenzyme isessential for chromosomal DNA replication in higher eukaryotes, unlike in yeasts.", "metadata": {}}
+{"_id": "9393969", "title": "", "text": "DAF-16/FOXO employs the chromatin remodeller SWI/SNF to promote stress resistance andlongevityOrganisms are constantly challenged by stresses and privations and require adaptive responsesfor their survival. The forkhead box O (FOXO) transcription factor DAF-16 (hereafter referred to asDAF-16/FOXO) is a central nexus in these responses, but despite its importance little is known about howit regulates its target genes. Proteomic identification of DAF-16/FOXO-binding partners in Caenorhabditiselegans and their subsequent functional evaluation by RNA interference revealed several candidateDAF-16/FOXO cofactors, most notably the chromatin remodeller SWI/SNF. DAF-16/FOXO and SWI/SNFform a complex and globally co-localize at DAF-16/FOXO target promoters. We show that specifically forgene activation, DAF-16/FOXO depends on SWI/SNF, facilitating SWI/SNF recruitment to targetpromoters, to activate transcription by presumed remodelling of local chromatin. For the animal, thistranslates into an essential role for SWI/SNF in DAF-16/FOXO-mediated processes, in particular dauerformation, stress resistance and the promotion of longevity. Thus, we give insight into the mechanisms ofDAF-16/FOXO-mediated transcriptional regulation and establish a critical link between ATP-dependentchromatin remodelling and lifespan regulation.", "metadata": {}}
+{"_id": "9394119", "title": "", "text": "Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovariancancer.IMPORTANCE Limited information about the relationship between specific mutations in BRCA1 orBRCA2 (BRCA1/2) and cancer risk exists. OBJECTIVE To identify mutation-specific cancer risks forcarriers of BRCA1/2. DESIGN, SETTING, AND PARTICIPANTS Observational study of women who wereascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 orBRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratiosfor breast and ovarian cancer based on mutation type, function, and nucleotide position. We alsoestimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk.EXPOSURES Mutations of BRCA1 or BRCA2. MAIN OUTCOMES AND MEASURES Breast and ovarian cancerrisks. RESULTS Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer,2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) withoutcancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682(6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. InBRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR =1.46; 95% CI, 1.22-1.74; P = 2 × 10(-6)), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P= .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% CI, 1.22-1.55; P = 6 × 10(-9)). We alsoidentified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) withRHR = 0.62 (95% CI, 0.56-0.70; P = 9 × 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95%CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 1.69-3.16; P = .00002).We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT(6174delT; RHR = 0.51; 95% CI, 0.44-0.60; P = 6 × 10(-17)). The second OCCR spanned c.6645 toc.7471 (OCCR2; RHR = 0.57; 95% CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediateddecay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancerdiagnosis for both BRCA1 and BRCA2 mutation carriers. CONCLUSIONS AND RELEVANCE Breast andovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, thesedata may have implications for risk assessment and cancer prevention decision making for carriers ofBRCA1 and BRCA2 mutations.", "metadata": {}}
+{"_id": "9412420", "title": "", "text": "Endogenous bone marrow MSCs are dynamic, fate-restricted participants in bone maintenance andregeneration.Mesenchymal stem cells (MSCs) commonly defined by in vitro functions have enteredclinical application despite little definition of their function in residence. Here, we report geneticpulse-chase experiments that define osteoblastic cells as short-lived and nonreplicative, requiringreplenishment from bone-marrow-derived, Mx1(+) stromal cells with \"MSC\" features. These cells respondto tissue stress and migrate to sites of injury, supplying new osteoblasts during fracture healing. Singlecell transplantation yielded progeny that both preserve progenitor function and differentiate intoosteoblasts, producing new bone. They are capable of local and systemic translocation and serialtransplantation. While these cells meet current definitions of MSCs in vitro, they are osteolineagerestricted in vivo in growing and adult animals. Therefore, bone-marrow-derived MSCs may be aheterogeneous population with the Mx1(+) population, representing a highly dynamic and stressresponsive stem/progenitor cell population of fate-restricted potential that feeds the high cellreplacement demands of the adult skeleton.", "metadata": {}}
+{"_id": "9420732", "title": "", "text": "Dscam and DSCAM: complex genes in simple animals, complex animals yet simple genes.Cadherins andthe immunoglobulin (Ig) proteins give rise to a multitude of surface receptors, which function as diversecell adhesion molecules (CAMs) or signal-transducing receptors. These functions are ofteninterdependent, and rely on a high degree of specificity in homophilic binding as well as heterophilicinteractions. The Drosophila receptor Dscam is an exceptional example of homophilic binding specificityinvolved in a number of important biological processes, such as neural wiring and innate immunity.Combinatorial use of alternatively spliced Ig-domains enables the generation of an estimated 18,000isoform-specific homophilic receptor pairs. Although isoform diversity of Dscam is unique to arthropods,recent genetic analysis of vertebrate DSCAM (Down Syndrome Cell Adhesion Molecule) genes hasrevealed an intriguing conservation of molecular functions underlying neural wiring. This review coversthe multiple functions of Dscam across different species highlighting its remarkable versatility as well asits conserved basic functions in neural development. We discuss how an unprecedented expansion ofcomplex alternative splicing has been uniquely employed by arthropods to generate diverse surfacereceptors, important for cell-cell communication, molecular self-recognition in neurons, and innateimmune defenses. We end with a speculative hypothesis reconciling the striking differences in Dscam andDSCAM gene structures with their conserved functions in molecular recognition underlying neural circuitformation.", "metadata": {}}
+{"_id": "9433958", "title": "", "text": "Differential innate immune response programs in neuronal subtypes determine susceptibility to infectionin the brain by positive stranded RNA virusesAlthough susceptibility of neurons in the brain to microbialinfection is a major determinant of clinical outcome, little is known about the molecular factors governingthis vulnerability. Here we show that two types of neurons from distinct brain regions showed differentialpermissivity to replication of several positive-stranded RNA viruses. Granule cell neurons of thecerebellum and cortical neurons from the cerebral cortex have unique innate immune programs thatconfer differential susceptibility to viral infection ex vivo and in vivo. By transducing cortical neurons withgenes that were expressed more highly in granule cell neurons, we identified three interferon-stimulatedgenes (ISGs; Ifi27, Irg1 and Rsad2 (also known as Viperin)) that mediated the antiviral effects againstdifferent neurotropic viruses. Moreover, we found that the epigenetic state and microRNA(miRNA)-mediated regulation of ISGs correlates with enhanced antiviral response in granule cell neurons.Thus, neurons from evolutionarily distinct brain regions have unique innate immune signatures, whichprobably contribute to their relative permissiveness to infection.", "metadata": {}}
+{"_id": "9440748", "title": "", "text": "Small-airway obstruction and emphysema in chronic obstructive pulmonary disease.BACKGROUND Themajor sites of obstruction in chronic obstructive pulmonary disease (COPD) are small airways (<2 mm indiameter). We wanted to determine whether there was a relationship between small-airway obstructionand emphysematous destruction in COPD. METHODS We used multidetector computed tomography (CT)to compare the number of airways measuring 2.0 to 2.5 mm in 78 patients who had various stages ofCOPD, as judged by scoring on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) scale, inisolated lungs removed from patients with COPD who underwent lung transplantation, and in donor(control) lungs. MicroCT was used to measure the extent of emphysema (mean linear intercept), thenumber of terminal bronchioles per milliliter of lung volume, and the minimum diameters andcross-sectional areas of terminal bronchioles. RESULTS On multidetector CT, in samples from patientswith COPD, as compared with control samples, the number of airways measuring 2.0 to 2.5 mm indiameter was reduced in patients with GOLD stage 1 disease (P=0.001), GOLD stage 2 disease (P=0.02),and GOLD stage 3 or 4 disease (P<0.001). MicroCT of isolated samples of lungs removed from patientswith GOLD stage 4 disease showed a reduction of 81 to 99.7% in the total cross-sectional area ofterminal bronchioles and a reduction of 72 to 89% in the number of terminal bronchioles (P<0.001). Acomparison of the number of terminal bronchioles and dimensions at different levels of emphysematousdestruction (i.e., an increasing value for the mean linear intercept) showed that the narrowing and loss ofterminal bronchioles preceded emphysematous destruction in COPD (P<0.001). CONCLUSIONS Theseresults show that narrowing and disappearance of small conducting airways before the onset ofemphysematous destruction can explain the increased peripheral airway resistance reported in COPD.(Funded by the National Heart, Lung, and Blood Institute and others.).", "metadata": {}}
+{"_id": "9451052", "title": "", "text": "Stepwise Histone Replacement by SWR1 Requires Dual Activation with Histone H2A.Z and CanonicalNucleosomeHistone variant H2A.Z-containing nucleosomes are incorporated at most eukaryoticpromoters. This incorporation is mediated by the conserved SWR1 complex, which replaces histone H2Ain canonical nucleosomes with H2A.Z in an ATP-dependent manner. Here, we show thatpromoter-proximal nucleosomes are highly heterogeneous for H2A.Z in Saccharomyces cerevisiae, withsubstantial representation of nucleosomes containing one, two, or zero H2A.Z molecules. SWR1-catalyzedH2A.Z replacement in vitro occurs in a stepwise and unidirectional fashion, one H2A.Z-H2B dimer at atime, producing heterotypic nucleosomes as intermediates and homotypic H2A.Z nucleosomes as endproducts. The ATPase activity of SWR1 is specifically stimulated by H2A-containing nucleosomes withoutensuing histone H2A eviction. Remarkably, further addition of free H2A.Z-H2B dimer leads tohyperstimulation of ATPase activity, eviction of nucleosomal H2A-H2B, and deposition of H2A.Z-H2B.These results suggest that the combination of H2A-containing nucleosome and free H2A.Z-H2B dimeracting as both effector and substrate for SWR1 governs the specificity and outcome of the replacementreaction.", "metadata": {}}
+{"_id": "9451684", "title": "", "text": "Logic of the yeast metabolic cycle: temporal compartmentalization of cellular processes.Budding yeastgrown under continuous, nutrient-limited conditions exhibit robust, highly periodic cycles in the form ofrespiratory bursts. Microarray studies reveal that over half of the yeast genome is expressed periodicallyduring these metabolic cycles. Genes encoding proteins having a common function exhibit similartemporal expression patterns, and genes specifying functions associated with energy and metabolismtend to be expressed with exceptionally robust periodicity. Essential cellular and metabolic events occurin synchrony with the metabolic cycle, demonstrating that key processes in a simple eukaryotic cell arecompartmentalized in time.", "metadata": {}}
+{"_id": "9460704", "title": "", "text": "Molecular pathways: induction of polyploidy as a novel differentiation therapy for leukemia.Differentiationtherapy has emerged as a powerful way to target specific hematologic malignancies. One of the bestexamples is the use of all-trans retinoic acid (ATRA) in acute promyelocytic leukemia (APL), which hassignificantly improved the outcome for patients with this specific form of acute myeloid leukemia (AML).In considering how differentiation therapy could be used in other forms of AML, we predicted thatcompounds that induce terminal differentiation of megakaryocytes would be effective therapies for themegakaryocytic form of AML, named acute megakaryocytic leukemia (AMKL). We also speculated thatsuch agents would reduce the burden of abnormal hematopoietic cells in primary myelofibrosis and alterthe differentiation of megakaryocytes in myelodysplastic syndromes. Using a high-throughput chemicalscreening approach, we identified small molecules that promoted many features of terminalmegakaryocyte differentiation, including the induction of polyploidization, the process by which cellsaccumulate DNA to 32N or greater. As the induction of polyploidization is an irreversible process, cellsthat enter this form of the cell cycle do not divide again. Thus, this would be an effective way to reducethe tumor burden. Clinical studies with polyploidy inducers, such as aurora kinase A inhibitors, are underway for a wide variety of malignancies, whereas trials specifically for AMKL and PMF are in development.This novel form of differentiation therapy may be clinically available in the not-too-distant future. ClinCancer Res; 19(22); 6084-8. ©2013 AACR.", "metadata": {}}
+{"_id": "9478135", "title": "", "text": "Dual mutations in the AML1 and FLT3 genes are associated with leukemogenesis in acute myeloblasticleukemia of the M0 subtypePoint mutations of the transcription factor AML1 are associated withleukemogenesis in acute myeloblastic leukemia (AML). Internal tandem duplications (ITDs) in thejuxtamembrane domain and mutations in the second tyrosine kinase domain of the Fms-like tyrosinekinase 3 (FLT3) gene represent the most frequent genetic alterations in AML. However, such mutationsper se appear to be insufficient for leukemic transformation. To evaluate whether both AML1 and FLT3mutations contribute to leukemogenesis, we analyzed mutations of these genes in AML M0 subtype inwhom AML1 mutations were predominantly observed. Of 51 patients, eight showed a mutation in theRunt domain of the AML1 gene: one heterozygous missense mutation with normal function, fiveheterozygous frameshift mutations and two biallelic nonsense or frameshift mutations, resulting inhaploinsufficiency or complete loss of the AML1 activities. On the other hand, a total of 10 of 49 patientsexamined had the FLT3 mutation. We detected the FLT3 mutation in five of eight (63%) patients withAML1 mutation, whereas five of 41 (12%) without AML1 mutation showed the FLT3 mutation (P=0.0055).These observations suggest that reduced AML1 activities predispose cells to the acquisition of theactivating FLT3 mutation as a secondary event leading to full transformation in AML M0.", "metadata": {}}
+{"_id": "9483851", "title": "", "text": "Unravelling mechanisms of p53-mediated tumour suppressionp53 is a crucial tumour suppressor thatresponds to diverse stress signals by orchestrating specific cellular responses, including transient cellcycle arrest, cellular senescence and apoptosis, which are all processes associated with tumoursuppression. However, recent studies have challenged the relative importance of these canonical cellularresponses for p53-mediated tumour suppression and have highlighted roles for p53 in modulating othercellular processes, including metabolism, stem cell maintenance, invasion and metastasis, as well ascommunication within the tumour microenvironment. In this Opinion article, we discuss the roles ofclassical p53 functions, as well as emerging p53-regulated processes, in tumour suppression.", "metadata": {}}
+{"_id": "9486930", "title": "", "text": "Stem cell-related \"self-renewal\" signature and high epidermal growth factor receptor expressionassociated with resistance to concomitant chemoradiotherapy in glioblastoma.PURPOSE Glioblastomasare notorious for resistance to therapy, which has been attributed to DNA-repair proficiency, a multitudeof deregulated molecular pathways, and, more recently, to the particular biologic behavior of tumorstem-like cells. Here, we aimed to identify molecular profiles specific for treatment resistance to thecurrent standard of care of concomitant chemoradiotherapy with the alkylating agent temozolomide.PATIENTS AND METHODS Gene expression profiles of 80 glioblastomas were interrogated for associationswith resistance to therapy. Patients were treated within clinical trials testing the addition of concomitantand adjuvant temozolomide to radiotherapy. RESULTS An expression signature dominated by HOX genes,which comprises Prominin-1 (CD133), emerged as a predictor for poor survival in patients treated withconcomitant chemoradiotherapy (n = 42; hazard ratio = 2.69; 95% CI, 1.38 to 5.26; P = .004). Thisassociation could be validated in an independent data set. Provocatively, the HOX cluster was reminiscentof a \"self-renewal\" signature (P = .008; Gene Set Enrichment Analysis) recently characterized in a mouseleukemia model. The HOX signature and EGFR expression were independent prognostic factors inmultivariate analysis, adjusted for the O-6-methylguanine-DNA methyltransferase (MGMT) methylationstatus, a known predictive factor for benefit from temozolomide, and age. Better outcome was associatedwith gene clusters characterizing features of tumor-host interaction including tumor vascularization andcell adhesion, and innate immune response. CONCLUSION This study provides first clinical evidence forthe implication of a \"glioma stem cell\" or \"self-renewal\" phenotype in treatment resistance ofglioblastoma. Biologic mechanisms identified here to be relevant for resistance will guide future targetedtherapies and respective marker development for individualized treatment and patient selection.", "metadata": {}}
+{"_id": "9498458", "title": "", "text": "Heterogeneity Underlies the Emergence of EGFRT790 Wild-Type Clones Following Treatment ofT790M-Positive Cancers with a Third-Generation EGFR Inhibitor.UNLABELLED Rociletinib is athird-generation EGFR inhibitor active in lung cancers with T790M, the gatekeeper mutation underlyingmost first-generation EGFR drug resistance. We biopsied patients at rociletinib progression to exploreresistance mechanisms. Among 12 patients with T790M-positive cancers at rociletinib initiation, six hadT790-wild-type rociletinib-resistant biopsies. Two T790-wild-type cancers underwent small cell lungcancer transformation; three T790M-positive cancers acquired EGFR amplification. We documentedT790-wild-type and T790M-positive clones coexisting within a single pre-rociletinib biopsy. Thepretreatment fraction of T790M-positive cells affected response to rociletinib. Longitudinal circulatingtumor DNA (ctDNA) analysis revealed an increase in plasma EGFR-activating mutation, and T790Mheralded rociletinib resistance in some patients, whereas in others the activating mutation increased butT790M remained suppressed. Together, these findings demonstrate the role of tumor heterogeneity whentherapies targeting a singular resistance mechanism are used. To further improve outcomes, combinationregimens that also target T790-wild-type clones are required. SIGNIFICANCE This report documents thathalf of T790M-positive EGFR-mutant lung cancers treated with rociletinib are T790-wild-type uponprogression, suggesting that T790-wild-type clones can emerge as the dominant source of resistance. Weshow that tumor heterogeneity has important clinical implications and that plasma ctDNA analyses cansometimes predict emerging resistance mechanisms.", "metadata": {}}
+{"_id": "9500590", "title": "", "text": "Extrathymic Generation of Regulatory T Cells in Placental Mammals Mitigates Maternal-FetalConflictRegulatory T (Treg) cells, whose differentiation and function are controlled by Xchromosome-encoded transcription factor Foxp3, are generated in the thymus (tTreg) andextrathymically (peripheral, pTreg), and their deficiency results in fatal autoimmunity. Here, wedemonstrate that a Foxp3 enhancer, conserved noncoding sequence 1 (CNS1), essential for pTreg butdispensable for tTreg cell generation, is present only in placental mammals. CNS1 is largely composed ofmammalian-wide interspersed repeats (MIR) that have undergone retrotransposition during earlymammalian radiation. During pregnancy, pTreg cells specific to a model paternal alloantigen weregenerated in a CNS1-dependent manner and accumulated in the placenta. Furthermore, when mated withallogeneic, but not syngeneic, males, CNS1-deficient females showed increased fetal resorptionaccompanied by increased immune cell infiltration and defective remodeling of spiral arteries. Our resultssuggest that, during evolution, a CNS1-dependent mechanism of extrathymic differentiation of Treg cellsemerged in placental animals to enforce maternal-fetal tolerance.", "metadata": {}}
+{"_id": "9505402", "title": "", "text": "Acquired EGFR C797S mutation mediates resistance to AZD9291 in non–small cell lung cancer harboringEGFR T790MHere we studied cell-free plasma DNA (cfDNA) collected from subjects with advanced lungcancer whose tumors had developed resistance to the epidermal growth factor receptor (EGFR) tyrosinekinase inhibitor (TKI) AZD9291. We first performed next-generation sequencing of cfDNA from sevensubjects and detected an acquired EGFR C797S mutation in one; expression of this mutant EGFRconstruct in a cell line rendered it resistant to AZD9291. We then performed droplet digital PCR on serialcfDNA specimens collected from 15 AZD9291-treated subjects. All were positive for the T790M mutationbefore treatment, but upon developing AZD9291 resistance three molecular subtypes emerged: six casesacquired the C797S mutation, five cases maintained the T790M mutation but did not acquire the C797Smutation and four cases lost the T790M mutation despite the presence of the underlying EGFR activatingmutation. Our findings provide insight into the diversity of mechanisms through which tumors acquireresistance to AZD9291 and highlight the need for therapies that are able to overcome resistancemediated by the EGFR C797S mutation.", "metadata": {}}
+{"_id": "9505448", "title": "", "text": "The Translation Initiation Factor 3f (eIF3f) Exhibits a Deubiquitinase Activity Regulating NotchActivationActivation of the mammalian Notch receptor after ligand binding relies on a succession ofevents including metalloprotease-cleavage, endocytosis, monoubiquitination, and eventually processingby the gamma-secretase, giving rise to a soluble, transcriptionally active molecule. The Notch1 receptorwas proposed to be monoubiquitinated before its gamma-secretase cleavage; the targeted lysine hasbeen localized to its submembrane domain. Investigating how this step might be regulated by adeubiquitinase (DUB) activity will provide new insight for understanding Notch receptor activation anddownstream signaling. An immunofluorescence-based screening of an shRNA library allowed us to identifyeIF3f, previously known as one of the subunits of the translation initiation factor eIF3, as a DUB targetingthe activated Notch receptor. We show that eIF3f has an intrinsic DUB activity. Knocking down eIF3fleads to an accumulation of monoubiquitinated forms of activated Notch, an effect counteracted bymurine WT eIF3f but not by a catalytically inactive mutant. We also show that eIF3f is recruited toactivated Notch on endocytic vesicles by the putative E3 ubiquitin ligase Deltex1, which serves as abridging factor. Finally, catalytically inactive forms of eIF3f as well as shRNAs targeting eIF3f repressNotch activation in a coculture assay, showing that eIF3f is a new positive regulator of the Notchpathway. Our results support two new and provocative conclusions: (1) The activated form of Notchneeds to be deubiquitinated before being processed by the gamma-secretase activity and entering thenucleus, where it fulfills its transcriptional function. (2) The enzyme accounting for this deubiquitinaseactivity is eIF3f, known so far as a translation initiation factor. These data improve our knowledge ofNotch signaling but also open new avenues of research on the Zomes family and the translation initiationfactors.", "metadata": {}}
+{"_id": "9507605", "title": "", "text": "Focal contacts as mechanosensors: externally applied local mechanical force induces growth of focalcontacts by an mDia1-dependent and ROCKindependent mechanismThe transition of cell–matrixadhesions from the initial punctate focal complexes into the mature elongated form, known as focalcontacts, requires GTPase Rho activity. In particular, activation of myosin II–driven contractility by a Rhotarget known as Rho-associated kinase (ROCK) was shown to be essential for focal contact formation. Todissect the mechanism of Rho-dependent induction of focal contacts and to elucidate the role of cellcontractility, we applied mechanical force to vinculin-containing dot-like adhesions at the cell edge usinga micropipette. Local centripetal pulling led to local assembly and elongation of these structures and totheir development into streak-like focal contacts, as revealed by the dynamics of green fluorescentprotein–tagged vinculin or paxillin and interference reflection microscopy. Inhibition of Rho activity by C3transferase suppressed this force-induced focal contact formation. However, constitutively active mutantsof another Rho target, the formin homology protein mDia1 (Watanabe, N., T. Kato, A. Fujita, T. Ishizaki,and S. Narumiya. 1999. Nat. Cell Biol. 1:136–143), were sufficient to restore force-induced focal contactformation in C3 transferase-treated cells. Force-induced formation of the focal contacts still occurred incells subjected to myosin II and ROCK inhibition. Thus, as long as mDia1 is active, external tension forcebypasses the requirement for ROCK-mediated myosin II contractility in the induction of focal contacts.Our experiments show that integrin-containing focal complexes behave as individual mechanosensorsexhibiting directional assembly in response to local force.", "metadata": {}}
+{"_id": "9513785", "title": "", "text": "Maternal Protein Restriction Affects Postnatal Growth and the Expression of Key Proteins Involved inLifespan Regulation in MiceWe previously reported that maternal protein restriction in rodents influencedthe rate of growth in early life and ultimately affected longevity. Low birth weight caused by maternalprotein restriction followed by catch-up growth (recuperated animals) was associated with shortenedlifespan whereas protein restriction and slow growth during lactation (postnatal low protein: PLP animals)increased lifespan. We aim to explore the mechanistic basis by which these differences arise. Here weinvestigated effects of maternal diet on organ growth, metabolic parameters and the expression ofinsulin/IGF1 signalling proteins and Sirt1 in muscle of male mice at weaning. PLP mice which experiencedprotein restriction during lactation had lower fasting glucose (P = 0.038) and insulin levels (P = 0.046)suggesting improved insulin sensitivity. PLP mice had higher relative weights (adjusted by body weight)of brain (P = 0.0002) and thymus (P = 0.031) compared to controls suggesting that enhanced functionalcapacity of these two tissues is beneficial to longevity. They also had increased expression of insulinreceptor substrate 1 (P = 0.021) and protein kinase C zeta (P = 0.046). Recuperated animals expresseddecreased levels of many insulin signalling proteins including PI3 kinase subunits p85alpha (P = 0.018),p110beta (P = 0.048) and protein kinase C zeta (P = 0.006) which may predispose these animals toinsulin resistance. Sirt1 protein expression was reduced in recuperated offspring. These observationssuggest that maternal protein restriction can affect major metabolic pathways implicated in regulation oflifespan at a young age which may explain the impact of maternal diet on longevity.", "metadata": {}}
+{"_id": "9538708", "title": "", "text": "‘Short stature in children - a questionnaire for parents’: a new instrument for growth disorder-specificpsychosocial adaptation in childrenRecent studies report comparable psychosocial adaptation in childrenwith or without a growth disorder. These findings may be due to a general lack of sensitive and specifictechniques for analysing and comparing their respective qualities of life. In this study we present a newquestionnaire for parents of short-statured children. We suggest both a qualitative and quantitativeapproach providing specific information about the relative extent of individual stress factors and sourcesof help. The parents of 442 children with growth retardation resulting from different aetiologiescompleted the questionnaire. Aprincipal component analysis of the scaled items revealed four dimensionsof psychosocial adaptation: suffering, future anxieties, behavioural problems and coping efforts. Theindex of internal consistency reliability was sufficient for all scales. The comparison of two selectedgrowth disorder groups (achondroplasia versus growth hormone deficiency) demonstrated growthdisorder-specific but not very different profiles of psychosocial adaptation. The qualitative analysisrevealed a shift in the stress factor patterns (achondroplasia, more physical restrictions). These findingsgive evidence for both the specificity and construct validity of the new instrument. Therefore, we mayconclude that this questionnaire is a helpful method in attaining growth disorder-specific informationabout individual stress factors, resources and psychosocial adaptation.", "metadata": {}}
+{"_id": "9539248", "title": "", "text": "Alphavirus-derived small RNAs modulate pathogenesis in disease vector mosquitoes.Mosquito-borneviruses cause significant levels of morbidity and mortality in humans and domesticated animals.Maintenance of mosquito-borne viruses in nature requires a biological transmission cycle that involvesalternating virus replication in a susceptible vertebrate and mosquito host. Although the vertebrateinfection is acute and often associated with disease, continual transmission of these viruses in naturedepends on the establishment of a persistent, nonpathogenic infection in the mosquito vector. Anantiviral RNAi response has been shown to limit the replication of RNA viruses in flies. However, theimportance of the RNAi pathway as an antiviral defense in mammals is unclear. Differences in theimmune responses of mammals and mosquitoes may explain why these viruses are not generallyassociated with pathology in the invertebrate host. We identified virus-derived small interfering RNAs(viRNAs), 21 nt in length, in Aedes aegypti infected with the mosquito-borne virus, Sindbis (SINV).viRNAs had an asymmetric distribution that spanned the length of the SINV genome. To determine therole of viRNAs in controlling pathogenic potential, mosquitoes were infected with recombinantalphaviruses expressing suppressors of RNA silencing. Decreased survival was observed in mosquitoes inwhich the accumulation of viRNAs was suppressed. These results suggest that an exogenous siRNApathway is essential to the survival of mosquitoes infected with alphaviruses and, thus, the maintenanceof these viruses in nature.", "metadata": {}}
+{"_id": "9539753", "title": "", "text": "Nuclear RNAi maintains heritable gene silencing in Caenorhabditis elegans.RNA interference (RNAi) isheritable in Caenorhabditis elegans; the progeny of C. elegans exposed to dsRNA inherit the ability tosilence genes that were targeted by RNAi in the previous generation. Here we investigate the mechanismof RNAi inheritance in C. elegans. We show that exposure of animals to dsRNA results in the heritableexpression of siRNAs and the heritable deposition of histone 3 lysine 9 methylation (H3K9me) marks inprogeny. siRNAs are detectable before the appearance of H3K9me marks, suggesting that chromatinmarks are not directly inherited but, rather, reestablished in inheriting progeny. Interestingly, H3K9memarks appear more prominently in inheriting progeny than in animals directly exposed to dsRNA,suggesting that germ-line transmission of silencing signals may enhance the efficiency of siRNA-directedH3K9me. Finally, we show that the nuclear RNAi (Nrde) pathway maintains heritable RNAi silencing in C.elegans. The Argonaute (Ago) NRDE-3 associates with heritable siRNAs and, acting in conjunction withthe nuclear RNAi factors NRDE-1, NRDE-2, and NRDE-4, promotes siRNA expression in inheritingprogeny. These results demonstrate that siRNA expression is heritable in C. elegans and define an RNAipathway that promotes the maintenance of RNAi silencing and siRNA expression in the progeny ofanimals exposed to dsRNA.", "metadata": {}}
+{"_id": "9547722", "title": "", "text": "Cancer survivors in the United States: prevalence across the survivorship trajectory and implications forcare.BACKGROUND Cancer survivors represent a growing population, heterogeneous in their need formedical care, psychosocial support, and practical assistance. To inform survivorship research andpractice, this manuscript will describe the prevalent population of cancer survivors in terms of overallnumbers and prevalence by cancer site and time since diagnosis. METHODS Incidence and survival datafrom 1975-2007 were obtained from the Surveillance, Epidemiology, and End Results Program andpopulation projections from the United States Census Bureau. Cancer prevalence for 2012 and beyondwas estimated using the Prevalence Incidence Approach Model, assuming constant future incidence andsurvival trends but dynamic projections of the U.S. population. RESULTS As of January 1, 2012,approximately 13.7 million cancer survivors were living in the United States with prevalence projected toapproach 18 million by 2022. Sixty-four percent of this population have survived 5 years or more; 40%have survived 10 years or more; and 15% have survived 20 years or more after diagnosis. Over the nextdecade, the number of people who have lived 5 years or more after their cancer diagnosis is projected toincrease approximately 37% to 11.9 million. CONCLUSIONS A coordinated agenda for research andpractice is needed to address cancer survivors' long-term medical, psychosocial, and practical needsacross the survivorship trajectory. IMPACT Prevalence estimates for cancer survivors across thesurvivorship trajectory will inform the national research agenda as well as future projections about thehealth service needs of this population.", "metadata": {}}
+{"_id": "9548440", "title": "", "text": "Human aneuploidy: mechanisms and new insights into an age-old problemTrisomic and monosomic(aneuploid) embryos account for at least 10% of human pregnancies and, for women nearing the end oftheir reproductive lifespan, the incidence may exceed 50%. The errors that lead to aneuploidy almostalways occur in the oocyte but, despite intensive investigation, the underlying molecular basis hasremained elusive. Recent studies of humans and model organisms have shed new light on the complexityof meiotic defects, providing evidence that the age-related increase in errors in the human female is notattributable to a single factor but to an interplay between unique features of oogenesis and a host ofendogenous and exogenous factors.", "metadata": {}}
+{"_id": "9550981", "title": "", "text": "The Drosophila hindgut lacks constitutively active adult stem cells but proliferates in response to tissuedamage.The adult Drosophila hindgut was recently reported to contain active, tissue-replenishing stemcells, like those of the midgut, but located within an anterior ring so as to comprise a single giant crypt.In contrast to this view, we observed no active stem cells and little cell turnover in adult hindgut tissuebased on clonal marking and BrdU incorporation studies. Again contradicting the previous proposal, weshowed that the adult hindgut is not generated by anterior stem cells during larval/pupal development.However, severe tissue damage within the hindgut elicits cell proliferation within a ring of putativequiescent stem cells at the anterior of the pylorus. Thus, the hindgut does not provide a model of tissuemaintenance by constitutively active stem cells, but has great potential to illuminate mechanisms ofstress-induced tissue repair.", "metadata": {}}
+{"_id": "9555784", "title": "", "text": "Vitamin d deficiency in postmenopausal women - biological correlates.INTRODUCTION Low vitamin D(VD) is associated with secondary hyperparathyroidism and both contribute to deleterious consequences(reduced bone mineral density (BMD), risk of fractures and falls). OBJECTIVE To study the VD status andbiological correlates in a group of postmenopausal women. MATERIAL AND METHODS We studied 123postmenopausal women evaluated in the C.I.Parhon National Institute of Endocrinology, the Pituitary andNeuroendocrine Diseases department. All cases had been reffered for the evaluation of BMD by thegeneral practitioner. The evaluation included serum measurements of total and ionised calcium,phosphorus, alkaline phosphatase (ALP), 25 hydroxi vitaminD (25OHD), parathyroid hormone (PTH),osteocalcin, betacrosslaps. Central DXA osteodensitometry was performed. RESULTS 91.9% of cases had25OHD serum levels below 30 ng/ml (74.8% had VD deficiency, 17.1% VD insufficiency). Only 8.1% hadsufficient VD levels. A history of fragility fractures was present in 45.83% of the osteoporotic patients,27.27% of the osteopenic ones and 15.15% of the women with normal BMD. 32 women (26%) were onVD supplementation at the time of evaluation. Among these subjects, the 25OHD level was significantlyhigher in those with prior fragility fractures (p=0.018) and osteoporosis (p=0.008). 25OHD concentrationnegatively correlated with PTH, alkaline phosphatase (ALP) and osteocalcin. The bone markers evaluatedhad a significant inverse correlation with the radius BMD, T and Z scores (p=0.004). 27.17% of the caseswith VD deficiency had secondary hyperparathyroidism. The 25OHD concentration was significantly lowerin these cases (p=0.000). CONCLUSIONS VD insufficiency is widely prevalent but still under-recognizedand under-treated, possibly leading to secondary hyperparathyroidism. The compliance to VDsupplementation is lower in subjects without osteoporosis or fragility fractures. Primary preventionmeasures should be more actively implemented.", "metadata": {}}
+{"_id": "9558539", "title": "", "text": "CD44v6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancermetastasis.Cancer stem cells drive tumor formation and metastasis, but how they acquire metastatictraits is not well understood. Here, we show that all colorectal cancer stem cells (CR-CSCs) expressCD44v6, which is required for their migration and generation of metastatic tumors. CD44v6 expression islow in primary tumors but demarcated clonogenic CR-CSC populations. Cytokines hepatocyte growthfactor (HGF), osteopontin (OPN), and stromal-derived factor 1α (SDF-1), secreted from tumor associatedcells, increase CD44v6 expression in CR-CSCs by activating the Wnt/β-catenin pathway, which promotesmigration and metastasis. CD44v6(-) progenitor cells do not give rise to metastatic lesions but, whentreated with cytokines, acquire CD44v6 expression and metastatic capacity. Importantly,phosphatidylinositol 3-kinase (PI3K) inhibition selectively killed CD44v6 CR-CSCs and reduced metastaticgrowth. In patient cohorts, low levels of CD44v6 predict increased probability of survival. Thus, themetastatic process in colorectal cancer is initiated by CSCs through the expression of CD44v6, which isboth a functional biomarker and therapeutic target.", "metadata": {}}
+{"_id": "9559146", "title": "", "text": "Senescent Cells, Tumor Suppression, and Organismal Aging: Good Citizens, Bad NeighborsCells fromorganisms with renewable tissues can permanently withdraw from the cell cycle in response to diversestress, including dysfunctional telomeres, DNA damage, strong mitogenic signals, and disruptedchromatin. This response, termed cellular senescence, is controlled by the p53 and RB tumor suppressorproteins and constitutes a potent anticancer mechanism. Nonetheless, senescent cells acquire phenotypicchanges that may contribute to aging and certain age-related diseases, including late-life cancer. Thus,the senescence response may be antagonistically pleiotropic, promoting early-life survival by curtailingthe development of cancer but eventually limiting longevity as dysfunctional senescent cells accumulate.", "metadata": {}}
+{"_id": "9580772", "title": "", "text": "Advances in high-resolution imaging--techniques for three-dimensional imaging of cellular structures.Afundamental goal in biology is to determine how cellular organization is coupled to function. To achievethis goal, a better understanding of organelle composition and structure is needed. Although visualizationof cellular organelles using fluorescence or electron microscopy (EM) has become a common tool for thecell biologist, recent advances are providing a clearer picture of the cell than ever before. In particular,advanced light-microscopy techniques are achieving resolutions below the diffraction limit and EMtomography provides high-resolution three-dimensional (3D) images of cellular structures. The ability toperform both fluorescence and electron microscopy on the same sample (correlative light and electronmicroscopy, CLEM) makes it possible to identify where a fluorescently labeled protein is located withrespect to organelle structures visualized by EM. Here, we review the current state of the art in 3Dbiological imaging techniques with a focus on recent advances in electron microscopy and fluorescencesuper-resolution techniques.", "metadata": {}}
+{"_id": "9588931", "title": "", "text": "Quercetin attenuates vascular calcification by inhibiting oxidative stress and mitochondrialfission.Vascular calcification is a strong independent predictor of increased cardiovascular morbidity andmortality and has a high prevalence among patients with chronic kidney disease. The present studyinvestigated the effects of quercetin on vascular calcification caused by oxidative stress and abnormalmitochondrial dynamics both in vitro and in vivo. Calcifying vascular smooth muscle cells (VSMCs) treatedwith inorganic phosphate (Pi) exhibited mitochondrial dysfunction, as demonstrated by decreasedmitochondrial potential and ATP production. Disruption of mitochondrial structural integrity was alsoobserved in a rat model of adenine-induced aortic calcification. Increased production of reactive oxygenspecies, enhanced expression and phosphorylation of Drp1, and excessive mitochondrial fragmentationwere also observed in Pi-treated VSMCs. These effects were accompanied by mitochondria-dependentapoptotic events, including release of cytochrome c from the mitochondria into the cytosol andsubsequent activation of caspase-3. Quercetin was shown to block Pi-induced apoptosis and calcificationof VSMCs by inhibiting oxidative stress and decreasing mitochondrial fission by inhibiting the expressionand phosphorylation of Drp1. Quercetin also significantly ameliorated adenine-induced aortic calcificationin rats. In summary, our findings suggest that quercetin attenuates calcification by reducing apoptosis ofVSMCs by blocking oxidative stress and inhibiting mitochondrial fission.", "metadata": {}}
+{"_id": "9591368", "title": "", "text": "The M/GP5 Glycoprotein Complex of Porcine Reproductive and Respiratory Syndrome Virus Binds theSialoadhesin Receptor in a Sialic Acid-Dependent MannerThe porcine reproductive and respiratorysyndrome virus (PRRSV) is a major threat to swine health worldwide and is considered the mostsignificant viral disease in the swine industry today. In past years, studies on the entry of the virus intoits host cell have led to the identification of a number of essential virus receptors and entry mediators.However, viral counterparts for these molecules have remained elusive and this has made rationaldevelopment of new generation vaccines impossible. The main objective of this study was to identify theviral counterparts for sialoadhesin, a crucial PRRSV receptor on macrophages. For this purpose, a solubleform of sialoadhesin was constructed and validated. The soluble sialoadhesin could bind PRRSV in a sialicacid-dependent manner and could neutralize PRRSV infection of macrophages, thereby confirming therole of sialoadhesin as an essential PRRSV receptor on macrophages. Although sialic acids are present onthe GP(3), GP(4) and GP(5) envelope glycoproteins, only the M/GP(5) glycoprotein complex of PRRSVwas identified as a ligand for sialoadhesin. The interaction was found to be dependent on the sialic acidbinding capacity of sialoadhesin and on the presence of sialic acids on GP(5). These findings not onlycontribute to a better understanding of PRRSV biology, but the knowledge and tools generated in thisstudy also hold the key to the development of a new generation of PRRSV vaccines.", "metadata": {}}
+{"_id": "9599194", "title": "", "text": "A versatile zero background T-vector system for gene cloning and functional genomics.With the recentavailability of complete genomic sequences of many organisms, high-throughput and cost-efficientsystems for gene cloning and functional analysis are in great demand. Although site-specificrecombination-based cloning systems, such as Gateway cloning technology, are extremely useful forefficient transfer of DNA fragments into multiple destination vectors, the two-step cloning process is timeconsuming and expensive. Here, we report a zero background TA cloning system that provides simpleand high-efficiency direct cloning of PCR-amplified DNA fragments with almost no self-ligation. Theimproved T-vector system takes advantage of the restriction enzyme XcmI to generate a T-overhangafter digestion and the negative selection marker gene ccdB to eliminate the self-ligation backgroundafter transformation. We demonstrate the feasibility and flexibility of the technology by developing a setof transient and stable transformation vectors for constitutive gene expression, gene silencing, proteintagging, protein subcellular localization detection, and promoter fragment activity analysis in plants.Because the system can be easily adapted for developing specialized expression vectors for otherorganisms, zero background TA provides a general, cost-efficient, and high-throughput platform thatcomplements the Gateway cloning system for gene cloning and functional genomics.", "metadata": {}}
+{"_id": "9600826", "title": "", "text": "GEP100-Arf6-AMAP1-Cortactin Pathway Frequently Used in Cancer Invasion Is Activated by VEGFR2 toPromote AngiogenesisAngiogenesis and cancer invasiveness greatly contribute to cancer malignancy. Arf6and its effector, AMAP1, are frequently overexpressed in breast cancer, and constitute a central pathwayto induce the invasion and metastasis. In this pathway, Arf6 is activated by EGFR via GEP100. Arf6 ishighly expressed also in human umbilical vein endothelial cells (HUVECs) and is implicated inangiogenesis. Here, we found that HUVECs also highly express AMAP1, and that vascular endothelialgrowth factor receptor-2 (VEGFR2) recruits GEP100 to activate Arf6. AMAP1 functions by binding tocortactin in cancer invasion and metastasis. We demonstrate that the sameGEP100-Arf6-AMAP1-cortactin pathway is essential for angiogenesis activities, including cell migrationand tubular formation, as well as for the enhancement of cell permeability and VE-cadherin endocytosisof VEGF-stimulated HUVECs. Components of this pathway are highly expressed in pathologicangiogenesis, and blocking of this pathway effectively inhibits VEGF- or tumor-induced angiogenesis andchoroidal neovascularization. The GEP100-Arf6-AMAP1-cortactin pathway, activated by receptor tyrosinekinases, appears to be common in angiogenesis and cancer invasion and metastasis, and provides theirnew therapeutic targets.", "metadata": {}}
+{"_id": "9604301", "title": "", "text": "Dynamics of Cryptococcus neoformans-Macrophage Interactions Reveal that Fungal BackgroundInfluences Outcome during Cryptococcal Meningoencephalitis in HumansUNLABELLED Cryptococcosis is amultifaceted fungal infection with variable clinical presentation and outcome. As in many infectiousdiseases, this variability is commonly assigned to host factors. To investigate whether the diversity ofCryptococcus neoformans clinical (ClinCn) isolates influences the interaction with host cells and theclinical outcome, we developed and validated new quantitative assays using flow cytometry and J774macrophages. The phenotype of ClinCn-macrophage interactions was determined for 54 ClinCn isolatesrecovered from cerebrospinal fluids (CSF) from 54 unrelated patients, based on phagocytic index (PI) and2-h and 48-h intracellular proliferation indexes (IPH2 and IPH48, respectively). Their phenotypes werehighly variable. Isolates harboring low PI/low IPH2 and high PI/high IPH2 values were associated withnonsterilization of CSF at week 2 and death at month 3, respectively. A subset of 9 ClinCn isolates withdifferent phenotypes exhibited variable virulence in mice and displayed intramacrophagic expressionlevels of the LAC1, APP1, VAD1, IPC1, PLB1, and COX1 genes that were highly variable among theisolates and correlated with IPH48. Variation in the expression of virulence factors is thus shown here todepend on not only experimental conditions but also fungal background. These results suggest that, inaddition to host factors, the patient's outcome can be related to fungal determinants. Deciphering themolecular events involved in C. neoformans fate inside host cells is crucial for our understanding ofcryptococcosis pathogenesis. IMPORTANCE Cryptococcus neoformans is a life-threatening human fungalpathogen that is responsible for an estimated 1 million cases of meningitis/year, predominantly inHIV-infected patients. The diversity of infecting isolates is well established, as is the importance of thehost factors. Interaction with macrophages is a major step in cryptococcosis pathogenesis. How thediversity of clinical isolates influences macrophages' interactions and impacts cryptococcosis outcome inhumans remains to be elucidated. Using new assays, we uncovered how yeast-macrophage interactionswere highly variable among clinical isolates and found an association between specific behaviors andcryptococcosis outcome. In addition, gene expression of some virulence factors and intracellularproliferation were correlated. While many studies have established that virulence factors can bedifferentially expressed as a function of experimental conditions, our study demonstrates that, under thesame experimental conditions, clinical isolates behaved differently, a diversity that could participate inthe variable outcome of infection in humans.", "metadata": {}}
+{"_id": "9612317", "title": "", "text": "Angiopoietin-2 at high concentration can enhance endothelial cell survival through thephosphatidylinositol 3′-kinase/Akt signal transduction pathwayThe angiopoietin-Tie2 system inendothelial cells is an important regulator of vasculogenesis and vascular integrity. High levels ofangiopoietin-2 (Ang2) mRNA are observed in vascular activation during tumorigenesis. Although Ang2 isknown to be a naturally occurring antagonist of angiopoietin-1 (Ang1) in vivo, the exact function of Ang2itself is not known. Here, we found that a high concentration of Ang2 (800 ng/ml) acts as an apoptosissurvival factor for endothelial cells during serum deprivation apoptosis. The survival effect of highconcentration Ang2 was blocked by pre-treatment with soluble Tie2 receptor and the PI 3′-kinase-specificinhibitors, wortmannin and LY294002. Accordingly, 800 ng/ml of Ang2 induced phosphorylation of Tie2,the p85 subunit of phosphatidylinositol 3′-kinase (PI 3′-kinase), and serine-threonine kinase Akt atSer473 in the human umbilical vein endothelial cells; lower concentrations of Ang2 (50–400 ng/ml) didnot produce notable effects. These findings indicate that at high concentrations, Ang2, like Ang1, can bean apoptosis survival factor for endothelial cells through the activation of the Tie2 receptor, PI 3′-kinaseand Akt, and thus may be a positive regulator of tumor angiogenesis.", "metadata": {}}
+{"_id": "9614443", "title": "", "text": "Lipoxin a4 analogs attenuate induction of intestinal epithelial proinflammatory gene expression andreduce the severity of dextran sodium sulfate-induced colitis.The anti-inflammatory eicosanoid lipoxinA(4) (LXA(4)), aspirin-triggered 15-epi-LXA(4), and their stable analogs down-regulate IL-8 secretionand subsequent recruitment of neutrophils by intestinal epithelia. In an effort to elucidate the mechanismby which these lipid mediators modulate cellular proinflammatory programs, we surveyed global epithelialgene expression using cDNA microarrays. LXA(4) analog alone did not significantly affect expression ofany of the >7000 genes analyzed. However, LXA(4) analog pretreatment attenuated induction ofapproximately 50% of the 125 genes up-regulated in response to the gastroenteritis-causing pathogenSalmonella typhimurium. A major subset of genes whose induction was reduced by LXA(4) analogpretreatment is regulated by NF-kappaB, suggesting that LXA(4) analog was influencing the activity ofthis transcription factor. Nanomolar concentrations of LXA(4) analog reduced NF-kappaB-mediatedtranscriptional activation in a LXA(4) receptor-dependent manner and inhibited induced degradation ofIkappaBalpha. LXA(4) analog did not affect earlier stimulus-induced signaling events that lead toIkappaBalpha degradation, such as S. typhimurium-induced epithelial Ca(2+) mobilization orTNF-alpha-induced phosphorylation of IkappaBalpha. To establish the in vivo relevance of these findings,we examined whether LXA(4) analogs could affect intestinal inflammation in vivo using the mouse modelof DSS-induced inflammatory colitis. Oral administration of LXA(4) analog(15-epi-16-para-fluoro-phenoxy-LXA(4), 10 microg/day) significantly reduced the weight loss,hematochezia, and mortality that characterize DSS colitis. Thus, LXA(4) analog-mediateddown-regulation of proinflammatory gene expression via inhibition of the NF-kappaB pathway can betherapeutic for diseases characterized by mucosal inflammation.", "metadata": {}}
+{"_id": "9617381", "title": "", "text": "Serum plant and other noncholesterol sterols, cholesterol metabolism and 22-year mortality amongmiddle-aged men.OBJECTIVE To evaluate long-term prognostic effect of serum noncholesterol sterols,including plant sterols, in middle-aged men with high cardiovascular disease (CVD) risk, without statins atbaseline. METHODS This was a prospective study of 232 men (mean age 60 years) at high risk of CVD in1985-1986. Most were hypercholesterolemic, 29 (12%) had a history of CVD or cancer, 6 (3%) haddiabetes, and 46 (20%) had metabolic syndrome (MS). Measured noncholesterol sterols (expressed asabsolute concentrations or ratios to serum cholesterol to standardize for cholesterol concentrations)included lathosterol and desmosterol (reflect cholesterol synthesis), and plant sterols (campesterol andsitosterol) and cholestanol (reflect cholesterol absorption). Main outcome measure was total mortality.RESULTS At baseline, markers of cholesterol synthesis and absorption showed expected inverseassociations. During the 22-year follow-up 101 men (43%) died. At baseline, nonsurvivors smoked more,exercised less and had more components of MS (although not filling strict criteria), whereas traditionalrisk factors of CVD were not significantly different. Of the noncholesterol sterols (either absolute or ratio),only sitosterol was significantly higher in survivors than in nonsurvivors (P=0.02). In multivariableanalyses, highest sitosterol-to-cholesterol tertile was associated with significantly lower mortality risk (HR0.51, 95% CI 0.30-0.87) as compared to lowest tertile. Other associations were nonsignificant, althougha \"global\" index of cholesterol metabolism (desmosterol-to-sitosterol ratio) suggested higher cholesterolsynthesis and lower absorption to be associated with higher total and CVD mortality. CONCLUSIONHigher serum plant sterol levels in middle-aged men predicted lower long-term mortality risk, possiblyreflecting an association between higher synthesis/lower absorption of cholesterol and mortality.", "metadata": {}}
+{"_id": "9622258", "title": "", "text": "Intracoronary autologous cardiac progenitor cell transfer in patients with hypoplastic left heart syndrome:the TICAP prospective phase 1 controlled trial.RATIONALE Hypoplastic left heart syndrome (HLHS)remains a lethal congenital cardiac defect. Recent studies have suggested that intracoronaryadministration of autologous cardiosphere-derived cells (CDCs) may improve ventricular function.OBJECTIVE The aim of this study was to test whether intracoronary delivery of CDCs is feasible and safein patients with hypoplastic left heart syndrome. METHODS AND RESULTS Between January 5, 2011, andJanuary 16, 2012, 14 patients (1.8±1.5 years) were prospectively assigned to receive intracoronaryinfusion of autologous CDCs 33.4±8.1 days after staged procedures (n=7), followed by 7 controls withstandard palliation alone. The primary end point was to assess the safety, and the secondary end pointincluded the preliminary efficacy to verify the right ventricular ejection fraction improvements betweenbaseline and 3 months. Manufacturing and intracoronary delivery of CDCs were feasible, and no seriousadverse events were reported within the 18-month follow-up. Patients treated with CDCs showed rightventricular ejection fraction improvement from baseline to 3-month follow-up (46.9%±4.6% to52.1%±2.4%; P=0.008). Compared with controls at 18 months, cardiac MRI analysis of CDC-treatedpatients showed a higher right ventricular ejection fraction (31.5%±6.8% versus 40.4%±7.6%;P=0.049), improved somatic growth (P=0.0005), reduced heart failure status (P=0.003), and lowerincidence of coil occlusion for collaterals (P=0.007). CONCLUSIONS Intracoronary infusion of autologousCDCs seems to be feasible and safe in children with hypoplastic left heart syndrome after staged surgery.Large phase 2 trials are warranted to examine the potential effects of cardiac function improvements andthe long-term benefits of clinical outcomes. CLINICAL TRIAL REGISTRATION URLhttp://www.clinicaltrials.gov. Unique identifier: NCT01273857.", "metadata": {}}
+{"_id": "9629682", "title": "", "text": "A Whole Brain Staining, Embedding, and Clearing Pipeline for Adult Zebrafish to Visualize CellProliferation and Morphology in 3-DimensionsThe field of macro-imaging has grown considerably with theappearance of innovative clearing methods and confocal microscopes with lasers capable of penetratingincreasing tissue depths. The ability to visualize and model the growth of whole organs as they developfrom birth, or with manipulation, disease or injury, provides new ways of thinking about development,tissue-wide signaling, and cell-to-cell interactions. The zebrafish (Danio rerio) has ascended from apredominantly developmental model to a leading adult model of tissue regeneration. The unmatchedneurogenic and regenerative capacity of the mature central nervous system, in particular, has receivedmuch attention, however tools to interrogate the adult brain are sparse. At present there exists nostraightforward methods of visualizing changes in the whole adult brain in 3-dimensions (3-D) to examinesystemic patterns of cell proliferation or cell populations of interest under physiological, injury, ordiseased conditions. The method presented here is the first of its kind to offer an efficient step-by-steppipeline from intraperitoneal injections of the proliferative marker, 5-ethynyl-2'-deoxyuridine (EdU), towhole brain labeling, to a final embedded and cleared brain sample suitable for 3-D imaging using opticalprojection tomography (OPT). Moreover, this method allows potential for imaging GFP-reporter lines andcell-specific antibodies in the presence or absence of EdU. The small size of the adult zebrafish brain, thehighly consistent degree of EdU labeling, and the use of basic clearing agents, benzyl benzoate, andbenzyl alcohol, makes this method highly tractable for most laboratories interested in understanding thevertebrate central nervous system in health and disease. Post-processing of OPT-imaged adult zebrafishbrains injected with EdU illustrate that proliferative patterns in EdU can readily be observed and analyzedusing IMARIS and/or FIJI/IMAGEJ software. This protocol will be a valuable tool to unlock new ways ofunderstanding systemic patterns in cell proliferation in the healthy and injured brain, brain-wide cellularinteractions, stem cell niche development, and changes in brain morphology.", "metadata": {}}
+{"_id": "9634465", "title": "", "text": "Single-Construct Polycistronic Doxycycline-Inducible Vectors Improve Direct Cardiac Reprogramming andCan Be Used to Identify the Critical Timing of Transgene ExpressionDirect reprogramming is a promisingapproach in regenerative medicine. Overexpression of the cardiac transcription factors Gata4, Mef2c, andTbx5 (GMT) or GMT plus Hand2 (GHMT) directly reprogram fibroblasts into cardiomyocyte-like cells(iCMs). However, the critical timing of transgene expression and the molecular mechanisms for cardiacreprogramming remain unclear. The conventional doxycycline (Dox)-inducible temporal transgeneexpression systems require simultaneous transduction of two vectors (pLVX-rtTA/pLVX-cDNA) harboringthe reverse tetracycline transactivator (rtTA) and the tetracycline response element (TRE)-controlledtransgene, respectively, leading to inefficient cardiac reprogramming. Herein, we developed asingle-construct-based polycistronic Dox-inducible vector (pDox-cDNA) expressing both the rtTA andTRE-controlled transgenes. Fluorescence activated cell sorting (FACS) analyses, quantitative RT-PCR, andimmunostaining revealed that pDox-GMT increased cardiac reprogramming three-fold compared to theconventional pLVX-rtTA/pLVX-GMT. After four weeks, pDox-GMT-induced iCMs expressed multiple cardiacgenes, produced sarcomeric structures, and beat spontaneously. Co-transduction of pDox-Hand2 withretroviral pMX-GMT increased cardiac reprogramming three-fold compared to pMX-GMT alone. TemporalDox administration revealed that Hand2 transgene expression is critical during the first two weeks ofcardiac reprogramming. Microarray analyses demonstrated that Hand2 represses cell cycle-promotinggenes and enhances cardiac reprogramming. Thus, we have developed an efficient temporal transgeneexpression system, which could be invaluable in the study of cardiac reprogramming.", "metadata": {}}
+{"_id": "9638032", "title": "", "text": "Increasing microtubule acetylation rescues axonal transport and locomotor deficits caused by LRRK2Roc-COR domain mutationsLeucine-rich repeat kinase 2 (LRRK2) mutations are the most common geneticcause of Parkinson's disease. LRRK2 is a multifunctional protein affecting many cellular processes and hasbeen described to bind microtubules. Defective microtubule-based axonal transport is hypothesized tocontribute to Parkinson's disease, but whether LRRK2 mutations affect this process to mediatepathogenesis is not known. Here we find that LRRK2 containing pathogenic Roc-COR domain mutations(R1441C, Y1699C) preferentially associates with deacetylated microtubules, and inhibits axonal transportin primary neurons and in Drosophila, causing locomotor deficits in vivo. In vitro, increasing microtubuleacetylation using deacetylase inhibitors or the tubulin acetylase αTAT1 prevents association of mutantLRRK2 with microtubules, and the deacetylase inhibitor trichostatin A (TSA) restores axonal transport. Invivo knockdown of the deacetylases HDAC6 and Sirt2, or administration of TSA rescues both axonaltransport and locomotor behavior. Thus, this study reveals a pathogenic mechanism and a potentialintervention for Parkinson's disease.", "metadata": {}}
+{"_id": "9641846", "title": "", "text": "G1 arrest and differentiation can occur independently of Rb family functionThe ability of progenitor cellsto exit the cell cycle is essential for proper embryonic development and homeostasis, but the mechanismsgoverning cell cycle exit are still not fully understood. Here, we tested the requirement for theretinoblastoma (Rb) protein and its family members p107 and p130 in G0/G1 arrest and differentiation inmammalian cells. We found that Rb family triple knockout (TKO) mouse embryos survive until days 9-11of gestation. Strikingly, some TKO cells, including in epithelial and neural lineages, are able to exit thecell cycle in G0/G1 and differentiate in teratomas and in culture. This ability of TKO cells to arrest inG0/G1 is associated with the repression of key E2F target genes. Thus, G1 arrest is not always dependenton Rb family members, which illustrates the robustness of cell cycle regulatory networks duringdifferentiation and allows for the identification of candidate pathways to inhibit the expansion of cancercells with mutations in the Rb pathway.", "metadata": {}}
+{"_id": "9646449", "title": "", "text": "Induction of ectopic eyes by targeted expression of the eyeless gene in Drosophila.The Drosophila geneeyeless (ey) encodes a transcription factor with both a paired domain and a homeodomain. It ishomologous to the mouse Small eye (Pax-6) gene and to the Aniridia gene in humans. These genes shareextensive sequence identity, the position of three intron splice sites is conserved, and these genes areexpressed similarly in the developing nervous system and in the eye during morphogenesis.Loss-of-function mutations in both the insect and in the mammalian genes have been shown to lead to areduction or absence of eye structures, which suggests that ey functions in eye morphogenesis. Bytargeted expression of the ey complementary DNA in various imaginal disc primordia of Drosophila,ectopic eye structures were induced on the wings, the legs, and on the antennae. The ectopic eyesappeared morphologically normal and consisted of groups of fully differentiated ommatidia with acomplete set of photoreceptor cells. These results support the proposition that ey is the master controlgene for eye morphogenesis. Because homologous genes are present in vertebrates, ascidians, insects,cephalopods, and nemerteans, ey may function as a master control gene throughout the metazoa.", "metadata": {}}
+{"_id": "9648896", "title": "", "text": "mir-1-mediated paracrine effect of cancer-associated fibroblasts on lung cancer cell proliferation andchemoresistance.Lung cancer is the leading cause of cancer-related mortality in humans worldwide.Moreover, the overall 5-year survival rate is only 15%. Pathologically almost 80% of all lung cancer casesare non-small cell lung cancer (NSCLC). Cancer-associated fibroblasts (CAFs) have been found to exist ina large number of NSCLCs. CAFs have been proven to promote tumor progression, metastasis andresistance to therapy through paracrine effects in most solid tumors. In the present study, firstly weisolated CAFs from patient tissues and demonstrated that they promoted cell proliferation andchemoresistance to cisplatin in the lung cancer cell lines A549 and 95D in a paracrine manner. Secondly,using ELISA and quantative PCR, we found that a higher amount of stromal cell-derived factor 1 (SDF-1)existed in the CAFs rather than that observed in the normal fibroblasts (NFs). Thirdly, we detected thatSDF-1 facilitated lung cancer cell proliferation and drug resistance via the CXCR4-mediated signalingpathway which involved NF-κB and Bcl-xL. Moreover, we also confirmed that the expression level ofSDF-1 in the CAFs was negatively regulated by microRNA mir-1 through microRNA overexpression andquantitative PCR. Overall, our data provide one explanation for the effects of CAFs on lung cancer cells.Meanwhile, our results also suggest CAFs as a potential therapeutic target in tumor treatment.", "metadata": {}}
+{"_id": "9650982", "title": "", "text": "Genome-wide association analyses in East Asians identify new susceptibility loci for colorectal cancerToidentify new genetic factors for colorectal cancer (CRC), we conducted a                 genome-wideassociation study in east Asians. By analyzing genome-wide data in 2,098                 cases and 5,749controls, we selected 64 promising SNPs for replication in an                 independent set of samples,including up to 5,358 cases and 5,922 controls. We                 identified four SNPs with association Pvalues of 8.58 ×                     10(-7) to 3.77 × 10(-10)                 in the combined analysis of all eastAsian samples. Three of the four were                 replicated in a study conducted in 26,060 individuals ofEuropean descent, with                 combined P values of 1.22 × 10(-10) for                 rs647161(5q31.1), 6.64 × 10(-9) for rs2423279                 (20p12.3) and 3.06 × 10(-8) forrs10774214                 (12p13.32 near the CCND2 gene), derived from meta-analysis of data fromboth                 east Asian and European-ancestry populations. This study identified three newCRC                 susceptibility loci and provides additional insight into the genetics and biologyof                 CRC.", "metadata": {}}
+{"_id": "9655347", "title": "", "text": "Long non-coding RNAs as novel players in β cell function and type 1 diabetesBACKGROUND Longnon-coding RNAs (lncRNAs) are a sub-class within non-coding RNA repertoire that have emerged ascrucial regulators of the gene expression in various pathophysiological conditions. lncRNAs displayremarkable versatility and wield their functions through interactions with RNA, DNA, or proteins.Accumulating body of evidence based on multitude studies has highlighted the role of lncRNAs in manyautoimmune and inflammatory diseases, including type 1 diabetes (T1D). This review highlights emergingroles of lncRNAs in immune and islet β cell function as well as some of the challenges and opportunities inunderstanding the pathogenesis of T1D and its complications. CONCLUSION We accentuate that thelncRNAs within T1D-loci regions in consort with regulatory variants and enhancer clusters orchestrate thechromatin remodeling in β cells and thereby act as cis/trans-regulatory determinants of islet celltranscriptional programs.", "metadata": {}}
+{"_id": "9658390", "title": "", "text": "Costs of the COPD. Differences between intensive care unit and respiratory intermediate careunit.INTRODUCTION To assess whether respiratory intermediate care units (RICUs) are cost effectivealternatives to intensive care units (ICUs) for patients with exacerbation of chronic obstructive pulmonarydisease (COPD). PATIENTS AND METHODS Multi-centre, prospective, bottom-up cost study performed in15 ICUs and 6 RICUs. COPD patients staying longer than 48 h were recruited; those coming from otherICUs/RICUs, with immune-deficiency or stroke, were excluded. After the ICU sample was standardised tothe RICU distribution of the reason-for-admission and infusion of a vasoactive drug on admission, 60 ICUpatients and 65 RICU patients remained, of the original 164 recruited. For each patient, besides clinicaldata on admission and discharge, daily information about the resources consumed were recorded andanalysed in terms of their costs. RESULTS Total cost per patient was lower in RICUs than in ICUs (754 vs.1507 Euro; P < 0.0001). In all items, except drugs and nutrition, we found a significant lower cost inRICUs. Dead patients were noticeably different in terms of disease severity between ICUs and RICUs,while surviving ones were not. CONCLUSIONS Our study suggests that some COPD patients, less severeand with pure respiratory failure, could be successfully and less costly treated in RICUs.", "metadata": {}}
+{"_id": "9669099", "title": "", "text": "eRNAs are required for p53-dependent enhancer activity and gene transcription.Binding within or nearbytarget genes involved in cell proliferation and survival enables the p53 tumor suppressor gene to regulatetheir transcription and cell-cycle progression. Using genome-wide chromatin-binding profiles, we describebinding of p53 also to regions located distantly from any known p53 target gene. Interestingly, many ofthese regions possess conserved p53-binding sites and all known hallmarks of enhancer regions. Wedemonstrate that these p53-bound enhancer regions (p53BERs) indeed contain enhancer activity andinteract intrachromosomally with multiple neighboring genes to convey long-distance p53-dependenttranscription regulation. Furthermore, p53BERs produce, in a p53-dependent manner, enhancer RNAs(eRNAs) that are required for efficient transcriptional enhancement of interacting target genes andinduction of a p53-dependent cell-cycle arrest. Thus, our results ascribe transcription enhancementactivity to p53 with the capacity to regulate multiple genes from a single genomic binding site. Moreover,eRNA production from p53BERs is required for efficient p53 transcription enhancement.", "metadata": {}}
+{"_id": "9675944", "title": "", "text": "Induction of pluripotent stem cells from mouse embryonic fibroblasts by Oct4 and Klf4 withsmall-molecule compounds.Somatic cells can be induced into pluripotent stem cells (iPSCs) with acombination of four transcription factors, Oct4/Sox2/Klf4/c-Myc or Oct4/Sox2/Nanog/LIN28. Thisprovides an enabling platform to obtain patient-specific cells for various therapeutic and researchapplications. However, several problems remain for this approach to be therapeutically relevant due todrawbacks associated with efficiency and viral genome integration. Recently, it was shown that neuralprogenitor cells (NPCs) transduced with Oct4/Klf4 can be reprogrammed into iPSCs. However, NPCsexpress Sox2 endogenously, possibly facilitating reprogramming in the absence of exogenous Sox2. Inthis study, we identified a small-molecule combination, BIX-01294 and BayK8644, that enablesreprogramming of Oct4/Klf4-transduced mouse embryonic fibroblasts, which do not endogenouslyexpress the factors essential for reprogramming. This study demonstrates that small molecules identifiedthrough a phenotypic screen can compensate for viral transduction of critical factors, such as Sox2, andimprove reprogramming efficiency.", "metadata": {}}
+{"_id": "9680193", "title": "", "text": "Vps22/EAP30 in ESCRT-II mediates endosomal sorting of growth factor and chemokine receptorsdestined for lysosomal degradation.The ubiquitin-binding protein Hrs and endosomal sorting complexrequired for transport (ESCRT)-I and ESCRT-III are involved in sorting endocytosed and ubiquitinatedreceptors to lysosomes for degradation and efficient termination of signaling. In this study, we haveinvestigated the role of the ESCRT-II subunit Vps22/EAP30 in degradative protein sorting of ubiquitinatedreceptors. Vps22 transiently expressed in HeLa cells was detected in endosomes containing endocytosedepidermal growth factor receptors (EGFRs) as well as Hrs and ESCRT-I and ESCRT-III. Depletion of Vps22by small interfering RNA, which was accompanied by decreased levels of other ESCRT-II subunits, greatlyreduced degradation of EGFR and its ligand EGF as well as the chemokine receptor CXCR4. EGFRaccumulated on the limiting membranes of early endosomes and aberrantly small multivesicular bodies inVps22-depleted cells. Phosphorylation and nuclear translocation of extracellular-signal-regulatedkinase1/2 downstream of the EGF-activated receptor were sustained by depletion of Hrs or the ESCRT-Isubunit Tsg101. In contrast, this was not the case when Vps22 was depleted. These results indicate animportant role for Vps22 in ligand-induced EGFR and CXCR4 turnover and suggest that termination ofEGF signaling occurs prior to ESCRT-II engagement.", "metadata": {}}
+{"_id": "9687772", "title": "", "text": "XPG stabilizes TFIIH, allowing transactivation of nuclear receptors: implications for Cockayne syndrome inXP-G/CS patients.Mutations in the human XPG gene give rise to an inherited photosensitive disorder,xeroderma pigmentosum (XP) associated with Cockayne syndrome (XP-G/CS). The clinical features of CSin XP-G/CS patients are difficult to explain on the basis of a defect in nucleotide excision repair (NER). Wefound that XPG forms a stable complex with TFIIH, which is active in transcription and NER. Mutations inXPG found in XP-G/CS patient cells that prevent the association with TFIIH also resulted in thedissociation of CAK and XPD from the core TFIIH. As a consequence, the phosphorylation andtransactivation of nuclear receptors were disturbed in XP-G/CS as well as xpg(-/-) MEF cells and could berestored by expression of wild-type XPG. These results provide an insight into the role of XPG in thestabilization of TFIIH and the regulation of gene expression and provide an explanation of some of theclinical features of XP-G/CS.", "metadata": {}}
+{"_id": "9696379", "title": "", "text": "Metabolic cycling in single yeast cells from unsynchronized steady-state populations limited on glucose orphosphate.Oscillations in patterns of expression of a large fraction of yeast genes are associated with the\"metabolic cycle,\" usually seen only in prestarved, continuous cultures of yeast. We used FISH of mRNAin individual cells to test the hypothesis that these oscillations happen in single cells drawn fromunsynchronized cultures growing exponentially in chemostats. Gene-expression data from synchronizedcultures were used to predict coincident appearance of mRNAs from pairs of genes in the unsynchronizedcells. Quantitative analysis of the FISH results shows that individual unsynchronized cells growing slowlybecause of glucose limitation or phosphate limitation show the predicted oscillations. We conclude thatthe yeast metabolic cycle is an intrinsic property of yeast metabolism and does not depend on eithersynchronization or external limitation of growth by the carbon source.", "metadata": {}}
+{"_id": "9704467", "title": "", "text": "in polyploid speciesWe developed the Yeast Gene Order Browser (YGOB; http://wolfe.gen.tcd.ie/ygob) tofacilitate visual comparisons and computational analysis of synteny relationships in yeasts. The datapresented in YGOB, currently covering seven species, are based on sets of homologous genes that havebeen intensively manually curated based on both sequence similarity and genomic context (synteny). Wereconciled different laboratories' lists of paralogous Saccharomyces cerevisiae gene pairs formed bygenome duplication (ohnologs), and present near-exhaustive lists of the ohnolog pairs retained in S.cerevisiae (551, including 22 previously unidentified), Saccharomyces castellii (599), and Candidaglabrata (404).", "metadata": {}}
+{"_id": "9705208", "title": "", "text": "Immune complex relay by subcapsular sinus macrophages and non-cognate B cells drives antibodyaffinity maturationSubcapsular sinus (SCS) macrophages capture antigens from lymph and present themintact for B cell encounter and follicular delivery. However, the properties of SCS macrophages are poorlydefined. Here we show SCS macrophage development depended on lymphotoxin-alpha1beta2, and thecells had low lysosomal enzyme expression and retained opsonized antigens on their surface. Intravitalimaging revealed immune complexes moving along macrophage processes into the follicle. Moreover,noncognate B cells relayed antigen opsonized by newly produced antibodies from the subcapsular regionto the germinal center, and affinity maturation was impaired when this transport process was disrupted.Thus, we characterize SCS macrophages as specialized antigen-presenting cells functioning at the apex ofan antigen transport chain that promotes humoral immunity.", "metadata": {}}
+{"_id": "9724974", "title": "", "text": "Promoter decoding of transcription factor dynamics involves a trade-off between noise and control ofgene expressionNumerous transcription factors (TFs) encode information about upstream signals in thedynamics of their activation, but how downstream genes decode these dynamics remains poorlyunderstood. Using microfluidics to control the nucleocytoplasmic translocation dynamics of the buddingyeast TF Msn2, we elucidate the principles that govern how different promoters convert dynamical Msn2input into gene expression output in single cells. Combining modeling and experiments, we classifypromoters according to their signal-processing behavior and reveal that multiple, distinct gene expressionprograms can be encoded in the dynamics of Msn2. We show that both oscillatory TF dynamics and slowpromoter kinetics lead to higher noise in gene expression. Furthermore, we show that the promoteractivation timescale is related to nucleosome remodeling. Our findings imply a fundamental trade-off:although the cell can exploit different promoter classes to differentially control gene expression using TFdynamics, gene expression noise fundamentally limits how much information can be encoded in thedynamics of a single TF and reliably decoded by promoters.", "metadata": {}}
+{"_id": "9730755", "title": "", "text": "GaAs nanopillar-array solar cells employing in situ surface passivationArrays of III-V direct-bandgapsemiconductor nanopillars represent promising photovoltaic candidates due to their inherent high opticalabsorption coefficients and minimized reflection arising from light trapping, efficient charge collection inthe radial direction and the ability to synthesize them on low-cost platforms. However, the increasedsurface area results in surface states that hamper the power conversion efficiency. Here, we report thefirst demonstration of GaAs nanopillar-array photovoltaics employing epitaxial passivation with air mass1.5 global power conversion efficiencies of 6.63%. High-bandgap epitaxial InGaP shells are grown in situand cap the radial p-n junctions to alleviate surface-state effects. Under light, the photovoltaic devicesexhibit open-circuit voltages of 0.44 V, short-circuit current densities of 24.3 mA cm(-2) and fill factors of62% with high external quantum efficiencies >70% across the spectral regime of interest. A noveltitanium/indium tin oxide annealed alloy is exploited as transparent ohmic anode.", "metadata": {}}
+{"_id": "9732010", "title": "", "text": "Roles of histone acetylation and chromatin remodeling factor in a meiotic recombination hotspot.Histoneacetyltransferases (HATs) and ATP-dependent chromatin remodeling factors (ADCRs) are involved inselective gene regulation via modulation of local chromatin configuration. Activation of the recombinationhotspot ade6-M26 of Schizosaccharomyces pombe is mediated by a cAMP responsive element (CRE)-likesequence, M26, and a heterodimeric ATF/CREB transcription factor, Atf1.Pcr1. Chromatin remodelingoccurs meiotically around M26. We examined the roles of HATs and ADCRs in chromatin remodelingaround M26. Histones H3 and H4 around M26 were hyperacetylated in an M26- and Atf1-dependentmanner early in meiosis. SpGcn5, the S. pombe homolog of Gcn5p, was required for the majority ofhistone H3 acetylation around M26 in vivo. Deletion of gcn5+ caused a significant delay in chromatinremodeling but only partial reduction of M26 meiotic recombination frequency. The snf22+ (aSwi2/Snf2-ADCR homologue) deletion and snf22+ gcn5+ double deletion abolished chromatin remodelingand significant reduction of meiotic recombination around M26. These results suggest that HATs andADCRs cooperatively alter local chromatin structure, as in selective transcription activation, to activatemeiotic recombination at M26 in a site-specific manner.", "metadata": {}}
+{"_id": "9737083", "title": "", "text": "The Somatic Genomic Landscape of GlioblastomaWe describe the landscape of somatic genomicalterations based on multidimensional and comprehensive characterization of more than 500 glioblastomatumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signaturereceptors, including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevatedmRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that thesurvival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNAmethylation may be a predictive biomarker for treatment response only in classical subtype GBM.Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of apathway as an alternative to inhibition of the target itself. These data will facilitate the discovery oftherapeutic and diagnostic target candidates, the validation of research and clinical observations and thegeneration of unanticipated hypotheses that can advance our molecular understanding of this lethalcancer.", "metadata": {}}
+{"_id": "9745001", "title": "", "text": "Radioiodine treatment of multinodular non-toxic goitre.OBJECTIVE To investigate the long term effect ofradioactive iodine on thyroid function and size in patients with non-toxic multinodular goitre. DESIGNConsecutive patients with multinodular non-toxic goitre selected for radioactive iodine treatment andfollowed for a minimum of 12 months (median 48 months) after an intended dose of 3.7 MBq/g thyroidtissue corrected to a 100% uptake of iodine-131 in 24 hours. PATIENTS 69 patients with a growingmultinodular non-toxic goitre causing local compression symptoms or cosmetic inconveniences. Thetreatment was chosen because of a high operative risk, previous thyroidectomy, or refusal to be operatedon. MAIN OUTCOME MEASUREMENTS Standard thyroid function variables and ultrasonically determinedthyroid volume before treatment as well as 1, 2, 3, 6, and 12 months after treatment and then once ayear. RESULTS 56 patients were treated with a single dose of 131I, 12 with two doses, and one with fourdoses. In 45 patients treated with one dose and remaining euthyroid the median thyroid volume wasreduced from 73 (interquartile range 50-106) ml to 29 (23-48) ml at 24 months in the 39 patients inwhom this was measured during follow up. The median reduction was 40 (22-48) ml (60% reduction, p <0.0001), half of which occurred within three months. Patients treated with two doses as well as thosedeveloping hypothyroidism and hyperthyroidism had a significant reduction in thyroid volume. Elevenpatients developed hypothyroidism (cumulative five year risk 22%, 95% confidence interval 4.8% to38.4%). Side effects were few: three cases of hyperthyroidism and two cases of radiation thyroiditis.Only one patient was dissatisfied with the result; she was referred for operation six months aftertreatment. CONCLUSIONS A substantial reduction in thyroid volume accompanied by a low incidence ofhypothyroidism and few side effects makes the use of radioactive iodine an attractive alternative tosurgery in selected cases of non-toxic multinodular goitre.", "metadata": {}}
+{"_id": "9748934", "title": "", "text": "Alterations in microRNA-124 and AMPA receptors contribute to social behavioral deficits in frontotemporaldementiaNeurodegenerative diseases, such as frontotemporal dementia (FTD), are often associated withbehavioral deficits, but the underlying anatomical and molecular causes remain poorly understood. Herewe show that forebrain-specific expression of FTD-associated mutant CHMP2B in mice causes severalage-dependent neurodegenerative phenotypes, including social behavioral impairments. The socialdeficits were accompanied by a change in AMPA receptor (AMPAR) composition, leading to an imbalancebetween Ca(2+)-permeable and Ca(2+)-impermeable AMPARs. Expression of most AMPAR subunits wasregulated by the brain-enriched microRNA miR-124, whose abundance was markedly decreased in thesuperficial layers of the cerebral cortex of mice expressing the mutant CHMP2B. We found similarchanges in miR-124 and AMPAR levels in the frontal cortex and induced pluripotent stem cell-derivedneurons from subjects with behavioral variant FTD. Moreover, ectopic miR-124 expression in the medialprefrontal cortex of mutant mice decreased AMPAR levels and partially rescued behavioral deficits.Knockdown of the AMPAR subunit Gria2 also alleviated social impairments. Our results identify apreviously undescribed mechanism involving miR-124 and AMPARs in regulating social behavior in FTDand suggest a potential therapeutic avenue.", "metadata": {}}
+{"_id": "9752604", "title": "", "text": "Activated AMPK boosts the Nrf2/HO-1 signaling axis—A role for the unfolded protein responseIn light ofthe emerging interplay between redox and metabolic signaling pathways we investigated the potentialcross talk between nuclear factor E2-related factor 2 (Nrf2) and AMP-activated kinase (AMPK), centralregulators of the cellular redox and energy balance, respectively. Making use of xanthohumol (XN) as anactivator of both the AMPK and the Nrf2 signaling pathway we show that AMPK exerts a positive influenceon Nrf2/heme oxygenase (HO)-1 signaling in mouse embryonic fibroblasts. Genetic ablation andpharmacological inhibition of AMPK blunts Nrf2-dependent HO-1 expression by XN already at the mRNAlevel. XN leads to AMPK activation via interference with mitochondrial function and activation of liverkinase B1 as upstream AMPK kinase. The subsequent AMPK-mediated enhancement of the Nrf2/HO-1response does not depend on inhibition of the mammalian target of rapamycin, inhibition of glycogensynthase kinase 3β, or altered abundance of Nrf2 (total and nuclear). However, reduced endoplasmicreticulum stress was identified and elaborated as a step in the AMPK-augmented Nrf2/HO-1 response.Overall, we shed more light on the hitherto incompletely understood cross talk between the LKB1/AMPKand the Nrf2/HO-1 axis revealing for the first time involvement of the unfolded protein response as anadditional player and suggesting tight cooperation between signaling pathways controlling cellular redox,energy, or protein homeostasis.", "metadata": {}}
+{"_id": "9754530", "title": "", "text": "The IDEAL recommendations and urological innovationLike other branches of surgery, Urology hasencountered major challenges in aligning the research processes by which new interventions areassessed with the principles of Evidence-Based Medicine. This article explains the IDEAL framework andrecommendations and illustrates how they might affect the evaluation of current controversial urologicalprocedures. From an inside perspective, we provide an overview of the efforts of the IDEAL WorkingGroup to date with special emphasis on the field of Urology. There are clear differences between drugsand interventions in the natural history of innovations. Since the conventional framework for conductingtrials of new treatments is largely based on the former, the evaluation of surgical innovations using thesame template can encounter significant problems. Difficulties in performing randomized controlled trialsof surgical techniques and the persistence of the case series as an important feature of the scientificliterature have been the two most controversial aspects of this mismatch between the subject of researchand the methodology used. The IDEAL framework provides a description of the process of innovation anddevelopment for surgical trials, and the associated recommendations provide a suggested alternativeapproach to developing study designs, which are appropriate for the specific problems of new techniques.IDEAL provides a new framework for surgical innovation that was developed with broad stakeholder inputfrom the surgical community and is expected to have a transformative impact on the way that urologistsperform clinical research.", "metadata": {}}
+{"_id": "9754833", "title": "", "text": "Prolonged conservative care versus early surgery in patients with sciatica caused by lumbar discherniation: two year results of a randomised controlled trial.OBJECTIVES To evaluate the effects of earlylumbar disc surgery compared with prolonged conservative care for patients with sciatica over two yearsof follow-up. DESIGN Randomised controlled trial. SETTING Nine Dutch hospitals. PARTICIPANTS 283patients with 6-12 weeks of sciatica. INTERVENTIONS Early surgery or an intended six months ofcontinued conservative treatment, with delayed surgery if needed. MAIN OUTCOME MEASURES Scoresfrom Roland disability questionnaire for sciatica, visual analogue scale for leg pain, and Likert self ratingscale of global perceived recovery. RESULTS Of the 141 patients assigned to undergo early surgery, 125(89%) underwent microdiscectomy. Of the 142 patients assigned to conservative treatment, 62 (44%)eventually required surgery, seven doing so in the second year of follow-up. There was no significantoverall difference between treatment arms in disability scores during the first two years (P=0.25).Improvement in leg pain was faster for patients randomised to early surgery, with a significant differencebetween \"areas under the curves\" over two years (P=0.05). This short term benefit of early surgery wasno longer significant by six months and continued to narrow between six months and 24 months. Patientsatisfaction decreased slightly between one and two years for both groups. At two years 20% of allpatients reported an unsatisfactory outcome. CONCLUSIONS Early surgery achieved more rapid relief ofsciatica than conservative care, but outcomes were similar by one year and these did not change duringthe second year. TRIAL REGISTRY ISRCT No 26872154.", "metadata": {}}
+{"_id": "9764256", "title": "", "text": "Human papillomavirus testing for the detection of high-grade cervical intraepithelial neoplasia andcancer: final results of the POBASCAM randomised controlled trial.BACKGROUND Human papillomavirus(HPV) testing is more sensitive for the detection of high-grade cervical lesions than is cytology, butdetection of HPV by DNA screening in two screening rounds 5 years apart has not been assessed. The aimof this study was to assess whether HPV DNA testing in the first screen decreases detection of cervicalintraepithelial neoplasia (CIN) grade 3 or worse, CIN grade 2 or worse, and cervical cancer in the secondscreening. METHODS In this randomised trial, women aged 29-56 years participating in the cervicalscreening programme in the Netherlands were randomly assigned to receive HPV DNA (GP5+/6+-PCRmethod) and cytology co-testing or cytology testing alone, from January, 1999, to September, 2002.Randomisation (in a 1:1 ratio) was done with computer-generated random numbers after the cervicalspecimen had been taken. At the second screening 5 years later, HPV DNA and cytology co-testing wasdone in both groups; researchers were masked to the patient's assignment. The primary endpoint wasthe number of CIN grade 3 or worse detected. Analysis was done by intention to screen. The trial is nowfinished and is registered, number ISRCTN20781131. FINDINGS 22,420 women were randomly assignedto the intervention group and 22 518 to the control group; 19 999 in the intervention group and 20,106in the control group were eligible for analysis at the first screen. At the second screen, 19 579 women inthe intervention group and 19,731 in the control group were eligible, of whom 16,750 and 16,743,respectively, attended the second screen. In the second round, CIN grade 3 or worse was less common inthe intervention group than in the control group (88 of 19 579 in the intervention group vs 122 of 19,731in the control group; relative risk 0·73, 95% CI 0·55-0·96; p=0·023). Cervical cancer was also lesscommon in the intervention group than in the control group (four of 19 579 in the intervention group vs14 of 19,731; 0·29, 0·10-0·87; p=0·031). In the baseline round, detection of CIN grade 3 or worse didnot differ significantly between groups (171 of 19 999 vs 150 of 20,106; 1·15, 0·92-1·43; p=0·239) butwas significantly more common in women with normal cytology (34 of 19,286 vs 12 of 19,373; 2·85,1·47-5·49; p=0·001). Furthermore, significantly more cases of CIN grade 2 or worse were detected in theintervention group than in the control group (267 of 19 999 vs 215 of 20,106; 1·25, 1·05-1·50;p=0·015). In the second screen, fewer HPV16-positive CIN grade 3 or worse were detected in theintervention group than in the control group (17 of 9481 vs 35 of 9354; 0·48, 0·27-0·85; p=0·012);detection of non-HPV16-positive CIN grade 3 or worse did not differ between groups (25 of 9481 vs 25 of9354; 0·99, 0·57-1·72; p=1·00). The cumulative detection of CIN grade 3 or worse and CIN grade 2 orworse did not differ significantly between study arms, neither for the whole study group (CIN grade 3 orworse: 259 of 19 999 vs 272 of 20,106; 0·96, 0·81-1·14, p=0·631; CIN grade 2 or worse: 427 of 19 999vs 399 of 20,106; 1·08, 0·94-1·24; p=0·292), nor for subgroups of women invited for the first time (CINgrade 3 or worse in women aged 29-33 years: 102 of 3139 vs 105 of 3128; 0·97, 0·74-1·27; CIN grade 2or worse in women aged 29-33 years: 153 of 3139 vs 151 of 3128; 1·01, 0·81-1·26; CIN grade 3 orworse in women aged 34-56 years: 157 of 16,860 vs 167 of 16 978; 0·95, 0·76-1·18; CIN grade 2 orworse in women aged 34-56 years: 274 of 16,860 vs 248 of 16 978; 1·11, 0·94-1·32). INTERPRETATIONImplementation of HPV DNA testing in cervical screening leads to earlier detection of clinically relevantCIN grade 2 or worse, which when adequately treated, improves protection against CIN grade 3 or worseand cervical cancer. Early detection of high-grade cervical legions caused by HPV16 was a majorcomponent of this benefit. Our results lend support to the use of HPV DNA testing for all women aged 29years and older. FUNDING Zorg Onderzoek Nederland (Netherlands Organisation for Health Research andDevelopment).", "metadata": {}}
+{"_id": "9767444", "title": "", "text": "Epigenetic therapy activates type I interferon signaling in murine ovarian cancer to reduceimmunosuppression and tumor burden.Ovarian cancer is the most lethal of all gynecological cancers, andthere is an urgent unmet need to develop new therapies. Epithelial ovarian cancer (EOC) is characterizedby an immune suppressive microenvironment, and response of ovarian cancers to immune therapies hasthus far been disappointing. We now find, in a mouse model of EOC, that clinically relevant doses of DNAmethyltransferase and histone deacetylase inhibitors (DNMTi and HDACi, respectively) reduce theimmune suppressive microenvironment through type I IFN signaling and improve response to immunecheckpoint therapy. These data indicate that the type I IFN response is required for effective in vivoantitumorigenic actions of the DNMTi 5-azacytidine (AZA). Through type I IFN signaling, AZA increasesthe numbers of CD45+ immune cells and the percentage of active CD8+ T and natural killer (NK) cells inthe tumor microenvironment, while reducing tumor burden and extending survival. AZA also increasesviral defense gene expression in both tumor and immune cells, and reduces the percentage ofmacrophages and myeloid-derived suppressor cells in the tumor microenvironment. The addition of anHDACi to AZA enhances the modulation of the immune microenvironment, specifically increasing T andNK cell activation and reducing macrophages over AZA treatment alone, while further increasing thesurvival of the mice. Finally, a triple combination of DNMTi/HDACi plus the immune checkpoint inhibitorα-PD-1 provides the best antitumor effect and longest overall survival, and may be an attractivecandidate for future clinical trials in ovarian cancer.", "metadata": {}}
+{"_id": "9769310", "title": "", "text": "IGF2 is parentally imprinted during human embryogenesis and in the Beckwith–Wiedemann syndromeThephenomenon of parental imprinting involves the preferential expression of one parental allele of a subsetof chromosomal genes and has so far only been documented in the mouse. We show here, by exploitingsequence polymorphisms in exon nine of the human insulin–like growth factor 2 (IGF2) gene, that onlythe paternally–inherited allele is active in embryonic and extra–embryonic cells from first trimesterpregnancies. In addition, only the paternal allele is expressed in tissues from a patient who suffered fromBeckwith–Wiedemann syndrome. Thus the parental imprinting of IGF2 appears to be evolutionarilyconserved from mouse to man and has implications for the generation of the Beckwith–Wiedemannsyndrome.", "metadata": {}}
+{"_id": "9769684", "title": "", "text": "Safety and reliability of Radio Frequency Identification Devices in Magnetic Resonance Imaging andComputed TomographyBACKGROUND Radio Frequency Identification (RFID) devices are becoming moreand more essential for patient safety in hospitals. The purpose of this study was to determine patientsafety, data reliability and signal loss wearing on skin RFID devices during magnetic resonance imaging(MRI) and computed tomography (CT) scanning. METHODS Sixty RFID tags of the type I-Code SLI, 13.56MHz, ISO 18000-3.1 were tested: Thirty type 1, an RFID tag with a 76 x 45 mm aluminum-etchedantenna and 30 type 2, a tag with a 31 x 14 mm copper-etched antenna. The signal loss, materialmovement and heat tests were performed in a 1.5 T and a 3 T MR system. For data integrity, the tagswere tested additionally during CT scanning. Standardized function tests were performed with alltransponders before and after all imaging studies. RESULTS There was no memory loss or data alterationin the RFID tags after MRI and CT scanning. Concerning heating (a maximum of 3.6 degrees C) anddevice movement (below 1 N/kg) no relevant influence was found. Concerning signal loss (artifacts 2 - 4mm), interpretability of MR images was impaired when superficial structures such as skin, subcutaneoustissues or tendons were assessed. CONCLUSIONS Patients wearing RFID wristbands are safe in 1.5 T and3 T MR scanners using normal operation mode for RF-field. The findings are specific to the RFID tags thatunderwent testing.", "metadata": {}}
+{"_id": "9784254", "title": "", "text": "LXR-Dependent Gene Expression Is Important for Macrophage Survival and the Innate ImmuneResponseThe liver X receptors (LXRs) are nuclear receptors with established roles in the regulation oflipid metabolism. We now show that LXR signaling not only regulates macrophage cholesterol metabolismbut also impacts antimicrobial responses. Mice lacking LXRs are highly susceptible to infection with theintracellular bacteria Listeria monocytogenes (LM). Bone marrow transplant studies point to alteredmacrophage function as the major determinant of susceptibility. LXR-null macrophages undergoaccelerated apoptosis when challenged with LM and exhibit defective bacterial clearance in vivo. Thesedefects result, at least in part, from loss of regulation of the antiapoptotic factor SPalpha, a direct targetfor regulation by LXRalpha. Expression of LXRalpha or SPalpha in macrophages inhibits apoptosis in thesetting of LM infection. Our results demonstrate that LXR-dependent gene expression plays anunexpected role in innate immunity and suggest that common nuclear receptor pathways mediatemacrophage responses to modified lipoproteins and intracellular pathogens.", "metadata": {}}
+{"_id": "9787715", "title": "", "text": "Alterations on peripheral B cell subsets following an acute uncomplicated clinical malaria infection inchildrenBACKGROUND The effects of Plasmodium falciparum on B-cell homeostasis have not been wellcharacterized. This study investigated whether an episode of acute malaria in young children results inchanges in the peripheral B cell phenotype. METHODS Using flow-cytofluorimetric analysis, the B cellphenotypes found in the peripheral blood of children aged 2-5 years were characterized during an episodeof acute uncomplicated clinical malaria and four weeks post-recovery and in healthy age-matchedcontrols. RESULTS There was a significant decrease in CD19+ B lymphocytes during acute malaria.Characterization of the CD19+ B cell subsets in the peripheral blood based on expression of IgD andCD38 revealed a significant decrease in the numbers of naive 1 CD38-IgD+ B cells while there was anincrease in CD38+IgD- memory 3 B cells during acute malaria. Further analysis of the peripheral B cellphenotype also identified an expansion of transitional CD10+CD19+ B cells in children following anepisode of acute malaria with up to 25% of total CD19+ B cell pool residing in this subset. CONCLUSIONChildren experiencing an episode of acute uncomplicated clinical malaria experienced profounddisturbances in B cell homeostasis.", "metadata": {}}
+{"_id": "9791313", "title": "", "text": "SETD2: an epigenetic modifier with tumor suppressor functionalityIn the past decade important progresshas been made in our understanding of the epigenetic regulatory machinery. It has become clear thatgenetic aberrations in multiple epigenetic modifier proteins are associated with various types of cancer.Moreover, targeting the epigenome has emerged as a novel tool to treat cancer patients. Recently, thefirst drugs have been reported that specifically target SETD2-negative tumors. In this review we discussthe studies on the associated protein, Set domain containing 2 (SETD2), a histone modifier for whichmutations have only recently been associated with cancer development. Our review starts with thestructural characteristics of SETD2 and extends to its corresponding function by combining studies onSETD2 function in yeast, Drosophila, Caenorhabditis elegans, mice, and humans. SETD2 is now generallyknown as the single human gene responsible for trimethylation of lysine 36 of Histone H3 (H3K36).H3K36me3 readers that recruit protein complexes to carry out specific processes, including transcriptionelongation, RNA processing, and DNA repair, determine the impact of this histone modification. Finally,we describe the prevalence of SETD2-inactivating mutations in cancer, with the highest frequency in clearcell Renal Cell Cancer, and explore how SETD2-inactivation might contribute to tumor development.", "metadata": {}}
+{"_id": "9796495", "title": "", "text": "Updated energy budgets for neural computation in the neocortex and cerebellum.The brain's energysupply determines its information processing power, and generates functional imaging signals. Theenergy use on the different subcellular processes underlying neural information processing has beenestimated previously for the grey matter of the cerebral and cerebellar cortex. However, these estimatesneed reevaluating following recent work demonstrating that action potentials in mammalian neurons aremuch more energy efficient than was previously thought. Using this new knowledge, this paper providesrevised estimates for the energy expenditure on neural computation in a simple model for the cerebralcortex and a detailed model of the cerebellar cortex. In cerebral cortex, most signaling energy (50%) isused on postsynaptic glutamate receptors, 21% is used on action potentials, 20% on resting potentials,5% on presynaptic transmitter release, and 4% on transmitter recycling. In the cerebellar cortex,excitatory neurons use 75% and inhibitory neurons 25% of the signaling energy, and most energy is usedon information processing by non-principal neurons: Purkinje cells use only 15% of the signaling energy.The majority of cerebellar signaling energy use is on the maintenance of resting potentials (54%) andpostsynaptic receptors (22%), while action potentials account for only 17% of the signaling energy use.", "metadata": {}}
+{"_id": "9813098", "title": "", "text": "Plasma homocysteine is a risk factor for recurrent vascular events in young patients with an ischaemicstroke or TIAYoung patients with an ischaemic stroke or transient ischaemic attack (TIA) often have novascular risk factors. Hyperhomocysteinaemia is an established risk factor for stroke in elderly patientsbut it is uncertain whether it is also important for the prognosis of young ischaemic stroke and TIApatients. We examined the possible effect of the plasma homocysteine level on the risk of recurrentvascular events in patients between 18 and 45 years of age. The study population consisted of 161consecutive patients with a recent cerebral infarction or TIA. Data on the primary event and thehomocysteine level were collected retrospectively from hospital records. General practitioners andpatients were contacted by telephone to record vascular events and the type of medication used duringthe follow–up period. Vascular events included cerebral infarction, TIA, pulmonary embolism, venousthrombosis, myocardial infarction and peripheral arterial disease. A Kaplan- Meier curve showed a doseeffect relationship between event-free survival time and tertiles of the homocysteine level (Log rankstatistic 5.91; p = 0.05). The Cox hazard ratio, after adjustment for homocysteine lowering treatment,was 1.7 (95 % CI, 1.1 to 2.8) for any vascular outcome event, 1.9 (95% CI, 1.1 to 3.0) for arterialoutcome events and 1.8 (95 % CI, 1.1 to 2.9) for cerebral outcome events. In spite of our small numberof outcome events we found a significant association at the 95% confidence level between homocysteinelevel and the risk of recurrent vascular events in young patients with an ischaemic stroke or TIA. Theassociation is of the same magnitude as in elderly people.", "metadata": {}}
+{"_id": "9814332", "title": "", "text": "LDL inhibits the mediation of cholesterol efflux from macrophage foam cells by apoA-I-containinglipoproteins. A putative mechanism for foam cell formation.Although the accumulation of cholesterol inmacrophages appears to be an initial step in atherogenesis, low-density lipoprotein (LDL), a major riskfactor for atherosclerosis, does not promote cholesterol accumulation in macrophages in its native form.On the other hand, apolipoprotein (apo) A-I-containing lipoprotein removes cholesterol fromcholesterol-loaded macrophages (foam cells) and prevents cholesterol from accumulating in the cells. Weexamined the effect of LDL on cholesterol removal by two species of apoA-I-containing lipoproteins, onecontaining only apoA-I (LpA-I) and the other containing apoA-I and apoA-II (LpA-I/A-II). When foamcells were incubated with LpA-I or LpA-I/A-II, cellular cholesterol mass was reduced. In contrast, whenLDL was added, the cholesterol-reducing capacities of these lipoproteins were dose-dependently inhibitedby LDL. In the presence of LDL, LpA-I and LpA-I/A-II removed free cholesterol preferentially from LDLrather than from the plasma membrane of foam cells. In addition, a fair amount of cellular cholesterolwas directly moved to LDL rather than to LpA-I or LpA-I/A-II. The cellular cholesterol that moved to LDLwas completely compensated for by the cholesterol influx from LDL to foam cells. Thus, net cholesterolefflux (a combination of influx and efflux) from foam cells was inhibited by LDL. These results, takentogether, indicate that LDL may accelerate foam cell formation by inhibiting cholesterol removal from thecells and that elevated levels of plasma LDL may become a risk factor for atherosclerosis by inhibiting thefunction of LpA-I and LpA-I/A-II at the cellular level.", "metadata": {}}
+{"_id": "9822397", "title": "", "text": "Sugar-sweetened beverages, weight gain, and incidence of type 2 diabetes in young and middle-agedwomen.CONTEXT Sugar-sweetened beverages like soft drinks and fruit punches contain large amounts ofreadily absorbable sugars and may contribute to weight gain and an increased risk of type 2 diabetes, butthese relationships have been minimally addressed in adults. OBJECTIVE To examine the associationbetween consumption of sugar-sweetened beverages and weight change and risk of type 2 diabetes inwomen. DESIGN, SETTING, AND PARTICIPANTS Prospective cohort analyses conducted from 1991 to1999 among women in the Nurses' Health Study II. The diabetes analysis included 91,249 women free ofdiabetes and other major chronic diseases at baseline in 1991. The weight change analysis included51,603 women for whom complete dietary information and body weight were ascertained in 1991, 1995,and 1999. We identified 741 incident cases of confirmed type 2 diabetes during 716,300 person-years offollow-up. MAIN OUTCOME MEASURES Weight gain and incidence of type 2 diabetes. RESULTS Those withstable consumption patterns had no difference in weight gain, but weight gain over a 4-year period washighest among women who increased their sugar-sweetened soft drink consumption from 1 or fewerdrinks per week to 1 or more drinks per day (multivariate-adjusted means, 4.69 kg for 1991 to 1995 and4.20 kg for 1995 to 1999) and was smallest among women who decreased their intake (1.34 and 0.15 kgfor the 2 periods, respectively) after adjusting for lifestyle and dietary confounders. Increasedconsumption of fruit punch was also associated with greater weight gain compared with decreasedconsumption. After adjustment for potential confounders, women consuming 1 or more sugar-sweetenedsoft drinks per day had a relative risk [RR] of type 2 diabetes of 1.83 (95% confidence interval [CI],1.42-2.36; P<.001 for trend) compared with those who consumed less than 1 of these beverages permonth. Similarly, consumption of fruit punch was associated with increased diabetes risk (RR for > or =1drink per day compared with <1 drink per month, 2.00; 95% CI, 1.33-3.03; P =.001). CONCLUSIONHigher consumption of sugar-sweetened beverages is associated with a greater magnitude of weight gainand an increased risk for development of type 2 diabetes in women, possibly by providing excessivecalories and large amounts of rapidly absorbable sugars.", "metadata": {}}
+{"_id": "9831859", "title": "", "text": "Pancreatic stellate cells: partners in crime with pancreatic cancer cells.Pancreatic stellate cells (PSC)produce the stromal reaction in pancreatic cancer, but their role in cancer progression is not fullyelucidated. We examined the influence of PSCs on pancreatic cancer growth using (a) an orthotopicmodel of pancreatic cancer and (b) cultured human PSCs (hPSC) and human pancreatic cancer cell linesMiaPaCa-2 and Panc-1. Athymic mice received an intrapancreatic injection of saline, hPSCs, MiaPaCa-2cells, or hPSCs + MiaPaCa-2. After 7 weeks, tumor size, metastases, and tumor histology were assessed.In vitro studies assessed the effect of cancer cell secretions on PSC migration and the effect of hPSCsecretions on cancer cell proliferation, apoptosis, and migration. Possible mediators of the effects of hPSCsecretions on cancer cell proliferation were examined using neutralizing antibodies. Compared with micereceiving MiaPaCa-2 cells alone, mice injected with hPSCs + MiaPaCa-2 exhibited (a) increased tumorsize and regional and distant metastasis, (b) fibrotic bands (desmoplasia) containing activated PSCswithin tumors, and (c) increased tumor cell numbers. In vitro studies showed that, in the presence ofpancreatic cancer cells, PSC migration was significantly increased. Furthermore, hPSC secretions inducedthe proliferation and migration, but inhibited the apoptosis, of MiaPaCa-2 and Panc-1 cells. Theproliferative effect of hPSC secretions on pancreatic cancer cells was inhibited in the presence ofneutralizing antibody to platelet-derived growth factor. Our studies indicate a significant interactionbetween pancreatic cancer cells and stromal cells (PSCs) and imply that pancreatic cancer cells recruitstromal cells to establish an environment that promotes cancer progression.", "metadata": {}}
+{"_id": "9846940", "title": "", "text": "Preoperative statin treatment reduces systemic inflammatory response and myocardial damage in cardiacsurgery.OBJECTIVE To determine if preoperative statin treatment is associated with a reduction insystemic inflammatory response (SIR) and myocardial damage markers following cardiac surgery withcardiopulmonary bypass (CPB). METHODS We study a prospective cohort of 138 patients who underwentcoronary and valvular surgery with CPB. We differentiate two study groups: patients with (group A,n=72) or without (group B, n=66) statins. Plasma levels of pro-inflammatory interleukins (tumournecrosis factor-alpha (TNF-alpha), interleukin (IL)-6, IL-8 and IL-2R), creatine phosphokinase (CPK),CPK-MB and troponin I were measured before and 1, 6, 24 and >72 h after surgery. RESULTS Thebaseline, operative and postoperative morbidity and mortality characteristics were similar for both thegroups. Group A had significantly lower postoperative levels of IL-6 than group B at 6h (68.8+/-5 pgml(-1) vs 108.9+/-108 pg ml(-1), p=0.01), 24h (71.7+/-7 pg ml(-1) vs 110.4+/-106 pg ml(-1), p=0.01)and before hospital discharge (21.6+/-12 pg ml(-1) vs 32.8+/-27 pg ml(-1), p=0.005), as well assignificantly lower average IL-6 levels in the first 24h following surgery (71.8+/-5 pgml(-1) vs112.8+/-82 pg ml(-1), p=0.002). The postoperative CPK-MB at 24h (19.7+/-23 ng ml(-1) vs 33.1+/-32ng ml(-1), p=0.02) and troponin I levels at the end of the intervention (2.2+/-2.2 ng ml(-1) vs 3.3+/-3.1ng ml(-1), p=0.03) and at 24h (4.1+/-3.5 ng ml(-1) vs 6.6+/-8 ng ml(-1), p=0.04) were alsosignificantly lower in the group treated with statins prior to surgery. CONCLUSIONS Preoperativetreatment with statins is associated with a lower biochemical parameters of SIR and myocardial damagefollowing cardiac surgery with CPB, regardless of it being coronary bypass grafting (CABG) or valvularsurgery.", "metadata": {}}
+{"_id": "9872468", "title": "", "text": "MEGA7: Molecular Evolutionary Genetics Analysis Version 7.0 for Bigger Datasets.We present the latestversion of the Molecular Evolutionary Genetics Analysis (Mega) software, which contains manysophisticated methods and tools for phylogenomics and phylomedicine. In this major upgrade, Mega hasbeen optimized for use on 64-bit computing systems for analyzing larger datasets. Researchers can nowexplore and analyze tens of thousands of sequences in Mega The new version also provides an advancedwizard for building timetrees and includes a new functionality to automatically predict gene duplicationevents in gene family trees. The 64-bit Mega is made available in two interfaces: graphical and commandline. The graphical user interface (GUI) is a native Microsoft Windows application that can also be used onMac OS X. The command line Mega is available as native applications for Windows, Linux, and Mac OS X.They are intended for use in high-throughput and scripted analysis. Both versions are available fromwww.megasoftware.net free of charge.", "metadata": {}}
+{"_id": "9875570", "title": "", "text": "DNA replication fidelityDNA replication fidelity is a key determinant of genome stability and is central tothe evolution of species and to the origins of human diseases. Here we review our current understandingof replication fidelity, with emphasis on structural and biochemical studies of DNA polymerases thatprovide new insights into the importance of hydrogen bonding, base pair geometry, andsubstrate-induced conformational changes to fidelity. These studies also reveal polymerase interactionswith the DNA minor groove at and upstream of the active site that influence nucleotide selectivity, theefficiency of exonucleolytic proofreading, and the rate of forming errors via strand misalignments. Wehighlight common features that are relevant to the fidelity of any DNA synthesis reaction, and considerwhy fidelity varies depending on the enzymes, the error, and the local sequence environment.", "metadata": {}}
+{"_id": "9878167", "title": "", "text": "Viable neutrophils release mitochondrial DNA to form neutrophil extracellular trapsNeutrophil extracellulartraps (NETs) represent extracellular structures able to bind and kill microorganisms. It is believed thatthey are generated by neutrophils undergoing cell death, allowing these dying or dead cells to killmicrobes. We show that, following priming with granulocyte/macrophage colony-stimulating factor(GM-CSF) and subsequent short-term toll-like receptor 4 (TLR4) or complement factor 5a (C5a) receptorstimulation, viable neutrophils are able to generate NETs. Strikingly, NETs formed by living cells containmitochondrial, but no nuclear, DNA. Pharmacological or genetic approaches to block reactive oxygenspecies (ROS) production suggested that NET formation is ROS dependent. Moreover, neutrophilpopulations stimulated with GM-CSF and C5a showed increased survival compared with restingneutrophils, which did not generate NETs. In conclusion, mitochondrial DNA release by neutrophils andNET formation do not require neutrophil death and do also not limit the lifespan of these cells.", "metadata": {}}
+{"_id": "9881829", "title": "", "text": "ATP-driven exchange of histone H2AZ variant catalyzed by SWR1 chromatin remodeling complex.Theconserved histone variant H2AZ has an important role in the regulation of gene expression and theestablishment of a buffer to the spread of silent heterochromatin. How histone variants such as H2AZ areincorporated into nucleosomes has been obscure. We have found that Swr1, a Swi2/Snf2-relatedadenosine triphosphatase, is the catalytic core of a multisubunit, histone-variant exchanger thatefficiently replaces conventional histone H2A with histone H2AZ in nucleosome arrays. Swr1 is requiredfor the deposition of histone H2AZ at specific chromosome locations in vivo, and Swr1 and H2AZcommonly regulate a subset of yeast genes. These findings define a previously unknown role for theadenosine triphosphate-dependent chromatin remodeling machinery.", "metadata": {}}
+{"_id": "9889151", "title": "", "text": "FACT Disrupts Nucleosome Structure by Binding H2A-H2B with Conserved Peptide Motifs.FACT, aheterodimer of Spt16 and Pob3, is an essential histone chaperone. We show that the H2A-H2B bindingactivity that is central to FACT function resides in short acidic regions near the C termini of each subunit.Mutations throughout these regions affect binding and cause correlated phenotypes that range from mildto lethal, with the largest individual contributions unexpectedly coming from an aromatic residue and anearby carboxylate residue within each domain. Spt16 and Pob3 bind overlapping sites on H2A-H2B, andSpt16-Pob3 heterodimers simultaneously bind two H2A-H2B dimers, the same stoichiometry as thecomponents of a nucleosome. An Spt16:H2A-H2B crystal structure explains the biochemical and geneticdata, provides a model for Pob3 binding, and implies a mechanism for FACT reorganization that weconfirm biochemically. Moreover, unexpected similarity to binding of ANP32E and Swr1 with H2A.Z-H2Breveals that diverse H2A-H2B chaperones use common mechanisms of histone binding and regulatingnucleosome functions.", "metadata": {}}
+{"_id": "9899292", "title": "", "text": "Role of AMP-activated protein kinase in mechanism of metformin action.Metformin is a widely used drugfor treatment of type 2 diabetes with no defined cellular mechanism of action. Its glucose-lowering effectresults from decreased hepatic glucose production and increased glucose utilization. Metformin'sbeneficial effects on circulating lipids have been linked to reduced fatty liver. AMP-activated proteinkinase (AMPK) is a major cellular regulator of lipid and glucose metabolism. Here we report thatmetformin activates AMPK in hepatocytes; as a result, acetyl-CoA carboxylase (ACC) activity is reduced,fatty acid oxidation is induced, and expression of lipogenic enzymes is suppressed. Activation of AMPK bymetformin or an adenosine analogue suppresses expression of SREBP-1, a key lipogenic transcriptionfactor. In metformin-treated rats, hepatic expression of SREBP-1 (and other lipogenic) mRNAs andprotein is reduced; activity of the AMPK target, ACC, is also reduced. Using a novel AMPK inhibitor, wefind that AMPK activation is required for metformin's inhibitory effect on glucose production byhepatocytes. In isolated rat skeletal muscles, metformin stimulates glucose uptake coincident with AMPKactivation. Activation of AMPK provides a unified explanation for the pleiotropic beneficial effects of thisdrug; these results also suggest that alternative means of modulating AMPK should be useful for thetreatment of metabolic disorders.", "metadata": {}}
+{"_id": "9904546", "title": "", "text": "Interferon alfa therapy for chronic hepatitis B in children: a multinational randomized controlledtrial.BACKGROUND & AIMS Treatment of chronic hepatitis B with interferon alfa is not approved inchildren. The aim of this study was to evaluate the safety and efficacy of interferon alfa (IFN-alpha) inchildren with chronic hepatitis B and increased transaminase levels. METHODS Children were given eitherIFN-alpha2b (6 megaunits/m2 thrice weekly for 24 weeks) or no treatment. Clearance of markers of viralreplication was evaluated 24 weeks after therapy and after 48 weeks of observation in controls. RESULTSOf 149 children enrolled, 144 were evaluable (70 treated and 74 controls). Serum hepatitis B e antigenand viral DNA became negative in 26% of treated children and 11% of controls (P < 0.05). Serumaminotransferase levels normalized and liver histology improved among responders. Hepatitis B surfaceantigen became undetectable in 10% of treated patients and 1% of controls. Female gender andinterferon treatment were the only significant predictors of response. Ethnic origin, baselineaminotransferase level, initial DNA levels, and histology did not correlate with response. Most adversereactions were mild or moderate, and dose was reduced in 24% of children. CONCLUSIONS In childrenwith chronic hepatitis B, INF-alpha promotes loss of viral replication markers and surface antigen andimproves aminotransferases and histology.", "metadata": {}}
+{"_id": "9909405", "title": "", "text": "ImmTACs for targeted cancer therapy: Why, what, how, and which.Overcoming immunosuppression andactivating a cytotoxic T cell response has the potential to halt the progression of cancer and, in somecircumstances, eradicate it. Designing therapeutic interventions that achieve this goal has provenchallenging, but now a greater understanding of the complexities of immune responses is beginning toproduce some notable breakthroughs. ImmTACs (immune-mobilising monoclonal TCRs against cancer)are a new class of bispecific reagents, based on soluble monoclonal T cell receptors, which have beenengineered to possess extremely high affinity for cognate tumour antigen. In this way, ImmTACsovercome the problem of low affinity tumour-specific T cells imposed by thymic selection and provideaccess to the large number of antigens presented as peptide-HLA complexes. Once bound to tumour cellsthe anti-CD3 effector end of the ImmTAC drives recruitment of polyclonal T cells to the tumour site,leading to a potent redirected T cell response and tumour cell destruction. Extensive in vitro testingcoupled with promising early clinical data has provided an enhanced appreciation of ImmTAC function invivo and indicates their potential therapeutic benefit in terms of a durable response and ultimately thebreaking of T cell tolerance. This review introduces ImmTACs in the context of immunotherapy, andoutlines their design, construction and mechanism of action, as well as examining target selection andaspects of preclinical safety testing.", "metadata": {}}
+{"_id": "9911547", "title": "", "text": "Angiopoietin-like protein 3 supports the activity of hematopoietic stem cells in the bone marrow niche.Thephysiologic roles of angiopoietin-like proteins (Angptls) in the hematopoietic system remain unknown.Here we show that hematopoietic stem cells (HSCs) in Angptl3-null mice are decreased in number andquiescence. HSCs transplanted into Angptl3-null recipient mice exhibited impaired repopulation. Bonemarrow sinusoidal endothelial cells express high levels of Angptl3 and are adjacent to HSCs. Importantly,bone marrow stromal cells or endothelium deficient in Angptl3 have a significantly decreased ability tosupport the expansion of repopulating HSCs. Angptl3 represses the expression of the transcription factorIkaros, whose unregulated overexpression diminishes the repopulation activity of HSCs. Angptl3, as anextrinsic factor, thus supports the stemness of HSCs in the bone marrow niche.", "metadata": {}}
+{"_id": "9929089", "title": "", "text": "Subsequent chemotherapy reverses acquired tyrosine kinase inhibitor resistance and restores response totyrosine kinase inhibitor in advanced non-small-cell lung cancerBACKGROUND Patients with advanced ormetastatic non-small cell lung cancer (NSCLC) can develop acquired resistance to epidermal growthfactor receptor tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib. Here, we report the successfultreatment with alternating chemotherapy and TKIs of two cases of advanced NSCLC who developedresistance to TKI. CASE PRESENTATION Two patients with advanced or metastatic NSCLC were treatedwith palliative chemotherapy followed by erlotinib/gefitinib. When TKI therapy failed, two cycles ofchemotherapy were provided, which were followed by re-challenge with erlotinib or gefitinib.CONCLUSION NSCLC patients with acquired TKI resistance should be managed aggressively wheneverpossible. Subsequent chemotherapy and target treatment is one of the reasonable choices for those withan initial dramatic clinical response with erlotinib/gefitinib treatment. Further studies are warranted tosubstantiate the association of erlotinib /gefitinib treatment with the efficacy of NSCLC patients withacquired TKI failure.", "metadata": {}}
+{"_id": "9955779", "title": "", "text": "Epigenetic Therapy Ties MYC Depletion to Reversing Immune Evasion and Treating LungCancerCombining DNA-demethylating agents (DNA methyltransferase inhibitors [DNMTis]) with histonedeacetylase inhibitors (HDACis) holds promise for enhancing cancer immune therapy. Herein,pharmacologic and isoform specificity of HDACis are investigated to guide their addition to a DNMTi, thusdevising a new, low-dose, sequential regimen that imparts a robust anti-tumor effect for non-small-celllung cancer (NSCLC). Using in-vitro-treated NSCLC cell lines, we elucidate an interferon α/β-basedtranscriptional program with accompanying upregulation of antigen presentation machinery, mediated inpart through double-stranded RNA (dsRNA) induction. This is accompanied by suppression of MYCsignaling and an increase in the T cell chemoattractant CCL5. Use of this combination treatment schemain mouse models of NSCLC reverses tumor immune evasion and modulates T cell exhaustion statetowards memory and effector T cell phenotypes. Key correlative science metrics emerge for an upcomingclinical trial, testing enhancement of immune checkpoint therapy for NSCLC.", "metadata": {}}
+{"_id": "9956893", "title": "", "text": "The Role of PPARγ in Advanced Glycation End Products-Induced Inflammatory Response in HumanChondrocytesOBJECTIVE Advances made in the past ten years highlight the notion that peroxisomeproliferator-activated receptors gamma (PPARγ) has protective properties in the pathophysiology ofosteoarthritis (OA). The aim of this study was to define the roles of PPARγ in AGEs-induced inflammatoryresponse in human chondrocytes. METHODS Primary human chondrocytes were stimulated with AGEs inthe presence or absence of neutralizing antibody against RAGE (anti-RAGE), MAPK specific inhibitors andPPARγ agonist pioglitazone. The expression of IL-1, MMP-13, TNF-α, PPARγ, nuclear NF-κB p65 andcytosol IκBα was determined by western blotting and real-time PCR. RESULTS AGEs could enhance theexpression of IL-1, TNF-α, and MMP-13, but the level of PPARγ was decreased in a time- anddose-dependent manner, which was inhibited by anti-RAGE, SB203580 (P38 MAPK specific inhibitor) andSP600125 (a selective inhibitor of JNK). PPARγ agonist pioglitazone could inhibit the effects ofAGEs-induced inflammatory response and PPARγ down-regulation. In human chondrocytes, AGEs couldinduce cytosol IκBα degradation and increase the level of nuclear NF-κB p65, which was inhibited byPPARγ agonist pioglitazone. CONCLUSIONS In primary human chondrocytes, AGEs could down-regulatePPARγ expression and increase the inflammatory mediators, which could be reversed by PPARγ agonistpioglitazone. Activation of RAGE by AGEs triggers a cascade of downstream signaling, including MAPKJNK/ p38, PPARγ and NF-κB. Taken together, PPARγ could be a potential target for pharmacologicintervention in the treatment of OA.", "metadata": {}}
+{"_id": "9967265", "title": "", "text": "Surgical versus medical treatment with cyclooxygenase inhibitors for symptomatic patent ductusarteriosus in preterm infants.BACKGROUND Patent ductus arteriosus (PDA) with significant left to rightshunt in preterm infants increases morbidity and mortality. Early closure of the ductus arteriosus may beachieved pharmacologically using cyclooxygenase inhibitors or by surgery. The efficacy of both treatmentmodalities is well established. However, the preferred initial treatment of a symptomatic PDA in a preterminfant, surgical ligation or treatment with indomethacin, has not been well established. OBJECTIVES Tocompare the effect of surgical ligation of PDA vs. medical treatment with cyclooxygenase inhibitors (usingindomethacin, ibuprofen, or mefenamic acid), each used as the initial treatment, on neonatal mortality inpreterm infants with a symptomatic PDA. SEARCH STRATEGY The standard search strategy of theCochrane Neonatal Review Group was used. This included search of electronic databases: CochraneCentral Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2007), MEDLINE (1966 -July 2007), CINAHL (1982 - July 2007), EMBASE (1980 - July 2007); and hand search of abstracts ofPediatric Academic Societies annual meetings published in Pediatric Research (1990 - April 2002) or online from May 2002 -July 2007. No language restrictions were applied. SELECTION CRITERIA All trials 1)using randomized or quasi-randomized patient allocation, 2) in preterm infants < 37 weeks gestationalage or low-birth-weight infants (< 2500 grams) with symptomatic PDA in the neonatal period (< 28 days)and 3) comparing surgical ligation with medical treatment with cyclooxygenase inhibitors, each used asthe initial treatment for closure of PDA. DATA COLLECTION AND ANALYSIS Assessment of methodologicalquality and extraction of data for included trials was undertaken independently by the authors. RevMan4.1 was used for analysis of the data. MAIN RESULTS Only one study, trial B in the report of Gersony1983, was found eligible. No additional studies were identified in the literature searches performed in July2007. The trial compared the effect of surgical ligation of PDA vs. medical treatment with indomethacin,each used as the primary treatment. No trials comparing surgery to other cyclooxygenase inhibitors(ibuprofen, mefenamic acid) were found. Trial B of Gersony 1983 enrolled 154 infants. The study foundno statistically significant difference between surgical closure and indomethacin treatment in mortalityduring hospital stay, chronic lung disease, other bleeding, necrotizing enterocolitis, sepsis, creatininelevel, or intraventricular hemorrhage. There was a statistically significant increase in the surgical group inincidence of pneumothorax [RR 2.68 (95% CI 1.45, 4.93); RD 0.25 (95% CI 0.11, 0.38); NNH 4 (95% CI3, 9)] and retinopathy of prematurity stage III and IV [RR 3.80 (95% CI 1.12, 12.93); RD 0.11 (95% CI0.02, 0.20), NNH 9 (95% CI 5, 50] compared to the indomethacin group. There was as expected astatistically significant decrease in failure of ductal closure rate in the surgical group as compared to theindomethacin group: [RR 0.04 (95% CI 0.01, 0.27); RD -0.32 (95% CI -0.43, -0.21), NNT 3 (95% CI 2,4)]. AUTHORS' CONCLUSIONS The data regarding net benefit/harm are insufficient to make a conclusionas to whether surgical ligation or medical treatment with indomethacin is preferred as initial treatment forsymptomatic PDA in preterm infants. It should be noted that three recent observational studies indicatedan increased risk for one or more of the following outcomes associated with PDA ligation; chronic lungdisease, retinopathy of prematurity and neurosensory impairment . It is possible that the duration of the\"waiting-time\" and transport to another facility with surgical capacity to have the PDA ligated couldadversely affect outcomes, as could the perioperative care.", "metadata": {}}
+{"_id": "9973014", "title": "", "text": "The Effect of Collinearity on Parameter Estimates in Nonlinear Mixed Effect ModelsPurpose. Todemonstrate how correlations among predictor variables in a population pharmacokinetic model affect theability to discern which covariates should enter into the structural pharmacokinetic model. Methods.Monte Carlo simulation was used to generate multiple-dose concentration-time data similar to that seenin a Phase III clinical trial. The drugs' pharmacokinetics were dependent on two covariates. Five data setswere simulated with increasing correlation between the two covariates. All data sets were analyzed usingNONMEM both with and without inclusion of the covariates in the structural pharmacokinetic model.Summary measures for ill-conditioning and sensitivity analysis were used to examine how increasingcorrelation among covariates affects the accuracy and precision of the parameter estimates. Results.When covariates were included in the structural pharmacokinetic model and the correlation betweencovariates increased, the standard error of the parameter estimates increased and the value ofparameter estimates themselves became increasingly biased. When the correlation between predictorvariables was 0.75, the standard errors of the parameter estimates were too large to declare statisticalsignificance. Conclusions. Correlations among predictor variables greater than 0.5 when entered into themodel simultaneously should be a warning to researchers because the (1) the accuracy of the parameterestimates themselves may be biased and (2) the precision of the estimates may be inflated due toill-conditioning.", "metadata": {}}
+{"_id": "9976969", "title": "", "text": "An analysis of age and gender influences on the relative risk for suicide and psychotropic drugself-poisoning.Psychiatric illness is a significant risk factor for both attempted and completed suicide andpsychotropic medications account for 80% of all drug overdoses involving prescription medications. Onechallenge facing clinicians is to balance the benefit of treatment against the risk of drug overdose. Theaim of the present study was to compare the age and gender distribution of patients prescribedpsychotropic drugs with patients attempting and completing suicide with these drugs. Data were obtainedfrom the Australian census and studies of general practitioner prescribing, patients who committedsuicide or presented with self-poisoning within a defined geographic area. The characteristics of thesepopulations were compared to calculate odds ratios for attempting or completing suicide withpsychotropic drugs, before and after correction for rates of prescription, in different age and gendergroups. The odds ratios (ORs) for self-poisoning were higher for those aged less than 45 years and yetthis group was least likely to be prescribed psychotropic drugs. Men had a much higher rate of completedsuicide using more lethal methods. The ORs for self-poisoning and suicide with psychotropic drugs, aftercorrection for prescription rates, for those aged 15 to 24 years were 11.1 and 1.7, respectively. Thoseaged 25 to 44 years had ORs of 4.9 and 4.3, and, by contrast, those over 75 years had ORs of 0.03 and0. Women were slightly more likely to poison themselves with psychotropic drugs (OR 1.2). However, thesituation reversed after correction for prescription rates (OR 0.69). It is concluded that greater cautionshould be exercised in prescribing for those under 45 years of age, given their relatively higher risk ofdrug overdose, and that the least toxic compounds should be used. The risk (of self-poisoning) amongthe elderly may have been overstated, so that some patients may have been denied the benefit ofadequate treatment.", "metadata": {}}
+{"_id": "9977329", "title": "", "text": "Cell death and immune privilege.The host response to pathogens involves complex inflammatoryresponses and immune reactions. While these are central to host defense and vital to clearing infections,they are often accompanied by injury to surrounding tissue. Most organ systems can tolerate theseresponses without permanent consequences. However, there are sites that limit the spread ofinflammation because it can threaten organ function. The most prominent examples of these are the eye,brain, and reproductive organs (testis, ovary), where even minor bouts of inflammation can havelong-term consequences for the survival of the organism. In these organs immune responses either donot proceed, or proceed in a manner different from other areas; thus, they are called \"immunologicallyprivileged. \" Here a functioning immune response can be the culprit that leads to disease.", "metadata": {}}
+{"_id": "9988425", "title": "", "text": "Niche-Independent Symmetrical Self-Renewal of a Mammalian Tissue Stem CellPluripotent mouseembryonic stem (ES) cells multiply in simple monoculture by symmetrical divisions. In vivo, however,stem cells are generally thought to depend on specialised cellular microenvironments and to undergopredominantly asymmetric divisions. Ex vivo expansion of pure populations of tissue stem cells hasproven elusive. Neural progenitor cells are propagated in combination with differentiating progeny infloating clusters called neurospheres. The proportion of stem cells in neurospheres is low, however, andthey cannot be directly observed or interrogated. Here we demonstrate that the complex neurosphereenvironment is dispensable for stem cell maintenance, and that the combination of fibroblast growthfactor 2 (FGF-2) and epidermal growth factor (EGF) is sufficient for derivation and continuous expansionby symmetrical division of pure cultures of neural stem (NS) cells. NS cells were derived first from mouseES cells. Neural lineage induction was followed by growth factor addition in basal culture media. In thepresence of only EGF and FGF-2, resulting NS cells proliferate continuously, are diploid, and clonogenic.After prolonged expansion, they remain able to differentiate efficiently into neurons and astrocytes invitro and upon transplantation into the adult brain. Colonies generated from single NS cells all produceneurons upon growth factor withdrawal. NS cells uniformly express morphological, cell biological, andmolecular features of radial glia, developmental precursors of neurons and glia. Consistent with thisprofile, adherent NS cell lines can readily be established from foetal mouse brain. Similar NS cells can begenerated from human ES cells and human foetal brain. The extrinsic factors EGF plus FGF-2 aresufficient to sustain pure symmetrical self-renewing divisions of NS cells. The resultant cultures constitutethe first known example of tissue-specific stem cells that can be propagated without accompanyingdifferentiation. These homogenous cultures will enable delineation of molecular mechanisms that define atissue-specific stem cell and allow direct comparison with pluripotent ES cells.", "metadata": {}}
+{"_id": "9993008", "title": "", "text": "A Bivalent Chromatin Structure Marks Key Developmental Genes in Embryonic Stem CellsThe most highlyconserved noncoding elements (HCNEs) in mammalian genomes cluster within regions enriched for genesencoding developmentally important transcription factors (TFs). This suggests that HCNE-rich regionsmay contain key regulatory controls involved in development. We explored this by examining histonemethylation in mouse embryonic stem (ES) cells across 56 large HCNE-rich loci. We identified a specificmodification pattern, termed \"bivalent domains,\" consisting of large regions of H3 lysine 27 methylationharboring smaller regions of H3 lysine 4 methylation. Bivalent domains tend to coincide with TF genesexpressed at low levels. We propose that bivalent domains silence developmental genes in ES cells whilekeeping them poised for activation. We also found striking correspondences between genome sequenceand histone methylation in ES cells, which become notably weaker in differentiated cells. These resultshighlight the importance of DNA sequence in defining the initial epigenetic landscape and suggest a novelchromatin-based mechanism for maintaining pluripotency.", "metadata": {}}
+{"_id": "9997636", "title": "", "text": "Ovarian Surface Epithelium in Patients with Severe Ovarian Infertility: A Potential Source of CellsExpressing Markers of Pluripotent/Multipotent Stem CellsThe aim of this study was to confirm thepresence of stem cells in the ovarian surface epithelium of patients with premature ovarian failure and nomature follicles and oocytes. In these patients, small round cells of unknown origin expressing SOX-2marker of pluripotency were observed among the epithelial cells just after the ovarian surface epitheliumscraping. These cells were an integral part of the ovarian surface epithelium. When the scraped cells werecultured in a medium with added follicular fluid to provide some ovarian niche, primitive oocyte-like cellsand typical round-shaped cell clusters positively stained on alkaline phosphatase, and markers ofpluripotency, such as SOX-2 and SSEA-4, were developed. These markers were expressed early and alsolater in the culture. Single oocyte-like cells expressed genes OCT4A, SOX-2, NANOG, NANOS, STELLA,CD9, LIN28, KLF4, GDF3, and MYC, characteristic for pluripotent stem cells. The results of this studyconfirmed the presence of putative stem cells in the ovarian surface epithelium of these patients andprovided some basis to create a stem cell line in the future.", "metadata": {}}
+{"_id": "10009203", "title": "", "text": "Structural Homeostasis: Compensatory Adjustments of Dendritic Arbor Geometry in Response toVariations of Synaptic InputAs the nervous system develops, there is an inherent variability in theconnections formed between differentiating neurons. Despite this variability, neural circuits form that arefunctional and remarkably robust. One way in which neurons deal with variability in their inputs isthrough compensatory, homeostatic changes in their electrical properties. Here, we show that neuronsalso make compensatory adjustments to their structure. We analysed the development of dendrites on anidentified central neuron (aCC) in the late Drosophila embryo at the stage when it receives its firstconnections and first becomes electrically active. At the same time, we charted the distribution ofpresynaptic sites on the developing postsynaptic arbor. Genetic manipulations of the presynaptic partnersdemonstrate that the postsynaptic dendritic arbor adjusts its growth to compensate for changes in theactivity and density of synaptic sites. Blocking the synthesis or evoked release of presynapticneurotransmitter results in greater dendritic extension. Conversely, an increase in the density ofpresynaptic release sites induces a reduction in the extent of the dendritic arbor. These growthadjustments occur locally in the arbor and are the result of the promotion or inhibition of growth ofneurites in the proximity of presynaptic sites. We provide evidence that suggest a role for thepostsynaptic activity state of protein kinase A in mediating this structural adjustment, which modifiesdendritic growth in response to synaptic activity. These findings suggest that the dendritic arbor, at leastduring early stages of connectivity, behaves as a homeostatic device that adjusts its size and geometry tothe level and the distribution of input received. The growing arbor thus counterbalances naturallyoccurring variations in synaptic density and activity so as to ensure that an appropriate level of input isachieved.", "metadata": {}}
+{"_id": "10010651", "title": "", "text": "Nutrition and physical activity guidelines for cancer survivors.Cancer survivors are often highly motivatedto seek information about food choices, physical activity, and dietary supplements to improve theirtreatment outcomes, quality of life, and overall survival. To address these concerns, the American CancerSociety (ACS) convened a group of experts in nutrition, physical activity, and cancer survivorship toevaluate the scientific evidence and best clinical practices related to optimal nutrition and physical activityafter the diagnosis of cancer. This report summarizes their findings and is intended to present health careproviders with the best possible information with which to help cancer survivors and their families makeinformed choices related to nutrition and physical activity. The report discusses nutrition and physicalactivity guidelines during the continuum of cancer care, briefly highlighting important issues duringcancer treatment and for patients with advanced cancer, but focusing largely on the needs of thepopulation of individuals who are disease free or who have stable disease following their recovery fromtreatment. It also discusses select nutrition and physical activity issues such as body weight, foodchoices, food safety, and dietary supplements; issues related to selected cancer sites; and commonquestions about diet, physical activity, and cancer survivorship.", "metadata": {}}
+{"_id": "10012166", "title": "", "text": "The role of protein clearance mechanisms in organismal ageing and age-related diseases.The ability tomaintain a functional proteome, or proteostasis, declines during the ageing process. Damaged andmisfolded proteins accumulate with age, impairing cell function and tissue homeostasis. The accumulationof damaged proteins contributes to multiple age-related diseases such as Alzheimer's, Parkinson's orHuntington's disease. Damaged proteins are degraded by the ubiquitin-proteasome system or throughautophagy-lysosome, key components of the proteostasis network. Modulation of either proteasomeactivity or autophagic-lysosomal potential extends lifespan and protects organisms from symptomsassociated with proteostasis disorders, suggesting that protein clearance mechanisms are directly linkedto ageing and age-associated diseases.", "metadata": {}}
+{"_id": "10015292", "title": "", "text": "A distinctive DNA damage response in human hematopoietic stem cells reveals an apoptosis-independentrole for p53 in self-renewal.Highly regenerative tissues such as blood must possess effective DNA damageresponses (DDR) that balance long-term regeneration with protection from leukemogenesis.Hematopoietic stem cells (HSCs) sustain life-long blood production, yet their response to DNA damageremains largely unexplored. We report that human HSCs exhibit delayed DNA double-strand breakrejoining, persistent gammaH2AX foci, and enhanced p53- and ASPP1-dependent apoptosis aftergamma-radiation compared to progenitors. p53 inactivation or Bcl-2 overexpression reducedradiation-induced apoptosis and preserved in vivo repopulating HSC function. Despite similar protectionfrom irradiation-induced apoptosis, only Bcl-2-overexpressing HSCs showed higher self-renewal capacity,establishing that intact p53 positively regulates self-renewal independently from apoptosis. The reducedself-renewal of HSCs with inactivated p53 was associated with increased spontaneous gammaH2AX foci insecondary transplants of HSCs. Our data reveal distinct physiological roles of p53 that together ensureoptimal HSC function: apoptosis regulation and prevention of gammaH2AX foci accumulation upon HSCself-renewal.", "metadata": {}}
+{"_id": "10017612", "title": "", "text": "Behavioral characterization of neuropeptide Y knockout mice.An extensive behavioral characterizationwas conducted with mice lacking the gene for neuropeptide Y (NPY) including response to 24 and 48 hfast and challenge with small molecule antagonists of NPY receptors implicated in mediating the feedingeffects of NPY (i.e., Y1 and Y5). In addition, wildtype (WT) and NPY knockout (KO) mice were tested inlocomotor monitors, elevated plus maze, inhibitory avoidance, acoustic startle, prepulse inhibition, andhot plate assays. One of the major findings was that the NPY KO mice have a reduced food intake relativeto WT controls in response to fasting. Also, based on data from the behavioral models, the NPY KO micemay have an anxiogenic-like phenotype, and appear to be hypoalgesic in the hot plate paradigm. Thedata from these studies provide further evidence of involvement of NPY in energy balance, anxiety, andpossibly nociception.", "metadata": {}}
+{"_id": "10024681", "title": "", "text": "Epigenetic-induced repression of microRNA-205 is associated with MED1 activation and a poorerprognosis in localized prostate cancerDeregulation of microRNA (miRNA) expression can have a criticalrole in carcinogenesis. Here we show in prostate cancer that miRNA-205 (miR-205) transcription iscommonly repressed and the MIR-205 locus is hypermethylated. LOC642587, the MIR-205 host gene ofunknown function, is also concordantly inactivated. We show that miR-205 targets mediator 1 (MED1,also called TRAP220 and PPARBP) for transcriptional silencing in normal prostate cells, leading toreduction in MED1 mRNA levels, and in total and active phospho-MED1 protein. Overexpression ofmiR-205 in prostate cancer cells negatively affects cell viability, consistent with a tumor suppressorfunction. We found that hypermethylation of the MIR-205 locus was strongly related with a decrease inmiR-205 expression and an increase in MED1 expression in primary tumor samples (n=14), whencompared with matched normal prostate (n=7). An expanded patient cohort (tumor n=149, matchednormal n=30) also showed significant MIR-205 DNA methylation in tumors compared with normal, andMIR-205 hypermethylation is significantly associated with biochemical recurrence (hazard ratio=2.005,95% confidence interval (1.109, 3.625), P=0.02), in patients with low preoperative prostate specificantigen. In summary, these results suggest that miR-205 is an epigenetically regulated tumor suppressorthat targets MED1 and may provide a potential biomarker in prostate cancer management.", "metadata": {}}
+{"_id": "10029891", "title": "", "text": "Th2 cytokine response in Major Depressive Disorder patients before treatmentIn Major DepressiveDisorder (MDD), the neuroendocrine and immune systems interactions are impaired. We investigated thepro/anti-inflammatory Th1/Th2 cytokine balance in MDD patients and in non-depressed control group.The MDD subjects showed higher levels of cortisol and TNF-alpha, increased CD3+CD8+ and NKpercentages, diminished B cell counts and no significant variations in CD3+CD4+ lymphocyte. Moreover,higher levels of IL-4 and IL-13 (Th2) and significantly lower measurements of IL-2 and IFN-gamma (Th1)cytokines were also observed in the MDD group. Overall, we propose that all these changes could berelated to the elevated cortisol levels seen in the MDD patients. Further studies are necessary to explorethese findings and its implication in future therapeutic approach of MDD patients.", "metadata": {}}
+{"_id": "10029970", "title": "", "text": "CDD: conserved domains and protein three-dimensional structureCDD, the Conserved Domain Database,is part of NCBI's Entrez query and retrieval system and is also accessible viahttp://www.ncbi.nlm.nih.gov/Structure/cdd/cdd.shtml. CDD provides annotation of protein sequenceswith the location of conserved domain footprints and functional sites inferred from these footprints.Pre-computed annotation is available via Entrez, and interactive search services accept single protein ornucleotide queries, as well as batch submissions of protein query sequences, utilizing RPS-BLAST torapidly identify putative matches. CDD incorporates several protein domain and full-length protein modelcollections, and maintains an active curation effort that aims at providing fine grained classifications formajor and well-characterized protein domain families, as supported by available proteinthree-dimensional (3D) structure and the published literature. To this date, the majority of protein 3Dstructures are represented by models tracked by CDD, and CDD curators are characterizing novel familiesthat emerge from protein structure determination efforts.", "metadata": {}}
+{"_id": "10039688", "title": "", "text": "Extensive diversity of Ig-superfamily proteins in the immune system of insects.The extensive somaticdiversification of immune receptors is a hallmark of higher vertebrates. However, whether moleculardiversity contributes to immune protection in invertebrates is unknown. We present evidence thatDrosophila immune-competent cells have the potential to express more than 18,000 isoforms of theimmunoglobulin (Ig)-superfamily receptor Down syndrome cell adhesion molecule (Dscam). Secretedprotein isoforms of Dscam were detected in the hemolymph, and hemocyte-specific loss of Dscamimpaired the efficiency of phagocytic uptake of bacteria, possibly due to reduced bacterial binding.Importantly, the molecular diversity of Dscam transcripts generated through a mechanism of alternativesplicing is highly conserved across major insect orders, suggesting an unsuspected molecular complexityof the innate immune system of insects.", "metadata": {}}
+{"_id": "10068634", "title": "", "text": "Preparing the outbreak assistance laboratory network in the Netherlands for the detection of the influenzavirus A(H1N1) variant.BACKGROUND Late April 2009, human infection with variant influenza virusA(H1N1)v emerged in the Northern Americas posing a threat that this virus may become the nextpandemic influenza virus. OBJECTIVES To prepare laboratories for surge capacity for molecular diagnosisof patients suspected for A(H1N1)v infection in the Netherlands. STUDY DESIGN A panel of 10 blindedspecimens containing seasonal A(H1N1) or A(H3N2), or A/Netherlands/602/2009(H1N1)v influenza virus,or negative control was distributed to the outbreak assistance laboratories (OAL) together with influenzavirus A (M-gene), swine influenza virus A (NP-gene) and influenza virus A(H1N1)v (H1v-gene) specificprimers and probes and protocol (CDC Atlanta, USA). Laboratories were asked to implement and test thisprotocol. RESULTS All OAL were able to detect A(H1N1)v using the CDC M-gene reagents, the majoritywith similar sensitivity as the in-house M-gene based assays. RT-PCRs used in routine diagnostic settingin the OAL specifically designed to detect H1, H3, or NS1 from seasonal influenza A viruses, did not or atvery low level cross-react with A(H1N1)v. The CDC swine NP-gene and H1v-gene RT-PCRs showedsomewhat reduced sensitivity compared to the CDC and in-house M-gene RT-PCRs. In contrast, in-housedeveloped A(H1N1)v specific H1v-gene and N1v-gene RT-PCRs showed equal sensitivity to CDC andin-house M-gene RT-PCRs. CONCLUSIONS The Dutch OAL are prepared for detection and specificidentification of A(H1N1)v, although some level of cross-reactivity was observed with seasonal influenzaviruses. Additionally, M-gene based generic influenza A virus detection is recommended to be able todetect emerging influenza A viruses in routine settings.", "metadata": {}}
+{"_id": "10071552", "title": "", "text": "Averting Obesity and Type 2 Diabetes in India through Sugar-Sweetened Beverage Taxation: AnEconomic-Epidemiologic Modeling StudyBACKGROUND Taxing sugar-sweetened beverages (SSBs) hasbeen proposed in high-income countries to reduce obesity and type 2 diabetes. We sought to estimatethe potential health effects of such a fiscal strategy in the middle-income country of India, where there isheterogeneity in SSB consumption, patterns of substitution between SSBs and other beverages after taxincreases, and vast differences in chronic disease risk within the population. METHODS AND FINDINGSUsing consumption and price variations data from a nationally representative survey of 100,855 Indianhouseholds, we first calculated how changes in SSB price alter per capita consumption of SSBs andsubstitution with other beverages. We then incorporated SSB sales trends, body mass index (BMI), anddiabetes incidence data stratified by age, sex, income, and urban/rural residence into a validatedmicrosimulation of caloric consumption, glycemic load, overweight/obesity prevalence, and type 2diabetes incidence among Indian subpopulations facing a 20% SSB excise tax. The 20% SSB tax wasanticipated to reduce overweight and obesity prevalence by 3.0% (95% CI 1.6%-5.9%) and type 2diabetes incidence by 1.6% (95% CI 1.2%-1.9%) among various Indian subpopulations over the period2014-2023, if SSB consumption continued to increase linearly in accordance with secular trends.However, acceleration in SSB consumption trends consistent with industry marketing models would beexpected to increase the impact efficacy of taxation, averting 4.2% of prevalent overweight/obesity (95%CI 2.5-10.0%) and 2.5% (95% CI 1.0-2.8%) of incident type 2 diabetes from 2014-2023. Given currentconsumption and BMI distributions, our results suggest the largest relative effect would be expectedamong young rural men, refuting our a priori hypothesis that urban populations would be isolatedbeneficiaries of SSB taxation. Key limitations of this estimation approach include the assumption thatconsumer expenditure behavior from prior years, captured in price elasticities, will reflect future behavioramong consumers, and potential underreporting of consumption in dietary recall data used to inform ourcalculations. CONCLUSION Sustained SSB taxation at a high tax rate could mitigate rising obesity andtype 2 diabetes in India among both urban and rural subpopulations.", "metadata": {}}
+{"_id": "10071590", "title": "", "text": "Acute myopericarditis after multiple vaccinations in an adolescent: case report and review of theliterature.We report a case of postvaccination acute myopericarditis in an adolescent. The patientpresented with acute chest pain, diffuse ST-segment elevation, and elevated cardiac enzyme levels.Cardiac MRI was consistent with acute myocarditis. He recovered within a few days with nonsteroidalantiinflammatory treatment and remains clinically stable, with improvement of MRI findings at the10-week follow-up. Postvaccination cases of myopericarditis reported in the pediatric literature are alsoreviewed.", "metadata": {}}
+{"_id": "10072941", "title": "", "text": "Cardiovascular protection with antihypertensive drugs in dialysis patients: systematic review andmeta-analysis.Epidemiological studies demonstrate that a lower blood pressure and decline in bloodpressure over months or years are associated with higher mortality in dialysis patients. In contrast,randomized, controlled trials lack power to establish benefits of antihypertensive therapy. Patients onlong-term dialysis participating in randomized, controlled trials and receiving antihypertensive drugtherapy were the subject of this meta-analysis. Outcomes assessed were the hazard ratio ofcardiovascular events and all-cause mortality in treated group compared with controls. Among 1202patients who we identified in 5 studies, the overall benefit of antihypertensive therapy compared with thecontrol or placebo group had a combined hazard ratio for cardiovascular events of 0.69 (95% CI: 0.56 to0.84) using a fixed-effects model and 0.62 (95% CI: 0.45 to 0.86) using a random-effects model. In asensitivity analysis, we found that the hypertensive group had a pooled hazard ratio of 0.49 (95% CI:0.35 to 0.67), but when normotensives were included in the trial, lesser cardiovascular protection wasseen (pooled hazard ratio of 0.86 [95% CI: 0.67 to 1.12]). Test for heterogeneity between hypertensiveand \"normotensive-included\" groups was significant (P<0.006). Similar results were seen for risk ratio fordeath and cardiovascular events. There was evidence of publication bias based on Egger's test and funnelplot. Randomized trials suggested a benefit of antihypertensive therapy among hemodialysis patients.Adequately powered randomized trials are required to confirm these observations, especially amongthose with hypertension.", "metadata": {}}
+{"_id": "10074251", "title": "", "text": "Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains.Protoplasmicastrocytes are increasingly thought to interact extensively with neuronal elements in the brain and toinfluence their activity. Recent reports have also begun to suggest that physiologically, and perhapsfunctionally, diverse forms of these cells may be present in the CNS. Our current understanding ofastrocyte form and distribution is based predominantly on studies that used the astrocytic marker glialfibrillary acidic protein (GFAP) and on studies using metal-impregnation techniques. The prevalentopinion, based on studies using these methods, is that astrocytic processes overlap extensively andprimarily share the underlying neuropil. However, both of these techniques have serious shortcomings forvisualizing the interactions among these structurally complex cells. In the present study, intracellularinjection combined with immunohistochemistry for GFAP show that GFAP delineates only approximately15% of the total volume of the astrocyte. As a result, GFAP-based images have led to incorrectconclusions regarding the interaction of processes of neighboring astrocytes. To investigate theseinteractions in detail, groups of adjacent protoplasmic astrocytes in the CA1 stratum radiatum wereinjected with fluorescent intracellular tracers of distinctive emissive wavelengths and analyzed usingthree-dimensional (3D) confocal analysis and electron microscopy. Our findings show that protoplasmicastrocytes establish primarily exclusive territories. The knowledge of how the complex morphology ofprotoplasmic astrocytes affects their 3D relationships with other astrocytes, oligodendroglia, neurons,and vasculature of the brain should have important implications for our understanding of nervous systemfunction.", "metadata": {}}
+{"_id": "10078024", "title": "", "text": "Leptin-receptor-expressing mesenchymal stromal cells represent the main source of bone formed byadult bone marrow.Studies of the identity and physiological function of mesenchymal stromal cells(MSCs) have been hampered by a lack of markers that permit both prospective identification and fatemapping in vivo. We found that Leptin Receptor (LepR) is a marker that highly enriches bone marrowMSCs. Approximately 0.3% of bone marrow cells were LepR(+) , 10% of which were CFU-Fs, accountingfor 94% of bone marrow CFU-Fs. LepR(+) cells formed bone, cartilage, and adipocytes in culture andupon transplantation in vivo. LepR(+) cells were Scf-GFP(+), Cxcl12-DsRed(high), and Nestin-GFP(low),markers which also highly enriched CFU-Fs, but negative for Nestin-CreER and NG2-CreER, markerswhich were unlikely to be found in CFU-Fs. Fate-mapping showed that LepR(+) cells arose postnatallyand gave rise to most bone and adipocytes formed in adult bone marrow, including bone regeneratedafter irradiation or fracture. LepR(+) cells were quiescent, but they proliferated after injury. Therefore,LepR(+) cells are the major source of bone and adipocytes in adult bone marrow.", "metadata": {}}
+{"_id": "10086360", "title": "", "text": "High-resolution sperm typing of meiotic recombination in the mouse MHC Ebeta gene.Meiotic crossoversdetected by pedigree analysis in the mouse MHC cluster into hotspots. To explore the properties ofhotspots, we subjected the class II E(beta) gene to high-resolution sperm crossover analysis. We confirmthe presence of a highly localized hotspot 1.0-1.6 kb wide in the second intron of E(beta) and show that itis flanked by DNA which is almost completely recombinationally inert. Mice heterozygous for haplotype sand another MHC haplotype show major haplotype-dependant variation in crossover rate but always thesame hotspot, even in crosses including the highly diverged p haplotype. Crossovers in reciprocalorientations occur at similar rates but show different distributions across the hotspot, with the position ofcentre points in the two orientations shifted on average by 400 bp. This asymmetry results in crossoverproducts showing biased gene conversion in favour of hotspot markers from the non-initiating haplotype,and supports the double-strand break repair model of recombination, with haplotype s as the mostefficient crossover initiator. The detailed behaviour of the E(beta) hotspot, including evidence for highlylocalized recombination initiation, is strikingly similar to human hotspots.", "metadata": {}}
+{"_id": "10128893", "title": "", "text": "Long-term survival of beta thalassemia major patients treated with hematopoietic stem celltransplantation compared with survival with conventional treatment.Allogeneic hematopoietic stem celltransplantation (HSCT) in thalassemia remains a challenge. We reported a single-centre case-controlstudy of a large cohort of 516 children and adult patients treated with HSCT or blood transfusion supportand iron chelation therapy; 258 patients (median age 12, range 1-45) underwent sibling (67%) orunrelated (33%) HSCT; 97 patients were adults (age ≥ 16 years). The median follow-up after HSCT was11 years (range 1-30). The conditioning regimen was busulfan (80.6%) or treosulfan-based (19.4%). Acohort of 258 age-sex matched conventionally treated (CT) patients was randomly selected. Intransplanted patients the 30-year overall survival (OS) and thalassemia-free survival (TFS) were 82.6 ±2.7% and 77.8 ± 2.9%, compared to the OS of 85.3 ± 2.7% in CT patients (P = NS); The incidence ofgrade II-IV acute and chronic graft versus host disease (GvHD) was 23.6% and 12.9% respectively. Theprobability of rejection was 6.9%. Transplant-related mortality (TRM) (13.8%) was similar to theprobability of dying of cardiovascular events in CT patients (12.2%). High-risk Pesaro score (class 3) wasassociated with lower OS (OR = 1.99, 95% C.I.=1.31-3.03) and TFS (OR = 1.54, 95% C.I.=1.12-2.12).In adult patients, the 23-years OS and TFS after HSCT were 70 ± 5% and 67.3 ± 5%, compared to 71.2± 5% of OS in CT (P = NS). Finally, treosulfan was associated with lower risk of acute GvHD (P = .004;OR = 0.28, 95% C.I.=0.12-0.67). In conclusion, the 30-year survival rate of ex-thalassemia patientsafter HSCT was similar to that expected in CT thalassemia patients, with the vast majority of HSCTsurvivors cured from thalassemia.", "metadata": {}}
+{"_id": "10145528", "title": "", "text": "Global analysis of ATM polymorphism reveals significant functional constraint.ATM, the gene that ismutated in ataxia-telangiectasia, is associated with cerebellar degeneration, abnormal proliferation ofsmall blood vessels, and cancer. These clinically important manifestations have stimulated interest indefining the sequence variation in the ATM gene. Therefore, we undertook a comprehensive survey ofsequence variation in ATM in diverse human populations. The protein-encoding exons of the gene (9,168bp) and the adjacent intron and untranslated sequences (14,661 bp) were analyzed in 93 individuals fromseven major human populations. In addition, the coding sequence was analyzed in one chimpanzee, onegorilla, one orangutan, and one Old World monkey. In human ATM, 88 variant sites were discovered bydenaturing high-performance liquid chromatography, which is 96%-100% sensitive for detection of DNAsequence variation. ATM was compared to 14 other autosomal genes for nucleotide diversity. Thenoncoding regions of ATM had diversity values comparable to other genes, but the coding regions hadvery low diversity, especially in the last 29% of the protein sequence. A test of the neutral evolutionhypothesis, through use of the Hudson/Kreitman/Aguadé statistic, revealed that this region of the humanATM gene was significantly constrained relative to that of the orangutan, the Old World monkey, and themouse, but not relative to that of the chimpanzee or the gorilla. ATM displayed extensive linkagedisequilibrium, consistent with suppression of meiotic recombination at this locus. Seven haplotypes weredefined. Two haplotypes accounted for 82% of all chromosomes analyzed in all major populations; twoothers carrying the same D126E missense polymorphism accounted for 33% of chromosomes in Africabut were never observed outside of Africa. The high frequency of this polymorphism may be due either toa population expansion within Africa or to selective pressure.", "metadata": {}}
+{"_id": "10162553", "title": "", "text": "Ablation and regeneration of tolerance-inducing medullary thymic epithelial cells after cyclosporine,cyclophosphamide, and dexamethasone treatment.Immunosuppressive drugs and cytotoxicchemotherapy agents are designed to kill or suppress autoreactive, alloaggressive, or hyperinflammatoryT cells, or disseminated malignancies. However, they also cause severe immunological side effectsranging from interrupted thymopoiesis and general immunodeficiency to, paradoxically, autoimmunity.Consistent with the cross-talk between thymocytes and stromal cells, we now show that these commontherapeutic agents have major effects on murine thymic epithelial cells (TEC), crucially required to rebuildimmunity posttreatment. We show that the immunosuppressant cyclosporine A, which has been linked toa thymus-dependent autoimmune syndrome in some patients, causes extensive loss of autoimmuneregulator (Aire(+)) tolerance-inducing MHC class II(high) medullary TEC (mTEC(high)). Post-cyclosporineA, Aire expression was restored within 7 days. Full recovery of the mTEC(high) subset occurred within 10days and was linked to a decrease in a relatively resistant MHC class II(low) mTEC subset (mTEC(low)),consistent with a previously described precursor-product relationship. Cyclophosphamide anddexamethasone caused more extensive ablation of thymocytes and stromal cells but again severelydepleted tolerance-inducing mTEC(high). Together, these data show that Aire(+) mTECs are highlysensitive to damage and that mTEC regeneration follows a conserved pattern regardless of the treatmentregimen used.", "metadata": {}}
+{"_id": "10165258", "title": "", "text": "GATA-3 regulates hematopoietic stem cell maintenance and cell-cycle entry.Maintaining hematopoieticstem cell (HSC) quiescence is a critical property for the life-long generation of blood cells. Approximately75% of cells in a highly enriched long-term repopulating HSC (LT-HSC) pool(Lin(-)Sca1(+)c-Kit(hi)CD150(+)CD48(-)) are quiescent, with only a small percentage of the LT-HSCs incycle. Transcription factor GATA-3 is known to be vital for the development of T cells at multiple stages inthe thymus and for Th2 differentiation in the peripheral organs. Although it is well documented thatGATA-3 is expressed in HSCs, a role for GATA-3 in any prethymic progenitor cell has not beenestablished. In the present study, we show that Gata3-null mutant mice generate fewer LT-HSCs and thatfewer Gata3-null LT-HSCs are in cycle. Furthermore, Gata3 mutant hematopoietic progenitor cells fail tobe recruited into an increased cycling state after 5-fluorouracil-induced myelosuppression. Therefore,GATA-3 is required for the maintenance of a normal number of LT-HSCs and for their entry into the cellcycle.", "metadata": {}}
+{"_id": "10165723", "title": "", "text": "CpG island methylator phenotype predicts progression of malignant melanoma.PURPOSE The CpG islandmethylator phenotype (CIMP) may be associated with development of malignancy through coordinatedinactivation of tumor suppressor and tumor-related genes (TRG) and methylation of multiple noncoding,methylated-in-tumor (MINT) loci. These epigenetic changes create a distinct CIMP pattern that has beenlinked to recurrence and survival in gastrointestinal cancers. Because epigenetic inactivation of TRGs alsohas been shown in malignant melanoma, we hypothesized the existence of a clinically significant CIMP incutaneous melanoma progression. EXPERIMENTAL DESIGN The methylation status of the CpG islandpromoter region of TRGs related to melanoma pathophysiology (WIF1, TFPI2, RASSF1A, RARbeta2,SOCS1, and GATA4) and a panel of MINT loci (MINT1, MINT2, MINT3, MINT12, MINT17, MINT25, andMINT31) in primary and metastatic tumors of different clinical stages (n=122) was assessed. RESULTSHere, we show an increase in hypermethylation of the TRGs WIF1, TFPI2, RASSF1A, and SOCS1 withadvancing clinical tumor stage. Furthermore, we find a significant positive association between themethylation status of MINT17, MINT31, and TRGs. The methylation status of MINT31 is associated withdisease outcome in stage III melanoma. CONCLUSIONS These findings show the significance of a CIMPpattern that is associated with advancing clinical stage of malignant melanoma. Future prospectivelarge-scale studies may determine if CIMP-positive primary melanomas are at high risk of metastasis orrecurrence.", "metadata": {}}
+{"_id": "10169908", "title": "", "text": "SLC1A5 mediates glutamine transport required for lung cancer cell growth and survival.PURPOSE Wehave previously identified solute-linked carrier family A1 member 5 (SLC1A5) as an overexpressedprotein in a shotgun proteomic analysis of stage I non-small cell lung cancer (NSCLC) when comparedwith matched controls. We hypothesized that overexpression of SLC1A5 occurs to meet the metabolicdemand for lung cancer cell growth and survival. EXPERIMENTAL DESIGN To test our hypothesis, we firstanalyzed the protein expression of SLC1A5 in archival lung cancer tissues by immunohistochemistry andimmunoblotting (N = 98) and in cell lines (N = 36). To examine SLC1A5 involvement in amino acidtransportation, we conducted kinetic analysis of l-glutamine (Gln) uptake in lung cancer cell lines in thepresence and absence of a pharmacologic inhibitor of SLC1A5, gamma-l-Glutamyl-p-Nitroanilide (GPNA).Finally, we examined the effect of Gln deprivation and uptake inhibition on cell growth, cell-cycleprogression, and growth signaling pathways of five lung cancer cell lines. RESULTS Our results show that(i) SLC1A5 protein is expressed in 95% of squamous cell carcinomas (SCC), 74% of adenocarcinomas(ADC), and 50% of neuroendocrine tumors; (ii) SLC1A5 is located at the cytoplasmic membrane and issignificantly associated with SCC histology and male gender; (iii) 68% of Gln is transported in aNa(+)-dependent manner, 50% of which is attributed to SLC1A5 activity; and (iv) pharmacologic andgenetic targeting of SLC1A5 decreased cell growth and viability in lung cancer cells, an effect mediated inpart by mTOR signaling. CONCLUSIONS These results suggest that SLC1A5 plays a key role in Glntransport controlling lung cancer cells' metabolism, growth, and survival.", "metadata": {}}
+{"_id": "10189634", "title": "", "text": "Eic1 links Mis18 with the CCAN/Mis6/Ctf19 complex to promote CENP-A assemblyCENP-A chromatinforms the foundation for kinetochore assembly. Replication-independent incorporation of CENP-A atcentromeres depends on its chaperone HJURP(Scm3), and Mis18 in vertebrates and fission yeast. Therecruitment of Mis18 and HJURP(Scm3) to centromeres is cell cycle regulated. Vertebrate Mis18associates with Mis18BP1(KNL2), which is critical for the recruitment of Mis18 and HJURP(Scm3). Weidentify two novel fission yeast Mis18-interacting proteins (Eic1 and Eic2), components of the Mis18complex. Eic1 is essential to maintain Cnp1(CENP-A) at centromeres and is crucial for kinetochoreintegrity; Eic2 is dispensable. Eic1 also associates with Fta7(CENP-Q/Okp1), Cnl2(Nkp2) andMal2(CENP-O/Mcm21), components of the constitutive CCAN/Mis6/Ctf19 complex. No Mis18BP1(KNL2)orthologue has been identified in fission yeast, consequently it remains unknown how the keyCnp1(CENP-A) loading factor Mis18 is recruited. Our findings suggest that Eic1 serves a functionanalogous to that of Mis18BP1(KNL2), thus representing the functional counterpart of Mis18BP1(KNL2) infission yeast that connects with a module within the CCAN/Mis6/Ctf19 complex to allow the temporallyregulated recruitment of the Mis18/Scm3(HJURP) Cnp1(CENP-A) loading factors. The novel interactionsidentified between CENP-A loading factors and the CCAN/Mis6/Ctf19 complex are likely to also contributeto CENP-A maintenance in other organisms.", "metadata": {}}
+{"_id": "10190462", "title": "", "text": "INTRANASAL INSULIN IMPROVES COGNITION AND MODULATES β-AMYLOID IN EARLY ADBackground:Reduced brain insulin signaling and low CSF-to-plasma insulin ratios have been observed in patients withAlzheimer disease (AD). Furthermore, intracerebroventricular or IV insulin administration improvememory, alter evoked potentials, and modulate neurotransmitters, possibly by augmenting low brainlevels. After intranasal administration, insulin-like peptides follow extracellular pathways to the brainwithin 15 minutes. Objective: We tested the hypothesis that daily intranasal insulin treatment wouldfacilitate cognition in patients with early AD or its prodrome, amnestic mild cognitive impairment (MCI).The proportion of verbal information retained after a delay period was the planned primary outcomemeasure. Secondary outcome measures included attention, caregiver rating of functional status, andplasma levels of insulin, glucose, β-amyloid, and cortisol. Methods: Twenty-five participants wererandomly assigned to receive either placebo (n = 12) or 20 IU BID intranasal insulin treatment (n = 13)using an electronic atomizer, and 24 participants completed the study. Participants, caregivers, and allclinical evaluators were blinded to treatment assignment. Cognitive measures and blood were obtained atbaseline and after 21 days of treatment. Results: Fasting plasma glucose and insulin were unchangedwith treatment. The insulin-treated group retained more verbal information after a delay compared withthe placebo-assigned group ( p = 0.0374). Insulin-treated subjects also showed improved attention ( p =0.0108) and functional status ( p = 0.0410). Insulin treatment raised fasting plasma concentrations ofthe short form of the β-amyloid peptide (Aβ40; p = 0.0471) without affecting the longer isoform (Aβ42),resulting in an increased Aβ40/42 ratio ( p = 0.0207). Conclusions: The results of this pilot study supportfurther investigation of the benefits of intranasal insulin for patients with Alzheimer disease, and suggestthat intranasal peptide administration may be a novel approach to the treatment of neurodegenerativedisorders.", "metadata": {}}
+{"_id": "10190778", "title": "", "text": "Maternal alloantigens promote the development of tolerogenic fetal regulatory T cells in utero.As theimmune system develops, T cells are selected or regulated to become tolerant of self antigens andreactive against foreign antigens. In mice, the induction of such tolerance is thought to be attributable tothe deletion of self-reactive cells. Here, we show that the human fetal immune system takes advantage ofan additional mechanism: the generation of regulatory T cells (Tregs) that suppress fetal immuneresponses. We find that substantial numbers of maternal cells cross the placenta to reside in fetal lymphnodes, inducing the development of CD4+CD25highFoxP3+ Tregs that suppress fetal antimaternalimmunity and persist at least until early adulthood. These findings reveal a form of antigen-specifictolerance in humans, induced in utero and probably active in regulating immune responses after birth.", "metadata": {}}
+{"_id": "10207180", "title": "", "text": "β-site amyloid precursor protein-cleaving enzyme 1(BACE1) inhibitor treatment induces Aβ5-X peptidesthrough alternative amyloid precursor protein cleavageINTRODUCTION The β-secretase enzyme, β-siteamyloid precursor protein-cleaving enzyme 1 (BACE1), cleaves amyloid precursor protein (APP) in thefirst step in β-amyloid (Aβ) peptide production. Thus, BACE1 is a key target for candidatedisease-modifying treatment of Alzheimer's disease. In a previous exploratory Aβ biomarker study, wefound that BACE1 inhibitor treatment resulted in decreased levels of Aβ1-34 together with increasedAβ5-40, suggesting that these Aβ species may be novel pharmacodynamic biomarkers in clinical trials.We have now examined whether the same holds true in humans. METHODS In an investigator-blind,placebo-controlled and randomized study, healthy subjects (n =18) were randomly assigned to receive asingle dose of 30 mg of LY2811376 (n =6), 90 mg of LY2811376 (n =6), or placebo (n =6). We usedhybrid immunoaffinity-mass spectrometry (HI-MS) and enzyme-linked immunosorbent assays to monitora variety of Aβ peptides. RESULTS Here, we demonstrate dose-dependent changes in cerebrospinal fluid(CSF) Aβ1-34, Aβ5-40 and Aβ5-X after treatment with the BACE1-inhibitor LY2811376. Aβ5-40 andAβ5-X increased dose-dependently, as reflected by two independent methods, while Aβ1-34dose-dependently decreased. CONCLUSION Using HI-MS for the first time in a study where subjects havebeen treated with a BACE inhibitor, we confirm that CSF Aβ1-34 may be useful in clinical trials on BACE1inhibitors to monitor target engagement. Since it is less hydrophobic than longer Aβ species, it is lesssusceptible to preanalytical confounding factors and may thus be a more stable marker. By independentmeasurement techniques, we also show that BACE1 inhibition in humans is associated withAPP-processing into N-terminally truncated Aβ peptides via a BACE1-independent pathway. TRIALREGISTRATION ClinicalTrials.gov NCT00838084. Registered: First received: January 23, 2009, Lastupdated: July 14, 2009, Last verified: July 2009.", "metadata": {}}
+{"_id": "10209731", "title": "", "text": "Cardiovascular diseases in Chinese, Malays, and Indians in Singapore. I. Differences in mortality.STUDYOBJECTIVE The aim of the study was to analyse differences in mortality from the main cardiovasculardiseases (ischaemic heart disease, hypertensive disease, and cerebrovascular disease) among Chinese,Malays, and Indians in Singapore. DESIGN The study was a survey using national death registration datain Singapore for the five years 1980 to 1984. The underlying cause of death, coded according to the ninthrevision of the International Classification of Diseases, was taken for the analyses. SETTING The studywas confined to the independent island state of Singapore, population 2.53 million (Chinese 76.5%,Malays 14.8%, Indians 6.4%, Others 2.3%). Death registration is thought to be complete. SUBJECTS Allregistered deaths in the age range 30-69 years during the study period were analysed by ethnic group.MEASUREMENT AND MAIN RESULTS Indians had higher mortality from ischaemic heart disease than theother ethnic groups in both sexes, with age-standardised relative risks of Indian v Chinese (males 3.8,females 3.4), Indian v Malay (males 1.9, females 1.6), and Malay v Chinese (males 2.0, females 2.2).The excess mortality in Indians declined with age. For hypertensive disease Malays had the highestmortality, with age-standardised relative risks of Malay v Chinese (males 3.4, females 4.4), Malay vIndian (males 2.0, females 2.5), and Indian v Chinese (males 1.6, females 1.6). For cerebrovasculardisease there was little ethnic difference except for lower rates in Chinese females, with age-standardisedrelative risks of Malay v Chinese (males 1.1, females 1.9), Malay v Indian (males 1.0, females 1.1), andIndian v Chinese (males 1.1, females 1.7). CONCLUSIONS There are significant differences in mortalityfrom the three main cardiovascular diseases in the different ethnic groups in Singapore.", "metadata": {}}
+{"_id": "10212612", "title": "", "text": "Protein localization in electron micrographs using fluorescence nanoscopyA complete portrait of a cellrequires a detailed description of its molecular topography: proteins must be linked to particularorganelles. Immunocytochemical electron microscopy can reveal locations of proteins with nanometerresolution but is limited by the quality of fixation, the paucity of antibodies and the inaccessibility ofantigens. Here we describe correlative fluorescence electron microscopy for the nanoscopic localization ofproteins in electron micrographs. We tagged proteins with the fluorescent proteins Citrine or tdEos andexpressed them in Caenorhabditis elegans, fixed the worms and embedded them in plastic. We imagedthe tagged proteins from ultrathin sections using stimulated emission depletion (STED) microscopy orphotoactivated localization microscopy (PALM). Fluorescence correlated with organelles imaged inelectron micrographs from the same sections. We used these methods to localize histones, amitochondrial protein and a presynaptic dense projection protein in electron micrographs.", "metadata": {}}
+{"_id": "10218447", "title": "", "text": "The flavonoid component isorhamnetin in vitro inhibits proliferation and induces apoptosis in Eca-109cells.Isorhamnetin is one member of flavonoid components which has been used in the treatment of heartdisease. Recently the in vitro anti-cancer effect of isorhamnetin on human esophageal squamouscarcinoma cell line Eca-109 was investigated in our lab. When Eca-109 cells were in vitro exposed to thegraded doses of isorhamnetin (0-80 microg/ml) for 48 h, respectively, isorhamnetin exhibited cytostaticeffect on the treated cells, with an IC(50) of 40+/-0.08 microg/ml as estimated by MTT assay. Inhibitionon proliferation by isorhamnetin was detected by trypan blue exclusion assay, clone formation test,immunocytochemical assay of PCNA and (3)H-thymidine uptake analysis. Cell cycle distribution wasmeasured by FCM. It was found that the viability of Eca-109 cells was significantly hampered byisorhamnetin. Compared with the negative control group, the treated group which was exposed toisorhamnetin had increased population in G(0)/G(1) phase from 74.6 to 84 while had a significantreduction in G(2)/M phase from 11.9 to 5.8. In addition to its cytostatic effect, isorhamnetin also showedstimulatory effect on apoptosis. Typical apoptotic morphology such as condensation and fragmentation ofnuclei and blebbing membrane of the apoptotic cells could be observed through transmission electronmicroscope. Moreover, the sharp increase in apoptosis rate between the control and treated group weredetected by FCM from 6.3 to 16.3. To explore the possible molecular mechanisms that underlie thegrowth inhibition and apoptosis stimulatory effects of isorhamnetin, the expressions of six proliferation-and death-related genes were detected by FCM. Expressions of bcl-2, c-myc and H-ras weredownregulated whereas Bax, c-fos and p53 were upregulated. However, the in vivo experiments wererequired to further confirm the anti-cancer effects of isorhamnetin. In conclusion, isorhamnetin appearsto be a potent drug against esophageal cancer due to its in vitro potential to not only inhibit proliferationbut also induce apoptosis of Eca-109 cells.", "metadata": {}}
+{"_id": "10247282", "title": "", "text": "Arachidonic Acid in the Diabetic Rat KidneyIn the rat isolated perfused kidney, arachidonic acid elicitscyclooxygenase-dependent vasoconstriction through activation of PGH2/TxA2 receptors; responses areenhanced in kidneys from diabetic rats. This study examined the roles ofcyclooxygenase-1/cyclooxygenase-2 in the enhanced renal vasoconstrictor effect of arachidonic acid instreptozotocin-diabetic rats. Release of 20-HETE was also determined, as this eicosanoid has beenreported to elicit cyclooxygenase-dependent vasoconstriction. We confirmed that vasoconstrictorresponses to arachidonic acid were enhanced in the diabetic rat kidney associated with a 2-fold-greaterincrease in the release of 6-ketoPGF1alpha, which was used as an index of cyclooxygenase activity. Oneand three micrograms of arachidonic acid increased perfusion pressure by 85+/-37 and 186+/-6 mm Hg,respectively, in diabetic rat kidneys compared with 3+/-1 and 17+/-8 mm Hg, respectively, in control ratkidneys. Inhibition of both cyclooxygenase isoforms with indomethacin (10 micromol/L) abolished thevasoconstrictor response to arachidonic acid in both diabetic and control rat kidneys, whereas inhibitionof cyclooxygenase-2 with nimesulide (5 micromol/L) reduced perfusion pressure responses to 1 and 3microg arachidonic acid only in the diabetic rat kidney to 15+/-8 and 108+/-26 mm Hg, respectively,consistent with a 3-fold increase in the renal cortical expression of cyclooxygenase-2. 20-HETE releasefrom the diabetic rat kidney was reduced almost 6-fold and was not increased in response to arachidonicacid. These results demonstrate that the renal vasoconstrictor effect of arachidonic acid is solelydependent on cyclooxygenase activity, with no evidence for a contribution from 20-HETE; in the diabeticrat, cyclooxygenase-2 activity contributes to the renal vasoconstrictor effect of arachidonic acid.", "metadata": {}}
+{"_id": "10247314", "title": "", "text": "Two sequence motifs from HIF-1alpha bind to the DNA-binding site of p53.There is evidence thathypoxia-inducible factor-1alpha (HIF-1alpha) interacts with the tumor suppressor p53. To characterizethe putative interaction, we mapped the binding of the core domain of p53 (p53c) to an array ofimmobilized HIF-1alpha-derived peptides and found two peptide-sequence motifs that bound to p53c withmicromolar affinity in solution. One sequence was adjacent to and the other coincided with the twoproline residues of the oxygen-dependent degradation domain (P402 and P564) that act as switches forthe oxygen-dependent regulation of HIF-1alpha. The binding affinity was independent of thehydroxylation state of P564. We found from NMR spectroscopy that these sequence motifs bind to theDNA-binding site of p53c. Because the two sequences are homologous and separated by 120 residues,and one is in a largely unstructured transactivation domain, we speculate that each sequence motif inHIF-1alpha binds to a different subunit of the p53 tetramer, leading to very tight binding. The bindingdata support the proposal that p53 provides a route for the degradation in hypoxic tumor cells ofHIF-1alpha that is not hydroxylated at the two proline residues.", "metadata": {}}
+{"_id": "10273147", "title": "", "text": "A functionally characterized test set of human induced pluripotent stem cellsHuman induced pluripotentstem cells (iPSCs) present exciting opportunities for studying development and for in vitro diseasemodeling. However, reported variability in the behavior of iPSCs has called their utility into question. Weestablished a test set of 16 iPSC lines from seven individuals of varying age, sex and health status, andextensively characterized the lines with respect to pluripotency and the ability to terminally differentiate.Under standardized procedures in two independent laboratories, 13 of the iPSC lines gave rise tofunctional motor neurons with a range of efficiencies similar to that of human embryonic stem cells(ESCs). Although three iPSC lines were resistant to neural differentiation, early neuralization rescuedtheir performance. Therefore, all 16 iPSC lines passed a stringent test of differentiation capacity despitevariations in karyotype and in the expression of early pluripotency markers and transgenes. This iPSCand ESC test set is a robust resource for those interested in the basic biology of stem cells and theirapplications.", "metadata": {}}
+{"_id": "10279084", "title": "", "text": "Differential regulation of MAP kinase activation by a novel splice variant of human MAP kinasephosphatase-2.MAP kinase phosphatase-2 (MKP-2) is a member of the family of dual specificityphosphatases that functions to inactivate the ERK and JNK MAP kinase signalling pathways. Here, weidentify a novel human MKP-2 variant (MKP-2-S) lacking the MAP kinase binding site but retaining thephosphatase catalytic domain. Endogenous MKP-2-S transcripts and proteins were found in PC3 prostateand MDA-MB-231 breast cancer cells and also human prostate biopsies. Cellular transfection of MKP-2-Sgave rise to a nuclear protein of 33kDa which displayed phosphatase activity comparable to the formerlydescribed long form of MKP-2 (MKP-2-L). Due to its lack of a kinase interacting motif (KIM), MKP-2-S didnot bind to JNK or ERK; MKP-2-L bound ERK and to a lesser extent JNK. Protein turnover of adenoviralexpressed MKP-2-S was accelerated relative to MKP-2-L, with a greater susceptibility toproteosomal-mediated degradation. MKP-2-S retained its ability to deactivate JNK in a similar manner asMKP-2-L and was an effective inhibitor of LPS-stimulated COX-2 induction. However, unlike MKP-2-L,MKP-2-S was unable to reverse serum-induced ERK activation or significantly inhibit endothelial cellproliferation. These findings reveal the occurrence of a novel splice variant of MKP-2 which is unable tobind ERK and may be significant in the dysregulation of MAP kinase activity in certain disease states,particularly in breast and prostate cancers.", "metadata": {}}
+{"_id": "10284593", "title": "", "text": "Myeloperoxidase acts as a profibrotic mediator of atrial fibrillationObservational clinical and ex vivostudies have established a strong association between atrial fibrillation and inflammation. However,whether inflammation is the cause or the consequence of atrial fibrillation and which specificinflammatory mediators may increase the atria's susceptibility to fibrillation remain elusive. Here weprovide experimental and clinical evidence for the mechanistic involvement of myeloperoxidase (MPO), aheme enzyme abundantly expressed by neutrophils, in the pathophysiology of atrial fibrillation.MPO-deficient mice pretreated with angiotensin II (AngII) to provoke leukocyte activation showed loweratrial tissue abundance of the MPO product 3-chlorotyrosine, reduced activity of matrixmetalloproteinases and blunted atrial fibrosis as compared to wild-type mice. Upon right atrialelectrophysiological stimulation, MPO-deficient mice were protected from atrial fibrillation, which wasreversed when MPO was restored. Humans with atrial fibrillation had higher plasma concentrations ofMPO and a larger MPO burden in right atrial tissue as compared to individuals devoid of atrial fibrillation.In the atria, MPO colocalized with markedly increased formation of 3-chlorotyrosine. Our datademonstrate that MPO is a crucial prerequisite for structural remodeling of the myocardium, leading to anincreased vulnerability to atrial fibrillation.", "metadata": {}}
+{"_id": "10300000", "title": "", "text": "Knowledge and use of secondary contraception among patients requesting termination of pregnancy.Theresults of a survey of 769 patients attending the St. James's University Fertility Control Clinic, England,for abortion services showed that patients seeing general practitioners were less knowledgeable thanthose attending specialist clinics. There was a demonstrated need for counseling on pill and condom useand protection against sexually transmitted diseases. Knowledge of postcoital methods was also found tobe lacking. The survey was conducted between April 1, 1991, and January 31, 1992. Respondentsincluded minorities such as Afro-Caribbean (8%) and Asian (9%). 307 of the cases were using a lesseffective form of contraception at the time of conception, usually a change from the pill to condoms. Ofthe 171 people reporting failure of contraception, 93 noted a split or leaking condom; 13, a condomfalling off during intercourse; 32, inconsistent use of condoms;l 32, forgetting to take contraceptive pillsor using antibiotics with the pill; and 1, a late injection of medroxyprogesterone acetate. 45 of the 309people who had conceived while using condoms recognized a potential condom failure, and only 20attempted any emergency contraceptive method such as the postcoital pill. Only 30% of the 171 patientswith recognized condom failure and 12% of the 210 who had not used any contraception had adequateknowledge of the existence, timing, and source of postcoital pills; i.e., 20% of 381. Only 2% of the 171nd 2% of the 381 patients, had knowledge of postcoital insertion of an intrauterine contraceptive device.Given the choice between and unplanned pregnancy and postcoital contraceptive, most (718 out of 769)preferred using postcoital contraception. Contraceptive information was given to 501 by a generalpractitioner, to 102 by a community family planning clinic, and 163 had no medical advice. There was arange of knowledge of postcoital contraceptive methods. Knowledge of how to deal with forgotten pills,severe vomiting, severe diarrhea, and concurrent antibiotic treatment among the 422 patients who hadever used the combined pill also was variable. 19% of the 372 patients treated by general practitionersknew 4 correct answers, but 50% of the 50 patients in community family planning clinics answeredcorrectly 4 times. Differences could not be explained by other demographic characteristics.", "metadata": {}}
+{"_id": "10300888", "title": "", "text": "Domestication and Divergence of Saccharomyces cerevisiae Beer YeastsWhereas domestication oflivestock, pets, and crops is well documented, it is still unclear to what extent microbes associated withthe production of food have also undergone human selection and where the plethora of industrial strainsoriginates from. Here, we present the genomes and phenomes of 157 industrial Saccharomycescerevisiae yeasts. Our analyses reveal that today's industrial yeasts can be divided into five sublineagesthat are genetically and phenotypically separated from wild strains and originate from only a fewancestors through complex patterns of domestication and local divergence. Large-scale phenotyping andgenome analysis further show strong industry-specific selection for stress tolerance, sugar utilization, andflavor production, while the sexual cycle and other phenotypes related to survival in nature show decay,particularly in beer yeasts. Together, these results shed light on the origins, evolutionary history, andphenotypic diversity of industrial yeasts and provide a resource for further selection of superior strains.PAPERCLIP.", "metadata": {}}
+{"_id": "10314816", "title": "", "text": "The ascendancy of Amblyomma americanum as a vector of pathogens affecting humans in the UnitedStates.Until the 1990s, Amblyomma americanum was regarded primarily as a nuisance species, but a tickof minor importance as a vector of zoonotic pathogens affecting humans. With the recent discoveries ofEhrlichia chaffeensis, Ehrlichia ewingii, and \"Borrelia lonestari,\" the public health relevance of lone starticks is no longer in question. During the next 25 years, the number of cases of human disease caused byA. americanum-associated pathogens will probably increase. Based on current trajectories and historicprecedents, the increase will be primarily driven by biological and environmental factors that alter thegeographic distribution and intensity of transmission of zoonotic pathogens. Sociologic and demographicchanges that influence the likelihood of highly susceptible humans coming into contact with infected lonestar ticks, in addition to advances in diagnostic capabilities and national surveillance efforts, will alsocontribute to the anticipated increase in the number of recognized cases of disease.", "metadata": {}}
+{"_id": "10326242", "title": "", "text": "Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhoodcancerPALB2 was recently identified as a nuclear binding partner of BRCA2. Biallelic BRCA2 mutationscause Fanconi anemia subtype FA-D1 and predispose to childhood malignancies. We identified pathogenicmutations in PALB2 (also known as FANCN) in seven families affected with Fanconi anemia and cancer inearly childhood, demonstrating that biallelic PALB2 mutations cause a new subtype of Fanconi anemia,FA-N, and, similar to biallelic BRCA2 mutations, confer a high risk of childhood cancer.", "metadata": {}}
+{"_id": "10335603", "title": "", "text": "Long tandem arrays of complex repeat units in Chironomus telomeres.A cloned 340-bp DNA fragmentexcised by EcoRI from the Chironomus pallividittatus genome has been localized to the telomeres by insitu hybridization as well as to connectives between telomeres. No hybridization was observed in otherregions of the chromosomes. Another cloned EcoRI fragment, 525 bp long has also been studied. Thisrepresents a partial duplication of the 340-bp sequence. Genomic blot hybridization experiments showthat the 340-bp sequence is a representative monomeric unit of tandemly repeated arrays which accountfor 1.2% of the Chironomus genome, on average 300 kb per telomere. The repeat unit contains twotypes of subrepeats each present twice per repeat unit. Northern blot hybridization experiments showthat the telomere-associated sequences are transcribed into a discrete RNA species approximately 20 kbin size. The evolution of this telomere-associated DNA is discussed.", "metadata": {}}
+{"_id": "10342807", "title": "", "text": "Localization of Na+ channel isoforms at the atrioventricular junction and atrioventricular node in therat.BACKGROUND The electrical activity of the atrioventricular node (AVN) is functionally heterogeneous,but how this relates to distinct cell types and the 3-dimensional structure of the AVN is unknown. Toaddress this, we have studied the expression of Na(V)1.5 and other Na+ channel isoforms in the AVN.METHODS AND RESULTS The rat AVN was identified by Masson's trichrome staining together withimmunolabeling of marker proteins: connexin40, connexin43, desmoplakin, atrial natriuretic peptide, andhyperpolarization-activated and cyclic nucleotide-gated channel 4. Na+ channel expression wasinvestigated with immunohistochemistry with isoform-specific Na+ channel antibodies. Na(V)1.1 wasdistributed in a similar manner to Na(V)1.5. Na(V)1.2 was not detected. Na(V)1.3 labeling was present innerve fibers and cell bodies (but not myocytes) and was abundant in the penetrating atrioventricular (AV)bundle and the common bundle but was much less abundant in other regions. Na(V)1.5 labeling wasabundant in the atrial and ventricular myocardium and the left bundle branch. Na(V)1.5 labeling wasabsent in the open node, penetrating AV bundle, AV ring bundle, and common bundle but present at areduced level in the inferior nodal extension and transitional zone. Na(V)1.6 was not detected.CONCLUSIONS Our findings provide molecular evidence of multiple electrophysiological cell types at theAV junction. Impaired AV conduction as a result of mutations in or loss of Na(V)1.5 must be the result ofimpaired conduction in the AVN inputs (inferior nodal extension and transitional zone) or output (bundlebranches) rather than the AVN itself (open node and penetrating AV bundle).", "metadata": {}}
+{"_id": "10354110", "title": "", "text": "Follicular B cell trafficking within the spleen actively restricts humoral immune responses.Follicular (FO)and marginal zone (MZ) B cells are maintained in distinct locations within the spleen, but the geneticbasis for this separation is still enigmatic. We now report that B cell sequestration requireslineage-specific regulation of migratory receptors by the transcription factor Klf2. Moreover, usinggene-targeted mice we show that altered splenic B cell migration confers a significant in vivogain-of-function phenotype to FO B cells, including the ability to quickly respond to MZ-associatedantigens and pathogens in a T cell-dependent manner. This work demonstrates that in wild-type animals,naive FO B cells are actively removed from the MZ, thus restricting their capacity to respond toblood-borne pathogens.", "metadata": {}}
+{"_id": "10359591", "title": "", "text": "Interleukin-2 and inflammation induce distinct transcriptional programs that promote the differentiationof effector cytolytic T cells.Interleukin(IL)-2 and inflammation regulate effector and memory cytolyticT-lymphocyte (CTL) generation during infection. We demonstrate a complex interplay between IL-2 andinflammatory signals during CTL differentiation. IL-2 stimulation induced the transcription factoreomesodermin (Eomes), upregulated perforin (Prf1) transcription, and repressed re-expression ofmemory CTL markers Bcl6 and IL-7Ralpha. Binding of Eomes and STAT5 to Prf1 cis-regulatory regionscorrelated with transcriptional initiation (increased recruitment of RNA polymerase II to the Prf1promoter). Inflammation (CpG, IL-12) enhanced expression of IL-2Ralpha and the transcription factorT-bet, but countered late Eomes and perforin induction while preventing IL-7Ralpha repression by IL-2.After infection of mice with lymphocytic choriomeningitis virus, IL-2Ralpha-deficient effector CD8(+) Tcells expressed more Bcl6 but less perforin and granzyme B, formed fewer KLRG-1(+) andT-bet-expressing CTL, and killed poorly. Thus, inflammation influences both effector and memory CTLdifferentiation, whereas persistent IL-2 stimulation promotes effector at the expense of memory CTLdevelopment.", "metadata": {}}
+{"_id": "10365749", "title": "", "text": "Neighbourhood risk factors for tuberculosis in Hong Kong.BACKGROUND Tuberculosis (TB) has beenreported to be associated with poverty, especially in developing countries. Hong Kong is one of the fewindustrialised areas with a high incidence of TB where previous reports on the effect of poverty atneighbourhood level have been conflicting. OBJECTIVE To examine the spatial distribution of TB and itsassociation with neighbourhood risk factors. METHOD A total of 17 294 TB cases notified from 2005 to2007 were mapped down to the District Council Constituency Area (DCCA) level, and were indirectlystandardised by age and sex using 2006 census population data. The standardised TB ratio wascorrelated with neighbourhood risk factors classified by family, ethnicity, economic and environmentaldomains. RESULTS The indirect age- and sex-standardised ratio demonstrated a spatially varied pattern,and was significantly associated with all neighbourhood factors on univariate analysis. Only maritalstatus, place of birth and low household income were independently associated with the standardised TBratio on multivariate analysis. CONCLUSION Despite the virtual elimination of absolute poverty by awell-developed social assistance scheme, low household income in the neighbourhood was significantlyassociated with TB, independently of place of birth, marital status and other risk factors.", "metadata": {}}
+{"_id": "10365787", "title": "", "text": "Genomic stability and tumour suppression by the APC/C cofactor Cdh1The anaphase promoting complexor cyclosome (APC/C) is a ubiquitin protein ligase that, together with Cdc20 or Cdh1, targets cell-cycleproteins for degradation. APC/C–Cdh1 specifically promotes protein degradation in late mitosis and G1.Mutant embryos lacking Cdh1 die at E9.5–E10.5 due to defects in the endoreduplication of trophoblastcells and placental malfunction. This lethality is prevented when Cdh1 is expressed in the placenta.Cdh1-deficient cells proliferate inefficiently and accumulate numeric and structural chromosomalaberrations, indicating that Cdh1 contributes to the maintenance of genomic stability. Cdh1 heterozygousanimals show increased susceptibility to spontaneous tumours, suggesting that Cdh1 functions as ahaploinsufficient tumour suppressor. These heterozygous mice also show several defects in behaviourassociated with increased proliferation of stem cells in the nervous system. These results indicate thatCdh1 is required for preventing unscheduled proliferation of specific progenitor cells and protectingmammalian cells from genomic instability.", "metadata": {}}
+{"_id": "10374686", "title": "", "text": "Developing primary palliative care.Although 65% of people with cancer want to die at home, only about30% are successful in doing so.1,2 A government committed to choice for patients must improve thisfigure.3 Developing palliative care services in primary care is essential for realising the expectations ofdying people. Such services could also offer important opportunities for extending supportive humanecare at an earlier stage, and to people not only with cancer but with chronic obstructive pulmonarydisease, motor neurone disease, and cardiac failure, for example, who also often have palliative careneeds. Primary care professionals have the potential and ability to provide end of life care for mostpatients, given adequate training, resources, and, when needed, specialist advice.4,5 They sharecommon values with palliative care specialists—holistic, patient centred care, delivered in the context offamilies and friends.6 However, until recently, apart from Macmillan general practitioners and nursefacilitators, few comprehensive workforce initiatives have been undertaken in primary care that focus onend of life care. Many cancer patients and their carers experience existential distress long before theydie.7 Recognising and alleviating such suffering is important, but it often goes unrecognised or isoverlooked by services focusing on the terminal phase of illnesses. Primary care teams may knowpatients over long periods of time. They can readily identify patients from cancer and chronic diseaseregisters who might benefit from an early palliative care approach. Such patients could be identified byclinicians asking one simple question of themselves: “Would I be surprised if my patient were to die in thenext 12 months?”8 By identifying such patients proactively we could deliver, simultaneously, activetreatment and patient centred supportive care, through a team with whom many patients have a valuedlong term relationship. Palliative care services need to be extended to patients with non-malignantconditions who have comparable concerns to and in some cases even greater unmet needs than cancerpatients.9 Progress by palliative medicine specialists is hampered by issues such as uncertainty about themost effective models of care, lack of non-cancer expertise, and concerns about pressure on specialistservices. General practitioners and community nurses can lead the way in providing a palliative careapproach for patients with terminal organ failure illness. The first step in such an approach is for the goalsof care to be discussed and agreed. Management plans are adjusted accordingly. Effective control ofsymptoms and maintaining quality of life are prioritised. In the light of these important opportunities it isregrettable that the new general medical services contract has not prioritised palliative care. By day,other developments to achieve the quality indicators are taking precedence. By night and at weekends,the new unscheduled care services (which are responsible for providing care for 75% of the hours in theweek) are even less well configured than previous out of hours provision to facilitate dying at home. Suchservices specialise in dealing with acute emergencies and, as such, often struggle to meet the medical,nursing, and social care needs of dying people and their families. These changes will greatly affect carefor dying people and may increase the number of hospital admissions. However, one important initiativeis gaining momentum within primary care. The Gold Standards Framework is a resource for organisingproactive palliative care in the community and is supported by funding from the Cancer ServicesCollaborative, Macmillan Cancer Relief, and the National Lottery.10 The framework provides a detailedguide to providing holistic, patient centred care and thereby facilitates effective care in the community.Other recently initiated mechanisms for developing primary palliative care include the training of generalpractitioners with a special interest in palliative care and the new end of life initiative in England toimprove palliative care provision by generalists and to share examples of good practice. To support suchdevelopments it is essential that primary palliative care is supported by an adequate academic base.11This is admittedly a challenging arena in which to undertake research, but progress has been made inrecent years in developing conceptual models and research architectures for studying end of life issues.Now we need to build on this work to ensure that the understanding and insights gleaned can betranslated into effective interventions. Every person with a progressive illness has a right to palliativecare.12 Patients desire a reassuring professional presence in the face of death. General practitioners andcommunity nurses are trusted by patients and are in a position to provide effective, equitable, and", "metadata": {}}
+{"_id": "10408324", "title": "", "text": "The effects of self-administering emergency contraception.BACKGROUND Emergency postcoitalcontraception prevents pregnancy, but it must be prescribed by a doctor and taken within 72 hours ofintercourse. It has been proposed that emergency contraception be made available without aprescription. We undertook a study to learn how women might behave if given a supply of emergencycontraceptive pills to keep at home. METHODS We assigned 553 women to be given a replaceable supplyof hormonal emergency contraceptive pills to take home (the treatment group) and 530 women to useemergency contraception obtained by visiting a doctor (the control group). The frequency of use ofemergency contraception, the use of other contraceptives, and the incidence of unwanted pregnancywere determined in both groups of women one year later. RESULTS The results for 549 women in thetreatment group and 522 women in the control group were available for analysis. Three hundredseventy-nine of the women in the treatment group (69 percent) and 326 of the women in the controlgroup (62 percent) contributed detailed information at follow-up. One hundred eighty of the women inthe treatment group (47 percent) used emergency contraception at least once. Among those whoreturned the study questionnaire, 98 percent used emergency contraception correctly. There were noserious adverse effects. Eighty-seven women in the control group (27 percent) used emergencycontraception at least once (P<0.001 for the comparison with the treatment group). The women in thetreatment group were not more likely to use emergency contraception repeatedly. Their use of othermethods of contraception was no different from that of the women in the control group. There were 18unintended pregnancies in the treatment group and 25 in the control group (relative risk, 0.7; 95 percentconfidence interval, 0.4 to 1.2). CONCLUSIONS Making emergency contraception more easily obtainabledoes no harm and may reduce the rate of unwanted pregnancies.", "metadata": {}}
+{"_id": "10423989", "title": "", "text": "A coactivator of pre-mRNA splicing.The nuclear matrix antigen recognized by the monoclonal antibody(mAb) B1C8 is a novel serine (S) and arginine (R)-rich protein associated with splicing complexes and isnamed here SRm160 (SR-related matrix protein of 160 kD). SRm160 contains multiple SR repeats, butunlike proteins of the SR family of splicing factors, lacks an RNA recognition motif. SRm160 and a relatedprotein SRm300 (the 300-kD nuclear matrix antigen recognized by mAb B4A11) form a complex that isrequired for the splicing of specific pre-mRNAs. The SRm160/300 complex associates with splicingcomplexes and promotes splicing through interactions with SR family proteins. Binding of SRm160/300 topre-mRNA is normally also dependent on U1 snRNP and is stabilized by U2 snRNP. Thus, SRm160/300forms multiple interactions with components bound directly to important sites within pre-mRNA. Theresults suggest that a complex of the nuclear matrix proteins SRm160 and SRm300 functions as acoactivator of pre-mRNA splicing.", "metadata": {}}
+{"_id": "10430148", "title": "", "text": "Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type2 diabetes: the PERISCOPE randomized controlled trial.CONTEXT No antidiabetic regimen hasdemonstrated the ability to reduce progression of coronary atherosclerosis. Commonly used oralglucose-lowering agents include sulfonylureas, which are insulin secretagogues, and thiazolidinediones,which are insulin sensitizers. OBJECTIVE To compare the effects of an insulin sensitizer, pioglitazone, withan insulin secretagogue, glimepiride, on the progression of coronary atherosclerosis in patients with type2 diabetes. DESIGN, SETTING, AND PARTICIPANTS Double-blind, randomized, multicenter trial at 97academic and community hospitals in North and South America (enrollment August 2003-March 2006) in543 patients with coronary disease and type 2 diabetes. INTERVENTIONS A total of 543 patientsunderwent coronary intravascular ultrasonography and were randomized to receive glimepiride, 1 to 4mg, or pioglitazone, 15 to 45 mg, for 18 months with titration to maximum dosage, if tolerated.Atherosclerosis progression was measured by repeat intravascular ultrasonography examination in 360patients at study completion. MAIN OUTCOME MEASURE Change in percent atheroma volume (PAV) frombaseline to study completion. RESULTS Least squares mean PAV increased 0.73% (95% CI, 0.33% to1.12%) with glimepiride and decreased 0.16% (95% CI, -0.57% to 0.25%) with pioglitazone(P = .002).An alternative analysis imputing values for noncompleters based on baseline characteristics showed anincrease in PAV of 0.64% (95% CI, 0.23% to 1.05%) for glimepiride and a decrease of 0.06% (-0.47% to0.35%) for pioglitazone (between-group P = .02). Mean (SD) baseline HbA(1c) levels were 7.4% (1.0%)in both groups and declined during treatment an average 0.55% (95% CI, -0.68% to -0.42%) withpioglitazone and 0.36% (95% CI, -0.48% to -0.24%) with glimepiride (between-group P = .03). In thepioglitazone group, compared with glimepiride, high-density lipoprotein levels increased 5.7 mg/dL (95%CI, 4.4 to 7.0 mg/dL; 16.0%) vs 0.9 mg/dL (95% CI, -0.3 to 2.1 mg/dL; 4.1%), and median triglyceridelevels decreased 16.3 mg/dL (95% CI, -27.7 to -11.0 mg/dL; 15.3%) vs an increase of 3.3 mg/dL (95%CI, -10.7 to 11.7 mg/dL; 0.6%) (P < .001 for both comparisons). Median fasting insulin levels decreasedwith pioglitazone and increased with glimepiride (P < .001). Hypoglycemia was more common in theglimepiride group and edema, fractures, and decreased hemoglobin levels occurred more frequently inthe pioglitazone group. CONCLUSION In patients with type 2 diabetes and coronary artery disease,treatment with pioglitazone resulted in a significantly lower rate of progression of coronaryatherosclerosis compared with glimepiride. TRIAL REGISTRATION clinicaltrials.gov Identifier:NCT00225277.", "metadata": {}}
+{"_id": "10443642", "title": "", "text": "Staphylococcus aureus RNAIII coordinately represses the synthesis of virulence factors and thetranscription regulator Rot by an antisense mechanism.RNAIII is the intracellular effector of thequorum-sensing system in Staphylococcus aureus. It is one of the largest regulatory RNAs (514nucleotides long) that are known to control the expression of a large number of virulence genes. Here, weshow that the 3' domain of RNAIII coordinately represses at the post-transcriptional level, the expressionof mRNAs that encode a class of virulence factors that act early in the infection process. We demonstratethat the 3' domain acts primarily as an antisense RNA and rapidly anneals to these mRNAs, forming longRNA duplexes. The interaction between RNAIII and the mRNAs results in repression of translationinitiation and triggers endoribonuclease III hydrolysis. These processes are followed by rapid depletion ofthe mRNA pool. In addition, we show that RNAIII and its 3' domain mediate translational repression of rotmRNA through a limited number of base pairings involving two loop-loop interactions. Since Rot is atranscriptional regulatory protein, we proposed that RNAIII indirectly acts on many downstream genes,resulting in the activation of the synthesis of several exoproteins. These data emphasize the multitude ofregulatory steps affected by RNAIII and its 3' domain in establishing a network of S. aureus virulencefactors.", "metadata": {}}
+{"_id": "10450300", "title": "", "text": "Human Cytomegalovirus Latency-Associated Proteins Elicit Immune-Suppressive IL-10 Producing CD4+ TCellsHuman cytomegalovirus (HCMV) is a widely prevalent human herpesvirus, which, after primaryinfection, persists in the host for life. In healthy individuals, the virus is well controlled by theHCMV-specific T cell response. A key feature of this persistence, in the face of a normally robust hostimmune response, is the establishment of viral latency. In contrast to lytic infection, which ischaracterised by extensive viral gene expression and virus production, long-term latency in cells of themyeloid lineage is characterised by highly restricted expression of viral genes, including UL138 and LUNA.Here we report that both UL138 and LUNA-specific T cells were detectable directly ex vivo in healthyHCMV seropositive subjects and that this response is principally CD4\u0000 T cell mediated. TheseUL138-specific CD4\u0000 T cells are able to mediate MHC class II restricted cytotoxicity and, importantly,show IFNγ effector function in the context of both lytic and latent infection. Furthermore, in contrast toCDCD4\u0000 T cells specific to antigens expressed solely during lytic infection, both the UL138 andLUNA-specific CD4\u0000 T cell responses included CD4\u0000 T cells that secreted the immunosuppressivecytokine cIL-10. We also show that cIL-10 expressing CD4\u0000 T-cells are directed against latentlyexpressed US28 and UL111A. Taken together, our data show that latency-associated gene products ofHCMV generate CD4\u0000 T cell responses in vivo, which are able to elicit effector function in response toboth lytic and latently infected cells. Importantly and in contrast to CD4\u0000 T cell populations, whichrecognise antigens solely expressed during lytic infection, include a subset of cells that secrete theimmunosuppressive cytokine cIL-10. This suggests that HCMV skews the T cell responses tolatency-associated antigens to one that is overall suppressive in order to sustain latent carriage in vivo.", "metadata": {}}
+{"_id": "10450725", "title": "", "text": "Pamidronate induced anti-proliferative, apoptotic, and anti-migratory effects in hepatocellularcarcinoma.BACKGROUND/AIMS The small GTPase of Ras and Rho families are widely involved in humantumorgenesis and metastasis. It has recently been reported that pamidronate inhibits the mevalonatepathway, which is required for the prenylation of the small GTPase. We demonstrated a possiblebeneficial use of pamidronate in the treatment of hepatocellular carcinoma (HCC). METHODS The effect ofpamidronate on cell proliferation was analyzed with five hepatoma cell lines using MTT assay. Apoptosiswas evaluated by staining with DAPI and a histon ELISA assay. A cell migration assay was performedusing the Modified Boyden Chamber. To analyze anti-proliferation effect of pamidronate in vivo, tumorvolumes were monitored with the intraperitoneal injection of pamidronate after subcutaneous inoculationof PLC/PRF/5 cells into nude mice. RESULTS Pamidronate inhibited cell growth for all hepatoma cell lines.The amount of membrane associated Ras and phosphorylated extracellular signal-regulated kinase 2(ERK 2) were reduced after pamidronate treatment. Pamidronate increased apoptosis and cleavage ofCaspase-3, and -9. Pamidronate suppressed membrane associated RhoA and cell motility. In vivo, tumorvolumes were significantly suppressed by pamidronate at three weeks (P<0.03). CONCLUSIONS Weconclude that pamidronate has therapeutic potential in inducing anti-proliferative, apoptotic, andanti-migratory effects in HCC.", "metadata": {}}
+{"_id": "10463997", "title": "", "text": "Defective regulation of adipose tissue autophagy in obesityObjectives: Autophagy is a highly regulatedprocess that has an important role in the control of a wide range of cellular functions, such as organellerecycling, nutrient availability and tissue differentiation. A recent study has shown an increasedautophagic activity in the adipose tissue of obese subjects, and a role for autophagy in obesity-associatedinsulin resistance was proposed. Body mass reduction is the most efficient approach to tackle insulinresistance in over-weight subjects; however, the impact of weight loss in adipose tissue autophagy isunknown. Subjects:Adipose tissue autophagy was evaluated in mice and humans. Results:First, a mousemodel of diet-induced obesity and diabetes was maintained on a 15-day, 40% caloric restriction. Atbaseline, markers of autophagy were increased in obese mice as compared with lean controls. Uponcaloric restriction, autophagy increased in the lean mice, whereas it decreased in the obese mice. Thereintroduction of ad libitum feeding was sufficient to rapidly reduce autophagy in the lean mice andincrease autophagy in the obese mice. In the second part of the study, autophagy was evaluated in thesubcutaneous adipose tissue of nine obese-non-diabetic and six obese-diabetic subjects undergoingbariatric surgery for body mass reduction. Specimens were collected during the surgery andapproximately 1 year later. Markers of systemic inflammation, such as tumor necrosis factor-1α,interleukin (IL)-6 and IL-1β were evaluated. As in the mouse model, human obesity was associated withincreased autophagy, and body mass reduction led to an attenuation of autophagy in the adipose tissue.Conclusion:Obesity and caloric overfeeding are associated with the defective regulation of autophagy inthe adipose tissue. The studies in obese-diabetic subjects undergoing improved metabolic controlfollowing calorie restriction suggest that autophagy and inflammation are regulated independently.", "metadata": {}}
+{"_id": "10474873", "title": "", "text": "Recovery of visual response of injured adult rat optic nerves treated with transglutaminase.Failure ofaxons of the central nervous system in adult mammals to regenerate spontaneously after injury isattributed in part to inhibitory molecules associated with oligodendrocytes. Regeneration of centralnervous system axons in fish is correlated with the presence of a transglutaminase. This enzymedimerizes interleukin-2, and the product is cytotoxic to oligodendrocytes in vitro. Application of thisnerve-derived transglutaminase to rat optic nerves, in which the injury had caused the loss of visualevoked potential response to light, promoted the recovery of that response within 6 weeks after injury.Transmission electron microscopy analysis revealed the concomitant appearance of axons in the distalstump of the optic nerve.", "metadata": {}}
+{"_id": "10482574", "title": "", "text": "Cell survival during complete nutrient deprivation depends on lipid droplet-fueled β-oxidation of fattyacids.Cells exposed to stress of different origins synthesize triacylglycerols and generate lipid droplets(LD), but the physiological relevance of this response is uncertain. Using complete nutrient deprivation ofcells in culture as a simple model of stress, we have addressed whether LD biogenesis has a protectiverole in cells committed to die. Complete nutrient deprivation induced the biogenesis of LD in human LN18glioblastoma and HeLa cells and also in CHO and rat primary astrocytes. In all cell types, death wasassociated with LD depletion and was accelerated by blocking LD biogenesis after pharmacologicalinhibition of Group IVA phospholipase A2 (cPLA2α) or down-regulation of ceramide kinase. Nutrientdeprivation also induced β-oxidation of fatty acids that was sensitive to cPLA2α inhibition, and cellsurvival in these conditions became strictly dependent on fatty acid catabolism. These results show that,during nutrient deprivation, cell viability is sustained by β-oxidation of fatty acids that requires biogenesisand mobilization of LD.", "metadata": {}}
+{"_id": "10485142", "title": "", "text": "Molecular and cytogenetic changes involved in the immortalization of nasopharyngeal epithelial cells bytelomerase.Nasopharyngeal carcinoma (NPC) is a common disease in Hong Kong and southern provincesof China. EBV infection is believed to play a critical role in the development of NPC. Previous studies onthe transformation mechanism of EBV genes were mostly performed in either NPC or nonnasopharyngealepithelial cells which may not be representative of premalignant nasopharyngeal epithelial cells.Establishment of a representative cell system would greatly facilitate the elucidation of the role of EBVinfection in the development of NPC. Using telomerase alone, we were able to establish an immortalizednasopharyngeal epithelial cell line from primary nonmalignant nasopharyngeal biopsies. Thetelomerase-immortalized nasopharyngeal epithelial cells are largely diploid in karyotype. Interestingly,this newly immortalized nasopharyngeal epithelial cell line, referred as NP460hTert, harbors geneticalterations previously identified in premalignant and malignant nasopharyngeal epithelial cells. Theseinclude inactivation of p16 by homozygous deletion of the p16(INK4A) locus and downregulation ofRASSF1A expression. The deletion of the p16(INK4A) locus appears to be the most crucial event for theimmortalization of nasopharyngeal epithelial cells by telomerase and precedes RASSF1A downregulation.In addition, detailed analysis of the cytogenetic changes by conventional cytogenetics, spectralkaryotyping (SKY) and array-based CGH revealed a gain of a 17q21-q25 fragment on 11p15 chromosomein all NP460hTert cells which occurred before deletion of the p16(INK4A) locus. Gain of 17q has beenpreviously reported in NPC. In addition, activation of NF-kappaB was observed in immortalizedNP460hTert cells at the later population doublings, and may play a role in the survival of immortalized NPepithelial cells. Id1 which is commonly expressed in various human cancers, including NPC, was alsoupregulated in the immortalized NP460hTert cells. Thus, the establishment of an immortalizednasopharyngeal epithelial cell line harboring common genetic alterations present in premalignant andcancerous nasopharyngeal epithelial cells may provide a valuable cell system to examine for early eventsinvolved in NPC carcinogenesis, particularly in elucidating the role of EBV infection in NPC development.", "metadata": {}}
+{"_id": "10486817", "title": "", "text": "Cellular nucleic acid binding protein suppresses tumor cell metastasis and induces tumor cell death bydownregulating heterogeneous ribonucleoprotein K in fibrosarcoma cells.BACKGROUND Cellular nucleicacid binding protein (CNBP) has been implicated in vertebrate craniofacial development and in myotonicdystrophy type 2 (DM2) and sporadic inclusion body myositis (sIBM) human diseases by controlling cellproliferation and survival to mediate neural crest expansion. CNBP has been found to bindsingle-stranded nucleic acid and promote rearrangements of nucleic acid secondary structure in anATP-independent manner, acting as a nucleic acid chaperone. METHODS A variety of methods were used,including cell viability assays, wound-scratch assays, chemotaxis assays, invasion assays, circulardichroic (CD) spectroscopy, NMR spectroscopy, chromatin immunoprecipitation, expression andpurification of recombinant human CNBP, electrophoretic mobility shift assay (EMSA), surface plasmonresonance (SPR), fluorescence resonance energy transfer (FRET) analyses, luciferase reporter assay,Western blotting, and isothermal titration calorimetry (ITC). RESULTS Up-regulation of CNBP inducedhuman fibrosarcoma cell death and suppressed fibrosarcoma cell motility and invasiveness. It was foundthat CNBP transcriptionally down-regulated the expression of heterogeneous ribonucleoprotein K (hnRNPK) through its conversion of a G-rich sequence into G-quadruplex in the promoter of hnRNP K.G-quadruplex stabilizing ligand tetra-(N-methyl-4-pyridyl) porphyrin (TMPyP4) could interact with andstabilize the G-quadruplex, resulting in downregulation of hnRNP K transcription. CONCLUSIONS CNBPoverexpression caused increase of cell death and suppression of cell metastasis through its induction ofG-quadruplex formation in the promoter of hnRNP K resulting in hnRNP K down-regulation. GENERALSIGNIFICANCE The present result provided a new solution for controlling hnRNP K expression, whichshould shed light on new anticancer drug design and development.", "metadata": {}}
+{"_id": "10491220", "title": "", "text": "The DHR96 nuclear receptor regulates xenobiotic responses in Drosophila.Exposure to xenobiotics suchas plant toxins, pollutants, or prescription drugs triggers a defense response, inducing genes that encodekey detoxification enzymes. Although xenobiotic responses have been studied in vertebrates, little efforthas been made to exploit a simple genetic system for characterizing the molecular basis of thiscoordinated transcriptional response. We show here that approximately 1000 transcripts are significantlyaffected by phenobarbital treatment in Drosophila. We also demonstrate that the Drosophila ortholog ofthe human SXR and CAR xenobiotic receptors, DHR96, plays a role in this response. A DHR96 null mutantdisplays increased sensitivity to the sedative effects of phenobarbital and the pesticide DDT as well asdefects in the expression of many phenobarbital-regulated genes. Metabolic and stress-response genesare also controlled by DHR96, implicating its role in coordinating multiple response pathways. This workestablishes a new model system for defining the genetic control of xenobiotic stress responses.", "metadata": {}}
+{"_id": "10494012", "title": "", "text": "A primate virus generates transformed human cells by fusionAmodel that explains both the origin andsporadic nature of cancer argues that cancer cells are a chance result of events that cause genomic andepigenetic variability. The prevailing view is that these events are mutations that affect chromosomesegregation or stability. However, genomic and epigenetic variability is also triggered by cell fusion, whichis often caused by viruses. Yet, cells fused by viruses are considered harmless because they die. Weprovide evidence that a primate virus uses both viral and exosomal proteins involved in cell fusion toproduce transformed proliferating human cells. Although normal cells indeed fail to proliferate afterfusion, expression of an oncogene or a mutated tumor suppressor p53 in just one of the fusion partners issufficient to produce heterogeneous progeny. We also show that this virus can produce viableoncogenically transformed cells by fusing cells that are otherwise destined to die. Therefore, we arguethat viruses can contribute to carcinogenesis by fusing cells.", "metadata": {}}
+{"_id": "10504681", "title": "", "text": "TAA1-Mediated Auxin Biosynthesis Is Essential for Hormone Crosstalk and Plant DevelopmentPlants haveevolved a tremendous ability to respond to environmental changes by adapting their growth anddevelopment. The interaction between hormonal and developmental signals is a critical mechanism in thegeneration of this enormous plasticity. A good example is the response to the hormone ethylene thatdepends on tissue type, developmental stage, and environmental conditions. By characterizing theArabidopsis wei8 mutant, we have found that a small family of genes mediates tissue-specific responsesto ethylene. Biochemical studies revealed that WEI8 encodes a long-anticipated tryptophanaminotransferase, TAA1, in the essential, yet genetically uncharacterized, indole-3-pyruvic acid (IPA)branch of the auxin biosynthetic pathway. Analysis of TAA1 and its paralogues revealed a link betweenlocal auxin production, tissue-specific ethylene effects, and organ development. Thus, the IPA route ofauxin production is key to generating robust auxin gradients in response to environmental anddevelopmental cues.", "metadata": {}}
+{"_id": "10509344", "title": "", "text": "A research agenda for public health workforce development.In the past decades, public health researchhas focused on categorical rather than cross-cutting or systems issues. Little research has been carriedout on the infrastructure required to support public health programs. This article describes the results ofan interactive process to develop a research agenda for public health workforce development to inform allthose with stakes in the public health system. This research is defined as a multidisciplinary field ofinquiry, both basic and applied, that examines the workforce in terms of costs, quality, accessibility,delivery, organization, financing, and outcomes of public health services to increase knowledge andunderstanding of the relationships among workforce and structure, processes, and effects of public healthservices. A logic model and five priority research areas resulted from meetings of expert panels during2000 to 2003. Innovative public and private partnerships will be required to advance cross-cutting andsystems-focused research.", "metadata": {}}
+{"_id": "10518721", "title": "", "text": "Parallel processing in the mammalian retinaOur eyes send different 'images' of the outside world to thebrain — an image of contours (line drawing), a colour image (watercolour painting) or an image ofmoving objects (movie). This is commonly referred to as parallel processing, and starts as early as thefirst synapse of the retina, the cone pedicle. Here, the molecular composition of the transmitter receptorsof the postsynaptic neurons defines which images are transferred to the inner retina. Within the secondsynaptic layer — the inner plexiform layer — circuits that involve complex inhibitory and excitatoryinteractions represent filters that select 'what the eye tells the brain'.", "metadata": {}}
+{"_id": "10526279", "title": "", "text": "Oxymetholone Therapy of Fanconi Anemia Suppresses Osteopontin Transcription and InducesHematopoietic Stem Cell CyclingAndrogens are widely used for treating Fanconi anemia (FA) and otherhuman bone marrow failure syndromes, but their mode of action remains incompletely understood. AgedFancd2(-/-) mice were used to assess the therapeutic efficacy of oxymetholone (OXM) and its mechanismof action. Eighteen-month-old Fancd2(-/-) mice recapitulated key human FA phenotypes, includingreduced bone marrow cellularity, red cell macrocytosis, and peripheral pancytopenia. As in humans,chronic OXM treatment significantly improved these hematological parameters and stimulated theproliferation of hematopoietic stem and progenitor cells. RNA-Seq analysis implicated downregulation ofosteopontin as an important potential mechanism for the drug's action. Consistent with the increasedstem cell proliferation, competitive repopulation assays demonstrated that chronic OXM therapyeventually resulted in stem cell exhaustion. These results expand our knowledge of the regulation ofhematopoietic stem cell proliferation and have direct clinical implications for the treatment of bonemarrow failure.", "metadata": {}}
+{"_id": "10530014", "title": "", "text": "A point mutation in KINDLIN3 ablates activation of three integrin subfamilies in humansMonogenicdeficiency diseases provide unique opportunities to define the contributions of individual molecules tohuman physiology and to identify pathologies arising from their dysfunction. Here we describe adeficiency disease in two human siblings that presented with severe bleeding, frequent infections andosteopetrosis at an early age. These symptoms are consistent with but more severe than those reportedfor people with leukocyte adhesion deficiency III (LAD-III). Mechanistically, these symptoms arose froman inability to activate the integrins expressed on hematopoietic cells, including platelets and leukocytes.Immortalized lymphocyte cell lines isolated from the two individuals showed integrin activation defects.Several proteins previously implicated in integrin activation, including Ras-associated protein-1 (RAP1)and calcium and diacylglycerol-regulated guanine nucleotide exchange factor-1 (CALDAG-GEF1), werepresent and functional in these cell lines. The genetic basis for this disease was traced to a point mutationin the coding region of the KINDLIN3 (official gene symbol FERMT3) gene. When wild-type KINDLIN-3was expressed in the immortalized lymphocytes, their integrins became responsive to activation signals.These results identify a genetic disease that severely compromises the health of the affected individualsand establish an essential role of KINDLIN-3 in integrin activation in humans. Furthermore, allogeneicbone marrow transplantation was shown to alleviate the symptoms of the disease.", "metadata": {}}
+{"_id": "10534299", "title": "", "text": "Fasting Activation of AgRP Neurons Requires NMDA Receptors and Involves Spinogenesis and IncreasedExcitatory ToneAgRP neuron activity drives feeding and weight gain whereas that of nearby POMCneurons does the opposite. However, the role of excitatory glutamatergic input in controlling theseneurons is unknown. To address this question, we generated mice lacking NMDA receptors (NMDARs) oneither AgRP or POMC neurons. Deletion of NMDARs from AgRP neurons markedly reduced weight, bodyfat and food intake whereas deletion from POMC neurons had no effect. Activation of AgRP neurons byfasting, as assessed by c-Fos, Agrp and Npy mRNA expression, AMPA receptor-mediated EPSCs,depolarization and firing rates, required NMDARs. Furthermore, AgRP but not POMC neurons havedendritic spines and increased glutamatergic input onto AgRP neurons caused by fasting was paralleledby an increase in spines, suggesting fasting induced synaptogenesis and spinogenesis. Thusglutamatergic synaptic transmission and its modulation by NMDARs play key roles in controlling AgRPneurons and determining the cellular and behavioral response to fasting.", "metadata": {}}
+{"_id": "10536636", "title": "", "text": "Prevalence and Causes of Blindness and Low Vision in Southern SudanBackground Blindness and lowvision are thought to be common in southern Sudan. However, the magnitude and geographicaldistribution are largely unknown. We aimed to estimate the prevalence of blindness and low vision,identify the main causes of blindness and low vision, and estimate targets for blindness preventionprograms in Mankien payam (district), southern Sudan.", "metadata": {}}
+{"_id": "10538985", "title": "", "text": "Origin of nitrite and nitrate in nasal and exhaled breath condensate and relation to nitric oxideformation.BACKGROUND Raised concentrations of nitrate and nitrite have been found in exhaled breathcondensate (EBC) in airway disease, and it has been postulated that this reflects increased nitric oxide(NO) metabolism. However, the chemical and anatomical origin of nitrate and nitrite in the airways hasnot yet been sufficiently studied. METHODS The fraction of exhaled NO at an exhalation flow rate of 50ml/s (FE(NO)) and nitrite and nitrate in EBC, nasal condensate, and saliva were measured in 17tracheostomised and 15 non-tracheostomised subjects, all of whom were non-smokers withoutrespiratory disease. Tracheal and oral samples were taken from the tracheostomised subjects and nasal(during velum closure) and oral samples from the non-tracheostomised subjects. Measurements wereperformed before and after sodium nitrate ingestion (10 mg/kg) and use of antibacterial mouthwash(chlorhexidine 0.2%). RESULTS In tracheostomised subjects oral FE(NO) increased by 90% (p<0.01)while tracheal FE(NO) was not affected 60 minutes after nitrate ingestion. Oral EBC nitrite levels wereincreased 23-fold at 60 minutes (p<0.001) whereas the nitrite levels in tracheal EBC showed only a minorincrease (fourfold, p<0.05). Nitrate was increased the same amount in oral and tracheal EBC at 60minutes (2.5-fold, p<0.05). In non-tracheostomised subjects oral FE(NO) and EBC nitrite increased afternitrate ingestion and after chlorhexidine mouthwash they approached baseline levels again (p<0.001).Nasal NO, nitrate, and nitrite were not affected by nitrate intake or mouthwash. At baseline, mouthwashwith deionised water did not affect nitrite in oral EBC or saliva, whereas significant reductions were seenafter antibacterial mouthwash (p<0.05 and p<0.001, respectively). CONCLUSIONS Besides the salivaryglands, plasma nitrate is taken up by the lower airways but not the nasal airways. Nitrate levels in EBCare thus influenced by dietary intake. Nitrate is reduced to nitrite by bacterial activity which takes placeprimarily in the oropharyngeal tract of healthy subjects. Only oropharyngeal nitrite seems to contribute toexhaled NO in non-inflamed airways, and there is also a substantial contribution of nitrite from theoropharyngeal tract during standard collection of EBC.", "metadata": {}}
+{"_id": "10542877", "title": "", "text": "AZD9150, a next-generation antisense oligonucleotide inhibitor of STAT3 with early evidence of clinicalactivity in lymphoma and lung cancerNext-generation sequencing technologies have greatly expandedour understanding of cancer genetics. Antisense technology is an attractive platform with the potential totranslate these advances into improved cancer therapeutics, because antisense oligonucleotide (ASO)inhibitors can be designed on the basis of gene sequence information alone. Recent human clinical datahave demonstrated the potent activity of systemically administered ASOs targeted to genes expressed inthe liver. We describe the preclinical activity and initial clinical evaluation of a class of ASOs containingconstrained ethyl modifications for targeting the gene encoding the transcription factor STAT3, anotoriously difficult protein to inhibit therapeutically. Systemic delivery of the unformulated ASO,AZD9150, decreased STAT3 expression in a broad range of preclinical cancer models and showedantitumor activity in lymphoma and lung cancer models. AZD9150 preclinical activity translated intosingle-agent antitumor activity in patients with highly treatment-refractory lymphoma and non–small celllung cancer in a phase 1 dose-escalation study.", "metadata": {}}
+{"_id": "10546779", "title": "", "text": "Evidence of a pluripotent human embryonic stem cell line derived from a cloned blastocyst.Somatic cellnuclear transfer (SCNT) technology has recently been used to generate animals with a common geneticcomposition. In this study, we report the derivation of a pluripotent embryonic stem (ES) cell line(SCNT-hES-1) from a cloned human blastocyst. The SCNT-hES-1 cells displayed typical ES cellmorphology and cell surface markers and were capable of differentiating into embryoid bodies in vitroand of forming teratomas in vivo containing cell derivatives from all three embryonic germ layers insevere combined immunodeficient mice. After continuous proliferation for more than 70 passages,SCNT-hES-1 cells maintained normal karyotypes and were genetically identical to the somatic nucleardonor cells. Although we cannot completely exclude the possibility that the cells had a parthenogeneticorigin, imprinting analyses support a SCNT origin of the derived human ES cells.", "metadata": {}}
+{"_id": "10548391", "title": "", "text": "Ultrarapid drug metabolism: PCR-based detection of CYP2D6 gene duplication.The enzyme debrisoquine4-hydroxylase (CYP2D6), which metabolizes many widely used drugs, is highly polymorphic. The activityof the enzyme ranges between subjects from ultrafast to a complete absence. Therefore, metaboliccapacity varies, producing intersubject differences in therapeutic efficacy and side effects at standardrecommended doses. Up to 7% of Caucasians may demonstrate ultrarapid drug metabolism (UM)because of inherited alleles with multiplicate functional CYP2D6 genes, causing an increased amount ofenzyme to be expressed. Identification of UM subjects is of potential clinical importance for adjustment ofdoses in drug therapy, as well as to avoid misidentification of noncompliance. In our study, we testedrecently designed PCR assays for the detection of the UM genotype. We found a 3.5% prevalence of UMscarrying duplicate active CYP2D6 genes in a population consisting of 202 psychiatric patients.", "metadata": {}}
+{"_id": "10555591", "title": "", "text": "The Actions of Synaptically Released Zinc at Hippocampal Mossy Fiber SynapsesZn2+ is present at highconcentrations in the synaptic vesicles of hippocampal mossy fibers. We have used Zn2+ chelators andthe mocha mutant mouse to address the physiological role of Zn2+ in this pathway. Zn2+ is not involvedin the unique presynaptic plasticities observed at mossy fiber synapses but is coreleased with glutamatefrom these synapses, both spontaneously and with electrical stimulation, where it exerts a strongmodulatory effect on the NMDA receptors. Zn2+ tonically occupies the high-affinity binding site of NMDAreceptors at mossy fiber synapses, whereas the lower affinity voltage-dependent Zn2+ binding site isoccupied during action potential driven-release. We conclude that Zn2+ is a modulatory neurotransmitterreleased from mossy fiber synapses and plays an important role in shaping the NMDA receptor responseat these synapses.", "metadata": {}}
+{"_id": "10557471", "title": "", "text": "Association between folate intake from different food sources in Norway and homocysteine status in adietary intervention among young male adults.The aim of the present investigation was to study theeffect of a dietary intervention which combined nutrition information with increased availability ofvegetables, fruits and wholegrain bread. The effect of the intervention was determined by changes in theintake of vegetables, fruits, wholegrain bread and estimated nutrients. Furthermore, the studyinvestigated whether changes in relative contribution from different food sources of folate were related tochanges in the concentration of plasma total homocysteine (p-tHcy). The 5-month intervention studyincluded 376 male recruits from the Norwegian National Guard, Vaernes (intervention group) and 105male recruits from the Norwegian National Guard, Heggelia (control group). The study resulted in anincrease in the total consumption of vegetables, fruits, berries and juice (P < 0.001) and of wholegrainbread (P < 0.001). The participants in the intervention group showed a higher increase in the intake ofdietary fibre (P < 0.001) and folate (P < 0.001) compared with the control group. The relativecontribution of folate intake from fruits, vegetables and wholegrain bread was higher in the interventiongroup compared with the control group (P < 0.001 for all). The increased intake of folate from wholegrainbread was inversely associated with a reduced concentration of p-tHcy (P = 0.017). In summary, thedietary intervention resulted in an increased intake of vegetables, fruits and wholegrain bread and asubsequent increase in folate intake from these food components. Reduction in the concentration ofp-tHcy was significantly related to an increased folate intake due to an increased consumption ofwholegrain bread.", "metadata": {}}
+{"_id": "10559501", "title": "", "text": "Beta interferon controls West Nile virus infection and pathogenesis in mice.Studies with mice lacking thecommon plasma membrane receptor for type I interferon (IFN-αβR(-)(/)(-)) have revealed that IFNsignaling restricts tropism, dissemination, and lethality after infection with West Nile virus (WNV) orseveral other pathogenic viruses. However, the specific functions of individual IFN subtypes remainuncertain. Here, using IFN-β(-)(/)(-) mice, we defined the antiviral and immunomodulatory function ofthis IFN subtype in restricting viral infection. IFN-β(-)(/)(-) mice were more vulnerable to WNV infectionthan wild-type mice, succumbing more quickly and with greater overall mortality, although the phenotypewas less severe than that of IFN-αβR(-)(/)(-) mice. The increased susceptibility of IFN-β(-)(/)(-) micewas accompanied by enhanced viral replication in different tissues. Consistent with a direct role for IFN-βin control of WNV replication, viral titers in ex vivo cultures of macrophages, dendritic cells, fibroblasts,and cerebellar granule cell neurons, but not cortical neurons, from IFN-β(-)(/)(-) mice were greater thanin wild-type cells. Although detailed immunological analysis revealed no major deficits in the quality orquantity of WNV-specific antibodies or CD8(+) T cells, we observed an altered CD4(+) CD25(+) FoxP3(+)regulatory T cell response, with greater numbers after infection. Collectively, these results suggest thatIFN-β controls WNV pathogenesis by restricting infection in key cell types and by modulating T cellregulatory networks.", "metadata": {}}
+{"_id": "10562341", "title": "", "text": "Frontrunners of T cell activation: Initial, localized Ca2+ signals mediated by NAADP and the type 1ryanodine receptorThe activation of T cells is the fundamental on switch for the adaptive immune system.Ca2+ signaling is essential for T cell activation and starts as initial, short-lived, localized Ca2+ signals.The second messenger nicotinic acid adenine dinucleotide phosphate (NAADP) forms rapidly upon T cellactivation and stimulates early Ca2+ signaling. We developed a high-resolution imaging technique usingmultiple fluorescent Ca2+ indicator dyes to characterize these early signaling events and investigate thechannels involved in NAADP-dependent Ca2+ signals. In the first seconds of activation of either primarymurine T cells or human Jurkat cells with beads coated with an antibody against CD3, we detected Ca2+signals with diameters close to the limit of detection and that were close to the activation site at theplasma membrane. In Jurkat cells in which the ryanodine receptor (RyR) was knocked down or in primaryT cells from RyR1−/− mice, either these early Ca2+ signals were not detected or the number of signalswas markedly reduced. Local Ca2+ signals observed within 20 ms upon microinjection of Jurkat cells withNAADP were also sensitive to RyR knockdown. In contrast, TRPM2 (transient receptor potential channel,subtype melastatin 2), a potential NAADP target channel, was not required for the formation of initialCa2+ signals in primary T cells. Thus, through our high-resolution imaging method, we characterizedearly Ca2+ release events in T cells and obtained evidence for the involvement of RyR and NAADP in suchsignals.", "metadata": {}}
+{"_id": "10574949", "title": "", "text": "A missense LAMB2 mutation causes congenital nephrotic syndrome by impairing lamininsecretion.Laminin β2 is a component of laminin-521, which is an important constituent of the glomerularbasement membrane (GBM). Null mutations in laminin β2 (LAMB2) cause Pierson syndrome, a severecongenital nephrotic syndrome with ocular and neurologic defects. In contrast, patients with LAMB2missense mutations, such as R246Q, can have less severe extrarenal defects but still exhibit congenitalnephrotic syndrome. To investigate how such missense mutations in LAMB2 cause proteinuria, wegenerated three transgenic lines of mice in which R246Q-mutant rat laminin β2 replaced the wild-typemouse laminin β2 in the GBM. These transgenic mice developed much less severe proteinuria than theirnontransgenic Lamb2-deficient littermates; the level of proteinuria correlated inversely withR246Q-LAMB2 expression. At the onset of proteinuria, expression and localization of proteins associatedwith the slit diaphragm and foot processes were normal, and there were no obvious ultrastructuralabnormalities. Low transgene expressors developed heavy proteinuria, foot process effacement, GBMthickening, and renal failure by 3 months, but high expressors developed only mild proteinuria by 9months. In vitro studies demonstrated that the R246Q mutation results in impaired secretion of laminin.Taken together, these results suggest that the R246Q mutation causes nephrotic syndrome by impairingsecretion of laminin-521 from podocytes into the GBM; however, increased expression of the mutantprotein is able to overcome this secretion defect and improve glomerular permselectivity.", "metadata": {}}
+{"_id": "10576136", "title": "", "text": "Interleukin-33 prevents apoptosis and improves survival after experimental myocardial infarction throughST2 signaling.BACKGROUND ST2 is an interleukin (IL)-1 receptor family member with membrane-bound(ST2L) and soluble (sST2) isoforms, and sST2 is a biomarker for poor outcome in patients withmyocardial infarction (MI). IL-33, the recently discovered ligand for ST2, activates nuclear factor kappaBand thus may regulate apoptotic cell death. We tested the hypothesis that IL-33 is cardioprotective afterMI through ST2 signaling. METHODS AND RESULTS IL-33 protected cultured cardiomyocytes fromhypoxia-induced apoptosis, and this cardioprotection was partially inhibited by sST2. IL-33 inducedexpression of the antiapoptotic factors XIAP, cIAP1, and survivin. To define the cardioprotective role ofIL-33 in vivo, we performed a blinded and randomized study of ischemia/reperfusion in rats. IL-33reduced cardiomyocyte apoptosis, suppressed caspase-3 activity, and increased expression of IAP familymember proteins. IL-33 decreased both infarct and fibrosis volumes at 15 days; furthermore, bothechocardiographic and hemodynamic studies revealed that IL-33 improved ventricular function. Todetermine whether cardioprotection by IL-33 is mediated through ST2 signaling, a randomized andblinded study of ST2(-/-) versus wild-type littermate mice was performed in 98 mice subjected to MI. At4 weeks after MI, IL-33 reduced ventricular dilation and improved contractile function in wild-type micebut not in ST2(-/-) mice. Finally, IL-33 improved survival after MI in wild-type but not in ST2(-/-) mice.CONCLUSIONS IL-33 prevents cardiomyocyte apoptosis and improves cardiac function and survival afterMI through ST2 signaling.", "metadata": {}}
+{"_id": "10577574", "title": "", "text": "The impact of open versus closed format ICU admission practices on the outcome of high risk surgicalpatients: a cohort analysisBACKGROUND In the year 2000, the organizational structure of the ICU in theZaandam Medical Centre (ZMC) changed from an open to a closed format ICU. The objective of this studywas to evaluate the effect of this organizational change on outcome in high risk surgical patients.METHODS The medical records of all consecutive high risk surgical patients admitted to the ICU from1996 to 1998 (open format) and from 2003 to 2005 (closed format), were reviewed. High-risk patientswere defined according to the Identification of Risk in Surgical patients (IRIS) score. Parameters studiedwere: mortality, morbidity, ICU length of stay (LOS) and hospital LOS. RESULTS Mortality of ICU patientswas 25.7% in the open format group and 15.8% in the closed format group (p = 0.01). Morbiditydecreased from 48.6% to 46.1% (p = 0.6). The average length of hospital stay was 17 days in the openformat group, and 21 days in the closed format group (p = 0.03). CONCLUSIONS High risk surgicalpatients in the ICU are patients that have undergone complex and often extensive surgery. Thesepatients are in need of specialized treatment and careful monitoring for maximum safety and optimalcare. Our results suggest that closed format is a more favourable setting than open format to minimizethe effects of high risk surgery, and to warrant safe outcome in this patient group.", "metadata": {}}
+{"_id": "10582939", "title": "", "text": "Induction therapy with autologous mesenchymal stem cells in living-related kidney transplants: arandomized controlled trial.CONTEXT Antibody-based induction therapy plus calcineurin inhibitors (CNIs)reduce acute rejection rates in kidney recipients; however, opportunistic infections and toxic CNI effectsremain challenging. Reportedly, mesenchymal stem cells (MSCs) have successfully treated graft-vs-hostdisease. OBJECTIVE To assess autologous MSCs as replacement of antibody induction for patients withend-stage renal disease who undergo ABO-compatible, cross-match-negative kidney transplants from aliving-related donor. DESIGN, SETTING, AND PATIENTS One hundred fifty-nine patients were enrolled inthis single-site, prospective, open-label, randomized study from February 2008-May 2009, whenrecruitment was completed. INTERVENTION Patients were inoculated with marrow-derived autologousMSC (1-2 x 10(6)/kg) at kidney reperfusion and two weeks later. Fifty-three patients receivedstandard-dose and 52 patients received low-dose CNIs (80% of standard); 51 patients in the controlgroup received anti-IL-2 receptor antibody plus standard-dose CNIs. MAIN OUTCOME MEASURES Theprimary measure was 1-year incidence of acute rejection and renal function (estimated glomerularfiltration rate [eGFR]); the secondary measure was patient and graft survival and incidence of adverseevents. RESULTS Patient and graft survival at 13 to 30 months was similar in all groups. After 6 months,4 of 53 patients (7.5%) in the autologous MSC plus standard-dose CNI group (95% CI, 0.4%-14.7%; P =.04) and 4 of 52 patients (7.7%) in the low-dose group (95% CI, 0.5%-14.9%; P = .046) compared with11 of 51 controls (21.6%; 95% CI, 10.5%-32.6%) had biopsy-confirmed acute rejection. None of thepatients in either autologous MSC group had glucorticoid-resistant rejection, whereas 4 patients (7.8%)in the control group did (95% CI, 0.6%-15.1%; overall P = .02). Renal function recovered faster amongboth MSC groups showing increased eGFR levels during the first month after surgery than the controlgroup. Patients receiving standard-dose CNI had a mean difference of 6.2 mL/min per 1.73 m(2) (95%CI, 0.4-11.9; P=.04) and those in the low-dose CNI of 10.0 mL/min per 1.73 m(2) (95% CI, 3.8-16.2;P=.002). Also, during the 1-year follow-up, combined analysis of MSC-treated groups revealedsignificantly decreased risk of opportunistic infections than the control group (hazard ratio, 0.42; 95% CI,0.20-0.85, P=.02)   CONCLUSION Among patients undergoing renal transplant, the use of autologousMSCs compared with anti-IL-2 receptor antibody induction therapy resulted in lower incidence of acuterejection, decreased risk of opportunistic infection, and better estimated renal function at 1 year. TRIALREGISTRATION clinicaltrials.gov Identifier: NCT00658073.", "metadata": {}}
+{"_id": "10605189", "title": "", "text": "Cerebral cortex assembly: generating and reprogramming projection neuron diversityThe mammaliancerebral cortex is responsible for the highest levels of associative, cognitive and motor functions. In thecentral nervous system (CNS) the cortex stands as a prime example of extreme neuronal diversity,broadly classified into excitatory projection neurons (PNs) and inhibitory interneurons (INs). We reviewhere recent progress made in understanding the strategies and mechanisms that shape PN diversityduring embryogenesis, and discuss how PN classes may be maintained, postnatally, for the life of theorganism. In addition, we consider the intriguing possibility that PNs may be amenable to directedreprogramming of their class-specific features to allow enhanced cortical plasticity in the adult.", "metadata": {}}
+{"_id": "10607877", "title": "", "text": "Mechanical modulation of receptor-ligand interactions at cell-cell interfaces.Cell surface receptors havebeen extensively studied because they initiate and regulate signal transduction cascades leading to avariety of functional cellular outcomes. An important class of immune receptors (e.g., T-cell antigenreceptors) whose ligands are anchored to the surfaces of other cells remain poorly understood. Themechanism by which ligand binding initiates receptor phosphorylation, a process termed \"receptortriggering\", remains controversial. Recently, direct measurements of the (two-dimensional)receptor-ligand complex lifetimes at cell-cell interface were found to be smaller than (three-dimensional)lifetimes in solution but the underlying mechanism is unknown. At the cell-cell interface, thereceptor-ligand complex spans a short intermembrane distance (15 nm) compared to long surfacemolecules (LSMs) whose ectodomains span >40 nm and these LSMs include phosphatases (e.g., CD45)that dephosphorylate the receptor. It has been proposed that size-based segregation of LSMs from areceptor-ligand complex is a mechanism of receptor triggering but it is unclear whether themechanochemistry supports such small-scale segregation. Here we present a nanometer-scalemathematical model that couples membrane elasticity with the compressional stiffness and lateralmobility of LSMs. We find robust supradiffusive segregation of LSMs from a single receptor-ligandcomplex. The model predicts that LSM redistribution will result in a time-dependent tension on thecomplex leading to a decreased two-dimensional lifetime. Interestingly, the model predicts a nonlinearrelationship between the three- and two-dimensional lifetimes, which can enhance the ability of receptorsto discriminate between similar ligands.", "metadata": {}}
+{"_id": "10608397", "title": "", "text": "High-performance neuroprosthetic control by an individual with tetraplegia.BACKGROUND Paralysis oramputation of an arm results in the loss of the ability to orient the hand and grasp, manipulate, and carryobjects, functions that are essential for activities of daily living. Brain-machine interfaces could provide asolution to restoring many of these lost functions. We therefore tested whether an individual withtetraplegia could rapidly achieve neurological control of a high-performance prosthetic limb using thistype of an interface. METHODS We implanted two 96-channel intracortical microelectrodes in the motorcortex of a 52-year-old individual with tetraplegia. Brain-machine-interface training was done for 13weeks with the goal of controlling an anthropomorphic prosthetic limb with seven degrees of freedom(three-dimensional translation, three-dimensional orientation, one-dimensional grasping). Theparticipant's ability to control the prosthetic limb was assessed with clinical measures of upper limbfunction. This study is registered with ClinicalTrials.gov, NCT01364480. FINDINGS The participant wasable to move the prosthetic limb freely in the three-dimensional workspace on the second day of training.After 13 weeks, robust seven-dimensional movements were performed routinely. Mean success rate ontarget-based reaching tasks was 91·6% (SD 4·4) versus median chance level 6·2% (95% CI 2·0-15·3).Improvements were seen in completion time (decreased from a mean of 148 s [SD 60] to 112 s [6]) andpath efficiency (increased from 0·30 [0·04] to 0·38 [0·02]). The participant was also able to use theprosthetic limb to do skilful and coordinated reach and grasp movements that resulted in clinicallysignificant gains in tests of upper limb function. No adverse events were reported. INTERPRETATION Withcontinued development of neuroprosthetic limbs, individuals with long-term paralysis could recover thenatural and intuitive command signals for hand placement, orientation, and reaching, allowing them toperform activities of daily living. FUNDING Defense Advanced Research Projects Agency, NationalInstitutes of Health, Department of Veterans Affairs, and UPMC Rehabilitation Institute.", "metadata": {}}
+{"_id": "10608822", "title": "", "text": "Phase locking and multiple oscillating attractors for the coupled mammalian clock and cell cycle.Dailysynchronous rhythms of cell division at the tissue or organism level are observed in many species andsuggest that the circadian clock and cell cycle oscillators are coupled. For mammals, despite knownmechanistic interactions, the effect of such coupling on clock and cell cycle progression, and hence itsbiological relevance, is not understood. In particular, we do not know how the temporal organization ofcell division at the single-cell level produces this daily rhythm at the tissue level. Here we usemultispectral imaging of single live cells, computational methods, and mathematical modeling to addressthis question in proliferating mouse fibroblasts. We show that in unsynchronized cells the cell cycle andcircadian clock robustly phase lock each other in a 1:1 fashion so that in an expanding cell population thetwo oscillators oscillate in a synchronized way with a common frequency. Dexamethasone-inducedsynchronization reveals additional clock states. As well as the low-period phase-locked state there aredistinct coexisting states with a significantly higher period clock. Cells transition to these states afterdexamethasone synchronization. The temporal coordination of cell division by phase locking to the clockat a single-cell level has significant implications because disordered circadian function is increasinglybeing linked to the pathogenesis of many diseases, including cancer.", "metadata": {}}
+{"_id": "10617916", "title": "", "text": "Moderate effect of artemisinin-based combination therapy on transmission of Plasmodiumfalciparum.Background. Artemisinin-based combination therapy (ACT) reduces microscopically confirmedgametocytemia and mosquito infection. However, molecular techniques have recently revealed highprevalences of submicroscopic gametocytemia. Our objective here was to determine the effect ofsulfadoxine-pyrimethamine (SP) monotherapy and treatment with SP plus amodiaquine (AQ), SP plusartesunate (AS), and artemether-lumefantrine (AL; Coartem) on submicroscopic gametocytemia andinfectiousness. Methods. Kenyan children (n=528) 6 months-10 years of age were randomized to 4treatment arms. Gametocytemia was determined by both microscopy and Pfs25 RNA-based quantitativenucleic acid sequence-based amplification (Pfs25 QT-NASBA). Transmission was determined bymembrane-feeding assays. Results. Gametocyte prevalence, as determined by Pfs25 QT-NASBA, was89.4% (219/245) at enrollment and decreased after treatment with SP plus AS, SP plus AQ, and AL.Membrane-feeding assays for a group of randomly selected children revealed that the proportion ofinfectious children was as much as 4-fold higher than expected when based on microscopy. ACT did notsignificantly reduce the proportion of infectious children but did reduce the proportion of infectedmosquitoes. Conclusions. Submicroscopic gametocytemia is common after treatment and contributesconsiderably to mosquito infection. Our findings should be interpreted in the context of transmissionintensity, but the effect of ACT on malaria transmission appears to be moderate and restricted to theduration of gametocyte carriage and the proportion of mosquitoes that are infected by carriers.", "metadata": {}}
+{"_id": "10624000", "title": "", "text": "Lip movements entrain the observers’ low-frequency brain oscillations to facilitate speechintelligibilityDuring continuous speech, lip movements provide visual temporal signals that facilitatespeech processing. Here, using MEG we directly investigated how these visual signals interact withrhythmic brain activity in participants listening to and seeing the speaker. First, we investigatedcoherence between oscillatory brain activity and speaker's lip movements and demonstrated significantentrainment in visual cortex. We then used partial coherence to remove contributions of the coherentauditory speech signal from the lip-brain coherence. Comparing this synchronization between differentattention conditions revealed that attending visual speech enhances the coherence between activity invisual cortex and the speaker's lips. Further, we identified a significant partial coherence between leftmotor cortex and lip movements and this partial coherence directly predicted comprehension accuracy.Our results emphasize the importance of visually entrained and attention-modulated rhythmic brainactivity for the enhancement of audiovisual speech processing.", "metadata": {}}
+{"_id": "10627801", "title": "", "text": "Loss of DExD/H box RNA helicase LGP2 manifests disparate antiviral responses.The DExD/H box RNAhelicase retinoic acid-inducible gene I (RIG-I) and the melanoma differentiation-associated gene 5(MDA5) are key intracellular receptors that recognize virus infection to produce type I IFN. A thirdhelicase gene, Lgp2, is homologous to Rig-I and Mda5 but lacks a caspase activation and recruitmentdomain. We generated Lgp2-deficient mice and report that the loss of this gene greatly sensitizes cells tocytosolic polyinosinic/polycytidylic acid-mediated induction of type I IFN. However, negative feedbackinhibition of IFN-beta transcription was found to be normal in the absence of LGP2, indicating that LGP2 isnot the primary negative regulator of type I IFN production. Our data further indicate that Lgp2-/- miceexhibited resistance to lethal vesicular stomatitis virus infection, a virus whose replicative RNAintermediates are recognized specifically by RIG-I rather than by MDA5 to trigger the production of type IIFN. However, mice lacking LGP2 were observed to exhibit a defect in type I IFN production in responseto infection by the encephalomyocarditis virus, the replication of which activates MDA5-dependent innateimmune responses. Collectively, our data indicate a disparate regulatory role for LGP2 in the triggering ofinnate immune signaling pathways following RNA virus infection.", "metadata": {}}
+{"_id": "10628767", "title": "", "text": "Three-dimensional, single-molecule fluorescence imaging beyond the diffraction limit by using adouble-helix point spread function.We demonstrate single-molecule fluorescence imaging beyond theoptical diffraction limit in 3 dimensions with a wide-field microscope that exhibits a double-helix pointspread function (DH-PSF). The DH-PSF design features high and uniform Fisher information and has 2dominant lobes in the image plane whose angular orientation rotates with the axial (z) position of theemitter. Single fluorescent molecules in a thick polymer sample are localized in single 500-msacquisitions with 10- to 20-nm precision over a large depth of field (2 microm) by finding the center ofthe 2 DH-PSF lobes. By using a photoactivatable fluorophore, repeated imaging of sparse subsets with aDH-PSF microscope provides superresolution imaging of high concentrations of molecules in all 3dimensions. The combination of optical PSF design and digital postprocessing with photoactivatablefluorophores opens up avenues for improving 3D imaging resolution beyond the Rayleigh diffraction limit.", "metadata": {}}
+{"_id": "10641162", "title": "", "text": "A unique cell division machinery in the Archaea.In contrast to the cell division machineries of bacteria,euryarchaea, and eukaryotes, no division components have been identified in the second main archaealphylum, Crenarchaeota. Here, we demonstrate that a three-gene operon, cdv, in the crenarchaeonSulfolobus acidocaldarius, forms part of a unique cell division machinery. The operon is induced at theonset of genome segregation and division, and the Cdv proteins then polymerize between segregatingnucleoids and persist throughout cell division, forming a successively smaller structure duringconstriction. The cdv operon is dramatically down-regulated after UV irradiation, indicating divisioninhibition in response to DNA damage, reminiscent of eukaryotic checkpoint systems. The cdv genesexhibit a complementary phylogenetic range relative to FtsZ-based archaeal division systems such that,in most archaeal lineages, either one or the other system is present. Two of the Cdv proteins, CdvB andCdvC, display homology to components of the eukaryotic ESCRT-III sorting complex involved in buddingof luminal vesicles and HIV-1 virion release, suggesting mechanistic similarities and a commonevolutionary origin.", "metadata": {}}
+{"_id": "10641715", "title": "", "text": "Modelling and rescuing neurodevelopmental defect of Down syndrome using induced pluripotent stemcells from monozygotic twins discordant for trisomy 21Down syndrome (trisomy 21) is the most commonviable chromosomal disorder with intellectual impairment and several other developmental abnormalities.Here, we report the generation and characterization of induced pluripotent stem cells (iPSCs) derivedfrom monozygotic twins discordant for trisomy 21 in order to eliminate the effects of the variability ofgenomic background. The alterations observed by genetic analysis at the iPSC level and at firstapproximation in early development illustrate the developmental disease transcriptional signature ofDown syndrome. Moreover, we observed an abnormal neural differentiation of Down syndrome iPSCs invivo when formed teratoma in NOD-SCID mice, and in vitro when differentiated into neuroprogenitorsand neurons. These defects were associated with changes in the architecture and density of neurons,astroglial and oligodendroglial cells together with misexpression of genes involved in neurogenesis,lineage specification and differentiation. Furthermore, we provide novel evidence that dual-specificitytyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) on chromosome 21 likely contributes tothese defects. Importantly, we found that targeting DYRK1A pharmacologically or by shRNA results in aconsiderable correction of these defects.", "metadata": {}}
+{"_id": "10648422", "title": "", "text": "Programmed death-1–induced interleukin-10 production by monocytes impairs CD4+ T cell activationduring HIV infectionViral replication and microbial translocation from the gut to the blood during HIVinfection lead to hyperimmune activation, which contributes to the decline in CD4+ T cell numbers duringHIV infection. Programmed death-1 (PD-1) and interleukin-10 (IL-10) are both upregulated during HIVinfection. Blocking interactions between PD-1 and programmed death ligand-1 (PD-L1) and betweenIL-10 and IL-10 receptor (IL-10R) results in viral clearance and improves T cell function in animal modelsof chronic viral infections. Here we show that high amounts of microbial products and inflammatorycytokines in the plasma of HIV-infected subjects lead to upregulation of PD-1 expression on monocytesthat correlates with high plasma concentrations of IL-10. Triggering of PD-1 expressed on monocytes byPD-L1 expressed on various cell types induced IL-10 production and led to reversible CD4+ T celldysfunction. We describe a new function for PD-1 whereby microbial products inhibit T cell expansion andfunction by upregulating PD-1 levels and IL-10 production by monocytes after binding of PD-1 by PD-L1.", "metadata": {}}
+{"_id": "10650521", "title": "", "text": "A general role for splicing enhancers in exon definition.Exonic splicing enhancers (ESEs) facilitate exondefinition by assisting in the recruitment of splicing factors to the adjacent intron. Here we demonstratethat suboptimal 5' and 3' splice sites are activated independently by ESEs when they are located ondifferent exons. However, when they are situated within a single exon, the same weak 5' and 3' splicesites are activated simultaneously by a single ESE. These findings demonstrate that a single ESEpromotes the recognition of both exon/intron junctions within the same step during exon definition. Ourresults suggest that ESEs recruit a multicomponent complex that minimally contains components of thesplicing machinery required for 5' and 3' splice site selection.", "metadata": {}}
+{"_id": "10660080", "title": "", "text": "SecDFyajC is not required for the maintenance of the proton motive force.SecDFyajC of Escherichia coli isrequired for efficient export of proteins in vivo. However, the functional role of SecDFyajC in proteintranslocation is unclear. We evaluated the postulated function of SecDFyajC in the maintenance of theproton motive force. As previously reported, inner membrane vesicles (IMVs) lacking SecDFyajC aredefective in the generation of a stable proton motive force when energized with succinate. Thisphenomenon is, however, not observed when NADH is used as an electron donor. Moreover, the protonmotive force generated in SecDFyajC-depleted vesicles stimulated translocation to the same extent asseen with IMVs containing SecDFyajC. Further analysis demonstrates that the reduced proton motiveforce with succinate in IMVs lacking SecDFyajC is due to a lower amount of the enzyme succinatedehydrogenase. The expression of this enzyme complex is repressed by growth on glucose media, thecondition used to deplete SecDFyajC. These results demonstrate that SecDFyajC is not required forproton motive force-driven protein translocation.", "metadata": {}}
+{"_id": "10666475", "title": "", "text": "The serine protease inhibitor SerpinA3N attenuates neuropathic pain by inhibiting T cell-derived leukocyteelastaseNeuropathic pain is a major, intractable clinical problem and its pathophysiology is not wellunderstood. Although recent gene expression profiling studies have enabled the identification of noveltargets for pain therapy, classical study designs provide unclear results owing to the differentialexpression of hundreds of genes across sham and nerve-injured groups, which can be difficult to validate,particularly with respect to the specificity of pain modulation. To circumvent this, we used two outbredlines of rats, which are genetically similar except for being genetically segregated as a result of selectivebreeding for differences in neuropathic pain hypersensitivity. SerpinA3N, a serine protease inhibitor, wasupregulated in the dorsal root ganglia (DRG) after nerve injury, which was further validated for its mousehomolog. Mice lacking SerpinA3N developed more neuropathic mechanical allodynia than wild-type (WT)mice, and exogenous delivery of SerpinA3N attenuated mechanical allodynia in WT mice. T lymphocytesinfiltrate the DRG after nerve injury and release leukocyte elastase (LE), which was inhibited bySerpinA3N derived from DRG neurons. Genetic loss of LE or exogenous application of a LE inhibitor(Sivelastat) in WT mice attenuated neuropathic mechanical allodynia. Overall, we reveal a novel andclinically relevant role for a member of the serpin superfamily and a leukocyte elastase and crosstalkbetween neurons and T cells in the modulation of neuropathic pain.", "metadata": {}}
+{"_id": "10669582", "title": "", "text": "Tissue Transglutaminase Is an Integrin-Binding Adhesion Coreceptor for FibronectinThe proteincross-linking enzyme tissue transglutaminase binds in vitro with high affinity to fibronectin via its 42-kDgelatin-binding domain. Here we report that cell surface transglutaminase mediates adhesion andspreading of cells on the 42-kD fibronectin fragment, which lacks integrin-binding motifs. Overexpressionof tissue transglutaminase increases its amount on the cell surface, enhances adhesion and spreading onfibronectin and its 42-kD fragment, enlarges focal adhesions, and amplifies adhesion-dependentphosphorylation of focal adhesion kinase. These effects are specific for tissue transglutaminase and arenot shared by its functional homologue, a catalytic subunit of factor XIII. Adhesive function of tissuetransglutaminase does not require its cross-linking activity but depends on its stable noncovalentassociation with integrins. Transglutaminase interacts directly with multiple integrins of β1 and β3subfamilies, but not with β2 integrins. Complexes of transglutaminase with integrins are formed insidethe cell during biosynthesis and accumulate on the surface and in focal adhesions. Together our resultsdemonstrate that tissue transglutaminase mediates the interaction of integrins with fibronectin, therebyacting as an integrin-associated coreceptor to promote cell adhesion and spreading.", "metadata": {}}
+{"_id": "10669939", "title": "", "text": "Imaging the expression of transfected genes in vivo.Imaging the expression of successful genetransduction has been demonstrated in vivo for the first time by using an appropriate combination of\"marker gene\" and \"marker substrate\" in an experimental animal model. The herpes simplex virus 1thymidine kinase (HSV1-tk) gene was selected as an example of a marker gene, and the recombinantSTK retrovirus containing HSV1-tk was used to transduce RG2 glioma cells in vitro and in vivo. RG2TK+cell lines expressing the HSV1-tk gene and three potential marker substrates for the HSV1-TK enzymewere evaluated. Radiolabeled 5-iodo-2'-fluoro-2'deoxy-1-beta-D-arabinofuranosyluracil (FIAU) wasshown to be a substantially better marker substrate for the HSV1-TK enzyme than 5-iodo-2'-deoxyuridineor ganciclovir. The magnitude of FIAU accumulation in different RG2TK+ clones corresponded to theirsensitivity to ganciclovir and to the level of HSV1-tk mRNA expression. Imaging the expression ofHSV1-tk in transduced RG2 tumor cells was demonstrated in animals using quantitative autoradiography;2-[14C]FIAU accumulation was shown to be high in RG2TK+ brain tumors growing in one hemisphere andvery low in nontransduced RG2 tumors in the contralateral hemisphere. Transduction of RG2 tumor cellswith the HSV-tk gene in vivo resulted in tumors which accumulated FIAU to high levels and producedclearly defined images. Given the level of FIAU accumulation in the transduced tumors, it is likely that aclinically applicable method for imaging HSV1-tk gene expression can be implemented using existingclinical imaging techniques.", "metadata": {}}
+{"_id": "10670430", "title": "", "text": "Engulfment of apoptotic cells: signals for a good mealThe clearance of apoptotic cells by phagocytes is anintegral component of normal life, and defects in this process can have significant implications for selftolerance and autoimmunity. Recent studies have provided new insights into the engulfment process,including how phagocytes seek apoptotic cells, how they recognize and ingest these targets and how theymaintain cellular homeostasis after the 'meal'. Several new factors that regulate engulfment have beenidentified, whereas the roles of some of the older players require revision. This Review focuses on theserecent developments and attempts to highlight some of the important questions in this field.", "metadata": {}}
+{"_id": "10675756", "title": "", "text": "Related IgA1 and IgG producing cells in blood and diseased mucosa in ulcerative colitis.BACKGROUNDUlcerative colitis (UC) is a chronic inflammatory bowel disease in which the colonic mucosa is infiltratedwith plasma cells producing IgG autoantibodies. It is not known whether this represents a local mucosalresponse which has switched to IgG or a peripheral response which may have been initiated by peripheralantigen which homed to the colonic mucosa. The clonal distribution of IgG secreting cells and isotypeswitched variants in UC is not known. AIMS To investigate the clonal distribution of mucosal IgG in UCand to search for related IgG and IgA secreting cells in normal and diseased mucosa and blood in UC. Toinvestigate characteristics which may discriminate between the mucosal and peripheral repertoire in thenormal mucosa and in UC. PATIENTS Blood and normal and diseased mucosa from two patients with UCwere studied. METHODS Immunoglobulin gene analysis and clone specific polymerase chain reaction wereused to study the clonal distribution and characteristics of IgG and related IgA in the mucosa and blood ofpatients with UC. RESULTS The IgG response in the mucosa of UC patients included widespread clones ofcells that were present in both the diseased mucosa and blood but that were scarce in normal mucosa.Clonally related IgA class switch variants, all IgA1, were detected but also only in the diseased mucosaand blood. This suggests that these clones home preferentially to the diseased mucosa. We showed thatJ(H)1 usage was characteristic of the peripheral repertoire, and that examples of J(H)1 usage wereobserved in mucosal IgG in UC. CONCLUSIONS Overall, these data are consistent with a model of UC inwhich a peripheral response is expressed and expanded in the colonic mucosa.", "metadata": {}}
+{"_id": "10692412", "title": "", "text": "Geovisual analytics to enhance spatial scan statistic interpretation: an analysis of U.S. cervical cancermortalityBACKGROUND Kulldorff's spatial scan statistic and its software implementation - SaTScan - arewidely used for detecting and evaluating geographic clusters. However, two issues make using themethod and interpreting its results non-trivial: (1) the method lacks cartographic support forunderstanding the clusters in geographic context and (2) results from the method are sensitive toparameter choices related to cluster scaling (abbreviated as scaling parameters), but the system providesno direct support for making these choices. We employ both established and novel geovisual analyticsmethods to address these issues and to enhance the interpretation of SaTScan results. We demonstrateour geovisual analytics approach in a case study analysis of cervical cancer mortality in theU.S.   RESULTS We address the first issue by providing an interactive visual interface to support theinterpretation of SaTScan results. Our research to address the second issue prompted a broaderdiscussion about the sensitivity of SaTScan results to parameter choices. Sensitivity has two components:(1) the method can identify clusters that, while being statistically significant, have heterogeneouscontents comprised of both high-risk and low-risk locations and (2) the method can identify clusters thatare unstable in location and size as the spatial scan scaling parameter is varied. To investigate clusterresult stability, we conducted multiple SaTScan runs with systematically selected parameters. Theresults, when scanning a large spatial dataset (e.g., U.S. data aggregated by county), demonstrate thatno single spatial scan scaling value is known to be optimal to identify clusters that exist at differentscales; instead, multiple scans that vary the parameters are necessary. We introduce a novel method ofmeasuring and visualizing reliability that facilitates identification of homogeneous clusters that are stableacross analysis scales. Finally, we propose a logical approach to proceed through the analysis of SaTScanresults. CONCLUSION The geovisual analytics approach described in this manuscript facilitates theinterpretation of spatial cluster detection methods by providing cartographic representation of SaTScanresults and by providing visualization methods and tools that support selection of SaTScan parameters.Our methods distinguish between heterogeneous and homogeneous clusters and assess the stability ofclusters across analytic scales. METHOD We analyzed the cervical cancer mortality data for the UnitedStates aggregated by county between 2000 and 2004. We ran SaTScan on the dataset fifty times withdifferent parameter choices. Our geovisual analytics approach couples SaTScan with our visual analyticplatform, allowing users to interactively explore and compare SaTScan results produced by differentparameter choices. The Standardized Mortality Ratio and reliability scores are visualized for all thecounties to identify stable, homogeneous clusters. We evaluated our analysis result by comparing it tothat produced by other independent techniques including the Empirical Bayes Smoothing and Kafadarspatial smoother methods. The geovisual analytics approach introduced here is developed andimplemented in our Java-based Visual Inquiry Toolkit.", "metadata": {}}
+{"_id": "10692948", "title": "", "text": "Neurological development of 5-year-old children receiving a low-saturated fat, low-cholesterol diet sinceinfancy: A randomized controlled trial.CONTEXT Early childhood introduction of nutritional habits aimed atatherosclerosis prevention is compatible with normal growth, but its effect on neurological development isunknown. OBJECTIVE To analyze how parental counseling aimed at keeping children's diets low insaturated fat and cholesterol influences neurodevelopment during the first 5 years of life. DESIGNRandomized controlled trial conducted between February 1990 and November 1996. SETTING Outpatientclinic of a university department in Turku, Finland. PARTICIPANTS A total of 1062 seven-month-oldinfants and their parents, recruited at well-baby clinics between 1990 and 1992. At age 5 years, 496children still living in the city of Turku were available to participate in neurodevelopmental testing.INTERVENTION Participants were randomly assigned to receive individualized counseling aimed atlimiting the child's fat intake to 30% to 35% of daily energy, with asaturated:monounsaturated:polyunsaturated fatty acid ratio of 1:1:1 and a cholesterol intake of less than200 mg/d (n = 540) or usual health education (control group, n = 522). MAIN OUTCOME MEASURESNutrient intake, serum lipid concentrations, and neurological development at 5 years, among children inthe intervention vs control groups. RESULTS Absolute and relative intakes of fat, saturated fatty acids,and cholesterol among children in the intervention group were markedly less than the respective valuesof control children. Mean (SD) percentages of daily energy at age 5 years for the intervention vs controlgroups were as follows: for total fat, 30.6% (4.5%) vs 33.4% (4.4%) (P<. 001); and for saturated fat,11.7% (2.3%) vs 14.5% (2.4%) (P<.001). Mean intakes of cholesterol were 164.2 mg (60.1 mg) and192.5 mg (71. 9 mg) (P<.001) for the intervention and control groups, respectively. Serum cholesterolconcentrations were continuously 3% to 5% lower in children in the intervention group than in children inthe control group. At age 5 years, mean (SD) serum cholesterol concentration of the intervention groupwas 4.27 (0.63) mmol/L (165 [24] mg/dL) and of the control group, 4.41 (0.74) mmol/L (170 [29]mg/dL) (P =.04). Neurological development of children in the intervention group was at least as good asthat of children in the control group. Relative risks for children in the intervention group to fail tests ofspeech and language skills, gross motor functioning plus perception, and visual motor skills were 0.95(90% confidence interval [CI], 0.60-1.49), 0.95 (90% CI, 0.58-1.55), and 0.65 (90% CI, 0.39-1.08),respectively (P =.85,.86, and.16, respectively, vs control children). CONCLUSION Our data indicate thatrepeated child-targeted dietary counseling of parents during the first 5 years of a child's life lessensage-associated increases in children's serum cholesterol and is compatible with normal neurologicaldevelopment. JAMA. 2000;284:993-1000", "metadata": {}}
+{"_id": "10697096", "title": "", "text": "Vasodilator responses of coronary resistance arteries of exercise-trained pigs.BACKGROUND The purposeof this study was to test the hypothesis that vasodilator responses of porcine coronary resistance arteriesare increased by exercise training. METHODS AND RESULTS Yucatan miniature swine were randomlydivided into groups of exercise-trained (ET) and sedentary (SED) control pigs. ET pigs were placed on aprogressive treadmill training program lasting 16 to 20 weeks, and SED pigs remained inactive during thesame time period. Coronary resistance arteries 64 to 157 microns in diameter were isolated for in vitroevaluation of relaxation responses to the endothelium-independent dilators sodium nitroprusside (1 x10(-10) to 1 x 10(-4) mol/L) and adenosine (1 x 10(-10) to 1 x 10(-5) mol/L) and to bradykinin (1 x10(-13) to 3 x 10(-7) mol/L), an endothelium-dependent agent. Relaxation responses to adenosine andsodium nitroprusside were not altered by exercise training. Endothelium-dependent relaxation tobradykinin was enhanced in coronary resistance arteries from ET pigs (IC50: ET, 0.07 +/- 0.02 nmol/L;SED, 1.59 +/- 0.09 nmol/L). To determine whether prostanoids and/or the nitric oxide synthase pathwaywere involved in the ET-induced changes in bradykinin-induced vasodilation, responses to bradykininwere examined in coronary resistance arteries from both ET and SED pigs in the presence ofindomethacin and in the presence of nitro-monomethyl L-arginine (L-NMMA). Both indomethacin andL-NMMA produced significant inhibition of the bradykinin-induced relaxation in vessels from both groups.Despite decreased bradykinin-induced relaxation after indomethacin, bradykinin-induced vasodilation wasstill enhanced in vessels from the ET group. L-NMMA caused greater inhibition of the bradykinin-inducedrelaxation in coronary resistance arteries from ET pigs relative to arteries from SED pigs and eliminatedthe training-induced enhancement of the bradykinin responses. CONCLUSIONS These results suggestthat exercise training enhances bradykinin-induced vasodilation through increased endothelium-derivedrelaxing factor/nitric oxide production by the L-arginine/nitric oxide synthase pathway.", "metadata": {}}
+{"_id": "10698739", "title": "", "text": "Modulation of mitochondrial function and morphology by interaction of Omi/HtrA2 with the mitochondrialfusion factor OPA1.Loss of Omi/HtrA2 function leads to nerve cell loss in mouse models and has beenlinked to neurodegeneration in Parkinson's and Huntington's disease. Omi/HtrA2 is a serine proteasereleased as a pro-apoptotic factor from the mitochondrial intermembrane space into the cytosol. Underphysiological conditions, Omi/HtrA2 is thought to be involved in protection against cellular stress, but thecytological and molecular mechanisms are not clear. Omi/HtrA2 deficiency caused an accumulation ofreactive oxygen species and reduced mitochondrial membrane potential. In Omi/HtrA2 knockout mouseembryonic fibroblasts, as well as in Omi/HtrA2 silenced human HeLa cells and Drosophila S2R+ cells, wefound elongated mitochondria by live cell imaging. Electron microscopy confirmed the mitochondrialmorphology alterations and showed abnormal cristae structure. Examining the levels of proteins involvedin mitochondrial fusion, we found a selective up-regulation of more soluble OPA1 protein.Complementation of knockout cells with wild-type Omi/HtrA2 but not with the protease mutant[S306A]Omi/HtrA2 reversed the mitochondrial elongation phenotype and OPA1 alterations. Finally,co-immunoprecipitation showed direct interaction of Omi/HtrA2 with endogenous OPA1. Thus, we showfor the first time a direct effect of loss of Omi/HtrA2 on mitochondrial morphology and demonstrate anovel role of this mitochondrial serine protease in the modulation of OPA1. Our results underscore acritical role of impaired mitochondrial dynamics in neurodegenerative disorders.", "metadata": {}}
+{"_id": "10699587", "title": "", "text": "Four prognostic groups predict long-term survival from prostate cancer following radiotherapy alone onRadiation Therapy Oncology Group clinical trials.PURPOSE Gleason score (GS), T stage, and pathologiclymph node status have been described as major independent predictors of death due to prostate cancerin men treated with external beam radiotherapy (XRT). In this analysis we combine these three factors todefine prognostic subgroups that correlate with disease-specific survival (DSS) death from prostatecancer. METHODS AND MATERIALS Men entered on one of four Radiation Therapy Oncology Group(RTOG) Phase III randomized trials between 1975 and 1992, for clinically localized prostate cancer (CAP)(n = 1557), were selected for this analysis. Patients were included if: 1) they were evaluable, and eligiblefor the trial; 2) they received no hormonal therapy with their initial treatment; and 3) follow-up wasavailable. For this study a DSS event was declared if: 1) death was certified as due to CAP; 2) death wasdue to complications of treatment; or 3) death was from unknown causes with active malignancy. Themedian follow-up for patients treated on early and late RTOG studies exceeded 11 and 6 yearsrespectively. Subgroups were identified based on their pretreatment GS, T-stage, and lymph node suchthat patients with similar risk of dying from prostate cancer were combined. RESULTS By combiningpatients with similar DSS, four subgroups were identified. Risk Group 1 patients had a GS = 2-6, andT1-2Nx; Group 2: GS = 2-6, T3Nx; or GS = 2-6, N+, or GS = 7, T1-2Nx; Group 3: T3Nx, GS = 7; or N+,GS = 7, or T1-2Nx, GS = 8-10; and Group 4 patients were T3Nx, GS = 8-10, or N+, GS = 8-10. The 5-,10-, and 15-year DSS was 96%, 86%, and 72%; 94%, 75%, and 61%; 83%, 62%, and 39%; and 64%,34%, and 27% for Groups 1 through 4, respectively. CONCLUSIONS Recognition of these four risk groupsprovides a basis for estimating the long-term DSS for men treated with XRT alone and should facilitatethe design of future prospective randomized trials.", "metadata": {}}
+{"_id": "10703001", "title": "", "text": "The pathogenesis of bleomycin-induced pulmonary fibrosis in mice.Administration of 0.5 mg bleomycin tomice twice weekly for 4 weeks induced pulmonary fibrosis. The initial site of injury was the intima ofpulmonary arteries and veins where endothelial cells became edematous and were separated from theunderlying basement membrane by large blebs. These lesions occurred after 2 weeks and wereassociated with infiltration of perivascular spaces by lymphocytes and plasma cells. Capillary endothelialblebbing and interstitial edema were observed after 4 weeks, when multifocal necrosis of type 1 alveolarepithelial cells was accompanied by fibrinous exudation into the alveoli. The process of repair wascharacterized by proliferation and metaplasia of type 2 epithelial cells, fibroblastic organization of alveolarfibrin and fibrosis of the interstitium within 8 to 12 weeks. The consistent induction of changes similar tothose of diffuse pulmonary fibrosis or fibrosing alveolitis in man suggests that bleomycin-induced injurymay provide a suitable model for the investigation of this ill-defined group of diseases.", "metadata": {}}
+{"_id": "10704438", "title": "", "text": "The DNA damage response during mitosis.Cells are equipped with a cell-intrinsic signaling network calledthe DNA damage response (DDR). This signaling network recognizes DNA lesions and initiates variousdownstream pathways to coordinate a cell cycle arrest with the repair of the damaged DNA. Alternatively,the DDR can mediate clearance of affected cells that are beyond repair through apoptosis or senescence.The DDR can be activated in response to DNA damage throughout the cell cycle, although the extent ofDDR signaling is different in each cell cycle phase. Especially in response to DNA double strand breaks,only a very marginal response was observed during mitosis. Early on it was recognized that cells whichare irradiated during mitosis continued division without repairing broken chromosomes. Although theseinitial observations indicated diminished DNA repair and lack of an acute DNA damage-induced cell cyclearrest, insight into the mechanistic re-wiring of DDR signaling during mitosis was only recently provided.Different mechanisms appear to be at play to inactivate specific signaling axes of the DDR network inmitosis. Importantly, mitotic cells not simply inactivate the entire DDR, but appear to mark their DNAdamage for repair after mitotic exit. Since the treatment of cancer frequently involves agents that induceDNA damage as well as agents that block mitotic progression, it is clinically relevant to obtain a betterunderstanding of how cancer cells deal with DNA damage during interphase versus mitosis. In thisreview, the molecular details concerning DDR signaling during mitosis as well as the consequences ofencountering DNA damage during mitosis for cellular fate are discussed.", "metadata": {}}
+{"_id": "10743131", "title": "", "text": "Model-based GeostatisticsGeostatistics is concerned with estimation and prediction problems for spatiallycontinuous phenomena, using data obtained at a limited number of spatial locations. Model-basedgeostatistics refers to the application of general statistical principles of modelling and inference togeostatisatical problems. This volume is the first book-length treatment of model-based geostatistics.", "metadata": {}}
+{"_id": "10749308", "title": "", "text": "Placebo-Controlled Trials and Active-Control Trials in the Evaluation of New Treatments. Part 1: Ethicaland Scientific IssuesPlacebo-controlled trials are used extensively in the development of newpharmaceuticals. They are sometimes challenged as unethical in settings in which patients could betreated with an existing therapy (1-7). The issues of when placebo controls are ethically acceptable andwhen they are scientifically necessary are important and worthy of discussion. The Ethics of PlaceboControls The Declaration of Helsinki The Declaration of Helsinki (8) is an international document thatdescribes ethical principles for clinical investigation. Those who contend that placebo controls areunethical whenever known effective therapy exists for a condition usually cite the following sentence inthe Declaration as support for that position: In any medical study, every patientincluding those of acontrol group, if anyshould be assured of the best proven diagnostic and therapeutic method. We believethat an interpretation of this sentence as barring placebo controls whenever an effective treatment existsis untenable. First, the requirement that all patients receive the best proven diagnostic and therapeuticmethod would bar not only placebo-controlled trials but also active-control and historically controlledtrials. When effective treatment exists, the patient receiving the investigational treatment instead of theestablished therapy is clearly not getting the best proven treatment. Second, it does not seem reasonableto consider as equivalent all failures to use known effective therapy. Historically, concerns about placebouse have usually arisen in the context of serious illness. There is universal agreement that use of placeboor otherwise untreated controls is almost always unethical when therapy shown to improve survival ordecrease serious morbidity is available. But in cases in which the treatment does not affect the patient'slong-term health, an ethical imperative to use existing therapy is not plausible. Can it be, for example,that because topical minoxidil or oral finasteride can grow hair, a placebo-controlled trial of a new remedyfor baldness is unethical? Is it really unethical to use placebos in short-term studies of drugs for allergicrhinitis, insomnia, anxiety, dermatoses, heartburn, or headaches in fully informed patients? We do notbelieve that there is a reasonable basis for arguing that such studies and many other placebo-controlledstudies of symptom relief are unethical and that an informed patient cannot properly be asked toparticipate in them. Third, there is good reason to doubt that the cited phrase was intended to discourageplacebo-controlled trials. The phrase under discussion was not part of the original 1964 Declaration butwas added in 1975 to reinforce the idea that the physicianpatient relationship must be respected just as itwould be in a purely therapeutic situation not involving research objectives (8). In the explanationaccompanying the 1975 change, the issue of placebo-controlled trials was not even mentioned (9). TheAmerican Medical Association (10), the World Health Organization (11), and the Council for InternationalOrganizations of Medical Sciences (12) have rejected the position that the Declaration uniformly barsplacebo-controlled trials when proven therapy is available. Informed Consent in Placebo-Controlled TrialsPatients asked to participate in a placebo-controlled trial must be informed of the existence of anyeffective therapy, must be able to explore the consequences of deferring such therapy with theinvestigator, and must provide fully informed consent. Concern about whether consent to participate intrials is as informed as we would like to believe is valid, but these concerns apply as much to the patient'sdecision to forgo known effective treatment and risk exposure to a potentially ineffective or even harmfulnew agent in an active-control trial as to a decision to accept possible persistence of symptoms in aplacebo-controlled trial. Thus, this problem is not unique to placebo-controlled trials. For the abovereasons, we conclude that placebo-controlled trials may be ethically conducted even when effectivetherapy exists, as long as patients will not be harmed by participation and are fully informed about theiralternatives. Although in many cases application of this standard will be fairly straightforward, in others itwill not, and there may be debate about the consequences of deferring treatment (13). Assessment ofEffectiveness with Active-Control Trials Clinical trials that, because of deficiencies in study design orconduct, are unlikely to provide scientifically valid and clinically meaningful results raise their own ethicalconcerns (12, 14). The remainder of this paper will address the inability of commonly proposedalternatives to placebo-controlled trials to evaluate the effectiveness of new treatments in many medical", "metadata": {}}
+{"_id": "10761515", "title": "", "text": "Breath-methane in patients with cancer of the large bowel.In 30 patients with cancer of the large bowel,24 (80%) had detectable levels of methane in their breath, compared with 25 (39%) of 64 patients withnon-malignant large-bowel disease and 83 (40%) of 208 subjects without large-bowel disease. Thesefindings suggest that there may be a difference in anaerobic intestinal flora between patients with cancerof the large bowel and those without the disease. This difference may antedate the development of thetumour or, alternatively, result from the tumour.", "metadata": {}}
+{"_id": "10765888", "title": "", "text": "Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities inadulthoodNeurogenesis is known to take place in the adult brain. This work identifies T lymphocytes andmicroglia as being important to the maintenance of hippocampal neurogenesis and spatial learningabilities in adulthood. Hippocampal neurogenesis induced by an enriched environment was associatedwith the recruitment of T cells and the activation of microglia. In immune-deficient mice, hippocampalneurogenesis was markedly impaired and could not be enhanced by environmental enrichment, but wasrestored and boosted by T cells recognizing a specific CNS antigen. CNS-specific T cells were also foundto be required for spatial learning and memory and for the expression of brain-derived neurotrophicfactor in the dentate gyrus, implying that a common immune-associated mechanism underlies differentaspects of hippocampal plasticity and cell renewal in the adult brain.", "metadata": {}}
+{"_id": "10766688", "title": "", "text": "Sperm cross-over activity in regions of the human genome showing extreme breakdown of markerassociation.Population diversity data have recently provided profound, albeit inferential, insights intomeiotic recombination across the human genome, revealing a landscape dominated by thousands ofcross-over hotspots. However, very few of these putative hotspots have been directly analyzed forcross-over activity. We now describe a search for very active hotspots, by using extreme breakdown ofmarker association as a guide for high-resolution sperm cross-over analysis. This strategy has led to theisolation of the most active cross-over hotspots yet described. Their morphology, sequence attributes,and cross-over processes are very similar to those seen at less active hotspots, but their activity in spermis poorly predicted from population diversity information. Several of these hotspots showed evidence forbiased gene conversion accompanying cross-over, in some cases associated with variation between menin cross-over activity and with two hotspots showing complete presence/absence polymorphism indifferent men. Hotspot polymorphism is very common at less active hotspots but curiously was not seenat any of the most active hotspots. This contrasts with the prediction that extreme hotspots should be themost vulnerable to attenuation by meiotic drive in favor of mutations that suppress recombination andshould therefore show rapid rate evolution and thus variation in activity between men. Finally, these veryintense hotspots provide a valuable resource for dissecting meiotic recombination processes andpathways in humans.", "metadata": {}}
+{"_id": "10786948", "title": "", "text": "An efficient nonviral method to generate integration-free human-induced pluripotent stem cells from cordblood and peripheral blood cells.The generation of induced pluripotent stem cells (iPSCs) provides theopportunity to use patient-specific somatic cells, which are a valuable source for disease modeling anddrug discovery. To promote research involving these cells, it is important to make iPSCs from easilyaccessible and less invasive tissues, like blood. We have recently reported the efficient generation ofhuman iPSCs from adult fibroblasts using a combination of plasmids encoding OCT3/4, SOX2, KLF4,L-MYC, LIN28, and shRNA for TP53. We herein report a modified protocol enabling efficient iPSC inductionfrom CD34+ cord blood cells and from peripheral blood isolated from healthy donors using these plasmidvectors. The original plasmid mixture could induce iPSCs; however, the efficiency was low. The additionof EBNA1, an essential factor for episomal amplification of the vectors, by an extra plasmid greatlyincreased the efficiency of iPSC induction, especially when the induction was performed from αβT cells.This improvement enabled the establishment of blood-derived iPSCs from seven healthy donors rangingin age from their 20s to their 60s. This induction method will be useful for the derivation ofpatient-specific integration-free iPSCs and would also be applicable to the generation of clinical-gradeiPSCs in the future.", "metadata": {}}
+{"_id": "10790846", "title": "", "text": "A rapamycin-sensitive signaling pathway contributes to long-term synaptic plasticity in thehippocampus.Many forms of long-lasting behavioral and synaptic plasticity require the synthesis of newproteins. For example, long-term potentiation (LTP) that endures for more than an hour requires bothtranscription and translation. The signal-transduction mechanisms that couple synaptic events to proteintranslational machinery during long-lasting synaptic plasticity, however, are not well understood. Onesignaling pathway that is stimulated by growth factors and results in the translation of specific mRNAsincludes the rapamycin-sensitive kinase mammalian target of rapamycin (mTOR, also known as FRAP andRAFT-1). Several components of this translational signaling pathway, including mTOR, eukaryoticinitiation factor-4E-binding proteins 1 and 2, and eukaryotic initiation factor-4E, are present in the rathippocampus as shown by Western blot analysis, and these proteins are detected in the cell bodies anddendrites in the hippocampal slices by immunostaining studies. In cultured hippocampal neurons, theseproteins are present in dendrites and are often found near the presynaptic protein, synapsin I. Atsynaptic sites, their distribution completely overlaps with a postsynaptic protein, PSD-95. Theseobservations suggest the postsynaptic localization of these proteins. Disruption of mTOR signaling byrapamycin results in a reduction of late-phase LTP expression induced by high-frequency stimulation; theearly phase of LTP is unaffected. Rapamycin also blocks the synaptic potentiation induced bybrain-derived neurotrophic factor in hippocampal slices. These results demonstrate an essential role forrapamycin-sensitive signaling in the expression of two forms of synaptic plasticity that require newprotein synthesis. The localization of this translational signaling pathway at postsynaptic sites mayprovide a mechanism that controls local protein synthesis at potentiated synapses.", "metadata": {}}
+{"_id": "10795063", "title": "", "text": "The FASEB Journal express article 10.1096/fj.00-0815fje. Published online June 27, 2001. Essential rolefor cholesterol in synaptic plasticity and neuronal degenerationSPECIFIC AIMSOur previous studiesimplied the relation between lipid metabolism and amyloid beta protein (Aβ) as ‘a missing link inAlzheimer’s puzzle’ [FASEB J., vol. 12, p. 1097 (1998)]. In the present study, we evaluated the role ofcholesterol in synaptic plasticity and neuronal degeneration by a combination of adult rat hippocampalslice technology, a well-established procedure for limited cholesterol efflux, lipid metabolic labeling,extracellular recording of CA1 field excitatory postsynaptic potentials (fEPSPs), and immunofluorescence.PRINCIPAL FINDINGS1. Increased cholesterol efflux impairs short- and long-term synapticplasticitySynaptic plasticity is a fundamental feature of the central nervous system (CNS) that allowssynapses to ‘remember’ previous activity and express plastic changes to fine-tune current synapticaction. In this study, we asked whether an increased cholesterol efflux induced ex vivo by normal humanCSF-HDL3 and methyl-β-cyclodextrin (MβCD) (a natural and model cholesterol ac...", "metadata": {}}
+{"_id": "10795340", "title": "", "text": "Functional inhibition of osteoblastic cells in an in vivo mouse model of myeloid leukemia.Pancytopenia is amajor cause of morbidity in acute myeloid leukemia (AML), yet its cause is unclear. Normal osteoblasticcells have been shown to support hematopoiesis. To define the effects of leukemia on osteoblastic cells,we used an immunocompetent murine model of AML. Leukemic mice had inhibition of osteoblastic cells,with decreased serum levels of the bone formation marker osteocalcin. Osteoprogenitor cells andendosteal-lining osteopontin(+) cells were reduced, and osteocalcin mRNA in CD45(-) marrow cells wasdiminished. This resulted in severe loss of mineralized bone. Osteoclasts were only transiently increasedwithout significant increases in bone resorption, and their inhibition only partially rescuedleukemia-induced bone loss. In vitro data suggested that a leukemia-derived secreted factor inhibitedosteoblastic cells. Because the chemokine CCL-3 was recently reported to inhibit osteoblastic function inmyeloma, we tested its expression in our model and in AML patients. Consistent with its potential novelrole in leukemic-dependent bone loss, CCL-3 mRNA was significantly increased in malignant marrow cellsfrom leukemic mice and from samples from AML patients. Based on these results, we propose thattherapeutic mitigation of leukemia-induced uncoupling of osteoblastic and osteoclastic cells mayrepresent a novel approach to promote normal hematopoiesis in patients with myeloid neoplasms.", "metadata": {}}
+{"_id": "10812605", "title": "", "text": "Fibroblast heterogeneity in the cancer woundFibroblasts regulate the structure and function of healthytissues, participate transiently in tissue repair after acute inflammation, and assume an aberrantstimulatory role during chronic inflammatory states including cancer. Such cancer-associated fibroblasts(CAFs) modulate the tumor microenvironment and influence the behavior of neoplastic cells in either atumor-promoting or tumor-inhibiting manner. These pleiotropic functions highlight the inherent plasticityof fibroblasts and may provide new avenues to understand and therapeutically intervene in malignancies.We discuss the emerging themes of CAF biology in the context of tumorigenesis and therapy.", "metadata": {}}
+{"_id": "10827901", "title": "", "text": "Cohort profile: the China Health and Retirement Longitudinal Study (CHARLS).The China Health andRetirement Longitudinal Study (CHARLS) is a nationally representative longitudinal survey of persons inChina 45 years of age or older and their spouses, including assessments of social, economic, and healthcircumstances of community-residents. CHARLS examines health and economic adjustments to rapidageing of the population in China. The national baseline survey for the study was conducted betweenJune 2011 and March 2012 and involved 17 708 respondents. CHARLS respondents are followed every 2years, using a face-to-face computer-assisted personal interview (CAPI). Physical measurements aremade at every 2-year follow-up, and blood sample collection is done once in every two follow-up periods.A pilot survey for CHARLS was conducted in two provinces of China in 2008, on 2685 individuals, whowere resurveyed in 2012. To ensure the adoption of best practices and international comparability ofresults, CHARLS was harmonized with leading international research studies in the Health and RetirementStudy (HRS) model. Requests for collaborations should be directed to Dr Yaohui Zhao(yhzhao@nsd.edu.cn). All data in CHARLS are maintained at the National School of Development ofPeking University and will be accessible to researchers around the world at the study website. The 2008pilot data for CHARLS are available at: http://charls.ccer.edu.cn/charls/. National baseline data for thestudy are expected to be released in January 2013.", "metadata": {}}
+{"_id": "10831818", "title": "", "text": "Central role of Th2/Tc2 lymphocytes in pattern II multiple sclerosis lesionsOBJECTIVE Multiple sclerosis(MS) is a disease of the central nervous system with marked heterogeneity in several aspects includingpathological processes. Based on infiltrating immune cells, deposition of humoral factors and loss ofoligodendrocytes and/or myelin proteins, four lesion patterns have been described. Pattern II ischaracterized by antibody and complement deposition in addition to T-cell infiltration. MS is considered aT-cell-mediated disease, but until now the study of pathogenic T cells has encountered major challenges,most importantly the limited access of brain-infiltrating T cells. Our objective was to identify, isolate, andcharacterize brain-infiltrating clonally expanded T cells in pattern II MS lesions. METHODS We usednext-generation sequencing to identify clonally expanded T cells in demyelinating pattern II brain autopsylesions, subsequently isolated these as T-cell clones from autologous cerebrospinal fluid and functionallycharacterized them. RESULTS We identified clonally expanded CD8(+) but also CD4(+) T cells indemyelinating pattern II lesions and for the first time were able to isolate these as live T-cell clones. Thefunctional characterization shows that T cells releasing Th2 cytokines and able to provide B cell helpdominate the T-cell infiltrate in pattern II brain lesions. INTERPRETATION Our data provide the firstfunctional evidence for a putative role of Th2/Tc2 cells in pattern II MS supporting the existence of thispathogenic phenotype and questioning the protective role that is generally ascribed to Th2 cells. Ourobservations are important to consider for future treatments of pattern II MS patients.", "metadata": {}}
+{"_id": "10846815", "title": "", "text": "Coordinated oscillations in cortical actin and Ca2+ correlate with cycles of vesicle secretionThe actincortex both facilitates and hinders the exocytosis of secretory granules. How cells consolidate these twoopposing roles was not well understood. Here we show that antigen activation of mast cells inducesoscillations in Ca(2+) and PtdIns(4,5)P(2) lipid levels that in turn drive cyclic recruitment of N-WASP andcortical actin level oscillations. Experimental and computational analysis argues that vesicle fusioncorrelates with the observed actin and Ca(2+) level oscillations. A vesicle secretion cycle starts with thecapture of vesicles by actin when cortical F-actin levels are high, followed by vesicle passage through thecortex when F-actin levels are low, and vesicle fusion with the plasma membrane when Ca(2+) levelssubsequently increase. Thus, cells employ oscillating levels of Ca(2+), PtdIns(4,5)P(2) and corticalF-actin to increase secretion efficiency, explaining how the actin cortex can function as a carrier as well asbarrier for vesicle secretion.", "metadata": {}}
+{"_id": "10852047", "title": "", "text": "WK175, a novel antitumor agent, decreases the intracellular nicotinamide adenine dinucleotideconcentration and induces the apoptotic cascade in human leukemia cells.We recently developed a classof novel antitumor agents that elicit a potent growth-inhibitory response in many tumor cells cultured invitro. WK175, a member of this class, was chosen as a model compound that showed strong in vitroefficacy. WK175 interferes with the intracellular steady-state level of NAD(+), resulting in a decreasedcellular NAD(+) concentration. We found that WK175 induces apoptotic cell death without anyDNA-damaging effect. The apoptotic death signaling pathway initiated by WK175 was examined in detail:mitochondrial membrane potential, cytochrome c release, caspase 3 activation, caspase 3 andpoly(ADP-ribose) polymerase cleavage, and the appearance of a sub-G(1) cell cycle population weredetermined in time course studies in THP-1 (a human monocytic leukemia cell line) cells. We foundactivation of this cascade after 24 h of treatment with 10 nM WK175. Induction of apoptosis wasprevented by bongkrekic acid, Z-Asp-Glu-Val-Asp-fluoromethylketone, andZ-Leu-Glu-His-Asp-fluoromethylketone, inhibitors of the mitochondrial permeability transition and ofcaspase 3 and 9, respectively, but not by Ac-Tyr-Val-Ala-Asp-CHO, a specific caspase 1 inhibitor,suggesting the involvement of the permeability transition pore, caspase 3, and caspase 9 in theWK175-induced apoptotic cascade. These results imply that decreased NAD(+) concentration initiates theapoptotic cascade, resulting in the antitumor effect of WK175.", "metadata": {}}
+{"_id": "10854174", "title": "", "text": "Husbands' involvement in delivery care utilization in rural Bangladesh: A qualitative studyBACKGROUNDA primary cause of high maternal mortality in Bangladesh is lack of access to professional delivery care.Examining the role of the family, particularly the husband, during pregnancy and childbirth is importantto understanding women's access to and utilization of professional maternal health services that canprevent maternal mortality. This qualitative study examines husbands' involvement during childbirth andprofessional delivery care utilization in a rural sub-district of Netrokona district, Bangladesh. METHODSUsing purposive sampling, ten households utilizing a skilled attendant during the birth of the youngestchild were selected and matched with ten households utilizing an untrained traditional birth attendant, ordhatri. Households were selected based on a set of inclusion criteria, such as approximate householdincome, ethnicity, and distance to the nearest hospital. Twenty semi-structured interviews wereconducted in Bangla with husbands in these households in June 2010. Interviews were transcribed,translated into English, and analyzed using NVivo 9.0. RESULTS By purposefully selecting households thatdiffered on the type of provider utilized during delivery, common themes--high costs, poor transportation,and long distances to health facilities--were eliminated as sufficient barriers to the utilization ofprofessional delivery care. Divergent themes, namely husbands' social support and perceived socialnorms, were identified as underlying factors associated with delivery care utilization. We found thathusbands whose wives utilized professional delivery care provided emotional, instrumental andinformational support to their wives during delivery and believed that medical intervention wasnecessary. By contrast, husbands whose wives utilized an untrained dhatri at home were uninvolvedduring delivery and believed childbirth should take place at home according to local traditions.CONCLUSIONS This study provides novel evidence about male involvement during childbirth in ruralBangladesh. These findings have important implications for program planners, who should pursueculturally sensitive ways to involve husbands in maternal health interventions and assess theeffectiveness of education strategies targeted at husbands.", "metadata": {}}
+{"_id": "10874408", "title": "", "text": "Mapping Meiotic Single-Strand DNA Reveals a New Landscape of DNA Double-Strand Breaks inSaccharomyces cerevisiaeDNA double-strand breaks (DSBs), which are formed by the Spo11 protein,initiate meiotic recombination. Previous DSB-mapping studies have used rad50S or sae2Δ mutants, whichare defective in break processing, to accumulate Spo11-linked DSBs, and report large (≥ 50 kb)“DSB-hot” regions that are separated by “DSB-cold” domains of similar size. Substantial recombinationoccurs in some DSB-cold regions, suggesting that DSB patterns are not normal in rad50S or sae2Δmutants. We therefore developed a novel method to map genome-wide, single-strand DNA(ssDNA)–associated DSBs that accumulate in processing-capable, repair-defective dmc1Δ and dmc1Δrad51Δ mutants. DSBs were observed at known hot spots, but also in most previously identified“DSB-cold” regions, including near centromeres and telomeres. Although approximately 40% of thegenome is DSB-cold in rad50S mutants, analysis of meiotic ssDNA from dmc1Δ shows that most of theseregions have substantial DSB activity. Southern blot assays of DSBs in selected regions in dmc1Δ,rad50S, and wild-type cells confirm these findings. Thus, DSBs are distributed much more uniformly thanwas previously believed. Comparisons of DSB signals in dmc1, dmc1 rad51, and dmc1 spo11 mutantstrains identify Dmc1 as a critical strand-exchange activity genome-wide, and confirm previousconclusions that Spo11-induced lesions initiate all meiotic recombination.", "metadata": {}}
+{"_id": "10883736", "title": "", "text": "Alterations in liver ATP homeostasis in human nonalcoholic steatohepatitis: a pilot study.CONTEXT Themechanisms that drive progression from fatty liver to steatohepatitis and cirrhosis are unknown. Inanimal models, obese mice with fatty livers are vulnerable to liver adenosine triphosphate (ATP) depletionand necrosis, suggesting that altered hepatic energy homeostasis may be involved. OBJECTIVE Todetermine if patients with fatty liver disease exhibit impaired recovery from hepatic ATP depletion.DESIGN Laboratory analysis of liver ATP stores monitored by nuclear magnetic resonance spectroscopybefore and after transient hepatic ATP depletion was induced by fructose injection. The study wasconducted between July 15 and August 30, 1998. SETTING University hospital. PATIENTS Eightconsecutive adults with biopsy-proven nonalcoholic steatohepatitis and 7 healthy age- and sex-matchedcontrols. MAIN OUTCOME MEASURE Level of ATP 1 hour after fructose infusion in patients vs controls.RESULTS In patients, serum aminotransferase levels were increased (P = .02 vs controls); albumin andbilirubin values were normal and clinical evidence of portal hypertension was absent in both groups.However, 2 patients had moderate fibrosis and 1 had cirrhosis on liver biopsy. Mean serum glucose,cholesterol, and triglyceride levels were similar between groups but patients weighed significantly morethan controls (P = .02). Liver ATP levels were similar in the 2 groups before fructose infusion anddecreased similarly in both after fructose infusion (P = .01 vs initial ATP levels). However, controlsreplenished their hepatic ATP stores during the 1-hour follow-up period (P<.02 vs minimum ATP) butpatients did not. Hence, patients' hepatic ATP levels were lower than those of controls at the end of thestudy (P = .04). Body mass index (BMI) correlated inversely with ATP recovery, even in controls (R =-0.768; P = .07). Although BMI was greater in patients than controls (P = .02) and correlated stronglywith fatty liver and serum aminotransferase elevations, neither of the latter 2 parameters nor thehistologic severity of fibrosis strongly predicted hepatic ATP recovery. CONCLUSIONS These data suggestthat recovery from hepatic ATP depletion becomes progressively less efficient as body mass increases inhealthy controls and is severely impaired in patients with obesity-related nonalcoholic steatohepatitis.", "metadata": {}}
+{"_id": "10889845", "title": "", "text": "Blockade of class IB phosphoinositide-3 kinase ameliorates obesity-induced inflammation and insulinresistance.Obesity and insulin resistance, the key features of metabolic syndrome, are closely associatedwith a state of chronic, low-grade inflammation characterized by abnormal macrophage infiltration intoadipose tissues. Although it has been reported that chemokines promote leukocyte migration byactivating class IB phosphoinositide-3 kinase (PI3Kγ) in inflammatory states, little is known about therole of PI3Kγ in obesity-induced macrophage infiltration into tissues, systemic inflammation, and thedevelopment of insulin resistance. In the present study, we used murine models of both diet-induced andgenetically induced obesity to examine the role of PI3Kγ in the accumulation of tissue macrophages andthe development of obesity-induced insulin resistance. Mice lacking p110γ (Pik3cg(-/-)), the catalyticsubunit of PI3Kγ, exhibited improved systemic insulin sensitivity with enhanced insulin signaling in thetissues of obese animals. In adipose tissues and livers of obese Pik3cg(-/-) mice, the numbers ofinfiltrated proinflammatory macrophages were markedly reduced, leading to suppression of inflammatoryreactions in these tissues. Furthermore, bone marrow-specific deletion and pharmacological blockade ofPI3Kγ also ameliorated obesity-induced macrophage infiltration and insulin resistance. These datasuggest that PI3Kγ plays a crucial role in the development of both obesity-induced inflammation andsystemic insulin resistance and that PI3Kγ can be a therapeutic target for type 2 diabetes.", "metadata": {}}
+{"_id": "10893238", "title": "", "text": "Identifying common impairments in frail and dependent older people: validation of the COPE assessmentfor non-specialised health workers in low resource primary health care settingsBACKGROUND Frail anddependent older people in resource-poor settings are poorly served by health systems that lack outreachcapacity. The COPE (Caring for Older PEople) multidimensional assessment tool is designed to helpcommunity health workers (CHWs) identify clinically significant impairments and deliver evidence-basedinterventions   METHODS Older people (n = 150) identified by CHWs as frail or dependent, were assessedat home by the CHW using the structured COPE assessment tool, generating information on impairmentsin nutrition, mobility, vision, hearing, continence, cognition, mood and behaviour. The older people werereassessed by local physicians who reached a clinical judgment regarding the presence or absence of thesame impairments based upon clinical examination guided by the EASY-Care assessment tool. RESULTSThe COPE tool was considered easy to administer, and gave CHWs a sense of empowerment tounderstand and act upon the needs of older people. Agreement between COPE assessment by CHW andclinician assessors was modest (ranged from 45.8 to 91.3 %) for most impairments. However, theprevalence of impairments was generally higher according to clinicians, particularly for visual impairment(98.7 vs 45.8 %), cognitive impairment (78.4 vs. 38.2 %) and depression (82.0 vs. 59.9 %). Most casesidentified by WHO-COPE were clinician confirmed (positive predictive values - 72.2 to 98.5 %), and levelsof disability and needs for care among those identified by COPE were higher than those additionallyidentified by the clinician alone. CONCLUSIONS The COPE is a feasible tool for the identification of specificimpairments in frail dependent older people in the community. Those identified are likely to be confirmedas having clinically relevant problems by clinicians working in the same service, and the COPE may beparticularly effective at targeting attention upon those with the most substantial unmet needs.", "metadata": {}}
+{"_id": "10906636", "title": "", "text": "The carboxyl terminus of human cytomegalovirus-encoded 7 transmembrane receptor US28 camouflagesagonism by mediating constitutive endocytosis.US28 is one of four 7 transmembrane (7TM) chemokinereceptors encoded by human cytomegalovirus and has been shown to both signal and endocytose in aligand-independent, constitutively active manner. Here we show that the constitutive activity andconstitutive endocytosis properties of US28 are separable entities in this viral chemokine receptor. Wegenerated chimeric and mutant US28 proteins that were altered in either their constitutive endocytic(US28 Delta 300, US28 Delta 317, US28-NK1-ctail, and US28-ORF74-ctail) or signaling properties(US28R129A). By using this series of mutants, we show that the cytoplasmic tail domain of US28 per seregulates receptor endocytosis, independent of the signaling ability of the core domain of US28. Theconstitutive endocytic property of the US28 c-tail was transposable to other 7TM receptors, the herpesvirus 8-encoded ORF74 and the tachykinin NK1 receptor (ORF74-US28-ctail and NK1-US28-ctail).Deletion of the US28 C terminus resulted in reduced constitutive endocytosis and consequently enhancedsignaling capacity of all receptors tested as assessed by inositol phosphate turnover, NF-kappa B, andcAMP-responsive element-binding protein transcription assays. We further show that the constitutiveendocytic property of US28 affects the action of its chemokine ligand fractalkine/CX3CL1 and show that inthe absence of the US28 C terminus, fractalkine/CX3CL1 acts as an agonist on US28. This demonstratesfor the first time that the endocytic properties of a 7TM receptor can camouflage the agonist properties ofa ligand.", "metadata": {}}
+{"_id": "10931595", "title": "", "text": "Geometry, epistasis, and developmental patterning.Developmental signaling networks are composed ofdozens of components whose interactions are very difficult to quantify in an embryo. Geometric reasoningenumerates a discrete hierarchy of phenotypic models with a few composite variables whose parametersmay be defined by in vivo data. Vulval development in the nematode Caenorhabditis elegans is a classicmodel for the integration of two signaling pathways; induction by EGF and lateral signaling throughNotch. Existing data for the relative probabilities of the three possible terminal cell types in diversegenetic backgrounds as well as timed ablation of the inductive signal favor one geometric model andsuffice to fit most of its parameters. The model is fully dynamic and encompasses both signaling andcommitment. It then predicts the correlated cell fate probabilities for a cross between any twobackgrounds/conditions. The two signaling pathways are combined additively, without interactions, andepistasis only arises from the nonlinear dynamical flow in the landscape defined by the geometric model.In this way, the model quantitatively fits genetic experiments purporting to show mutual pathwayrepression. The model quantifies the contributions of extrinsic vs. intrinsic sources of noise in thepenetrance of mutant phenotypes in signaling hypomorphs and explains available experiments with noadditional parameters. Data for anchor cell ablation fix the parameters needed to define Notch autocrinesignaling.", "metadata": {}}
+{"_id": "10937190", "title": "", "text": "Table of ContentsThe morphogenesis of the C. elegans embryo is largely controlled by the developmentof the epidermis, also known as the hypodermis, a single epithelial layer that surrounds the animal.Morphogenesis of the epidermis involves cell-cell interactions with internal tissues, such as thedeveloping nervous system and musculature. Genetic analysis of mutants with aberrant epidermalmorphology has defined multiple steps in epidermal morphogenesis. In the wild type, epidermal cells aregenerated on the dorsal side of the embryo among the progeny of four early embryonic blastomeres.Specification of epidermal fate is regulated by a hierarchy of transcription factors. After specification,dorsal epidermal cells rearrange, a process known as dorsal intercalation. Most epidermal cells fuse togenerate multinucleate syncytia. The dorsally located epidermal sheet undergoes epiboly to enclose therest of the embryo in a process known as ventral enclosure; this movement requires both an intactepidermal layer and substrate neuroblasts. At least three distinct types of cellular behavior underlie theenclosure of different regions of the epidermis. Following enclosure, the epidermis elongates, a processdriven by coordinated cell shape changes. Epidermal actin microfilaments, microtubules, andintermediate filaments all play roles in elongation, as do body wall muscles. The final shape of theepidermis is maintained by the collagenous exoskeleton, secreted by the apical surface of the epidermis.", "metadata": {}}
+{"_id": "10944947", "title": "", "text": "High-throughput sequencing reveals extensive variation in human-specific L1 content in individual humangenomes.Using high-throughput sequencing, we devised a technique to determine the insertion sites ofvirtually all members of the human-specific L1 retrotransposon family in any human genome. Usingdiagnostic nucleotides, we were able to locate the approximately 800 L1Hs copies correspondingspecifically to the pre-Ta, Ta-0, and Ta-1 L1Hs subfamilies, with over 90% of sequenced readscorresponding to human-specific elements. We find that any two individual genomes differ at an averageof 285 sites with respect to L1 insertion presence or absence. In total, we assayed 25 individuals, 15 ofwhich are unrelated, at 1139 sites, including 772 shared with the reference genome and 367nonreference L1 insertions. We show that L1Hs profiles recapitulate genetic ancestry, and determine thechromosomal distribution of these elements. Using these data, we estimate that the rate of L1retrotransposition in humans is between 1/95 and 1/270 births, and the number of dimorphic L1elements in the human population with gene frequencies greater than 0.05 is between 3000 and 10,000.", "metadata": {}}
+{"_id": "10958594", "title": "", "text": "Nationwide trends in incidence, treatment and survival of colorectal cancer patients with synchronousmetastasesThe aim of this study was to determine trends in incidence, treatment and survival ofcolorectal cancer (CRC) patients with synchronous metastases (Stage IV) in the Netherlands. Thisnationwide population-based study included 160,278 patients diagnosed with CRC between 1996 and2011. We evaluated changes in stage distribution, location of synchronous metastases and treatment infour consecutive periods, using Chi square tests for trend. Median survival in months was determined,using Kaplan–Meier analysis. The proportion of Stage IV CRC patients (n = 33,421) increased from 19 %(1996–1999) to 23 % (2008–2011, p < 0.001). This was predominantly due to a major increase in theincidence of lung metastases (1.7–5.0 % of all CRC patients). During the study period, the primary tumorwas resected less often in Stage IV patients (65–46 %) and the use of systemic treatment has increased(29–60 %). Also an increase in metastasectomy was found in patients with one metastatic site, especiallyin patients with liver-only disease (5–18 %, p < 0.001). Median survival of all Stage IV CRC patientsincreased from 7 to 12 months. Especially in patients with metastases confined to the liver or lungs thisimprovement in survival was apparent (9–16 and 12–24 months respectively, both p < 0.001). In thelast two decades, more lung metastases were detected and an increasing proportion of Stage IV CRCpatients was treated with systemic therapy and/or metastasectomy. Survival of patients has significantlyimproved. However, the prognosis of Stage IV patients becomes increasingly diverse.", "metadata": {}}
+{"_id": "10976596", "title": "", "text": "The curious case of the tumour virus: 50 years of Burkitt's lymphomaBurkitt's lymphoma (BL) was firstdescribed 50 years ago, and the first human tumour virus Epstein–Barr virus (EBV) was discovered in BLtumours soon after. Since then, the role of EBV in the development of BL has become more and moreenigmatic. Only recently have we finally begun to understand, at the cellular and molecular levels, thecomplex and interesting interaction of EBV with B cells that creates a predisposition for the developmentof BL. Here, we discuss the intertwined histories of EBV and BL and their relationship to the cofactors inBL pathogenesis: malaria and the MYC translocation.", "metadata": {}}
+{"_id": "10982689", "title": "", "text": "Nanotoxicology: An Emerging Discipline Evolving from Studies of Ultrafine ParticlesAlthough humans havebeen exposed to airborne nanosized particles (NSPs; < 100 nm) throughout their evolutionary stages,such exposure has increased dramatically over the last century due to anthropogenic sources. The rapidlydeveloping field of nanotechnology is likely to become yet another source through inhalation, ingestion,skin uptake, and injection of engineered nanomaterials. Information about safety and potential hazards isurgently needed. Results of older biokinetic studies with NSPs and newer epidemiologic and toxicologicstudies with airborne ultrafine particles can be viewed as the basis for the expanding field ofnanotoxicology, which can be defined as safety evaluation of engineered nanostructures andnanodevices. Collectively, some emerging concepts of nanotoxicology can be identified from the results ofthese studies. When inhaled, specific sizes of NSPs are efficiently deposited by diffusional mechanisms inall regions of the respiratory tract. The small size facilitates uptake into cells and transcytosis acrossepithelial and endothelial cells into the blood and lymph circulation to reach potentially sensitive targetsites such as bone marrow, lymph nodes, spleen, and heart. Access to the central nervous system andganglia via translocation along axons and dendrites of neurons has also been observed. NSPs penetratingthe skin distribute via uptake into lymphatic channels. Endocytosis and biokinetics are largely dependenton NSP surface chemistry (coating) and in vivo surface modifications. The greater surface area per masscompared with larger-sized particles of the same chemistry renders NSPs more active biologically. Thisactivity includes a potential for inflammatory and pro-oxidant, but also antioxidant, activity, which canexplain early findings showing mixed results in terms of toxicity of NSPs to environmentally relevantspecies. Evidence of mitochondrial distribution and oxidative stress response after NSP endocytosis pointsto a need for basic research on their interactions with subcellular structures. Additional considerations forassessing safety of engineered NSPs include careful selections of appropriate and relevantdoses/concentrations, the likelihood of increased effects in a compromised organism, and also thebenefits of possible desirable effects. An interdisciplinary team approach (e.g., toxicology, materialsscience, medicine, molecular biology, and bioinformatics, to name a few) is mandatory for nanotoxicologyresearch to arrive at an appropriate risk assessment.", "metadata": {}}
+{"_id": "10984005", "title": "", "text": "ADHD medications and risk of serious cardiovascular events in young and middle-aged adults.CONTEXTMore than 1.5 million US adults use stimulants and other medications labeled for treatment ofattention-deficit/hyperactivity disorder (ADHD). These agents can increase heart rate and blood pressure,raising concerns about their cardiovascular safety. OBJECTIVE To examine whether current use ofmedications prescribed primarily to treat ADHD is associated with increased risk of serious cardiovascularevents in young and middle-aged adults. DESIGN, SETTING, AND PARTICIPANTS Retrospective,population-based cohort study using electronic health care records from 4 study sites (OptumInsightEpidemiology, Tennessee Medicaid, Kaiser Permanente California, and the HMO Research Network),starting in 1986 at 1 site and ending in 2005 at all sites, with additional covariate assessment using 2007survey data. Participants were adults aged 25 through 64 years with dispensed prescriptions formethylphenidate, amphetamine, or atomoxetine at baseline. Each medication user (n = 150,359) wasmatched to 2 nonusers on study site, birth year, sex, and calendar year (443,198 total users andnonusers). MAIN OUTCOME MEASURES Serious cardiovascular events, including myocardial infarction(MI), sudden cardiac death (SCD), or stroke, with comparison between current or new users and remoteusers to account for potential healthy-user bias. RESULTS During 806,182 person-years of follow-up(median, 1.3 years per person), 1357 cases of MI, 296 cases of SCD, and 575 cases of stroke occurred.There were 107,322 person-years of current use (median, 0.33 years), with a crude incidence per 1000person-years of 1.34 (95% CI, 1.14-1.57) for MI, 0.30 (95% CI, 0.20-0.42) for SCD, and 0.56 (95% CI,0.43-0.72) for stroke. The multivariable-adjusted rate ratio (RR) of serious cardiovascular events forcurrent use vs nonuse of ADHD medications was 0.83 (95% CI, 0.72-0.96). Among new users of ADHDmedications, the adjusted RR was 0.77 (95% CI, 0.63-0.94). The adjusted RR for current use vs remoteuse was 1.03 (95% CI, 0.86-1.24); for new use vs remote use, the adjusted RR was 1.02 (95% CI,0.82-1.28); the upper limit of 1.28 corresponds to an additional 0.19 events per 1000 person-years atages 25-44 years and 0.77 events per 1000 person-years at ages 45-64 years. CONCLUSIONS Amongyoung and middle-aged adults, current or new use of ADHD medications, compared with nonuse orremote use, was not associated with an increased risk of serious cardiovascular events. Apparentprotective associations likely represent healthy-user bias.", "metadata": {}}
+{"_id": "10991183", "title": "", "text": "The Rho GEFs LARG and GEF-H1 regulate the mechanical response to force on integrinsHow individualcells respond to mechanical forces is of considerable interest to biologists as force affects many aspects ofcell behaviour. The application of force on integrins triggers cytoskeletal rearrangements and growth ofthe associated adhesion complex, resulting in increased cellular stiffness, also known as reinforcement.Although RhoA has been shown to play a role during reinforcement, the molecular mechanisms thatregulate its activity are unknown. By combining biochemical and biophysical approaches, we identifiedtwo guanine nucleotide exchange factors (GEFs), LARG and GEF-H1, as key molecules that regulate thecellular adaptation to force. We show that stimulation of integrins with tensional force triggers activationof these two GEFs and their recruitment to adhesion complexes. Surprisingly, activation of LARG andGEF-H1 involves distinct signalling pathways. Our results reveal that LARG is activated by the Src familytyrosine kinase Fyn, whereas GEF-H1 catalytic activity is enhanced by ERK downstream of a signallingcascade that includes FAK and Ras.", "metadata": {}}
+{"_id": "10993232", "title": "", "text": "Cell death from antibiotics without the involvement of reactive oxygen species.Recent observations havesuggested that classic antibiotics kill bacteria by stimulating the formation of reactive oxygen species(ROS). If true, this notion might guide new strategies to improve antibiotic efficacy. In this study, themodel was directly tested. Contrary to the hypothesis, antibiotic treatment did not accelerate theformation of hydrogen peroxide in Escherichia coli and did not elevate intracellular free iron, an essentialreactant for the production of lethal damage. Lethality persisted in the absence of oxygen, and DNArepair mutants were not hypersensitive, undermining the idea that toxicity arose from oxidative DNAlesions. We conclude that these antibiotic exposures did not produce ROS and that lethality more likelyresulted from the direct inhibition of cell-wall assembly, protein synthesis, and DNA replication.", "metadata": {}}
+{"_id": "11011905", "title": "", "text": "Pioneer Transcription Factors Target Partial DNA Motifs on Nucleosomes to InitiateReprogrammingPioneer transcription factors (TFs) access silent chromatin and initiate cell-fate changes,using diverse types of DNA binding domains (DBDs). FoxA, the paradigm pioneer TF, has a winged helixDBD that resembles linker histone and thereby binds its target sites on nucleosomes and in compactedchromatin. Herein, we compare the nucleosome and chromatin targeting activities of Oct4 (POU DBD),Sox2 (HMG box DBD), Klf4 (zinc finger DBD), and c-Myc (bHLH DBD), which together reprogram somaticcells to pluripotency. Purified Oct4, Sox2, and Klf4 proteins can bind nucleosomes in vitro, and in vivothey preferentially target silent sites enriched for nucleosomes. Pioneer activity relates simply to theability of a given DBD to target partial motifs displayed on the nucleosome surface. Such partial motifrecognition can occur by coordinate binding between factors. Our findings provide insight into howpioneer factors can target naive chromatin sites.", "metadata": {}}
+{"_id": "11016410", "title": "", "text": "Experimental Evolution of an RNA Virus in Wild Birds: Evidence for Host-Dependent Impacts onPopulation Structure and Competitive FitnessWithin hosts, RNA viruses form populations that aregenetically and phenotypically complex. Heterogeneity in RNA virus genomes arises due to error-pronereplication and is reduced by stochastic and selective mechanisms that are incompletely understood.Defining how natural selection shapes RNA virus populations is critical because it can inform treatmentparadigms and enhance control efforts. We allowed West Nile virus (WNV) to replicate in wild-caughtAmerican crows, house sparrows and American robins to assess how natural selection shapes RNA viruspopulations in ecologically relevant hosts that differ in susceptibility to virus-induced mortality. After fivesequential passages in each bird species, we examined the phenotype and population diversity of WNVthrough fitness competition assays and next generation sequencing. We demonstrate that fitness gainsoccur in a species-specific manner, with the greatest replicative fitness gains in robin-passaged WNV andthe least in WNV passaged in crows. Sequencing data revealed that intrahost WNV populations werestrongly influenced by purifying selection and the overall complexity of the viral populations was similaramong passaged hosts. However, the selective pressures that control WNV populations seem to be birdspecies-dependent. Specifically, crow-passaged WNV populations contained the most unique mutations(~1.7× more than sparrows, ~3.4× more than robins) and defective genomes (~1.4× greater thansparrows, ~2.7× greater than robins), but the lowest average mutation frequency (about equal tosparrows, ~2.6× lower than robins). Therefore, our data suggest that WNV replication in the mostdisease-susceptible bird species is positively associated with virus mutational tolerance, likely viacomplementation, and negatively associated with the strength of selection. These differences in geneticcomposition most likely have distinct phenotypic consequences for the virus populations. Taken together,these results reveal important insights into how different hosts may contribute to the emergence of RNAviruses.", "metadata": {}}
+{"_id": "11016788", "title": "", "text": "sasCIF: an extension of core Crystallographic Information File for SASData acquisition packagesdeveloped at different small angle scattering facilities use different formats both for raw and processeddata storage. To facilitate the data exchange between laboratories, a consensus in the small anglescattering community has been reached on an ASCII format for one-dimensional data which includes aself-describing header containing relevant information about the sample and instrumental conditionsfollowed by raw or reduced data in a tabular form. This format called sasCIF was implemented as anextension of core CIF (Crystallographic Information File) dictionary.", "metadata": {}}
+{"_id": "11020556", "title": "", "text": "Migratory dendritic cells transfer antigen to a lymph node-resident dendritic cell population for efficientCTL priming.Skin dendritic cells (DCs) are thought to act as key initiators of local T cell immunity. Herewe show that after skin infection with herpes simplex virus (HSV), cytotoxic T lymphocyte (CTL)activation required MHC class I-restricted presentation by nonmigratory CD8(+) DCs rather thanskin-derived DCs. Despite a lack of direct presentation by migratory DCs, blocking their egress frominfected skin substantially inhibited class I-restricted presentation and HSV-specific CTL responses. Theseresults support the argument for initial transport of antigen by migrating DCs, followed by its transfer tothe lymphoid-resident DCs for presentation and CTL priming. Given that relatively robust CTL responseswere seen with small numbers of skin-emigrant DCs, we propose that this inter-DC antigen transferfunctions to amplify presentation across a larger network of lymphoid-resident DCs for efficient T cellactivation.", "metadata": {}}
+{"_id": "11020675", "title": "", "text": "Thrombopoietin-induced Polyploidization of Bone Marrow Megakaryocytes Is Due to a Unique RegulatoryMechanism in Late MitosisMegakaryocytes undergo a unique differentiation program, becoming polyploidthrough repeated cycles of DNA synthesis without concomitant cell division. However, the mechanismunderlying this polyploidization remains totally unknown. It has been postulated that polyploidization isdue to a skipping of mitosis after each round of DNA replication. We carried out immunohistochemicalstudies on mouse bone marrow megakaryocytes during thrombopoietin- induced polyploidization andfound that during this process megakaryocytes indeed enter mitosis and progress through normalprophase, prometaphase, metaphase, and up to anaphase A, but not to anaphase B, telophase, orcytokinesis. It was clearly observed that multiple spindle poles were formed as the polyploidmegakaryocytes entered mitosis; the nuclear membrane broke down during prophase; the sisterchromatids were aligned on a multifaced plate, and the centrosomes were symmetrically located oneither side of each face of the plate at metaphase; and a set of sister chromatids moved into the multiplecentrosomes during anaphase A. We further noted that the pair of spindle poles in anaphase were locatedin close proximity to each other, probably because of the lack of outward movement of spindle polesduring anaphase B. Thus, the reassembling nuclear envelope may enclose all the sister chromatids in asingle nucleus at anaphase and then skip telophase and cytokinesis. These observations clearly indicatethat polyploidization of megakaryocytes is not simply due to a skipping of mitosis, and that themegakaryocytes must have a unique regulatory mechanism in anaphase, e.g., factors regulatinganaphase such as microtubule motor proteins might be involved in this polyploidization process.", "metadata": {}}
+{"_id": "11026600", "title": "", "text": "Unifying Viral Genetics and Human Transportation Data to Predict the Global Transmission Dynamics ofHuman Influenza H3N2Information on global human movement patterns is central to spatialepidemiological models used to predict the behavior of influenza and other infectious diseases. Yet itremains difficult to test which modes of dispersal drive pathogen spread at various geographic scalesusing standard epidemiological data alone. Evolutionary analyses of pathogen genome sequencesincreasingly provide insights into the spatial dynamics of influenza viruses, but to date they have largelyneglected the wealth of information on human mobility, mainly because no statistical framework existswithin which viral gene sequences and empirical data on host movement can be combined. Here, weaddress this problem by applying a phylogeographic approach to elucidate the global spread of humaninfluenza subtype H3N2 and assess its ability to predict the spatial spread of human influenza A virusesworldwide. Using a framework that estimates the migration history of human influenza whilesimultaneously testing and quantifying a range of potential predictive variables of spatial spread, weshow that the global dynamics of influenza H3N2 are driven by air passenger flows, whereas at more localscales spread is also determined by processes that correlate with geographic distance. Our analysesfurther confirm a central role for mainland China and Southeast Asia in maintaining a source populationfor global influenza diversity. By comparing model output with the known pandemic expansion of H1N1during 2009, we demonstrate that predictions of influenza spatial spread are most accurate when data onhuman mobility and viral evolution are integrated. In conclusion, the global dynamics of influenza virusesare best explained by combining human mobility data with the spatial information inherent in sampledviral genomes. The integrated approach introduced here offers great potential for epidemiologicalsurveillance through phylogeographic reconstructions and for improving predictive models of diseasecontrol.", "metadata": {}}
+{"_id": "11041152", "title": "", "text": "Microtubule sliding activity of a kinesin-8 promotes spindle assembly and spindle length controlMolecularmotors play critical roles in the formation of mitotic spindles, either through controlling the stability ofindividual microtubules, or by crosslinking and sliding microtubule arrays. Kinesin-8 motors are bestknown for their regulatory roles in controlling microtubule dynamics. They containmicrotubule-destabilizing activities, and restrict spindle length in a wide variety of cell types andorganisms. Here, we report an antiparallel microtubule-sliding activity of the budding yeast kinesin-8,Kip3. The in vivo importance of this sliding activity was established through the identification ofcomplementary Kip3 mutants that separate the sliding activity and microtubule-destabilizing activity. Inconjunction with Cin8, a kinesin-5 family member, the sliding activity of Kip3 promotes bipolar spindleassembly and the maintenance of genome stability. We propose a slide-disassemble model where thesliding and destabilizing activity of Kip3 balance during pre-anaphase. This facilitates normal spindleassembly. However, the destabilizing activity of Kip3 dominates in late anaphase, inhibiting spindleelongation and ultimately promoting spindle disassembly.", "metadata": {}}
+{"_id": "11043831", "title": "", "text": "A Pharmacological Map of the PI3-K Family Defines a Role for p110α in Insulin SignalingPhosphoinositide3-kinases (PI3-Ks) are an important emerging class of drug targets, but the unique roles of PI3-Kisoforms remain poorly defined. We describe here an approach to pharmacologically interrogate the PI3-Kfamily. A chemically diverse panel of PI3-K inhibitors was synthesized, and their target selectivity wasbiochemically enumerated, revealing cryptic homologies across targets and chemotypes. Crystalstructures of three inhibitors bound to p110gamma identify a conformationally mobile region that isuniquely exploited by selective compounds. This chemical array was then used to define the PI3-Kisoforms required for insulin signaling. We find that p110alpha is the primary insulin-responsive PI3-K incultured cells, whereas p110beta is dispensable but sets a phenotypic threshold for p110alpha activity.Compounds targeting p110alpha block the acute effects of insulin treatment in vivo, whereas a p110betainhibitor has no effect. These results illustrate systematic target validation using a matrix of inhibitorsthat span a protein family.", "metadata": {}}
+{"_id": "11048759", "title": "", "text": "Identification of Epstein-Barr virus nuclear antigen 1 protein domains that direct interactions at a distancebetween DNA-bound proteins.The EBNA1 protein of Epstein-Barr virus (EBV) binds to and activates DNAreplication from the EBV latent origin of replication, oriP, via a direct interaction with the twononcontiguous subelements of oriP. The EBNA1 molecules bound to the oriP subelements interactefficiently with each other by a DNA looping mechanism. We have previously mapped a region of EBNA1(termed the looping region) that is required to mediate the interaction of the EBNA1 molecules bound tothe oriP subelements. We now demonstrate that two fragments of this region of EBNA1, which consistlargely of an eight amino acid repeat, can mediate homotypic interactions when transferred to anotherDNA-binding protein. Protein interactions mediated by the EBNA1 looping region appear to be dependenton DNA binding since these interactions were detected between DNA-bound forms of the proteins only.", "metadata": {}}
+{"_id": "11071351", "title": "", "text": "Primary prevention of hypertension: clinical and public health advisory from The National High BloodPressure Education Program.The National High Blood Pressure Education Program CoordinatingCommittee published its first statement on the primary prevention of hypertension in 1993. This articleupdates the 1993 report, using new and further evidence from the scientific literature. Currentrecommendations for primary prevention of hypertension involve a population-based approach and anintensive targeted strategy focused on individuals at high risk for hypertension. These 2 strategies arecomplementary and emphasize 6 approaches with proven efficacy for prevention of hypertension: engagein moderate physical activity; maintain normal body weight; limit alcohol consumption; reduce sodiumintake; maintain adequate intake of potassium; and consume a diet rich in fruits, vegetables, and low-fatdairy products and reduced in saturated and total fat. Applying these approaches to the generalpopulation as a component of public health and clinical practice can help prevent blood pressure fromincreasing and can help decrease elevated blood pressure levels for those with high normal bloodpressure or hypertension.", "metadata": {}}
+{"_id": "11083121", "title": "", "text": "Formins: intermediates in signal-transduction cascades that affect cytoskeletal reorganization.The controlof cell growth and polarity depends on a dynamic actin cytoskeleton that has the ability to reorganize inresponse to developmental and environmental stimuli. In animals and fungi, formins are just one of thefour major classes of poly-L-proline-containing (PLP) proteins that form part of the signal-transductioncascade that leads to rearrangement of the actin cytoskeleton. Analysis of the Arabidopsis genomesequence indicates that, unlike animals and fungi, formins are the only class of conserved profilin-bindingPLP proteins in plants. Moreover, plant formins show significant structural differences compared with theiranimal and fungal counterparts, raising the possibility that plant formins are subject to novel mechanismsof control or perform unique roles in plants.", "metadata": {}}
+{"_id": "11090688", "title": "", "text": "Genetic variability in GLP-1 receptor is associated with inter-individual differences in weight loweringpotential of liraglutide in obese women with PCOS: a pilot studyThe weight lowering potential ofglucagon-like peptide 1 (GLP-1) receptor agonists (RAs) is inter-individually different and clinicallyunpredictable. The potential role of genetic variability of GLP-1R on body weight response to GLP-1 RAs inobese women with polycystic ovary syndrome (PCOS) has not yet been evaluated. Fifty-seven obesewomen with PCOS (aged 30.7 ± 7.0, BMI 38.6 ± 5.3 kg/m2) were assigned to liraglutide 1.2 mg QD s.c.for 12 weeks and classified as strong responders regarding weight loss if they lost 5 % or more of theirinitial body weight. They were genotyped for common GLP-1R single nucleotide polymorphisms (SNPs)rs6923761 and rs10305420. Changes of measures of obesity were measured before and at the end of thetreatment. Twenty out of 57 subjects were strong responders and lost 7.38 ± 1.74 compared to 2.11 ±2.17 kg lost in poor responders. Carriers of at least one polymorphic rs10305420 allele had poortreatment response compared to carriers of two wild type alleles (OR = 0.27, 95 % CI = 0.09–0.85, P =0.025). Carriers of at least one polymorphic rs6923761 allele tended to have stronger treatmentresponse compared to carriers of two wild type alleles (OR = 3.06, 95 % CI = 0.96–9.74, P = 0.058).Fasting glucose and glucose after oral glucose tolerance test (OGTT) comparably decreased in bothgroups when compared to baseline, whereas no within treatment differences were found in androgenprofile. Gastrointestinal adverse events were transit and balanced between strong and poor responders.GLP-1R rs10305420 polymorphism explained some of the inter-individual differences in response toliraglutide regarding weight loss in obese PCOS women.", "metadata": {}}
+{"_id": "11109043", "title": "", "text": "Cost-effectiveness of aromatase inhibitor co-treatment for controlled ovarian stimulation.BACKGROUNDTo compare the clinical results and the cost-effectiveness of using the aromatase inhibitor, letrozole, inconjunction with FSH and FSH alone for controlled ovarian stimulation (COS) in patients undergoingintrauterine insemination (IUI) for a variety of indications. METHODS Four hundred and thirty-twoconsecutive patients who underwent 872 IUI cycles were included. The study population was composedof two groups. Group I included 308 patients who underwent 589 IUI cycles with letrozole and FSH forthe following indications: anovulation (143 cycles), male factor infertility (147 cycles), unexplainedinfertility (250 cycles), endometriosis (18 cycles) and combined indications (31 cycles). Group II included124 patients who underwent 283 IUI cycles who received FSH only for the following indications: ovarianfactor infertility (82 cycles), male factor infertility (66 cycles), unexplained infertility (114 cycles),endometriosis (13 cycles) and other indications (8 cycles). Main outcome measures included number ofmature follicles >16 mm in diameter, dose of FSH used per cycle, clinical pregnancy rate andcost-effectiveness ratio per pregnancy. RESULTS FSH dose required for ovarian stimulation wassignificantly lower when letrozole was used (P < 0.0001). Although a significantly higher number offollicles >16 mm and endometrial thickness at the day of hCG administration (P < 0.0001) were observedin Group II, pregnancy rate per started (14.4 versus 15.9%) and per completed cycles (15.77 versus18.07%) was the same in Group I and Group II, respectively. IUI cancellation rate was significantly lowerwith letrozole treatment (P = 0.05%). The cost per cycle was significantly lower in Group I versus GroupII (468.93 Can dollars +/- 418.18 versus 1067.28 +/- 921.43; P < 0.0001). The cost-effectiveness ratiowas 3249.42 dollars in the letrozole group and 6712.00 dollars in the FSH-only group. CONCLUSION Aletrozole-FSH combination could be an effective ovarian stimulation protocol in IUI cycles. Such aprotocol may be more cost-effective than FSH alone because of the difference of FSH dose and cost. Arandomized controlled trial is needed to further substantiate this finding.", "metadata": {}}
+{"_id": "11117498", "title": "", "text": "The cost effectiveness of stereotactic radiosurgery versus surgical resection in the treatment of solitarymetastatic brain tumors.Solitary metastatic brain tumors are the most common intracranial neoplasmsencountered by neurosurgeons. Surgical resection of brain metastasis with whole brain radiotherapy(WBR) significantly increases survival in comparison with WBR alone. Stereotactic radiosurgery (SR)seems to provide results that are similar to those of surgical resection. To analyze the economic efficiencyof these different treatments, we compared the results of surgical resection and SR as reported in themedical literature between 1974 and 1994. We included studies in which: 1) at least 75% of patientsreceived WBR; 2) study dates were in the computed tomography era (after 1975); 3) operativemorbidity, mortality, and median survival were reported; 4) study dates were not included in a morerecent update or review; 5) tumor histologies were reported; and 6) the cobalt-60 gamma unit was usedfor SR. Three surgical resection studies and one SR study met all entry requirements. The WBR baselinewas developed from two prospective, randomized trials and used for incremental cost effectivenessanalysis. We developed a model of typical resource usage for uncomplicated procedures, reportedcomplications, and subsequent craniotomies (for recurrent tumor or radiation necrosis) for bothtreatment options. Costs were estimated from the societal viewpoint using the 1992 Medicare ProviderAnalysis and Review database with average cost:charge ratios for surgery and WBR. A survey of capitaland operating costs from five sites was used for radiosurgery. Our analysis revealed that radiosurgeryhad a lower uncomplicated procedure cost ($20,209 versus $27,587), a lower average complication costper case ($2,534 versus $2,874), and a lower total cost per procedure ($22,743 versus $30,461), wasmore cost effective ($24,811 versus $32,149 per life year), and had a better incremental costeffectiveness ($40,648 versus $52,384 per life year) than surgical resection. A sensitivity analysisrevealed that large changes in key assumptions would be required to change the analysis outcome.Equalization of the incremental cost effectiveness of the two treatments would require one of thefollowing: 1) a 38.7% reduction in SR annual case volume, 2) a 34.7% increase in SR procedure cost, 3)a 18.8% reduction in surgical resection procedure cost, 4) a 240.5% increase in SR morbidity cost, 5) a12.7% reduction in SR median survival, 6) a 16.8% increase in surgical resection median survival.Elimination of all surgical resection morbidity cost would still result in superior incremental costeffectiveness for SR.(ABSTRACT TRUNCATED AT 400 WORDS)", "metadata": {}}
+{"_id": "11117679", "title": "", "text": "Trans-ancestry mutational landscape of hepatocellular carcinoma genomesDiverse epidemiological factorsare associated with hepatocellular carcinoma (HCC) prevalence in different populations. However, theglobal landscape of the genetic changes in HCC genomes underpinning different epidemiological andancestral backgrounds still remains uncharted. Here a collection of data from 503 liver cancer genomesfrom different populations uncovered 30 candidate driver genes and 11 core pathway modules.Furthermore, a collaboration of two large-scale cancer genome projects comparatively analyzed thetrans-ancestry substitution signatures in 608 liver cancer cases and identified unique mutationalsignatures that predominantly contribute to Asian cases. This work elucidates previously unexploredancestry-associated mutational processes in HCC development. A combination of hotspot TERT promotermutation, TERT focal amplification and viral genome integration occurs in more than 68% of cases,implicating TERT as a central and ancestry-independent node of hepatocarcinogenesis. Newly identifiedalterations in genes encoding metabolic enzymes, chromatin remodelers and a high proportion of mTORpathway activations offer potential therapeutic and diagnostic opportunities.", "metadata": {}}
+{"_id": "11141995", "title": "", "text": "Organization of the mitotic chromosome.Mitotic chromosomes are among the most recognizablestructures in the cell, yet for over a century their internal organization remains largely unsolved. Weapplied chromosome conformation capture methods, 5C and Hi-C, across the cell cycle and revealed twodistinct three-dimensional folding states of the human genome. We show that the highlycompartmentalized and cell type-specific organization described previously for nonsynchronous cells isrestricted to interphase. In metaphase, we identified a homogenous folding state that islocus-independent, common to all chromosomes, and consistent among cell types, suggesting a generalprinciple of metaphase chromosome organization. Using polymer simulations, we found that metaphaseHi-C data are inconsistent with classic hierarchical models and are instead best described by a linearlyorganized longitudinally compressed array of consecutive chromatin loops.", "metadata": {}}
+{"_id": "11156883", "title": "", "text": "Compensatory anti-inflammatory response syndrome.The concept of 'Compensatory anti-inflammatoryresponse syndrome' (CARS) was proposed in 1997 by Roger Bone (1941-1997) to qualify theconsequences of the counter-regulatory mechanisms initiated to limit the overzealous inflammatoryprocess in patients with infectious (sepsis) or non-infectious systemic inflammatory response syndrome(SIRS). One major consequence of CARS is the modification of the immune status that could favour theenhanced susceptibility of intensive care patients to nosocomial infections. Indeed, most animal 'two-hit'models illustrate an enhanced sensitivity to infection after a first insult. However, this observation ishighly dependent on the experimental procedure. Numerous functions of circulating leukocytes arealtered in sepsis and SIRS patients, as well as in animal models of sepsis or SIRS. However, this is rathera reprogramming of circulating leukocytes, since there is not a global defect of the immune cellsfunctions. Furthermore, within tissues, leukocytes are rather primed or activated thanimmunosuppressed. Thus, CARS may be considered as an adapted compartmentalized response with theaim to silence some acute proinflammatory genes, and to maintain the possible expression of certaingenes involved in the anti-infectious process.", "metadata": {}}
+{"_id": "11172205", "title": "", "text": "Quantum dots spectrally distinguish multiple species within the tumor milieu in vivoA solid tumor is anorgan composed of cancer and host cells embedded in an extracellular matrix and nourished by bloodvessels. A prerequisite to understanding tumor pathophysiology is the ability to distinguish and monitoreach component in dynamic studies. Standard fluorophores hamper simultaneous intravital imaging ofthese components. Here, we used multiphoton microscopy techniques and transgenic mice thatexpressed green fluorescent protein, and combined them with the use of quantum dot preparations. Weshow that these fluorescent semiconductor nanocrystals can be customized to concurrently image anddifferentiate tumor vessels from both the perivascular cells and the matrix. Moreover, we used them tomeasure the ability of particles of different sizes to access the tumor. Finally, we successfully monitoredthe recruitment of quantum dot–labeled bone marrow–derived precursor cells to the tumor vasculature.These examples show the versatility of quantum dots for studying tumor pathophysiology and creatingavenues for treatment.", "metadata": {}}
+{"_id": "11181416", "title": "", "text": "Arginase I: a limiting factor for nitric oxide and polyamine synthesis by activated macrophages?Becausearginase hydrolyzes arginine to produce ornithine and urea, it has the potential to regulate nitric oxide(NO) and polyamine synthesis. We tested whether expression of the cytosolic isoform of arginase(arginase I) was limiting for NO or polyamine production by activated RAW 264.7 macrophage cells. RAW264.7 cells, stably transfected to overexpress arginase I or beta-galactosidase, were treated withinterferon-gamma to induce type 2 NO synthase or with lipopolysaccharide or 8-bromo-cAMP (8-BrcAMP)to induce ornithine decarboxylase. Overexpression of arginase I had no effect on NO synthesis. Incontrast, cells overexpressing arginase I produced twice as much putrescine after activation than did cellsexpressing beta-galactosidase. Cells overexpressing arginase I also produced more spermidine aftertreatment with 8-BrcAMP than did cells expressing beta-galactosidase. Thus endogenous levels ofarginase I are limiting for polyamine synthesis, but not for NO synthesis, by activated macrophage cells.This study also demonstrates that it is possible to alter arginase I levels sufficiently to affect polyaminesynthesis without affecting induced NO synthesis.", "metadata": {}}
+{"_id": "11195653", "title": "", "text": "Opposing Effects of PKCθ and WASp on Symmetry Breaking and Relocation of the ImmunologicalSynapseThe immunological synapse (IS) is a junction between the T cell and antigen-presenting cell andis composed of supramolecular activation clusters (SMACs). No studies have been published on naive Tcell IS dynamics. Here, we find that IS formation during antigen recognition comprises cycles of stable ISformation and autonomous naive T cell migration. The migration phase is driven by PKCtheta, which islocalized to the F-actin-dependent peripheral (p)SMAC. PKCtheta(-/-) T cells formed hyperstable IS invitro and in vivo and, like WT cells, displayed fast oscillations in the distal SMAC, but they showedreduced slow oscillations in pSMAC integrity. IS reformation is driven by the Wiscott Aldrich Syndromeprotein (WASp). WASp(-/-) T cells displayed normal IS formation but were unable to reform IS aftermigration unless PKCtheta was inhibited. Thus, opposing effects of PKCtheta and WASp control ISstability through pSMAC symmetry breaking and reformation.", "metadata": {}}
+{"_id": "11200685", "title": "", "text": "Integrins regulate microtubule nucleating activity of centrosome through mitogen-activated proteinkinase/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase (MEK/ERK)signaling.Microtubule nucleation is an essential step in the formation of the microtubule cytoskeleton. Werecently showed that androgen and Src promote microtubule nucleation and γ-tubulin accumulation atthe centrosome. Here, we explore the mechanisms by which androgen and Src regulate these processesand ask whether integrins play a role. We perturb integrin function by a tyrosine-to-alanine substitutionin membrane-proximal NPIY motif in the integrin β1 tail and show that this mutant substantiallydecreases microtubule nucleation and γ-tubulin accumulation at the centrosome. Because androgenstimulation promotes the interaction of the androgen receptor with Src, resulting in PI3K/AKT andMEK/ERK signaling, we asked whether these pathways are inhibited by the mutant integrin and whetherthey regulate microtubule nucleation. Our results indicate that the formation of the androgenreceptor-Src complex and the activation of downstream pathways are significantly suppressed when cellsare adhered by the mutant integrin. Inhibitor studies indicate that microtubule nucleation requiresMEK/ERK but not PI3K/AKT signaling. Importantly, the expression of activated RAF-1 is sufficient torescue microtubule nucleation inhibited by the mutant integrin by promoting the centrosomalaccumulation of γ-tubulin. Our data define a novel paradigm of integrin signaling, where integrinsregulate microtubule nucleation by promoting the formation of androgen receptor-Src signalingcomplexes to activate the MEK/ERK signaling pathway.", "metadata": {}}
+{"_id": "11201004", "title": "", "text": "Consumption of added sugars from liquid but not solid sources predicts impaired glucose homeostasisand insulin resistance among youth at risk of obesity.Little is known about longitudinal associationsbetween added sugar consumption (solid and liquid sources) and glucose-insulin homeostasis amongyouth. Caucasian children (8-10 y) with at least one obese biological parent were recruited in the QUébecAdipose and Lifestyle InvesTigation in Youth (QUALITY) cohort (n = 630) and followed-up 2 y later (n =564). Added sugars were assessed by 3 24-h dietary recalls at baseline. Two-year changes wereexamined in multivariate linear regression models, adjusting for baseline level, age, sex, Tanner stage,energy intake, fat mass (dual-energy X-ray absorptiometry), and physical activity (7 d accelerometer).Added sugar intake in either liquid or solid sources was not related to changes in adiposity measures (fatmass, body mass index, or waist circumference). However, a higher consumption (10 g/d) of addedsugars from liquid sources was associated with 0.04 mmol/L higher fasting glucose, 2.3 pmol/L higherfasting insulin, 0.1 unit higher homeostasis model assessment of insulin resistance (HOMA-IR), and 0.4unit lower Matsuda-insulin sensitivity index (Matsuda-ISI) in all participants (P < 0.01). No associationswere observed with consumption of added sugars from solid sources. Overweight/obese children atbaseline had greater increases in adiposity indicators, fasting insulin, and HOMA-IR and decreases inMatsuda-ISI during those 2 y than normal-weight children. Consumption of added sugars from liquid orsolid sources was not associated with changes in adiposity, but liquid added sugars were a risk factor forthe development of impaired glucose homeostasis and insulin resistance over 2 y among youth at risk ofobesity.", "metadata": {}}
+{"_id": "11230569", "title": "", "text": "Towards an improved investment approach for an effective response to HIV/AIDS.Substantial changesare needed to achieve a more targeted and strategic approach to investment in the response to theHIV/AIDS epidemic that will yield long-term dividends. Until now, advocacy for resources has been doneon the basis of a commodity approach that encouraged scaling up of numerous strategies in parallel,irrespective of their relative effects. We propose a strategic investment framework that is intended tosupport better management of national and international HIV/AIDS responses than exists with thepresent system. Our framework incorporates major efficiency gains through community mobilisation,synergies between programme elements, and benefits of the extension of antiretroviral therapy forprevention of HIV transmission. It proposes three categories of investment, consisting of six basicprogrammatic activities, interventions that create an enabling environment to achieve maximumeffectiveness, and programmatic efforts in other health and development sectors related to HIV/AIDS.The yearly cost of achievement of universal access to HIV prevention, treatment, care, and support by2015 is estimated at no less than US$22 billion. Implementation of the new investment framework wouldavert 12·2 million new HIV infections and 7·4 million deaths from AIDS between 2011 and 2020compared with continuation of present approaches, and result in 29·4 million life-years gained. Theframework is cost effective at $1060 per life-year gained, and the additional investment proposed wouldbe largely offset from savings in treatment costs alone.", "metadata": {}}
+{"_id": "11233339", "title": "", "text": "Pivotal Roles of T-Helper 17-Related Cytokines, IL-17, IL-22, and IL-23, in InflammatoryDiseasesT-helper 17 (Th17) cells are characterized by producing interleukin-17 (IL-17, also calledIL-17A), IL-17F, IL-21, and IL-22 and potentially TNF- α and IL-6 upon certain stimulation. IL-23, whichpromotes Th17 cell development, as well as IL-17 and IL-22 produced by the Th17 cells plays essentialroles in various inflammatory diseases, such as experimental autoimmune encephalomyelitis, rheumatoidarthritis, colitis, and Concanavalin A-induced hepatitis. In this review, we summarize the characteristicsof the functional role of Th17 cells, with particular focus on the Th17 cell-related cytokines such as IL-17,IL-22, and IL-23, in mouse models and human inflammatory diseases.", "metadata": {}}
+{"_id": "11238784", "title": "", "text": "LXRS and FXR: the yin and yang of cholesterol and fat metabolism.Liver X receptors (LXRs) and farnesoidX receptor (FXR) are nuclear receptors that function as intracellular sensors for sterols and bile acids,respectively. In response to their ligands, these receptors induce transcriptional responses that maintaina balanced, finely tuned regulation of cholesterol and bile acid metabolism. LXRs also permit the efficientstorage of carbohydrate- and fat-derived energy, whereas FXR activation results in an overall decrease intriglyceride levels and modulation of glucose metabolism. The elegant, dual interplay between these tworeceptor systems suggests that they coevolved to constitute a highly sensitive and efficient system forthe maintenance of total body fat and cholesterol homeostasis. Emerging evidence suggests that thetissue-specific action of these receptors is also crucial for the proper function of the cardiovascular,immune, reproductive, endocrine pancreas, renal, and central nervous systems. Together, LXRs and FXRrepresent potential therapeutic targets for the treatment and prevention of numerous metabolic andlipid-related diseases.", "metadata": {}}
+{"_id": "11238951", "title": "", "text": "Kaposi's sarcoma-associated herpesvirus/human herpesvirus type 8-positive solid lymphomas: atissue-based variant of primary effusion lymphoma.Kaposi's sarcoma-associated herpesvirus (KSHV),also termed human herpesvirus type 8, is consistently identified in Kaposi's sarcoma, primary effusionlymphoma (PEL), and multicentric Castleman's disease. Here we report four cases of KSHV-bearing solidlymphomas that occurred in AIDS patients (cases 1 to 3) and in a human immunodeficiency virus(HIV)-seronegative person (case 4). The patients presented extranodal masses in the abdomen (cases 1,3, and 4) or skin (case 2), and nodal involvement, together with Kaposi's sarcoma (case 3). Thegastrointestinal tract was involved in two patients (cases 1 and 3). The patients did not develop alymphomatous effusion. KSHV was detected in the tumor cells of all cases by immunohistochemistry andby polymerase chain reaction. Epstein-Barr virus was detected in two of the HIV-related cases. AllKSHV-positive solid lymphomas exhibited PEL-like cell morphology. To investigate the relationship ofthese disorders to PEL and to other AIDS-associated diffuse large cell lymphomas, KSHV-positive solidlymphomas were tested for the expression of a set of genes that were previously shown by gene profilinganalysis to define PEL tumor cells. The results showed that expression of this set of genes inKSHV-positive lymphomas is similar to that of PEL but distinct from KSHV-negative AIDS-associateddiffuse large cell lymphomas. Because pathobiological features of KSHV-positive solid lymphomas closelymimic those of PEL, our results suggest that KSHV-positive solid lymphomas should be considered as atissue-based variant of classical PEL, irrespective of HIV status.", "metadata": {}}
+{"_id": "11244195", "title": "", "text": "STAR: ultrafast universal RNA-seq aligner.MOTIVATION Accurate alignment of high-throughput RNA-seqdata is a challenging and yet unsolved problem because of the non-contiguous transcript structure,relatively short read lengths and constantly increasing throughput of the sequencing technologies.Currently available RNA-seq aligners suffer from high mapping error rates, low mapping speed, readlength limitation and mapping biases. RESULTS To align our large (>80 billon reads) ENCODETranscriptome RNA-seq dataset, we developed the Spliced Transcripts Alignment to a Reference (STAR)software based on a previously undescribed RNA-seq alignment algorithm that uses sequential maximummappable seed search in uncompressed suffix arrays followed by seed clustering and stitching procedure.STAR outperforms other aligners by a factor of >50 in mapping speed, aligning to the human genome550 million 2 × 76 bp paired-end reads per hour on a modest 12-core server, while at the same timeimproving alignment sensitivity and precision. In addition to unbiased de novo detection of canonicaljunctions, STAR can discover non-canonical splices and chimeric (fusion) transcripts, and is also capableof mapping full-length RNA sequences. Using Roche 454 sequencing of reverse transcription polymerasechain reaction amplicons, we experimentally validated 1960 novel intergenic splice junctions with an80-90% success rate, corroborating the high precision of the STAR mapping strategy. AVAILABILITY ANDIMPLEMENTATION STAR is implemented as a standalone C++ code. STAR is free open source softwaredistributed under GPLv3 license and can be downloaded from http://code.google.com/p/rna-star/.", "metadata": {}}
+{"_id": "11246427", "title": "", "text": "Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures:results from the Fracture Intervention Trial.CONTEXT Alendronate sodium reduces fracture risk inpostmenopausal women who have vertebral fractures, but its effects on fracture risk have not beenstudied for women without vertebral fractures. OBJECTIVE To test the hypothesis that 4 years ofalendronate would decrease the risk of clinical and vertebral fractures in women who have low bonemineral density (BMD) but no vertebral fractures. DESIGN Randomized, blinded, placebo-controlled trial.SETTING Eleven community-based clinical research centers. SUBJECTS Women aged 54 to 81 years witha femoral neck BMD of 0.68 g/cm2 or less (Hologic Inc, Waltham, Mass) but no vertebral fracture; 4432were randomized to alendronate or placebo and 4272 (96%) completed outcome measurements at thefinal visit (an average of 4.2 years later). INTERVENTION All participants reporting calcium intakes of1000 mg/d or less received a supplement containing 500 mg of calcium and 250 IU of cholecalciferol.Subjects were randomly assigned to either placebo or 5 mg/d of alendronate sodium for 2 years followedby 10 mg/d for the remainder of the trial. MAIN OUTCOME MEASURES Clinical fractures confirmed byx-ray reports, new vertebral deformities detected by morphometric measurements on radiographs, andBMD measured by dual x-ray absorptiometry. RESULTS Alendronate increased BMD at all sites studied(P<.001) and reduced clinical fractures from 312 in the placebo group to 272 in the intervention group,but not significantly so (14% reduction; relative hazard [RH], 0.86; 95% confidence interval [CI],0.73-1.01). Alendronate reduced clinical fractures by 36% in women with baseline osteoporosis at thefemoral neck (>2.5 SDs below the normal young adult mean; RH, 0.64; 95% CI, 0.50-0.82;treatment-control difference, 6.5%; number needed to treat [NNT], 15), but there was no significantreduction among those with higher BMD (RH, 1.08; 95% CI, 0.87-1.35). Alendronate decreased the riskof radiographic vertebral fractures by 44% overall (relative risk, 0.56; 95% CI, 0.39-0.80;treatment-control difference, 1.7%; NNT, 60). Alendronate did not increase the risk of gastrointestinal orother adverse effects. CONCLUSIONS In women with low BMD but without vertebral fractures, 4 years ofalendronate safely increased BMD and decreased the risk of first vertebral deformity. Alendronatesignificantly reduced the risk of clinical fractures among women with osteoporosis but not among womenwith higher BMD.", "metadata": {}}
+{"_id": "11250124", "title": "", "text": "AP-1/sigma1B-adaptin mediates endosomal synaptic vesicle recycling, learning and memory.Synapticvesicle recycling involves AP-2/clathrin-mediated endocytosis, but it is not known whether the endosomalpathway is also required. Mice deficient in the tissue-specific AP-1-sigma1B complex have impairedsynaptic vesicle recycling in hippocampal synapses. The ubiquitously expressed AP-1-sigma1A complexmediates protein sorting between the trans-Golgi network and early endosomes. Vertebrates expressthree sigma1 subunit isoforms: A, B and C. The expressions of sigma1A and sigma1B are highest in thebrain. Synaptic vesicle reformation in cultured neurons from sigma1B-deficient mice is reduced uponstimulation, and large endosomal intermediates accumulate. The sigma1B-deficient mice have reducedmotor coordination and severely impaired long-term spatial memory. These data reveal a molecularmechanism for a severe human X-chromosome-linked mental retardation.", "metadata": {}}
+{"_id": "11253758", "title": "", "text": "Update of the FANTOM web resource: high resolution transcriptome of diverse cell types inmammalsUpon the first publication of the fifth iteration of the Functional Annotation of MammalianGenomes collaborative project, FANTOM5, we gathered a series of primary data and database systemsinto the FANTOM web resource (http://fantom.gsc.riken.jp) to facilitate researchers to exploretranscriptional regulation and cellular states. In the course of the collaboration, primary data and analysisresults have been expanded, and functionalities of the database systems enhanced. We believe that ourdata and web systems are invaluable resources, and we think the scientific community will benefit for thisrecent update to deepen their understanding of mammalian cellular organization. We introduce thecontents of FANTOM5 here, report recent updates in the web resource and provide future perspectives.", "metadata": {}}
+{"_id": "11254040", "title": "", "text": "Adverse Events Associated With the Treatment of Multidrug-Resistant Tuberculosis: A Systematic Reviewand Meta-analysis.Multidrug-resistant tuberculosis (MDR-TB) is a growing public health problem. Due tolong duration of therapy and concurrent use of multiple second-line drugs, adverse drug events (ADEs)are regarded as the most important clinical consideration in patients undergoing anti-MDR-TB treatment.To evaluate the frequency and type of treatment-related ADEs owing to MDR-TB therapy. The CochraneLibrary, MEDLINE, and EMBASE were searched from inception through October 1, 2012, with additionalmanual search of International Journal of Tuberculosis and Lung Disease. Studies with available ADEswere selected if MDR-TB patients were treated with regimen including second-line drugs. Pooledestimations of incidence for each specific type of ADEs were calculated with 95% confidence intervalsusing random-effects model. Of the 5346 patients included, 2602 (57.3%) experienced at least 1 kind ofADE. The 3 most common side effects were gastrointestinal disorders (32.1%), ototoxicity (14.6%), andpsychiatric disorders (13.2%). Subgroup analyses based on each characteristic (study population,previous tuberculosis treated, human immunodeficiency virus prevalence, and length of treatment) didnot show any significant difference between groups. Additionally, among 1519 patients who developedADEs with available data of impact on MDR-TB therapy, 70.4% required change of MDR-TB treatment.Adverse events were common among MDR-TB cases, occurring in more than half of the cases, with overtwo-thirds requiring change of anti-MDR-TB treatment. MDR-TB patients should be monitored closely andmanaged aggressively for side effects during therapy, especially for ototoxicity and psychiatric disorders.", "metadata": {}}
+{"_id": "11254556", "title": "", "text": "Presynaptically Localized Cyclic GMP-Dependent Protein Kinase 1 Is a Key Determinant of Spinal SynapticPotentiation and Pain HypersensitivitySynaptic long-term potentiation (LTP) at spinal neurons directlycommunicating pain-specific inputs from the periphery to the brain has been proposed to serve as atrigger for pain hypersensitivity in pathological states. Previous studies have functionally implicated theNMDA receptor-NO pathway and the downstream second messenger, cGMP, in these processes. BecausecGMP can broadly influence diverse ion-channels, kinases, and phosphodiesterases, pre- as well aspost-synaptically, the precise identity of cGMP targets mediating spinal LTP, their mechanisms of action,and their locus in the spinal circuitry are still unclear. Here, we found that Protein Kinase G1 (PKG-I)localized presynaptically in nociceptor terminals plays an essential role in the expression of spinal LTP.Using the Cre-lox P system, we generated nociceptor-specific knockout mice lacking PKG-I specifically inpresynaptic terminals of nociceptors in the spinal cord, but not in post-synaptic neurons or elsewhere(SNS-PKG-I(-/-) mice). Patch clamp recordings showed that activity-induced LTP at identified synapsesbetween nociceptors and spinal neurons projecting to the periaqueductal grey (PAG) was completelyabolished in SNS-PKG-I(-/-) mice, although basal synaptic transmission was not affected. Analyses ofsynaptic failure rates and paired-pulse ratios indicated a role for presynaptic PKG-I in regulating theprobability of neurotransmitter release. Inositol 1,4,5-triphosphate receptor 1 and myosin light chainkinase were recruited as key phosphorylation targets of presynaptic PKG-I in nociceptive neurons. Finally,behavioural analyses in vivo showed marked defects in SNS-PKG-I(-/-) mice in several models ofactivity-induced nociceptive hypersensitivity, and pharmacological studies identified a clear contributionof PKG-I expressed in spinal terminals of nociceptors. Our results thus indicate that presynapticmechanisms involving an increase in release probability from nociceptors are operational in theexpression of synaptic LTP on spinal-PAG projection neurons and that PKG-I localized in presynapticnociceptor terminals plays an essential role in this process to regulate pain sensitivity.", "metadata": {}}
+{"_id": "11255504", "title": "", "text": "A Sleeping Beauty mutagenesis screen reveals a tumor suppressor role for Ncoa2/Src-2 in livercancer.The Sleeping Beauty (SB) transposon mutagenesis system is a powerful tool that facilitates thediscovery of mutations that accelerate tumorigenesis. In this study, we sought to identify mutations thatcooperate with MYC, one of the most commonly dysregulated genes in human malignancy. We performeda forward genetic screen with a mouse model of MYC-induced liver cancer using SB-mediatedmutagenesis. We sequenced insertions in 63 liver tumor nodules and identified at least 16 genes/loci thatcontribute to accelerated tumor development. RNAi-mediated knockdown in a liver progenitor cell linefurther validate three of these genes, Ncoa2/Src-2, Zfx, and Dtnb, as tumor suppressors in liver cancer.Moreover, deletion of Ncoa2/Src-2 in mice predisposes to diethylnitrosamine-induced liver tumorigenesis.These findings reveal genes and pathways that functionally restrain MYC-mediated liver tumorigenesisand therefore may provide targets for cancer therapy.", "metadata": {}}
+{"_id": "11256632", "title": "", "text": "Protein-Protein Interaction Inhibition (2P2I)-Oriented Chemical Library Accelerates HitDiscovery.Protein-protein interactions (PPIs) represent an enormous source of opportunity for therapeuticintervention. We and others have recently pinpointed key rules that will help in identifying the nextgeneration of innovative drugs to tackle this challenging class of targets within the next decade. We usedthese rules to design an oriented chemical library corresponding to a set of diverse \"PPI-like\" modulatorswith cores identified as privileged structures in therapeutics. In this work, we purchased the resulting1664 structurally diverse compounds and evaluated them on a series of representative protein-proteininterfaces with distinct \"druggability\" potential using homogeneous time-resolved fluorescence (HTRF)technology. For certain PPI classes, analysis of the hit rates revealed up to 100 enrichment factorscompared with nonoriented chemical libraries. This observation correlates with the predicted\"druggability\" of the targets. A specific focus on selectivity profiles, the three-dimensional (3D) molecularmodes of action resolved by X-ray crystallography, and the biological activities of identified hits targetingthe well-defined \"druggable\" bromodomains of the bromo and extraterminal (BET) family are presentedas a proof-of-concept. Overall, our present study illustrates the potency of machine learning-basedoriented chemical libraries to accelerate the identification of hits targeting PPIs. A generalization of thismethod to a larger set of compounds will accelerate the discovery of original and potent probes for thischallenging class of targets.", "metadata": {}}
+{"_id": "11271123", "title": "", "text": "Molecular characterization of endometrial cancer: a correlative study assessing microsatellite instability,MLH1 hypermethylation, DNA mismatch repair protein expression, and PTEN, PIK3CA, KRAS, and BRAFmutation analysis.Endometrial cancer is associated with numeric and structural chromosomalabnormalities, microsatellite instability (MSI), and alterations that activate oncogenes and inactivatetumor suppressor genes. The aim of this study was to characterize a set of endometrial cancers usingmultiple molecular genetic and immunohistochemical techniques. Ninety-six cases were examined forgenomic alterations by MSI, MLH1 promoter hypermethylation, p53 and mismatch repair proteinexpression (MLH1, MSH2, MSH6, PMS2), and PTEN, PIK3CA, KRAS, and BRAF mutation analysis. At least1 alteration was identified in 48 of 87 (55%) specimens tested for PTEN, making it the most commonabnormality in this study. A PIK3CA alteration was observed in 16 (17%) specimens. Twenty-nine of 94(31%) MSI tested tumors exhibited an MSI-H phenotype. Of the 29 MSI-H cases, 24 (83%) were positivefor methylation of the MLH1 promoter region. Twenty-three (82%) of the 28 MSI-H cases withimmunohistochemistry results showed loss of expression of MLH1/PMS2 (n=19), MSH2/MSH6 (n=2), orMSH6 only (n=2). Of the 19 MSI-H cases with loss of MLH1/PMS2 on immunohistochemistry, 18 werepositive, and 1 was equivocal for MLH1 promoter hypermethylation. Twelve of 94 cases (13%) analyzedfor KRAS mutations were found to have a mutation. No BRAF V600E mutations were indentified. Thisstudy provides a comprehensive molecular genetic analysis of commonly analyzed targets in a largecohort of endometrial cancers.", "metadata": {}}
+{"_id": "11280569", "title": "", "text": "Identification of indole-3-carboxylic acid as mediator of priming against Plectosphaerellacucumerina.Plant resistance against the necrotrophic pathogen Plectosphaerella cucumerina is mediatedby a combination of several hormonal-controlled signalling pathways. The priming agent β-aminobutyricacid (BABA) is able to induce effective resistance against this pathogen by stimulating callose-rich cellwall depositions. In the present research it is demonstrated that BABA-Induced Resistance (BABA-IR)against P. cucumerina in Arabidopsis has additional components such as the induction of defencesmediated by indolic derivatives. Chromatographic approach for the detection and characterization ofmetabolites enhanced by BABA compared with water-treated plants only when the challenge is presenthas been developed. The metabolites matching this criteria are considered to be primed by BABA. Theanalytic procedure is based on the combination of liquid chromatography (LC) with a triple quadrupole(TQD) detector in a precursor ion scanning mode. Using this analytical system a signal in negativeelectro-spray mode of 160 m/z is primed by BABA in infected plants. A subsequent exact mass analysis ina quadrupole time-of-flight mass spectrometer demonstrated that this ion was the indole-derivativemetabolite indole-3-carboxylic acid (I3CA). The identity of indole-3-carboxilic acid was definitivelyconfirmed by comparing its retention time and fragmentation spectra with a commercial standard.Quantification of I3CA in primed plants showed that this indolic metabolite is specifically primed by BABAupon P. cucumerina infection, while other indolic compounds such as IAA and camalexin are not. Takingtogether these observations with the known role of callose in priming against this pathogen, suggeststhat priming is not a single mechanism but rather a multicomponent defence.", "metadata": {}}
+{"_id": "11288846", "title": "", "text": "Evaluation of networks of randomized trials.Randomized trials may be designed and interpreted as singleexperiments or they may be seen in the context of other similar or relevant evidence. The amount andcomplexity of available randomized evidence vary for different topics. Systematic reviews may be usefulin identifying gaps in the existing randomized evidence, pointing to discrepancies between trials, andplanning future trials. A new, promising, but also very much debated extension of systematic reviews,mixed treatment comparison (MTC) meta-analysis, has become increasingly popular recently. MTCmeta-analysis may have value in interpreting the available randomized evidence from networks of trialsand can rank many different treatments, going beyond focusing on simple pairwise-comparisons.Nevertheless, the evaluation of networks also presents special challenges and caveats. In this article, wereview the statistical methodology for MTC meta-analysis. We discuss the concept of inconsistency andmethods that have been proposed to evaluate it as well as the methodological gaps that remain. Weintroduce the concepts of network geometry and asymmetry, and propose metrics for the evaluation ofthe asymmetry. Finally, we discuss the implications of inconsistency, network geometry and asymmetryin informing the planning of future trials.", "metadata": {}}
+{"_id": "11289247", "title": "", "text": "Metabolic regulation by the mitochondrial phosphatase PTPMT1 is required for hematopoietic stem celldifferentiation.The regulation and coordination of mitochondrial metabolism with hematopoietic stem cell(HSC) self-renewal and differentiation is not fully understood. Here we report that depletion of PTPMT1, aPTEN-like mitochondrial phosphatase, in inducible or hematopoietic-cell-specific knockout mice resultedin hematopoietic failure due to changes in the cell cycle and a block in the differentiation of HSCs.Surprisingly, the HSC pool was increased by \u000040-fold in PTPMT1 knockout mice. Reintroduction ofwild-type PTPMT1, but not catalytically deficient PTPMT1 or truncated PTPMT1 lacking mitochondriallocalization, restored differentiation capabilities of PTPMT1 knockout HSCs. Further analysesdemonstrated that PTPMT1 deficiency altered mitochondrial metabolism and that phosphatidylinositolphosphate substrates of PTPMT1 directly enhanced fatty-acid-induced activation of mitochondrialuncoupling protein 2. Intriguingly, depletion of PTPMT1 from myeloid, T lymphoid, or B lymphoidprogenitors did not cause any defects in lineage-specific knockout mice. This study establishes a crucialrole of PTPMT1 in the metabolic regulation of HSC function.", "metadata": {}}
+{"_id": "11291348", "title": "", "text": "GSK-3-mediated phosphorylation enhances Maf-transforming activity.The Maf oncoproteins are b-Ziptranscription factors of the AP-1 superfamily. They are involved in developmental, metabolic, andtumorigenic processes. Maf proteins are overexpressed in about 50% of human multiple myelomas. Here,we show that Maf-transforming activity is controlled by GSK-3-dependent phosphorylation and thatphosphorylation by GSK-3 can increase the oncogenic activity of a protein. Using microarray analysis, weidentify a gene-expression subprogram regulated by GSK-3-mediated Maf phosphorylation involved inextracellular matrix remodeling and relevant to cancer progression. We also demonstrate that GSK-3triggers MafA sequential phosphorylation on residues S61, T57, T53, and S49, inducing its ubiquitinationand degradation. Paradoxically, this phosphorylation increases MafA-transcriptional activity through therecruitment of the coactivator P/CAF. We further demonstrate that P/CAF protects MafA fromubiquitination and degradation, suggesting that, upon the release of the coactivator complex, MafAbecomes polyubiquitinated and degraded to allow the response to terminate.", "metadata": {}}
+{"_id": "11328820", "title": "", "text": "NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoidarthritis.The early events leading to the development of rheumatoid arthritis (RA) remain unclear, butformation of autoantibodies to citrullinated protein antigens (ACPAs) is considered a key pathogenicevent. Neutrophils isolated from patients with various autoimmune diseases display enhanced neutrophilextracellular trap (NET) formation, a phenomenon that exposes autoantigens in the context ofimmunostimulatory molecules. We investigated whether aberrant NETosis occurs in RA, determined itstriggers, and examined its deleterious inflammatory consequences. Enhanced NETosis was observed incirculating and RA synovial fluid neutrophils compared to neutrophils from healthy controls and frompatients with osteoarthritis (OA). Further, netting neutrophils infiltrated RA synovial tissue, rheumatoidnodules, and skin. NETosis correlated with ACPA presence and levels and with systemic inflammatorymarkers. RA sera and immunoglobulin fractions from RA patients with high levels of ACPA and/orrheumatoid factor significantly enhanced NETosis, and the NETs induced by these autoantibodiesdisplayed distinct protein content. Indeed, during NETosis, neutrophils externalized the citrullinatedautoantigens implicated in RA pathogenesis, and anti-citrullinated vimentin antibodies potently inducedNET formation. Moreover, the inflammatory cytokines interleukin-17A (IL-17A) and tumor necrosisfactor-α (TNF-α) induced NETosis in RA neutrophils. In turn, NETs significantly augmented inflammatoryresponses in RA and OA synovial fibroblasts, including induction of IL-6, IL-8, chemokines, and adhesionmolecules. These observations implicate accelerated NETosis in RA pathogenesis, through externalizationof citrullinated autoantigens and immunostimulatory molecules that may promote aberrant adaptive andinnate immune responses in the joint and in the periphery, and perpetuate pathogenic mechanisms inthis disease.", "metadata": {}}
+{"_id": "11335781", "title": "", "text": "Is autoimmunity the Achilles' heel of cancer immunotherapy?The emergence of immuno-oncology as thefirst broadly successful strategy for metastatic cancer will require clinicians to integrate this new pillar ofmedicine with chemotherapy, radiation, and targeted small-molecule compounds. Of equal importance isgaining an understanding of the limitations and toxicities of immunotherapy. Immunotherapy was initiallyperceived to be a relatively less toxic approach to cancer treatment than other available therapies—andsurely it is, when compared to those. However, as the use of immunotherapy becomes more common,especially as first- and second-line treatments, immunotoxicity and autoimmunity are emerging as theAchilles' heel of immunotherapy. In this Perspective, we discuss evidence that the occurrence ofimmunotoxicity bodes well for the patient, and describe mechanisms that might be related to theinduction of autoimmunity. We then explore approaches to limit immunotoxicity, and discuss the futuredirections of research and reporting that are needed to diminish it.", "metadata": {}}
+{"_id": "11335860", "title": "", "text": "Trophoblast differentiation defect in human embryonic stem cells lacking PIG-A and GPI-anchoredcell-surface proteins.Pluripotent human embryonic stem (hES) cells can differentiate into various celltypes derived from the three embryonic germ layers and extraembryonic tissues such as trophoblasts.The mechanisms governing lineage choices of hES cells are largely unknown. Here, we report that weestablished two independent hES cell clones lacking a group of cell surface molecules,glycosyl-phosphatidyl-inositol-anchored proteins (GPI-APs). The GPI-AP deficiency in these two hESclones is due to the deficiency in the gene expression of PIG-A (phosphatidyl-inositol-glycan class A),which is required for the first step of GPI synthesis. GPI-AP-deficient hES cells were capable of formingembryoid bodies and initiating cell differentiation into the three embryonic germ layers. However,GPI-AP-deficient hES cells failed to form trophoblasts after differentiation induction by embryoid bodyformation or by adding exogenous BMP4. The defect in trophoblast formation was due to the lack ofGPI-anchored BMP coreceptors, resulting in the impairment of full BMP4 signaling activation in theGPI-AP-deficient hES cells. These data reveal that GPI-AP-enhanced full activation of BMP signaling isrequired for human trophoblast formation.", "metadata": {}}
+{"_id": "11336632", "title": "", "text": "CRISPR Interference Limits Horizontal Gene Transfer in Staphylococci by Targeting DNAHorizontal genetransfer (HGT) in bacteria and archaea occurs through phage transduction, transformation, orconjugation, and the latter is particularly important for the spread of antibiotic resistance. Clustered,regularly interspaced, short palindromic repeat (CRISPR) loci confer sequence-directed immunity againstphages. A clinical isolate of Staphylococcus epidermidis harbors a CRISPR spacer that matches thenickase gene present in nearly all staphylococcal conjugative plasmids. Here we show that CRISPRinterference prevents conjugation and plasmid transformation in S. epidermidis. Insertion of aself-splicing intron into nickase blocks interference despite the reconstitution of the target sequence inthe spliced mRNA, which indicates that the interference machinery targets DNA directly. We conclude thatCRISPR loci counteract multiple routes of HGT and can limit the spread of antibiotic resistance inpathogenic bacteria.", "metadata": {}}
+{"_id": "11344428", "title": "", "text": "Development of leukemia in donor cells after allogeneic stem cell transplantation--a survey of theEuropean Group for Blood and Marrow Transplantation (EBMT).Leukemia in donor cells (donor cellleukemia; DCL) has been reported as a rare but severe complication of allogeneic stem celltransplantation (SCT). However, the incidence, potential pathogenetic factors, therapeutic options andoutcome of patients suffering from DCL and the leukemia risk of their donors are not well defined. Aquestionnaire survey was carried out within European Blood and Marrow Transplantation Group (EBMT)centers. Ninety-one EBMT centers participated in this survey, covering 10489 allogeneic SCT between12/1982 and 09/2003. Fourteen cases of DCL, most with a myeloid phenotype (7 cases of acute myeloidleukemia, 3 each of acute lymphocytic leukemia and 1 case of chronic myeloid leukemia) were identified.Demonstration of donor cell origin included molecular analysis of chimerism in most cases. DCL type andcytogenetic alterations were independent from the original disease. The median time betweentransplantation and diagnosis of DCL was 17 months (4-164). No type of conditioning, donor, graftmanipulation, graft-versus-host disease prophylaxis or subsequent complications were identified as riskfactors for DCL. Chemotherapy induced remissions in DCL and 2 of 5 patients remain alive in remissionafter a second transplant. None of the stem cell donors developed hematologic malignancies (medianfollow-up period of 9 years; range 6-30 years). DCL is an extremely rare complication of allogeneic SCTin which treatment attempts with chemotherapy and a second SCT are justified. Donors are not at anincreased risk of developing hematologic malignancies.", "metadata": {}}
+{"_id": "11349166", "title": "", "text": "Lack of evidence of transfusion transmission of Creutzfeldt-Jakob disease in a US surveillancestudy.BACKGROUND Since 2004, several reported transfusion transmissions of variant Creutzfeldt-Jakobdisease (vCJD) in the United Kingdom have reawakened concerns about the possible risk of similartransmissions of nonvariant or classic forms of CJD. STUDY DESIGN AND METHODS Patients with a CJDdiagnosis and a history of donating blood were reported to the study coordinator. Through review ofblood distribution and hospital records, the recipients of blood components from these donors wereidentified. We then determined each recipient's vital status and, if deceased, the cause(s) of deathidentified by matching the recipient's personal identifiers with the Centers for Disease Control andPrevention's National Death Index database. We conducted such searches after recipients were enrolledin this study and annually thereafter for those who remained alive. RESULTS The study included a total of36 blood donors who subsequently developed CJD and 436 recipients. Through 2006, 91 of theserecipients were still alive, 329 were deceased, and 16 were lost to follow-up. After transfusion, thesethree groups had survived a total of 2096.0 person-years. A total of 144 recipients survived 5 years orlonger after transfusion and 68 of them had received blood donated 60 or fewer months before the onsetof CJD in the donor. We identified no recipient with CJD. CONCLUSIONS The current results of this large,ongoing lookback study show no evidence of transfusion transmission of CJD. They reinforce theconclusion that the risk, if any, of transfusion transmission of prion disease by CJD donors is significantlylower than the comparable risk of such transmission by vCJD donors.", "metadata": {}}
+{"_id": "11359243", "title": "", "text": "Large-scale hypomethylated blocks associated with Epstein-Barr virus-induced B-cellimmortalization.Altered DNA methylation occurs ubiquitously in human cancer from the earliestmeasurable stages. A cogent approach to understanding the mechanism and timing of altered DNAmethylation is to analyze it in the context of carcinogenesis by a defined agent. Epstein-Barr virus (EBV)is a human oncogenic herpesvirus associated with lymphoma and nasopharyngeal carcinoma, but alsoused commonly in the laboratory to immortalize human B-cells in culture. Here we have performedwhole-genome bisulfite sequencing of normal B-cells, activated B-cells, and EBV-immortalized B-cellsfrom the same three individuals, in order to identify the impact of transformation on the methylome.Surprisingly, large-scale hypomethylated blocks comprising two-thirds of the genome were induced byEBV immortalization but not by B-cell activation per se. These regions largely corresponded tohypomethylated blocks that we have observed in human cancer, and they were associated withgene-expression hypervariability, similar to human cancer, and consistent with a model of epigenomicchange promoting tumor cell heterogeneity. We also describe small-scale changes in DNA methylationnear CpG islands. These results suggest that methylation disruption is an early and critical step inmalignant transformation.", "metadata": {}}
+{"_id": "11360430", "title": "", "text": "Stem cell self-renewal specified by JAK-STAT activation in response to a support cell cue.Stem cellsgenerate many differentiated, short-lived cell types, such as blood, skin, and sperm, throughout adultlife. Stem cells maintain a long-term capacity to divide, producing daughter cells that either self-renew orinitiate differentiation. Although the surrounding microenvironment or \"niche\" influences stem cell fatedecisions, few signals that emanate from the niche to specify stem cell self-renewal have been identified.Here we demonstrate that the apical hub cells in the Drosophila testis act as a cellular niche that supportsstem cell self-renewal. Hub cells express the ligand Unpaired (Upd), which activates the Januskinase-signal transducer and activator of transcription (JAK-STAT) pathway in adjacent germ cells tospecify self-renewal and continual maintenance of the germ line stem cell population.", "metadata": {}}
+{"_id": "11360768", "title": "", "text": "Effects of interventions in pregnancy on maternal weight and obstetric outcomes: meta-analysis ofrandomised evidenceOBJECTIVE To evaluate the effects of dietary and lifestyle interventions in pregnancyon maternal and fetal weight and to quantify the effects of these interventions on obstetric outcomes.DESIGN Systematic review and meta-analysis. DATA SOURCES Major databases from inception toJanuary 2012 without language restrictions. STUDY SELECTION Randomised controlled trials thatevaluated any dietary or lifestyle interventions with potential to influence maternal weight duringpregnancy and outcomes of pregnancy. DATA SYNTHESIS Results summarised as relative risks fordichotomous data and mean differences for continuous data. RESULTS We identified 44 relevantrandomised controlled trials (7278 women) evaluating three categories of interventions: diet, physicalactivity, and a mixed approach. Overall, there was 1.42 kg reduction (95% confidence interval 0.95 to1.89 kg) in gestational weight gain with any intervention compared with control. With all interventionscombined, there were no significant differences in birth weight (mean difference -50 g, -100 to 0 g) andthe incidence of large for gestational age (relative risk 0.85, 0.66 to 1.09) or small for gestational age(1.00, 0.78 to 1.28) babies between the groups, though by itself physical activity was associated withreduced birth weight (mean difference -60 g, -120 to -10 g). Interventions were associated with areduced the risk of pre-eclampsia (0.74, 0.60 to 0.92) and shoulder dystocia (0.39, 0.22 to 0.70), withno significant effect on other critically important outcomes. Dietary intervention resulted in the largestreduction in maternal gestational weight gain (3.84 kg, 2.45 to 5.22 kg), with improved pregnancyoutcomes compared with other interventions. The overall evidence rating was low to very low forimportant outcomes such as pre-eclampsia, gestational diabetes, gestational hypertension, and pretermdelivery. CONCLUSIONS Dietary and lifestyle interventions in pregnancy can reduce maternal gestationalweight gain and improve outcomes for both mother and baby. Among the interventions, those based ondiet are the most effective and are associated with reductions in maternal gestational weight gain andimproved obstetric outcomes.", "metadata": {}}
+{"_id": "11369420", "title": "", "text": "Tetraspanin 3 Is Required for the Development and Propagation of Acute Myelogenous Leukemia.AcuteMyelogenous Leukemia (AML) is an aggressive cancer that strikes both adults and children and isfrequently resistant to therapy. Thus, identifying signals needed for AML propagation is a critical steptoward developing new approaches for treating this disease. Here, we show that Tetraspanin 3 is a targetof the RNA binding protein Musashi 2, which plays a key role in AML. We generated Tspan3 knockoutmice that were born without overt defects. However, Tspan3 deletion impaired leukemia stem cellself-renewal and disease propagation and markedly improved survival in mouse models of AML.Additionally, Tspan3 inhibition blocked growth of AML patient samples, suggesting that Tspan3 is alsoimportant in human disease. As part of the mechanism, we show that Tspan3 deficiency disabledresponses to CXCL12/SDF-1 and led to defects in AML localization within the niche. These identify Tspan3as an important regulator of aggressive leukemias and highlight a role for Tspan3 in oncogenesis.", "metadata": {}}
+{"_id": "11390393", "title": "", "text": "Reorganization of enhancer patterns in transition from naive to primed pluripotency.Naive and primedpluripotency is characterized by distinct signaling requirements, transcriptomes, and developmentalproperties, but both cellular states share key transcriptional regulators: Oct4, Sox2, and Nanog. Here, wedemonstrate that transition between these two pluripotent states is associated with widespread Oct4relocalization, mirrored by global rearrangement of enhancer chromatin landscapes. Our genomic andbiochemical analyses identified candidate mediators of primed state-specific Oct4 binding, including Otx2and Zic2/3. Even when differentiation cues are blocked, premature Otx2 overexpression is sufficient toexit the naive state, induce transcription of a substantial subset of primed pluripotency-associated genes,and redirect Oct4 to previously inaccessible enhancer sites. However, the ability of Otx2 to engage newenhancer regions is determined by its levels, cis-encoded properties of the sites, and the signalingenvironment. Our results illuminate regulatory mechanisms underlying pluripotency and suggest that thecapacity of transcription factors such as Otx2 and Oct4 to pioneer new enhancer sites is highly contextdependent.", "metadata": {}}
+{"_id": "11401602", "title": "", "text": "Topoisomerase II plays an essential role as a swivelase in the late stage of SV40 chromosome replicationin vitro.The effects of topoisomerases I and II on the replication of SV40 DNA were examined using an invitro replication system of purified proteins that constitutes the monopolymerase system. In the presenceof the two topoisomerases, two distinct nascent DNAs were formed. One product arising from thereplication of the leading template strand was approximately half the size of the template DNA, whereasthe other product derived from the lagging template strand consisted of short DNAs. These products weresynthesized from both SV40 naked DNA and SV40 chromosomes. For the replication of SV40 naked DNA,either topoisomerase I or II maintained replication fork movement and supported complete leadingstrand synthesis. When SV40 chromosomes were replicated with the same proteins, reactions containingonly topoisomerase I produced shorter leading strands. However, mature size DNA products accumulatedin reactions supplemented with topoisomerase II, as well as in reactions containing only topoisomeraseII. In the presence of crude extracts of HeLa cells, VP-16, a specific inhibitor of topoisomerase II, blockedelongation of the nascent DNA during the replication of SV40 chromosomes. These results indicate thattopoisomerase II plays a crucial role as a swivelase in the late stage of SV40 chromosome replication invitro.", "metadata": {}}
+{"_id": "11411060", "title": "", "text": "Bromodomain Proteins Contribute to Maintenance of Bloodstream Form Stage Identity in the AfricanTrypanosomeTrypanosoma brucei, the causative agent of African sleeping sickness, is transmitted to itsmammalian host by the tsetse. In the fly, the parasite's surface is covered with invariant procyclin, whilein the mammal it resides extracellularly in its bloodstream form (BF) and is densely covered with highlyimmunogenic Variant Surface Glycoprotein (VSG). In the BF, the parasite varies this highly immunogenicsurface VSG using a repertoire of ~2500 distinct VSG genes. Recent reports in mammalian systems pointto a role for histone acetyl-lysine recognizing bromodomain proteins in the maintenance of stem cell fate,leading us to hypothesize that bromodomain proteins may maintain the BF cell fate in trypanosomes.Using small-molecule inhibitors and genetic mutants for individual bromodomain proteins, we performedRNA-seq experiments that revealed changes in the transcriptome similar to those seen in cellsdifferentiating from the BF to the insect stage. This was recapitulated at the protein level by theappearance of insect-stage proteins on the cell surface. Furthermore, bromodomain inhibition disruptstwo major BF-specific immune evasion mechanisms that trypanosomes harness to evade mammalianhost antibody responses. First, monoallelic expression of the antigenically varied VSG is disrupted.Second, rapid internalization of antibodies bound to VSG on the surface of the trypanosome is blocked.Thus, our studies reveal a role for trypanosome bromodomain proteins in maintaining bloodstream stageidentity and immune evasion. Importantly, bromodomain inhibition leads to a decrease in virulence in amouse model of infection, establishing these proteins as potential therapeutic drug targets fortrypanosomiasis. Our 1.25Å resolution crystal structure of a trypanosome bromodomain in complex withI-BET151 reveals a novel binding mode of the inhibitor, which serves as a promising starting point forrational drug design.", "metadata": {}}
+{"_id": "11414664", "title": "", "text": "Timing requirements for insulin/IGF-1 signaling in C. elegans.The insulin/IGF-1 (where IGF-1 isinsulin-like growth factor-1) signaling pathway influences longevity, reproduction, and diapause in manyorganisms. Because of the fundamental importance of this system in animal physiology, we asked whenduring the animal's life it is required to regulate these different processes. We find that in Caenorhabditiselegans, the pathway acts during adulthood, to relatively advanced ages, to influence aging. In contrast,it regulates diapause during development. In addition, the pathway controls longevity and reproductionindependently of one another. Together our findings show that life-span regulation can be dissociatedtemporally from phenotypes that might seem to decrease the quality of life.", "metadata": {}}
+{"_id": "11415809", "title": "", "text": "Predominance of Type 1 Innate Lymphoid Cells in the Rectal Mucosa of Patients With Non-Celiac WheatSensitivity: Reversal After a Wheat-Free DietOBJECTIVES Non-celiac wheat sensitivity (NCWS) is definedas a reaction to ingested wheat after exclusion of celiac disease and wheat allergy. As its pathogenesis isincompletely understood, we evaluated the inflammatory response in the rectal mucosa of patients withwell-defined NCWS. METHODS The prospective study included 22 patients with irritable bowel syndrome(IBS)-like clinical presentation, diagnosed with NCWS by double-blind placebo-controlled challenge. EightIBS patients not improving on wheat-free diet were used as controls. Two weeks after oral challenge wasperformed with 80 grams of wheat daily, cells were isolated from rectal biopsies and thoroughlycharacterized by fluorescence-activated cell sorting analysis for intracellular cytokines and surfacemarkers. RESULTS Rectal biopsies from wheat-challenged NCWS patients showed that a significantmucosal CD45(+) infiltrate consisted of CD3(+) and CD3(-) lymphocytes, with the latter spontaneouslyproducing more interferon (IFN)-γ than IBS controls. About 30% of IFN-γ-producing CD45(+) cells wereT-bet(+), CD56(-), NKP44(-), and CD117(-), defining them as a type-1 innate lymphoid cells (ILC1).IFN-γ-producing ILC1 cells significantly decreased in 10 patients analyzed 2 weeks after they resumed awheat-free diet. CONCLUSIONS These data indicate that, in patients with active NCWS, IFN-γ-producingILC1 cells infiltrate rectal mucosa and support a role for this innate lymphoid cell population in thepathogenesis of NCWS.", "metadata": {}}
+{"_id": "11419230", "title": "", "text": "Folding and Self-Assembly of the TatA Translocation Pore Based on a Charge Zipper MechanismWepropose a concept for the folding and self-assembly of the pore-forming TatA complex from theTwin-arginine translocase and of other membrane proteins based on electrostatic \"charge zippers. \" Eachsubunit of TatA consists of a transmembrane segment, an amphiphilic helix (APH), and a C-terminaldensely charged region (DCR). The sequence of charges in the DCR is complementary to the chargepattern on the APH, suggesting that the protein can be \"zipped up\" by a ladder of seven salt bridges. Thelength of the resulting hairpin matches the lipid bilayer thickness, hence a transmembrane pore couldself-assemble via intra- and intermolecular salt bridges. The steric feasibility was rationalized bymolecular dynamics simulations, and experimental evidence was obtained by monitoring themonomer-oligomer equilibrium of specific charge mutants. Similar \"charge zippers\" are proposed forother membrane-associated proteins, e.g., the biofilm-inducing peptide TisB, the human antimicrobialpeptide dermcidin, and the pestiviral E(RNS) protein.", "metadata": {}}
+{"_id": "11420613", "title": "", "text": "Molecular mechanisms of ribosomal protein gene coregulation.The 137 ribosomal protein genes (RPGs) ofSaccharomyces provide a model for gene coregulation. We examined the positional and functionalorganization of their regulators (Rap1 [repressor activator protein 1], Fhl1, Ifh1, Sfp1, and Hmo1), thetranscription machinery (TFIIB, TFIID, and RNA polymerase II), and chromatin at near-base-pairresolution using ChIP-exo, as RPGs are coordinately reprogrammed. Where Hmo1 is enriched, Fhl1, Ifh1,Sfp1, and Hmo1 cross-linked broadly to promoter DNA in an RPG-specific manner and demarcated bygeneral minor groove widening. Importantly, Hmo1 extended 20-50 base pairs (bp) downstream fromFhl1. Upon RPG repression, Fhl1 remained in place. Hmo1 dissociated, which was coupled to an upstreamshift of the +1 nucleosome, as reflected by the Hmo1 extension and core promoter region. Fhl1 andHmo1 may create two regulatable and positionally distinct barriers, against which chromatin remodelersposition the +1 nucleosome into either an activating or a repressive state. Consistent with in vitrostudies, we found that specific TFIID subunits, in addition to cross-linking at the core promoter, madeprecise cross-links at Rap1 sites, which we interpret to reflect native Rap1-TFIID interactions. Ourfindings suggest how sequence-specific DNA binding regulates nucleosome positioning and transcriptioncomplex assembly >300 bp away and how coregulation coevolved with coding sequences.", "metadata": {}}
+{"_id": "11428884", "title": "", "text": "Lipoatrophy and severe metabolic disturbance in mice with fat-specific deletion of PPARγ.Adipose tissue isan important metabolic organ, the dysfunction of which is associated with the development of obesity,diabetes mellitus, and cardiovascular disease. The nuclear receptor peroxisome proliferator-activatedreceptor gamma (PPARγ) is considered the master regulator of adipocyte differentiation and function.Although its cell-autonomous role in adipogenesis has been clearly demonstrated in cell culture, previousfat-specific knockouts of the murine PPARγ gene did not demonstrate a dramatic phenotype in vivo. Here,using Adipoq-Cre mice to drive adipose-specific recombination, we report a unique fat-specific PPARγknockout (PPARγ FKO) mouse model with almost no visible brown and white adipose tissue at age 3 mo.As a consequence, PPARγ FKO mice had hugely enlarged pancreatic islets, massive fatty livers, anddramatically elevated levels of blood glucose and serum insulin accompanied by extreme insulinresistance. PPARγ FKO mice also exhibited delayed hair coat formation associated with absence of dermalfat, disrupted mammary gland development with loss of mammary fat pads, and high bone mass withloss of bone marrow fat, indicating the critical roles of adipose PPARγ in these tissues. Together, our datareveal the necessity of fat PPARγ in adipose formation, whole-body metabolic homeostasis, and normaldevelopment of fat-containing tissues.", "metadata": {}}
+{"_id": "11441172", "title": "", "text": "Fluconazole prophylaxis: can we eliminate invasive Candida infections in the neonatal ICU?PURPOSE OFREVIEW Owing to the high mortality, risk of neurodevelopmental impairment and end-organ involvementwith fungal infections in the neonate, prevention of invasive Candida infections in extremely preterminfants should be a priority for each neonatal ICU. RECENT FINDINGS Even with prompt or empirictreatment, mortality and neurodevelopmental impairment is high (57%) in infants <1000 g. Multiplestudies have been performed with fluconazole prophylaxis, including a recent multicenter randomizedcontrolled trial. All of the studies have demonstrated efficacy and safety with no increase or emergence offungal resistance. Analysis of these studies demonstrates that fluconazole prophylaxis decreased theincidence of invasive Candida infections in high-risk infants <1000 g by 91% (P = 0.0004) and all infants<1500 g by 85% (P < 0.0001). The mortality rate from all causes was 25% lower (P = 0.029).Furthermore, studies have demonstrated that all Candida-related mortality can be eliminated in an entireneonatal ICU by targeting fluconazole prophylaxis in infants <1000 g.   SUMMARY Targeting fluconazoleprophylaxis to infants who are either <1000 g or < or =27 weeks is highly effective, safe andinexpensive, and can eliminate these infections as a cause of neurodevelopmental impairment andmortality.", "metadata": {}}
+{"_id": "11457219", "title": "", "text": "Fumarase deficiency in dichorionic diamniotic twins.Fumarase deficiency is a rare autosomal recessiveinborn error of metabolism of the Krebs Tricarboxylic Acid cycle. A heavy neurological disease burden isimparted by fumarase deficiency, commonly manifesting as microcephaly, dystonia, global developmentaldelay, seizures, and lethality in the infantile period. Heterozygous carriers also carry an increased risk ofdeveloping hereditary leiomyomatosis and renal cell carcinoma. We describe a non-consanguineousfamily in whom a dichorionic diamniotic twin pregnancy resulted in twin boys with fumarase deficiencyproven at the biochemical, enzymatic, and molecular levels. Their clinical phenotype included hepaticinvolvement. A novel mutation in the fumarate hydratase gene was identified in this family.", "metadata": {}}
+{"_id": "11459139", "title": "", "text": "Angiopoietin-2 is increased in sepsis and inversely associated with nitric oxide-dependent microvascularreactivityINTRODUCTION Angiopoietin-2 (ang-2), an angiogenic peptide released by endothelial cellWeibel-Palade bodies (WPBs), increases endothelial activation and vascular permeability. Ang-2 is raisedin severe sepsis but the mechanisms underlying this are not known. Nitric oxide (NO) inhibits WPBexocytosis, and bioavailability of endothelial NO is decreased in sepsis. We hypothesized that endothelialNO bioavailability would be inversely correlated with ang-2 concentrations in sepsis. METHODS Plasmaang-2, vascular endothelial growth factor (VEGF) and endothelial-active cytokines were assessed in 83patients with early sepsis and 41 hospital controls, and related to reactive hyperaemia-peripheral arterialtonometry, RH-PAT, a measure of endothelial NO bioavailability. RESULTS Plasma Ang-2 was elevated insepsis (median [interquartile range (IQR)], ng/ml: severe sepsis 12.4 [8.5-33.4], sepsis without organfailure 6.1 [5.0-10.4], controls 2.7 [2.2-3.6], P < 0.0001). It correlated inversely with RH-PAT (r = -0.38,P < 0.0001) and positively with IL-6 (r = 0.57, P < 0.0001) and degree of organ failure (sequential organfunction assessment score) (r = 0.58, P < 0.0001). The correlation of ang-2 with RH-PAT persisted aftercontrolling for sepsis severity. In a longitudinal mixed-effects model, recovery of RH-PAT over time wasassociated with decline in ang-2. CONCLUSIONS Ang-2 is elevated in proportion to sepsis severity, andinversely correlated with NO-dependent microvascular reactivity. Impaired endothelial NO bioavailabilitymay contribute to increased endothelial cell release of ang-2, endothelial activation and capillary leak.Agents that increase endothelial NO bioavailability or inhibit WPB exocytosis and/or Ang-2 activity mayhave therapeutic potential in sepsis.", "metadata": {}}
+{"_id": "11469078", "title": "", "text": "Ecologic versus individual-level sources of bias in ecologic estimates of contextual health effects.Anumber of authors have attempted to defend ecologic (aggregate) studies by claiming that the goal ofthose studies is estimation of ecologic (contextual or group-level) effects rather than individual-leveleffects. Critics of these attempts point out that ecologic effect estimates are inevitably used as estimatesof individual effects, despite disclaimers. A more subtle problem is that ecologic variation in thedistribution of individual effects can bias ecologic estimates of contextual effects. The conditions leadingto this bias are plausible and perhaps even common in studies of ecosocial factors and health outcomesbecause social context is not randomized across typical analysis units (administrative regions). Bydefinition, ecologic data contain only marginal observations on the joint distribution of individually definedconfounders and outcomes, and so identify neither contextual nor individual-level effects. While ecologicstudies can still be useful given appropriate caveats, their problems are better addressed by multilevelstudy designs, which obtain and use individual as well as group-level data. Nonetheless, such studiesoften share certain special problems with ecologic studies, including problems due to inappropriateaggregation and problems due to temporal changes in covariate distributions.", "metadata": {}}
+{"_id": "11475379", "title": "", "text": "Left–right asymmetry in the vertebrate embryo: from early information to higher-levelintegrationAlthough vertebrates seem to be essentially bilaterally symmetrical on the exterior, there arenumerous interior left–right asymmetries in the disposition and placement of internal organs. Theseasymmetries are established during embryogenesis by complex epigenetic and genetic cascades. Recentstudies in a range of model organisms have made important progress in understanding how this lateralityinformation is generated and conveyed to large regions of the embryo. Both commonalities anddivergences are emerging in the mechanisms that different vertebrates use in left–right axis specification.Recent evidence also provides intriguing links between the establishment of left–right asymmetries andthe symmetrical elongation of the anterior–posterior axis.", "metadata": {}}
+{"_id": "11481946", "title": "", "text": "Obesity, type 2 diabetes, and cancer: the insulin and IGF connection.Epidemiological studies suggest apositive association between obesity and type 2 diabetes mellitus (T2D) with the risk of cancer andcancer-related mortality. Insulin resistance, hyperinsulinemia, increased levels of IGF, elevated levels ofsteroid and peptide hormones, and inflammatory markers appear to play a role in the connectionbetween these different diseases. Medications, such as metformin and exogenous insulin, used to treatT2D may affect the risk of cancer and cancer-related mortality. Newer therapies targeting the insulin andIGF1 systems are being developed for use in cancer therapy.", "metadata": {}}
+{"_id": "11484808", "title": "", "text": "Non-coding RNAs: Functions and applications in endocrine-related cancer.A significant fraction of thehuman genome is transcribed as non-coding RNAs (ncRNAs). This non-coding transcriptome haschallenged the notion of the central dogma and its involvement in transcriptional and post-transcriptionalregulation of gene expression is well established. Interestingly, several ncRNAs are dysregulated incancer and current non-coding transcriptome research aims to use our increasing knowledge of thesencRNAs for the development of cancer biomarkers and anti-cancer drugs. In endocrine-related cancers,for which survival rates can be relatively low, there is a need for such advancements. In this review, weaimed to summarize the roles and clinical implications of recently discovered ncRNAs, including longncRNAs, PIWI-interacting RNAs, tRNA- and Y RNA-derived ncRNAs, and small nucleolar RNAs, inendocrine-related cancers affecting both sexes. We focus on recent studies highlighting discoveries inncRNA biology and expression in cancer, and conclude with a discussion on the challenges and futuredirections, including clinical application. ncRNAs show great promise as diagnostic tools and therapeutictargets, but further work is necessary to realize the potential of these unconventional transcripts.", "metadata": {}}
+{"_id": "11498670", "title": "", "text": "NMR structural and kinetic characterization of a homeodomain diffusing and hopping on nonspecificDNA.Nonspecific protein-DNA interactions are inherently dynamic and involve both diffusion of the proteinalong the DNA and hopping of the protein from one DNA molecule or segment to another. Understandinghow gene regulatory proteins interact nonspecifically with DNA in terms of both structure and dynamics ischallenging because the experimental observables are an ensemble average of many rapidly exchangingstates. By using a variety of NMR spectroscopic techniques, including relaxation analysis, paramagneticrelaxation enhancement, and residual dipolar couplings, we have characterized structural and kineticaspects of the interaction of the HoxD9 homeodomain with a nonspecific, 24-bp DNA duplex in a systemin which the protein is not constrained to any particular site. The data reveal that HoxD9 binds tononspecific DNA with the same binding mode and orientation as that observed in the specific complex.The mobility, however, of Arg side-chains contacting the DNA is increased in the nonspecific complexrelative to the specific one. The kinetics of intermolecular translocation between two different nonspecificDNA molecules have also been analyzed and reveal that at high DNA concentrations (such as thosepresent in vivo) direct transfer from one nonspecific complex to another nonspecific DNA molecule occurswithout going through the intermediary of free protein. This finding provides a simple mechanism foraccelerating the target search in vivo for the specific site in a sea of nonspecific sites by permitting moreeffective sampling of available DNA sites as the protein jumps from one segment to another.", "metadata": {}}
+{"_id": "11527199", "title": "", "text": "MHC Haplotype Matching for Unrelated Hematopoietic Cell TransplantationBackground  Current criteriafor the selection of unrelated donors for hematopoietic cell transplantation (HCT) include matching for thealleles of each human leukocyte antigen (HLA) locus within the major histocompatibility complex (MHC).Graft-versus-host disease (GVHD), however, remains a significant and potentially life-threateningcomplication even after HLA-identical unrelated HCT. The MHC harbors more than 400 genes, but thetotal number of transplantation antigens is unknown. Genes that influence transplantation outcome couldbe identified by using linkage disequilibrium (LD)-mapping approaches, if the extended MHC haplotypesof the unrelated donor and recipient could be defined.", "metadata": {}}
+{"_id": "11527822", "title": "", "text": "The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two differentmechanisms. Genes Dev 13The SIR genes are determinants of life span in yeast mother cells. Here weshow that life span regulation by the Sir proteins is independent of their role in nonhomologous endjoining. The short life span of a sir3 or sir4 mutant is due to the simultaneous expression of a and alphamating-type information, which indirectly causes an increase in rDNA recombination and likely increasesthe production of extrachromosomal rDNA circles. The short life span of a sir2 mutant also reveals adirect failure to repress recombination generated by the Fob1p-mediated replication block in the rDNA.Sir2p is a limiting component in promoting yeast longevity, and increasing the gene dosage extends thelife span in wild-type cells. A possible role of the conserved SIR2 in mammalian aging is discussed.", "metadata": {}}
+{"_id": "11532028", "title": "", "text": "Meta-analysis identifies common variants associated with body mass index in East AsiansMultiple geneticloci associated with obesity or body mass index (BMI) have been identified through genome-wideassociation studies conducted predominantly in populations of European ancestry. We performed ameta-analysis of associations between BMI and approximately 2.4 million SNPs in 27,715 east Asians,which was followed by in silico and de novo replication studies in 37,691 and 17,642 additional eastAsians, respectively. We identified ten BMI-associated loci at genome-wide significance (P < 5.0 ×10(-8)), including seven previously identified loci (FTO, SEC16B, MC4R, GIPR-QPCTL, ADCY3-DNAJC27,BDNF and MAP2K5) and three novel loci in or near the CDKAL1, PCSK1 and GP2 genes. Three additionalloci nearly reached the genome-wide significance threshold, including two previously identified loci in theGNPDA2 and TFAP2B genes and a newly identified signal near PAX6, all of which were associated withBMI with P < 5.0 × 10(-7). Findings from this study may shed light on new pathways involved in obesityand demonstrate the value of conducting genetic studies in non-European populations.", "metadata": {}}
+{"_id": "11532659", "title": "", "text": "Phosphorylation of histone H3(T118) alters nucleosome dynamics and remodelingNucleosomes, thefundamental units of chromatin structure, are regulators and barriers to transcription, replication andrepair. Post-translational modifications (PTMs) of the histone proteins within nucleosomes regulate theseDNA processes. Histone H3(T118) is a site of phosphorylation [H3(T118ph)] and is implicated inregulation of transcription and DNA repair. We prepared H3(T118ph) by expressed protein ligation anddetermined its influence on nucleosome dynamics. We find H3(T118ph) reduces DNA-histone binding by2  kcal/mol, increases nucleosome mobility by 28-fold and increases DNA accessibility near the dyadregion by 6-fold. Moreover, H3(T118ph) increases the rate of hMSH2-hMSH6 nucleosome disassemblyand enables nucleosome disassembly by the SWI/SNF chromatin remodeler. These studies suggest thatH3(T118ph) directly enhances and may reprogram chromatin remodeling reactions.", "metadata": {}}
+{"_id": "11535539", "title": "", "text": "Mechanosignaling through YAP and TAZ drives fibroblast activation and fibrosis.Pathological fibrosis isdriven by a feedback loop in which the fibrotic extracellular matrix is both a cause and consequence offibroblast activation. However, the molecular mechanisms underlying this process remain poorlyunderstood. Here we identify yes-associated protein (YAP) (homolog of drosophila Yki) and transcriptionalcoactivator with PDZ-binding motif (TAZ) (also known as Wwtr1), transcriptional effectors of the Hippopathway, as key matrix stiffness-regulated coordinators of fibroblast activation and matrix synthesis. YAPand TAZ are prominently expressed in fibrotic but not healthy lung tissue, with particularly pronouncednuclear expression of TAZ in spindle-shaped fibroblastic cells. In culture, both YAP and TAZ accumulate inthe nuclei of fibroblasts grown on pathologically stiff matrices but not physiologically compliant matrices.Knockdown of YAP and TAZ together in vitro attenuates key fibroblast functions, including matrixsynthesis, contraction, and proliferation, and does so exclusively on pathologically stiff matrices.Profibrotic effects of YAP and TAZ operate, in part, through their transcriptional target plasminogenactivator inhibitor-1, which is regulated by matrix stiffness independent of transforming growth factor-βsignaling. Immortalized fibroblasts conditionally expressing active YAP or TAZ mutant proteins overcomesoft matrix limitations on growth and promote fibrosis when adoptively transferred to the murine lung,demonstrating the ability of fibroblast YAP/TAZ activation to drive a profibrotic response in vivo.Together, these results identify YAP and TAZ as mechanoactivated coordinators of the matrix-drivenfeedback loop that amplifies and sustains fibrosis.", "metadata": {}}
+{"_id": "11557602", "title": "", "text": "Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXR alpha.LXR alpha is a nuclearreceptor that has previously been shown to regulate the metabolic conversion of cholesterol to bile acids.Here we define a role for this transcription factor in the control of cellular cholesterol efflux. Wedemonstrate that retroviral expression of LXR alpha in NIH 3T3 fibroblasts or RAW264.7 macrophagesand/or treatment of these cells with oxysterol ligands of LXR results in 7- to 30-fold induction of themRNA encoding the putative cholesterol/phospholipid transporter ATP-binding cassette (ABC)A1. Incontrast, induction of ABCA1 mRNA in response to oxysterols is attenuated in cells that constitutivelyexpress dominant-negative forms of LXR alpha or LXR beta that lack the AF2 transcriptional activationdomain. We further demonstrate that expression of LXR alpha in NIH 3T3 fibroblasts and/or treatment ofthese cells with oxysterols is sufficient to stimulate cholesterol efflux to extracellular apolipoprotein AI.The ability of oxysterol ligands of LXR to stimulate efflux is dramatically reduced in Tangier fibroblasts,which carry a loss of function mutation in the ABCA1 gene. Taken together, these results indicate thatcellular cholesterol efflux is controlled, at least in part, at the level of transcription by a nuclearreceptor-signaling pathway. They suggest a model in which activation of LXRs by oxysterols in responseto cellular sterol loading leads to induction of the ABCA1 transporter and the stimulation of lipid efflux toextracellular acceptors. These findings have important implications for our understanding of mammaliancholesterol homeostasis and suggest new opportunities for pharmacological regulation of cellular lipidmetabolism.", "metadata": {}}
+{"_id": "11565780", "title": "", "text": "Circadian regulation of intracellular G-protein signalling mediates intercellular synchrony and rhythmicityin the suprachiasmatic nucleusSynchronous oscillations of thousands of cellular clocks in thesuprachiasmatic nucleus (SCN), the circadian centre, are coordinated by precisely timed cell-cellcommunication, the principle of which is largely unknown. Here we show that the amount of RGS16(regulator of G protein signalling 16), a protein known to inactivate Gαi, increases at a selective circadiantime to allow time-dependent activation of intracellular cyclic AMP signalling in the SCN. Gene ablation ofRgs16 leads to the loss of circadian production of cAMP and as a result lengthens circadian period ofbehavioural rhythm. The temporally precise regulation of the cAMP signal by clock-controlled RGS16 isneeded for the dorsomedial SCN to maintain a normal phase-relationship to the ventrolateral SCN. Thus,RGS16-dependent temporal regulation of intracellular G protein signalling coordinates the intercellularsynchrony of SCN pacemaker neurons and thereby defines the 24 h rhythm in behaviour.", "metadata": {}}
+{"_id": "11568270", "title": "", "text": "MDC1 collaborates with TopBP1 in DNA replication checkpoint controlHuman TopBP1 is a major player inthe control of the DNA replication checkpoint. In this study, we identified MDC1, a key checkpoint proteininvolved in the cellular response to DNA double-strand breaks, as a TopBP1-associated protein. Thespecific TopBP1-MDC1 interaction is mediated by the fifth BRCT domain of TopBP1 and the Ser-Asp-Thr(SDT) repeats of MDC1. In addition, we demonstrated that TopBP1 accumulation at stalled replicationforks is promoted by the H2AX/MDC1 signaling cascade. Moreover, MDC1 is important for ATR-dependentChk1 activation in response to replication stress. Collectively, our data suggest that MDC1 facilitatesseveral important steps in both cellular DNA damage response and the DNA replication checkpoint.", "metadata": {}}
+{"_id": "11569583", "title": "", "text": "Deregulated DNA polymerase β strengthens ionizing radiation-induced nucleotidic and chromosomalinstabilitiesDNA polymerase β (Pol β) is an error-prone enzyme which has been found to beoverexpressed in several human tumors. By using a couple of recombinant CHO cells differing only fromthe exogenous expression of Pol β, we showed here that cells overexpressing Pol β are much moresensitive to IR treatments by increasing apoptosis. We also found that the surviving cells displayed anhypermutator phenotype which could be explained by different pathways involving Pol β, such as (i) anincreased capacity to incorporate into DNA the mutagenic dGTP analog, 8-oxo-dGTP, one of the mostabundant purine-derived nucleotides exposed to γ-irradiation, (ii) the induction of IR-induced DNA breaksand (iii) accumulation of chromosome aberrations induced by radiation. Alteration of Pol β expression inirradiated cells thus appears to strengthen both cell death and genetic changes associated with amalignant phenotype. These data provide new insights into the cellular response to radiations and theassociated carcinogenic consequences.", "metadata": {}}
+{"_id": "11578459", "title": "", "text": "Chromosome 7 gain and DNA hypermethylation at the HOXA10 locus are associated with expression of astem cell related HOX-signature in glioblastomaBACKGROUND HOX genes are a family of developmentalgenes that are expressed neither in the developing forebrain nor in the normal brain. Aberrant expressionof a HOX-gene dominated stem-cell signature in glioblastoma has been linked with increased resistanceto chemo-radiotherapy and sustained proliferation of glioma initiating cells. Here we describe theepigenetic and genetic alterations and their interactions associated with the expression of this signaturein glioblastoma. RESULTS We observe prominent hypermethylation of the HOXA locus 7p15.2 inglioblastoma in contrast to non-tumoral brain. Hypermethylation is associated with a gain of chromosome7, a hallmark of glioblastoma, and may compensate for tumor-driven enhanced gene dosage as a rescuemechanism by preventing undue gene expression. We identify the CpG island of the HOXA10 alternativepromoter that appears to escape hypermethylation in the HOX-high glioblastoma. An additive effect ofgene copy gain at 7p15.2 and DNA methylation at key regulatory CpGs in HOXA10 is significantlyassociated with HOX-signature expression. Additionally, we show concordance between methylationstatus and presence of active or inactive chromatin marks in glioblastoma-derived spheres that areHOX-high or HOX-low, respectively. CONCLUSIONS Based on these findings, we propose co-evolution andinteraction between gene copy gain, associated with a gain of chromosome 7, and additional epigeneticalterations as key mechanisms triggering a coordinated, but inappropriate, HOX transcriptional programin glioblastoma.", "metadata": {}}
+{"_id": "11581157", "title": "", "text": "Probing the phenomenon of trained immunity in invertebrates during a transgenerational study, usingbrine shrimp Artemia as a model systemThe invertebrate's innate immune system was reported to showsome form of adaptive features, termed trained immunity. However, the memory characteristics of innateimmune system and the mechanisms behind such phenomena remain unclear. Using the invertebratemodel Artemia, we verified the possibility or impossibility of trained immunity, examining the presence orabsence of enduring memory against homologous and heterologous antigens (Vibrio spp.) during atransgenerational study. We also determined the mechanisms behind such phenomenon. Our resultsshowed the occurrence of memory and partial discrimination in Artemia's immune system, as manifestedby increased resistance, for three successive generations, of the progenies of Vibrio-exposed ancestorstowards a homologous bacterial strain, rather than to a heterologous strain. This increased resistancephenotype was associated with elevated levels of hsp70 and hmgb1 signaling molecules and alteration inthe expression of key innate immunity-related genes. Our results also showed stochastic pattern in theacetylation and methylation levels of H4 and H3K4me3 histones, respectively, in the progenies whoseancestors were challenged. Overall results suggest that innate immune responses in invertebrates havethe capacity to be trained, and epigenetic reprogramming of (selected) innate immune effectors is likelyto have central place in the mechanisms leading to trained immunity.", "metadata": {}}
+{"_id": "11603066", "title": "", "text": "Using Structural Information to Change the Phosphotransfer Specificity of a Two-Component ChemotaxisSignalling ComplexTwo-component signal transduction pathways comprising histidine protein kinases(HPKs) and their response regulators (RRs) are widely used to control bacterial responses toenvironmental challenges. Some bacteria have over 150 different two-component pathways, and thespecificity of the phosphotransfer reactions within these systems is tightly controlled to prevent unwantedcrosstalk. One of the best understood two-component signalling pathways is the chemotaxis pathway.Here, we present the 1.40 A crystal structure of the histidine-containing phosphotransfer domain of thechemotaxis HPK, CheA(3), in complex with its cognate RR, CheY(6). A methionine finger on CheY(6) thatnestles in a hydrophobic pocket in CheA(3) was shown to be important for the interaction and was foundto only occur in the cognate RRs of CheA(3), CheY(6), and CheB(2). Site-directed mutagenesis of thismethionine in combination with two adjacent residues abolished binding, as shown by surface plasmonresonance studies, and phosphotransfer from CheA(3)-P to CheY(6). Introduction of this methionine andan adjacent alanine residue into a range of noncognate CheYs, dramatically changed their specificity,allowing protein interaction and rapid phosphotransfer from CheA(3)-P. The structure presented here hasallowed us to identify specificity determinants for the CheA-CheY interaction and subsequently tosuccessfully reengineer phosphotransfer signalling. In summary, our results provide valuable insight intohow cells mediate specificity in one of the most abundant signalling pathways in biology, two-componentsignal transduction.", "metadata": {}}
+{"_id": "11614737", "title": "", "text": "Combination varenicline and bupropion SR for tobacco-dependence treatment in cigarette smokers: arandomized trial.IMPORTANCE Combining pharmacotherapies for tobacco-dependence treatment mayincrease smoking abstinence. OBJECTIVE To determine efficacy and safety of varenicline and bupropionsustained-release (SR; combination therapy) compared with varenicline (monotherapy) in cigarettesmokers. DESIGN, SETTING, AND PARTICIPANTS Randomized, blinded, placebo-controlled multicenterclinical trial with a 12-week treatment period and follow-up through week 52 conducted between October2009 and April 2013 at 3 midwestern clinical research sites. Five hundred six adult (≥18 years) cigarettesmokers were randomly assigned and 315 (62%) completed the study. INTERVENTIONS Twelve weeks ofvarenicline and bupropion SR or varenicline and placebo. MAIN OUTCOMES AND MEASURES Primaryoutcome was abstinence rates at week 12, defined as prolonged (no smoking from 2 weeks after thetarget quit date) abstinence and 7-day point-prevalence (no smoking past 7 days) abstinence. Secondaryoutcomes were prolonged and point-prevalence smoking abstinence rates at weeks 26 and 52. Outcomeswere biochemically confirmed. RESULTS At 12 weeks, 53.0% of the combination therapy group achievedprolonged smoking abstinence and 56.2% achieved 7-day point-prevalence smoking abstinencecompared with 43.2% and 48.6% in varenicline monotherapy (odds ratio [OR], 1.49; 95% CI, 1.05-2.12;P = .03 and OR, 1.36; 95% CI, 0.95-1.93; P = .09, respectively). At 26 weeks, 36.6% of the combinationtherapy group achieved prolonged and 38.2% achieved 7-day point-prevalence smoking abstinencecompared with 27.6% and 31.9% in varenicline monotherapy (OR, 1.52; 95% CI, 1.04-2.22; P = .03 andOR, 1.32; 95% CI, 0.91-1.91; P = .14, respectively). At 52 weeks, 30.9% of the combination therapygroup achieved prolonged and 36.6% achieved 7-day point-prevalence smoking abstinence comparedwith 24.5% and 29.2% in varenicline monotherapy (OR, 1.39; 95% CI, 0.93-2.07; P = .11 and OR, 1.40;95% CI, 0.96-2.05; P = .08, respectively). Participants receiving combination therapy reported moreanxiety (7.2% vs 3.1%; P = .04) and depressive symptoms (3.6% vs 0.8%; P = .03). CONCLUSIONSAND RELEVANCE Among cigarette smokers, combined use of varenicline and bupropion, compared withvarenicline alone, increased prolonged abstinence but not 7-day point prevalence at 12 and 26 weeks.Neither outcome was significantly different at 52 weeks. Further research is required to determine therole of combination therapy in smoking cessation. TRIAL REGISTRATION clinicaltrials.gov Identifier:http://clinicaltrials.gov/show/NCT00935818.", "metadata": {}}
+{"_id": "11615242", "title": "", "text": "Effect of a C/EBP gene replacement on mitochondrial biogenesis in fat cells.CCAAT/enhancer-bindingproteins, C/EBPalpha and C/EBPbeta, are required for fat cell differentiation and maturation. Previousstudies showed that replacement of C/EBPalpha with C/EBPbeta, generating the beta/beta alleles in themouse genome, prevents lipid accumulation in white adipose tissue (WAT). In this study, beta/beta micelived longer and had higher energy expenditure than their control littermates due to increased WATenergy oxidation. The WAT of beta/beta mice was enriched with metabolically active, thermogenicmitochondria known for energy burning. The beta/beta allele exerted its effect through the elevatedexpression of the G protein alpha stimulatory subunit (Galphas) in WAT. Galphas, when overexpressed infat-laden 3T3-L1 cells, stimulated mitochondrial biogenesis similar to that seen in the WAT of beta/betamice, and effectively diminished the stored lipid pool.", "metadata": {}}
+{"_id": "11615422", "title": "", "text": "Variable breakpoints target PAX5 in patients with dicentric chromosomes: a model for the basis ofunbalanced translocations in cancer.The search for target genes involved in unbalanced acquiredchromosomal abnormalities has been largely unsuccessful, because the breakpoints of theserearrangements are too variable. Here, we use the example of dicentric chromosomes in B cell precursoracute lymphoblastic leukemia to show that, despite this heterogeneity, single genes are targeted througha variety of mechanisms. FISH showed that, although they were heterogeneous, breakpoints on 9presulted in the partial or complete deletion of PAX5. Molecular copy number counting further delineatedthe breakpoints and facilitated cloning with long-distance inverse PCR. This approach identified 5 fusiongene partners with PAX5: LOC392027 (7p12.1), SLCO1B3 (12p12), ASXL1 (20q11.1), KIF3B (20q11.21),and C20orf112 (20q11.1). In each predicted fusion protein, the DNA-binding paired domain of PAX5 waspresent. Using quantitative PCR, we demonstrated that both the deletion and gene fusion events resultedin the same underexpression of PAX5, which extended to the differential expression of the PAX5 targetgenes, EBF1, ALDH1A1, ATP9A, and FLT3. Further molecular analysis showed deletion and mutation ofthe homologous PAX5 allele, providing further support for the key role of PAX5. Here, we show thatspecific gene loci may be the target of heterogeneous translocation breakpoints in human cancer, actingthrough a variety of mechanisms. This approach indicates an application for the identification of cancergenes in solid tumours, where unbalanced chromosomal rearrangements are particularly prevalent andfew genes have been identified. It can be extrapolated that this strategy will reveal that the samemechanisms operate in cancer pathogenesis in general.", "metadata": {}}
+{"_id": "11616424", "title": "", "text": "Copyright \u0000 1996, American Society for Microbiology Endotoxin-Induced Enhancement of Glucose InfluxintoHypoglycemia is among the most injurious metabolic disorders caused by endotoxemia. Inexperimental endotoxemia with lipopolysaccharide (LPS) in animals, a marked glucose consumption isobserved in macrophage-rich organs. However, the direct effect of LPS on the uptake of glucose bymacrophages has not been fully understood, and the present study was undertaken to shed light on thispoint. The consumption and uptake of glucose, as measured with 2-deoxy-D-[3H]glucose, by murineperitoneal exudate macrophages in culture were accelerated two- to threefold by stimulation with 3 ng ofLPS per ml. The rate of glucose uptake reached a plateau after 20 min of stimulation and remained at themaximum as long as LPS was present. Northern (RNA) blot analysis with cDNA probes for five knownisoforms of glucose transporter (GLUT) revealed that the expression of GLUT by macrophages wasrestricted to the GLUT1 isoform during LPS stimulation and the amount of GLUT1 mRNA was increased bythe stimulation. These results suggest that macrophage responses to LPS are supported by a rapid andsustained glucose influx via GLUT1 and that this is a participating factor in the development of systemichypoglycemia when endotoxemia is prolonged.", "metadata": {}}
+{"_id": "11624482", "title": "", "text": "Factors associated with American Board of Medical Specialties member board certification among USmedical school graduates.CONTEXT Certification by an American Board of Medical Specialties (ABMS)member board is emerging as a measure of physician quality. OBJECTIVE To identify demographic andeducational factors associated with ABMS member board certification of US medical school graduates.DESIGN, SETTING, AND PARTICIPANTS Retrospective study of a national cohort of 1997-2000 USmedical school graduates, grouped by specialty choice at graduation and followed up through March 2,2009. In separate multivariable logistic regression models for each specialty category, factors associatedwith ABMS member board certification were identified. MAIN OUTCOME MEASURE ABMS member boardcertification. RESULTS Of 42,440 graduates in the study sample, 37,054 (87.3%) were board certified.Graduates in all specialty categories with first-attempt passing scores in the highest tertile (vsfirst-attempt failing scores) on US Medical Licensing Examination Step 2 Clinical Knowledge were morelikely to be board certified; adjusted odds ratios (AORs) varied by specialty category, with the lowestodds for emergency medicine (87.4% vs 73.6%; AOR, 1.82; 95% CI, 1.03-3.20) and highest odds forradiology (98.1% vs 74.9%; AOR, 13.19; 95% CI, 5.55-31.32). In each specialty category except familymedicine, graduates self-identified as underrepresented racial/ethnic minorities (vs white) were less likelyto be board certified, ranging from 83.5% vs 95.6% in the pediatrics category (AOR, 0.44; 95% CI,0.33-0.58) to 71.5% vs 83.7% in the other nongeneralist specialties category (AOR, 0.79; 95% CI,0.64-0.96). With each $50,000 unit increase in debt (vs no debt), graduates choosingobstetrics/gynecology were less likely to be board certified (AOR, 0.89; 95% CI, 0.83-0.96), andgraduates choosing family medicine were more likely to be board certified (AOR, 1.13; 95% CI,1.01-1.26). CONCLUSION Demographic and educational factors were associated with board certificationamong US medical school graduates in every specialty category examined; findings varied amongspecialty categories.", "metadata": {}}
+{"_id": "11630388", "title": "", "text": "Body-mass index and mortality in Korean men and women.BACKGROUND Obesity is associated withdiverse health risks, but the role of body weight as a risk factor for death remains controversial.METHODS We examined the association between body weight and the risk of death in a 12-yearprospective cohort study of 1,213,829 Koreans between the ages of 30 and 95 years. We examined82,372 deaths from any cause and 48,731 deaths from specific diseases (including 29,123 from cancer,16,426 from atherosclerotic cardiovascular disease, and 3362 from respiratory disease) in relation to thebody-mass index (BMI) (the weight in kilograms divided by the square of the height in meters). RESULTSIn both sexes, the average baseline BMI was 23.2, and the rate of death from any cause had a J-shapedassociation with the BMI, regardless of cigarette-smoking history. The risk of death from any cause waslowest among patients with a BMI of 23.0 to 24.9. In all groups, the risk of death from respiratory causeswas higher among subjects with a lower BMI, and the risk of death from atherosclerotic cardiovasculardisease or cancer was higher among subjects with a higher BMI. The relative risk of death associated withBMI declined with increasing age. CONCLUSIONS Underweight, overweight, and obese men and womenhad higher rates of death than men and women of normal weight. The association of BMI with deathvaried according to the cause of death and was modified by age, sex, and smoking history.", "metadata": {}}
+{"_id": "11659421", "title": "", "text": "Human iPSC-based modeling of late-onset disease via progerin-induced aging.Reprogramming somaticcells to induced pluripotent stem cells (iPSCs) resets their identity back to an embryonic age and, thus,presents a significant hurdle for modeling late-onset disorders. In this study, we describe a strategy forinducing aging-related features in human iPSC-derived lineages and apply it to the modeling ofParkinson's disease (PD). Our approach involves expression of progerin, a truncated form of lamin Aassociated with premature aging. We found that expression of progerin in iPSC-derived fibroblasts andneurons induces multiple aging-related markers and characteristics, including dopamine-specificphenotypes such as neuromelanin accumulation. Induced aging in PD iPSC-derived dopamine neuronsrevealed disease phenotypes that require both aging and genetic susceptibility, such as pronounceddendrite degeneration, progressive loss of tyrosine hydroxylase (TH) expression, and enlargedmitochondria or Lewy-body-precursor inclusions. Thus, our study suggests that progerin-induced agingcan be used to reveal late-onset age-related disease features in hiPSC-based disease models.", "metadata": {}}
+{"_id": "11661377", "title": "", "text": "SNAREs — engines for membrane fusionSince the discovery of SNARE proteins in the late 1980s, SNAREshave been recognized as key components of protein complexes that drive membrane fusion. Despiteconsiderable sequence divergence among SNARE proteins, their mechanism seems to be conserved andis adaptable for fusion reactions as diverse as those involved in cell growth, membrane repair, cytokinesisand synaptic transmission. A fascinating picture of these robust nanomachines is emerging.", "metadata": {}}
+{"_id": "11666252", "title": "", "text": "Maintaining the norm: T-cell homeostasisThe persistence of naive and memory T cells has long been ofinterest to immunologists, but the factors that influence the survival and homeostasis of these subsetshave remained obscure. In recent years, it has become evident that the homeostasis of both naive andmemory T-cell pools is highly dynamic and tightly regulated by internal stimuli, including cytokines andself-peptide–MHC ligands for the T-cell receptor. These homeostatic mechanisms might have a vitalinfluence on the capacity of the T-cell pool to respond to both foreign and self-antigens.", "metadata": {}}
+{"_id": "11674288", "title": "", "text": "Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stemcellsInduced pluripotent stem cells (iPSCs) have been derived from various somatic cell populationsthrough ectopic expression of defined factors. It remains unclear whether iPSCs generated from differentcell types are molecularly and functionally similar. Here we show that iPSCs obtained from mousefibroblasts, hematopoietic and myogenic cells exhibit distinct transcriptional and epigenetic patterns.Moreover, we demonstrate that cellular origin influences the in vitro differentiation potentials of iPSCsinto embryoid bodies and different hematopoietic cell types. Notably, continuous passaging of iPSCslargely attenuates these differences. Our results suggest that early-passage iPSCs retain a transientepigenetic memory of their somatic cells of origin, which manifests as differential gene expression andaltered differentiation capacity. These observations may influence ongoing attempts to use iPSCs fordisease modeling and could also be exploited in potential therapeutic applications to enhancedifferentiation into desired cell lineages.", "metadata": {}}
+{"_id": "11674596", "title": "", "text": "Spatiotemporal control of mitosis by the conserved spindle matrix protein MegatorA putative spindlematrix has been hypothesized to mediate chromosome motion, but its existence and functionality remaincontroversial. In this report, we show that Megator (Mtor), the Drosophila melanogaster counterpart ofthe human nuclear pore complex protein translocated promoter region (Tpr), and the spindle assemblycheckpoint (SAC) protein Mad2 form a conserved complex that localizes to a nuclear derived spindlematrix in living cells. Fluorescence recovery after photobleaching experiments supports that Mtor isretained around spindle microtubules, where it shows distinct dynamic properties. Mtor/Tpr promotes therecruitment of Mad2 and Mps1 but not Mad1 to unattached kinetochores (KTs), mediating normal mitoticduration and SAC response. At anaphase, Mtor plays a role in spindle elongation, thereby affectingnormal chromosome movement. We propose that Mtor/Tpr functions as a spatial regulator of the SAC,which ensures the efficient recruitment of Mad2 to unattached KTs at the onset of mitosis and properspindle maturation, whereas enrichment of Mad2 in a spindle matrix helps confine the action of adiffusible \"wait anaphase\" signal to the vicinity of the spindle.", "metadata": {}}
+{"_id": "11705328", "title": "", "text": "Randomized trial of folic acid supplementation and serum homocysteine levels.BACKGROUND Loweringserum homocysteine levels with folic acid is expected to reduce mortality from ischemic heart disease.Homocysteine reduction is known to be maximal at a folic acid dosage of 1 mg/d, but the effect of lowerdoses (relevant to food fortification) is unclear. METHODS We randomized 151 patients with ischemicheart disease to 1 of 5 dosages of folic acid (0.2, 0.4, 0.6, 0.8, and 1.0 mg/d) or placebo. Fasting bloodsamples for serum homocysteine and serum folate analysis were taken initially, after 3 months ofsupplementation, and 3 months after folic acid use was discontinued. RESULTS Median serumhomocysteine level decreased with increasing folic acid dosage, to a maximum at 0.8 mg of folic acid perday, when the homocysteine reduction (placebo adjusted) was 2.7 micromol/L (23%), similar to theknown effect of folic acid dosages of 1 mg/d and above. The higher a person's initial serum homocysteinelevel, the greater was the response to folic acid, but there were statistically significant reductionsregardless of the initial level. Serum folate level increased approximately linearly (5.5 nmol/L for every0.1 mg of folic acid). Within-person fluctuations over time in serum homocysteine levels, measured in theplacebo group, were large compared with the effect of folic acid, indicating that monitoring of thereduction in an individual is impractical. CONCLUSIONS A dosage of folic acid of 0.8 mg/d appearsnecessary to achieve the maximum reduction in serum homocysteine level across the range ofhomocysteine levels in the population. Current US food fortification levels will achieve only a smallproportion of the achievable homocysteine reduction.", "metadata": {}}
+{"_id": "11710511", "title": "", "text": "Adherens junctions in Drosophila retinal morphogenesis.Adherens junctions and their core molecularcomponents, classic cadherins, make major contributions to animal morphogenesis. Although thesignificance of cadherins in development is generally accepted, the mechanisms regulating adherensjunction function during morphogenesis remain a subject of intense research. Adherens junctions areinvolved in the organization of simple cellular patterns, and more complex cell shape changes and cellmovements that depend on the dynamic modulation of adherens junctions.", "metadata": {}}
+{"_id": "11716783", "title": "", "text": "Multiple roles of vascular endothelial growth factor (VEGF) in skeletal development, growth, andrepair.Publisher Summary This chapter discusses the developmental roles of vascular endothelial growthfactor (VEGF) in skeletal morphogenesis, speculates on the future directions of research in this area, anddescribes some of the challenges in the field. VEGF regulates osteoclastic differentiation, migration, andactivity. VEGF is, therefore, a key coordinator of the entire process. VEGF is necessary for osteoclasticactivity both at the stage when the primary ossification center is established and later during bonegrowth. A number of studies have led to the identification of VEGF as a critical factor for the survival ofchondrocytes. Several factors with important roles in regulating bone formation also induce theexpression of VEGF by osteoblasts. Prostaglandins E1 and E2, BMP-4, BMP-6, BMP-7, FGF-2, TGF-β,endothelin-1, IGF-1, and vitamin D3 can all induce VEGF expression in osteoblasts by activating a varietyof signaling pathways. Bone fractures can heal in two divergent ways, similar to the two ways of formingbone during embryonic development. Stabilized fractures heal by intramembranous ossification, andunstable fractures undergo endochondral ossification. The similarity between the embryonic bonedevelopment and repair of fractured bones, coupled with the finding that VEGF is expressed at sites ofbone fracture, suggests that VEGF is involved in bone repair as it is in bone development.", "metadata": {}}
+{"_id": "11718220", "title": "", "text": "Effectiveness of thigh-length graduated compression stockings to reduce the risk of deep vein thrombosisafter stroke (CLOTS trial 1): a multicentre, randomised controlled trialBACKGROUND Deep veinthrombosis (DVT) and pulmonary embolism are common after stroke. In small trials of patientsundergoing surgery, graduated compression stockings (GCS) reduce the risk of DVT. National strokeguidelines extrapolating from these trials recommend their use in patients with stroke despite insufficientevidence. We assessed the effectiveness of thigh-length GCS to reduce DVT after stroke. METHODS Inthis outcome-blinded, randomised controlled trial, 2518 patients who were admitted to hospital within 1week of an acute stroke and who were immobile were enrolled from 64 centres in the UK, Italy, andAustralia. Patients were allocated via a central randomisation system to routine care plus thigh-lengthGCS (n=1256) or to routine care plus avoidance of GCS (n=1262). A technician who was blinded totreatment allocation undertook compression Doppler ultrasound of both legs at about 7-10 days and,when practical, again at 25-30 days after enrolment. The primary outcome was the occurrence ofsymptomatic or asymptomatic DVT in the popliteal or femoral veins. Analyses were by intention to treat.This study is registered, number ISRCTN28163533. FINDINGS All patients were included in the analyses.The primary outcome occurred in 126 (10.0%) patients allocated to thigh-length GCS and in 133 (10.5%)allocated to avoid GCS, resulting in a non-significant absolute reduction in risk of 0.5% (95% CI -1.9% to2.9%). Skin breaks, ulcers, blisters, and skin necrosis were significantly more common in patientsallocated to GCS than in those allocated to avoid their use (64 [5%] vs 16 [1%]; odds ratio 4.18, 95% CI2.40-7.27). INTERPRETATION These data do not lend support to the use of thigh-length GCS in patientsadmitted to hospital with acute stroke. National guidelines for stroke might need to be revised on thebasis of these results. FUNDING Medical Research Council (UK), Chief Scientist Office of ScottishGovernment, Chest Heart and Stroke Scotland, Tyco Healthcare (Covidien) USA, and UK Stroke ResearchNetwork.", "metadata": {}}
+{"_id": "11721286", "title": "", "text": "Streptococcus pneumoniae early response genes to human lung epithelial cellsBACKGROUNDStreptococcus pneumoniae infection starts from colonization of the host respiratory tract whereinteraction with host respiratory tract epithelial cells occurs. To investigate pneumococcal genes that areinvolved in the early stage of interaction with host epithelial cells, transcriptional responses of anencapsulated pathogenic pneumococcal strain TIGR4 upon exposure to human lung epithelial cells A549for 0.5 h and 1 h time periods were investigated by using TIGR (JCVI) microarray technology. Geneexpression changes were validated by quantitative real-time PCR (qRT-PCR) analysis. FINDINGS Weobserved different transcriptional profiles at two incubation time periods in which most gene expressionswere down-regulated at 0.5 h but up-regulated at 1 h. Many genes associated with ribonucleotidebiosynthesis were down-regulated at both time points, whereas the genes associated with cell envelope,energy metabolism, transport and protein synthesis were mostly up-regulated at 1 h. Furthermore, theseprofiles were compared to the transcriptomes of a TIGR4-derived strain in response to humanmacrophages for the same time periods. We found one set of genes that exhibited similar expressionchanges upon exposure to both types of host cells, including cell envelope-associated bgaA (SP0648) andnanA (SP1693), and uncharacterized gene clusters such as SP1677-SP1680 and SP1688-SP1690.CONCLUSION These data indicate that at the early stage of interaction with host epithelial cells, acomplex gene regulation and expression change occur in bacteria. Some of them might play an essentialrole during pathogen-host interactions and for the establishment of infection.", "metadata": {}}
+{"_id": "11721676", "title": "", "text": "Proteomic identification of a novel isoform of collapsin response mediator protein-2 in spinal nervesperipheral to dorsal root ganglia.Primary afferent fibers are originated from pseudounipolar sensory cellsin dorsal root ganglia (DRG) and transmit external stimuli received in the skin to the spinal cord. Here weundertook a proteomic approach to uncover the polarity of primary afferent fibers. Lumbar spinal nervesegments, peripheral and central to DRG, were dissected from 5-wk-old Wistar rats and the lysates weresubjected to large-sized 2-DE at pH 5-6. Among approximately 800 protein spots detected in the centraland peripheral fractions, one of the unique spots in the peripheral fraction with MW of 60 kDa and pI of5.6 was identified as an isoform of collapsin response mediator protein-2 (CRMP-2) by MALDI-TOF MSand Western blots with anti-CRMP-2 antibodies that recognize 1-17 and 486-528 residues. Since thisnovel spot was detected only in the peripheral fraction, but not in the central fraction, DRG, and otherregions of the brain, it was named periCRMP-2. The C-terminal fragment of CRMP-2 was not detected inperiCRMP-2 by MS analyses. Expression of periCRMP-2 decreased following sciatic nerve injury. Theseresults suggest that periCRMP-2 is a C-terminal truncated isoform polarized in the peripheral side ofspinal nerves and may be involved in nerve degeneration and regeneration.", "metadata": {}}
+{"_id": "11728637", "title": "", "text": "Empirical statistical estimates for sequence similarity searchesThe FASTA package of sequencecomparison programs has been modified to provide accurate statistical estimates for local sequencesimilarity scores with gaps. These estimates are derived using the extreme value distribution from themean and variance of the local similarity scores of unrelated sequences after the scores have beencorrected for the expected effect of library sequence length. This approach allows accurate estimates tobe calculated for both FASTA and Smith-Waterman similarity scores for protein/protein, DNA/DNA, andprotein/translated-DNA comparisons. The accuracy of the statistical estimates is summarized for 54protein families using FASTA and Smith-Waterman scores. Probability estimates calculated from thedistribution of similarity scores are generally conservative, as are probabilities calculated using theAltschul-Gish lambda, kappa, and eta parameters. The performance of several alternative methods forcorrecting similarity scores for library-sequence length was evaluated using 54 protein superfamilies fromthe PIR39 database and 110 protein families from the Prosite/SwissProt rel. 34 database. Bothregression-scaled and Altschul-Gish scaled scores perform significantly better than unscaledSmith-Waterman or FASTA similarity scores. When the Prosite/ SwissProt test set is used,regression-scaled scores perform slightly better; when the PIR database is used, Altschul-Gish scaledscores perform best. Thus, length-corrected similarity scores improve the sensitivity of databasesearches. Statistical parameters that are derived from the distribution of similarity scores from thethousands of unrelated sequences typically encountered in a database search provide accurate estimatesof statistical significance that can be used to infer sequence homology.", "metadata": {}}
+{"_id": "11738716", "title": "", "text": "Steroid hormone signalling links reproduction to lifespan in dietary-restricted Caenorhabditiselegans.Dietary restriction (DR) increases healthspan and longevity in many species, including primates,but it is often accompanied by impaired reproductive function. Whether signals associated with thereproductive system contribute to or are required for DR effects on lifespan has not been established.Here we show that expression of the cytochrome P450 DAF-9/CYP450 and production of the steroidhormone Δ(7)-dafachronic acid (DA) are increased in C. elegans subjected to DR. DA signalling throughthe non-canonical nuclear hormone receptor NHR-8/NHR and the nutrient-responsive kinaselet-363/mTOR is essential for DR-mediated longevity. Steroid signalling also affects germline plasticity inresponse to nutrient deprivation and this is required to achieve lifespan extension. These datademonstrate that steroid signalling links germline physiology to lifespan when nutrients are limited, andestablish a central role for let-363/mTOR in integrating signals derived from nutrients and steroidhormones.", "metadata": {}}
+{"_id": "11742219", "title": "", "text": "Regulation and effects of hypothalamic galanin: relation to dietary fat, alcohol ingestion, circulating lipidsand energy homeostasis.Galanin (GAL) is known to stimulate feeding behavior. This peptide has differentproperties and functions from other feeding stimulants, e.g., neuropeptide Y and agouti-related protein.Hypothalamic GAL is relatively unresponsive to food deprivation and to changes in corticosterone, glucoseutilization, dietary carbohydrate and leptin. This indicates that this peptide is not essential underconditions when food is scarce or low-energy, high-carbohydrate diets are being consumed. In contrast,recent evidence suggests that GAL in the paraventricular nucleus (PVN) functions in close relation todietary fat and alcohol. In particular, it mediates functions that allow animals to adapt to conditions ofpositive energy balance involving excess consumption of these nutrients. This peptide in the PVN isstimulated by a high-fat diet and also by alcohol. It is stimulated by an increase in circulating lipidscaused by a fat-rich meal or alcohol consumption, and it rises during the middle of the active feedingcycle, when fat consumption and triglycerides naturally rise. When centrally injected, GAL in the PVNincreases the consumption of food and alcohol. Moreover, it produces a significantly stronger feedingresponse in rats maintained on a fat-rich diet, which also promotes alcohol intake. This evidence supportsthe existence of non-homeostatic, positive feedback circuits between GAL and both dietary fat andalcohol. These circuits are believed to contribute to the large meal size, over-consumption of alcohol, andobesity which are generally associated with fat-rich foods.", "metadata": {}}
+{"_id": "11748341", "title": "", "text": "Evidence-based interventions for improvement of maternal and child nutrition: what can be done and atwhat cost?Maternal undernutrition contributes to 800,000 neonatal deaths annually through small forgestational age births; stunting, wasting, and micronutrient deficiencies are estimated to underlie nearly3·1 million child deaths annually. Progress has been made with many interventions implemented at scaleand the evidence for effectiveness of nutrition interventions and delivery strategies has grown since TheLancet Series on Maternal and Child Undernutrition in 2008. We did a comprehensive update ofinterventions to address undernutrition and micronutrient deficiencies in women and children and usedstandard methods to assess emerging new evidence for delivery platforms. We modelled the effect onlives saved and cost of these interventions in the 34 countries that have 90% of the world's children withstunted growth. We also examined the effect of various delivery platforms and delivery options usingcommunity health workers to engage poor populations and promote behaviour change, access anduptake of interventions. Our analysis suggests the current total of deaths in children younger than 5years can be reduced by 15% if populations can access ten evidence-based nutrition interventions at90% coverage. Additionally, access to and uptake of iodised salt can alleviate iodine deficiency andimprove health outcomes. Accelerated gains are possible and about a fifth of the existing burden ofstunting can be averted using these approaches, if access is improved in this way. The estimated totaladditional annual cost involved for scaling up access to these ten direct nutrition interventions in the 34focus countries is Int$9·6 billion per year. Continued investments in nutrition-specific interventions toavert maternal and child undernutrition and micronutrient deficiencies through community engagementand delivery strategies that can reach poor segments of the population at greatest risk can make a greatdifference. If this improved access is linked to nutrition-sensitive approaches--ie, women'sempowerment, agriculture, food systems, education, employment, social protection, and safetynets--they can greatly accelerate progress in countries with the highest burden of maternal and childundernutrition and mortality.", "metadata": {}}
+{"_id": "11771811", "title": "", "text": "FGF regulates TGF-β signaling and endothelial-to-mesenchymal transition via control of let-7 miRNAexpression.Maintenance of normal endothelial function is critical to various aspects of blood vesselfunction, but its regulation is poorly understood. In this study, we show that disruption of baselinefibroblast growth factor (FGF) signaling to the endothelium leads to a dramatic reduction in let-7 miRNAlevels that, in turn, increases expression of transforming growth factor (TGF)-β ligands and receptors andactivation of TGF-β signaling, leading to endothelial-to-mesenchymal transition (Endo-MT). We also findthat Endo-MT is an important driver of neointima formation in a murine transplant arteriopathy modeland in rejection of human transplant lesions. The decline in endothelial FGF signaling input is due to theappearance of an FGF resistance state that is characterized by inflammation-dependent reduction inexpression and activation of key components of the FGF signaling cascade. These results establish FGFsignaling as a critical factor in maintenance of endothelial homeostasis and point to an unexpected role ofEndo-MT in vascular pathology.", "metadata": {}}
+{"_id": "11774598", "title": "", "text": "Nuclear Receptors, RXR, and the Big BangIsolation of genes encoding the receptors for steroids,retinoids, vitamin D, and thyroid hormone and their structural and functional analysis revealed anevolutionarily conserved template for nuclear hormone receptors. This discovery sparked identification ofnumerous genes encoding related proteins, termed orphan receptors. Characterization of these orphanreceptors and, in particular, of the retinoid X receptor (RXR) positioned nuclear receptors at the epicenterof the \"Big Bang\" of molecular endocrinology. This Review provides a personal perspective on nuclearreceptors and explores their integrated and coordinated signaling networks that are essential formulticellular life, highlighting the RXR heterodimer and its associated ligands and transcriptionalmechanism.", "metadata": {}}
+{"_id": "11784947", "title": "", "text": "A genome-wide short hairpin RNA screening of jurkat T-cells for human proteins contributing toproductive HIV-1 replication.Short interfering RNAs (siRNAs) have been used to inhibit HIV-1 replication.The durable inhibition of HIV-1 replication by RNA interference has been impeded, however, by a highmutation rate when viral sequences are targeted and by cytotoxicity when cellular genes are knockeddown. To identify cellular proteins that contribute to HIV-1 replication that can be chronically silencedwithout significant cytotoxicity, we employed a shRNA library that targets 54,509 human transcripts. Weused this library to select a comprehensive population of Jurkat T-cell clones, each expressing a singlediscrete shRNA. The Jurkat clones were then infected with HIV-1. Clones that survived viral infectionrepresent moieties silenced for a human mRNA needed for virus replication, but whose chronicknockdown did not cause cytotoxicity. Overall, 252 individual Jurkat mRNAs were identified. Twenty-twoof these mRNAs were secondarily verified for their contributions to HIV-1 replication. Five mRNAs, NRF1,STXBP2, NCOA3, PRDM2, and EXOSC5, were studied for their effect on steps of the HIV-1 life cycle. Wediscuss the similarities and differences between our shRNA findings for HIV-1 using a spreading infectionassay in human Jurkat T-cells and results from other investigators who used siRNA-based screenings inHeLa or 293T cells.", "metadata": {}}
+{"_id": "11822354", "title": "", "text": "UNR facilitates the interaction of MLE with the lncRNA roX2 during Drosophila dosagecompensation.Dosage compensation is a regulatory process that balances the expression ofX-chromosomal genes between males (XY) and females (XX). In Drosophila, this requires non-codingRNAs and RNA-binding proteins (RBPs) whose specific functions remain elusive. Here we show that theDrosophila RBP UNR promotes the targeting of the activating male-specific-lethal complex to theX-chromosome by facilitating the interaction of two crucial subunits: the RNA helicase MLE and the longnon-coding RNA roX2.", "metadata": {}}
+{"_id": "11831598", "title": "", "text": "BMP/SMAD1 signaling sets a threshold for the left/right pathway in lateral plate mesoderm and limitsavailability of SMAD4.Bistability in developmental pathways refers to the generation of binary outputsfrom graded or noisy inputs. Signaling thresholds are critical for bistability. Specification of the left/right(LR) axis in vertebrate embryos involves bistable expression of transforming growth factor beta(TGFbeta) member NODAL in the left lateral plate mesoderm (LPM) controlled by feed-forward andfeedback loops. Here we provide evidence that bone morphogenetic protein (BMP)/SMAD1 signaling setsa repressive threshold in the LPM essential for the integrity of LR signaling. Conditional deletion of Smad1in the LPM led to precocious and bilateral pathway activation. NODAL expression from both the left andright sides of the node contributed to bilateral activation, indicating sensitivity of mutant LPM to noisyinput from the LR system. In vitro, BMP signaling inhibited NODAL pathway activation and formation of itsdownstream SMAD2/4-FOXH1 transcriptional complex. Activity was restored by overexpression of SMAD4and in embryos, elevated SMAD4 in the right LPM robustly activated LR gene expression, an effectreversed by superactivated BMP signaling. We conclude that BMP/SMAD1 signaling sets a bilateral,repressive threshold for NODAL-dependent Nodal activation in LPM, limiting availability of SMAD4. Thisrepressive threshold is essential for bistable output of the LR system.", "metadata": {}}
+{"_id": "11837657", "title": "", "text": "Human Macrophages Infected with a High Burden of ESAT-6-Expressing M. tuberculosis UndergoCaspase-1- and Cathepsin B-Independent NecrosisMycobacterium tuberculosis (Mtb) infects lungmacrophages, which instead of killing the pathogen can be manipulated by the bacilli, creating anenvironment suitable for intracellular replication and spread to adjacent cells. The role of host cell deathduring Mtb infection is debated because the bacilli have been shown to be both anti-apoptotic, keepingthe host cell alive to avoid the antimicrobial effects of apoptosis, and pro-necrotic, killing the hostmacrophage to allow infection of neighboring cells. Since mycobacteria activate the NLRP3 inflammasomein macrophages, we investigated whether Mtb could induce one of the recently describedinflammasome-linked cell death modes pyroptosis and pyronecrosis. These are mediated throughcaspase-1 and cathepsin-B, respectively. Human monocyte-derived macrophages were infected withvirulent (H37Rv) Mtb at a multiplicity of infection (MOI) of 1 or 10. The higher MOI resulted in stronglyenhanced release of IL-1β, while a low MOI gave no IL-1β response. The infected macrophages werecollected and cell viability in terms of the integrity of DNA, mitochondria and the plasma membrane wasdetermined. We found that infection with H37Rv at MOI 10, but not MOI 1, over two days led to extensiveDNA fragmentation, loss of mitochondrial membrane potential, loss of plasma membrane integrity, andHMGB1 release. Although we observed plasma membrane permeabilization and IL-1β release frominfected cells, the cell death induced by Mtb was not dependent on caspase-1 or cathepsin B. It was,however, dependent on mycobacterial expression of ESAT-6. We conclude that as virulent Mtb reaches athreshold number of bacilli inside the human macrophage, ESAT-6-dependent necrosis occurs, activatingcaspase-1 in the process.", "metadata": {}}
+{"_id": "11840194", "title": "", "text": "Differentiation of Human Induced-Pluripotent Stem Cells into Smooth-Muscle Cells: Two NovelProtocolsConventional protocols for differentiating human induced-pluripotent stem cells (hiPSCs) intosmooth-muscle cells (SMCs) can be inefficient and generally fail to yield cells with a specific SMCphenotype (i.e., contractile or synthetic SMCs). Here, we present two novel hiPSC-SMC differentiationprotocols that yield SMCs with predominantly contractile or synthetic phenotypes. Flow cytometryanalyses of smooth-muscle actin (SMA) expression indicated that ~45% of the cells obtained with eachprotocol assumed an SMC phenotype, and that the populations could be purified to ~95% via metabolicselection. Assessments of cellular mRNA and/or protein levels indicated that SMA, myosin heavy chain II,collagen 1, calponin, transgelin, connexin 43, and vimentin expression in the SMCs obtained via theContractile SMC protocol and in SMCs differentiated via a traditional protocol were similar, while SMCsproduced via the Sythetic SMC protocol expressed less calponin, more collagen 1, and more connexin 43.Differences were also observed in functional assessments of the two SMC populations: thetwo-dimensional surface area of Contractile SMCs declined more extensively (to 12% versus 44% oforiginal size) in response to carbachol treatment, while quantification of cell migration and proliferationwere greater in Synthetic SMCs. Collectively, these data demonstrate that our novel differentiationprotocols can efficiently generate SMCs from hiPSCs.", "metadata": {}}
+{"_id": "11844791", "title": "", "text": "Conserved Histone Variant H2A.Z Protects Euchromatin from the Ectopic Spread of SilentHeterochromatinBoundary elements hinder the spread of heterochromatin, yet these sites do not fullyaccount for the preservation of adjacent euchromatin. Histone variant H2A.Z (Htz1 in yeast) replacesconventional H2A in many nucleosomes. Microarray analysis revealed that HTZ1-activated genes clusternear telomeres. The reduced expression of most of these genes in htz1Delta cells was reversed by thedeletion of SIR2 (sir2Delta) suggesting that H2A.Z antagonizes telomeric silencing. Other Htz1-activatedgenes flank the silent HMR mating-type locus. Their requirement for Htz1 can be bypassed by sir2Delta orby a deletion encompassing the silencing nucleation sites in HMR. In htz1Delta cells, Sir2 and Sir3 spreadinto flanking euchromatic regions, producing changes in histone H4 acetylation and H3 4-methylationindicative of ectopic heterochromatin formation. Htz1 is enriched in these euchromatic regions and actssynergistically with a boundary element to prevent the spread of heterochromatin. Thus, euchromatinand heterochromatin each contains components that antagonize switching to the opposite chromatinstate.", "metadata": {}}
+{"_id": "11844826", "title": "", "text": "COMMD proteins, a novel family of structural and functional homologs of MURR1.MURR1 is amultifunctional protein that inhibits nuclear factor kappaB (NF-kappaB), a transcription factor withpleiotropic functions affecting innate and adaptive immunity, apoptosis, cell cycle regulation, andoncogenesis. Here we report the discovery of a new family of proteins with homology to MURR1. Theseproteins form multimeric complexes and were identified in a biochemical screen for MURR1-associatedfactors. The family is defined by the presence of a conserved and unique motif termed the COMM (coppermetabolism gene MURR1) domain, which functions as an interface for protein-protein interactions. LikeMURR1, several of these factors also associate with and inhibit NF-kappaB. The proteins designated asCOMMD or COMM domain containing 1-10 are extensively conserved in multicellular eukaryotic organismsand define a novel family of structural and functional homologs of MURR1. The prototype of this family,MURR1/COMMD1, suppresses NF-kappaB not by affecting nuclear translocation or binding of NF-kappaBto cognate motifs; rather, it functions in the nucleus by affecting the association of NF-kappaB withchromatin.", "metadata": {}}
+{"_id": "11861374", "title": "", "text": "Occurrence of chromosome 9 and p53 alterations in multifocal dysplasia and carcinoma in situ of humanurinary bladderTo define the genetic changes of flat urothelial lesions, carcinoma in situ (CIS) andmoderate dysplasias (DII) were investigated for alterations in the two chromosomal regions mostfrequently involved in bladder cancer. Overall, 33 CIS and 16 DII from 21 patients were used tomicrodissect urothelium. Dual color fluorescence in situ hybridization (FISH) using gene locus probes of9q22 (FACC), 9p21 (CDK), 17p13 (p53), and related centromeric probes was applied on interphasenuclei. In parallel, preamplified DNA of these samples was used for loss of heterozygosity (LOH) analyseswith eight microsatellite markers on chromosomes 9p, 9q and 17p, and for sequencing of exons 5-9 ofp53. Data indicated nearly identical deletion frequencies for chromosomes 9 and 17 for CIS (chromosome9, 86%; p53, 84%). DII showed a lower deletion rate in comparison with CIS (chromosome 9, 75%; p53,53%). A very high correlation between the results of FISH and LOH analyses was found. p53 mutationswere detected in 12 of 15 patients (CIS, 72%; DII, 67%). In three of 16 patients with multifocal tumors,oligoclonal lesions were identified by LOH analyses, a finding further supported by sequencing of p53, bywhich two different p53 deletions were detected in two cases. In conclusion, data from microdissected flaturothelial lesions indicate that chromosome 9 deletions cannot be regarded as indicators of papillarygrowth, because they are found frequently in both types of flat lesions of the urothelium: thoseassociated with papillary tumors and those that are not. The similar distribution and lower amount ofgenetic changes in DII render DII a possible precursor lesion of CIS.", "metadata": {}}
+{"_id": "11862753", "title": "", "text": "Fresh meat and further processing characteristics of ham muscles from finishing pigs fed ractopaminehydrochloride.Ractopamine hydrochloride (RAC) has consistently led to an advantage in carcass cuttingyields of finishing pigs and remains a common feed additive in US finishing pig diets. Less is known aboutthe effect of RAC on further processing characteristics. Some researchers have reported advantages inultimate pH of the LM in pigs fed RAC. If a greater ultimate pH was also observed in hams, the increasedpH could affect further processing characteristics and lead to better protein interaction and improvedtextural properties. The objective of this experiment was to determine if RAC-fed pigs yielded hams witha greater ultimate pH, and if so, whether or not that advantage improves textural properties and waterretention of further processed hams. Two hundred hams from barrows and gilts fed RAC or control dietswere selected based on HCW. Hams were fabricated into 5 separate pieces to determine cutting yields,and 6 muscles were evaluated for ultimate pH. Hams were processed to make cured and smoked hams.Ractopamine increased cutting yields of the whole ham (P < 0.0001), inside (P < 0.01), outside (P <0.01), and knuckle (P < 0.01) when expressed as a percentage of chilled side weight. Ultimate pH of therectus femoris, vastus lateralis, and semitendinosus were all 0.06 pH units greater (P < 0.05), the bicepsfemoris was 0.04 pH units greater (P = 0.02), and the semimembranosus and adductor muscles were0.03 pH units greater in pigs fed 7.4 mg/kg of RAC when compared with control pigs. Cured hams fromRAC-fed pigs were heavier at all stages of production. No differences were detected in binding strengths(P = 0.88) or protein fat-free values (P = 0.13) between RAC (9.06 kg and 20.37) and control hams(9.01 kg and 20.13). Ractopamine increased cutting yields, total weight of cured hams, and ultimatemuscle pH. Ractopamine can be fed to pigs to achieve the desired growth characteristic advantages andcutting yields without affecting further processed ham characteristics.", "metadata": {}}
+{"_id": "11868606", "title": "", "text": "Translocated LPS Might Cause Endotoxin Tolerance in Circulating Monocytes of Cystic FibrosisPatientsCystic Fibrosis (CF) is an inherited pleiotropic disease that results from abnormalities in the genecodes of a chloride channel. The lungs of CF patients are chronically infected by several pathogens butbacteraemia have rarely been reported in this pathology. Besides that, circulating monocytes in CFpatients exhibit a patent Endotoxin Tolerance (ET) state since they show a significant reduction of theinflammatory response to bacterial stimulus. Despite a previous description of this phenomenon, thedirect cause of ET in CF patients remains unknown. In this study we have researched the possible role ofmicrobial/endotoxin translocation from a localized infection to the bloodstream as a potential cause of ETinduction in CF patients. Plasma analysis of fourteen CF patients revealed high levels of LPS compared tohealthy volunteers and patients who suffer from Chronic Obstructive Pulmonary Disease. Experiments invitro showed that endotoxin concentrations found in plasma of CF patients were enough to induce an ETphenotype in monocytes from healthy controls. In agreement with clinical data, we failed to detectbacterial DNA in CF plasma. Our results suggest that soluble endotoxin present in bloodstream of CFpatients causes endotoxin tolerance in their circulating monocytes.", "metadata": {}}
+{"_id": "11880289", "title": "", "text": "Effect of mammographic screening from age 40 years on breast cancer mortality in the UK Age trial at 17years' follow-up: a randomised controlled trial.BACKGROUND Age-specific effects of mammographicscreening, and the timing of such effects, are a matter of debate. The results of the UK Age trial, whichcompared the effect of invitation to annual mammographic screening from age 40 years withcommencement of screening at age 50 years on breast cancer mortality, have been reported at 10 yearsof follow-up and showed no significant difference in mortality between the trial groups. Here, we reportthe results of the UK Age trial after 17 years of follow-up. METHODS Women aged 39-41 from 23 UK NHSBreast Screening Programme units years were randomly assigned by individual randomisation (1:2) toeither an intervention group offered annual screening by mammography up to and including the calendaryear of their 48th birthday or to a control group receiving usual medical care (invited for screening at age50 years and every 3 years thereafter). Both groups were stratified by general practice. We comparedbreast cancer incidence and mortality by time since randomisation. Analyses included all womenrandomly assigned who could be traced with the National Health Service Central Register and who hadnot died or emigrated before entry. The primary outcome measures were mortality from breast cancer(defined as deaths with breast cancer coded as the underlying cause of death) and breast cancerincidence, including in-situ, invasive, and total incidence. Because there is an interest in the timing of themortality effect, we analysed the results in different follow-up periods. This trial is registered, numberISRCTN24647151. FINDINGS Between Oct 14, 1990, and Sept 25, 1997, 160 921 participants wererandomly assigned; 53 883 women in the intervention group and 106 953 assigned to usual medical carewere included in this analysis. After a median follow-up of 17 years (IQR 16·8-18·8), the rate ratio (RR)for breast cancer mortality was 0·88 (95% CI 0·74-1·04) from tumours diagnosed during the interventionphase. A significant reduction in breast cancer mortality was noted in the intervention group comparedwith the control group in the first 10 years after diagnosis (RR 0·75, 0·58-0·97) but not thereafter (RR1·02, 0·80-1·30) from tumours diagnosed during the intervention phase. The overall breast cancerincidence during 17 year follow-up was similar between the intervention group and the control group (RR0·98, 0·93-1·04). INTERPRETATION Our results support an early reduction in mortality from breastcancer with annual mammography screening in women aged 40-49 years. Further data are needed tofully understand long-term effects. Cumulative incidence figures suggest at worst a small amount ofoverdiagnosis. FUNDING National Institute for Health Research Health Technology Assessmentprogramme and the American Cancer Society. Past funding was received from the Medical ResearchCouncil, Cancer Research UK, the UK Department of Health, and the US National Cancer Institute.", "metadata": {}}
+{"_id": "11884292", "title": "", "text": "Concordance, disease progression, and heritability of coeliac disease in Italian twins.BACKGROUND ANDAIMS We adopted the twin method to disentangle the genetic and environmental components ofsusceptibility to coeliac disease (CD). We estimated disease concordance rate by zygosity and HLAgenotypes, discordance times, progression rates to disease, and heritability. METHODS We crosslinkedthe Italian Twin Registry with the membership lists of the Italian Coeliac Disease Association andrecruited 23 monozygotic (MZ) and 50 dizygotic (DZ) twin pairs with at least one affected member.Zygosity was assigned by DNA fingerprinting, and HLA-DQ and DR alleles were genotyped. Disease statuswas ascertained by antiendomysial, anti-human tissue transglutaminase antibodies, and bowel biopsy.RESULTS Concordance was significantly higher in MZ (83.3% probandwise, 71.4% pairwise) than in DZ(16.7% probandwise, 9.1% pairwise) pairs. Concordance was not affected by sex or HLA genotype of theco-twin and being MZ was significantly associated with the occurrence of CD (Cox adjusted hazard ratio14.3 (95% confidence interval 4.0-50.3)). In 90% of concordant pairs the discordance time was <or=2years. MZ and DZ co-twins had 70% and 9% cumulative probability of having symptomatic or silentforms of CD, respectively, within five years. Under ACE (additive genetic, common, and unsharedenvironmental factors) models, with CD population prevalences of 1/91 and 1/1000, heritability estimateswere 87% and 57%, respectively. CONCLUSION MZ pairs have a high probability of being concordant,regardless of sex or HLA genotype. Most of the affected co-twins receive a diagnosis within two years. Aremarkable proportion of phenotypic variance is due to genetic factors.", "metadata": {}}
+{"_id": "11884867", "title": "", "text": "A literature review of the safety of medical body area network devices in magnetic resonanceimagingElectro-magnetic fields and wireless technology are part of modern life. The use of MagneticResonance Imaging (MRI) machines for clarification of internal human structures and function inhealthcare is increasing. The rapid development of wireless devices, their miniaturization and theirapplication as clinical tools creates an expanding intersection zone. Although safety standards for devicesin MRI machines have been previously published, it is not clear that newer wireless technologies,including devices used in Medical Body Area Networks (MBAN) have been rigorously tested or disclosed.We undertook a review of the clinical scientific literature and the United States Food and DrugAdministration adverse events database to discover whether this is a significant issue. There are currentlyno published studies specifically addressing the safety of wireless devices potentially used in MBAN in MRImachines. We suggest the addition of a research track to clarify the safety of MBAN devices in MRImachines. Informed design of current and future MBAN components, devices and systems can avoidpotential patient adverse events due to the un-intended consequences of the concurrent use of thesetechnologies in MRI machines.", "metadata": {}}
+{"_id": "11886686", "title": "", "text": "Synaptic glutamate release by ventromedial hypothalamic neurons is part of the neurocircuitry thatprevents hypoglycemia.The importance of neuropeptides in the hypothalamus has been experimentallyestablished. Due to difficulties in assessing function in vivo, the roles of the fast-acting neurotransmittersglutamate and GABA are largely unknown. Synaptic vesicular transporters (VGLUTs for glutamate andVGAT for GABA) are required for vesicular uptake and, consequently, synaptic release ofneurotransmitters. Ventromedial hypothalamic (VMH) neurons are predominantly glutamatergic andexpress VGLUT2. To evaluate the role of glutamate release from VMH neurons, we generated micelacking VGLUT2 selectively in SF1 neurons (a major subset of VMH neurons). These mice havehypoglycemia during fasting secondary to impaired fasting-induced increases in the glucose-raisingpancreatic hormone glucagon and impaired induction in liver of mRNAs encoding PGC-1alpha and thegluconeogenic enzymes PEPCK and G6Pase. Similarly, these mice have defective counterregulatoryresponses to insulin-induced hypoglycemia and 2-deoxyglucose (an antimetabolite). Thus, glutamaterelease from VMH neurons is an important component of the neurocircuitry that functions to preventhypoglycemia.", "metadata": {}}
+{"_id": "11887584", "title": "", "text": "c-Src and cooperating partners in human cancer.The proto-oncogene c-src is rarely mutated in humancancers, and when overexpressed in normal cells is non- or weakly oncogenic. These observations haveraised doubts about the involvement of c-src in the etiology of human tumors. However, recent studieshave shown that c-Src, a non-receptor tyrosine kinase, exhibits elevated protein levels and activity innumerous types of human cancers. Furthermore, it has been found to be a critical component of multiplesignaling pathways that regulate proliferation, survival, metastasis, and angiogenesis. Because of itsimportant role in these oncogenic processes, it represents a therapeutic target ripe for exploitation.", "metadata": {}}
+{"_id": "11899391", "title": "", "text": "Type 1 diabetes-associated IL2RA variation lowers IL-2 signaling and contributes to diminishedCD4+CD25+ regulatory T cell function.Numerous reports have demonstrated that CD4(+)CD25(+)regulatory T cells (Tregs) from individuals with a range of human autoimmune diseases, including type 1diabetes, are deficient in their ability to control autologous proinflammatory responses when comparedwith nondiseased, control individuals. Treg dysfunction could be a primary, causal event or may resultfrom perturbations in the immune system during disease development. Polymorphisms in genesassociated with Treg function, such as IL2RA, confer a higher risk of autoimmune disease. Although thissuggests a primary role for defective Tregs in autoimmunity, a link between IL2RA gene polymorphismsand Treg function has not been examined. We addressed this by examining the impact of an IL2RAhaplotype associated with type 1 diabetes on Treg fitness and suppressive function. Studies wereconducted using healthy human subjects to avoid any confounding effects of disease. We demonstratedthat the presence of an autoimmune disease-associated IL2RA haplotype correlates with diminished IL-2responsiveness in Ag-experienced CD4(+) T cells, as measured by phosphorylation of STAT5a, and isassociated with lower levels of FOXP3 expression by Tregs and a reduction in their ability to suppressproliferation of autologous effector T cells. These data offer a rationale that contributes to the molecularand cellular mechanisms through which polymorphisms in the IL-2RA gene affect immune regulation, andconsequently upon susceptibility to autoimmune and inflammatory diseases.", "metadata": {}}
+{"_id": "11900630", "title": "", "text": "Hematopoietic stem cells and other hematopoietic cells show broad resistance to chemotherapeuticagents in vivo when overexpressing bcl-2.Objective. Chemotherapeutic agents function by inducingapoptosis and their effectiveness depends on the balance of pro- and anti-apoptotic proteins in cells. Dueto the complicated interactions of the many proteins involved, it has been difficult to determine in tumorswhether overexpression of single genes is prognostic for increased resistance. Therefore, we studied theinfluence of bcl-2 overexpression on resistance to chemotherapeutics in a transgenic mouse system. Thisallowed us to study a wide variety of cells, including important but rare populations such ashematopoietic stem cells (HSC).Methods. H2K-bcl-2 transgenic and wild-type (WT) mice were treatedwith several agents(5-fluoruracil, cyclophosphamide, and busulfan) to determine the contribution ofincreased amounts of bcl-2 to the response to these chemotherapeutics in vivo. Populations wereenumerated using flow cytometry. HSC were studied by FACS purification and long-term reconstitutionassays in vivo and resistance was confirmed by short-term proliferation assays with different amounts ofchemotherapeutics in vitro. Results. bcl-2 overexpression alone protects many cell types, thoughprotection levels differ between populations and agents. However, even sensitive populations return topretreatment levels faster in transgenic mice. bcl-2 overexpression also prevents the dramatic changes inHSC following 5-FU treatment (downregulation of c-kit, upregulation of Lin, less efficient long-termreconstitution). In vitro studies directly demonstrate increased resistance of bcl-2 overexpressing HSC tochemotherapeutic agents. Conclusions. Increased expression of bcl-2 in HSC and their progeny endowsthese cells with broad resistance to chemotherapeutic agents. The ability to (differentially) regulatesensitivity to apoptosis of bystander and tumor cells is clinically important.", "metadata": {}}
+{"_id": "11902109", "title": "", "text": "Direct sensing of systemic and nutritional signals by hematopoietic progenitors in DrosophilaTheDrosophila lymph gland is a haematopoietic organ in which progenitor cells, which are most akin to thecommon myeloid progenitor in mammals, proliferate and differentiate into three types of maturecell--plasmatocytes, crystal cells and lamellocytes--the functions of which are reminiscent of mammalianmyeloid cells. During the first and early second instars of larval development, the lymph gland containsonly progenitors, whereas in the third instar, a medial region of the primary lobe of the lymph glandcalled the medullary zone contains these progenitors, and maturing blood cells are found juxtaposed in aperipheral region designated the cortical zone. A third group of cells referred to as the posterior signallingcentre functions as a haematopoietic niche. Similarly to mammalian myeloid cells, Drosophila blood cellsrespond to multiple stresses including hypoxia, infection and oxidative stress. However, how systemicsignals are sensed by myeloid progenitors to regulate cell-fate determination has not been well described.Here, we show that the haematopoietic progenitors of Drosophila are direct targets of systemic (insulin)and nutritional (essential amino acid) signals, and that these systemic signals maintain the progenitors bypromoting Wingless (WNT in mammals) signalling. We expect that this study will promote investigation ofsuch possible direct signal sensing mechanisms by mammalian myeloid progenitors.", "metadata": {}}
+{"_id": "11903247", "title": "", "text": "Regulation of autophagy by cytoplasmic p53Multiple cellular stressors, including activation of the tumoursuppressor p53, can stimulate autophagy. Here we show that deletion, depletion or inhibition of p53 caninduce autophagy in human, mouse and nematode cells subjected to knockout, knockdown orpharmacological inhibition of p53. Enhanced autophagy improved the survival of p53-deficient cancercells under conditions of hypoxia and nutrient depletion, allowing them to maintain high ATP levels.Inhibition of p53 led to autophagy in enucleated cells, and cytoplasmic, not nuclear, p53 was able torepress the enhanced autophagy of p53−/− cells. Many different inducers of autophagy (for example,starvation, rapamycin and toxins affecting the endoplasmic reticulum) stimulated proteasome-mediateddegradation of p53 through a pathway relying on the E3 ubiquitin ligase HDM2. Inhibition of p53degradation prevented the activation of autophagy in several cell lines, in response to several distinctstimuli. These results provide evidence of a key signalling pathway that links autophagy to thecancer-associated dysregulation of p53.", "metadata": {}}
+{"_id": "11913139", "title": "", "text": "The Neurobiology of Sleep: Genetics, cellular physiology and subcortical networksTo appreciate theneural underpinnings of sleep, it is important to view this universal mammalian behaviour at multiplelevels of its biological organization. Molecularly, the circadian rhythm of sleep involves interlockingpositive- and negative-feedback mechanisms of circadian genes and their protein products in cells of thesuprachiasmatic nucleus that are entrained to ambient conditions by light. Circadian information isintegrated with information on homeostatic sleep need in nuclei of the anterior hypothalamus. Thesenuclei interact with arousal systems in the posterior hypothalamus, basal forebrain and brainstem tocontrol sleep onset. During sleep, an ultradian oscillator in the mesopontine junction controls the regularalternation of rapid eye movement (REM) and non-REM sleep. Sleep cycles are accompanied byneuromodulatory influences on forebrain structures that influence behaviour, consciousness andcognition.", "metadata": {}}
+{"_id": "11915280", "title": "", "text": "Suppression of intestinal neoplasia by deletion of Dnmt3bAberrant gene silencing accompanied by DNAmethylation is associated with neoplastic progression in many tumors that also show global loss of DNAmethylation. Using conditional inactivation of de novo methyltransferase Dnmt3b in Apc(Min/+) mice, wedemonstrate that the loss of Dnmt3b has no impact on microadenoma formation, which is considered theearliest stage of intestinal tumor formation. Nevertheless, we observed a significant decrease in theformation of macroscopic colonic adenomas. Interestingly, many large adenomas showed regions withDnmt3b inactivation, indicating that Dnmt3b is required for initial outgrowth of macroscopic adenomasbut is not required for their maintenance. These results support a role for Dnmt3b in the transition stagebetween microadenoma formation and macroscopic colonic tumor growth and further suggest thatDnmt3b, and by extension de novo methylation, is not required for maintaining tumor growth after thistransition stage has occurred.", "metadata": {}}
+{"_id": "11921405", "title": "", "text": "Epithelium-intrinsic NAIP/NLRC4 inflammasome drives infected enterocyte expulsion to restrictSalmonella replication in the intestinal mucosa.The gut mucosal epithelium separates the host from themicrobiota, but enteropathogens such as Salmonella Typhimurium (S.Tm) can invade and breach thisbarrier. Defenses against such acute insults remain incompletely understood. Using a murine model ofSalmonella enterocolitis, we analyzed mechanisms limiting pathogen loads in the epithelium during earlyinfection. Although the epithelium-invading S.Tm replicate initially, this intraepithelial replicative niche isrestricted by expulsion of infected enterocytes into the lumen. This mechanism is compromised ifinflammasome components (NAIP1-6, NLRC4, caspase-1/-11) are deleted, or ablated specifically in theepithelium, resulting in \u0000100-fold higher intraepithelial loads and accelerated lymph node colonization.Interestingly, the cytokines downstream of inflammasome activation, interleukin (IL)-1α/β and IL-18,appear dispensable for epithelial restriction of early infection. These data establish the role of anepithelium-intrinsic inflammasome, which drives expulsion of infected cells to restrict the pathogen'sintraepithelial proliferation. This may represent a general defense mechanism against mucosal infections.", "metadata": {}}
+{"_id": "11922370", "title": "", "text": "GEMC1 is a TopBP1 interacting protein required for chromosomal DNA replicationMany of the factorsrequired for chromosomal DNA replication have been identified in unicellular eukaryotes. However, DNAreplication is poorly understood in multicellular organisms. Here, we report the identification of GEMC1(geminin coiled-coil containing protein 1), a novel vertebrate protein required for chromosomal DNAreplication. GEMC1 is highly conserved in vertebrates and is preferentially expressed in proliferating cells.Using Xenopus laevis egg extract we show that Xenopus GEMC1 (xGEMC1) binds to the checkpoint andreplication factor TopBP1, which promotes binding of xGEMC1 to chromatin during pre-replicationcomplex (pre-RC) formation. We demonstrate that xGEMC1 interacts directly with replication factors suchas Cdc45 and the kinase Cdk2-CyclinE, through which it is heavily phosphorylated. PhosphorylatedxGEMC1 stimulates initiation of DNA replication, whereas depletion of xGEMC1 prevents the onset of DNAreplication owing to the impairment of Cdc45 loading onto chromatin. Similarly, inhibition of GEMC1expression with morpholino and siRNA oligos prevents DNA replication in embryonic and somaticvertebrate cells. These data suggest that GEMC1 promotes initiation of chromosomal DNA replication inmulticellular organisms by mediating TopBP1- and Cdk2-dependent recruitment of Cdc45 onto replicationorigins.", "metadata": {}}
+{"_id": "11933721", "title": "", "text": "Does an arthroscopic suture bridge technique maintain repair integrity?: a serial evaluation byultrasonography.UNLABELLED Biomechanical studies suggest a suture bridge technique enhances rotatorcuff tendon footprint contact area, holding strength, and mean contact pressure. Based on these studies,we asked whether (1) the suture bridge technique would provide a high rate of cuff integrity aftersurgery, (2) the status of the repaired cuff would change with time, (3) preoperative factors could predictpostoperative cuff integrity, and (4) patients with retears had less favorable pain, functional scores,range of motion (ROM), and muscle strength compared with those with intact repairs. We prospectivelyfollowed 78 patients with arthroscopic repairs in whom we used the suture bridge technique. The integrityof the rotator cuff repair was determined using ultrasonographic evaluation at 4.5 and 12 months aftersurgery. Ultrasonography revealed intact cuffs in 91% at 4.5 months postoperatively, all of which weremaintained at the 12-month followup. Failure rates were 17.6% (three of 17) for massive tears, 11.1%(two of 18) for large tears, 6.3% (two of 32) for medium tears, and no failures for small tears.Preoperative fatty degeneration of the supraspinatus muscle was a strong predictor of cuff integrity. Wefound no correlation between the integrity and clinical outcomes except for a temporary decrease ofabduction strength at 6 months. Arthroscopic repair using suture bridge technique can achieve a lowretear rate in shoulders treated for rotator cuff tears, but the occurrence of retear did not influence theoutcome. LEVEL OF EVIDENCE Level IV, therapeutic study. See Guidelines for Authors for a completedescription of levels of evidence.", "metadata": {}}
+{"_id": "11935250", "title": "", "text": "Widespread and tissue specific age-related DNA methylation changes in mice.Aberrant methylation ofpromoter CpG islands in cancer is associated with silencing of tumor-suppressor genes, andage-dependent hypermethylation in normal appearing mucosa may be a risk factor for human coloncancer. It is not known whether this age-related DNA methylation phenomenon is specific to humantissues. We performed comprehensive DNA methylation profiling of promoter regions in aging mouseintestine using methylated CpG island amplification in combination with microarray analysis. Bycomparing C57BL/6 mice at 3-mo-old versus 35-mo-old for 3627 detectable autosomal genes, we found774 (21%) that showed increased methylation and 466 (13%) that showed decreased methylation. Weused pyrosequencing to quantitatively validate the microarray data and confirmed linear age-relatedmethylation changes for all 12 genomic regions examined. We then examined 11 changed genomic locifor age-related methylation in other tissues. Of these, three of 11 showed similar changes in lung, sevenof 11 changed in liver, and six of 11 changed in spleen, though to a lower degree than the changes seenin colon. There was partial conservation between age-related hypermethylation in human and mouseintestines, and Polycomb targets in embryonic stem cells were enriched among the hypermethylatedgenes. Our findings demonstrate a surprisingly high rate of hyper- and hypomethylation as a function ofage in normal mouse small intestine tissues and a strong tissue-specificity to the process. We concludethat epigenetic deregulation is a common feature of aging in mammals.", "metadata": {}}
+{"_id": "11936877", "title": "", "text": "Environmental and economic costs of soil erosion and conservation benefits.Soil erosion is a majorenvironmental threat to the sustainability and productive capacity of agriculture. During the last 40 years,nearly one-third of the world's arable land has been lost by erosion and continues to be lost at a rate ofmore than 10 million hectares per year. With the addition of a quarter of a million people each day, theworld population's food demand is increasing at a time when per capita food productivity is beginning todecline.", "metadata": {}}
+{"_id": "11939159", "title": "", "text": "Association between influenza vaccination and cardiovascular outcomes in high-risk patients: ameta-analysis.IMPORTANCE Among nontraditional cardiovascular risk factors, recent influenzalikeinfection is associated with fatal and nonfatal atherothrombotic events. OBJECTIVES To determine ifinfluenza vaccination is associated with prevention of cardiovascular events. DATA SOURCES AND STUDYSELECTION A systematic review and meta-analysis of MEDLINE (1946-August 2013), EMBASE(1947-August 2013), and the Cochrane Library Central Register of Controlled Trials (inception-August2013) for randomized clinical trials (RCTs) comparing influenza vaccine vs placebo or control in patientsat high risk of cardiovascular disease, reporting cardiovascular outcomes either as efficacy or safetyevents. DATA EXTRACTION AND SYNTHESIS Two investigators extracted data independently on trialdesign, baseline characteristics, outcomes, and safety events from published manuscripts andunpublished supplemental data. High-quality studies were considered those that described an appropriatemethod of randomization, allocation concealment, blinding, and completeness of follow-up. MAINOUTCOMES AND MEASURES Random-effects Mantel-Haenszel risk ratios (RRs) and 95% CIs were derivedfor composite cardiovascular events, cardiovascular mortality, all-cause mortality, and individualcardiovascular events. Analyses were stratified by subgroups of patients with and without a history ofacute coronary syndrome (ACS) within 1 year of randomization. RESULTS Five published and 1unpublished randomized clinical trials of 6735 patients (mean age, 67 years; 51.3% women; 36.2% witha cardiac history; mean follow-up time, 7.9 months) were included. Influenza vaccine was associatedwith a lower risk of composite cardiovascular events (2.9% vs 4.7%; RR, 0.64 [95% CI, 0.48-0.86], P =.003) in published trials. A treatment interaction was detected between patients with (RR, 0.45 [95% CI,0.32-0.63]) and without (RR, 0.94 [95% CI, 0.55-1.61]) recent ACS (P for interaction = .02). Resultswere similar with the addition of unpublished data. CONCLUSIONS AND RELEVANCE In a meta-analysis ofRCTs, the use of influenza vaccine was associated with a lower risk of major adverse cardiovascularevents. The greatest treatment effect was seen among the highest-risk patients with more activecoronary disease. A large, adequately powered, multicenter trial is warranted to address these findingsand assess individual cardiovascular end points.", "metadata": {}}
+{"_id": "11943989", "title": "", "text": "Baby hands that move to the rhythm of language: hearing babies acquiring sign languages babble silentlyon the handsThe \"ba, ba, ba\" sound universal to babies' babbling around 7 months captures scientificattention because it provides insights into the mechanisms underlying language acquisition and vestigesof its evolutionary origins. Yet the prevailing mystery is what is the biological basis of babbling, with onehypothesis being that it is a non-linguistic motoric activity driven largely by the baby's emerging controlover the mouth and jaw, and another being that it is a linguistic activity reflecting the babies' earlysensitivity to specific phonetic-syllabic patterns. Two groups of hearing babies were studied over time(ages 6, 10, and 12 months), equal in all developmental respects except for the modality of languageinput (mouth versus hand): three hearing babies acquiring spoken language (group 1: \"speech-exposed\")and a rare group of three hearing babies acquiring sign language only, not speech (group 2:\"sign-exposed\"). Despite this latter group's exposure to sign, the motoric hypothesis would predict similarhand activity to that seen in speech-exposed hearing babies because language acquisition insign-exposed babies does not involve the mouth. Using innovative quantitative Optotrak 3-Dmotion-tracking technology, applied here for the first time to study infant language acquisition, weobtained physical measurements similar to a speech spectrogram, but for the hands. Here we discoveredthat the specific rhythmic frequencies of the hands of the sign-exposed hearing babies differed dependingon whether they were producing linguistic activity, which they produced at a low frequency ofapproximately 1 Hz, versus non-linguistic activity, which they produced at a higher frequency ofapproximately 2.5 Hz - the identical class of hand activity that the speech-exposed hearing babiesproduced nearly exclusively. Surprisingly, without benefit of the mouth, hearing sign-exposed babiesalone babbled systematically on their hands. We conclude that babbling is fundamentally a linguisticactivity and explain why the differentiation between linguistic and non-linguistic hand activity in a singlemanual modality (one distinct from the human mouth) could only have resulted if all babies are born witha sensitivity to specific rhythmic patterns at the heart of human language and the capacity to use them.", "metadata": {}}
+{"_id": "11951999", "title": "", "text": "The Ten-Eleven Translocation-2 (TET2) gene in hematopoiesis and hematopoietic diseasesTen-ElevenTranslocation-2 (TET2) inactivation through loss-of-function mutation, deletion and IDH1/2 (IsocitrateDehydrogenase 1 and 2) gene mutation is a common event in myeloid and lymphoid malignancies. TET2gene mutations similar to those observed in myeloid and lymphoid malignancies also accumulate withage in otherwise healthy subjects with clonal hematopoiesis. TET2 is one of the three proteins of the TET(Ten-Eleven Translocation) family, which are evolutionarily conserved dioxygenases that catalyze theconversion of 5-methyl-cytosine (5-mC) to 5-hydroxymethyl-cytosine (5-hmC) and promote DNAdemethylation. TET dioxygenases require 2-oxoglutarate, oxygen and Fe(II) for their activity, which isenhanced in the presence of ascorbic acid. TET2 is the most expressed TET gene in the hematopoietictissue, especially in hematopoietic stem cells. In addition to their hydroxylase activity, TET proteinsrecruit the O-linked β-D-N-acetylglucosamine (O-GlcNAc) transferase (OGT) enzyme to chromatin, whichpromotes post-transcriptional modifications of histones and facilitates gene expression. The TET2 level isregulated by interaction with IDAX, originating from TET2 gene fission during evolution, and by themicroRNA miR-22. TET2 has pleiotropic roles during hematopoiesis, including stem-cell self-renewal,lineage commitment and terminal differentiation of monocytes. Analysis of Tet2 knockout mice, which areviable and fertile, demonstrated that Tet2 functions as a tumor suppressor whose haploinsufficiencyinitiates myeloid and lymphoid transformations. This review summarizes the recently identified TET2physiological and pathological functions and discusses how this knowledge influences our therapeuticapproaches in hematological malignancies and possibly other tumor types.", "metadata": {}}
+{"_id": "11953232", "title": "", "text": "Impaired Awareness of Hypoglycemia in a Population-Based Sample of Children and Adolescents WithType 1 DiabetesOBJECTIVE To determine the prevalence and clinical associations of impaired awarenessof hypoglycemia in a population-based sample of children and adolescents with type 1 diabetes.RESEARCH DESIGN AND METHODS A validated questionnaire was administered to 656 patients with type1 diabetes over a 6-month period to determine hypoglycemia awareness status. Case ascertainment was79% of the clinic population. The rate of severe hypoglycemia was determined by data collectedprospectively in the preceding year. RESULTS Impaired awareness of hypoglycemia was present in 29%of patients. Patients with impaired awareness of hypoglycemia had an earlier onset of diabetes (P <0.001), were younger (P < 0.001), and had lower mean levels of A1C since diabetes onset (P = 0.006)and at their last visit (P = 0.001). The overall rate of severe hypoglycemia was 24.5 episodes per 100patient-years in the preceding year. The severe hypoglycemia rate was higher in those with impairedawareness of hypoglycemia (37.1 vs. 19.3 episodes per 100 patient-years, P < 0.001). Among patientsaged <6 years (n = 46), 59% of care providers reported impaired awareness of hypoglycemia, and therate of severe hypoglycemia was significantly higher in those reporting impaired awareness (33.3 vs. 52episodes per 100 patient-years, P = 0.02). More patients with recurrent hypoglycemia reported impairedawareness of hypoglycemia (47 vs. 28%, P = 0.03). CONCLUSIONS A significant proportion of childrenand adolescents with type 1 diabetes have impaired awareness of hypoglycemia. Screening for impairedawareness is an important component of routine diabetes care and can identify patients at increased riskof a severe hypoglycemic event.", "metadata": {}}
+{"_id": "11968641", "title": "", "text": "Enhancing circadian clock function in cancer cells inhibits tumor growthBACKGROUND Circadian clockscontrol cell cycle factors, and circadian disruption promotes cancer. To address whether enhancingcircadian rhythmicity in tumor cells affects cell cycle progression and reduces proliferation, we comparedgrowth and cell cycle events of B16 melanoma cells and tumors with either a functional or dysfunctionalclock. RESULTS We found that clock genes were suppressed in B16 cells and tumors, but treatmentsinducing circadian rhythmicity, such as dexamethasone, forskolin and heat shock, triggered rhythmicclock and cell cycle gene expression, which resulted in fewer cells in S phase and more in G1 phase.Accordingly, B16 proliferation in vitro and tumor growth in vivo was slowed down. Similar effects wereobserved in human colon carcinoma HCT-116 cells. Notably, the effects of dexamethasone were not dueto an increase in apoptosis nor to an enhancement of immune cell recruitment to the tumor. Knockingdown the essential clock gene Bmal1 in B16 tumors prevented the effects of dexamethasone on tumorgrowth and cell cycle events. CONCLUSIONS Here we demonstrated that the effects of dexamethasoneon cell cycle and tumor growth are mediated by the tumor-intrinsic circadian clock. Thus, our workreveals that enhancing circadian clock function might represent a novel strategy to control cancerprogression.", "metadata": {}}
+{"_id": "11983390", "title": "", "text": "Distinct functions of nucleotide-binding/hydrolysis sites in the four AAA modules of cytoplasmicdynein.Cytoplasmic dynein is a microtubule-based motor protein that is responsible for most intracellularretrograde transports along microtubule filaments. The motor domain of dynein contains six tandemlylinked AAA (ATPases associated with diverse cellular activities) modules, with the first four containingpredicted nucleotide-binding/hydrolysis sites (P1-P4). To dissect the functions of these multiplenucleotide-binding/hydrolysis sites, we expressed and purified Dictyostelium dynein motor domains inwhich mutations were introduced to block nucleotide binding at each of the four AAA modules, and thenexamined their detailed biochemical properties. The P1 mutant was trapped in a strong-binding stateeven in the presence of ATP and lost its motile activity. The P3 mutant also showed a high affinity formicrotubules in the presence of ATP and lost most of the microtubule-activated ATPase activity, butretained microtubule sliding activity, although the sliding velocity of the mutant was more than 20-foldslower than that of the wild type. In contrast, mutation in the P2 or P4 site did not affect the apparentbinding affinity of the mutant for microtubules in the presence of ATP, but reduced ATPase andmicrotubule sliding activities. These results indicate that ATP binding and its hydrolysis only at the P1 siteare essential for the motor activities of cytoplasmic dynein, and suggest that the othernucleotide-binding/hydrolysis sites regulate the motor activities. Among them, nucleotide binding at theP3 site is not essential but is critical for microtubule-activated ATPase and motile activities of cytoplasmicdynein.", "metadata": {}}
+{"_id": "11992632", "title": "", "text": "Over-expression of RCAN1 causes Down syndrome-like hippocampal deficits that alter learning andmemory.People with Down syndrome (DS) exhibit abnormal brain structure. Alterations affectingneurotransmission and signalling pathways that govern brain function are also evident. A large number ofgenes are simultaneously expressed at abnormal levels in DS; therefore, it is a challenge to determinewhich gene(s) contribute to specific abnormalities, and then identify the key molecular pathwaysinvolved. We generated RCAN1-TG mice to study the consequences of RCAN1 over-expression andinvestigate the contribution of RCAN1 to the brain phenotype of DS. RCAN1-TG mice exhibit structuralbrain abnormalities in those areas affected in DS. The volume and number of neurons within thehippocampus is reduced and this correlates with a defect in adult neurogenesis. The density of dendriticspines on RCAN1-TG hippocampal pyramidal neurons is also reduced. Deficits in hippocampal-dependentlearning and short- and long-term memory are accompanied by a failure to maintain long-termpotentiation (LTP) in hippocampal slices. In response to LTP induction, we observed diminished calciumtransients and decreased phosphorylation of CaMKII and ERK1/2-proteins that are essential for themaintenance of LTP and formation of memory. Our data strongly suggest that RCAN1 plays an importantrole in normal brain development and function and its up-regulation likely contributes to the neuraldeficits associated with DS.", "metadata": {}}
+{"_id": "12009265", "title": "", "text": "Vitamins E and C in the prevention of prostate and total cancer in men: the Physicians' Health Study IIrandomized controlled trial.CONTEXT Many individuals take vitamins in the hopes of preventing chronicdiseases such as cancer, and vitamins E and C are among the most common individual supplements. Alarge-scale randomized trial suggested that vitamin E may reduce risk of prostate cancer; however, fewtrials have been powered to address this relationship. No previous trial in men at usual risk has examinedvitamin C alone in the prevention of cancer. OBJECTIVE To evaluate whether long-term vitamin E or Csupplementation decreases risk of prostate and total cancer events among men. DESIGN, SETTING, ANDPARTICIPANTS The Physicians' Health Study II is a randomized, double-blind, placebo-controlled factorialtrial of vitamins E and C that began in 1997 and continued until its scheduled completion on August 31,2007. A total of 14,641 male physicians in the United States initially aged 50 years or older, including1307 men with a history of prior cancer at randomization, were enrolled. INTERVENTION Individualsupplements of 400 IU of vitamin E every other day and 500 mg of vitamin C daily. MAIN OUTCOMEMEASURES Prostate and total cancer. RESULTS During a mean follow-up of 8.0 years, there were 1008confirmed incident cases of prostate cancer and 1943 total cancers. Compared with placebo, vitamin Ehad no effect on the incidence of prostate cancer (active and placebo vitamin E groups, 9.1 and 9.5events per 1000 person-years; hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.85-1.09; P =.58) or total cancer (active and placebo vitamin E groups, 17.8 and 17.3 cases per 1000 person-years;HR, 1.04; 95% CI, 0.95-1.13; P = .41). There was also no significant effect of vitamin C on total cancer(active and placebo vitamin C groups, 17.6 and 17.5 events per 1000 person-years; HR, 1.01; 95% CI,0.92-1.10; P = .86) or prostate cancer (active and placebo vitamin C groups, 9.4 and 9.2 cases per 1000person-years; HR, 1.02; 95% CI, 0.90-1.15; P = .80). Neither vitamin E nor vitamin C had a significanteffect on colorectal, lung, or other site-specific cancers. Adjustment for adherence and exclusion of thefirst 4 or 6 years of follow-up did not alter the results. Stratification by various cancer risk factorsdemonstrated no significant modification of the effect of vitamin E on prostate cancer risk or either agenton total cancer risk. CONCLUSIONS In this large, long-term trial of male physicians, neither vitamin E norC supplementation reduced the risk of prostate or total cancer. These data provide no support for the useof these supplements for the prevention of cancer in middle-aged and older men. TRIAL REGISTRATIONclinicaltrials.gov Identifier: NCT00270647.", "metadata": {}}
+{"_id": "12014458", "title": "", "text": "Micromanagers of gene expression: the potentially widespread influence of metazoan microRNAsWepropose that the microRNA milieu, unique to each cell type, productively dampens the expression ofthousands of mRNAs and provides important context for the evolution of all metazoan mRNA sequences.For genes that should not be expressed in a particular cell type, protein output is lowered toinconsequential levels. For other genes, dosage is adjusted in a manner that allows for customizedexpression in different cell types while achieving a more uniform level within each cell type. In theseways, the microRNAs add an extensive layer of gene control that integrates with transcriptional and otherregulatory processes to expand the complexity of metazoan gene expression.", "metadata": {}}
+{"_id": "12030318", "title": "", "text": "The Kinase Regulator Mob1 Acts as a Patterning Protein for Stentor MorphogenesisMorphogenesis andpattern formation are vital processes in any organism, whether unicellular or multicellular. But in contrastto the developmental biology of plants and animals, the principles of morphogenesis and patternformation in single cells remain largely unknown. Although all cells develop patterns, they are mostobvious in ciliates; hence, we have turned to a classical unicellular model system, the giant ciliate Stentorcoeruleus. Here we show that the RNA interference (RNAi) machinery is conserved in Stentor. UsingRNAi, we identify the kinase coactivator Mob1--with conserved functions in cell division andmorphogenesis from plants to humans-as an asymmetrically localized patterning protein required forglobal patterning during development and regeneration in Stentor. Our studies reopen the door forStentor as a model regeneration system.", "metadata": {}}
+{"_id": "12030680", "title": "", "text": "Measurement and clinical monitoring of human lymphocyte clonality by massively parallel VDJpyrosequencing.The complex repertoire of immune receptors generated by B and T cells enablesrecognition of diverse threats to the host organism. In this work, we show that massively parallel DNAsequencing of rearranged immune receptor loci can provide direct detection and tracking of immunediversity and expanded clonal lymphocyte populations in physiological and pathological contexts. DNAwas isolated from blood and tissue samples, a series of redundant primers was used to amplify diverseDNA rearrangements, and the resulting mixtures of barcoded amplicons were sequenced using long-readultra deep sequencing. Individual DNA molecules were then characterized on the basis of DNA segmentsthat had been joined to make a functional (or nonfunctional) immune effector. Current experimentaldesigns can accommodate up to 150 samples in a single sequence run, with the depth of sequencingsufficient to identify stable and dynamic aspects of the immune repertoire in both normal and diseasedcircumstances. These data provide a high-resolution picture of immune spectra in normal individuals andin patients with hematological malignancies, illuminating, in the latter case, both the initial behavior ofclonal tumor populations and the later suppression or re-emergence of such populations after treatment.", "metadata": {}}
+{"_id": "12030735", "title": "", "text": "Can we apply the National Cholesterol Education Program Adult Treatment Panel definition of themetabolic syndrome to Asians?OBJECTIVE Limited information is available about the metabolic syndromein Asians. Furthermore, the definition of central obesity using waist circumference may not be appropriatefor Asians. The objectives of this study were to determine the optimal waist circumference for diagnosingcentral obesity in Asians and to estimate the prevalence of the metabolic syndrome in an Asianpopulation. RESEARCH DESIGN AND METHODS We used data from the 1998 Singapore National HealthSurvey, a cross-sectional survey involving 4,723 men and women of Chinese, Malay, and Asian-Indianethnicity aged 18-69 years. Receiver operating characteristic analysis suggested that waist circumference>80 cm in women and >90 cm in men was a more appropriate definition of central obesity in thispopulation. The prevalence of the metabolic syndrome was then determined using the NationalCholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria with and without themodified waist circumference criteria. RESULTS In Asians, decreasing waist circumference increased thecrude prevalence of the metabolic syndrome from 12.2 to 17.9%. Using the modified Asian criteria, theprevalence of the metabolic syndrome increased from 2.9% in those aged 18-30 years to 31.0% in thoseaged 60-69 years. It was more common in men (prevalence 20.9% in men versus 15.5% in women; P <0.001) and Asian Indians (prevalence 28.8% in Asian-Indians, 24.2% in Malays, and 14.8% in Chinese; P< 0.001). CONCLUSIONS NCEP ATP III criteria, applied to an Asian population, will underestimate thepopulation at risk. With a lower waist circumference cutoff, the prevalence of the metabolic syndrome iscomparable to that in Western populations. Ethnic differences are likely to exist between populationsacross Asia.", "metadata": {}}
+{"_id": "12039953", "title": "", "text": "Serotonin and fluoxetine levels in plasma and platelets after fluoxetine treatment in depressivepatients.Depression is a mood disorder characterized by complex alterations of neurotransmitters such asserotonin, norepinephrine, and dopamine. In particular, there is substantial evidence of abnormalities inserotonin neurotransmission. Peripheral parameters of serotoninergic transmission, such as the5-hydroxytryptamine content of plasma and platelets, have been used to identify biochemical alterationsrelated to depression. In recent years, these parameters have also been used to examine the mechanismof action of antidepressive drugs such as the selective serotonin reuptake inhibitors. This studyinvestigated the interaction between the plasma and platelet levels of fluoxetine and serotonin afterfluoxetine administration to depressed patients. Twelve patients affected by major depression (accordingto the DSM-IV criteria) received a single oral dose of fluoxetine in the morning: 5 mg in the first 5 days,10 mg from day 6 to day 10, and 20 mg from day 11 to day 40. Blood samples were collected at 0, 7, 10,and 24 hours after drug administration on the day 1 of fluoxetine 5 mg and on the 1st and the 30th dayof fluoxetine 20 mg (days 11 and 40 of treatment, respectively). Plasma fluoxetine and serotonin levelsincreased after drug administration, reaching the highest levels on the 30th day of fluoxetine 20 mg.Fluoxetine levels were also detectable in platelets, with a time variation similar to plasma values. Plateletserotonin levels decreased after drug administration, and the lowest values were observed on the 30thday of fluoxetine 20 mg.", "metadata": {}}
+{"_id": "12040627", "title": "", "text": "The histone acetyltransferase MOF is a key regulator of the embryonic stem cell core transcriptionalnetwork.Pluripotent embryonic stem cells (ESCs) maintain self-renewal and the potential for rapidresponse to differentiation cues. Both ESC features are subject to epigenetic regulation. Here we showthat the histone acetyltransferase Mof plays an essential role in the maintenance of ESC self-renewal andpluripotency. ESCs with Mof deletion lose characteristic morphology, alkaline phosphatase (AP) staining,and differentiation potential. They also have aberrant expression of the core transcription factors Nanog,Oct4, and Sox2. Importantly, the phenotypes of Mof null ESCs can be partially suppressed by Nanogoverexpression, supporting the idea that Mof functions as an upstream regulator of Nanog in ESCs.Genome-wide ChIP-sequencing and transcriptome analyses further demonstrate that Mof is an integralcomponent of the ESC core transcriptional network and that Mof primes genes for diverse developmentalprograms. Mof is also required for Wdr5 recruitment and H3K4 methylation at key regulatory loci,highlighting the complexity and interconnectivity of various chromatin regulators in ESCs.", "metadata": {}}
+{"_id": "12058271", "title": "", "text": "Role of the CXCR4/SDF-1 chemokine axis in circulating neutrophil homeostasis.The bone marrow is theprimary site for neutrophil production and release into the circulation. Because the CXC chemokinereceptor-4/stromal derived factor-1 (CXCR4/SDF-1) axis plays a central role in the interactions ofhematopoietic stem cells, lymphocytes, and developing neutrophils in the marrow, we investigatedwhether reciprocal CXCR4-dependent mechanisms might be involved in neutrophil release andsubsequent return to the marrow following circulation. Neutralizing antibody to CXCR4 reduced marrowretention of infused neutrophils (45.7% +/- 0.5% to 6.9% +/- 0.5%) and was found to mobilizeneutrophils from marrow (34.4% +/- 4.4%). Neutrophil CXCR4 expression and SDF-1-induced calciumflux decreased with maturation and activation of the cells, corresponding to the decreased marrowhoming associated with these characteristics in vivo. Infusion of the inflammatory mediator and CXCR2ligand KC led to mobilization of neutrophils from marrow by itself and was augmented 3-fold by low dosesof CXCR4-blocking antibody that otherwise had no mobilizing effect. Examination of KC and SDF-1calcium signaling demonstrated that the effect of KC may, in part, be due to heterologous desensitizationto SDF-1. These results suggest that the CXCR4/SDF-1 axis is critical in circulating neutrophilhomeostasis and that it may participate in the rapid release of neutrophils from the marrow duringinflammation through a novel interaction with inflammatory CXC chemokines.", "metadata": {}}
+{"_id": "12074066", "title": "", "text": "Vitamin D and prevention of colorectal cancer.BACKGROUND Inadequate photosynthesis or oral intake ofVitamin D are associated with high incidence rates of colorectal cancer, but the dose-responserelationship has not been adequately studied. METHODS Dose-response gradients from observationalstudies of Vitamin D intake and serum 25-hydroxyvitamin D were plotted as trend lines. The point oneach linear trend line corresponding to an odds ratio of 0.50 provided the prediagnostic Vitamin D intakeor 25-hydroxyvitamin D concentration associated with 50% lower risk compared to <100IU/day VitaminD or <13ng/ml serum 25-hydroxyvitamin D. Medians of these values were determined. RESULTS Overall,individuals with >or=1000IU/day oral Vitamin D (p<0.0001) or >or=33ng/ml (82nmol/l) serum25-hydroxyvitamin D (p<0.01) had 50% lower incidence of colorectal cancer compared to referencevalues. CONCLUSIONS Intake of 1000IU/day of Vitamin D, half the safe upper intake established by theNational Academy of Sciences, was associated with 50% lower risk. Serum 25-hydroxyvitamin D of33ng/ml, which is known to be safe, also was associated with 50% lower risk. Prompt public health actionis needed to increase intake of Vitamin D(3) to 1000IU/day, and to raise 25-hydroxyvitamin D byencouraging a modest duration of sunlight exposure.", "metadata": {}}
+{"_id": "12086599", "title": "", "text": "Repeat expansion in the budding yeast ribosomal DNA can occur independently of the canonicalhomologous recombination machineryMajor eukaryotic genomic elements, including the ribosomal DNA(rDNA), are composed of repeated sequences with well-defined copy numbers that must be maintainedby regulated recombination. Although mechanisms that instigate rDNA recombination have beenidentified, none are directional and they therefore cannot explain precise repeat number control. Here, weshow that yeast lacking histone chaperone Asf1 undergo reproducible rDNA repeat expansions. Theseexpansions do not require the replication fork blocking protein Fob1 and are therefore independent ofknown rDNA expansion mechanisms. We propose the existence of a regulated rDNA repeat gain pathwaythat becomes constitutively active in asf1Δ mutants. Cells lacking ASF1 accumulate rDNA repeats withhigh fidelity in a processive manner across multiple cell divisions. The mechanism of repeat gain isdependent on highly repetitive sequence but, surprisingly, is independent of the homologousrecombination proteins Rad52, Rad51 and Rad59. The expansion mechanism is compromised bymutations that decrease the processivity of DNA replication, which leads to progressive loss of rDNArepeats. Our data suggest that a novel mode of break-induced replication occurs in repetitive DNA that isdependent on high homology but does not require the canonical homologous recombination machinery.", "metadata": {}}
+{"_id": "12086818", "title": "", "text": "cDNA and genomic cloning of lacritin, a novel secretion enhancing factor from the human lacrimalgland.Multiple extracellular factors are hypothesized to promote the differentiation of unstimulated and/orstimulated secretory pathways in exocrine secretory cells, but the identity of differentiation factors,particularly those organ-specific, remain largely unknown. Here, we report on the identification of a novelsecreted glycoprotein, lacritin, that enhances exocrine secretion in overnight cultures of lacrimal acinarcells which otherwise display loss of secretory function. Lacritin mRNA and protein are highly expressed inhuman lacrimal gland, moderately in major and minor salivary glands and slightly in thyroid. No lacritinmessage or protein is detected elsewhere among more than 50 human tissues examined. Lacritindisplays partial similarity to the glycosaminoglycan-binding region of brain-specific neuroglycan C (32 %identity over 102 amino acid residues) and to the possibly mucin-like amino globular region of fibulin-2(30 % identity over 81 amino acid residues), and localizes primarily to secretory granules and secretoryfluid. The lacritin gene consists of five exons, displays no alternative splicing and maps to 12q13.Recombinant lacritin augments unstimulated but not stimulated acinar cell secretion, promotes ductal cellproliferation, and stimulates signaling through tyrosine phosphorylation and release of calcium. It bindscollagen IV, laminin-1, entactin/nidogen-1, fibronectin and vitronectin, but not collagen I, heparin or EGF.As an autocrine/paracrine enhancer of the lacrimal constitutive secretory pathway, ductal cell mitogenand stimulator of corneal epithelial cells, lacritin may play a key role in the function of the lacrimalgland-corneal axis.", "metadata": {}}
+{"_id": "12087063", "title": "", "text": "The structure of informal care: are there differences by race?This study investigated whether there arerace differences in the structure of informal caregiving networks. Data on 3,793 functionally impairedpersons age 65 and over from the 1989 National Long-Term Care Survey were analyzed. The size of thetotal caregiver network and the unpaid network did not differ by race, but the likelihood of there being anon-immediate family member among unpaid caregivers was higher among disabled older blacks. Thesefindings raise questions about whether race differences in nursing home utilization and paid long-termcare services, documented in other studies, can be explained by differences in caregiving arrangements.", "metadata": {}}
+{"_id": "12100854", "title": "", "text": "Proteomic and genomic approaches reveal critical functions of H3K9 methylation and HeterochromatinProtein-1γ in reprogramming to pluripotencyReprogramming of somatic cells into induced pluripotentstem cells (iPSCs) involves a marked reorganization of chromatin. To identify post-translational histonemodifications that change in global abundance during this process, we have applied a quantitativemass-spectrometry-based approach. We found that iPSCs, compared with both the starting fibroblastsand a late reprogramming intermediate (pre-iPSCs), are enriched for histone modifications associatedwith active chromatin, and depleted for marks of transcriptional elongation and a subset of repressivemodifications including H3K9me2/me3. Dissecting the contribution of H3K9 methylation toreprogramming, we show that the H3K9 methyltransferases Ehmt1, Ehmt2 and Setdb1 regulate globalH3K9me2/me3 levels and that their depletion increases iPSC formation from both fibroblasts andpre-iPSCs. Similarly, we find that inhibition of heterochromatin protein-1γ (Cbx3), a protein known torecognize H3K9 methylation, enhances reprogramming. Genome-wide location analysis revealed thatCbx3 predominantly binds active genes in both pre-iPSCs and pluripotent cells but with a strikinglydifferent distribution: in pre-iPSCs, but not in embryonic stem cells, Cbx3 associates with activetranscriptional start sites, suggesting a developmentally regulated role for Cbx3 in transcriptionalactivation. Despite largely non-overlapping functions and the predominant association of Cbx3 with activetranscription, the H3K9 methyltransferases and Cbx3 both inhibit reprogramming by repressing thepluripotency factor Nanog. Together, our findings demonstrate that Cbx3 and H3K9 methylation restrictlate reprogramming events, and suggest that a marked change in global chromatin character constitutesan epigenetic roadblock for reprogramming.", "metadata": {}}
+{"_id": "12100963", "title": "", "text": "Tissue exit: a novel control point in the accumulation of antigen-specific CD8 T cells in the influenza avirus-infected lung.Memory/effector T cells efficiently migrate into extralymphoid tissues and sites ofinfection, providing immunosurveillance and a first line of defense against invading pathogens. Eventhough it is a potential means to regulate the size, quality, and duration of a tissue infiltrate, T cell egressfrom infected tissues is poorly understood. Using a mouse model of influenza A virus infection, we foundthat CD8 effector T cells egressed from the infected lung in a CCR7-dependent manner. In contrast,following antigen recognition, effector CD8 T cell egress decreased and CCR7 function was reduced invivo and in vitro, indicating that the exit of CD8 T cells from infected tissues is tightly regulated. Our datasuggest that the regulation of T cell egress is a mechanism to retain antigen-specific effectors at the siteof infection to promote viral clearance, while decreasing the numbers of bystander T cells and preventingovert inflammation.", "metadata": {}}
+{"_id": "12102963", "title": "", "text": "The relation between dietary flavonol intake and coronary heart disease mortality: a meta-analysis ofprospective cohort studiesObjective: To assess the association of dietary flavonol intake with thesubsequent risk of coronary heart disease (CHD) mortality. Design: Meta-analysis of prospective cohortstudies published before September 2001. Studies were identified by MEDLINE and EMBASE searches andby scanning relevant reference lists. The following information was extracted from published reports: sizeof cohort, mean age, mean duration of follow-up, number of fatal CHD events, mean flavonol intake,main sources of flavonol intake, degree of adjustment for potential confounders, and the relation of CHDmortality to dietary flavonol intake measured at baseline. Results: Seven prospective cohorts of men andwomen were identified including a total of 2087 fatal CHD events. Comparison of individuals in the topthird with those in the bottom third of dietary flavonol intake yielded a combined risk ratio of 0.80 (95%CI 0.69–0.93) after adjustment for known CHD risk factors and other dietary components. Conclusion:This overview of prospective cohort studies indicates that high dietary intake of flavonols from a smallnumber of fruits and vegetables, tea and red wine may be associated with a reduced risk from CHDmortality in free-living populations. Sponsorship: Institute for International Health, University of Sydney.", "metadata": {}}
+{"_id": "12122482", "title": "", "text": "MRI in the diagnosis of MS: a prospective study with comparison of clinical evaluation, evoked potentials,oligoclonal banding, and CT.We compared the diagnostic capabilities of MRI to CT, evoked potentials (EP),and CSF oligoclonal banding analysis in a prospective evaluation of 200 patients with suspected multiplesclerosis (MS). MRI was the best method for demonstrating dissemination in space. An abnormalappropriate EP in monosymptomatic disease was usually supported by MRI and CSF analysis as beingpredictive of MS as a clinical diagnosis. A normal appropriate EP study was not satisfactory because MRIand CSF analysis often did not support a diagnosis of non-MS. When there is agreement between three ofthese paraclinical studies, the diagnosis of MS is probably unequivocal. For use in research studies,laboratory-supported definite MS (LSDMS) could be diagnosed in 85 patients of the total 200 (42.5%), in19/38 (50%) of optic neuritis (ON) patients, and in 24/52 (46%) of chronic progressive myelopathy(CPM) patients. MRI was 100% successful in identifying patients who qualified for LSDMS in the ON andCPM groups. In a short follow-up (less than 1 year), 19/200 (10%) went on to develop clinically definiteMS (CDMS), and MRI predicted that diagnosis in 18/19 (95%). Only long-term follow-up will show howwell these studies and the category of LSDMS predict the development of CDMS. The clinical diagnosis ofMS (CDMS), even though only 95% accurate, must remain the gold standard.", "metadata": {}}
+{"_id": "12130067", "title": "", "text": "Osteoclasts promote the formation of hematopoietic stem cell niches in the bone marrowFormation of thehematopoietic stem cell (HSC) niche in bone marrow (BM) is tightly associated with endochondralossification, but little is known about the mechanisms involved. We used the oc/oc mouse, a mousemodel with impaired endochondral ossification caused by a loss of osteoclast (OCL) activity, to investigatethe role of osteoblasts (OBLs) and OCLs in the HSC niche formation. The absence of OCL activity resultedin a defective HSC niche associated with an increased proportion of mesenchymal progenitors butreduced osteoblastic differentiation, leading to impaired HSC homing to the BM. Restoration of OCLactivity reversed the defect in HSC niche formation. Our data demonstrate that OBLs are required forestablishing HSC niches and that osteoblastic development is induced by OCLs. These findings broadenour knowledge of the HSC niche formation, which is critical for understanding normal and pathologicalhematopoiesis.", "metadata": {}}
+{"_id": "12130200", "title": "", "text": "A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in USphysicians.OBJECTIVE To assess prospectively the risk of coronary heart disease associated with elevatedplasma levels of homocyst(e)ine. DESIGN Nested case-control study using prospectively collected bloodsamples. SETTING Participants in the Physicians' Health Study. PARTICIPANTS A total of 14,916 malephysicians, aged 40 to 84 years, with no prior myocardial infarction (MI) or stroke provided plasmasamples at baseline and were followed up for 5 years. Samples from 271 men who subsequentlydeveloped MI were analyzed for homocyst(e)ine levels together with paired controls, matched by age andsmoking. MAIN OUTCOME MEASURE Acute MI or death due to coronary disease. RESULTS Levels ofhomocyst(e)ine were higher in cases than in controls (11.1 +/- 4.0 [SD] vs 10.5 +/- 2.8 nmol/mL; P =.03). The difference was attributable to an excess of high values among men who later had MIs. Therelative risk for the highest 5% vs the bottom 90% of homocyst(e)ine levels was 3.1 (95% confidenceinterval, 1.4 to 6.9; P = .005). After additional adjustment for diabetes, hypertension, aspirinassignment, Quetelet's Index, and total/high-density lipoprotein cholesterol, this relative risk was 3.4(95% confidence interval, 1.3 to 8.8) (P = .01). Thirteen controls and 31 cases (11%) had values abovethe 95th percentile of the controls. CONCLUSIONS Moderately high levels of plasma homocyst(e)ine areassociated with subsequent risk of MI independent of other coronary risk factors. Because high levels canoften be easily treated with vitamin supplements, homocyst(e)ine may be an independent, modifiable riskfactor.", "metadata": {}}
+{"_id": "12130690", "title": "", "text": "Involvement of transient receptor potential vanilloid 1 receptors in protease-activated receptor-2-inducedjoint inflammation and nociception.Protease-activated receptor-2 (PAR-2) is a G-protein-coupled receptoractivated through proteolytic cleavage. It is localized on epithelial, endothelial and inflammatory cells, aswell as on transient receptor potential vanilloid 1 (TRPV1) receptor-expressing neurones. It plays animportant role in inflammatory/nociceptive processes. Since there are few reports concerning PAR-2function in joints, the effects of intraarticular PAR-2 activation on joint pain and inflammation werestudied. Secondary hyperalgesia/allodynia, spontaneous weight distribution, swelling and inflammatorycytokine production were measured and the involvement of TRPV1 ion channels was investigated in ratsand mice. Injection of the PAR-2 receptor agonist SLIGRL-NH(2) into the knee decreased touch sensitivityand weight bearing of the ipsilateral hindlimb in both species. Secondary mechanicalallodynia/hyperalgesia and impaired weight distribution were significantly reduced by the TRPV1antagonist SB366791 in rats and by the genetic deletion of this receptor in mice. PAR-2 activation did notcause significant joint swelling, but increased IL-1beta concentration which was not influenced by the lackof the TRPV1 channel. For comparison, intraplantar SLIGRL-NH(2) evoked similar primary mechanicalhyperalgesia and impaired weight distribution in both WT and TRPV1 deficient mice, but oedema wassmaller in the knockouts. The inactive peptide, LRGILS-NH(2), injected into either site did not induce anyinflammatory or nociceptive changes. These data provide evidence for a significant role of TRPV1receptors in secondary mechanical hyperalgesia/allodynia and spontaneous pain induced by PAR-2receptor activation in the knee joint. Although intraplantar PAR-2 activation-induced oedema is alsoTRPV1 receptor-mediated, primary mechanical hyperalgesia, impaired weight distribution and IL-1betaproduction are independent of this channel.", "metadata": {}}
+{"_id": "12145359", "title": "", "text": "Relationship between reduced forced expiratory volume in one second and the risk of lung cancer: asystematic review and meta-analysis.BACKGROUND Individuals with severely impaired lung functionhave an increased risk of lung cancer. Whether milder reductions in forced expiratory volume in 1 second(FEV(1)) also increase the risk of lung cancer is controversial. Moreover, there is little consensus onwhether men and women have similar risks for lung cancer for similar decreases in FEV(1). METHODS Asearch was conducted of PubMed and EMBASE from January 1966 to January 2005 and studies thatexamined the relationship between FEV1 and lung cancer were identified. The search was limited tostudies that were population based, employed a prospective design, were large in size (> or = 5000participants), and adjusted for cigarette smoking status. RESULTS Twenty eight abstracts were identified,six of which did not report FEV1 and eight did not adjust for smoking. Included in this report are fourstudies that reported FEV1 in quintiles. The risk of lung cancer increased with decreasing FEV1.Compared with the highest quintile of FEV1 (> 100% of predicted), the lowest quintile of FEV1 (<approximately 70% of predicted) was associated with a 2.23 fold (95% confidence interval (CI) 1.73 to2.86) increase in the risk for lung cancer in men and a 3.97 fold increase in women (95% CI 1.93 to8.25). Even relatively small decrements in FEV1 ( approximately 90% of predicted) increased the risk forlung cancer by 30% in men (95% CI 1.05 to 1.62) and 2.64 fold in women (95% CI 1.30 to 5.31).CONCLUSION Reduced FEV1 is strongly associated with lung cancer. Even a relatively modest reductionin FEV1 is a significant predictor of lung cancer, especially among women.", "metadata": {}}
+{"_id": "12149169", "title": "", "text": "Functional Architecture of RNA Polymerase ISynthesis of ribosomal RNA (rRNA) by RNA polymerase (Pol)I is the first step in ribosome biogenesis and a regulatory switch in eukaryotic cell growth. Here we reportthe 12 A cryo-electron microscopic structure for the complete 14-subunit yeast Pol I, a homology modelfor the core enzyme, and the crystal structure of the subcomplex A14/43. In the resulting hybridstructure of Pol I, A14/43, the clamp, and the dock domain contribute to a unique surface interacting withpromoter-specific initiation factors. The Pol I-specific subunits A49 and A34.5 form a heterodimer nearthe enzyme funnel that acts as a built-in elongation factor and is related to the Pol II-associated factorTFIIF. In contrast to Pol II, Pol I has a strong intrinsic 3'-RNA cleavage activity, which requires theC-terminal domain of subunit A12.2 and, apparently, enables ribosomal RNA proofreading and 3'-endtrimming.", "metadata": {}}
+{"_id": "12152977", "title": "", "text": "SWI/SNF-Brg1 regulates self-renewal and occupies core pluripotency-related genes in embryonic stemcells.The SWI/SNF-Brg1 chromatin remodeling protein plays critical roles in cell-cycle control anddifferentiation through regulation of gene expression. Loss of Brg1 in mice results in early embryoniclethality, and recent studies have implicated a role for Brg1 in somatic stem cell self-renewal anddifferentiation. However, little is known about Brg1 function in preimplantation embryos and embryonicstem (ES) cells. Here we report that Brg1 is required for ES cell self-renewal and pluripotency. RNAinterference-mediated knockdown of Brg1 in blastocysts caused aberrant expression of Oct4 and Nanog.In ES cells, knockdown of Brg1 resulted in phenotypic changes indicative of differentiation,downregulation of self-renewal and pluripotency genes (e.g., Oct4, Sox2, Sall4, Rest), and upregulationof differentiation genes. Using genome-wide promoter analysis (chromatin immunoprecipitation) wefound that Brg1 occupied the promoters of key pluripotency-related genes, including Oct4, Sox2, Nanog,Sall4, Rest, and Polycomb group (PcG) proteins. Moreover, Brg1 co-occupied a subset of Oct4, Sox2,Nanog, and PcG protein target genes. These results demonstrate an important role for Brg1 in regulatingself-renewal and pluripotency in ES cells.", "metadata": {}}
+{"_id": "12156187", "title": "", "text": "Rapid induction of Alternative Lengthening of Telomeres by depletion of the histone chaperone ASF1Themechanism of activation of the alternative lengthening of telomeres (ALT) pathway of mammalianchromosome-end maintenance has been unclear. We have now discovered that co-depletion of thehistone chaperones ASF1a and ASF1b in human cells induced all hallmarks of ALT in both primary andcancer cells. These included the formation of ALT-associated PML (promyelocytic leukemia) bodies(APBs), the presence of extrachromosomal telomeric DNA species, an elevated frequency of telomericsister chromatid exchanges (t-SCE) events and intertelomeric exchange of an integrated tag. Theinduction of ALT characteristics in this setting led to the simultaneous suppression of telomerase. Wedetermined that ALT induction is positively regulated by the proteins RAD17 and BLM and negativelyregulated by EXO1 and DNA2. The induction of ALT phenotypes as a consequence of ASF1 depletionstrongly supports the hypothesis that ALT is a consequence of histone management dysfunction.", "metadata": {}}
+{"_id": "12172346", "title": "", "text": "Targeting bromodomains: epigenetic readers of lysine acetylationLysine acetylation is a key mechanismthat regulates chromatin structure; aberrant acetylation levels have been linked to the development ofseveral diseases. Acetyl-lysine modifications create docking sites for bromodomains, which are smallinteraction modules found on diverse proteins, some of which have a key role in theacetylation-dependent assembly of transcriptional regulator complexes. These complexes can theninitiate transcriptional programmes that result in phenotypic changes. The recent discovery of potent andhighly specific inhibitors for the BET (bromodomain and extra-terminal) family of bromodomains hasstimulated intensive research activity in diverse therapeutic areas, particularly in oncology, where BETproteins regulate the expression of key oncogenes and anti-apoptotic proteins. In addition, targeting BETbromodomains could hold potential for the treatment of inflammation and viral infection. Here, wehighlight recent progress in the development of bromodomain inhibitors, and their potential applicationsin drug discovery.", "metadata": {}}
+{"_id": "12197393", "title": "", "text": "Arachidonic acid cytochrome P450 epoxygenase pathway.Cytochrome P450 (CYP) epoxygenases convertarachidonic acid to four epoxyeicosatrienoic acid (EET) regioisomers, 5,6-, 8,9-, 11,12-, and 14,15-EET,that function as autacrine and paracrine mediators. EETs produce vascular relaxation by activatingsmooth muscle large-conductance Ca2+-activated K+ channels (BKCa). In addition, they haveanti-inflammatory effects on blood vessels and in the kidney, promote angiogenesis, and protect ischemicmyocardium and brain. CYP epoxygenases also convert eicosapentaenoic acid to vasoactiveepoxy-derivatives, and endocannabinoids containing 11,12- and 14,15-EET are formed. Many EET actionsappear to be initiated by EET binding to a membrane receptor that activates ion channels and intracellularsignal transduction pathways. However, EETs also are taken up by cells, are incorporated intophospholipids, and bind to cytosolic proteins and nuclear receptors, suggesting that some functions mayoccur through direct interaction of the EET with intracellular effector systems. Soluble epoxide hydrolase(sEH) converts EETs to dihydroxyeicosatrienoic acids (DHETs). Because this attenuates many of thefunctional effects of EETs, sEH inhibition is being evaluated as a mechanism for increasing and prolongingthe beneficial actions of EETs.", "metadata": {}}
+{"_id": "12205576", "title": "", "text": "Physical activity at 36 years: patterns and childhood predictors in a longitudinal study.OBJECTIVE Theaim was to describe the sex and socioeconomic differences in patterns of physical activity at work and inleisure time of men and women aged 36 years, and to investigate factors in childhood and adolescencewhich predict high rates of participation in sports and recreational activities in later life. DESIGN Datacollected in childhood, adolescence, and at 36 years on members of a national prospective birth cohortstudy were used. SETTING The population sample was resident in England, Scotland, and Wales.SUBJECTS A stratified sample of about 3500 men and women was studied regularly from birth until 43years. MEASUREMENTS AND MAIN RESULTS More men than women reported high rates of sports andrecreational activities, gardening, and do-it-yourself. In contrast women reported higher rates of bicyclingand walking. Higher levels of education were associated with frequent participation in sports. Individualsoften engaged in one type of activity without necessarily engaging in other types. Those who were mostactive in sport had been above average at sports in school, more outgoing socially in adolescence, hadfewer health problems in childhood, were better educated, and had more mothers with a secondaryeducation than those who were less active. CONCLUSIONS Studies that examine the relationship betweenphysical activity and chronic disease should consider a broad range of pursuits rather than extrapolatingfrom only one area of physical activity, and in their explanations should take account of the possible roleof childhood characteristics. The findings suggest the importance of developing skills and habits inchildhood as well as of encouraging healthier exercise habits in adults who may have had fewopportunities or low motivation previously.", "metadata": {}}
+{"_id": "12206390", "title": "", "text": "Residual lifetime risk for developing hypertension in middle-aged women and men: The FraminghamHeart Study.CONTEXT The long-term risk for developing hypertension is best described by the lifetimerisk statistic. The lifetime risk for hypertension and trends in this risk over time are unknown.OBJECTIVES To estimate the residual lifetime risk for hypertension in older US adults and to evaluatetemporal trends in this risk. DESIGN, SETTING, AND PARTICIPANTS Community-based prospectivecohort study of 1298 participants from the Framingham Heart Study who were aged 55 to 65 years andfree of hypertension at baseline (1976-1998). MAIN OUTCOME MEASURES Residual lifetime risk (lifetimecumulative incidence not adjusted for competing causes of mortality) for hypertension, defined as bloodpressure of 140/90 mm Hg or greater or use of antihypertensive medications. RESULTS The residuallifetime risks for developing hypertension and stage 1 high blood pressure or higher(greater-than-or-equal to 140/90 mm Hg regardless of treatment) were 90% in both 55- and 65-year-oldparticipants. The lifetime probability of receiving antihypertensive medication was 60%. The risk forhypertension remained unchanged for women, but it was approximately 60% higher for men in thecontemporary 1976-1998 period compared with an earlier 1952-1975 period. In contrast, the residuallifetime risk for stage 2 high blood pressure or higher (greater-than-or-equal to 160/100 mm Hgregardless of treatment) was considerably lower in both sexes in the recent period (35%-57% in1952-1975 vs 35%-44% in 1976-1998), likely due to a marked increase in treatment of individuals withsubstantially elevated blood pressure. CONCLUSION The residual lifetime risk for hypertension formiddle-aged and elderly individuals is 90%, indicating a huge public health burden. Although the declinein lifetime risk for stage 2 high blood pressure or higher represents a major achievement, efforts shouldbe directed at the primary prevention of hypertension.", "metadata": {}}
+{"_id": "12207167", "title": "", "text": "Adverse effects of excessive consumption of amino acids.PHENYLALANINE TOXICITY 158 Developing the0. -M ethylphenylalanine Model. . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160 Useof the a-Methyl phenylalanine Model in Brain Protein Synthesis . . . . . . . . . . . . . . . . . . . 161 TYROSINETOXICITY 162 General Nutritional Observations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . 162 Factors Affecting Tissue Concentrations of Tyrosine . ... .. .. .. ...... . . . . .. .. . . 163 Probable Cause of Tyrosine Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . 164 A New Animal Model for Human Tyrosinemia II 165 TRYPTOPHAN TOXICITy 165General Nutritional Observations . .. ....... . ....... . .... . . .. . . . .. . .. . .. ..... ......... 165 Factors AffectingTryptophan Toxicity . . . .. . . . . . . . .... . ........ 166 Tryptophan and Ruminant Interstitial PulmonaryEmphysema and Edema ..... . . . . . . . 167 HISTIDINE TOXICITY 168 General Nutritional Observations...... ........ . . . . ..... . ...... .. . 168 Metabolic Aspects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . .. . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169 Alleviation of Histidine Toxicity . . . . . . . .. . . . . . . . . . . . . . . . . . . . . ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170 METHIONINE TOXICITY171 General Nutritional Observations . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . 171 Tissue Damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . 172 Protective Effect of Glycine, Serine, or Retinol . . . ......... . ......... . ......... .. . .. . . ...... 172 Chemical Characteristics Related to the Toxicity of Methionine . .. . . . . . . . . . . . . . . . . . . . . . . 173 Damaging Effects of Methanethiol. . . . . . . . . . . . . . . . . . . . . . . . . .. .. . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . 173 Met\u0000io,!ine To\u0000i.city in Chickens 174 EthlOnmeTOxIcIty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . .. . . . . . . ... . 174", "metadata": {}}
+{"_id": "12207340", "title": "", "text": "Mechanism and regulation of DNA end resection in eukaryotes.The repair of DNA double-strand breaks(DSBs) by homologous recombination (HR) is initiated by nucleolytic degradation of the 5'-terminatedstrands in a process termed end resection. End resection generates 3'-single-stranded DNA tails,substrates for Rad51 to catalyze homologous pairing and DNA strand exchange, and for activation of theDNA damage checkpoint. The commonly accepted view is that end resection occurs by a two-stepmechanism. In the first step, Sae2/CtIP activates the Mre11-Rad50-Xrs2/Nbs1 (MRX/N) complex toendonucleolytically cleave the 5'-terminated DNA strands close to break ends, and in the second stepExo1 and/or Dna2 nucleases extend the resected tracts to produce long 3'-ssDNA-tailed intermediates.Initiation of resection commits a cell to repair a DSB by HR because long ssDNA overhangs are poorsubstrates for non-homologous end joining (NHEJ). Thus, the initiation of end resection has emerged as acritical control point for repair pathway choice. Here, I review recent studies on the mechanism of endresection and how this process is regulated to ensure the most appropriate repair outcome.", "metadata": {}}
+{"_id": "12209494", "title": "", "text": "Multiple-dose activated charcoal in acute self-poisoning: a randomised controlled trialBACKGROUND Thecase-fatality for intentional self-poisoning in the rural developing world is 10-50-fold higher than that inindustrialised countries, mostly because of the use of highly toxic pesticides and plants. We thereforeaimed to assess whether routine treatment with multiple-dose activated charcoal, to interruptenterovascular or enterohepatic circulations, offers benefit compared with no charcoal in such anenvironment. METHODS We did an open-label, parallel group, randomised, controlled trial of six 50 gdoses of activated charcoal at 4-h intervals versus no charcoal versus one 50 g dose of activated charcoalin three Sri Lankan hospitals. 4632 patients were randomised to receive no charcoal (n=1554), one doseof charcoal (n=1545), or six doses of charcoal (n=1533); outcomes were available for 4629 patients.2338 (51%) individuals had ingested pesticides, whereas 1647 (36%) had ingested yellow oleander(Thevetia peruviana) seeds. Mortality was the primary outcome measure. Analysis was by intention totreat. The trial is registered with controlled-trials.com as ISRCTN02920054. FINDINGS Mortality did notdiffer between the groups. 97 (6.3%) of 1531 participants in the multiple-dose group died, comparedwith 105 (6.8%) of 1554 in the no charcoal group (adjusted odds ratio 0.96, 95% CI 0.70-1.33). Nodifferences were noted for patients who took particular poisons, were severely ill on admission, or whopresented early. INTERPRETATION We cannot recommend the routine use of multiple-dose activatedcharcoal in rural Asia Pacific; although further studies of early charcoal administration might be useful,effective affordable treatments are urgently needed.", "metadata": {}}
+{"_id": "12217662", "title": "", "text": "Post-prenylation-processing enzymes as new targets in oncogenesisRAS and many other oncogenicproteins undergo a complex series of post-translational modifications that are initiated by the addition ofan isoprenoid lipid through a process known as prenylation. Following prenylation, these proteins usuallyundergo endoproteolytic processing by the RCE1 protease and then carboxyl methylation by a uniquemethyltransferase known as isoprenylcysteine carboxyl methyltransferase (ICMT). Although inhibitorsthat have been designed to target the prenylation step are now in advanced-stage clinical trials, theirutility and efficacy seem to be limited. Recent findings, however, indicate that the inhibition of thesepost-prenylation-processing steps — particularly that of ICMT-catalysed methylation — might provide abetter approach to the control of cancer-cell proliferation.", "metadata": {}}
+{"_id": "12224536", "title": "", "text": "Trends in sugar-sweetened beverage consumption among youth and adults in the United States:1999-2010.BACKGROUND Reducing sugar-sweetened beverage (SSB) consumption is a recommendedstrategy to promote optimal health. OBJECTIVE The objective was to describe trends in SSB consumptionamong youth and adults in the United States. DESIGN We analyzed energy intake from SSBs among22,367 youth aged 2-19 y and 29,133 adults aged ≥20 y who participated in a 24-h dietary recall as partof NHANES, a nationally representative sample of the US population with a cross-sectional design,between 1999 and 2010. SSBs included soda, fruit drinks, sports and energy drinks, sweetened coffeeand tea, and other sweetened beverages. Patterns of SSB consumption, including location of consumptionand meal occasion associated with consumption, were also examined. RESULTS In 2009-2010, youthconsumed a mean (±SE) of 155 ± 7 kcal/d from SSBs, and adults consumed an age-adjusted mean(±SE) of 151 ± 5 kcal/d from SSBs--a decrease from 1999 to 2000 of 68 kcal/d and 45 kcal/d,respectively (P-trend < 0.001 for each). In 2009-2010, SSBs contributed 8.0% ± 0.4% and 6.9% ±0.2% of daily energy intake among youth and adults, respectively, which reflected a decrease comparedwith 1999-2000 (P-trend < 0.001 for both). Decreases in SSB consumption, both in the home and awayfrom home and also with both meals and snacks, occurred over the 12-y study duration (P-trend < 0.01for each). CONCLUSION A decrease in SSB consumption among youth and adults in the United Stateswas observed between 1999 and 2010.", "metadata": {}}
+{"_id": "12225214", "title": "", "text": "Ubiquitination on nonlysine residues by a viral E3 ubiquitin ligase.Ubiquitination controls a broad range ofcellular functions. The last step of the ubiquitination pathway is regulated by enzyme type 3 (E3)ubiquitin ligases. E3 enzymes are responsible for substrate specificity and catalyze the formation of anisopeptide bond between a lysine residue of the substrate (or the N terminus of the substrate) andubiquitin. MIR1 and MIR2 are two E3 ubiquitin ligases encoded by Kaposi's sarcoma-associatedherpesvirus that mediate the ubiquitination of major histocompatibility complex class I (MHC I) moleculesand subsequent internalization. Here, we found that MIR1, but not MIR2, promoted down-regulation ofMHC I molecules lacking lysine residues in their intracytoplasmic domain. In the presence of MIR1, theseMHC I molecules were ubiquitinated, and their association with ubiquitin was sensitive tobeta2-mercaptoethanol, unlike lysine-ubiquitin bonds. This form of ubiquitination required a cysteineresidue in the intracytoplasmic tail of MHC I molecules. An MHC I molecule containing a single cysteineresidue in an artificial glycine and alanine intracytoplasmic domain was endocytosed and degraded in thepresence of MIR1. Thus, ubiquitination can occur on proteins lacking accessible lysines or an accessible Nterminus.", "metadata": {}}
+{"_id": "12232678", "title": "", "text": "All dosage compensation is local: Gene-by-gene regulation of sex-biased expression on the chicken ZchromosomeRecent reports have suggested that birds lack a mechanism of wholesale dosagecompensation for the Z sex chromosome. This discovery was rather unexpected, as all other animalsinvestigated with chromosomal mechanisms of sex determination have some method to counteract theeffects of gene dosage of the dominant sex chromosome in males and females. Despite the lack of aglobal mechanism of avian dosage compensation, the pattern of gene expression difference betweenmales and females varies a great deal for individual Z-linked genes. This suggests that some genes maybe individually dosage compensated, and that some less-than-global pattern of dosage compensation,such as local or temporal, exists on the avian Z chromosome. We used global gene expression profiling inmales and females for both somatic and gonadal tissue at several time points in the life cycle of thechicken to assess the pattern of sex-biased gene expression on the Z chromosome. Average fold-changebetween males and females varied somewhat among tissue time-point combinations, with embryonicbrain samples having the smallest gene dosage effects, and adult gonadal tissue having the largestdegree of male bias. Overall, there were no neighborhoods of overall dosage compensation along the Z.Taken together, this suggests that dosage compensation is regulated on the Z chromosome entirely on agene-by-gene level, and can vary during the life cycle and by tissue type. This regulation may be anindication of how critical a given gene's functionality is, as the expression level for essential genes will betightly regulated in order to avoid perturbing important pathways and networks with differentialexpression levels in males and females.", "metadata": {}}
+{"_id": "12236208", "title": "", "text": "Hormone replacement therapy prevents bone loss in patients with inflammatory bowel disease.Patientswith inflammatory bowel disease have an increased prevalence of osteoporosis, and suffer high rates ofspinal bone loss. Hormone replacement therapy (HRT) is effective in the treatment and prevention ofosteoporosis but has not been studied in patients with inflammatory bowel disease. A two yearprospective study of HRT in inflammatory bowel disease was performed in 47 postmenopausal womenaged 44 to 67 years with ulcerative colitis (25) or Crohn's disease (22). Patients had radial and spinalbone density measured annually by single photon absorptiometry and quantitative computed tomographyrespectively. The mean (95% confidence intervals) annual change in radial bone density was +1.42%/yr(+0.58 to +2.26; P < 0.005) and for spinal bone +2.60%/yr (+1.06 to +4.15; p < 0.005). There was nosignificant correlation between rates of change of bone density at the two sites, or between the rates ofchange and the initial bone density either in the radius or spine. Twelve patients were given prednisoloneduring the study, and their rates of change for spinal bone density were lower, but values were notstatistically significantly different from those who did not receive corticosteroids. Changes in bone densityfor patients with ulcerative colitis and Crohn's disease were not significantly different. The change in bonedensity did not correlate with the patients' age or number of years after the menopause. It is concludedthat HRT is effective in prevention of bone loss in postmenopausal women with inflammatory boweldisease.", "metadata": {}}
+{"_id": "12240507", "title": "", "text": "Disruption of the 5S RNP–Mdm2 interaction significantly improves the erythroid defect in a mouse modelfor Diamond-Blackfan anemiaDiamond-Blackfan anemia (DBA) is a congenital erythroid hypoplasiacaused by haploinsufficiency of genes encoding ribosomal proteins (RPs). Perturbed ribosome biogenesisin DBA has been shown to induce a p53-mediated ribosomal stress response. However, the mechanismsof p53 activation and its relevance for the erythroid defect remain elusive. Previous studies haveindicated that activation of p53 is caused by the inhibition of mouse double minute 2 (Mdm2), the mainnegative regulator of p53, by the 5S ribonucleoprotein particle (RNP). Meanwhile, it is not clear whetherthis mechanism solely mediates the p53-dependent component found in DBA. To approach this question,we crossed our mouse model for RPS19-deficient DBA with Mdm2C305F knock-in mice that have adisrupted 5S RNP–Mdm2 interaction. Upon induction of the Rps19 deficiency, Mdm2C305F reversed thep53 response and improved expansion of hematopoietic progenitors in vitro, and ameliorated the anemiain vivo. Unexpectedly, disruption of the 5S RNP–Mdm2 interaction also led to selective defect inerythropoiesis. Our findings highlight the sensitivity of erythroid progenitor cells to aberrations in p53homeostasis mediated by the 5S RNP–Mdm2 interaction. Finally, we provide evidence indicating thatphysiological activation of the 5S RNP-Mdm2-p53 pathway may contribute to functional decline of thehematopoietic system in a cell-autonomous manner over time.", "metadata": {}}
+{"_id": "12258338", "title": "", "text": "Pharmacist participation on physician rounds and adverse drug events in the intensive care unit.CONTEXTPharmacist review of medication orders in the intensive care unit (ICU) has been shown to preventerrors, and pharmacist consultation has reduced drug costs. However, whether pharmacist participationin the ICU at the time of drug prescribing reduces adverse events has not been studied. OBJECTIVE Tomeasure the effect of pharmacist participation on medical rounds in the ICU on the rate of preventableadverse drug events (ADEs) caused by ordering errors. DESIGN Before-after comparison between phase1 (baseline) and phase 2 (after intervention implemented) and phase 2 comparison with a control unitthat did not receive the intervention. SETTING A medical ICU (study unit) and a coronary care unit(control unit) in a large urban teaching hospital. PATIENTS Seventy-five patients randomly selected fromeach of 3 groups: all admissions to the study unit from February 1, 1993, through July 31, 1993(baseline) and all admissions to the study unit (postintervention) and control unit from October 1, 1994,through July 7, 1995. In addition, 50 patients were selected at random from the control unit during thebaseline period. INTERVENTION A senior pharmacist made rounds with the ICU team and remained in theICU for consultation in the morning, and was available on call throughout the day. MAIN OUTCOMEMEASURES Preventable ADEs due to ordering (prescribing) errors and the number, type, and acceptanceof interventions made by the pharmacist. Preventable ADEs were identified by review of medical recordsof the randomly selected patients during both preintervention and postintervention phases. Pharmacistsrecorded all recommendations, which were then analyzed by type and acceptance. RESULTS The rate ofpreventable ordering ADEs decreased by 66% from 10.4 per 1000 patient-days (95% confidence interval[CI], 7-14) before the intervention to 3.5 (95% CI, 1-5; P<.001) after the intervention. In the controlunit, the rate was essentially unchanged during the same time periods: 10.9 (95% CI, 6-16) and 12.4(95% CI, 8-17) per 1000 patient-days. The pharmacist made 366 recommendations related to drugordering, of which 362 (99%) were accepted by physicians. CONCLUSIONS The presence of a pharmaciston rounds as a full member of the patient care team in a medical ICU was associated with a substantiallylower rate of ADEs caused by prescribing errors. Nearly all the changes were readily accepted byphysicians.", "metadata": {}}
+{"_id": "12265561", "title": "", "text": "Ligand-target interactions: what can we learn from NMR?The conformation of the ligand in complex witha macromolecular target can be studied by nuclear magnetic resonance (NMR) in solution for both tightlyand weakly forming complexes. In the weak binding regime (k(off) > 10(4) Hz), the structure of thebound ligand is accessible also for very large complexes (>100 kDa), which are not amenable to NMRstudies in the tight binding regime. Here I review the state-of-the-art NMR methodology used forscreening ligands and for the structural investigation of bound ligand conformations, in both tight andweak binding regimes. The advantages and disadvantages of each approach are critically described. TheNMR methodology used to investigate transiently forming complexes has expanded considerably in thepast few years, opening new possibilities for a detailed description of ligand-target interactions. Novelmethods for the determination of the bound ligand conformation, in particular transferredcross-correlated relaxation, are thoroughly reviewed, and their advantages with respect to establishedmethodology are discussed, using the epothilone-tubulin complex as a primary example.", "metadata": {}}
+{"_id": "12271486", "title": "", "text": "MotifMap: integrative genome-wide maps of regulatory motif sites for model speciesBACKGROUND Acentral challenge of biology is to map and understand gene regulation on a genome-wide scale. For anygiven genome, only a small fraction of the regulatory elements embedded in the DNA sequence havebeen characterized, and there is great interest in developing computational methods to systematicallymap all these elements and understand their relationships. Such computational efforts, however, aresignificantly hindered by the overwhelming size of non-coding regions and the statistical variability andcomplex spatial organizations of regulatory elements and interactions. Genome-wide catalogs ofregulatory elements for all model species simply do not yet exist. RESULTS The MotifMap system usesdatabases of transcription factor binding motifs, refined genome alignments, and a comparative genomicstatistical approach to provide comprehensive maps of candidate regulatory elements encoded in thegenomes of model species. The system is used to derive new genome-wide maps for yeast, fly, worm,mouse, and human. The human map contains 519,108 sites for 570 matrices with a False Discovery Rateof 0.1 or less. The new maps are assessed in several ways, for instance using high-throughputexperimental ChIP-seq data and AUC statistics, providing strong evidence for their accuracy andcoverage. The maps can be usefully integrated with many other kinds of omic data and are available athttp://motifmap.igb.uci.edu/.   CONCLUSIONS MotifMap and its integration with other data provide afoundation for analyzing gene regulation on a genome-wide scale, and for automatically generatingregulatory pathways and hypotheses. The power of this approach is demonstrated and discussed usingthe P53 apoptotic pathway and the Gli hedgehog pathways as examples.", "metadata": {}}
+{"_id": "12280462", "title": "", "text": "Inhibition of apical sodium-dependent bile acid transporter as a novel treatment for diabetes.Bile acidsare recognized as metabolic modulators. The present study was aimed at evaluating the effects of apotent Asbt inhibitor (264W94), which blocks intestinal absorption of bile acids, on glucose homeostasisin Zucker Diabetic Fatty (ZDF) rats. Oral administration of 264W94 for two wk increased fecal bile acidconcentrations and elevated non-fasting plasma total Glp-1. Treatment of 264W94 significantly decreasedHbA1c and glucose, and prevented the drop of insulin levels typical of ZDF rats in a dose-dependentmanner. An oral glucose tolerance test revealed up to two-fold increase in plasma total Glp-1 andthree-fold increase in insulin in 264W94 treated ZDF rats at doses sufficient to achieve glycemic control.Tissue mRNA analysis indicated a decrease in farnesoid X receptor (Fxr) activation in small intestines andthe liver but co-administration of a Fxr agonist (GW4064) did not attenuate 264W94 induced glucoselowering effects. In summary, our results demonstrate that inhibition of Asbt increases bile acids in thedistal intestine, promotes Glp-1 release and may offer a new therapeutic strategy for type 2 diabetesmellitus.", "metadata": {}}
+{"_id": "12315072", "title": "", "text": "Early chromatin unfolding by RUNX1: a molecular explanation for differential requirements duringspecification versus maintenance of the hematopoietic gene expression program.At the cellular level,development progresses through successive regulatory states, each characterized by their specific geneexpression profile. However, the molecular mechanisms regulating first the priming and thenmaintenance of gene expression within one developmental pathway are essentially unknown. Thehematopoietic system represents a powerful experimental model to address these questions and here wehave focused on a regulatory circuit playing a central role in myelopoiesis: the transcription factor PU.1,its target gene colony-stimulating-factor 1 receptor (Csf1r), and key upstream regulators such as RUNX1.We find that during ontogeny, chromatin unfolding precedes the establishment of active histone marksand the formation of stable transcription factor complexes at the Pu.1 locus and we show that chromatinremodeling is mediated by the transient binding of RUNX1 to Pu.1 cis-elements. By contrast, chromatinreorganization of Csf1r requires prior expression of PU.1 together with RUNX1 binding. Once the fullhematopoietic program is established, stable transcription factor complexes and active chromatin can bemaintained without RUNX1. Our experiments therefore demonstrate how individual transcription factorsfunction in a differentiation stage-specific manner to differentially affect the initiation versus maintenanceof a developmental program.", "metadata": {}}
+{"_id": "12324049", "title": "", "text": "Whole-genome fingerprint of the DNA methylome during human B cell differentiationWe analyzed theDNA methylome of ten subpopulations spanning the entire B cell differentiation program bywhole-genome bisulfite sequencing and high-density microarrays. We observed that non-CpGmethylation disappeared upon B cell commitment, whereas CpG methylation changed extensively duringB cell maturation, showing an accumulative pattern and affecting around 30% of all measured CpG sites.Early differentiation stages mainly displayed enhancer demethylation, which was associated withupregulation of key B cell transcription factors and affected multiple genes involved in B cell biology. Latedifferentiation stages, in contrast, showed extensive demethylation of heterochromatin and methylationgain at Polycomb-repressed areas, and genes with apparent functional impact in B cells were notaffected. This signature, which has previously been linked to aging and cancer, was particularlywidespread in mature cells with an extended lifespan. Comparing B cell neoplasms with their normalcounterparts, we determined that they frequently acquire methylation changes in regions alreadyundergoing dynamic methylation during normal B cell differentiation.", "metadata": {}}
+{"_id": "12337611", "title": "", "text": "LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppressionLIN28B regulatesdevelopmental processes by modulating microRNAs (miRNAs) of the let-7 family. A role for LIN28B incancer has been proposed but has not been established in vivo. Here, we report that LIN28B showedgenomic aberrations and extensive overexpression in high-risk neuroblastoma compared to several othertumor entities and normal tissues. High LIN28B expression was an independent risk factor for adverseoutcome in neuroblastoma. LIN28B signaled through repression of the let-7 miRNAs and consequentlyresulted in elevated MYCN protein expression in neuroblastoma cells. LIN28B–let-7–MYCN signalingblocked differentiation of normal neuroblasts and neuroblastoma cells. These findings were fullyrecapitulated in a mouse model in which LIN28B expression in the sympathetic adrenergic lineageinduced development of neuroblastomas marked by low let-7 miRNA levels and high MYCN proteinexpression. Interference with this pathway might offer therapeutic perspectives.", "metadata": {}}
+{"_id": "12358173", "title": "", "text": "Platelet-derived endothelial cell growth factor expression correlates with tumour angiogenesis andprognosis in non-small-cell lung cancer.Angiogenesis is a recently described prognostic factor innon-small-cell lung cancer. Platelet-derived endothelial cell growth factor (PD-ECGF), shown to be theenzyme thymidine phosphorylase (TP), induces angiogenesis in vitro and in vivo. High intracellular levelsof the enzyme are associated with increased chemosensitivity to pyrimidine antimetabolites. PD-ECGF/TPexpression was evaluated immunohistochemically in surgically resected specimens from 107 patients withoperable non-small-cell lung cancer using the P-GF,44C monoclonal antibody. High expression ofPD-ECGF/TP was found in 25% of cases and was associated with high vascular grade (P = 0.01).Fourteen of 32 (44%) high vascular grade tumours showed a positive reactivity for PD-ECGF/TP vs 13/75(17%) of low/medium vascular grade. Positive expression was observed more frequently in T2-stagedcases than in T1 (P = 0.04). While overall survival was not affected (P = 0.09), subset analysis revealedthat node-negative patients with positive PD-ECGF/TP expression had a worse prognosis (P = 0.04). Theresults suggest that PD-ECGF/TP may be an important molecule involved in angiogenesis innon-small-cell lung cancer. Up-regulation of the enzyme defines a more aggressive tumour phenotype inpatients with node-negative disease. Assessment of vascular grade and PD-ECGF/TP expression shouldbe taken into account in the design of randomized trials assessing the role of adjuvant chemotherapy innon-small-cell lung cancer.", "metadata": {}}
+{"_id": "12364109", "title": "", "text": "The association between psychological distance and construal level: evidence from an implicit associationtest.According to construal level theory (N. Liberman, Y. Trope, & E. Stephan, in press; Y. Trope & N.Liberman, 2003), people use a more abstract, high construal level when judging, perceiving, andpredicting more psychologically distal targets, and they judge more abstract targets as being morepsychologically distal. The present research demonstrated that associations between more distance andhigher level of construal also exist on a pure conceptual level. Eight experiments used the ImplicitAssociation Test (IAT; A. G. Greenwald, D. E. McGhee, & J. L. K. Schwartz, 1998) to demonstrate anassociation between words related to construal level (low vs. high) and words related to four dimensionsof distance (proximal vs. distal): temporal distance, spatial distance, social distance, and hypotheticality.In addition to demonstrating an association between level of construal and psychological distance, thesefindings also corroborate the assumption that all 4 dimensions of psychological distance are related tolevel of construal in a similar way and support the notion that they all are forms of psychological distance.", "metadata": {}}
+{"_id": "12370190", "title": "", "text": "A load driver device for engineering modularity in biological networksThe behavior of gene modules incomplex synthetic circuits is often unpredictable. After joining modules to create a circuit, downstreamelements (such as binding sites for a regulatory protein) apply a load to upstream modules that cannegatively affect circuit function. Here we devised a genetic device named a load driver that mitigates theimpact of load on circuit function, and we demonstrate its behavior in Saccharomyces cerevisiae. Theload driver implements the design principle of timescale separation: inclusion of the load driver's fastphosphotransfer processes restores the capability of a slower transcriptional circuit to respond totime-varying input signals even in the presence of substantial load. Without the load driver, we observedcircuit behavior that suffered from a 76% delay in response time and a 25% decrease in systembandwidth due to load. With the addition of a load driver, circuit performance was almost completelyrestored. Load drivers will serve as fundamental building blocks in the creation of complex, higher-levelgenetic circuits.", "metadata": {}}
+{"_id": "12370881", "title": "", "text": "Inflammatory monocyte/macrophage modulation by liposome-entrapped spironolactone amelioratesacute lung injury in mice.AIM To examine the therapeutic/preventive potential of liposome-encapsulatedspironolactone (SP; Lipo-SP) for acute lung injury (ALI) and fibrosis. MATERIALS & METHODS Lipo-SPwas prepared by the film-ultrasonic method, and physicochemical and pharmacokinetic characterized fororal administration (10 and 20 mg/kg for SP-loaded liposome; 20 mg/kg for free SP) in a mouse modelbleomycin-induced ALI. RESULTS Lipo-SP enhanced bioavailability of SP with significant amelioration inlung pathology. Mechanistically, SP-mediated mineralocorticoid receptor antagonism contributes toinflammatory monocyte/macrophage modulation via an inhibitory effect on Ly6C(hi)monocytosis-directed M2 polarization of alveolar macrophages. Moreover, Lipo-SP at lower dose (10mg/kg) exhibited more improvement in body weight gain. CONCLUSION Our data highlight Lipo-SP as apromising approach with therapeutic/preventive potential for ALI and fibrosis.", "metadata": {}}
+{"_id": "12383365", "title": "", "text": "Passive Surveillance for I. scapularis Ticks: Enhanced Analysis for Early Detection of Emerging LymeDisease RiskABSTRACT Lyme disease (LD) is emerging in Canada because of the northward expansion ofthe geographic range of the tick vector Ixodes scapularis (Say). Early detection of emerging areas of LDrisk is critical to public health responses, but the methods to do so on a local scale are lacking. Passivetick surveillance has operated in Canada since 1990 but this method lacks specificity for identifying areaswhere tick populations are established because of dispersion of ticks from established LD risk areas bymigratory birds. Using data from 70 field sites in Quebec visited previously, we developed a logisticregression model for estimating the risk of I. scapularis population establishment based on the number ofticks submitted in passive surveillance and a model-derived environmental suitability index.Sensitivity-specificity plots were used to select an optimal threshold value of the linear predictor from themodel as the signal for tick population establishment. This value was used to produce an “Alert Map”identifying areas where the passive surveillance data suggested ticks were establishing in Quebec. AlertMap predictions were validated by field surveillance at 76 sites: the prevalence of established I.scapularis populations was significantly greater in areas predicted as high-risk by the Alert map (29 out of48) than in areas predicted as moderate-risk (4 out of 30) (P < 0.001). This study suggests that AlertMaps created using this approach can provide a usefully rapid and accurate tool for early identification ofemerging areas of LD risk at a geographic scale appropriate for local disease control and preventionactivities.", "metadata": {}}
+{"_id": "12409683", "title": "", "text": "Reduction of transmission from malaria patients by artemisinin combination therapies: a pooled analysisof six randomized trialsBACKGROUND Artemisinin combination therapies (ACT), which are increasinglybeing introduced for treatment of Plasmodium falciparum malaria, are more effective against sexualstage parasites (gametocytes) than previous first-line antimalarials and therefore have the potential toreduce parasite transmission. The size of this effect is estimated in symptomatic P. falciparum infections.METHODS Data on 3,174 patients were pooled from six antimalarial trials conducted in The Gambia andKenya. Multivariable regression was used to investigate the role of ACT versus non-artemisininantimalarial treatment, treatment failure, presence of pre-treatment gametocytes and submicroscopicgametocytaemia on transmission to mosquitoes and the area under the curve (AUC) of gametocytedensity during the 28 days of follow up. RESULTS ACT treatment was associated with a significantreduction in the probability of being gametocytaemic on the day of transmission experiments (OR 0.2095% CI 0.16-0.26), transmission to mosquitoes by slide-positive gametocyte carriers (OR mosquitoinfection 0.49 95% CI 0.33-0.73) and AUC of gametocyte density (ratio of means 0.35 95% CI0.31-0.41). Parasitological treatment failure did not account for the difference between ACT andnon-artemisinin impact. The presence of slide-positive gametocytaemia prior to treatment significantlyreduced ACT impact on gametocytaemia (p < 0.001). Taking account of submicroscopic gametocytaemiareduced estimates of ACT impact in a high transmission setting in Kenya, but not in a lower transmissionsetting in the Gambia. CONCLUSION Treatment with ACT significantly reduces infectiousness of individualpatients with uncomplicated falciparum malaria compared to previous first line treatments. Rapidtreatment of cases before gametocytaemia is well developed may enhance the impact of ACT ontransmission.", "metadata": {}}
+{"_id": "12411274", "title": "", "text": "Skeletal Myogenic Progenitors Originating from Embryonic Dorsal Aorta Coexpress Endothelial andMyogenic Markers and Contribute to Postnatal Muscle Growth and RegenerationSkeletal muscle invertebrates is derived from somites, epithelial structures of the paraxial mesoderm, yet many unrelatedreports describe the occasional appearance of myogenic cells from tissues of nonsomite origin,suggesting either transdifferentiation or the persistence of a multipotent progenitor. Here, we show thatclonable skeletal myogenic cells are present in the embryonic dorsal aorta of mouse embryos. This findingis based on a detailed clonal analysis of different tissue anlagen at various developmental stages. In vitro,these myogenic cells show the same morphology as satellite cells derived from adult skeletal muscle, andexpress a number of myogenic and endothelial markers. Surprisingly, the latter are also expressed byadult satellite cells. Furthermore, it is possible to clone myogenic cells from limbs of mutant c-Met-/-embryos, which lack appendicular muscles, but have a normal vascular system. Upon transplantation,aorta-derived myogenic cells participate in postnatal muscle growth and regeneration, and fuse withresident satellite cells. The potential of the vascular system to generate skeletal muscle cells may explainobservations of nonsomite skeletal myogenesis and raises the possibility that a subset of satellite cellsmay derive from the vascular system.", "metadata": {}}
+{"_id": "12428137", "title": "", "text": "Mapping of a gene for severe pediatric gastroesophageal reflux to chromosome 13q14.CONTEXTGastroesophageal reflux (GER) has not previously been widely regarded as a hereditary disease. A fewreports have suggested, however, that a genetic component may contribute to the incidence of GER,especially in its severe or chronic forms. OBJECTIVE To identify a genetic locus that cosegregates with asevere pediatric GER phenotype in families with multiple affected members. DESIGN A genome-wide scanof families affected by severe pediatric GER using polymorphic microsatellite markers spaced at anaverage of 8 centimorgans (cM), followed by haplotyping and by pairwise and multipoint linkageanalyses. SETTING General US community, with research performed in a university tertiary care hospital.SUBJECTS Affected and unaffected family members from 5 families having multiple individuals affectedby severe pediatric GER, identified through a patient support group. MAIN OUTCOME MEASURESDetermination of inheritance patterns and linkage of a genetic locus with the severe pediatric GERphenotype by logarithm-of-odds (lod) score analysis, considering a lod score of 3 or greater as evidenceof linkage. RESULTS In these families, severe pediatric GER followed an autosomal dominant hereditarypattern with high penetrance. A gene for severe pediatric GER was mapped to a 13-cM region onchromosome 13q between microsatellite markers D13S171 and D13S263. A maximum multifamily2-point lod score of 5.58 and a maximum multifamily multipoint lod score of 7.15 were obtained formarker D13S1253 at map position 35 cM when presumptively affected persons were modeled asunknown (a maximum multipoint score of 4.88 was obtained when presumptively affected persons weremodeled as unaffected). CONCLUSION These data suggest that a gene for severe pediatric GER maps tochromosome 13q14. JAMA. 2000;284:325-334", "metadata": {}}
+{"_id": "12428497", "title": "", "text": "Accelerating Policy Decisions to Adopt Haemophilus influenzae Type b Vaccine: A Global, MultivariableAnalysisBACKGROUND Adoption of new and underutilized vaccines by national immunization programs isan essential step towards reducing child mortality. Policy decisions to adopt new vaccines in highmortality countries often lag behind decisions in high-income countries. Using the case of Haemophilusinfluenzae type b (Hib) vaccine, this paper endeavors to explain these delays through the analysis ofcountry-level economic, epidemiological, programmatic and policy-related factors, as well as the role ofthe Global Alliance for Vaccines and Immunisation (GAVI Alliance). METHODS AND FINDINGS Data for147 countries from 1990 to 2007 were analyzed in accelerated failure time models to identify factors thatare associated with the time to decision to adopt Hib vaccine. In multivariable models that control forGross National Income, region, and burden of Hib disease, the receipt of GAVI support speeded the timeto decision by a factor of 0.37 (95% CI 0.18-0.76), or 63%. The presence of two or more neighboringcountry adopters accelerated decisions to adopt by a factor of 0.50 (95% CI 0.33-0.75). For each 1%increase in vaccine price, decisions to adopt are delayed by a factor of 1.02 (95% CI 1.00-1.04). Globalrecommendations and local studies were not associated with time to decision. CONCLUSIONS This studysubstantiates previous findings related to vaccine price and presents new evidence to suggest that GAVIeligibility is associated with accelerated decisions to adopt Hib vaccine. The influence of neighboringcountry decisions was also highly significant, suggesting that approaches to support the adoption of newvaccines should consider supply- and demand-side factors.", "metadata": {}}
+{"_id": "12428814", "title": "", "text": "Haemolysin coregulated protein is an exported receptor and chaperone of type VI secretionsubstrates.Secretion systems require high-fidelity mechanisms to discriminate substrates among the vastcytoplasmic pool of proteins. Factors mediating substrate recognition by the type VI secretion system(T6SS) of Gram-negative bacteria, a widespread pathway that translocates effector proteins into targetbacterial cells, have not been defined. We report that haemolysin coregulated protein (Hcp), aring-shaped hexamer secreted by all characterized T6SSs, binds specifically to cognate effectormolecules. Electron microscopy analysis of an Hcp-effector complex from Pseudomonas aeruginosarevealed the effector bound to the inner surface of Hcp. Further studies demonstrated that interactionwith the Hcp pore is a general requirement for secretion of diverse effectors encompassing severalenzymatic classes. Though previous models depict Hcp as a static conduit, our data indicate it is achaperone and receptor of substrates. These unique functions of a secreted protein highlight fundamentaldifferences between the export mechanism of T6 and other characterized secretory pathways.", "metadata": {}}
+{"_id": "12438901", "title": "", "text": "Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosisof oestrogen receptor-positive breast cancer: ATLAS, a randomised trialBACKGROUND For women withoestrogen receptor (ER)-positive early breast cancer, treatment with tamoxifen for 5 years substantiallyreduces the breast cancer mortality rate throughout the first 15 years after diagnosis. We aimed toassess the further effects of continuing tamoxifen to 10 years instead of stopping at 5 years. METHODSIn the worldwide Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial, 12,894 women with earlybreast cancer who had completed 5 years of treatment with tamoxifen were randomly allocated tocontinue tamoxifen to 10 years or stop at 5 years (open control). Allocation (1:1) was by centralcomputer, using minimisation. After entry (between 1996 and 2005), yearly follow-up forms recordedany recurrence, second cancer, hospital admission, or death. We report effects on breast canceroutcomes among the 6846 women with ER-positive disease, and side-effects among all women (withpositive, negative, or unknown ER status). Long-term follow-up still continues. This study is registered,number ISRCTN19652633. FINDINGS Among women with ER-positive disease, allocation to continuetamoxifen reduced the risk of breast cancer recurrence (617 recurrences in 3428 women allocated tocontinue vs 711 in 3418 controls, p=0·002), reduced breast cancer mortality (331 deaths vs 397 deaths,p=0·01), and reduced overall mortality (639 deaths vs 722 deaths, p=0·01). The reductions in adversebreast cancer outcomes appeared to be less extreme before than after year 10 (recurrence rate ratio[RR] 0·90 [95% CI 0·79–1·02] during years 5–9 and 0·75 [0·62–0·90] in later years; breast cancermortality RR 0·97 [0·79–1·18] during years 5–9 and 0·71 [0·58–0·88] in later years). The cumulative riskof recurrence during years 5–14 was 21·4% for women allocated to continue versus 25·1% for controls;breast cancer mortality during years 5–14 was 12·2% for women allocated to continue versus 15·0% forcontrols (absolute mortality reduction 2·8%). Treatment allocation seemed to have no effect on breastcancer outcome among 1248 women with ER-negative disease, and an intermediate effect among 4800women with unknown ER status. Among all 12,894 women, mortality without recurrence from causesother than breast cancer was little affected (691 deaths without recurrence in 6454 women allocated tocontinue versus 679 deaths in 6440 controls; RR 0·99 [0·89–1·10]; p=0·84). For the incidence(hospitalisation or death) rates of specific diseases, RRs were as follows: pulmonary embolus 1·87 (95%CI 1·13–3·07, p=0·01 [including 0·2% mortality in both treatment groups]), stroke 1·06 (0·83–1·36),ischaemic heart disease 0·76 (0·60–0·95, p=0·02), and endometrial cancer 1·74 (1·30–2·34, p=0·0002).The cumulative risk of endometrial cancer during years 5–14 was 3·1% (mortality 0·4%) for womenallocated to continue versus 1·6% (mortality 0·2%) for controls (absolute mortality increase 0·2%).INTERPRETATION For women with ER-positive disease, continuing tamoxifen to 10 years rather thanstopping at 5 years produces a further reduction in recurrence and mortality, particularly after year 10.These results, taken together with results from previous trials of 5 years of tamoxifen treatment versusnone, suggest that 10 years of tamoxifen treatment can approximately halve breast cancer mortalityduring the second decade after diagnosis. FUNDING Cancer Research UK, UK Medical Research Council,AstraZeneca UK, US Army, EU-Biomed.", "metadata": {}}
+{"_id": "12440953", "title": "", "text": "Roles for MicroRNAs in Conferring Robustness to Biological ProcessesBiological systems use a variety ofmechanisms to maintain their functions in the face of environmental and genetic perturbations.Increasing evidence suggests that, among their roles as posttranscriptional repressors of geneexpression, microRNAs (miRNAs) help to confer robustness to biological processes by reinforcingtranscriptional programs and attenuating aberrant transcripts, and they may in some network contextshelp suppress random fluctuations in transcript copy number. These activities have importantconsequences for normal development and physiology, disease, and evolution. Here, we will discussexamples and principles of miRNAs that contribute to robustness in animal systems.", "metadata": {}}
+{"_id": "12442311", "title": "", "text": "Six-Year Follow-Up of Impact of Co-proxamol Withdrawal in England and Wales on Prescribing andDeaths: Time-Series StudyBACKGROUND The analgesic co-proxamol (paracetamol/dextropropoxyphenecombination) has been widely involved in fatal poisoning. Concerns about its safety/effectiveness profileand widespread use for suicidal poisoning prompted its withdrawal in the UK in 2005, with partialwithdrawal between 2005 and 2007, and full withdrawal in 2008. Our objective in this study was toassess the association between co-proxamol withdrawal and prescribing and deaths in England and Walesin 2005-2010 compared with 1998-2004, including estimation of possible substitution effects by otheranalgesics. METHODS AND FINDINGS We obtained prescribing data from the NHS Health and Social CareInformation Centre (England) and Prescribing Services Partneriaeth Cydwasanaethau GIG Cymru(Wales), and mortality data from the Office for National Statistics. We carried out an interruptedtime-series analysis of prescribing and deaths (suicide, open verdicts, accidental poisonings) involvingsingle analgesics. The reduction in prescribing of co-proxamol following its withdrawal in 2005 wasaccompanied by increases in prescribing of several other analgesics (co-codamol, paracetamol, codeine,co-dydramol, tramadol, oxycodone, and morphine) during 2005-2010 compared with 1998-2004. Thesechanges were associated with major reductions in deaths due to poisoning with co-proxamol receivingverdicts of suicide and undetermined cause of -21 deaths (95% CI -34 to -8) per quarter, equating toapproximately 500 fewer suicide deaths (-61%) over the 6 years 2005-2010, and -25 deaths (95% CI-38 to -12) per quarter, equating to 600 fewer deaths (-62%) when accidental poisoning deaths wereincluded. There was little observed change in deaths involving other analgesics, apart from an increase inoxycodone poisonings, but numbers were small. Limitations were that the study was based on deathsinvolving single drugs alone and changes in deaths involving prescribed morphine could not be assessed.CONCLUSIONS During the 6 years following the withdrawal of co-proxamol in the UK, there was a majorreduction in poisoning deaths involving this drug, without apparent significant increase in deathsinvolving other analgesics.", "metadata": {}}
+{"_id": "12443371", "title": "", "text": "Apolipoprotein E genotype and concussion in college athletes.OBJECTIVE To evaluate the associationbetween apolipoprotein E (APOE) polymorphisms (E2, C/T Arg158Cys; E4, T/C Cys112Arg; and promoter,g-219t) and the history of concussion in college athletes. We hypothesized that carrying 1 or more APOErare (or minor) allele assessed in this study would be associated with having a history of 1 or moreconcussions. DESIGN Multicenter cross-sectional study. SETTING University athletic facilities.PARTICIPANTS One hundred ninety-six male football (n = 163) and female soccer (n = 33) collegeathletes volunteered. INTERVENTIONS Written concussion history questionnaire and saliva samples forgenotyping. MAIN OUTCOME MEASURES Self-reported history of a documented concussion and rare APOEgenotype (E2, E4, promoter). RESULTS There was a significant association (Wald χ² = 3.82; P = 0.05;odds ratio = 9.8) between carrying all APOE rare alleles and the history of a previous concussion. Therewas also a significant association (Wald χ² = 3.96, P = 0.04, odds ratio = 8.4) between carrying theAPOE promoter minor allele and experiencing 2 or more concussions. CONCLUSIONS Carriers of all 3APOE rare (or minor) alleles assessed in this study were nearly 10 times more likely to report a previousconcussion and may be at a greater risk of concussion versus noncarriers. Promoter minor allele carrierswere 8.4 times more likely to report multiple concussions and may be at a greater risk of multipleconcussions versus noncarriers. Research involving larger samples of individuals with multipleconcussions and carriers of multiple APOE rare alleles is warranted.", "metadata": {}}
+{"_id": "12451492", "title": "", "text": "Plasma soluble corin and N-terminal pro-atrial natriuretic peptide levels in pregnancy inducedhypertension.OBJECTIVE One of the theories involved in the pathogenesis of pregnancy inducedhypertension involves salt and water retention. We aimed to measure the proenzyme convertase corin,responsible for pro-atrial natriuretic peptide (ANP) cleavage to active ANP, in plasma of hypertensivepregnant females. STUDY DESIGN Sixty pregnant females suffering from pregnancy inducedhypertension in second and third trimesters of pregnancy were compared to twenty eight healthypregnant females of the same gestational period. Concomitant urine and plasma samples were collectedfor the determination of some biochemical parameters. Plasma soluble corin and N-terminal (NT) pro-ANP(1-98) values were determined in both groups using enzyme immunoassays. RESULTS Plasma solublecorin mean value was significantly higher in the patient group compared to the control group. Upondividing the patient group according to blood pressure, plasma NT pro-ANP showed significantly highermean value in the group with blood pressure\u0000140/90mmHg compared to the group with bloodpressure<140/90mmHg and control group. CONCLUSIONS High plasma soluble corin and NT pro-ANPvalues in hypertensive pregnant females particularly those with blood pressure\u0000140/90mmHg speculatesan ANP receptor/ post receptor signaling defect, which would aggravate the pregnancy inducedhypertensive state.", "metadata": {}}
+{"_id": "12462961", "title": "", "text": "GATA-4 and GATA-6 modulate tissue-specific transcription of the human gene for P450c17 by directinteraction with Sp1.Cytochrome P450c17 catalyzes steroidogenic 17alpha-hydroxylase and 17,20 lyaseactivities. Expression of the gene for P450c17 is cAMP dependent, tissue specific, developmentallyprogrammed, and varies among species. Binding of Sp1, Sp3, and NF1-C (nuclear factor 1-C) to the first227 bp of 5'flanking DNA (-227/LUC) is crucial for basal transcription in human NCI-H295A adrenal cells.Human placental JEG-3 cells contain Sp1, Sp3, and NF1, but do not express -227/LUC, even whentransfected with a vector expressing steroidogenic factor 1 (SF-1). Therefore, other factors are essentialfor basal expression of P450c17. Deoxyribonuclease I footprinting and EMSAs identified a GATAconsensus site at -64/-58 and an SF-1 site at -58/-50. RT-PCR identified GATA-4, GATA-6, and SF-1 inNCI-H295A cells and GATA-2 and GATA-3, but not GATA-4, GATA-6, or SF-1 in JEG-3 cells.Cotransfection of either GATA-4 or GATA-6 without SF-1 activated -227/LUC in JEG-3 cells, butcotransfection of GATA-2 or GATA-3 with or without SF-1 did not. Surprisingly, mutation of the GATAbinding site in -227/LUC increased GATA-4 or GATA-6 induced activity, whereas mutation of the Sp1/Sp3site decreased it. Furthermore, promoter constructs including the GATA site, but excluding the Sp1/Sp3site at -196/-188, were not activated by GATA-4 or GATA-6, suggesting an interaction between Sp1/Sp3and GATA-4 or GATA-6. Glutathione-S-transferase pull-down experiments and coimmunoprecipitationdemonstrated interaction between GATA-4 or GATA-6 and Sp1, but not Sp3. Chromatinimmunoprecipitation assays confirmed that this GATA-4/6 interaction with Sp1 occurred at the Sp site inthe P450c17 promoter in NCI-H295A cells. Demethylation with 5-aza-2-deoxycytidine permitted JEG-3cells to express endogenous P450c17, SF-1, GATA-4, GATA-6, and transfected -227/LUC. Thus, GATA-4or GATA-6 and Sp1 together regulate expression of P450c17 in adrenal NCI-H295A cells and methylationof P450c17, GATA-4 and GATA-6 silence the expression of P450c17 in placental JEG-3 cells.", "metadata": {}}
+{"_id": "12470783", "title": "", "text": "Performance of an abbreviated version of the Lubben Social Network Scale among three Europeancommunity-dwelling older adult populations.PURPOSE There is a need for valid and reliable short scalesthat can be used to assess social networks and social supports and to screen for social isolation in olderpersons. DESIGN AND METHODS The present study is a cross-national and cross-cultural evaluation ofthe performance of an abbreviated version of the Lubben Social Network Scale (LSNS-6), which was usedto screen for social isolation among community-dwelling older adult populations in three Europeancountries. Based on the concept of lack of redundancy of social ties we defined clinical cut-points of theLSNS-6 for identifying persons deemed at risk for social isolation. RESULTS Among all three samples, theLSNS-6 and two subscales (Family and Friends) demonstrated high levels of internal consistency, stablefactor structures, and high correlations with criterion variables. The proposed clinical cut-points showedgood convergent validity, and classified 20% of the respondents in Hamburg, 11% of those in Solothurn(Switzerland), and 15% of those in London as at risk for social isolation. IMPLICATIONS We conclude thatabbreviated scales such as the LSNS-6 should be considered for inclusion in practice protocols ofgerontological practitioners. Screening older persons based on the LSNS-6 provides quantitativeinformation on their family and friendship ties, and identifies persons at increased risk for social isolationwho might benefit from in-depth assessment and targeted interventions.", "metadata": {}}
+{"_id": "12471115", "title": "", "text": "The PneuCarriage Project: A Multi-Centre Comparative Study to Identify the Best Serotyping Methods forExamining Pneumococcal Carriage in Vaccine Evaluation StudiesBACKGROUND The pneumococcus is adiverse pathogen whose primary niche is the nasopharynx. Over 90 different serotypes exist, andnasopharyngeal carriage of multiple serotypes is common. Understanding pneumococcal carriage isessential for evaluating the impact of pneumococcal vaccines. Traditional serotyping methods arecumbersome and insufficient for detecting multiple serotype carriage, and there are few data comparingthe new methods that have been developed over the past decade. We established the PneuCarriageproject, a large, international multi-centre study dedicated to the identification of the best pneumococcalserotyping methods for carriage studies. METHODS AND FINDINGS Reference sample sets weredistributed to 15 research groups for blinded testing. Twenty pneumococcal serotyping methods wereused to test 81 laboratory-prepared (spiked) samples. The five top-performing methods were used to test260 nasopharyngeal (field) samples collected from children in six high-burden countries. Sensitivity andpositive predictive value (PPV) were determined for the test methods and the reference method(traditional serotyping of >100 colonies from each sample). For the alternate serotyping methods, theoverall sensitivity ranged from 1% to 99% (reference method 98%), and PPV from 8% to 100%(reference method 100%), when testing the spiked samples. Fifteen methods had ≥70% sensitivity todetect the dominant (major) serotype, whilst only eight methods had ≥70% sensitivity to detect minorserotypes. For the field samples, the overall sensitivity ranged from 74.2% to 95.8% (reference method93.8%), and PPV from 82.2% to 96.4% (reference method 99.6%). The microarray had the highestsensitivity (95.8%) and high PPV (93.7%). The major limitation of this study is that not all of theavailable alternative serotyping methods were included. CONCLUSIONS Most methods were able todetect the dominant serotype in a sample, but many performed poorly in detecting the minor serotypepopulations. Microarray with a culture amplification step was the top-performing method. Results fromthis comprehensive evaluation will inform future vaccine evaluation and impact studies, particularly inlow-income settings, where pneumococcal disease burden remains high.", "metadata": {}}
+{"_id": "12486491", "title": "", "text": "Ribosome-Mediated Specificity in Hox mRNA Translation and Vertebrate Tissue PatterningHistorically, theribosome has been viewed as a complex ribozyme with constitutive rather than regulatory capacity inmRNA translation. Here we identify mutations of the Ribosomal Protein L38 (Rpl38) gene in miceexhibiting surprising tissue-specific patterning defects, including pronounced homeotic transformations ofthe axial skeleton. In Rpl38 mutant embryos, global protein synthesis is unchanged; however thetranslation of a select subset of Homeobox mRNAs is perturbed. Our data reveal that RPL38 facilitates80S complex formation on these mRNAs as a regulatory component of the ribosome to confertranscript-specific translational control. We further show that Rpl38 expression is markedly enriched inregions of the embryo where loss-of-function phenotypes occur. Unexpectedly, a ribosomal protein (RP)expression screen reveals dynamic regulation of individual RPs within the vertebrate embryo. Collectively,these findings suggest that RP activity may be highly regulated to impart a new layer of specificity in thecontrol of gene expression and mammalian development.", "metadata": {}}
+{"_id": "12489130", "title": "", "text": "Growth and invasion of human melanomas in human skin grafted to immunodeficient mice.An orthotopicmodel of human melanoma was developed in which malignant cells were injected into human skin graftedto nude and SCID mice. Melanoma cells proliferated and invaded the human skin grafts withcharacteristic patterns. Three of six melanomas grew as multiple nodules and infiltered the grafts withoutmajor architectural changes in the dermis, whereas the others invaded the dermis along collagen fiberswith prominent endothelial vessels. By contrast, melanoma cells inoculated into mouse skin grew asdiffusely expanding nodules that did not invade the murine dermis. In human skin grafts, humanmelanoma cells were angiogenic for human blood vessels, and murine vessels were only found at theperiphery of grafts. Tumor cells invaded the human vessels, and four out of seven cell lines metastasizedto lungs, suggesting that this model is useful to determine in vivo the interactions between normal andmalignant human cells.", "metadata": {}}
+{"_id": "12489688", "title": "", "text": "Myeloperoxidase: friend and foe.Neutrophilic polymorphonuclear leukocytes (neutrophils) are highlyspecialized for their primary function, the phagocytosis and destruction of microorganisms. When coatedwith opsonins (generally complement and/or antibody), microorganisms bind to specific receptors on thesurface of the phagocyte and invagination of the cell membrane occurs with the incorporation of themicroorganism into an intracellular phagosome. There follows a burst of oxygen consumption, and much,if not all, of the extra oxygen consumed is converted to highly reactive oxygen species. In addition, thecytoplasmic granules discharge their contents into the phagosome, and death of the ingestedmicroorganism soon follows. Among the antimicrobial systems formed in the phagosome is one consistingof myeloperoxidase (MPO), released into the phagosome during the degranulation process, hydrogenperoxide (H2O2), formed by the respiratory burst and a halide, particularly chloride. The initial product ofthe MPO-H2O2-chloride system is hypochlorous acid, and subsequent formation of chlorine, chloramines,hydroxyl radicals, singlet oxygen, and ozone has been proposed. These same toxic agents can bereleased to the outside of the cell, where they may attack normal tissue and thus contribute to thepathogenesis of disease. This review will consider the potential sources of H2O2 for the MPO-H2O2-halidesystem; the toxic products of the MPO system; the evidence for MPO involvement in the microbicidalactivity of neutrophils; the involvement of MPO-independent antimicrobial systems; and the role of theMPO system in tissue injury. It is concluded that the MPO system plays an important role in themicrobicidal activity of phagocytes.", "metadata": {}}
+{"_id": "12513042", "title": "", "text": "Role of microsomal prostaglandin E synthase-1 in the facilitation of angiogenesis and the healing ofgastric ulcers.The importance of prostaglandin E(2) in various pathophysiological events emphasizes thenecessity of understanding the role of PGE synthases (PGESs) in vivo. However, there has been no reporton the functional relevance of microsomal PGES-1 (mPGES-1) to the physiological healing processes ofgastric ulcers, or to angiogenesis, which is indispensable to the healing processes. In this report, wetested whether mPGES-1 plays a role in the healing of gastric ulcers and in the enhancement ofangiogenesis using mPGES-1 knockout mice (mPGES-1 KO mice) and their wild-type (WT) counterparts.Gastric ulcers were induced by the serosal application of 100% acetic acid, and the areas of the ulcerswere measured thereafter. mPGES-1 together with cyclooxygenase-2 were induced in the granulationtissues compared with normal stomach tissues. The healing of acetic acid-induced ulcers was significantlydelayed in mPGES-1 KO mice compared with WT. This was accompanied with reduced angiogenesis inulcer granulation tissues, as estimated by CD31 mRNA levels determined by real-time PCR and themicrovessel density in granulation tissues. The mRNA levels of proangiogenic growth factors, such astransforming growth factor-β, basic fibroblast growth factor, and connective tissue growth factor in ulcergranulation tissues determined were reduced in mPGES-1 KO mice compared with WT. The presentresults suggest that mPGES-1 enhances the ulcer-healing processes and the angiogenesis indispensableto ulcer healing, and that a selective mPGES-1 inhibitor should be used with care in patients with gastriculcers.", "metadata": {}}
+{"_id": "12513972", "title": "", "text": "Echocardiographic Evidence of Innate Aortopathy in the Human Intracranial AneurysmBACKGROUNDIntracranial aneurysm (IA) is significantly more prevalent in patients with coarctation of the aorta orbicuspid aortic valve than in the general population, suggesting a common pathophysiology connecting IAand aortopathy. Here, we analyzed echocardiographic aortic root dimension (ARD) in patients with IA toconfirm this possibility. METHODS From January 2008 to December 2010, 260 consecutive patients withIA who were admitted to our institution for coil embolization or for acute stroke management and whoalso underwent echocardiography were enrolled. We hypothesized that patients with large, ruptured, ormultiple IAs are more likely to harbor co-prevalent aortopathy as measured by ARD compared to patientswith small, isolated, unruptured IAs. Eccentric group was defined as patients aged <55 years with at leastone ruptured aneurysm, an aneurysm ≥7 mm in size, or multiple aneurysms; the remainder wasclassified into a non-eccentric group. Clinical, angiographic, and echocardiographic findings of the twogroups were compared. RESULTS ARD was significantly larger in the eccentric group than in thenon-eccentric group (P = 0.049), and the difference was confirmed by multivariable analysis (P = 0.02).Subgroup analysis of patients aged <55 years showed similar result for ARD (P = 0.03), whereashypertension was more associated with the non-eccentric group (P = 0.01). In addition, height wasinversely related to aneurysm size after adjustment for age, sex, weight, ARD, smoking status, andnumber of aneurysms (P = 0.004). CONCLUSIONS A certain group of IA patients share a commonintrinsic wall defect with aortopathy. Shared neural crest cell origin may give rise to this phenomenon.", "metadata": {}}
+{"_id": "12549585", "title": "", "text": "Aortic and large artery compliance in end-stage renal failure.Pulse wave velocity (PWV) was measured inthe aorta, right leg and arm of 90 control subjects (CS) and 92 hemodialysis patients (HD) of the sameage and mean arterial pressure (MAP). Blood chemistry, including blood lipids, and echographicdimensions of the aorta, were measured in all subjects. Presence of aortic calcification was evaluated byabdominal X-ray and echography. Whereas femoral and brachial PWV were only slightly increased in HD(P less than 0.05), the aortic PWV was significantly elevated (1113 +/- 319 cm/sec) in comparison withCS (965 +/- 216 cm/sec; P = 0.0016). Aortic diameters were larger in HD, both at the root of aorta (32.7+/- 4 vs. 28.2 +/- 2.8 mm; P less than 0.0001) and aortic bifurcation (16.9 +/- 3.1 vs. 14.6 +/- 2.2 mm;P less than 0.0001). Although the MAP was similar in HD (109.9 +/- 19.3 mm Hg) and CS (110.2 +/-17.2 mm Hg), the pulse pressure was significantly increased in HD patients (76.6 +/- 23.7 vs. 63.9 +/-22 mm Hg; P = 0.007). In the two populations, aortic PWV was found to increase with age (P less than0.0001) and MAP (P less than 0.0001). The presence of aortic calcification showed only a borderlinerelationship with the increase in aortic PWV (P = 0.050 in CS and P = 0.069 in HD). As change in PWV isdirectly related to change in distensibility, and the aortic diameters were increased in HD, these resultsindicate that aortic wall compliance is decreased in HD, resulting in an increase in the pulsatilecomponent of arterial pressure.(ABSTRACT TRUNCATED AT 250 WORDS)", "metadata": {}}
+{"_id": "12552297", "title": "", "text": "The DNA polymerase λ is required for the repair of non-compatible DNA double strand breaks by NHEJ inmammalian cellsDNA polymerase lambda (polλ) is a recently identified DNA polymerase whose cellularfunction remains elusive. Here we show, that polλ participates at the molecular level in a chromosomalcontext, in the repair of DNA double strand breaks (DSB) via non-homologous end joining (NHEJ) inmammalian cells. The expression of a catalytically inactive form of polλ (polλDN) decreases the frequencyof NHEJ events in response to I-Sce-I-induced DSB whereas inactivated forms of its homologues polβ andpolμ do not. Only events requiring DNA end processing before ligation are affected; this defect isassociated with large deletions arising in the vicinity of the induced DSB. Furthermore, polλDN-expressingcells exhibit increased sensitization and genomic instability in response to ionizing radiation similar to thatof NHEJ-defective cells. Our data support a requirement for polλ in repairing a subset of DSB in genomicDNA, thereby contributing to the maintenance of genetic stability mediated by the NHEJ pathway.", "metadata": {}}
+{"_id": "12561083", "title": "", "text": "Angina with \"normal\" coronary arteries: sex differences in outcomes.BACKGROUND Several studies havedemonstrated that women with nonobstructive coronary disease have a high rate of subsequentinvestigations, rehospitalizations for recurrent chest pain, and repeat coronary angiography. The sexspecificity of this finding is unclear. We therefore undertook an evaluation of sex differences inrehospitalization for acute coronary syndrome (ACS) or chest pain in patients with \"angiographicallynormal\" coronaries. METHODS A retrospective cohort study using prospectively collected angiographicand clinical data on all patients in British Columbia, Canada, presenting for their first cardiaccatheterization with suspected ischemic heart disease but angiographically normal coronaries. RESULTSAmong 32,856 patients, 7.1% of men versus 23.3% of women were angiographically normal (P < .001).Among angiographically normal patients, women were older and more likely to present withhypertension, prior stroke, chronic obstructive pulmonary disease, and peripheral vascular disease thanmen, but Canadian Cardiovascular Society class of angina did not vary by sex. Within 1 year, 1.0% died,(19 women, 18 men, P = .27) and 0.6% had a stroke (13 women, 9 men, P = .91). Readmission tohospital for ACS or chest pain requiring catheterization was significantly higher in women compared tomen (adjusted OR 4.06; 95% CI 1.15-14.31). CONCLUSIONS In a contemporary, population-basedcohort presenting for cardiac catheterization for suspected ischemia, women with angiographically normalcoronaries were >4 times more likely to be readmitted to hospital for ACS/chest pain within 180 dayscompared to men. The observed sex difference has important social and economic implications andsuggests that traditional diagnostic methods may not be optimal for women.", "metadata": {}}
+{"_id": "12580014", "title": "", "text": "Keratin-dependent regulation of Aire and gene expression in skin tumor keratinocytesExpression of theintermediate filament protein keratin 17 (K17) is robustly upregulated in inflammatory skin diseases andin many tumors originating in stratified and pseudostratified epithelia. We report that autoimmuneregulator (Aire), a transcriptional regulator, is inducibly expressed in human and mouse tumorkeratinocytes in a K17-dependent manner and is required for timely onset of Gli2-induced skintumorigenesis in mice. The induction of Aire mRNA in keratinocytes depends on a functional interactionbetween K17 and the heterogeneous nuclear ribonucleoprotein hnRNP K. Further, K17 colocalizes withAire protein in the nucleus of tumor-prone keratinocytes, and each factor is bound to a specific promoterregion featuring an NF-κB consensus sequence in a relevant subset of K17- and Aire-dependentproinflammatory genes. These findings provide radically new insight into keratin intermediate filamentand Aire function, along with a molecular basis for the K17-dependent amplification of inflammatory andimmune responses in diseased epithelia.", "metadata": {}}
+{"_id": "12582729", "title": "", "text": "Flow-Dependent Regulation of Kruppel-Like Factor 2 Is Mediated by MicroRNA-92a.BACKGROUNDUpregulated by atheroprotective flow, the transcription factor Krüppel-like factor 2 (KLF2) is crucial formaintaining endothelial function. MicroRNAs (miRNAs) are noncoding small RNAs that regulate geneexpression at the posttranscriptional level. We examined the role of miRNAs, particularly miR-92a, in theatheroprotective flow-regulated KLF2. METHODS AND RESULTS Dicer knockdown increased the level ofKLF2 mRNA in human umbilical vein endothelial cells, suggesting that KLF2 is regulated by miRNA. Insilico analysis predicted that miR-92a could bind to the 3' untranslated region of KLF2 mRNA.Overexpression of miR-92a decreased the expression of KLF2 and the KLF2-regulated endothelial nitricoxide synthase and thrombomodulin at mRNA and protein levels. A complementary finding is thatmiR-92a inhibitor increased the mRNA and protein expression of KLF2, endothelial nitric oxide synthase,and thrombomodulin. Subsequent studies revealed that atheroprotective laminar flow downregulated thelevel of miR-92a precursor to induce KLF2, and the level of this flow-induced KLF2 was reduced bymiR-92a precursor. Furthermore, miR-92a level was lower in human umbilical vein endothelial cellsexposed to the atheroprotective pulsatile shear flow than under atheroprone oscillatory shear flow.Anti-Ago1/2 immunoprecipitation coupled with real-time polymerase chain reaction revealed thatpulsatile shear flow decreased the functional targeting of miR-92a precursor/KLF2 mRNA in humanumbilical vein endothelial cells. Consistent with these findings, mouse carotid arteries receiving miR-92aprecursor exhibited impaired vasodilatory response to flow. CONCLUSIONS Atheroprotective flow patternsdecrease the level of miR-92a, which in turn increases KLF2 expression to maintain endothelialhomeostasis.", "metadata": {}}
+{"_id": "12584053", "title": "", "text": "Effectiveness of a diabetes education and self management programme (DESMOND) for people withnewly diagnosed type 2 diabetes mellitus: three year follow-up of a cluster randomised controlled trial inprimary careOBJECTIVE To measure whether the benefits of a single education and self managementstructured programme for people with newly diagnosed type 2 diabetes mellitus are sustained at threeyears. DESIGN Three year follow-up of a multicentre cluster randomised controlled trial in primary care,with randomisation at practice level. SETTING 207 general practices in 13 primary care sites in the UnitedKingdom. PARTICIPANTS 731 of the 824 participants included in the original trial were eligible forfollow-up. Biomedical data were collected on 604 (82.6%) and questionnaire data on 513 (70.1%)participants. INTERVENTION A structured group education programme for six hours delivered in thecommunity by two trained healthcare professional educators compared with usual care. MAIN OUTCOMEMEASURES The primary outcome was glycated haemoglobin (HbA(1c)) levels. The secondary outcomeswere blood pressure, weight, blood lipid levels, smoking status, physical activity, quality of life, beliefsabout illness, depression, emotional impact of diabetes, and drug use at three years. RESULTS HbA(1c)levels at three years had decreased in both groups. After adjusting for baseline and cluster the differencewas not significant (difference -0.02, 95% confidence interval -0.22 to 0.17). The groups did not differ forthe other biomedical and lifestyle outcomes and drug use. The significant benefits in the interventiongroup across four out of five health beliefs seen at 12 months were sustained at three years (P<0.01).Depression scores and quality of life did not differ at three years. CONCLUSION A single programme forpeople with newly diagnosed type 2 diabetes mellitus showed no difference in biomedical or lifestyleoutcomes at three years although there were sustained improvements in some illness beliefs. TRIALREGISTRATION Current Controlled Trials ISRCTN17844016.", "metadata": {}}
+{"_id": "12588500", "title": "", "text": "Acetylation of Histone H3 Lysine 56 Regulates Replication-Coupled Nucleosome AssemblyChromatinassembly factor 1 (CAF-1) and Rtt106 participate in the deposition of newly synthesized histones ontoreplicating DNA to form nucleosomes. This process is critical for the maintenance of genome stability andinheritance of functionally specialized chromatin structures in proliferating cells. However, the molecularfunctions of the acetylation of newly synthesized histones in this DNA replication-coupled nucleosomeassembly pathway remain enigmatic. Here we show that histone H3 acetylated at lysine 56 (H3K56Ac) isincorporated onto replicating DNA and, by increasing the binding affinity of CAF-1 and Rtt106 for histoneH3, H3K56Ac enhances the ability of these histone chaperones to assemble DNA into nucleosomes.Genetic analysis indicates that H3K56Ac acts in a nonredundant manner with the acetylation of theN-terminal residues of H3 and H4 in nucleosome assembly. These results reveal a mechanism by whichH3K56Ac regulates replication-coupled nucleosome assembly mediated by CAF-1 and Rtt106.", "metadata": {}}
+{"_id": "12622860", "title": "", "text": "Selective inhibition of Ras-dependent cell growth by farnesylthiosalisylicacid.S-trans,trans-Farnesylthiosalicylic acid (FTS) is a novel farnesylated rigid carboxylic acid derivative.In cell-free systems, it acts as a potent competitive inhibitor (Ki = 2.6 microM) of the enzyme prenylatedprotein methyltransferase (PPMTase), which methylates the carboxyl-terminal S-prenylcysteine in a largenumber of prenylated proteins including Ras. In such systems, FTS inhibits Ras methylation but not Rasfarnesylation. Inhibition of the PPMTase by FTS in homogenates or membranes of a variety of tissues andcell lines is inferred from a block in the methylation of exogenously added substrates such asN-acetyl-S-trans,trans-farnesyl-L-cysteine and of endogenous substrates including small GTP-bindingproteins. FTS can also inhibit methylation of these proteins in intact cells (e.g. in Rat-1 fibroblasts,Ras-transformed Rat-1, and B16 melanoma cells). Unlike in cell-free systems, however, relatively highconcentrations of FTS (50-100 microM) are required for partial blocking (10-40%) of protein methylationin the intact cells. Thus, FTS is a weak inhibitor of methylation in intact cells. Because methylation is thelast step in the processing of Ras and related proteins, FTS is not likely to affect steps that precede it,e.g. protein prenylation. This may explain why the growth and gross morphology of a variety of culturedcell types (including Chinese hamster ovary, NIH3T3, Rat1, B16 melanoma, and PC12) is not affected byup to 25 microM FTS and is consistent with the observed lack of FTS-induced cytotoxicity. Nevertheless,FTS reduces the levels of Ras in cell membranes and can inhibit Ras-dependent cell growth in vitro,independently of methylation. It inhibits the growth of human Ha-ras-transformed cells (EJ cells) andreverses their transformed morphology in a dose-dependent manner (0.1-10 microM). The drug does notinterfere with the growth of cells transformed by v-Raf or T-antigen but inhibits the growth ofErbB2-transformed cells and blocks the mitogenic effects of epidermal and basic fibroblast growth factors,thus implying its selectivity toward Ras growth signaling, possibly via modulation of Ras-Rafcommunication. Taken together, the results raise the possibility that FTS may specifically interfere withthe interaction of Ras with a farnesylcysteine recognition domain in the cell membrane.(ABSTRACTTRUNCATED AT 400 WORDS)", "metadata": {}}
+{"_id": "12631182", "title": "", "text": "NADPH oxidase controls phagosomal pH and antigen cross-presentation in human dendritic cells.Thephagocyte NADPH oxidase (NOX2) is critical for the bactericidal activity of phagocytic cells and plays amajor role in innate immunity. We showed recently that NOX2 activity in mouse dendritic cells (DCs)prevents acidification of phagosomes, promoting antigen cross-presentation. In order to investigate therole of NOX2 in the regulation of the phagosomal pH in human DCs, we analyzed the production ofreactive oxygen species (ROS) and the phagosomal/endosomal pH in monocyte-derived DCs andmacrophages (M(diameter)s) from healthy donors or patients with chronic granulomatous disease (CGD).As expected, we found that human M(diameter)s acidify their phagosomes more efficiently than humanDCs. Accordingly, the expression of the vacuolar proton ATPase (V-H(+)-ATPase) was higher inM(diameter)s than in DCs. Phagosomal ROS production, however, was also higher in M(diameter)s thanin DCs, due to higher levels of gp91phox expression and recruitment to phagosomes. In contrast, in theabsence of active NOX2, the phagosomal and endosomal pH decreased. Both in the presence of a NOX2inhibitor and in DCs derived from patients with CGD, the cross-presentation of 2 model tumor antigenswas impaired. We conclude that NOX2 activity participates in the regulation of the phagosomal andendosomal pH in human DCs, and is required for efficient antigen cross-presentation.", "metadata": {}}
+{"_id": "12631697", "title": "", "text": "Activation of fast skeletal muscle troponin as a potential therapeutic approach for treating neuromusculardiseasesLimited neural input results in muscle weakness in neuromuscular disease because of a reductionin the density of muscle innervation, the rate of neuromuscular junction activation or the efficiency ofsynaptic transmission. We developed a small-molecule fast-skeletal-troponin activator, CK-2017357, as ameans to increase muscle strength by amplifying the response of muscle when neural input is otherwisediminished secondary to neuromuscular disease. Binding selectively to the fast-skeletal-troponincomplex, CK-2017357 slows the rate of calcium release from troponin C and sensitizes muscle to calcium.As a consequence, the force-calcium relationship of muscle fibers shifts leftwards, as does theforce-frequency relationship of a nerve-muscle pair, so that CK-2017357 increases the production ofmuscle force in situ at sub-maximal nerve stimulation rates. Notably, we show that sensitization of thefast-skeletal-troponin complex to calcium improves muscle force and grip strength immediately afteradministration of single doses of CK-2017357 in a model of the neuromuscular disease myastheniagravis. Troponin activation may provide a new therapeutic approach to improve physical activity indiseases where neuromuscular function is compromised.", "metadata": {}}
+{"_id": "12640810", "title": "", "text": "Cortactin regulates cofilin and N-WASp activities to control the stages of invadopodium assembly andmaturationInvadopodia are matrix-degrading membrane protrusions in invasive carcinoma cells. Themechanisms regulating invadopodium assembly and maturation are not understood. We have dissectedthe stages of invadopodium assembly and maturation and show that invadopodia use cortactinphosphorylation as a master switch during these processes. In particular, cortactin phosphorylation wasfound to regulate cofilin and Arp2/3 complex-dependent actin polymerization. Cortactin directly bindscofilin and inhibits its severing activity. Cortactin phosphorylation is required to release this inhibition socofilin can sever actin filaments to create barbed ends at invadopodia to support Arp2/3-dependent actinpolymerization. After barbed end formation, cortactin is dephosphorylated, which blocks cofilin severingactivity thereby stabilizing invadopodia. These findings identify novel mechanisms for actinpolymerization in the invadopodia of metastatic carcinoma cells and define four distinct stages ofinvadopodium assembly and maturation consisting of invadopodium precursor formation, actinpolymerization, stabilization, and matrix degradation.", "metadata": {}}
+{"_id": "12641252", "title": "", "text": "Calreticulin exposure dictates the immunogenicity of cancer cell deathAnthracyclin-treated tumor cells areparticularly effective in eliciting an anticancer immune response, whereas other DNA-damaging agentssuch as etoposide and mitomycin C do not induce immunogenic cell death. Here we show thatanthracyclins induce the rapid, preapoptotic translocation of calreticulin (CRT) to the cell surface.Blockade or knockdown of CRT suppressed the phagocytosis of anthracyclin-treated tumor cells bydendritic cells and abolished their immunogenicity in mice. The anthracyclin-induced CRT translocationwas mimicked by inhibition of the protein phosphatase 1/GADD34 complex. Administration ofrecombinant CRT or inhibitors of protein phosphatase 1/GADD34 restored the immunogenicity of celldeath elicited by etoposide and mitomycin C, and enhanced their antitumor effects in vivo. These dataidentify CRT as a key feature determining anticancer immune responses and delineate a possible strategyfor immunogenic chemotherapy.", "metadata": {}}
+{"_id": "12642224", "title": "", "text": "In vivo disruption of Xenopus U3 snRNA affects ribosomal RNA processing.DNA oligonucleotidecomplementary to sequences in the 5' third of U3 snRNA were injected into Xenopus oocyte nuclei todisrupt endogenous U3 snRNA. The effect of this treatment on rRNA processing was examined. We foundthat some toads have a single rRNA processing pathway, whereas in other toads, two rRNA processingpathways can coexist in a single oocyte. U3 snRNA disruption in toads with the single rRNA processingpathway caused a reduction in 20S and '32S' pre-rRNA. In addition, in toads with two rRNA processingpathways, an increase in '36S' pre-rRNA of the second pathway is observed. This is the first in vivodemonstration that U3 snRNA plays a role in rRNA processing. Cleavage site #3 is at the boundary of ITS1 and 5.8S and links all of the affected rRNA intermediates: 20S and '32S' are the products of site #3cleavage in the first pathway and '36S' is the substrate for cleavage at site #3 in the second pathway. Wepostulate that U3 snRNP folds pre-rRNA into a conformation dictating correct cleavage at processing site#3.", "metadata": {}}
+{"_id": "12643937", "title": "", "text": "A genome-wide siRNA screen reveals diverse cellular processes and pathways that mediate genomestability.Signaling pathways that respond to DNA damage are essential for the maintenance of genomestability and are linked to many diseases, including cancer. Here, a genome-wide siRNA screen wasemployed to identify additional genes involved in genome stabilization by monitoring phosphorylation ofthe histone variant H2AX, an early mark of DNA damage. We identified hundreds of genes whosedownregulation led to elevated levels of H2AX phosphorylation (gammaH2AX) and revealed links tocellular complexes and to genes with unclassified functions. We demonstrate a widespread role formRNA-processing factors in preventing DNA damage, which in some cases is caused by aberrantRNA-DNA structures. Furthermore, we connect increased gammaH2AX levels to the neurological disorderCharcot-Marie-Tooth (CMT) syndrome, and we find a role for several CMT proteins in the DNA-damageresponse. These data indicate that preservation of genome stability is mediated by a larger network ofbiological processes than previously appreciated.", "metadata": {}}
+{"_id": "12650610", "title": "", "text": "Alphavbeta6-Fyn signaling promotes oral cancer progression.We have previously shown that the integrinbeta6 is neo-expressed in invasive oral squamous cell carcinoma (SCC) and is correlated with oral tumorprogression. However, the mechanism by which the integrin beta6 promotes oral tumor progression isnot well understood. The purpose of the present study was to determine whether integrin beta6 signalingactivates Fyn and thus promotes oral squamous cell carcinoma progression. We analyzed the integrinbeta6 signaling complex and investigated the function of these signaling molecules in oral SCC cells. Wefound that, upon ligation of the integrin beta6 with fibronectin, beta6 complexed with Fyn and activatedit. The activation of Fyn recruited and activated focal adhesion kinase to this complex. This complex wasnecessary to activate Shc and to couple beta6 signaling to the Raf-ERK/MAPK pathway. This pathwaytranscriptionally activated the matrix metalloproteinase-3 gene and promoted oral SCC cell proliferationand experimental metastasis in vivo. These findings indicate that integrin beta6 signaling activates Fynand thus promotes oral cancer progression.", "metadata": {}}
+{"_id": "12652963", "title": "", "text": "miRNA-dependent gene silencing involving Ago2-mediated cleavage of a circular antisenseRNA.MicroRNAs (miRNAs) are \u000022 nt non-coding RNAs that typically bind to the 3' UTR of target mRNAsin the cytoplasm, resulting in mRNA destabilization and translational repression. Here, we report thatmiRNAs can also regulate gene expression by targeting non-coding antisense transcripts in human cells.Specifically, we show that miR-671 directs cleavage of a circular antisense transcript of the CerebellarDegeneration-Related protein 1 (CDR1) locus in an Ago2-slicer-dependent manner. The resultingdownregulation of circular antisense has a concomitant decrease in CDR1 mRNA levels, independently ofheterochromatin formation. This study provides the first evidence for non-coding antisense transcripts asfunctional miRNA targets, and a novel regulatory mechanism involving a positive correlation betweenmRNA and antisense circular RNA levels.", "metadata": {}}
+{"_id": "12658073", "title": "", "text": "Regulation of Serum Amyloid A3 (SAA3) in Mouse Colonic Epithelium and Adipose Tissue by the IntestinalMicrobiotaThe gut microbiota has been proposed as an environmental factor that affects the developmentof metabolic and inflammatory diseases in mammals. Recent reports indicate that gut bacteria-derivedlipopolysaccharide (LPS) can initiate obesity and insulin resistance in mice; however, the molecularinteractions responsible for microbial regulation of host metabolism and mediators of inflammation havenot been studied in detail. Hepatic serum amyloid A (SAA) proteins are markers and proposed mediatorsof inflammation that exhibit increased levels in serum of insulin-resistant mice. Adipose tissue-derivedSAA3 displays monocyte chemotactic activity and may play a role in metabolic inflammation associatedwith obesity and insulin resistance. To investigate a potential mechanistic link between the intestinalmicrobiota and induction of proinflammatory host factors, we performed molecular analyses of germ-free,conventionally raised and genetically modified Myd88-/- mouse models. SAA3 expression was determinedto be significantly augmented in adipose (9.9+/-1.9-fold; P<0.001) and colonic tissue (7.0+/-2.3-fold;P<0.05) by the presence of intestinal microbes. In the colon, we provided evidence that SAA3 is partiallyregulated through the Toll-like receptor (TLR)/MyD88/NF-kappaB signaling axis. We identified epithelialcells and macrophages as cellular sources of SAA3 in the colon and found that colonic epithelialexpression of SAA3 may be part of an NF-kappaB-dependent response to LPS from gut bacteria. In vitroexperiments showed that LPS treatments of both epithelial cells and macrophages induced SAA3expression (27.1+/-2.5-fold vs. 1.6+/-0.1-fold, respectively). Our data suggest that LPS, and potentiallyother products of the indigenous gut microbiota, might elevate cytokine expression in tissues and thusexacerbate chronic low-grade inflammation observed in obesity.", "metadata": {}}
+{"_id": "12662435", "title": "", "text": "Reversing the tide — diagnosis and prevention of T2DM in populations of African descentAbstract |Populations of African descent are at the forefront of the worldwide epidemic of type 2 diabetes mellitus(T2DM). The burden of T2DM is amplified by diagnosis after preventable complications of the diseasehave occurred. Earlier detection would result in a reduction in undiagnosed T2DM, more accuratestatistics, more informed resource allocation and better health. An underappreciated factor contributingto undiagnosed T2DM in populations of African descent is that screening tests for hyperglycaemia,specifically, fasting plasma glucose and HbA1c, perform sub\u0000optimally in these populations. To offsetthis problem, combining tests or adding glycated albumin (a nonfasting marker of glycaemia), might bethe way forward. However, differences in diet, exercise, BMI, environment, gene\u0000environmentinteractions and the prevalence of sickle cell trait mean that neither diagnostic tests nor interventions willbe uniformly effective in individuals of African, Caribbean or African\u0000American descent. Among thesethree populations of African descent, intensive lifestyle interventions have been reported in only theAfrican\u0000American population, in which they have been found to provide effective primary prevention ofT2DM but not secondary prevention. Owing to a lack of health literacy and poor glycaemic control inAfrica and the Caribbean, customized lifestyle interventions might achieve both secondary and primaryprevention. Overall, diagnosis and prevention of T2DM requires innovative strategies that are sensitive tothe diversity that exists within populations of African descent.", "metadata": {}}
+{"_id": "12667988", "title": "", "text": "Biofeedback and relaxation in the treatment of migraine headaches: comparative effectiveness andphysiological correlates.Twenty-seven migraine headache patients were divided into three equal groupswhich received thermal biofeedback, frontalis EMG biofeedback, or relaxation training. Training was givenunder \"massed\" practice conditions (nine sessions per week) and consisted of 18 training sessions and sixtest-generalisation sessions. While improvements in headaches were observed in all groups, the bestimprovements took place in the thermal biofeedback group, which had almost complete elimination ofmigraine attacks by the end of training, and maintained that performance as long as six months aftertraining. Examination of the patterns of skin temperature and EMG changes in the three groups over thecourse of training also points to a relationship between skin temperature control and reduction inmigraine headache symptomatology, and suggests that this relationship is worthy of furtherinvestigation.", "metadata": {}}
+{"_id": "12669325", "title": "", "text": "Fine-scale chromatin interaction maps reveal the cis-regulatory landscape of human lincRNAgenesHigh-throughput methods based on chromosome conformation capture have greatly advanced ourunderstanding of the three-dimensional (3D) organization of genomes but are limited in resolution bytheir reliance on restriction enzymes. Here we describe a method called DNase Hi-C for comprehensivelymapping global chromatin contacts. DNase Hi-C uses DNase I for chromatin fragmentation, leading togreatly improved efficiency and resolution over that of Hi-C. Coupling this method with DNA-capturetechnology provides a high-throughput approach for targeted mapping of fine-scale chromatinarchitecture. We applied targeted DNase Hi-C to characterize the 3D organization of 998 large intergenicnoncoding RNA (lincRNA) promoters in two human cell lines. Our results revealed that expression oflincRNAs is tightly controlled by complex mechanisms involving both super-enhancers and the Polycombrepressive complex. Our results provide the first glimpse of the cell type-specific 3D organization oflincRNA genes.", "metadata": {}}
+{"_id": "12670680", "title": "", "text": "BASOPHILS AND THE T HELPER 2 ENVIRONMENT CAN PROMOTE THE DEVELOPMENT OF LUPUSNEPHRITISIn systemic lupus erythematosus (SLE), self-reactive antibodies can target the kidney (lupusnephritis), leading to functional failure and possible mortality. We report that activation of basophils byautoreactive IgE causes their homing to lymph nodes, promoting T helper type 2 (T(H)2) celldifferentiation and enhancing the production of self-reactive antibodies that cause lupus-like nephritis inmice lacking the Src family protein tyrosine kinase Lyn (Lyn(-/-) mice). Individuals with SLE also haveelevated serum IgE, self-reactive IgEs and activated basophils that express CD62 ligand (CD62L) and themajor histocompatibility complex (MHC) class II molecule human leukocyte antigen-DR (HLA-DR),parameters that are associated with increased disease activity and active lupus nephritis. Basophils werealso present in the lymph nodes and spleen of subjects with SLE. Thus, in Lyn(-/-) mice, basophils andIgE autoantibodies amplify autoantibody production that leads to lupus nephritis, and in individuals withSLE IgE autoantibodies and activated basophils are factors associated with disease activity and nephritis.", "metadata": {}}
+{"_id": "12672066", "title": "", "text": "Behavioral treatment of obesity in patients encountered in primary care settings: a systematicreview.IMPORTANCE In 2011, the Centers for Medicare & Medicaid Services (CMS) approved intensivebehavioral weight loss counseling for approximately 14 face-to-face, 10- to 15-minute sessions over 6months for obese beneficiaries in primary care settings, when delivered by physicians and otherCMS-defined primary care practitioners. OBJECTIVE To conduct a systematic review of behavioralcounseling for overweight and obese patients recruited from primary care, as delivered by primary carepractitioners working alone or with trained interventionists (eg, medical assistants, registered dietitians),or by trained interventionists working independently. EVIDENCE REVIEW We searched PubMed, CINAHL,and EMBASE for randomized controlled trials published between January 1980 and June 2014 thatrecruited overweight and obese patients from primary care; provided behavioral counseling (ie, diet,exercise, and behavioral therapy) for at least 3 months, with at least 6 months of postrandomizationfollow-up; included at least 15 participants per treatment group and objectively measured weights; andhad a comparator, an intention-to-treat analysis, and attrition of less than 30% at 1 year or less than40% at longer follow-up. FINDINGS Review of 3304 abstracts yielded 12 trials, involving 3893participants, that met inclusion-exclusion criteria and prespecified quality ratings. No studies were foundin which primary care practitioners delivered counseling that followed the CMS guidelines. Mean 6-monthweight changes from baseline in the intervention groups ranged from a loss of 0.3 kg to 6.6 kg. In thecontrol group, mean change ranged from a gain of 0.9 kg to a loss of 2.0 kg. Weight loss in both groupsgenerally declined with longer follow-up (12-24 months). Interventions that prescribed both reducedenergy intake (eg, ≥ 500 kcal/d) and increased physical activity (eg, ≥150 minutes a week of walking),with traditional behavioral therapy, generally produced larger weight loss than interventions without all 3specific components. In the former trials, more treatment sessions, delivered in person or by telephoneby trained interventionists, were associated with greater mean weight loss and likelihood of patientslosing 5% or more of baseline weight. CONCLUSIONS AND RELEVANCE Intensive behavioral counselingcan induce clinically meaningful weight loss, but there is little research on primary care practitionersproviding such care. The present findings suggest that a range of trained interventionists, who delivercounseling in person or by telephone, could be considered for treating overweight or obesity in patientsencountered in primary care settings.", "metadata": {}}
+{"_id": "12685434", "title": "", "text": "Guanylate binding protein 1 is a novel effector of EGFR-driven invasion in glioblastomaAlthough GBP1(guanylate binding protein 1) was among the first interferon-inducible proteins identified, its function isstill largely unknown. Epidermal growth factor receptor (EGFR) activation by amplification or mutation isone of the most frequent genetic lesions in a variety of human tumors. These include glioblastomamultiforme (GBM), which is characterized by independent but interrelated features of extensive invasioninto normal brain parenchyma, rapid growth, necrosis, and angiogenesis. In this study, we show thatEGFR activation promoted GBP1 expression in GBM cell lines through a signaling pathway involving Srcand p38 mitogen-activated protein kinase. Moreover, we identified YY1 (Yin Yang 1) as the downstreamtranscriptional regulator regulating EGFR-driven GBP1 expression. GBP1 was required for EGFR-mediatedMMP1 (matrix metalloproteinase 1) expression and glioma cell invasion in vitro. Although deregulation ofGBP1 expression did not affect glioma cell proliferation, overexpression of GBP1 enhanced glioma cellinvasion through MMP1 induction, which required its C-terminal helical domain and was independent of itsGTPase activity. Reducing GBP1 levels by RNA interference in invasive GBM cells also markedly inhibitedtheir ability to infiltrate the brain parenchyma of mice. GBP1 expression was high and positivelycorrelated with EGFR expression in human GBM tumors and cell lines, particularly those of the neuralsubtype. Together, these findings establish GBP1 as a previously unknown link between EGFR activity andMMP1 expression and nominate it as a novel potential therapeutic target for inhibiting GBM invasion.", "metadata": {}}
+{"_id": "12691537", "title": "", "text": "ATP binding to PAN or the 26S ATPases causes association with the 20S proteasome, gate opening, andtranslocation of unfolded proteins.The archaeal ATPase complex PAN, the homolog of the eukaryotic 26Sproteasome-regulatory ATPases, was shown to associate transiently with the 20S proteasome uponbinding of ATP or ATPgammaS, but not ADP. By electron microscopy (EM), PAN appears as a two-ringstructure, capping the 20S, and resembles two densities in the 19S complex. The N termini of thearchaeal 20S alpha subunits were found to function as a gate that prevents entry of seven-residuepeptides but allows entry of tetrapeptides. Upon association with the 20S particle, PAN stimulates gateopening. Although degradation of globular proteins requires ATP hydrolysis, the PAN-20S complex withATPgammaS translocates and degrades unfolded and denatured proteins. Rabbit 26S proteasomes alsodegrade these unfolded proteins upon ATP binding, without hydrolysis. Thus, although unfolding requiresenergy from ATP hydrolysis, ATP binding alone supports ATPase-20S association, gate opening, andtranslocation of unfolded substrates into the proteasome, which can occur by facilitated diffusion throughthe ATPase.", "metadata": {}}
+{"_id": "12705056", "title": "", "text": "Cytokines and anti-cytokine biologicals in autoimmunity: present and future.The increasingunderstanding of the role of cytokines in autoimmunity, and the observation that tumour necrosis factoralpha (TNFalpha) is central to the inflammatory and destructive process common to several humanautoimmune diseases, has led to a new generation of therapeutics, the TNFalpha blocking agents. In thisarticle, we review the current knowledge of the role of cytokines in autoimmunity as unravelled by studiesboth in the laboratory and the clinic. In addition, we discuss future prospects of the anti-TNFalphatherapy that may involve combination therapy with other anti-cytokine or anti-T cell biologicals, or theuse of small chemicals targeting molecules involved in TNFalpha production such as NF-kappaB and p38MAPK. The future developments of anti-TNFalpha and anti-cytokine therapy in general will be interesting.", "metadata": {}}
+{"_id": "12709184", "title": "", "text": "Vegetarian dietary patterns and mortality in Adventist Health Study 2.IMPORTANCE Some evidencesuggests vegetarian dietary patterns may be associated with reduced mortality, but the relationship isnot well established. OBJECTIVE To evaluate the association between vegetarian dietary patterns andmortality. DESIGN Prospective cohort study; mortality analysis by Cox proportional hazards regression,controlling for important demographic and lifestyle confounders. SETTING Adventist Health Study 2(AHS-2), a large North American cohort. PARTICIPANTS A total of 96,469 Seventh-day Adventist menand women recruited between 2002 and 2007, from which an analytic sample of 73,308 participantsremained after exclusions. EXPOSURES Diet was assessed at baseline by a quantitative food frequencyquestionnaire and categorized into 5 dietary patterns: nonvegetarian, semi-vegetarian, pesco-vegetarian,lacto-ovo-vegetarian, and vegan. MAIN OUTCOME AND MEASURE The relationship between vegetariandietary patterns and all-cause and cause-specific mortality; deaths through 2009 were identified from theNational Death Index. RESULTS There were 2570 deaths among 73,308 participants during a meanfollow-up time of 5.79 years. The mortality rate was 6.05 (95% CI, 5.82-6.29) deaths per 1000person-years. The adjusted hazard ratio (HR) for all-cause mortality in all vegetarians combined vsnonvegetarians was 0.88 (95% CI, 0.80-0.97). The adjusted HR for all-cause mortality in vegans was0.85 (95% CI, 0.73-1.01); in lacto-ovo-vegetarians, 0.91 (95% CI, 0.82-1.00); in pesco-vegetarians,0.81 (95% CI, 0.69-0.94); and in semi-vegetarians, 0.92 (95% CI, 0.75-1.13) compared withnonvegetarians. Significant associations with vegetarian diets were detected for cardiovascular mortality,noncardiovascular noncancer mortality, renal mortality, and endocrine mortality. Associations in menwere larger and more often significant than were those in women. CONCLUSIONS AND RELEVANCEVegetarian diets are associated with lower all-cause mortality and with some reductions in cause-specificmortality. Results appeared to be more robust in males. These favorable associations should beconsidered carefully by those offering dietary guidance.", "metadata": {}}
+{"_id": "12737132", "title": "", "text": "TEAD mediates YAP-dependent gene induction and growth control.The YAP transcription coactivator hasbeen implicated as an oncogene and is amplified in human cancers. Recent studies have established thatYAP is phosphorylated and inhibited by the Hippo tumor suppressor pathway. Here we demonstrate thatthe TEAD family transcription factors are essential in mediating YAP-dependent gene expression. TEAD isalso required for YAP-induced cell growth, oncogenic transformation, and epithelial-mesenchymaltransition. CTGF is identified as a direct YAP target gene important for cell growth. Moreover, thefunctional relationship between YAP and TEAD is conserved in Drosophila Yki (the YAP homolog) andScalloped (the TEAD homolog). Our study reveals TEAD as a new component in the Hippo pathwayplaying essential roles in mediating biological functions of YAP.", "metadata": {}}
+{"_id": "12742164", "title": "", "text": "Direct isolation of human central nervous system stem cells.Stem cells, which are clonogenic cells withself-renewal and multilineage differentiation properties, have the potential to replace or repair damagedtissue. We have directly isolated clonogenic human central nervous system stem cells (hCNS-SC) fromfresh human fetal brain tissue, using antibodies to cell surface markers and fluorescence-activated cellsorting. These hCNS-SC are phenotypically 5F3 (CD133)(+), 5E12(+), CD34(-), CD45(-), andCD24(-/lo). Single CD133(+) CD34(-) CD45(-) sorted cells initiated neurosphere cultures, and theprogeny of clonogenic cells could differentiate into both neurons and glial cells. Single cells fromneurosphere cultures initiated from CD133(+) CD34(-) CD45(-) cells were again replated as single cellsand were able to reestablish neurosphere cultures, demonstrating the self-renewal potential of this highlyenriched population. Upon transplantation into brains of immunodeficient neonatal mice, thesorted/expanded hCNS-SC showed potent engraftment, proliferation, migration, and neuraldifferentiation.", "metadata": {}}
+{"_id": "12762485", "title": "", "text": "p53 mutation in breast cancer. Correlation with cell kinetics and cell of origin.AIM Several studies haveinvestigated the expression of the cytokeratins (CKs), vimentin, the epithelial growth factor receptor(EGFR), the oestrogen receptor (ER), and the progesterone receptor (PgR), in breast cancer, but no studyhas directly compared p53 mutations with these phenotypic and differentiation markers in the same case.The present study was designed to provide some of this information. METHODS The expression of the p53and bcl-2 proteins was evaluated by immunohistochemistry in relation to phenotypic characteristics andcellular kinetic parameters (mitotic index and apoptotic index) in 37 cases of ductal carcinoma in situ(DCIS) and 27 cases of infiltrating ductal carcinoma (IDC) of the breast. In addition, p53 gene mutationwas examined by polymerase chain reaction single strand conformation polymorphism analysis (SSCP).RESULTS Thirteen cases (eight DCIS and five IDC) showed expression of CK8, CK14, CK18, vimentin, andEGFR, consistent with a stem cell phenotype, whereas 44 cases (27 DCIS and 17 IDC) showed expressionof CK8 and CK1, weak or negative expression of CK18, but were negative for vimentin and EGFR,consistent with a luminal cell phenotype. DCIS and IDC cases with a stem cell phenotype were ER/PgRnegative and intermediately or poorly differentiated. In contrast, the cases with luminal cell phenotypewere ER/PgR positive and well or intermediately differentiated. In addition, intermediately or poorlydifferentiated cases with a stem cell phenotype showed higher proliferative activity (per cent of MIB-lpositive cells) than did intermediately or well differentiated cases with a luminal cell phenotype. BothDCIS and IDC cases with a stem cell phenotype were p53 positive and bcl-2 negative byimmunohistochemistry. In IDC, p53 expression was associated with a reduction of both mitotic index andapoptotic index compared with DCIS. Most of the tumours showing a more differentiated phenotype(luminal) were p53 negative and bcl-2 positive. In these cases, cell kinetic parameters increased fromDCIS to IDC. These data suggest the existence of subsets of DCIS and IDC that, because of theirphenotypic characteristics, could be derived from subpopulations of normal breast cells having differentcontrol mechanisms of cell proliferation and neoplastic progression. CONCLUSIONS These results arecompatible with the hypothesis that the phenotype of the cell of origin constrains both tumour phenotypeand the choice of genetic events; however, the occurrence of p53 mutants by chance during neoplastictransformation cannot be excluded.", "metadata": {}}
+{"_id": "12770738", "title": "", "text": "Cardiorespiratory fitness and body mass index as predictors of cardiovascular disease mortality amongmen with diabetes.BACKGROUND Questions remain as to whether higher levels of cardiorespiratoryfitness, a measure of regular physical activity, are associated with lower risk of cardiovascular disease(CVD) mortality in overweight and obese individuals with diabetes. Our objective was to quantify theindependent and joint relations of cardiorespiratory fitness (hereafter, fitness) and body mass index(BMI; calculated as weight in kilograms divided by the square of height in meters) with CVD mortality inmen with diabetes. METHODS This study was conducted using prospective observational data from theAerobics Center Longitudinal Study. Study participants comprised 2316 men with no history of stroke ormyocardial infarction and who were diagnosed as having diabetes (mean [SD] age, 50 [10] years); had amedical examination, including a maximal exercise test during 1970 to 1997 with mortality surveillanceto December 31, 1998; and had a BMI of 18.5 or greater and less than 35.0. The main outcome measurewas CVD mortality across levels of fitness with stratification by BMI. RESULTS We identified 179 CVDdeaths during a mean (SD) follow-up of 15.9 (7.9) years and 36,710 man-years of exposure. In a modelcontaining age, examination year, fasting glucose level, systolic blood pressure, parental history ofpremature CVD, total cholesterol level, cigarette smoking, abnormal resting, and exerciseelectrocardiograms, a significantly higher adjusted risk of mortality was observed in men with a lowfitness level who were normal weight (hazard ratio, 2.7 [95% confidence interval, 1.3-5.7]), overweight(hazard ratio, 2.7 [95% confidence interval, 1.4-5.1]), and class 1 obese (hazard ratio, 2.8 [95%confidence interval, 1.4-5.1]) compared with normal weight men with a high fitness level. CONCLUSIONIn this cohort of men with diabetes, low fitness level was associated with increased risk of CVD mortalitywithin normal weight, overweight, and class 1 obese weight categories.", "metadata": {}}
+{"_id": "12779444", "title": "", "text": "Effect of screening on cervical cancer mortality in England and Wales: analysis of trends with an ageperiod cohort model.The number of women dying from cervical cancer in 1997 was 7% lower than in1996 and has fallen by over 25% since 1992.1 Such rapid change must be at least partly due to cervicalscreening, although strong cohort effects have caused large fluctuations in cervical mortality in the past.2We modelled mortality data, taking into account the effects of age and year of birth and looking fortrends in time within four age groups to estimate the beneficial effects of cervical screening. We obtainedmortality data, in 5 year age bands, from death registrations in England and Wales and calculated ratesusing mid-year population estimates. Mortality since 1993 was adjusted upwards by 4% because ofchanges in classification of cause of death.3  We modelled the data assuming that the age specificmortality is the product of a smoothly varying age effect, birth cohort effect, and age dependent …", "metadata": {}}
+{"_id": "12785130", "title": "", "text": "The regulation of N-methyl-D-aspartate receptors by Src kinase.Src family kinases (SFKs) play criticalroles in the regulation of many cellular functions by growth factors, G-protein-coupled receptors andligand-gated ion channels. Recent data have shown that SFKs serve as a convergent point of multiplesignaling pathways regulating N-methyl-d-aspartate (NMDA) receptors in the central nervous system.Multiple SFK molecules, such as Src and Fyn, closely associate with their substrate, NMDA receptors, viaindirect and direct binding mechanisms. The NMDA receptor is associated with an SFK signaling complexconsisting of SFKs; the SFK-activating phosphatase, protein tyrosine phosphatase α; and theSFK-inactivating kinase, C-terminal Src kinase. Early studies have demonstrated that intramolecularinteractions with the SH2 or SH3 domain lock SFKs in a closed conformation. Disruption of theinterdomain interactions can induce the activation of SFKs with multiple signaling pathways involved inregulation of this process. The enzyme activity of SFKs appears 'graded', exhibiting different levelscoinciding with activation states. It has also been proposed that the SH2 and SH3 domains may stimulatecatalytic activity of protein tyrosine kinases, such as Abl. Recently, it has been found that the enzymeactivity of neuronal Src protein is associated with its stability, and that the SH2 and SH3 domaininteractions may act not only to constrain the activation of neuronal Src, but also to regulate the enzymeactivity of active neuronal Src. Collectively, these findings demonstrate novel mechanisms underlying theregulation of SFKs.", "metadata": {}}
+{"_id": "12787125", "title": "", "text": "The art and design of genetic screens: RNA interferenceThe remarkable gene knockdown technique ofRNAi has opened exciting new avenues for genetic screens in model organisms and human cells. Here wedescribe the current state of the art for RNAi screening, and stress the importance of well-designedassays and of analytical approaches for large-scale screening experiments, from high-throughput screensusing simplified homogenous assays to microscopy and whole-animal experiments. Like classical geneticscreens in the past, the success of large-scale RNAi surveys depends on a careful development ofphenotypic assays and their interpretation in a relevant biological context.", "metadata": {}}
+{"_id": "12789595", "title": "", "text": "Computer assisted learning in undergraduate medical education.It is becoming “a truth universallyacknowledged” that the education of undergraduate medical students will be enhanced through the use ofcomputer assisted learning. Access to the wide range of online options illustrated in the figure mustsurely make learning more exciting, effective, and likely to be retained. This assumption is potentially butby no means inevitably correct. ### Box 1: Why fund computer assisted learning? Computer assistedlearning is inevitable —Individual lecturers and departments are already beginning to introduce a widerange of computer based applications, sometimes in a haphazard way. Planned and coordinateddevelopment is better than indiscriminate expansion  It is convenient and flexible —Courses supported bycomputer assisted learning applications may require fewer face to face lectures and seminars and placefewer geographical and temporal constraints on staff and students. Students at peripheral hospitals orprimary care centres may benefit in particular  Unique presentational benefits —Computer presentation isparticularly suited to subjects that are visually intensive, detail oriented, and difficult to conceptualise,such as complex biochemical processes or microscopic images.1 Furthermore, “virtual” cases may reducethe need to use animal or human tissue in learning  Personalised learning —Each learner can progress athis or her preferred pace. They can repeat, interrupt, and resume at will, which may have particularadvantages for weaker students  Economies of scale —Once an application has been set up, theincremental cost of offering it to additional students is relatively small  Competitive advantage —Potentialapplicants may use the quality of information technology to discriminate between medical schools. A“leading edge” virtual campus is likely to attract good students  Achieves the ultimate goal of highereducation —The goal is to link people into learning communities. Computer applications, especially theinternet and world wide web, are an extremely efficient way of doing this2  Expands pedagogical horizons—The most controversial argument for … RETURN TO TEXT", "metadata": {}}
+{"_id": "12794099", "title": "", "text": "Combined Impact of Health Behaviours and Mortality in Men and Women: The EPIC-Norfolk ProspectivePopulation StudyBACKGROUND There is overwhelming evidence that behavioural factors influence health,but their combined impact on the general population is less well documented. We aimed to quantify thepotential combined impact of four health behaviours on mortality in men and women living in the generalcommunity. METHODS AND FINDINGS We examined the prospective relationship between lifestyle andmortality in a prospective population study of 20,244 men and women aged 45-79 y with no knowncardiovascular disease or cancer at baseline survey in 1993-1997, living in the general community in theUnited Kingdom, and followed up to 2006. Participants scored one point for each health behaviour:current non-smoking, not physically inactive, moderate alcohol intake (1-14 units a week) and plasmavitamin C >50 mmol/l indicating fruit and vegetable intake of at least five servings a day, for a total scoreranging from zero to four. After an average 11 y follow-up, the age-, sex-, body mass-, and socialclass-adjusted relative risks (95% confidence intervals) for all-cause mortality(1,987 deaths) for men andwomen who had three, two, one, and zero compared to four health behaviours were respectively, 1.39(1.21-1.60), 1.95 (1.70--2.25), 2.52 (2.13-3.00), and 4.04 (2.95-5.54) p < 0.001 trend. Therelationships were consistent in subgroups stratified by sex, age, body mass index, and social class, andafter excluding deaths within 2 y. The trends were strongest for cardiovascular causes. The mortality riskfor those with four compared to zero health behaviours was equivalent to being 14 y younger inchronological age. CONCLUSIONS Four health behaviours combined predict a 4-fold difference in totalmortality in men and women, with an estimated impact equivalent to 14 y in chronological age.", "metadata": {}}
+{"_id": "12800122", "title": "", "text": "Increased Cell Bond Tension Governs Cell Sorting at the Drosophila Anteroposterior CompartmentBoundarySubdividing proliferating tissues into compartments is an evolutionarily conserved strategy ofanimal development [1-6]. Signals across boundaries between compartments can result in localexpression of secreted proteins organizing growth and patterning of tissues [1-6]. Sharp and straightinterfaces between compartments are crucial for stabilizing the position of such organizers and thereforefor precise implementation of body plans. Maintaining boundaries in proliferating tissues requiresmechanisms to counteract cell rearrangements caused by cell division; however, the nature of suchmechanisms remains unclear. Here we quantitatively analyzed cell morphology and the response to thelaser ablation of cell bonds in the vicinity of the anteroposterior compartment boundary in developingDrosophila wings. We found that mechanical tension is approximately 2.5-fold increased on cell bondsalong this compartment boundary as compared to the remaining tissue. Cell bond tension is decreased inthe presence of Y-27632 [7], an inhibitor of Rho-kinase whose main effector is Myosin II [8]. Simulationsusing a vertex model [9] demonstrate that a 2.5-fold increase in local cell bond tension suffices to guidethe rearrangement of cells after cell division to maintain compartment boundaries. Our results provide aphysical mechanism in which the local increase in Myosin II-dependent cell bond tension directs cellsorting at compartment boundaries.", "metadata": {}}
+{"_id": "12801438", "title": "", "text": "Plant products as antimicrobial agents.The use of and search for drugs and dietary supplements derivedfrom plants have accelerated in recent years. Ethnopharmacologists, botanists, microbiologists, andnatural-products chemists are combing the Earth for phytochemicals and \"leads\" which could bedeveloped for treatment of infectious diseases. While 25 to 50% of current pharmaceuticals are derivedfrom plants, none are used as antimicrobials. Traditional healers have long used plants to prevent or cureinfectious conditions; Western medicine is trying to duplicate their successes. Plants are rich in a widevariety of secondary metabolites, such as tannins, terpenoids, alkaloids, and flavonoids, which have beenfound in vitro to have antimicrobial properties. This review attempts to summarize the current status ofbotanical screening efforts, as well as in vivo studies of their effectiveness and toxicity. The structure andantimicrobial properties of phytochemicals are also addressed. Since many of these compounds arecurrently available as unregulated botanical preparations and their use by the public is increasing rapidly,clinicians need to consider the consequences of patients self-medicating with these preparations.", "metadata": {}}
+{"_id": "12804937", "title": "", "text": "Nature, Nurture, or Chance: Stochastic Gene Expression and Its ConsequencesGene expression is afundamentally stochastic process, with randomness in transcription and translation leading to cell-to-cellvariations in mRNA and protein levels. This variation appears in organisms ranging from microbes tometazoans, and its characteristics depend both on the biophysical parameters governing gene expressionand on gene network structure. Stochastic gene expression has important consequences for cellularfunction, being beneficial in some contexts and harmful in others. These situations include the stressresponse, metabolism, development, the cell cycle, circadian rhythms, and aging.", "metadata": {}}
+{"_id": "12805683", "title": "", "text": "Nuclear Hormone Receptor NHR-49 Controls Fat Consumption and Fatty Acid Composition in C.elegansMammalian nuclear hormone receptors (NHRs), such as liver X receptor, farnesoid X receptor,and peroxisome proliferator-activated receptors (PPARs), precisely control energy metabolism.Consequently, these receptors are important targets for the treatment of metabolic diseases, includingdiabetes and obesity. A thorough understanding of NHR fat regulatory networks has been limited,however, by a lack of genetically tractable experimental systems. Here we show that deletion of theCaenorhabditis elegans NHR gene nhr-49 yielded worms with elevated fat content and shortened lifespan. Employing a quantitative RT-PCR screen, we found that nhr-49 influenced the expression of 13genes involved in energy metabolism. Indeed, nhr-49 served as a key regulator of fat usage, modulatingpathways that control the consumption of fat and maintain a normal balance of fatty acid saturation. Wefound that the two phenotypes of the nhr-49 knockout were linked to distinct pathways and wereseparable: The high-fat phenotype was due to reduced expression of enzymes in fatty acid β-oxidation,and the shortened adult life span resulted from impaired expression of a stearoyl-CoA desaturase.Despite its sequence relationship with the mammalian hepatocyte nuclear factor 4 receptor, the biologicalactivities of nhr-49 were most similar to those of the mammalian PPARs, implying an evolutionarilyconserved role for NHRs in modulating fat consumption and composition. Our findings in C. elegansprovide novel insights into how NHR regulatory networks are coordinated to govern fat metabolism.", "metadata": {}}
+{"_id": "12810152", "title": "", "text": "Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease amongwomen.CONTEXT Hyperhomocysteinemia is caused by genetic and lifestyle influences, including lowintakes of folate and vitamin B6. However, prospective data relating intake of these vitamins to risk ofcoronary heart disease (CHD) are not available. OBJECTIVE To examine intakes of folate and vitamin B6in relation to the incidence of nonfatal myocardial infarction (MI) and fatal CHD. DESIGN Prospectivecohort study. SETTING AND PATIENTS In 1980, a total of 80082 women from the Nurses' Health Studywith no previous history of cardiovascular disease, cancer, hypercholesterolemia, or diabetes completed adetailed food frequency questionnaire from which we derived usual intake of folate and vitamin B6. MAINOUTCOME MEASURE Nonfatal MI and fatal CHD confirmed by World Health Organization criteria.RESULTS During 14 years of follow-up, we documented 658 incident cases of nonfatal MI and 281 casesof fatal CHD. After controlling for cardiovascular risk factors, including smoking and hypertension andintake of alcohol, fiber, vitamin E, and saturated, polyunsaturated, and trans fat, the relative risks (RRs)of CHD between extreme quintiles were 0.69 (95% confidence interval [CI], 0.55-0.87) for folate(median intake, 696 microg/d vs 158 microg/d) and 0.67 (95% CI, 0.53-0.85) for vitamin B6 (medianintake, 4.6 mg/d vs 1.1 mg/d). Controlling for the same variables, the RR was 0.55 (95% CI, 0.41-0.74)among women in the highest quintile of both folate and vitamin B6 intake compared with the oppositeextreme. Risk of CHD was reduced among women who regularly used multiple vitamins (RR=0.76; 95%CI, 0.65-0.90), the major source of folate and vitamin B6, and after excluding multiple vitamin users,among those with higher dietary intakes of folate and vitamin B6. In a subgroup analysis, compared withnondrinkers, the inverse association between a high-folate diet and CHD was strongest among womenwho consumed up to 1 alcoholic beverage per day (RR =0.69; 95% CI, 0.49-0.97) or more than 1 drinkper day (RR=0.27; 95% CI, 0.13-0.58). CONCLUSION These results suggest that intake of folate andvitamin B6 above the current recommended dietary allowance may be important in the primaryprevention of CHD among women.", "metadata": {}}
+{"_id": "12821938", "title": "", "text": "Control of oocyte meiotic maturation and fertilization.Sexual reproduction depends upon meiosis for thegeneration of haploid gamete nuclei, which unite after fertilization to form the diploid zygote. The oocytesof most animal species arrest during meiotic prophase, and complete meiosis in response to intercellularsignaling in a process called meiotic maturation. Oocyte meiotic maturation is defined by the transitionbetween diakinesis and metaphase of meiosis I and is accompanied by nuclear envelope breakdown,rearrangement of the cortical cytoskeleton, and meiotic spindle assembly. Thus, the meiotic maturationprocess is essential for meiosis and prepares the oocyte for fertilization. In C. elegans, the processes ofmeiotic maturation, ovulation, and fertilization are temporally coupled: sperm utilize the major spermprotein as a hormone to trigger oocyte meiotic maturation, and in turn, the maturing oocyte signals itsown ovulation thereby facilitating fertilization. This chapter highlights recent advances in understandingmeiotic maturation signaling and gametic interactions required for fertilization.", "metadata": {}}
+{"_id": "12824568", "title": "", "text": "From Cell Differentiation to Cell Collectives: Bacillus subtilis Uses Division of Labor to MigrateTheorganization of cells, emerging from cell-cell interactions, can give rise to collective properties. Theseproperties are adaptive when together cells can face environmental challenges that they separatelycannot. One particular challenge that is important for microorganisms is migration. In this study, weshow how flagellum-independent migration is driven by the division of labor of two cell types that appearduring Bacillus subtilis sliding motility. Cell collectives organize themselves into bundles (called \"van Goghbundles\") of tightly aligned cell chains that form filamentous loops at the colony edge. We show, bytime-course microscopy, that these loops migrate by pushing themselves away from the colony. Theformation of van Gogh bundles depends critically on the synergistic interaction of surfactin-producing andmatrix-producing cells. We propose that surfactin-producing cells reduce the friction between cells andtheir substrate, thereby facilitating matrix-producing cells to form bundles. The folding properties of thesebundles determine the rate of colony expansion. Our study illustrates how the simple organization of cellswithin a community can yield a strong ecological advantage. This is a key factor underlying the diverseorigins of multicellularity.", "metadata": {}}
+{"_id": "12827098", "title": "", "text": "Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution fromcirculating monocytes.Despite accumulating evidence suggesting local self-maintenance of tissuemacrophages in the steady state, the dogma remains that tissue macrophages derive from monocytes.Using parabiosis and fate-mapping approaches, we confirmed that monocytes do not show significantcontribution to tissue macrophages in the steady state. Similarly, we found that after depletion of lungmacrophages, the majority of repopulation occurred by stochastic cellular proliferation in situ in amacrophage colony-stimulating factor (M-Csf)- and granulocyte macrophage (GM)-CSF-dependentmanner but independently of interleukin-4. We also found that after bone marrow transplantation, hostmacrophages retained the capacity to expand when the development of donor macrophages wascompromised. Expansion of host macrophages was functional and prevented the development of alveolarproteinosis in mice transplanted with GM-Csf-receptor-deficient progenitors. Collectively, these resultsindicate that tissue-resident macrophages and circulating monocytes should be classified as mononuclearphagocyte lineages that are independently maintained in the steady state.", "metadata": {}}
+{"_id": "12839939", "title": "", "text": "Registration and real-time visualization of transcranial magnetic stimulation with 3-D MR imagesThispaper describes a method for registering and visualizing in real-time the results of transcranial magneticstimulations (TMS) in physical space on the corresponding anatomical locations in MR images of thebrain. The method proceeds in three main steps. First, the patient scalp is digitized in physical space witha magnetic-field digitizer, following a specific digitization pattern. Second, a registration processminimizes the mean square distance between those points and a segmented scalp surface extracted fromthe magnetic resonance image. Following this registration, the physician can follow the change in coilposition in real-time through the visualization interface and adjust the coil position to the desiredanatomical location. Third, amplitude of motor evoked potentials can be projected onto the segmentedbrain in order to create functional brain maps. The registration has subpixel accuracy in a study withsimulated data, while we obtain a point to surface root-mean-square error of 1.17/spl plusmn/0.38 mmin a 24 subject study.", "metadata": {}}
+{"_id": "12866641", "title": "", "text": "Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductaladenocarcinoma.Pancreatic ductal adenocarcinomas (PDAs) are characterized by a robustfibroinflammatory response. We show here that this desmoplastic reaction generates inordinately highinterstitial fluid pressures (IFPs), exceeding those previously measured or theorized for solid tumors, andinduces vascular collapse, while presenting substantial barriers to perfusion, diffusion, and convection ofsmall molecule therapeutics. We identify hyaluronan, or hyaluronic acid (HA), as the primary matrixdeterminant of these barriers and show that systemic administration of an enzymatic agent can ablatestromal HA from autochthonous murine PDA, normalize IFP, and re-expand the microvasculature. Incombination with the standard chemotherapeutic, gemcitabine, the treatment permanently remodels thetumor microenvironment and consistently achieves objective tumor responses, resulting in a neardoubling of overall survival.", "metadata": {}}
+{"_id": "12869200", "title": "", "text": "Circulating adiponectin, leptin and adiponectin-leptin ratio and endometrial cancer risk: Evidence from ameta-analysis of epidemiologic studies.We performed this meta-analysis of epidemiologic studies toinvestigate the associations between circulating adiponectin, leptin and adiponectin-leptin (A/L) ratio andendometrial cancer risk. Relevant manuscripts were identified by searching PubMed and ISI Web ofScience databases as well as by manual searching the references cited in retrieved manuscripts.Random-effects models were used to estimate summary odds ratio (SOR) and 95% confidence intervals(CIs) for aforementioned associations. Fourteen manuscripts with 13 studies (five nested case-controland eight case-control studies) cumulatively involving a total of 1,963 endometrial cancer cases and3,503 noncases were included in the analyses. Overall, comparing persons with circulating concentrationsof adiponectin, leptin and A/L ratio in the top tertile with persons with concentrations of these biomarkersin the bottom tertile yielded SORs of 0.47 (95% CI: 0.34-0.65; I(2)  = 63.7%; n = 13), 2.19 (95% CI:1.44-3.31; I(2)  = 64.2%; n = 7),and 0.45 (95% CI: 0.24-0.86; I(2)  = 90.1%; n = 5), respectively.Notably, there was an 18% reduction in risk for per each 5 μg/mL increment in circulating adiponectinconcentrations (SOR = 0.82; 95% CI: 0.74-0.90; I(2)  = 49%; n = 8). Stratifying by studycharacteristics and whether these studies considered or adjusted for potential confounders, the findingswere robust in the analyses of circulating adiponectin and leptin. No evidence of publication bias wasdetected. In conclusion, the findings from this meta-analysis suggest that increased circulatingadiponectin and A/L ratio or decreased leptin concentrations were associated with reduced risk ofendometrial cancer. Further prospective designed studies are warranted to confirm our findings.", "metadata": {}}
+{"_id": "12871002", "title": "", "text": "CDE-1 Affects Chromosome Segregation through Uridylation of CSR-1-Bound siRNAsWe have studied thefunction of a conserved germline-specific nucleotidyltransferase protein, CDE-1, in RNAi and chromosomesegregation in C. elegans. CDE-1 localizes specifically to mitotic chromosomes in embryos. Thislocalization requires the RdRP EGO-1, which physically interacts with CDE-1, and the Argonaute proteinCSR-1. We found that CDE-1 is required for the uridylation of CSR-1 bound siRNAs, and that in theabsence of CDE-1 these siRNAs accumulate to inappropriate levels, accompanied by defects in bothmeiotic and mitotic chromosome segregation. Elevated siRNA levels are associated with erroneous genesilencing, most likely through the inappropriate loading of CSR-1 siRNAs into other Argonaute proteins.We propose a model in which CDE-1 restricts specific EGO-1-generated siRNAs to the CSR-1 mediated,chromosome associated RNAi pathway, thus separating it from other endogenous RNAi pathways. Theconserved nature of CDE-1 suggests that similar sorting mechanisms may operate in other animals,including mammals.", "metadata": {}}
+{"_id": "12871281", "title": "", "text": "Localized diacylglycerol drives the polarization of the microtubule-organizing center in T cellsThereorientation of the T cell microtubule-organizing center (MTOC) toward the antigen-presenting cellenables the directional secretion of cytokines and lytic factors. By single-cell photoactivation of the T cellantigen receptor, we show that MTOC polarization is driven by localized accumulation of diacylglycerol(DAG). MTOC reorientation was closely preceded first by production of DAG and then by recruitment ofthe microtubule motor protein dynein. Blocking DAG production or disrupting the localization of DAGimpaired MTOC recruitment. Localized DAG accumulation was also required for cytotoxic T cell–mediatedkilling. Furthermore, photoactivation of DAG itself was sufficient to induce transient polarization. Our dataidentify a DAG-dependent pathway that signals through dynein to control microtubule polarity in T cells.", "metadata": {}}
+{"_id": "12880573", "title": "", "text": "Dual roles of plcA in Listeria monocytogenes pathogenesis.The plcA gene of Listeria monocytogenesencodes a secreted phosphatidylinositol-specific phospholipase C (Pl-PLC). Recent studies haveestablished that transposon mutations within plcA result in avirulence for mice and pleiotropic effectswhen examined in tissue-culture models of infection. Genetic analysis reveals that many of the effects ofthe transposon insertions are due to loss of readthrough transcription from plcA into the downstreamgene prfA, which encodes an essential transcription factor of numerous L. monocytogenes virulencegenes. Construction of an in-frame deletion within plcA had no effect on expression of prfA thus allowingdirect assignment of a role of the Pl-PLC in pathogenesis. Pl-PLC was shown to play a significant role inmediating escape of L. monocytogenes from phagosomes of primary murine macrophages. Interestingly,this defect manifested itself in vivo in the liver but not in the spleen of infected mice.", "metadata": {}}
+{"_id": "12881593", "title": "", "text": "Fine-tuning in regulation of Clp protein content in Bacillus subtilis.Clp-controlled proteolysis in Bacillussubtilis seems to play a substantial role, particularly under stress conditions. Calibrated Western blotanalyses were used to estimate the approximate numbers of heat-inducible Clp molecules within a singlecell. According to these numbers, the different Clp ATPases do not seem to compete for the proteolyticsubunit ClpP. Coimmunoprecipitation experiments revealed the predicted specific ClpX-ClpP, ClpC-ClpP,and ClpE-ClpP interactions. ClpE and ClpX are rapidly degraded in wild-type cells during permanent heatstress but remained almost stable in a clpP mutant, suggesting ClpP-dependent degradation. Inparticular, ClpCP appeared to be involved in the degradation of the short-lived ClpE ATPase, indicating anegative \"autoregulatory\" circuit for this particular Clp ATPase at the posttranslational level. Analysis ofthe half-life of stress-inducible clp mRNAs during exponential growth and heat shock revealed preciseregulation of the synthesis of each Clp protein at the posttranscriptional level as well to meet the needs ofB. subtilis.", "metadata": {}}
+{"_id": "12885341", "title": "", "text": "A C-Type Lectin Collaborates with a CD45 Phosphatase Homolog to Facilitate West Nile Virus Infection ofMosquitoesWest Nile virus (WNV) is the most common arthropod-borne flavivirus in the United States;however, the vector ligand(s) that participate in infection are not known. We now show that an Aedesaegypti C-type lectin, mosGCTL-1, is induced by WNV, interacts with WNV in a calcium-dependentmanner, and facilitates infection in vivo and in vitro. A mosquito homolog of human CD45 in A. aegypti,designated mosPTP-1, recruits mosGCTL-1 to enable viral attachment to cells and to enhance viral entry.In vivo experiments show that mosGCTL-1 and mosPTP-1 function as part of the same pathway and arecritical for WNV infection of mosquitoes. A similar phenomenon was also observed in Culexquinquefasciatus, a natural vector of WNV, further demonstrating that these genes participate in WNVinfection. During the mosquito blood-feeding process, WNV infection was blocked in vivo with mosGCTL-1antibodies. A molecular understanding of flaviviral-arthropod interactions may lead to strategies tocontrol viral dissemination in nature.", "metadata": {}}
+{"_id": "12887068", "title": "", "text": "Use of human embryonic stem cells to model pediatric gliomas with H3.3K27M histone mutationOver70% of diffuse intrinsic pediatric gliomas, an aggressive brainstem tumor, harbor heterozygous mutationsthat create a K27M amino acid substitution (methionine replaces lysine 27) in the tail of histone H3.3.The role of the H3.3K27M mutation in tumorigenesis is not fully understood. Here, we use a humanembryonic stem cell system to model this tumor. We show that H3.3K27M expression synergizes withp53 loss and PDGFRA activation in neural progenitor cells derived from human embryonic stem cells,resulting in neoplastic transformation. Genome-wide analyses indicate a resetting of the transformedprecursors to a developmentally more primitive stem cell state, with evidence of major modifications ofhistone marks at several master regulator genes. Drug screening assays identified a compound targetingthe protein menin as an inhibitor of tumor cell growth in vitro and in mice.", "metadata": {}}
+{"_id": "12892137", "title": "", "text": "Basis for avid homologous DNA strand exchange by human Rad51 and RPA.Human Rad51 (hRad51), amember of a conserved family of general recombinases, is shown here to have an avid capability to makeDNA joints between homologous DNA molecules and promote highly efficient DNA strand exchange of thepaired molecules over at least 5.4 kilobase pairs. Furthermore, maximal efficiency of homologous DNApairing and strand exchange is strongly dependent on the heterotrimeric single-stranded DNA bindingfactor hRPA and requires conditions that lessen interactions of the homologous duplex with thehRad51-single-stranded DNA nucleoprotein filament. The homologous DNA pairing and strand exchangesystem described should be valuable for dissecting the action mechanism of hRad51 and for decipheringits functional interactions with other recombination factors.", "metadata": {}}
+{"_id": "12899460", "title": "", "text": "A multiple indicators multiple causes model of late-life depression in Latin AmericancountriesBACKGROUND The Euro-D depression scale consists of symptom clusters that may bedifferentially related to demographic and cognitive characteristics in older adults. This hypothesis needsfurther investigation and the role of measurement bias on substantive conclusions remains to beestablished. METHOD The study sample comprised 10,405 community-dwelling older adults from six LatinAmerican countries. We applied a Multiple Indicators Multiple Causes (MIMIC) model for a concurrentinvestigation of measurement bias and of the association between Euro-D symptom clusters andbackground variables. RESULTS The factorial validity of Euro-D, with a two-dimensionalstructure--affective suffering and motivation disturbance, was consistently supported in all countries.Although complete measurement invariance could not be assumed across countries, measurement biaswas minor. Both Euro-D factors were unrelated to age, but related to gender, as well as to impairment inmemory and verbal fluency. Gender differences were larger for affective suffering than for motivationdisturbance, whereas differences in verbal fluency impairment were more strongly related to motivationdisturbance. LIMITATIONS Our analytic strategies could only examine invariance at the level of indicatorthresholds. The generalisability of current findings needs to be examined in clinical populations. A widerset of cognitive tests is needed. We did not examine the compositional factors that could have accountedfor the variation in Euro-D scores across countries, as this was beyond the aims of the paper.CONCLUSION The current study adds evidence for the construct validity of Euro-D and for the possibledifferential association of depression symptom-clusters with gender and verbal fluency in older adults. Anunderstanding of the heterogeneity of late-life depression may carry clinical implications for the diagnosisand treatment of depression in old age.", "metadata": {}}
+{"_id": "12899612", "title": "", "text": "Microvesicles derived from human umbilical cord mesenchymal stem cells stimulated by hypoxia promoteangiogenesis both in vitro and in vivo.Although mesenchymal stem cells (MSCs) have been increasinglytrialed to treat a variety of diseases, the underlying mechanisms remain still elusive. In this study,human umbilical cord (UC)-derived MSCs were stimulated by hypoxia, and the membrane microvesicles(MVs) in the supernatants were collected by ultracentrifugation, observed under an electron microscope,and the origin was identified with the flow cytometric technique. The results showed that upon hypoxicstimulus, MSCs released a large quantity of MVs of ~100 nm in diameter. The MVs were phenotypicallysimilar to the parent MSCs, except that the majority of them were negative for the receptor ofplatelet-derived growth factor. DiI-labeling assay revealed that MSC-MVs could be internalized intohuman UC endothelial cells (UC-ECs) within 8 h after they were added into the culture medium.Carboxyfluorescein succinimidyl ester-labeling technique and MTT test showed that MSC-MVs promotedthe proliferation of UC-ECs in a dose-dependent manner. Further, MVs could enhance in vitro capillarynetwork formation of UC-ECs in a Matrigel matrix. In a rat hindlimb ischemia model, both MSCs andMSC-MVs were shown to improve significantly the blood flow recovery compared with the control medium(P<0.0001), as assessed by laser Doppler imaging analysis. These data indicate that MV releasing is oneof the major mechanisms underlying the effectiveness of MSC therapy by promoting angiogenesis.", "metadata": {}}
+{"_id": "12903921", "title": "", "text": "Evaluation of oxidative status and depression-like responses in Brown Norway rats with acute myeloidleukemiaIt has been proved that oxidative stress increases when leukemia is accompanied by depression.This fact may indicate the role of oxidative stress in the development of depression in cancer patients.The aim of this study was to determine whether the acute myeloid leukemia of Brown Norway rats, whichis accompanied by oxidative stress, evoked behavioral and receptor changes resembling alterationscharacteristic of rat models of depression. The rats were divided into two groups: leukemic rats andhealthy control. Leukemia was induced through intraperitoneal injection of 10(7) promyelocytic leukemiacells to the Brown Norway rats. Depression-like behavior was evaluated in the forced swim test at 30 or34 days after leukemic cells injection. The rats were killed after the evaluation and the spleen, braincortex and hippocampus were excised. The red-ox state was assessed in homogenates of tissues bymeasuring total glutathione (GSH) content, the ferric ion reducing ability of plasma (FRAP) level,expression of heme oxygenase-1 (HO-1), biliverdin reductase (BvR) and ferritin mRNA, superoxidedismutase (SOD) activity, as well as malondialdehyde (MDA) concentration. Radioligand binding assaywas used to assess of the effect of leukemia on cortical receptors. Leukemic cells were identified usingRM-124 antibody by FACS Calibur flow cytometry. Leukemia influenced locomotory activity as well asforced swim test behavior in a 34-day series of experiments. Signs of oxidative stress in leukemic ratswere observed in each examined stage of leukemia development. The FRAP values and glutathionecontents, were significantly lowered whereas HO-1 mRNA expression, and malonodialdehydeconcentrations were significantly increased in the spleen and brain structures of leukemic rats incomparison with the healthy controls. A significant increase in the potency of glycine to displace[(3)H]L-689,560 from the strychnine-insensitive glycine site of the N-methyl-D-aspartic (NMDA)receptors receptor complex in cortical homogenates of the leukemic rats in 30- and 34-day experimentalseries was observed in comparison with the control. Upregulation of 5-HT(2A) receptors was observed inrat cortex after 30 days of leukemia development but not in 34-days series compared with the control. Itis concluded that disturbances in antioxidant system in brain cortex were accompanied by an activation ofglycine sites of the NMDA receptor complex, regardless of stage of leukemia development, which arecharacteristic of model of depression. Findings of our study demonstrate the link between glutamatergicactivity, oxidative stress and leukemia.", "metadata": {}}
+{"_id": "12909503", "title": "", "text": "Distinct roles for DNA-PK, ATM and ATR in RPA phosphorylation and checkpoint activation in response toreplication stressDNA damage encountered by DNA replication forks poses risks of genomedestabilization, a precursor to carcinogenesis. Damage checkpoint systems cause cell cycle arrest,promote repair and induce programed cell death when damage is severe. Checkpoints are critical parts ofthe DNA damage response network that act to suppress cancer. DNA damage and perturbation ofreplication machinery causes replication stress, characterized by accumulation of single-stranded DNAbound by replication protein A (RPA), which triggers activation of ataxia telangiectasia and Rad3 related(ATR) and phosphorylation of the RPA32, subunit of RPA, leading to Chk1 activation and arrest.DNA-dependent protein kinase catalytic subunit (DNA-PKcs) [a kinase related to ataxia telangiectasiamutated (ATM) and ATR] has well characterized roles in DNA double-strand break repair, but poorlyunderstood roles in replication stress-induced RPA phosphorylation. We show that DNA-PKcs mutant cellsfail to arrest replication following stress, and mutations in RPA32 phosphorylation sites targeted byDNA-PKcs increase the proportion of cells in mitosis, impair ATR signaling to Chk1 and confer a G2/Marrest defect. Inhibition of ATR and DNA-PK (but not ATM), mimic the defects observed in cells expressingmutant RPA32. Cells expressing mutant RPA32 or DNA-PKcs show sustained H2AX phosphorylation inresponse to replication stress that persists in cells entering mitosis, indicating inappropriate mitotic entrywith unrepaired damage.", "metadata": {}}
+{"_id": "12922760", "title": "", "text": "The essential Schizosaccharomyces pombe Pfh1 DNA helicase promotes fork movement pastG-quadruplex motifs to prevent DNA damageBACKGROUND G-quadruplexes (G4s) are stablenon-canonical DNA secondary structures consisting of stacked arrays of four guanines, each held togetherby Hoogsteen hydrogen bonds. Sequences with the ability to form these structures in vitro, G4 motifs,are found throughout bacterial and eukaryotic genomes. The budding yeast Pif1 DNA helicase, as well asseveral bacterial Pif1 family helicases, unwind G4 structures robustly in vitro and suppress G4-inducedDNA damage in S. cerevisiae in vivo. RESULTS We determined the genomic distribution and evolutionaryconservation of G4 motifs in four fission yeast species and investigated the relationship between G4motifs and Pfh1, the sole S. pombe Pif1 family helicase. Using chromatin immunoprecipitation combinedwith deep sequencing, we found that many G4 motifs in the S. pombe genome were associated with Pfh1.Cells depleted of Pfh1 had increased fork pausing and DNA damage near G4 motifs, as indicated by highDNA polymerase occupancy and phosphorylated histone H2A, respectively. In general, G4 motifs wereunderrepresented in genes. However, Pfh1-associated G4 motifs were located on the transcribed strandof highly transcribed genes significantly more often than expected, suggesting that Pfh1 has a function inreplication or transcription at these sites. CONCLUSIONS In the absence of functional Pfh1, unresolvedG4 structures cause fork pausing and DNA damage of the sort associated with human tumors.", "metadata": {}}
+{"_id": "12932176", "title": "", "text": "Wnt7a signaling promotes dendritic spine growth and synaptic strength throughCa²\u0000/Calmodulin-dependent protein kinase II.The balance between excitatory and inhibitory synapses iscrucial for normal brain function. Wnt proteins stimulate synapse formation by increasing synapticassembly. However, it is unclear whether Wnt signaling differentially regulates the formation of excitatoryand inhibitory synapses. Here, we demonstrate that Wnt7a preferentially stimulates excitatory synapseformation and function. In hippocampal neurons, Wnt7a increases the number of excitatory synapses,whereas inhibitory synapses are unaffected. Wnt7a or postsynaptic expression of Dishevelled-1 (Dvl1), acore Wnt signaling component, increases the frequency and amplitude of miniature excitatorypostsynaptic currents (mEPSCs), but not miniature inhibitory postsynaptic currents (mIPSCs). Wnt7aincreases the density and maturity of dendritic spines, whereas Wnt7a-Dvl1-deficient mice exhibit defectsin spine morphogenesis and mossy fiber-CA3 synaptic transmission in the hippocampus. Using apostsynaptic reporter for Ca(2+)/Calmodulin-dependent protein kinase II (CaMKII) activity, wedemonstrate that Wnt7a rapidly activates CaMKII in spines. Importantly, CaMKII inhibition abolishes theeffects of Wnt7a on spine growth and excitatory synaptic strength. These data indicate that Wnt7asignaling is critical to regulate spine growth and synaptic strength through the local activation of CaMKIIat dendritic spines. Therefore, aberrant Wnt7a signaling may contribute to neurological disorders in whichexcitatory signaling is disrupted.", "metadata": {}}
+{"_id": "12943966", "title": "", "text": "Bitter taste receptors and α-gustducin regulate the secretion of ghrelin with functional effects on foodintake and gastric emptying.Ghrelin is a hunger hormone with gastroprokinetic properties but the factorscontrolling ghrelin secretion from the stomach are unknown. Bitter taste receptors (T2R) and thegustatory G proteins, α-gustducin (gust) and α-transducin, are expressed in the gut and are involved inthe chemosensation of nutrients. This study aimed to investigate whether T2R-agonists affect (i) ghrelinrelease via α-gustducin and (ii) food intake and gastric emptying via the release of ghrelin. The mousestomach contains two ghrelin cell populations: cells containing octanoyl and desoctanoyl ghrelin, whichwere colocalized with α-gustducin and α-transducin, and cells staining for desoctanoyl ghrelin. Gavage ofT2R-agonists increased plasma octanoyl ghrelin levels in WT mice but the effect was partially blunted ingust(-/-) mice. Intragastric administration of T2R-agonists increased food intake during the first 30 minin WT but not in gust(-/-) and ghrelin receptor knockout mice. This increase was accompanied by anincrease in the mRNA expression of agouti-related peptide in the hypothalamus of WT but not of gust(-/-)mice. The temporary increase in food intake was followed by a prolonged decrease (next 4 h), whichcorrelated with an inhibition of gastric emptying. The delay in emptying, which was partially counteractedby ghrelin, was not mediated by cholecystokinin and GLP-1 but involved a direct inhibitory effect ofT2R-agonists on gastric contractility. This study is unique in providing functional evidence that activationof bitter taste receptors stimulates ghrelin secretion. Modulation of endogenous ghrelin levels by tastantsmay provide novel therapeutic applications for the treatment of weight -and gastrointestinal motilitydisorders.", "metadata": {}}
+{"_id": "12948892", "title": "", "text": "Ca2+-permeable AMPA receptors regulate growth of human glioblastoma via Akt activation.Evidence hasbeen accumulated that glioblastoma cells release and exploit glutamate for proliferation and migration byautocrine or paracrine loops through Ca2+-permeable AMPA-type glutamate receptors. Here, we showthat Ca2+ signaling mediated by AMPA receptor regulates the growth and motility of glioblastoma cellsvia activation of Akt. Ca2+ supplied through Ca2+-permeable AMPA receptor phosphorylated Akt atSer-473, thereby facilitating proliferation and mobility. A dominant-negative form of Akt inhibited cellproliferation and migration accelerated by overexpression of Ca2+-permeable AMPA receptor. Incontrast, introduction of a constitutively active form of Akt rescued tumor cells from apoptosis induced bythe conversion of Ca2+-permeable AMPA receptor to Ca2+-impermeable receptors by the delivery ofGluR2 cDNA. Therefore, Akt functions as downstream effectors for Ca2+-signaling mediated by AMPAreceptor in glioblastoma cells. The activation of the glutamate-AMPA receptor-Akt pathway maycontribute to the high degree of anaplasia and invasive growth of human glioblastoma. This novelpathway might give an alternative therapeutic target.", "metadata": {}}
+{"_id": "12956194", "title": "", "text": "The Extracellular Surface of the GLP-1 Receptor Is a Molecular Trigger for Biased AgonismLigand-directedsignal bias offers opportunities for sculpting molecular events, with the promise of better, safertherapeutics. Critical to the exploitation of signal bias is an understanding of the molecular eventscoupling ligand binding to intracellular signaling. Activation of class B G protein-coupled receptors isdriven by interaction of the peptide N terminus with the receptor core. To understand how this drivessignaling, we have used advanced analytical methods that enable separation of effects onpathway-specific signaling from those that modify agonist affinity and mapped the functionalconsequence of receptor modification onto three-dimensional models of a receptor-ligand complex. Thisyields molecular insights into the initiation of receptor activation and the mechanistic basis for biasedagonism. Our data reveal that peptide agonists can engage different elements of the receptorextracellular face to achieve effector coupling and biased signaling providing a foundation for rationaldesign of biased agonists.", "metadata": {}}
+{"_id": "12966719", "title": "", "text": "A local macrophage chemokine network sustains protective tissue-resident memory CD4 T cellsCD8tissue-resident memory T (TRM) cells provide efficient local control of viral infection, but the role of CD4TRM is less clear. Here, by using parabiotic mice, we show that a preexisting pool of CD4 TRM cells in thegenital mucosa was required for full protection from a lethal herpes simplex virus 2 (HSV-2) infection.Chemokines secreted by a local network of macrophages maintained vaginal CD4 TRM in memorylymphocyte clusters (MLCs), independently of circulating memory T cells. CD4 TRM cells within the MLCswere enriched in clones that expanded in response to HSV-2. Our results highlight the need for vaccinestrategies that enable establishment of TRM cells for protection from a sexually transmitted virus andprovide insights as to how such a pool might be established.", "metadata": {}}
+{"_id": "12991445", "title": "", "text": "Influence of smoking and plasma factors on patency of femoropopliteal vein grafts.OBJECTIVE Todetermine the effects of smoking, plasma lipids, lipoproteins, apolipoproteins, and fibrinogen on thepatency of saphenous vein femoropopliteal bypass grafts at one year. DESIGN Prospective study ofpatients with saphenous vein femoropopliteal bypass grafts entered into a multicentre trial. SETTINGSurgical wards, outpatient clinics, and home visits coordinated by two tertiary referral centres in Londonand Birmingham. PATIENTS 157 Patients (mean age 66.6 (SD 8.2) years), 113 with patent grafts and 44with occluded grafts one year after bypass. MAIN OUTCOME MEASURE Cumulative percentage patency atone year. RESULTS Markers for smoking (blood carboxyhaemoglobin concentration (p less than 0.05) andplasma thiocyanate concentration (p less than 0.01) and plasma concentrations of fibrinogen (p less than0.001) and apolipoproteins AI (p less than 0.04) and (a) (p less than 0.05) were significantly higher inpatients with occluded grafts. Serum cholesterol concentrations were significantly higher in patients withgrafts that remained patent one year after bypass (p less than 0.005). Analysis of the smoking markersindicated that a quarter of patients (40) were untruthful in their claims to have stopped smoking. Basedon smoking markers, patency of grafts in smokers was significantly lower at one year by life tableanalysis than in non-smokers (63% v 84%, p less than 0.02). Patency was significantly higher by lifetable analysis in patients with a plasma fibrinogen concentration below the median than in those with aconcentration above (90% v 57%, p less than 0.0002). Surprisingly, increased plasma low densitylipoprotein cholesterol concentration was significantly associated with improved patency at one year(85%) at values above the median compared with patency (only 68%) at values in the lower half of therange (p less than 0.02). CONCLUSIONS Plasma fibrinogen concentration was the most importantvariable predicting graft occlusion, followed by smoking markers. A more forceful approach is needed tostop patients smoking; therapeutic measures to improve patency of vein grafts should focus ondecreasing plasma fibrinogen concentration rather than serum cholesterol concentration.", "metadata": {}}
+{"_id": "12994780", "title": "", "text": "No effect of dietary fat on short-term weight gain in mice treated with atypical antipsychoticdrugsRationale:Atypical antipsychotic drugs (AAD) induce significant weight gain in female C57BL/6Jmice. The effect of dietary fat on weight gain and serum lipids in this model is unknown. Objectives: Testthe hypothesis that the obesigenic effects of these drugs are greater in the presence of a high-fat diet.Methods:Female C57BL/6J mice were treated with atypical antipsychotics for 3 weeks and fed either alow-fat or high-fat diet (4.6 vs 15.6% fat by wt). Food intake (FI), body weight (BW), body composition,and serum lipids were measured during treatment with optimized doses of olanzapine, quetiapine, andrisperidone. Energy intake (EI) and feed efficiency (FE) were calculated. Group differences in changewere analyzed via repeated measures analysis of variance (ANOVA). Serum lipid concentrations, EI andFE were compared using two-way ANOVA.Results:AAD-treated mice gained significantly more weightthan controls after 3 weeks (P<0.001). Treatment and diet had significant effects on FI and EI over time(P<0.001). AAD-treated mice had significantly higher FE than controls (P<0.05); however, there was nosignificant drug by diet interaction (P=0.65). Risperidone low-fat mice gained significantly more absolutefat mass than placebo low-fat mice (P<0.05). All treatment groups, except quetiapine low-fat andolanzapine high-fat, gained significantly more absolute lean mass than placebo controls (P<0.05).Cholesterol levels were significantly lower in quetiapine and risperidone than placebo (P<0.05).Risperidone low-fat mice had significantly higher triglyceride levels than placebo and risperidone high-fatmice (P<0.05).Conclusions:A high-fat diet does not increase AAD-induced BW gain in female mice duringa 3-week treatment period.", "metadata": {}}
+{"_id": "13000926", "title": "", "text": "The role of free radicals in cold injuries.Cold injury is a tissue trauma produced by exposure to freezingtemperatures and even brief exposure to a severely cold and windy environment. Rewarming of frozentissue is associated with blood reperfusion and the simultaneous generation of free oxygen radicals. Inthis review is discussed the current understanding of the mechanism of action of free oxygen radicals asrelated to cold injury during rewarming. Decreased energy stores during ischaemia lead to theaccumulation of adenine nucleotides and liberation of free fatty acids due to the breakdown of lipidmembranes. On rewarming, free fatty acids are metabolized via cyclo-oxygenase and adenine nucleotidesare metabolized via the xanthine oxidase pathway. These may be the source of free oxygen radicals.Leukocytes may also play a major role in the pathogenesis of cold injury. Oxygen radical scavengers,such as superoxide dismutase and catalase, may help to reduce the cold induced injury but their action islimited due to the inability readily to cross the plasma membrane. Lipid soluble antioxidants are likely tobe more effective scavengers because of their presence in membranes where peroxidative reactions canbe arrested.", "metadata": {}}
+{"_id": "13001323", "title": "", "text": "SIRT1 deacetylase in SF1 neurons protects against metabolic imbalance.Chronic feeding on high-caloriediets causes obesity and type 2 diabetes mellitus (T2DM), illnesses that affect hundreds of millions. Thus,understanding the pathways protecting against diet-induced metabolic imbalance is of paramountmedical importance. Here, we show that mice lacking SIRT1 in steroidogenic factor 1 (SF1) neurons arehypersensitive to dietary obesity owing to maladaptive energy expenditure. Also, mutant mice haveincreased susceptibility to developing dietary T2DM due to insulin resistance in skeletal muscle.Mechanistically, these aberrations arise, in part, from impaired metabolic actions of the neuropeptideorexin-A and the hormone leptin. Conversely, mice overexpressing SIRT1 in SF1 neurons are moreresistant to diet-induced obesity and insulin resistance due to increased energy expenditure andenhanced skeletal muscle insulin sensitivity. Our results unveil important protective roles of SIRT1 in SF1neurons against dietary metabolic imbalance.", "metadata": {}}
+{"_id": "13002003", "title": "", "text": "mTOR supports long-term self-renewal and suppresses mesoderm and endoderm activities of humanembryonic stem cells.Despite the recent identification of the transcriptional regulatory circuitry involvingSOX2, NANOG, and OCT-4, the intracellular signaling networks that control pluripotency of humanembryonic stem cells (hESCs) remain largely undefined. Here, we demonstrate an essential role for theserine/threonine protein kinase mammalian target of rapamycin (mTOR) in regulating hESC long-termundifferentiated growth. Inhibition of mTOR impairs pluripotency, prevents cell proliferation, andenhances mesoderm and endoderm activities in hESCs. At the molecular level, mTOR integrates signalsfrom extrinsic pluripotency-supporting factors and represses the transcriptional activities of a subset ofdevelopmental and growth-inhibitory genes, as revealed by genome-wide microarray analyses.Repression of the developmental genes by mTOR is necessary for the maintenance of hESC pluripotency.These results uncover a novel signaling mechanism by which mTOR controls fate decisions in hESCs. Ourfindings may contribute to effective strategies for tissue repair and regeneration.", "metadata": {}}
+{"_id": "13007205", "title": "", "text": "Intrinsic genetic characteristics determine tumor-modifying capacity of fibroblasts: matrixmetalloproteinase-3 5A/5A genotype enhances breast cancer cell invasionStromal fibroblasts cancontribute to tumor invasion through the release of matrix metalloproteinases (MMPs). Population studieshave suggested that single nucleotide polymorphisms (SNPs) in MMP genes influence levels of expressionand may be associated with breast cancer risk and with disease progression. This study directly examinedthe impact of MMP SNP genotype on the ability of host fibroblasts to promote tumor cell invasion. Primarybreast fibroblasts were isolated from patients with (n = 13) or without (n = 19) breast cancer, and theirability to promote breast cancer cell invasion was measured in in vitro invasion assays. Fibroblastinvasion-promoting capacity (IPC) was analyzed in relation to donor type (tumor or non-tumor patient),MMP-1, MMP-3, and MMP-9 SNP genotype and MMP activity using independent samples t test andanalysis of variance. All statistical tests were two-sided. Tumor-derived fibroblasts promoted higher levelsof invasion than normal fibroblasts (p = 0.041). When IPC was related to genotype, higher levels of IPCwere generated by tumor fibroblasts with the high-expressing MMP-3 5A/5A genotype compared with the5A/6A and 6A/6A genotypes (p = 0.05 and 0.07, respectively), and this was associated with enhancedMMP-3 release. The functional importance of MMP-3 was demonstrated by enhanced invasion in thepresence of recombinant MMP-3, whereas reduction occurred in the presence of a specific MMP-3inhibitor. An inverse relationship was demonstrated between fibroblast IPC and the high-expressingMMP-1 genotype (p = 0.031), but no relationship was seen with MMP-9 SNP status. In contrast, normalfibroblasts showed no variation in IPC in relation to MMP genotype, with MMP-3 5A/5A fibroblastsexhibiting significantly lower levels of IPC than their tumor-derived counterparts (p = 0.04). This studyhas shown that tumor-derived fibroblasts exhibit higher levels of IPC than normal fibroblasts and that theMMP-3 5A/5A genotype contributes to this through enhanced MMP-3 release. Despite a high-expressinggenotype, normal fibroblasts do not exhibit higher IPC or enhanced MMP release. This suggests that morecomplex changes occur in tumor-derived fibroblasts, enabling full expression of the MMP SNP genotypeand these possibly are epigenetic in nature. The results do suggest that, in women with breast cancer, ahigh-expressing MMP-3 genotype may promote tumor progression more effectively.", "metadata": {}}
+{"_id": "13011249", "title": "", "text": "Hallmarks of Cancer: The Next GenerationThe hallmarks of cancer comprise six biological capabilitiesacquired during the multistep development of human tumors. The hallmarks constitute an organizingprinciple for rationalizing the complexities of neoplastic disease. They include sustaining proliferativesignaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducingangiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability,which generates the genetic diversity that expedites their acquisition, and inflammation, which fostersmultiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks ofpotential generality to this list-reprogramming of energy metabolism and evading immune destruction. Inaddition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire ofrecruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the\"tumor microenvironment. \" Recognition of the widespread applicability of these concepts will increasinglyaffect the development of new means to treat human cancer.", "metadata": {}}
+{"_id": "13023410", "title": "", "text": "BCR/ABL oncogenic kinase promotes unfaithful repair of the reactive oxygen species-dependent DNAdouble-strand breaks.The oncogenic BCR/ABL tyrosine kinase induces constitutive DNA damage inPhiladelphia chromosome (Ph)-positive leukemia cells. We find that BCR/ABL-induced reactive oxygenspecies (ROSs) cause chronic oxidative DNA damage resulting in double-strand breaks (DSBs) in S andG(2)/M cell cycle phases. These lesions are repaired by BCR/ABL-stimulated homologous recombinationrepair (HRR) and nonhomologous end-joining (NHEJ) mechanisms. A high mutation rate is detected inHRR products in BCR/ABL-positive cells, but not in the normal counterparts. In addition, large deletionsare found in NHEJ products exclusively in BCR/ABL cells. We propose that the following series of eventsmay contribute to genomic instability of Ph-positive leukemias: BCR/ABL --> ROSs --> oxidative DNAdamage --> DSBs in proliferating cells --> unfaithful HRR and NHEJ repair.", "metadata": {}}
+{"_id": "13025574", "title": "", "text": "Cancer risks attributable to low doses of ionizing radiation: assessing what we really know.High doses ofionizing radiation clearly produce deleterious consequences in humans, including, but not exclusively,cancer induction. At very low radiation doses the situation is much less clear, but the risks of low-doseradiation are of societal importance in relation to issues as varied as screening tests for cancer, the futureof nuclear power, occupational radiation exposure, frequent-flyer risks, manned space exploration, andradiological terrorism. We review the difficulties involved in quantifying the risks of low-dose radiationand address two specific questions. First, what is the lowest dose of x- or gamma-radiation for whichgood evidence exists of increased cancer risks in humans? The epidemiological data suggest that it isapproximately 10-50 mSv for an acute exposure and approximately 50-100 mSv for a protractedexposure. Second, what is the most appropriate way to extrapolate such cancer risk estimates to stilllower doses? Given that it is supported by experimentally grounded, quantifiable, biophysical arguments,a linear extrapolation of cancer risks from intermediate to very low doses currently appears to be themost appropriate methodology. This linearity assumption is not necessarily the most conservativeapproach, and it is likely that it will result in an underestimate of some radiation-induced cancer risks andan overestimate of others.", "metadata": {}}
+{"_id": "13027590", "title": "", "text": "Laparoscopic uterosacral nerve ablation for alleviating chronic pelvic pain: a randomized controlledtrial.CONTEXT Chronic pelvic pain is a common condition with a major effect on health-related quality oflife, work productivity, and health care use. Operative interruption of nerve trunks in the uterosacralligaments by laparoscopic uterosacral nerve ablation (LUNA) is a treatment option for patients withchronic pelvic pain. OBJECTIVE To assess the effectiveness of LUNA in patients with chronic pelvic pain.DESIGN, SETTING, AND PARTICIPANTS Randomized controlled trial of 487 women with chronic pelvicpain lasting longer than 6 months without or with minimal endometriosis, adhesions, or pelvicinflammatory disease, who were recruited to the study by consultant gynecological surgeons from 18 UKhospitals between February 1998 and December 2005. Follow-up was conducted by questionnairesmailed at 3 and 6 months and at 1, 2, 3, and 5 years. INTERVENTION Bilateral LUNA or laparoscopywithout pelvic denervation (no LUNA); participants were blinded to the treatment allocation. MAINOUTCOME MEASURES The primary outcome was pain, which was assessed by a visual analogue scale.Data concerning the 3 types of pain (noncyclical pain, dysmenorrhea, and dyspareunia) were analyzedseparately as was the worst pain level experienced from any of these 3 types of pain. The secondaryoutcome was health-related quality of life, which was measured using a generic instrument (EuroQoLEQ-5D and EQ-VAS). RESULTS After a median follow-up of 69 months, there were no significantdifferences reported on the visual analogue pain scales for the worst pain (mean difference between theLUNA group and the no LUNA group, -0.04 cm [95% confidence interval {CI}, -0.33 to 0.25 cm]; P =.80), noncyclical pain (-0.11 cm [95% CI, -0.50 to 0.29 cm]; P = .60), dysmenorrhea (-0.09 cm [95%CI, -0.49 to 0.30 cm]; P = .60), or dyspareunia (0.18 cm [95% CI, -0.22 to 0.62 cm]; P = .40). Nodifferences were observed between the LUNA group and the no LUNA group for quality of life.CONCLUSION Among women with chronic pelvic pain, LUNA did not result in improvements in pain,dysmenorrhea, dyspareunia, or quality of life compared with laparoscopy without pelvic denervation.TRIAL REGISTRATION controlled-trials.com Identifier: ISRCTN41196151.", "metadata": {}}
+{"_id": "13030852", "title": "", "text": "Identification of bone and liver metastases from breast cancer by measurement of plasma alkalinephosphatase isoenzyme activity.Plasma alkaline phosphatase isoenzyme activities were determined inpatients with breast cancer to diagnose and monitor bone and liver metastases. Bone alkalinephosphatase activity was increased in 21 of 50 patients (42%) with radiologically confirmed bonemetastases, while total alkaline phosphatase activity was increased in only 10 of 50 (20%); liver alkalinephosphatase activity was raised in 12 of 25 patients (48%) with liver metastases. All patients with livermetastases had bone metastases. Bone alkaline phosphatase activity was significantly higher in patientswith symptomatic bone disease. Isoenzyme determination provided additional information that wouldhave changed patient management in five of 20 patients who were monitored serially. Measurement ofalkaline phosphatase isoenzyme activity, though less sensitive than imaging procedures, can assist inscreening for, and in early detection of, a high proportion of bone and liver metastases, and can provideuseful objective evidence of their response to treatment.", "metadata": {}}
+{"_id": "13031967", "title": "", "text": "Recommendations on how to ensure the safety and effectiveness of biosimilars in Latin America: a pointof viewThe use of biotechnology-derived medicines has significantly increased in recent decades.Although biosimilars undergo rigorous characterization as well as clinical studies to document their safetyand effectiveness, they are highly complex molecules and small changes in the purification andproduction process of a biosimilar can have major implications in its safety and effectiveness profile. InLatin America, regulatory authorities have begun to establish well-described and standardized pathwaysthat permit a biosimilar to gain commercial licensure. In order to be certain that a biosimilar reaches itspotential in ordinary clinical use, an intensive post-licensing monitoring system must be established sinceit is the only means to ascertain the true similarity between the original biologic and its biosimilar.Pharmacovigilance allows national authorities to determine a drug's performance in the marketplace. Aneffective tracking and pharmacovigilance system for biological medicines has many steps and processes.To aid policy makers in Latin American in addressing the many issues surrounding the establishment ofan effective pharmacovigilance system, the Americas Health Foundation convened a group of experts todiscuss the topic and develop recommendations for implementation. The group discussed currentchallenges and gaps in pharmacovigilance in Latin America, paying close attention to the major issuesassociated with traceability and pharmacovigilance of biosimilars following their approval. Therecommendations developed should enable countries to accurately document the safety and performanceof a biosimilar as experienced by patients under real-life conditions and have a significant impact on thesuccessful implementation of pharmacovigilance of biosimilars throughout the region.", "metadata": {}}
+{"_id": "13036442", "title": "", "text": "Coordinated regulation of sulfur and phospholipid metabolism reflects the importance of methylation inthe growth of yeastA yeast strain lacking Met4p, the primary transcriptional regulator of the sulfurassimilation pathway, cannot synthesize methionine. This apparently simple auxotroph did not grow wellin rich media containing excess methionine, forming small colonies on yeast extract/peptone/dextroseplates. Faster-growing large colonies were abundant when overnight cultures were plated, suggestingthat spontaneous suppressors of the growth defect arise with high frequency. To identify the suppressormutations, we used genome-wide single-nucleotide polymorphism and standard genetic analyses. Themost common suppressors were loss-of-function mutations in OPI1, encoding a transcriptional repressorof phospholipid metabolism. Using a new system that allows rapid and specific degradation of Met4p, wecould study the dynamic expression of all genes following loss of Met4p. Experiments using this systemwith and without Opi1p showed that Met4 activates and Opi1p represses genes that maintain levels ofS-adenosylmethionine (SAM), the substrate for most methyltransferase reactions. Cells lacking Met4pgrow normally when either SAM is added to the media or one of the SAM synthetase genes isoverexpressed. SAM is used as a methyl donor in three Opi1p-regulated reactions to create the abundantmembrane phospholipid, phosphatidylcholine. Our results show that rapidly growing cells requiresignificant methylation, likely for the biosynthesis of phospholipids.", "metadata": {}}
+{"_id": "13042119", "title": "", "text": "Glossary of reference terms for alternative test methods and their validation.This glossary was developedto provide technical references to support work in the field of the alternatives to animal testing. It wascompiled from various existing reference documents coming from different sources and is meant to be apoint of reference on alternatives to animal testing. Giving the ever-increasing number of alternative testmethods and approaches being developed over the last decades, a combination, revision, andharmonization of earlier published collections of terms used in the validation of such methods is required.The need to update previous glossary efforts came from the acknowledgement that new words haveemerged with the development of new approaches, while others have become obsolete, and the meaningof some terms has partially changed over time. With this glossary we intend to provide guidance onissues related to the validation of new or updated testing methods consistent with current approaches.Moreover, because of new developments and technologies, a glossary needs to be a living, constantlyupdated document. An Internet-based version based on this compilation may be found athttp://altweb.jhsph.edu/, allowing the addition of new material.", "metadata": {}}
+{"_id": "13048272", "title": "", "text": "Combinatorial transcriptional control in blood stem/progenitor cells: genome-wide analysis of ten majortranscriptional regulators.Combinatorial transcription factor (TF) interactions control cellular phenotypesand, therefore, underpin stem cell formation, maintenance, and differentiation. Here, we report thegenome-wide binding patterns and combinatorial interactions for ten key regulators of bloodstem/progenitor cells (SCL/TAL1, LYL1, LMO2, GATA2, RUNX1, MEIS1, PU.1, ERG, FLI-1, and GFI1B),thus providing the most comprehensive TF data set for any adult stem/progenitor cell type to date.Genome-wide computational analysis of complex binding patterns, followed by functional validation,revealed the following: first, a previously unrecognized combinatorial interaction between a heptad of TFs(SCL, LYL1, LMO2, GATA2, RUNX1, ERG, and FLI-1). Second, we implicate direct protein-proteininteractions between four key regulators (RUNX1, GATA2, SCL, and ERG) in stabilizing complex binding toDNA. Third, Runx1(+/-)::Gata2(+/-) compound heterozygous mice are not viable with severehematopoietic defects at midgestation. Taken together, this study demonstrates the power ofgenome-wide analysis in generating novel functional insights into the transcriptional control of stem andprogenitor cells.", "metadata": {}}
+{"_id": "13069283", "title": "", "text": "Influence of CYP2D6 Polymorphisms on Serum Levels of Tamoxifen Metabolites in Spanish Women withBreast CancerBACKGROUND Estrogen receptor-positive breast cancer tumors depend on estrogensignaling for their growth and replication and can be treated by anti-estrogen therapy with tamoxifen.Polymorphisms of the CYP2D6 and CYP2C19 genes are associated with an impaired response totamoxifen. The study objective was to investigate the impact of genetic polymorphisms in CYP2D6 andCYP2C19 on the pharmacokinetics of tamoxifen and its metabolites in Spanish women with estrogenreceptor-positive breast cancer who were candidates for tamoxifen therapy. METHODS We studied 90women with estrogen receptor-positive breast cancer, using the AmpliChip CYP450 test to determineCYP2D6 and CYP2C19 gene variants. Plasma levels of tamoxifen and its metabolites were quantified byhigh-performance liquid chromatography. RESULTS The CYP2D6 phenotype was extensive metabolizer in80%, intermediate metabolizer in 12.2%, ultra-rapid metabolizer in 2.2%, and poor metabolizer in 5.6%of patients, and the allele frequency was 35.0% for allele (*)1, 21.0% for *2, and 18.9% for *4. All poormetabolizers in this series were *4/*4, and their endoxifen and 4-hydroxy tamoxifen levels were 25%lower than those of extensive metabolizers. CYP2C19*2 allele, which has been related to breast canceroutcomes, was detected in 15.6% of the studied alleles. CONCLUSION CYP2D6*4/*4 genotype wasinversely associated with 4-hydroxy tamoxifen and endoxifen levels. According to these results, CYP2D6and CYP2C19 genotyping appears advisable before the prescription of tamoxifen therapy.", "metadata": {}}
+{"_id": "13070316", "title": "", "text": "Role of tumor associated macrophages in tumor angiogenesis and lymphangiogenesisTumor angiogenesisis an essential process for supplying rapidly growing malignant tissues with essential nutrients andoxygen. An angiogenic switch allows tumor cells to survive and grow, and provides them access tovasculature resulting in metastatic disease. Monocyte-derived macrophages recruited and reprogrammedby tumor cells serve as a major source of angiogenic factors boosting the angiogenic switch. Tumorendothelium releases angiopoietin-2 and further facilitates recruitment of TIE2 receptor expressingmonocytes (TEM) into tumor sites. Tumor-associated macrophages (TAM) sense hypoxia in avascularareas of tumors, and react by production of angiogenic factors such as VEGFA. VEGFA stimulateschemotaxis of endothelial cells (EC) and macrophages. In some tumors, TAM appeared to be a majorsource of MMP9. Elevated expression of MMP9 by TAM mediates extracellular matrix (ECM) degradationand the release of bioactive VEGFA. Other angiogenic factors released by TAM include basic fibroblastgrowth factor (bFGF), thymidine phosphorylase (TP), urokinase-type plasminogen activator (uPA), andadrenomedullin (ADM). The same factors used by macrophages for the induction of angiogenesis [likevascular endothelial growth factor A (VEGF-A) and MMP9] support lymphangiogenesis. TAM can expressLYVE-1, one of the established markers of lymphatic endothelium. TAM support tumor lymphangiogenesisnot only by secretion of pro-lymphangiogenic factors but also by trans-differentiation into lymphatic EC.New pro-angiogenic factor YKL-40 belongs to a family of mammalian chitinase-like proteins (CLP) that actas cytokines or growth factors. Human CLP family comprises YKL-40, YKL-39, and SI-CLP. Production ofall three CLP in macrophages is antagonistically regulated by cytokines. It was recently established thatYKL-40 induces angiogenesis in vitro and in animal tumor models. YKL-40-neutralizing monoclonalantibody blocks tumor angiogenesis and progression. The role of YKL-39 and SI-CLP in tumorangiogenesis and lymphangiogenesis remains to be investigated.", "metadata": {}}
+{"_id": "13071728", "title": "", "text": "The HIV Treatment Gap: Estimates of the Financial Resources Needed versus Available for Scale-Up ofAntiretroviral Therapy in 97 Countries from 2015 to 2020BACKGROUND The World Health Organization(WHO) released revised guidelines in 2015 recommending that all people living with HIV, regardless ofCD4 count, initiate antiretroviral therapy (ART) upon diagnosis. However, few studies have projected theglobal resources needed for rapid scale-up of ART. Under the Health Policy Project, we conductedmodeling analyses for 97 countries to estimate eligibility for and numbers on ART from 2015 to 2020,along with the facility-level financial resources required. We compared the estimated financialrequirements to estimated funding available. METHODS AND FINDINGS Current coverage levels andfuture need for treatment were based on country-specific epidemiological and demographic data.Simulated annual numbers of individuals on treatment were derived from three scenarios: (1)continuation of countries' current policies of eligibility for ART, (2) universal adoption of aspects of theWHO 2013 eligibility guidelines, and (3) expanded eligibility as per the WHO 2015 guidelines and meetingthe Joint United Nations Programme on HIV/AIDS \"90-90-90\" ART targets. We modeled uncertainty in theannual resource requirements for antiretroviral drugs, laboratory tests, and facility-level personnel andoverhead. We estimate that 25.7 (95% CI 25.5, 26.0) million adults and 1.57 (95% CI 1.55, 1.60) millionchildren could receive ART by 2020 if countries maintain current eligibility plans and increase coveragebased on historical rates, which may be ambitious. If countries uniformly adopt aspects of the WHO 2013guidelines, 26.5 (95% CI 26.0 27.0) million adults and 1.53 (95% CI 1.52, 1.55) million children could beon ART by 2020. Under the 90-90-90 scenario, 30.4 (95% CI 30.1, 30.7) million adults and 1.68 (95% CI1.63, 1.73) million children could receive treatment by 2020. The facility-level financial resources neededfor scaling up ART in these countries from 2015 to 2020 are estimated to be US$45.8 (95% CI 45.4,46.2) billion under the current scenario, US$48.7 (95% CI 47.8, 49.6) billion under the WHO 2013scenario, and US$52.5 (95% CI 51.4, 53.6) billion under the 90-90-90 scenario. After projecting recentexternal and domestic funding trends, the estimated 6-y financing gap ranges from US$19.8 billion toUS$25.0 billion, depending on the costing scenario and the U.S. President's Emergency Plan for AIDSRelief contribution level, with the gap for ART commodities alone ranging from US$14.0 to US$16.8billion. The study is limited by excluding above-facility and other costs essential to ART service deliveryand by the availability and quality of country- and region-specific data. CONCLUSIONS The projectednumber of people receiving ART across three scenarios suggests that countries are unlikely to meet the90-90-90 treatment target (81% of people living with HIV on ART by 2020) unless they adopt atest-and-offer approach and increase ART coverage. Our results suggest that future resource needs forART scale-up are smaller than stated elsewhere but still significantly threaten the sustainability of theglobal HIV response without additional resource mobilization from domestic or innovative financingsources or efficiency gains. As the world moves towards adopting the WHO 2015 guidelines, advances intechnology, including the introduction of lower-cost, highly effective antiretroviral regimens, whose valueare assessed here, may prove to be \"game changers\" that allow more people to be on ART with theresources available.", "metadata": {}}
+{"_id": "13072112", "title": "", "text": "Distinction and relationship between elongation rate and processivity of RNA polymerase II in vivo.Anumber of proteins and drugs have been implicated in the process of transcriptional elongation by RNApolymerase (Pol) II, but the factors that govern the elongation rate (nucleotide additions per min) andprocessivity (nucleotide additions per initiation event) in vivo are poorly understood. Here, we show thata mutation in the Rpb2 subunit of Pol II reduces both the elongation rate and processivity in vivo. Incontrast, none of the putative elongation factors tested affect the elongation rate, although mutations inthe THO complex and in Spt4 significantly reduce processivity. The drugs 6-azauracil and mycophenolicacid reduce both the elongation rate and processivity, and this processivity defect is aggravated bymutations in Spt4, TFIIS, and CTDK-1. Our results suggest that, in vivo, a reduced rate of Pol IIelongation leads to premature dissociation along the chromatin template and that Pol II processivity canbe uncoupled from elongation rate.", "metadata": {}}
+{"_id": "13072113", "title": "", "text": "Neurite sprouting and synapse deterioration in the aging Caenorhabditis elegans nervoussystem.Caenorhabditis elegans is a powerful model for analysis of the conserved mechanisms thatmodulate healthy aging. In the aging nematode nervous system, neuronal death and/or detectable loss ofprocesses are not readily apparent, but because dendrite restructuring and loss of synaptic integrity arehypothesized to contribute to human brain decline and dysfunction, we combined fluorescencemicroscopy and electron microscopy (EM) to screen at high resolution for nervous system changes. Wereport two major components of morphological change in the aging C. elegans nervous system: (1)accumulation of novel outgrowths from specific neurons, and (2) physical decline in synaptic integrity.Novel outgrowth phenotypes, including branching from the main dendrite or new growth from somata,appear at a high frequency in some aging neurons, but not all. Mitochondria are often associated withage-associated branch sites. Lowered insulin signaling confers some maintenance of ALM and PLM neuronstructural integrity into old age, and both DAF-16/FOXO and heat shock factor transcription factor HSF-1exert neuroprotective functions. hsf-1 can act cell autonomously in this capacity. EM evaluation insynapse-rich regions reveals a striking decline in synaptic vesicle numbers and a diminution ofpresynaptic density size. Interestingly, old animals that maintain locomotory prowess exhibit lesssynaptic decline than same-age decrepit animals, suggesting that synaptic integrity correlates withlocomotory healthspan. Our data reveal similarities between the aging C. elegans nervous system andmammalian brain, suggesting conserved neuronal responses to age. Dissection of neuronal agingmechanisms in C. elegans may thus influence the development of brain healthspan-extending therapies.", "metadata": {}}
+{"_id": "13083189", "title": "", "text": "Determinants of adolescent physical activity and inactivity patterns.OBJECTIVES Despite recognition ofthe important influence of environmental determinants on physical activity patterns, minimal empiricalresearch has been done to assess the impact of environmental/contextual determinants of physicalactivity. This article aims to investigate environmental and sociodemographic determinants of physicalactivity and inactivity patterns among subpopulations of US adolescents. We define environmentaldeterminants as modifiable factors in the physical environment that impose a direct influence on theopportunity to engage in physical activity. The present research examines environmental andsociodemographic determinants of physical activity and inactivity with the implication that these findingscan point toward societal-level intervention strategies for increasing physical activity and decreasinginactivity among adolescents. STUDY DESIGN AND METHODOLOGY The study population consists ofnationally representative data from the 1996 National Longitudinal Study of Adolescent Health on 17 766US adolescents enrolled in US middle and high schools (including 3933 non-Hispanic blacks, 3148Hispanics, and 1337 Asians). Hours/week of inactivity (TV/video viewing and video/computer games) andtimes/week of moderate to vigorous physical activity were collected by questionnaire. Outcome variableswere moderate to vigorous physical activity and inactivity, which were broken into categories (physicalactivity: 0-2 times/week, 3-4 times/week, and >/=5 times/week; inactivity: 0-10 hours/week, 11-24hours/week, and >/=25 hours/week). Sociodemographic and environmental correlates of physicalactivity and inactivity were used as exposure and control variables and included sex, age, urbanresidence, participation in school physical education program, use of community recreation center, totalreported incidents of serious crime in neighborhood, socioeconomic status, ethnicity, generation ofresidence in the United States, presence of mother/father in household, pregnancy status, work status,in-school status, region, and month of interview. Logistic regression models of high versus low andmedium physical activity and inactivity were used to investigate sex and ethnic interactions in relation toenvironmental and sociodemographic factors to examine evidence for the potential impact of physicaleducation and recreation programs and sociodemographic factors on physical activity and inactivitypatterns. RESULTS Moderate to vigorous physical activity was lower and inactivity higher for non-Hispanicblack and Hispanic adolescents. Participation in school physical education programs was considerably lowfor these adolescents and decreased with age. Participation in daily school physical education (PE)program classes (adjusted odds ratio [AOR]: 2.21; confidence interval [CI]: 1.82-2.68) and use of acommunity recreation center (AOR: 1.75; CI: 1.56-1.96) were associated with an increased likelihood ofengaging in high level moderate to vigorous physical activity. Maternal education was inverselyassociated with high inactivity patterns; for example, having a mother with a graduate or professionaldegree was associated with an AOR of.61 (CI:.48-.76) for high inactivity. High family income wasassociated with increased moderate to vigorous physical activity (AOR: 1.43; CI: 1.22-1.67) anddecreased inactivity (AOR:.70; CI:.59-.82). High neighborhood serious crime level was associated with adecreased likelihood of falling in the highest category of moderate to vigorous physical activity (AOR:.77;CI:.66-.91). CONCLUSIONS These results show important associations between modifiable environmentalfactors, such as participation in school PE and community recreation programs, with activity patterns ofadolescents. Despite the marked and significant impact of participation in school PE programs on physicalactivity patterns of US adolescents, few adolescents participated in such school PE programs; only 21.3%of all adolescents", "metadata": {}}
+{"_id": "13097856", "title": "", "text": "Suicide prevention strategies: a systematic review.CONTEXT In 2002, an estimated 877,000 lives werelost worldwide through suicide. Some developed nations have implemented national suicide preventionplans. Although these plans generally propose multiple interventions, their effectiveness is rarelyevaluated. OBJECTIVES To examine evidence for the effectiveness of specific suicide-preventiveinterventions and to make recommendations for future prevention programs and research. DATASOURCES AND STUDY SELECTION Relevant publications were identified via electronic searches ofMEDLINE, the Cochrane Library, and PsychINFO databases using multiple search terms related to suicideprevention. Studies, published between 1966 and June 2005, included those that evaluated preventativeinterventions in major domains; education and awareness for the general public and for professionals;screening tools for at-risk individuals; treatment of psychiatric disorders; restricting access to lethalmeans; and responsible media reporting of suicide. DATA EXTRACTION Data were extracted on primaryoutcomes of interest: suicidal behavior (completion, attempt, ideation), intermediary or secondaryoutcomes (treatment seeking, identification of at-risk individuals, antidepressant prescription/use rates,referrals), or both. Experts from 15 countries reviewed all studies. Included articles were those thatreported on completed and attempted suicide and suicidal ideation; or, where applicable, intermediateoutcomes, including help-seeking behavior, identification of at-risk individuals, entry into treatment, andantidepressant prescription rates. We included 3 major types of studies for which the research questionwas clearly defined: systematic reviews and meta-analyses (n = 10); quantitative studies, eitherrandomized controlled trials (n = 18) or cohort studies (n = 24); and ecological, or population- basedstudies (n = 41). Heterogeneity of study populations and methodology did not permit formalmeta-analysis; thus, a narrative synthesis is presented. DATA SYNTHESIS Education of physicians andrestricting access to lethal means were found to prevent suicide. Other methods including publiceducation, screening programs, and media education need more testing. CONCLUSIONS Physicianeducation in depression recognition and treatment and restricting access to lethal methods reduce suiciderates. Other interventions need more evidence of efficacy. Ascertaining which components of suicideprevention programs are effective in reducing rates of suicide and suicide attempt is essential in order tooptimize use of limited resources.", "metadata": {}}
+{"_id": "13106686", "title": "", "text": "Oxidative damage of DNA confers resistance to cytosolic nuclease TREX1 degradation and potentiatesSTING-dependent immune sensing.Immune sensing of DNA is critical for antiviral immunity but can alsotrigger autoimmune diseases such as lupus erythematosus (LE). Here we have provided evidence for theinvolvement of a damage-associated DNA modification in the detection of cytosolic DNA. The oxidizedbase 8-hydroxyguanosine (8-OHG), a marker of oxidative damage in DNA, potentiated cytosolic immunerecognition by decreasing its susceptibility to 3' repair exonuclease 1 (TREX1)-mediated degradation.Oxidizative modifications arose physiologically in pathogen DNA during lysosomal reactive oxygen species(ROS) exposure, as well as in neutrophil extracellular trap (NET) DNA during the oxidative burst. 8-OHGwas also abundant in UV-exposed skin lesions of LE patients and colocalized with type I interferon (IFN).Injection of oxidized DNA in the skin of lupus-prone mice induced lesions that closely matched respectivelesions in patients. Thus, oxidized DNA represents a prototypic damage-associated molecular pattern(DAMP) with important implications for infection, sterile inflammation, and autoimmunity.", "metadata": {}}
+{"_id": "13108582", "title": "", "text": "IL-18 induction of osteopontin mediates cardiac fibrosis and diastolic dysfunction in mice.Osteopontin(OPN), a key component of the extracellular matrix, is associated with the fibrotic process during tissueremodeling. OPN and the cytokine interleukin (IL)-18 have been shown to be overexpressed in an arrayof human cardiac pathologies. In the present study, we determined the role of IL-18 in the regulation ofcardiac OPN expression and the subsequent interstitial fibrosis and diastolic dysfunction. Wedemonstrated parallel increases in IL-18, OPN expression, and interstitial fibrosis in murine models of leftventricular pressure and volume overload. Exogenous recombinant (r)IL-18 administered for 2 wkincreased cardiac OPN expression, interstitial fibrosis, and diastolic dysfunction. Stimulation of the Thelper (Th)1 lymphocyte phenotype with a selective toll-like receptor (TLR)9 agonist induced cardiacIL-18 and OPN expression, which was associated with increased cardiac fibrillar collagen concentrationsand interstitial fibrosis resulting in diastolic dysfunction. rIL-18 induced OPN expression and protein levelsin primary of cardiac fibroblast cultures. Conditioned media from TLR9-stimulated T lymphocyte culturesinduced IL-18 and OPN expression in cardiac fibroblasts, while blockade of the IL-18 receptor with aneutralizing antibody abolished the increase in OPN expression. Furthermore, a mutation in thetranscriptional factor interferon regulatory factor (IRF)1 or IRF1 small interfering RNA (siRNA) resulted inthe decreased expression of IL-18 and OPN in cardiac fibroblasts. With pressure overload, IRF1-mutantmice showed downregulation of IL-18 and OPN expression in cardiac tissue, reduced cardiac fibroticdevelopment, and increased left ventricular function compared with wild type. These results providedirect evidence that the induction of IL-18 regulates OPN-mediated cardiac fibrosis and diastolicdysfunction.", "metadata": {}}
+{"_id": "13116880", "title": "", "text": "Hematopoietic stem cell: self-renewal versus differentiation.The mammalian blood system, containingmore than 10 distinct mature cell types, stands on one specific cell type, hematopoietic stem cell (HSC).Within the system, only HSCs possess the ability of both multipotency and self-renewal. Multipotency isthe ability to differentiate into all functional blood cells. Self-renewal is the ability to give rise to HSC itselfwithout differentiation. Since mature blood cells (MBCs) are predominantly short-lived, HSCscontinuously provide more differentiated progenitors while properly maintaining the HSC pool sizethroughout life by precisely balancing self-renewal and differentiation. Thus, understanding themechanisms of self-renewal and differentiation of HSC has been a central issue. In this review, we focuson the hierarchical structure of the hematopoietic system, the current understanding ofmicroenvironment and molecular cues regulating self-renewal and differentiation of adult HSCs, and thecurrently emerging systems approaches to understand HSC biology.", "metadata": {}}
+{"_id": "13123189", "title": "", "text": "RSEM: accurate transcript quantification from RNA-Seq data with or without a referencegenomeBACKGROUND RNA-Seq is revolutionizing the way transcript abundances are measured. A keychallenge in transcript quantification from RNA-Seq data is the handling of reads that map to multiplegenes or isoforms. This issue is particularly important for quantification with de novo transcriptomeassemblies in the absence of sequenced genomes, as it is difficult to determine which transcripts areisoforms of the same gene. A second significant issue is the design of RNA-Seq experiments, in terms ofthe number of reads, read length, and whether reads come from one or both ends of cDNA fragments.RESULTS We present RSEM, an user-friendly software package for quantifying gene and isoformabundances from single-end or paired-end RNA-Seq data. RSEM outputs abundance estimates, 95%credibility intervals, and visualization files and can also simulate RNA-Seq data. In contrast to otherexisting tools, the software does not require a reference genome. Thus, in combination with a de novotranscriptome assembler, RSEM enables accurate transcript quantification for species without sequencedgenomes. On simulated and real data sets, RSEM has superior or comparable performance toquantification methods that rely on a reference genome. Taking advantage of RSEM's ability to effectivelyuse ambiguously-mapping reads, we show that accurate gene-level abundance estimates are bestobtained with large numbers of short single-end reads. On the other hand, estimates of the relativefrequencies of isoforms within single genes may be improved through the use of paired-end reads,depending on the number of possible splice forms for each gene. CONCLUSIONS RSEM is an accurate anduser-friendly software tool for quantifying transcript abundances from RNA-Seq data. As it does not relyon the existence of a reference genome, it is particularly useful for quantification with de novotranscriptome assemblies. In addition, RSEM has enabled valuable guidance for cost-efficient design ofquantification experiments with RNA-Seq, which is currently relatively expensive.", "metadata": {}}
+{"_id": "13135544", "title": "", "text": "A synthetic Escherichia coli predator–prey ecosystemWe have constructed a synthetic ecosystemconsisting of two Escherichia coli populations, which communicate bi-directionally through quorumsensing and regulate each other's gene expression and survival via engineered gene circuits. Oursynthetic ecosystem resembles canonical predator-prey systems in terms of logic and dynamics. Thepredator cells kill the prey by inducing expression of a killer protein in the prey, while the prey rescue thepredators by eliciting expression of an antidote protein in the predator. Extinction, coexistence andoscillatory dynamics of the predator and prey populations are possible depending on the operatingconditions as experimentally validated by long-term culturing of the system in microchemostats. A simplemathematical model is developed to capture these system dynamics. Coherent interplay betweenexperiments and mathematical analysis enables exploration of the dynamics of interacting populations ina predictable manner.", "metadata": {}}
+{"_id": "13162391", "title": "", "text": "Funnel trap for the capture of phlebotomine sand flies (Diptera: Psychodidae) from tree holes.A funneltrap that fitted over holes leading into hollow trees was used to capture adult phlebotomine sand flies,Lutzomyia shannoni Dyar, on Ossabaw Island, Chatham County, Ga. These insects rested in hollow treesduring the day and were collected by funnel traps as they egressed from the tree holes at night. The trapis lightweight, durable, inexpensive, waterproof, and selective. Using this trap, greater than 100 healthyL. shannoni ++were captured per night by a single investigator during July and August 1988 when adultflies were abundant on the island.", "metadata": {}}
+{"_id": "13172737", "title": "", "text": "Cystine/glutamate exchange regulates metabotropic glutamate receptor presynaptic inhibition ofexcitatory transmission and vulnerability to cocaine seeking.Withdrawal from chronic cocaine reducesextracellular glutamate levels in the nucleus accumbens by decreasing cystine/glutamate exchange (xc-).Activating xc- with N-acetylcysteine restores extracellular glutamate and prevents cocaine-induced drugseeking. It was hypothesized that the activation of xc- prevents drug seeking by increasing glutamatergictone on presynaptic group II metabotropic glutamate receptors (mGluR2/3) and thereby inhibitingexcitatory transmission. In the first experiment, the capacity of glutamate derived from xc- to regulateexcitatory transmission via mGluR2/3 was determined. Physiological levels of cystine (100-300 nm) wererestored to acute tissue slices from the nucleus accumbens or prefrontal cortex. Cystine increasedglutamate efflux and decreased miniature EPSC (mEPSC) and spontaneous EPSC (sEPSC) frequency aswell as evoked EPSC amplitude. These effects of cystine were presynaptic, because there was no changein mEPSC or sEPSC amplitude, and an increase in the evoked EPSC paired-pulse facilitation ratio. Thecystine-induced reduction in EPSCs was reversed by blocking either xc- or mGluR2/3. In the secondexperiment, blocking mGluR2/3 prevented the ability of N-acetylcystine to inhibit the reinstatement ofdrug seeking in rats trained to self-administer cocaine. These data demonstrate that nonsynapticglutamate derived from xc- modulates synaptic glutamate release and thereby regulates cocaine-induceddrug seeking.", "metadata": {}}
+{"_id": "13179318", "title": "", "text": "Survival analysis: time-dependent effects and time-varying risk factors.In traditional Kaplan-Meier or Coxregression analysis, usually a risk factor measured at baseline is related to mortality thereafter. Duringfollow-up, however, things may change: either the effect of a fixed baseline risk factor may vary overtime, resulting in a weakening or strengthening of associations over time, or the risk factor itself mayvary over time. In this paper, short-term versus long-term effects (so-called time-dependent effects) of afixed baseline risk factor are addressed. An example is presented showing that underweight is a strongrisk factor for mortality in dialysis patients, especially in the short run. In contrast, overweight is a riskfactor for mortality, which is stronger in the long run than in the short run. In addition, the analysis ofhow time-varying risk factors (so-called time-dependent risk factors) are related to mortality isdemonstrated by paying attention to the pitfall of adjusting for sequelae. The proper analysis of effectsover time should be driven by a clear research question. Both kinds of research questions, that is those oftime-dependent effects as well those of time-dependent risk factors, can be analyzed withtime-dependent Cox regression analysis. It will be shown that using time-dependent risk factors usuallyimplies focusing on short-term effects only.", "metadata": {}}
+{"_id": "13189693", "title": "", "text": "Control of interneuron dendritic growth through NRG1/erbB4-mediated kalirin-7 disinhibitionNeuregulin 1(NRG1) is a secreted trophic factor that activates the postsynaptic erbB4 receptor tyrosine kinase. BothNRG1 and erbB4 have been repeatedly associated with schizophrenia, but their downstream targets arenot well characterized. ErbB4 is highly abundant in interneurons, and NRG1-mediated erbB4 activationhas been shown to modulate interneuron function, but the role for NRG1-erbB4 signaling in regulatinginterneuron dendritic growth is not well understood. Here we show that NRG1/erbB4 promote the growthof dendrites in mature interneurons through kalirin, a major dendritic Rac1-GEF. Recent studies haveshown associations of the KALRN gene with schizophrenia. Our data point to an essential role ofphosphorylation in kalirin-7's C terminus as the critical site for these effects. As reduced interneurondendrite length occurs in schizophrenia, understanding how NRG1-erbB4 signaling modulates interneurondendritic morphogenesis might shed light on disease-related alterations in cortical circuits.", "metadata": {}}
+{"_id": "13205096", "title": "", "text": "Use of gene-expression profiling to identify prognostic subclasses in adult acute myeloidleukemia.BACKGROUND In patients with acute myeloid leukemia (AML), the presence or absence ofrecurrent cytogenetic aberrations is used to identify the appropriate therapy. However, the currentclassification system does not fully reflect the molecular heterogeneity of the disease, and treatmentstratification is difficult, especially for patients with intermediate-risk AML with a normal karyotype.METHODS We used complementary-DNA microarrays to determine the levels of gene expression inperipheral-blood samples or bone marrow samples from 116 adults with AML (including 45 with a normalkaryotype). We used unsupervised hierarchical clustering analysis to identify molecular subgroups withdistinct gene-expression signatures. Using a training set of samples from 59 patients, we applied a novelsupervised learning algorithm to devise a gene-expression-based clinical-outcome predictor, which wethen tested using an independent validation group comprising the 57 remaining patients. RESULTSUnsupervised analysis identified new molecular subtypes of AML, including two prognostically relevantsubgroups in AML with a normal karyotype. Using the supervised learning algorithm, we constructed anoptimal 133-gene clinical-outcome predictor, which accurately predicted overall survival among patientsin the independent validation group (P=0.006), including the subgroup of patients with AML with anormal karyotype (P=0.046). In multivariate analysis, the gene-expression predictor was a strongindependent prognostic factor (odds ratio, 8.8; 95 percent confidence interval, 2.6 to 29.3; P<0.001).CONCLUSIONS The use of gene-expression profiling improves the molecular classification of adult AML.", "metadata": {}}
+{"_id": "13205803", "title": "", "text": "Perspectives on public health workforce research.The Centers for Disease Control and Prevention Office ofWorkforce and Career Development is committed to developing a competent, sustainable, and diversepublic health workforce through evidence-based training, career and leadership development, andstrategic workforce planning to improve population health outcomes. This article reviews the previousefforts in identifying priorities of public health workforce research, which are summarized as eight majorresearch themes. We outline a strategic framework for public health workforce research that includes sixfunctional areas (ie, definition and standards, data, methodology, evaluation, policy, and disseminationand translation). To conceptualize and prioritize development of an actionable public health researchagenda, we constructed a matrix of key challenges in workforce analysis by public health workforcecategories. Extensive reviews were conducted to identify valuable methods, models, and approaches topublic health workforce research. We explore new tools and approaches for addressing priority areas forpublic health workforce and career development research and assess how tools from multiple disciplinesof social sciences can guide the development of a research framework for advancing public healthworkforce research and policy.", "metadata": {}}
+{"_id": "13221399", "title": "", "text": "Gene targeting using zinc finger nucleasesThe ability to achieve site-specific manipulation of themammalian genome has widespread implications for basic and applied research. Gene targeting is aprocess in which a DNA molecule introduced into a cell replaces the corresponding chromosomal segmentby homologous recombination, and thus presents a precise way to manipulate the genome. In the past,the application of gene targeting to mammalian cells has been limited by its low efficiency. Zinc fingernucleases (ZFNs) show promise in improving the efficiency of gene targeting by introducing DNAdouble-strand breaks in target genes, which then stimulate the cell's endogenous homologousrecombination machinery. Recent results have shown that ZFNs can be used to create targetingfrequencies of up to 20% in a human disease-causing gene. Future work will be needed to translate thesein vitro findings to in vivo applications and to determine whether zinc finger nucleases create undesiredgenomic instability.", "metadata": {}}
+{"_id": "13223806", "title": "", "text": "relative expression results in real-timeReal-time reverse transcription followed by polymerase chainreaction (RT-PCR) is the most suitable method for the detection and quantification of mRNA. It offers highsensitivity, good reproducibility and a wide quantification range. Today, relative expression is increasinglyused, where the expression of a target gene is standardised by a non-regulated reference gene. Severalmathematical algorithms have been developed to compute an expression ratio, based on real-time PCRefficiency and the crossing point deviation of an unknown sample versus a control. But all publishedequations and available models for the calculation of relative expression ratio allow only for thedetermination of a single transcription difference between one control and one sample. Therefore a newsoftware tool was established, named REST (relative expression software tool), which compares twogroups, with up to 16 data points in a sample and 16 in a control group, for reference and up to fourtarget genes. The mathematical model used is based on the PCR efficiencies and the mean crossing pointdeviation between the sample and control group. Subsequently, the expression ratio results of the fourinvestigated transcripts are tested for significance by a randomisation test. Herein, development andapplication of REST is explained and the usefulness of relative expression in real-time PCR using REST isdiscussed. The latest software version of REST and examples for the correct use can be downloaded athttp://www.wzw.tum.de/gene-quantification/.", "metadata": {}}
+{"_id": "13223957", "title": "", "text": "Pain attacks in non-complicated and complicated gallstone disease have a characteristic pattern and areaccompanied by dyspepsia in most patients: the results of a prospective study.OBJECTIVE The cardinalindication for surgical treatment of gallstones is pain attacks. However, following cholecystectomy, 20%of patients remain symptomatic. It is unclear to what extent post-cholecystectomy symptoms can beascribed to persistence of preoperative symptoms or to new pathology. The pain and digestive pattern ingallstone patients has not been defined in a recent setting with ultrasonography as the diagnosticmethod. The aim of this study was to characterize a pain pattern that is typical for gallstone disease andto describe the extent of associated dyspepsia. MATERIAL AND METHODS A total of 220 patients withsymptomatic gallstone disease including complicated disease (acute cholecystitis and common bile ductstones) were interviewed using detailed questionnaires to disclose pain patterns and symptoms ofindigestion. RESULTS All patients had pain in the right upper quadrant (RUQ) including the upper midlineepigastrium. The pain was localized to the right subcostal area in 20% and to the upper epigastrium in14%, and in the rest (66%) it was more evenly distributed. An area of maximal pain could be defined in90%. Maximal pain was located under the costal arch in 51% of patients and in the epigastrium in 41%,but in 3% behind the sternum and in 5% in the back. The pain was referred to the back in 63% of thepatients. The mean visual analogue scale (VAS) score was very high: 90 mm on a 0-100 scale. A patternof incipient or low-grade warning pain with a subsequent relatively steady state until subsiding in thesame fashion was present in 90% of the patients. An urge to walk around was experienced by 71%. Painattacks usually occurred in the late evening or at night (77%), with 85% of the attacks lasting for morethan one hour and almost never less than half an hour. Sixty-six percent of the patients were intolerantto at least one kind of food, but only 48% to fatty foods. Symptoms of functional indigestion(gastroesophageal reflux, dyspepsia or irritable bowel symptoms) were seen in the vast majority inassociation with attacks. CONCLUSIONS Gallstone-associated pain follows a certain pattern in themajority of patients. The pain is located in a defined area with a point of maximum intensity, is usuallyreferred, and occurs mainly at night with duration of more than one hour. The majority of patientsexperience functional indigestion, mainly of the reflux type or dyspepsia.", "metadata": {}}
+{"_id": "13230773", "title": "", "text": "Prevalence and cardiovascular disease correlates of low cardiorespiratory fitness in adolescents andadults.CONTEXT Population surveys indicate that physical activity levels are low in the United States. Oneconsequence of inactivity, low cardiorespiratory fitness, is an established risk factor for cardiovasculardisease (CVD) morbidity and mortality, but the prevalence of cardiorespiratory fitness has not beenquantified in representative US population samples. OBJECTIVES To describe the prevalence of lowfitness in the US population aged 12 through 49 years and to relate low fitness to CVD risk factors in thispopulation. DESIGN, SETTING, AND PARTICIPANTS Inception cohort study using data from thecross-sectional nationally representative National Health and Nutrition Examination Survey 1999-2002.Participants were adolescents (aged 12-19 years; n = 3110) and adults (aged 20-49 years; n = 2205)free from previously diagnosed CVD who underwent submaximal graded exercise treadmill testing toachieve at least 75% to 90% of their age-predicted maximum heart rate. Maximal oxygen consumption(VO2max) was estimated by measuring the heart rate response to reference levels of submaximal work.MAIN OUTCOME MEASURES Low fitness defined using percentile cut points of estimated VO2max fromexisting external referent populations; anthropometric and other CVD risk factors measured according tostandard methods. RESULTS Low fitness was identified in 33.6% of adolescents (approximately 7.5million US adolescents) and 13.9% of adults (approximately 8.5 million US adults); the prevalence wassimilar in adolescent females (34.4%) and males (32.9%) (P = .40) but was higher in adult females(16.2%) than in males (11.8%) (P = .03). Non-Hispanic blacks and Mexican Americans were less fit thannon-Hispanic whites. In all age-sex groups, body mass index and waist circumference were inverselyassociated with fitness; age- and race-adjusted odds ratios of overweight or obesity (body mass index >or =25) ranged from 2.1 to 3.7 (P<.01 for all), comparing persons with low fitness with those withmoderate or high fitness. Total cholesterol levels and systolic blood pressure were higher and levels ofhigh-density lipoprotein cholesterol were lower among participants with low vs high fitness. CONCLUSIONLow fitness in adolescents and adults is common in the US population and is associated with an increasedprevalence of CVD risk factors.", "metadata": {}}
+{"_id": "13231899", "title": "", "text": "In situ regulation of DC subsets and T cells mediates tumor regression in mice.Vaccines are largelyineffective for patients with established cancer, as advanced disease requires potent and sustainedactivation of CD8(+) cytotoxic T lymphocytes (CTLs) to kill tumor cells and clear the disease. Recentstudies have found that subsets of dendritic cells (DCs) specialize in antigen cross-presentation and in theproduction of cytokines, which regulate both CTLs and T regulatory (Treg) cells that shut down effector Tcell responses. Here, we addressed the hypothesis that coordinated regulation of a DC network, andplasmacytoid DCs (pDCs) and CD8(+) DCs in particular, could enhance host immunity in mice. We usedfunctionalized biomaterials incorporating various combinations of an inflammatory cytokine, immunedanger signal, and tumor lysates to control the activation and localization of host DC populations in situ.The numbers of pDCs and CD8(+) DCs, and the endogenous production of interleukin-12, all correlatedstrongly with the magnitude of protective antitumor immunity and the generation of potent CD8(+) CTLs.Vaccination by this method maintained local and systemic CTL responses for extended periods whileinhibiting FoxP3 Treg activity during antigen clearance, resulting in complete regression of distant andestablished melanoma tumors. The efficacy of this vaccine as a monotherapy against large invasivetumors may be a result of the local activity of pDCs and CD8(+) DCs induced by persistent danger andantigen signaling at the vaccine site. These results indicate that a critical pattern of DC subsets correlateswith the evolution of therapeutic antitumor responses and provide a template for future vaccine design.", "metadata": {}}
+{"_id": "13235609", "title": "", "text": "VEGF inhibits tumor cell invasion and mesenchymal transition through a MET/VEGFR2 complex.Inhibitionof VEGF signaling leads to a proinvasive phenotype in mouse models of glioblastoma multiforme (GBM)and in a subset of GBM patients treated with bevacizumab. Here, we demonstrate that vascularendothelial growth factor (VEGF) directly and negatively regulates tumor cell invasion through enhancedrecruitment of the protein tyrosine phosphatase 1B (PTP1B) to a MET/VEGFR2 heterocomplex, therebysuppressing HGF-dependent MET phosphorylation and tumor cell migration. Consequently, VEGFblockade restores and increases MET activity in GBM cells in a hypoxia-independent manner, whileinducing a program reminiscent of epithelial-to-mesenchymal transition highlighted by a T-cadherin toN-cadherin switch and enhanced mesenchymal features. Inhibition of MET in GBM mouse models blocksmesenchymal transition and invasion provoked by VEGF ablation, resulting in substantial survival benefit.", "metadata": {}}
+{"_id": "13242763", "title": "", "text": "Interaction between Oct3/4 and Cdx2 Determines Trophectoderm DifferentiationTrophectoderm (TE), thefirst differentiated cell lineage of mammalian embryogenesis, forms the placenta, a structure unique tomammalian development. The differentiation of TE is a hallmark event in early mammalian development,but molecular mechanisms underlying this first differentiation event remain obscure. Embryonic stem(ES) cells can be induced to differentiate into the TE lineage by forced repression of the POU-familytranscription factor, Oct3/4. We show here that this event can be mimicked by overexpression ofCaudal-related homeobox 2 (Cdx2), which is sufficient to generate proper trophoblast stem (TS) cells.Cdx2 is dispensable for trophectoderm differentiation induced by Oct3/4 repression but essential for TScell self-renewal. In preimplantation embryos, Cdx2 is initially coexpressed with Oct3/4 and they form acomplex for the reciprocal repression of their target genes in ES cells. This suggests that reciprocalinhibition between lineage-specific transcription factors might be involved in the first differentiation eventof mammalian development.", "metadata": {}}
+{"_id": "13244602", "title": "", "text": "SSEA-1 is an enrichment marker for tumor-initiating cells in human glioblastoma.CD133+ populations ofhuman glioblastoma multiforme (GBM) cells are reportedly enriched for tumor stem cells (TSCs) ortumor-initiating cells (TICs). Approximately 40% of freshly isolated GBM specimens, however, do notcontain CD133+ tumor cells, raising the possibility that CD133 may not be a universal enrichment markerfor GBM TSCs/TICs. Here we demonstrate that stage-specific embryonic antigen 1(SSEA-1/LeX)+ GBMcells fulfill the functional criteria for TSC/TIC, since (1) SSEA-1+ cells are highly tumorigenic in vivo,unlike SSEA-1- cells; (2) SSEA-1+ cells can give rise to both SSEA-1+ and SSEA-1- cells, therebyestablishing a cellular hierarchy; and (3) SSEA-1+ cells have self-renewal and multilineage differentiationpotentials. A distinct subpopulation of SSEA-1+ cells was present in all but one of the primary GBMsexamined (n = 24), and most CD133+ tumor cells were also SSEA-1+, suggesting that SSEA-1 may be ageneral TSC/TIC enrichment marker in human GBMs.", "metadata": {}}
+{"_id": "13245542", "title": "", "text": "Temporal regulation of topoisomerase IV activity in E. coli.We isolated a mutant allele of dnaX, encodingthe tau and gamma subunits of the DNA polymerase III holoenzyme, that causes extreme cellfilamentation but does not affect either cell growth or DNA replication. This phenotype results from adefect in daughter chromosome decatenation during rapid growth. In these cells, ParC, one subunit oftopoisomerase IV, no longer associated with the replication factory, as occurs in wild-type cells, and wasinstead distributed uniformly on the nucleoid; the distribution of ParE, the other subunit of topoisomeraseIV, was unaffected. In addition, the majority of topoisomerase IV activity in synchronized cell populationswas restricted to late in the cell cycle, when replication was essentially complete. These observationssuggest that topoisomerase IV activity in vivo might be dependent on release of ParC from the replicationfactory.", "metadata": {}}
+{"_id": "13256155", "title": "", "text": "Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy foradvanced cancer (SHIVA): a multicentre, open-label, proof-of-concept, randomised, controlled phase 2trial.BACKGROUND Molecularly targeted agents have been reported to have anti-tumour activity forpatients whose tumours harbour the matching molecular alteration. These results have led to increasedoff-label use of molecularly targeted agents on the basis of identified molecular alterations. We assessedthe efficacy of several molecularly targeted agents marketed in France, which were chosen on the basisof tumour molecular profiling but used outside their indications, in patients with advanced cancer forwhom standard-of-care therapy had failed. METHODS The open-label, randomised, controlled phase 2SHIVA trial was done at eight French academic centres. We included adult patients with any kind ofmetastatic solid tumour refractory to standard of care, provided they had an Eastern CooperativeOncology Group performance status of 0 or 1, disease that was accessible for a biopsy or resection of ametastatic site, and at least one measurable lesion. The molecular profile of each patient's tumour wasestablished with a mandatory biopsy of a metastatic tumour and large-scale genomic testing. We onlyincluded patients for whom a molecular alteration was identified within one of three molecular pathways(hormone receptor, PI3K/AKT/mTOR, RAF/MEK), which could be matched to one of ten regimensincluding 11 available molecularly targeted agents (erlotinib, lapatinib plus trastuzumab, sorafenib,imatinib, dasatinib, vemurafenib, everolimus, abiraterone, letrozole, tamoxifen). We randomly assignedthese patients (1:1) to receive a matched molecularly targeted agent (experimental group) or treatmentat physician's choice (control group) by central block randomisation (blocks of size six). Randomisationwas done centrally with a web-based response system and was stratified according to the Royal MarsdenHospital prognostic score (0 or 1 vs 2 or 3) and the altered molecular pathway. Clinicians and patientswere not masked to treatment allocation. Treatments in both groups were given in accordance with theapproved product information and standard practice protocols at each institution and were continued untilevidence of disease progression. The primary endpoint was progression-free survival in theintention-to-treat population, which was not assessed by independent central review. We assessed safetyin any patients who received at least one dose of their assigned treatment. This trial is registered withClinicalTrials.gov, number NCT01771458. FINDINGS Between Oct 4, 2012, and July 11, 2014, wescreened 741 patients with any tumour type. 293 (40%) patients had at least one molecular alterationmatching one of the 10 available regimens. At the time of data cutoff, Jan 20, 2015, 195 (26%) patientshad been randomly assigned, with 99 in the experimental group and 96 in the control group. All patientsin the experimental group started treatment, as did 92 in the control group. Two patients in the controlgroup received a molecularly targeted agent: both were included in their assigned group for efficacyanalyses, the patient who received an agent that was allowed in the experimental group was included inthe experimental group for the purposes of safety analyses, while the other patient, who received amolecularly targeted agent and chemotherapy, was kept in the control group for safety analyses. Medianfollow-up was 11·3 months (IQR 5·8-11·6) in the experimental group and 11·3 months (8·1-11·6) in thecontrol group at the time of the primary analysis of progression-free survival. Median progression-freesurvival was 2·3 months (95% CI 1·7-3·8) in the experimental group versus 2·0 months (1·8-2·1) in thecontrol group (hazard ratio 0·88, 95% CI 0·65-1·19, p=0·41). In the safety population, 43 (43%) of 100patients treated with a molecularly targeted agent and 32 (35%) of 91 patients treated with cytotoxicchemotherapy had grade 3-4 adverse events (p=0·30). INTERPRETATION The use of molecularlytargeted agents outside their indications does not improve progression-free survival compared withtreatment at physician's choice in heavily pretreated patients with cancer. Off-label use of molecularlytargeted agents should be discouraged, but enrolment in clinical trials should be encouraged to assesspredictive biomarkers of efficacy.", "metadata": {}}
+{"_id": "13277039", "title": "", "text": "CRTC2 (TORC2) contributes to the transcriptional response to fasting in the liver but is not required forthe maintenance of glucose homeostasis.The liver contributes to glucose homeostasis by promotingeither storage or production of glucose, depending on the physiological state. The cAMP responseelement-binding protein (CREB) is a principal regulator of genes involved in coordinating the hepaticresponse to fasting, but its mechanism of gene activation remains controversial. We derived CRTC2(CREB-regulated transcription coactivator 2, previously TORC2)-deficient mice to assess the contributionof this cofactor to hepatic glucose metabolism in vivo. CRTC2 mutant hepatocytes showed reducedglucose production in response to glucagon, which correlated with decreased CREB binding to severalgluconeogenic genes. However, despite attenuated expression of CREB target genes, including PEPCK,G6Pase, and PGC-1alpha, no hypoglycemia was observed in mutant mice. Collectively, these resultsprovide genetic evidence supporting a role for CRTC2 in the transcriptional response to fasting, butindicate only a limited contribution of this cofactor to the maintenance of glucose homeostasis.", "metadata": {}}
+{"_id": "13277118", "title": "", "text": "Ancient Hybridization and an Irish Origin for the Modern Polar Bear MatrilineBACKGROUND Polar bears(Ursus maritimus) are among those species most susceptible to the rapidly changing arctic climate, andtheir survival is of global concern. Despite this, little is known about polar bear species history. Futureconservation strategies would significantly benefit from an understanding of basic evolutionaryinformation, such as the timing and conditions of their initial divergence from brown bears (U. arctos) ortheir response to previous environmental change. RESULTS We used a spatially explicit phylogeographicmodel to estimate the dynamics of 242 brown bear and polar bear matrilines sampled throughout the last120,000 years and across their present and past geographic ranges. Our results show that the presentdistribution of these matrilines was shaped by a combination of regional stability and rapid, long-distancedispersal from ice-age refugia. In addition, hybridization between polar bears and brown bears may haveoccurred multiple times throughout the Late Pleistocene. CONCLUSIONS The reconstructed matrilinealhistory of brown and polar bears has two striking features. First, it is punctuated by dramatic and discreteclimate-driven dispersal events. Second, opportunistic mating between these two species as their rangesoverlapped has left a strong genetic imprint. In particular, a likely genetic exchange with extinct Irishbrown bears forms the origin of the modern polar bear matriline. This suggests that interspecifichybridization not only may be more common than previously considered but may be a mechanism bywhich species deal with marginal habitats during periods of environmental deterioration.", "metadata": {}}
+{"_id": "13277623", "title": "", "text": "FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth anddifferentiationFBW7 (F-box and WD repeat domain-containing 7) is the substrate recognition componentof an evolutionary conserved SCF (complex of SKP1, CUL1 and F-box protein)-type ubiquitin ligase.SCFFBW7 degrades several proto-oncogenes that function in cellular growth and division pathways,including MYC, cyclin E, Notch and JUN. FBW7 is also a tumour suppressor, the regulatory network ofwhich is perturbed in many human malignancies. Numerous cancer-associated mutations in FBW7 and itssubstrates have been identified, and loss of FBW7 function causes chromosomal instability andtumorigenesis. This Review focuses on structural and functional aspects of FBW7 and its role in thedevelopment of cancer.", "metadata": {}}
+{"_id": "13282296", "title": "", "text": "Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus.CONTEXTAlthough acute hypoglycemia may be associated with cognitive impairment in children with type 1diabetes, no studies to date have evaluated whether hypoglycemia is a risk factor for dementia in olderpatients with type 2 diabetes. OBJECTIVE To determine if hypoglycemic episodes severe enough torequire hospitalization are associated with an increased risk of dementia in a population of older patientswith type 2 diabetes followed up for 27 years. DESIGN, SETTING, AND PATIENTS A longitudinal cohortstudy from 1980-2007 of 16,667 patients with a mean age of 65 years and type 2 diabetes who aremembers of an integrated health care delivery system in northern California. MAIN OUTCOME MEASUREHypoglycemic events from 1980-2002 were collected and reviewed using hospital discharge andemergency department diagnoses. Cohort members with no prior diagnoses of dementia, mild cognitiveimpairment, or general memory complaints as of January 1, 2003, were followed up for a dementiadiagnosis through January 15, 2007. Dementia risk was examined using Cox proportional hazardregression models, adjusted for age, sex, race/ethnicity, education, body mass index, duration ofdiabetes, 7-year mean glycated hemoglobin, diabetes treatment, duration of insulin use, hyperlipidemia,hypertension, cardiovascular disease, stroke, transient cerebral ischemia, and end-stage renal disease.RESULTS At least 1 episode of hypoglycemia was diagnosed in 1465 patients (8.8%) and dementia wasdiagnosed in 1822 patients (11%) during follow-up; 250 patients had both dementia and at least 1episode of hypoglycemia (16.95%). Compared with patients with no hypoglycemia, patients with singleor multiple episodes had a graded increase in risk with fully adjusted hazard ratios (HRs): for 1 episode(HR, 1.26; 95% confidence interval [CI], 1.10-1.49); 2 episodes (HR, 1.80; 95% CI, 1.37-2.36); and 3or more episodes (HR, 1.94; 95% CI, 1.42-2.64). The attributable risk of dementia between individualswith and without a history of hypoglycemia was 2.39% per year (95% CI, 1.72%-3.01%). Results werenot attenuated when medical utilization rates, length of health plan membership, or time since initialdiabetes diagnosis were added to the model. When examining emergency department admissions forhypoglycemia for association with risk of dementia (535 episodes), results were similar (compared withpatients with 0 episodes) with fully adjusted HRs: for 1 episode (HR, 1.42; 95% CI, 1.12-1.78) and for 2or more episodes (HR, 2.36; 95% CI, 1.57-3.55). CONCLUSIONS Among older patients with type 2diabetes, a history of severe hypoglycemic episodes was associated with a greater risk of dementia.Whether minor hypoglycemic episodes increase risk of dementia is unknown.", "metadata": {}}
+{"_id": "13283919", "title": "", "text": "Defective mast cell effector functions in mice lacking the CRACM1 pore subunit of store-operated calciumrelease–activated calcium channelsCRACM1 (also called Orai1) constitutes the pore subunit ofstore-operated calcium release–activated calcium channels. A point mutation in the gene encodingCRACM1 is associated with severe combined immunodeficiency disease in humans. Here we generatedCRACM1-deficient mice in which β-galactosidase activity 'reported' CRACM1 expression.CRACM1-deficient mice were smaller in size. Mast cells derived from CRACM1-deficient mice showedgrossly defective degranulation and cytokine secretion, and the allergic reactions elicited in vivo wereinhibited in CRACM1-deficient mice. We detected robust CRACM1 expression in skeletal muscles andsome regions of the brain, heart and kidney but not in the lymphoid regions of thymus and spleen. Incontrast, we found CRACM2 expression to be much higher in mouse T cells. In agreement with thosefindings, the store-operated calcium influx and development and proliferation of CRACM1-deficient T cellswas unaffected. Thus, CRACM1 is crucial in mouse mast cell effector function, but mouse T cell calciumrelease–activated calcium channels are functional in the absence of CRACM1.", "metadata": {}}
+{"_id": "13290521", "title": "", "text": "MicroRNA-7: A miRNA with expanding roles in development and disease.MicroRNAs (miRNAs) are a familyof short, non-coding RNA molecules (\u000022nt) involved in post-transcriptional control of gene expression.They act via base-pairing with mRNA transcripts that harbour target sequences, resulting in acceleratedmRNA decay and/or translational attenuation. Given miRNAs mediate the expression of moleculesinvolved in many aspects of normal cell development and functioning, it is not surprising that aberrantmiRNA expression is closely associated with many human diseases. Their pivotal role in driving a range ofnormal cellular physiology as well as pathological processes has established miRNAs as potentialtherapeutics, as well as potential diagnostic and prognostic tools in human health. MicroRNA-7 (miR-7) isa highly conserved miRNA which displays restricted spatiotemporal expression during development and inmaturity. In humans and mice, mature miR-7 is generated from three different genes, illustratingunexpected redundancy and also the importance of this miRNA in regulating key cellular processes. Inthis review we examine the expanding role of miR-7 in the context of health, with emphasis on organdifferentiation and development, as well as in various mammalian diseases, particularly of the brain,heart, endocrine pancreas and skin, as well as in cancer. The more we learn about miR-7, the more werealise the complexity of its regulation and potential functional application both from a biomarker andtherapeutic perspective.", "metadata": {}}
+{"_id": "13293033", "title": "", "text": "Integration-free induced pluripotent stem cells model genetic and neural developmental features of downsyndrome etiology.Down syndrome (DS) is the most frequent cause of human congenital mentalretardation. Cognitive deficits in DS result from perturbations of normal cellular processes both duringdevelopment and in adult tissues, but the mechanisms underlying DS etiology remain poorly understood.To assess the ability of induced pluripotent stem cells (iPSCs) to model DS phenotypes, as a prototypicalcomplex human disease, we generated bona fide DS and wild-type (WT) nonviral iPSCs by episomalreprogramming. DS iPSCs selectively overexpressed chromosome 21 genes, consistent with gene dosage,which was associated with deregulation of thousands of genes throughout the genome. DS and WT iPSCswere neurally converted at >95% efficiency and had remarkably similar lineage potency, differentiationkinetics, proliferation, and axon extension at early time points. However, at later time points DS culturesshowed a twofold bias toward glial lineages. Moreover, DS neural cultures were up to two times moresensitive to oxidative stress-induced apoptosis, and this could be prevented by the antioxidantN-acetylcysteine. Our results reveal a striking complexity in the genetic alterations caused by trisomy 21that are likely to underlie DS developmental phenotypes, and indicate a central role for defective earlyglial development in establishing developmental defects in DS brains. Furthermore, oxidative stresssensitivity is likely to contribute to the accelerated neurodegeneration seen in DS, and we provide proofof concept for screening corrective therapeutics using DS iPSCs and their derivatives. Nonviral DS iPSCscan therefore model features of complex human disease in vitro and provide a renewable and ethicallyunencumbered discovery platform.", "metadata": {}}
+{"_id": "13296399", "title": "", "text": "In Vivo CRISPR/Cas9 Gene Editing Corrects Retinal Dystrophy in the S334ter-3 Rat Model of AutosomalDominant Retinitis PigmentosaReliable genome editing via Clustered Regularly Interspaced ShortPalindromic Repeat (CRISPR)/Cas9 may provide a means to correct inherited diseases in patients. Asproof of principle, we show that CRISPR/Cas9 can be used in vivo to selectively ablate the rhodopsin genecarrying the dominant S334ter mutation (Rho(S334)) in rats that model severe autosomal dominantretinitis pigmentosa. A single subretinal injection of guide RNA/Cas9 plasmid in combination withelectroporation generated allele-specific disruption of Rho(S334), which prevented retinal degenerationand improved visual function.", "metadata": {}}
+{"_id": "13312471", "title": "", "text": "Vitamin D insufficiency and the blunted PTH response in established osteoporosis: the role of magnesiumdeficiencyVitamin D insufficiency is common, however within individuals, not all manifest the biochemicaleffects of PTH excess. This further extends to patients with established osteoporosis. The mechanismunderlying the blunted PTH response is unclear but may be related to magnesium (Mg) deficiency. Theaims of this study were to compare in patients with established osteoporosis and differing degrees ofvitamin D and PTH status : (1) the presence of Mg deficiency using the standard Mg loading test (2)evaluate the effects of Mg loading on the calcium-PTH endocrine axis (3) determine the effects of oral,short term Mg supplementation on the calcium-PTH endocrine axis and bone turnover. 30 patients (10women in 3 groups) were evaluated prospectively measuring calcium, PTH, Mg retention (Mg loadingtest), dietary nutrient intake (calcium, vitamin D, Mg) and bone turnover markers (serum CTX & P1CP).Multivariate analysis controlling for potential confounding baseline variable was undertaken for themeasured outcomes. All subjects, within the low vitamin D and low PTH group following the magnesiumloading test had evidence of Mg depletion [mean(SD) retention 70.3%(12.5)] and showed an increase incalcium 0.06(0.01) mmol/l [95% CI 0.03, 0.09, p=0.007], together with a rise in PTH 13.3 ng/l (4.5)[95% CI 3.2, 23.4, p=0.016] compared to baseline. Following oral supplementation bone turnoverincreased: CTX 0.16 (0.06) mcg/l [95%CI 0.01, 0.32 p=0.047]; P1CP 13.1 (5.7) mcg/l [95% CI 0.29,26.6 p=0.049]. In subjects with a low vitamin D and raised PTH mean retention was 55.9%(14.8) and inthe vitamin replete group 36.1%(14.4), with little change in both acute markers of calcium homeostasisand bone turnover markers following both the loading test and oral supplementation. This study confirmsthat in patients with established osteoporosis, there is also a distinct group with a low vitamin D and ablunted PTH level and that Mg deficiency (as measured by the Mg loading test) is an importantcontributing factor.", "metadata": {}}
+{"_id": "13322804", "title": "", "text": "Novel syndromes associated with JC virus infection of neurons and meningeal cells: no longer a grayarea.PURPOSE OF REVIEW The availability of a growing number of immunomodulatory medications overthe past few years has been associated with various JC virus (JCV)-associated brain syndromes inpatients with autoimmune diseases, including multiple sclerosis, Crohn's disease, and psoriasis that hadnot been previously recognized as predisposing factors for progressive multifocal leukoencephalopathy.This review covers the three novel syndromes discovered in the last decade that are caused by JCVinfection of neurons and meningeal cells. RECENT FINDINGS For more than 30 years, JCV was thought toexclusively infect oligodendrocytes and astrocytes in the white matter of the brain of immunosuppressedindividuals. We now recognize that JCV-infected glial cells are frequently located at the gray-white matterjunction or exclusively within the gray matter causing demyelination in the cortex. Mutations in JCV cantrigger a change in tropism leading to involvement of other cell types, such as neurons and meningealcells, causing clinically distinct entities. These new features of JCV infection provide challenges forclinicians taking care of affected patients and investigators studying the biology of this polyomavirus, itspathogenesis, and tropism. SUMMARY We hope that increasing awareness of these syndromes will lead toearly diagnosis, and pave the way for new avenues of research to better understand all aspects of JCVpathogenesis and develop efficient therapies for our patients. However, we need to remain vigilant andopen to the possibility that additional JC variants or yet unknown polyomaviruses may also be associatedwith neurological diseases.", "metadata": {}}
+{"_id": "13329980", "title": "", "text": "Phosphoinositide 3-kinase signalling pathways in tumor progression, invasion and angiogenesis.AIMSAND BACKGROUND The PI3 kinase signalling pathway is now accepted as being at least as important asthe ras-MAP kinase pathway in cell survival and proliferation, and hence its potential role in cancer is ofgreat interest. The purpose of this review is briefly to examine evidence for an involvement of PI3K inhuman cancers, discuss the mechanisms by which its activation promotes tumor progression, andconsider its utility as a novel target for anticancer therapy. METHODS AND STUDY DESIGN A Medlinereview of recent literature concerning the role of PI3 kinase in tumor progression--mechanisms of actionand clinical implications. RESULTS Evidence is presented that misregulation of the PI3 kinase pathway isa feature of many common cancers, either by loss of the suppressor protein PTEN, or by constitutiveactivation of PI3 kinase isoforms or downstream elements such as AKT and mTOR. This activationpotentiates not only cell survival and proliferation, but also cytoskeletal deformability and motility; keyelements in tumor invasion. In addition the PI3K pathway is implicated in many aspects of angiogenesis,including upregulation of angiogenic cytokines due to tumor hypoxia or oncogene activation andendothelial cell responses to them. These cytokines signal though receptors such as VEGF-R, FGF-R andTie-2 and potentiate processes essential for neoangiogenesis including cell proliferation, migration,differentiation into tubules and \"invasion\" of these capillary sprouts into extracellular matrix (ECM).CONCLUSIONS A more complete understanding of the role of the PI3 kinase pathway in cancer will leadthe way to the development of more potent and selective inhibitors which should be a useful adjunct toconventional therapies, potentially interfering with tumor progression at several pivotal points; inparticular cell survival, invasion and angiogenesis.", "metadata": {}}
+{"_id": "13338820", "title": "", "text": "Complementary foods for infant feeding in developing countries: their nutrient adequacy andimprovementObjective: To assess the energy and nutrient adequacy of a variety of complementary foodsused in parts of Africa, India, Papua New Guinea, the Philippines and Thailand. Method: The energy,nutrient and anti-nutrient (dietary fibre and phytic acid) content (per 100 g as eaten, per 100 kcal, andper day) of twenty-three plant-based complementary foods consumed in developing countries wascalculated from food composition values based on chemical analysis for the trace minerals, non-starchpolysaccharide and phytic acid, and the literature. Results were compared with the estimated nutrientneeds (per day; per 100 kcal) from complementary foods for infants 9–11 months, assuming a breastmilk intake of average volume and composition and three complementary feedings per day, each of 250g. Results: Complementary foods should provide approximately 25–50% of total daily requirements forprotein, riboflavin and copper; 50–75% for thiamin, calcium and manganese; and 75–100% forphosphorus, zinc and iron. Most or all appear to meet the estimated daily nutrient needs (per day; per100 kcal) from complementary foods for protein, thiamin and copper (per day), but not for calcium, iron,and in some cases zinc, even if moderate bioavailability for iron and zinc is assumed. Some of thosebased on rice are also inadequate in riboflavin (per day; per 100 kcal).Conclusions: Even if strategies toimprove the bioavailability of iron and zinc are employed, they are probably insufficient to overcome thedeficits in calcium, iron and zinc. Therefore, research on the feasibility of fortifying plant-basedcomplementary foods in developing countries with calcium, iron and zinc is urgently required.Sponsorship: This study was supported by the Micronutrient Initiative through the Canadian InternationalDevelopment Agency.", "metadata": {}}
+{"_id": "13350374", "title": "", "text": "Early aging and age-related pathologies in mice deficient in BMAL1, the core componentof the circadianclock.Mice deficient in the circadian transcription factor BMAL1 (brain and muscle ARNT-like protein) haveimpaired circadian behavior and demonstrate loss of rhythmicity in the expression of target genes. Herewe report that Bmal1(-/-) mice have reduced lifespans and display various symptoms of premature agingincluding sarcopenia, cataracts, less subcutaneous fat, organ shrinkage, and others. The early agingphenotype correlates with increased levels of reactive oxygen species in some tissues of the Bmal1(-/-)animals. These findings, together with data on CLOCK/BMAL1-dependent control of stress responses,may provide a mechanistic explanation for the early onset of age-related pathologies in the absence ofBMAL1.", "metadata": {}}
+{"_id": "13368032", "title": "", "text": "A self-inactivating lentiviral vector for SCID-X1 gene therapy that does not activate LMO2 expression inhuman T cells.To develop safer and more effective vectors for gene therapy of X-linked severe combinedimmunodeficiency (SCID-X1), we have evaluated new self-inactivating lentiviral vectors based on the HIVvirus. The CL20i4-hgamma(c)-Revgen vector contains the entire human common gamma chain(gamma(c)) genomic sequence driven by the gamma(c) promoter. The CL20i4-EF1alpha-hgamma(c)OPTvector uses a promoter fragment from the eukaryotic elongation factor alpha (EF1alpha) gene to expressa codon-optimized human gamma(c) cDNA. Both vectors contain a 400-bp insulator fragment from thechicken beta-globin locus within the self-inactivating long-terminal repeat. Transduction of bone marrowcells using either of these vectors restored T, B, and natural killer lymphocyte development and functionin a mouse SCID-X1 transplantation model. Transduction of human CD34(+) bone marrow cells fromSCID-X1 patients with either vector restored T-cell development in an in vitro assay. In safety studiesusing a Jurkat LMO2 activation assay, only the CL20i4-EF1alpha-hgamma(c)OPT vector lacked the abilityto transactivate LMO2 protein expression, whereas the CL20i4-hgamma(c)-Revgen vector significantlyactivated LMO2 protein expression. In addition, the CL20i4-EF1alpha-hgamma(c)OPT vector has notcaused any tumors in transplanted mice. We conclude that the CL20i4-EF1alpha-hgamma(c)OPT vectormay be suitable for testing in a clinical trial based on these preclinical demonstrations of efficacy andsafety.", "metadata": {}}
+{"_id": "13373629", "title": "", "text": "Genetic Variants at Newly Identified Lipid Loci Are Associated with Coronary Heart Disease in a ChineseHan PopulationBACKGROUND Recent genome-wide association studies (GWAS) have mapped severalnovel loci influencing blood lipid levels in Caucasians. We sought to explore whether the genetic variantsat newly identified lipid-associated loci were associated with CHD susceptibility in a Chinese Hanpopulation. METHODOLOGY/PRINCIPAL FINDINGS We conducted a two-stage case-control study in aChinese Han population. The first-stage, consisting of 1,376 CHD cases and 1,376 sex and age-frequency matched controls, examined 5 novel lipid-associated single-nucleotide polymorphisms (SNPs)identified from GWAS among Caucasians in relation to CHD risk in Chinese. We then validated significantSNPs in the second-stage, consisting of 1,269 cases and 2,745 controls. We also tested associationsbetween SNPs within the five novel loci and blood lipid levels in 4,121 controls. We identified two novelSNPs (rs599839 in CELSR2-PSRC1-SORT1 and rs16996148 in NCAN-CILP2) that were significantlyassociated with reduced CHD risk in Chinese (odds ratios (95% confidence intervals) in the dominantmodel 0.76 (0.61-0.90; P = 0.001), 0.67 (0.57-0.77; P = 3.4×10(-8)), respectively). Multiple linearregression analyses using dominant model showed that rs599839 was significantly associated withdecreased LDL levels (P = 0.022) and rs16996148 was significantly associated with increased LDL andHDL levels (P = 2.9×10(-4) and 0.001, respectively). CONCLUSIONS/SIGNIFICANCE We identified twonovel SNPs (rs599839 and rs16996148) at newly identified lipid-associated loci that were significantlyassociated with CHD susceptibility in a Chinese Han population.", "metadata": {}}
+{"_id": "13380011", "title": "", "text": "Spare respiratory capacity rather than oxidative stress regulates glutamate excitotoxicity after partialrespiratory inhibition of mitochondrial complex I with rotenone.Partial inhibition of mitochondrialrespiratory complex I by rotenone reproduces aspects of Parkinson's disease in rodents. The hypothesisthat rotenone enhancement of neuronal cell death is attributable to oxidative stress was tested in anacute glutamate excitotoxicity model using primary cultures of rat cerebellar granule neurons. As little as5 nM rotenone increased mitochondrial superoxide (O2*-) levels and potentiated glutamate-inducedcytoplasmic Ca2+ deregulation, the first irreversible stage of necrotic cell death. However, the potentcell-permeant O2*- trap manganese tetrakis (N-ethylpyridinium-2yl) porphyrin failed to prevent theeffects of the inhibitor. The bioenergetic consequences of rotenone addition were quantified bymonitoring cell respiration. Glutamate activation of NMDA receptors used the full respiratory capacity ofthe in situ mitochondria, and >80% of the glutamate-stimulated respiration was attributable to increasedcellular ATP demand. Rotenone at 20 nM inhibited basal and carbonyl cyanidep-trifluoromethoxyphenylhydrazone-stimulated cell respiration and caused respiratory failure in thepresence of glutamate. ATP synthase inhibition by oligomycin was also toxic in the presence of glutamate.We conclude that the cell vulnerability in the rotenone model of partial complex I deficiency under thesespecific conditions is primarily determined by spare respiratory capacity rather than oxidative stress.", "metadata": {}}
+{"_id": "13380980", "title": "", "text": "Isolated liver perfusion for non-resectable liver tumours: a review.Many treatments have been proposedfor non-resectable primary or secondary hepatic cancer but the results have generally beendisappointing. Isolated Hepatic Perfusion (IHP) was first attempted four decades ago but it gainedacceptance only recently, after spectacular tumour responses were obtained by isolated limb perfusionwith melphalan and tumour necrosis factor (TNF) for melanomas and sarcomas. Surgical isolation of theliver is a technically demanding operation that allows the safe administration of high doses ofchemotherapeutics and TNF. Percutaneous techniques using balloon occlusion catheters are simpler butresult in higher leakage rates from the perfusion circuit into the systemic circulation. Several phase I-IItrials indicate that IHP can yield high tumour response rates, even when there is resistance to systemicchemotherapy. However, no significant advantage in overall survival has been demonstrated so far. IHPoffers unique pharmacokinetic advantages for locoregional chemotherapy and biotherapy. It might alsoallow gene therapy with limited systemic exposure and toxicity. At present, IHP nevertheless remains anexperimental treatment modality which should therefore be used in controlled trials only.", "metadata": {}}
+{"_id": "13384318", "title": "", "text": "Combinatorial control of exon recognition.Pre-mRNA splicing is a fundamental process required for theexpression of most metazoan genes. It is carried out by the spliceosome, which catalyzes the removal ofnoncoding intronic sequences to assemble exons into mature mRNAs prior to export and translation.Given the complexity of higher eukaryotic genes and the relatively low level of splice site conservation,the precision of the splicing machinery in recognizing and pairing splice sites is impressive. Intronsranging in size from <100 up to 100,000 bases are removed efficiently. At the same time, a large numberof alternative splicing events are observed between different cell types, during development, or duringother biological processes. This extensive alternative splicing implies a significant flexibility of thespliceosome to identify and process exons within a given pre-mRNA. To reach this flexibility, splice siteselection in higher eukaryotes has evolved to depend on multiple parameters such as splice site strength,the presence or absence of splicing regulators, RNA secondary structures, the exon/intron architecture,and the process of pre-mRNA synthesis itself. The relative contributions of each of these parameterscontrol how efficiently splice sites are recognized and flanking introns are removed.", "metadata": {}}
+{"_id": "13398997", "title": "", "text": "High CTLA-4 expression on Th17 cells results in increased sensitivity to CTLA-4 coinhibition andresistance to belatacept.The CD28/cytotoxic T-lymphocyte antigen 4 (CTLA-4)blocker belataceptselectively inhibits alloreactive T cell responses but is associated with a high incidence of acute rejectionfollowing renal transplantation,which led us to investigate the etiology of belatacept–resistant graftrejection. T cells can differentiate into functionally distinct subsets of memory T cellsthat collectivelyenable protection against diverse classes of pathogens and can cross-react with allogeneicantigen andmediate graft rejection. T helper 17(Th17) cells are a pro-inflammatory CD4+ lineage that providesimmunity to pathogens and are pathogenic in autoimmune disease. We found that T helper 1 (Th1)andTh17 memory compartments contained a similar frequency of divided cells following allogeneicstimulation. Compared to Th1 cells, Th17 memory cells expressed significantly higher levels of thecoinhibitory molecule CTLA-4. Stimulation in the presence of belatacept inhibited Th1 responses butaugmented Th17 cells due to greater sensitivity to coinhibition by CTLA-4. Th17 cells from renaltransplant recipients were resistant to ex vivo CD28/CTLA-4 blockade with belatacept, and an elevatedfrequency of Th17 memory cells was associated with acute rejection during belatacept therapy. Thesedata highlight important differences in costimulatory and coinhibitory requirements of CD4+ memorysubsets, and demonstrate that the heterogeneity of pathogen-derived memory has implications forimmunomodulation strategies.", "metadata": {}}
+{"_id": "13400643", "title": "", "text": "A small molecule modulates Jumonji histone demethylase activity and selectively inhibits cancergrowthThe pharmacological inhibition of general transcriptional regulators has the potential to blockgrowth through targeting multiple tumorigenic signalling pathways simultaneously. Here, using aninnovative cell-based screen, we identify a structurally unique small molecule (named JIB-04) thatspecifically inhibits the activity of the Jumonji family of histone demethylases in vitro, in cancer cells, andin tumours in vivo. Unlike known inhibitors, JIB-04 is not a competitive inhibitor of α-ketoglutarate. Incancer, but not in patient-matched normal cells, JIB-04 alters a subset of transcriptional pathways andblocks viability. In mice, JIB-04 reduces tumour burden and prolongs survival. Importantly, we find thatpatients with breast tumours that overexpress Jumonji demethylases have significantly lower survival.Thus, JIB-04, a novel inhibitor of Jumonji demethylases in vitro and in vivo, constitutes a unique potentialtherapeutic and research tool against cancer, and validates the use of unbiased cellular screens todiscover chemical modulators with disease relevance.", "metadata": {}}
+{"_id": "13411519", "title": "", "text": "Gq protein alpha subunits Galphaq and Galpha11 are localized at postsynaptic extra-junctional membraneof cerebellar Purkinje cells and hippocampal pyramidal cells.Following cell surface receptor activation, thealpha subunit of the Gq subclass of GTP-binding proteins activates the phosphoinositide signallingpathway. Here we examined the expression and localization of Gq protein alpha subunits in the adultmouse brain by in situ hybridization and immunohistochemistry. Of the four members of the Gq proteinalpha subunits, Galphaq and Galpha11 were transcribed predominantly in the brain. The highesttranscriptional level of Galphaq was observed in cerebellar Purkinje cells (PCs) and hippocampalpyramidal cells, while that of Galpha11 was noted in hippocampal pyramidal cells. Antibody against theC-terminal peptide common to Galphaq and Galpha11 strongly labelled the cerebellar molecular layer andhippocampal neuropil layers. In these regions, immunogold preferentially labelled the cytoplasmic face ofpostsynaptic cell membrane of PCs and pyramidal cells. Immunoparticles were distributed along theextra-junctional cell membrane of spines, dendrites and somata, but were almost excluded from thejunctional membrane. By double immunofluorescence, Galphaq/Galpha11 was extensively colocalizedwith metabotropic glutamate receptor mGluR1alpha in dendritic spines of PCs and with mGluR5 in thoseof hippocampal pyramidal cells. Together with concentrated localization of mGluR1alpha and mGluR5 in aperi-junctional annulus on PC and pyramidal cell synapses (Baude et al. 1993, Neuron, 11, 771-787;Luján et al. 1996, Eur. J. Neurosci., 8, 1488-1500), the present molecular-anatomical findings suggestthat peri-junctional stimulation of the group I metabotropic glutamate receptors is mediated by Galphaqand/or Galpha11, leading to the activation of the intracellular effector, phospholipase Cbeta.", "metadata": {}}
+{"_id": "13439128", "title": "", "text": "The Bloom's syndrome gene product is homologous to RecQ helicasesThe Bloom's syndrome (BS) gene,BLM, plays an important role in the maintenance of genomic stability in somatic cells. A candidate for BLMwas identified by direct selection of a cDNA derived from a 250 kb segment of the genome to which BLMhad been assigned by somatic crossover point mapping. In this novel mapping method, cells were usedfrom persons with BS that had undergone intragenic recombination within BLM. cDNA analysis of thecandidate gene identified a 4437 bp cDNA that encodes a 1417 amino acid peptide with homology to theRecQ helicases, a subfamily of DExH box-containing DNA and RNA helicases. The presence ofchain-terminating mutations in the candidate gene in persons with BS proved that it was BLM.", "metadata": {}}
+{"_id": "13441037", "title": "", "text": "Preventing obesity in children and adolescents.In this review, we address the natural history of obesity inchildren, the most promising family- and school-based approaches to the prevention of obesity, and thebarriers and opportunities associated with secondary prevention. In childhood, the most importantperiods of risk appear to be the periods of adiposity rebound and adolescence. Caution regarding theperiod of adiposity rebound is still warranted, because it is not yet clear that early rebound is attributableto changes in body fat. Families and schools represent the most important foci for preventive efforts inchildren and adolescents. One productive approach is to proceed from an examination of factors thataffect energy balance to the identification of more proximal influences on those factors. This approachmay help to narrow the strategies necessary to prevent or treat childhood obesity. For example,television viewing affects both energy intake and energy expenditure, and therefore represents a logicaltarget for interventions. Anticipatory guidance by pediatricians may offer an effective mechanism bywhich to change parental attitudes and practices regarding television viewing. A similar process is used toemphasize the potential influence of school-based interventions directed at changes in food choices andsedentary behavior.", "metadata": {}}
+{"_id": "13441537", "title": "", "text": "Culture of Preimplantation Mouse Embryos Affects Fetal Development and the Expression of ImprintedGenes1Abstract Culture of preimplantation mammalian embryos and cells can influence their subsequentgrowth and differentiation. Previously, we reported that culture of mouse embryonic stem cells isassociated with deregulation of genomic imprinting and affects the potential for these cells to develop intonormal fetuses. The purpose of our current study was to determine whether culture of preimplantationmouse embryos in a chemically defined medium (M16) with or without fetal calf serum (FCS) can affecttheir subsequent development and imprinted gene expression. Only one third of the blastocysts that hadbeen cultured from two-cell embryos in M16 medium complemented with FCS developed into viable Day14 fetuses after transfer into recipients. These M16 + FCS fetuses were reduced in weight as comparedwith controls and M16 fetuses and had decreased expression of the imprinted H19 and insulin-like growthfactor 2 genes associated with a gain of DNA methylation at an imprinting control region upstream ofH19. They also displayed increased expression of the imprinted gene Grb10. The growth factor receptorbinding gene Grb7, in contrast, was strongly reduced in its expression in most of the M16 + FCS fetuses.No alterations were detected for the imprinted gene Mest. Preimplantation culture in the presence ofserum can influence the regulation of multiple growth-related imprinted genes, thus leading to aberrantfetal growth and development.", "metadata": {}}
+{"_id": "13445579", "title": "", "text": "Results of screening for intracranial aneurysms in patients with coarctation of the aorta.BACKGROUNDAND PURPOSE IAs are found in 2.3% of adults; the mean age at detection is 52 years. Prevalence is<0.5% in young adults. Early studies suggest that 10%-50% of patients with aortic coarctation have IAs.Screening recommendations are variable. We sought to examine the prevalence of IAs through screeningwith MRA. MATERIALS AND METHODS Consecutive patients older than 16 years of age with coarctationundergoing brain MRA between May 1999 and October 2007 were included. MRA was performed by usinga 1.5T scanner with a 3D time-of-flight protocol; simultaneous MR imaging was performed of the heartand aorta. Cerebral MRAs were double-reported by a neuroradiologist. Statistics are described as mean ±SD and median ± range. Continuous variables were compared by using Student t tests andMann-Whitney U tests (categoric variables, by using the Fisher exact test). RESULTS One hundredseventeen MRAs were double-reported. The median age was 29 ± 11 years (range, 16-59 years). IAswere found in 12 patients (10.3%). The mean diameter of IAs was 3.9 mm (range, 2.0-8.0 mm). Patientswith aneurysms were older (median, 37 years; range, 16-50 years) than those without (median, 23years; range, 16-59 years; Z = -2.01, P = .04). Hypertension was more common in those with IAs (IA83% versus no IA 43%, P = .01). There was no association between ascending aortopathy, bicuspidaortic valves, and IAs. CONCLUSIONS Patients with coarctation have a higher prevalence of IAs,occurring at an earlier age than in population studies. Whether routine screening is appropriate for thisgroup of patients is unclear. Hypertension is likely to be an important pathophysiologic factor.", "metadata": {}}
+{"_id": "13448422", "title": "", "text": "A new look at the heart in diabetes mellitus: from ailing to failingThis review discusses some of themechanisms inherent in diabetes that predispose patients to increased cardiac morbidity and mortality.Single photon emission computerized tomography or photon emission tomography with radioactivelabeled analogues of norepinephrine have shown that cardiac sympathetic dysfunction and incompetenceare early and also late abnormalities in patients with Type I (insulin-dependent) and Type II(non-insulin-dependent) diabetes mellitus. Furthermore, myocardial blood flow assessment with photonemission tomography has shown that in patients without myocardial perfusion deficits,endothelial-dependent vasodilatation is severely reduced in relation to cardiac sympathetic dysfunction.In addition, signs of endothelial activation have also been found early in patients with Type I and Type IIdiabetes in whom vascular disease has not been clinically detected. This activation in conjunction withglycaemic control is important in determining macrovascular mortality. Cardiac sympathetic dysfunctionis partially restored to normal with near normalisation of glycaemia. Interpretations. Recentlyunrecognized “subtle” changes predispose the heart to failure, after ischaemia-induced remodelling, andarteriosclerotic plaques to instability and rupture. These changes act in conjunction with effects, driven byhyperglycaemia and diabetes, on the endothelium of large blood vessels, e. g. on nitric oxide release oron protein kinase-C β activation. Meticulous glucose control early on and rapid recompensation ofhyperglycaemia in patients with acute coronary syndrome are part of a successful intensive multifactorialapproach to prevent the heart in diabetes converting from ailing to failing. [Diabetologia (2000) 43:1455–1469]", "metadata": {}}
+{"_id": "13450938", "title": "", "text": "Genetic and epigenetic mutations affect the DNA binding capability of human ZFP57 in transient neonataldiabetes type 1In the mouse, ZFP57 contains three classical Cys2His2 zinc finger domains (ZF) andrecognizes the methylated TGC(met)CGC target sequence using the first and the second ZFs. In thisstudy, we demonstrate that the human ZFP57 (hZFP57) containing six Cys2His2 ZFs, binds the samemethylated sequence through the third and the fourth ZFs, and identify the aminoacids critical for DNAinteraction. In addition, we present evidences indicating that hZFP57 mutations and hypomethylation ofthe TNDM1 ICR both associated with Transient Neonatal Diabetes Mellitus type 1 result in loss of hZFP57binding to the TNDM1 locus, likely causing PLAGL1 activation.", "metadata": {}}
+{"_id": "13458119", "title": "", "text": "Physiological astrocytic calcium levels stimulate glutamate release to modulate adjacentneurons.Astrocytes can release glutamate in a calcium-dependent manner and consequently signal toadjacent neurons. Whether this glutamate release pathway is used during physiological signaling or isrecruited only under pathophysiological conditions is not well defined. One reason for this lack ofunderstanding is the limited knowledge about the levels of calcium necessary to stimulate glutamaterelease from astrocytes and about how they compare with the range of physiological calcium levels inthese cells. We used flash photolysis to raise internal calcium in astrocytes, while monitoring astrocyticcalcium levels and glutamate, which evoked slow inward currents that were recordedelectrophysiologically from single neurons grown on microislands of astrocytes. With this approach, wedemonstrate that modest changes of astrocytic calcium, from 84 to 140 nM, evoke substantialglutamatergic currents in neighboring neurons (-391 pA), with a Hill coefficient of 2.1 to 2.7. Because theagonists glutamate, norepinephrine, and dopamine all raise calcium in astrocytes to levels exceeding 1.8microM, these quantitative studies demonstrate that the astrocytic glutamate release pathway is engagedat physiological levels of internal calcium. Consequently, the calcium-dependent release of glutamatefrom astrocytes functions within an appropriate range of astrocytic calcium levels to be used as asignaling pathway within the functional nervous system.", "metadata": {}}
+{"_id": "13464392", "title": "", "text": "Albumin and furosemide therapy in hypoproteinemic patients with acute lung injury.OBJECTIVEHypoproteinemia, fluid retention, and weight gain are associated with development of acute lung injuryand mortality in critically ill patients, without proof of cause and effect. We designed a clinical trial todetermine whether diuresis and colloid replacement in hypoproteinemic patients with acute lung injurywould improve pulmonary physiology. DESIGN Prospective, randomized, double-blind, placebo-controlledtrial. SETTING All adult intensive care units from two university hospitals. PATIENTS Thirty-sevenmechanically-ventilated patients with acute lung injury and serum total protein </=5.0g/dL.   INTERVENTIONS Five-day protocolized regimen of 25 g of human serum albumin every 8 hrs withcontinuous infusion furosemide, or dual placebo, targeted to diuresis, weight loss, and serum totalprotein. MEASUREMENTS AND MAIN RESULTS Measured outcomes included change in weight, serumtotal protein, fluid balance, hemodynamics, respiratory system compliance, and oxygenation. Baselinecharacteristics were similar between groups (treatment, n = 19; control, n = 18), with trauma being themajor cause of acute lung injury. Diuresis and weight loss over 5 days (5.3 kg more in the treatmentgroup, p =.04) was accompanied by improvements in the Pao2/Fio2 ratio in the treatment group within24 hrs (from 171 to 236, p =.02). Respiratory mechanics were unchanged. Mean arterial pressureincreased from 80 to 88 mm Hg (p =.10), and heart rate decreased from 110 to 95 beats/min (p =.008)over time in the treatment group. No difference in mortality was observed, with favorable trends inmeasures of intensive care. CONCLUSIONS Albumin and furosemide therapy improves fluid balance,oxygenation, and hemodynamics in hypoproteinemic patients with acute lung injury. Determining theeffect of this simple therapy on cost, outcomes, and other patient populations requires further study.", "metadata": {}}
+{"_id": "13466517", "title": "", "text": "Advances in functional and structural mr image analysis and implementation as fslThe techniquesavailable for the interrogation and analysis of neuroimaging data have a large influence in determiningthe flexibility, sensitivity, and scope of neuroimaging experiments. The development of suchmethodologies has allowed investigators to address scientific questions that could not previously beanswered and, as such, has become an important research area in its own right. In this paper, wepresent a review of the research carried out by the Analysis Group at the Oxford Centre for FunctionalMRI of the Brain (FMRIB). This research has focussed on the development of new methodologies for theanalysis of both structural and functional magnetic resonance imaging data. The majority of the researchlaid out in this paper has been implemented as freely available software tools within FMRIB's SoftwareLibrary (FSL).", "metadata": {}}
+{"_id": "13466622", "title": "", "text": "Metformin—mode of action and clinical implications for diabetes and cancerMetformin has been themainstay of therapy for diabetes mellitus for many years; however, the mechanistic aspects of metforminaction remained ill-defined. Recent advances revealed that this drug, in addition to its glucose-loweringaction, might be promising for specifically targeting metabolic differences between normal and abnormalmetabolic signalling. The knowledge gained from dissecting the principal mechanisms by which metforminworks can help us to develop novel treatments. The centre of metformin's mechanism of action is thealteration of the energy metabolism of the cell. Metformin exerts its prevailing, glucose-lowering effect byinhibiting hepatic gluconeogenesis and opposing the action of glucagon. The inhibition of mitochondrialcomplex I results in defective cAMP and protein kinase A signalling in response to glucagon. Stimulationof 5′-AMP-activated protein kinase, although dispensable for the glucose-lowering effect of metformin,confers insulin sensitivity, mainly by modulating lipid metabolism. Metformin might influencetumourigenesis, both indirectly, through the systemic reduction of insulin levels, and directly, via theinduction of energetic stress; however, these effects require further investigation. Here, we discuss theupdated understanding of the antigluconeogenic action of metformin in the liver and the implications ofthe discoveries of metformin targets for the treatment of diabetes mellitus and cancer.", "metadata": {}}
+{"_id": "13469921", "title": "", "text": "Characteristics of the Earliest Cross-Neutralizing Antibody Response to HIV-1Recent cross-sectionalanalyses of HIV-1+ plasmas have indicated that broadly cross-reactive neutralizing antibody responsesare developed by 10%-30% of HIV-1+ subjects. The timing of the initial development of such anti-viralresponses is unknown. It is also unknown whether the emergence of these responses coincides with theappearance of antibody specificities to a single or multiple regions of the viral envelope glycoprotein(Env). Here we analyzed the cross-neutralizing antibody responses in longitudinal plasmas collected soonafter and up to seven years after HIV-1 infection. We find that anti-HIV-1 cross-neutralizing antibodyresponses first become evident on average at 2.5 years and, in rare cases, as early as 1 year followinginfection. If cross-neutralizing antibody responses do not develop during the first 2-3 years of infection,they most likely will not do so subsequently. Our results indicate a potential link between thedevelopment of cross-neutralizing antibody responses and specific activation markers on T cells, and withplasma viremia levels. The earliest cross-neutralizing antibody response targets a limited number of Envregions, primarily the CD4-binding site and epitopes that are not present on monomeric Env, but on thevirion-associated trimeric Env form. In contrast, the neutralizing activities of plasmas from subjects thatdid not develop cross-neutralizing antibody responses target epitopes on monomeric gp120 other thanthe CD4-BS. Our study provides information that is not only relevant to better understanding theinteraction of the human immune system with HIV but may guide the development of effectiveimmunization protocols. Since antibodies to complex epitopes that are present on the virion-associatedenvelope spike appear to be key components of earliest cross-neutralizing activities of HIV-1+ plasmas,then emphasis should be made to elicit similar antibodies by vaccination.", "metadata": {}}
+{"_id": "13481731", "title": "", "text": "Gender, age, and heart failure with preserved left ventricular systolic function.OBJECTIVES This studywas designed to determine if women are more likely than men to have heart failure (HF) with preservedsystolic function after adjustment for potential confounders, including age. BACKGROUND Although priorevidence suggests an independent association between female gender and preserved left ventricularsystolic function (LVSF) in patients with HF, existing studies are limited by referral biases, small samplesizes, or the inability to adjust for a wide range of potential confounding variables. METHODS This is across-sectional study using data from retrospective medical chart abstraction of a national sample ofMedicare beneficiaries hospitalized with the principal discharge diagnosis of HF in acute-carenongovernmental hospitals in the U.S. between April 1998 and March 1999. Patients were eligible for thisanalysis if they were age 65 years or older, had documentation of LVSF, and corroboration of thediagnosis of HF. We used multivariable logistic regression to identify the correlates of preserved LVSF,which was defined as qualitatively normal function or quantitatively reported ejection fraction > or =0.50.Stratified regressions by gender were performed to identify significant interactions. RESULTS Of the19,710 patients in the analysis, preserved LVSF was present in 6,700 (35%), 79% of whom were women.In contrast, among the 12,956 patients with impaired LVSF, only 49% were women. Patients withpreserved LVSF were 1.5 years older than those with impaired LVSF. After adjustment for age and otherpatient factors, female gender remained strongly associated with preserved LVSF (calculated risk ratio =1.71; 95% confidence interval 1.63 to 1.78). The association was consistent in all age groups, and wassimilar in patients with or without coronary artery disease, hypertension, pulmonary disease, renalinsufficiency, or atrial fibrillation. CONCLUSIONS In elderly patients hospitalized with HF, preservedsystolic function is primarily a condition of women, independent of important demographic and clinicalcharacteristics.", "metadata": {}}
+{"_id": "13481880", "title": "", "text": "YAP/TAZ-Dependent Reprogramming of Colonic Epithelium Links ECM Remodeling to TissueRegenerationTissue regeneration requires dynamic cellular adaptation to the wound environment. It iscurrently unclear how this is orchestrated at the cellular level and how cell fate is affected by severetissue damage. Here we dissect cell fate transitions during colonic regeneration in a mouse dextransulfate sodium (DSS) colitis model, and we demonstrate that the epithelium is transiently reprogrammedinto a primitive state. This is characterized by de novo expression of fetal markers as well as suppressionof markers for adult stem and differentiated cells. The fate change is orchestrated by remodeling theextracellular matrix (ECM), increased FAK/Src signaling, and ultimately YAP/TAZ activation. In a definedcell culture system recapitulating the extracellular matrix remodeling observed in vivo, we show that acollagen 3D matrix supplemented with Wnt ligands is sufficient to sustain endogenous YAP/TAZ andinduce conversion of cell fate. This provides a simple model for tissue regeneration, implicating cellularreprogramming as an essential element.", "metadata": {}}
+{"_id": "13492264", "title": "", "text": "SummaryGlomerular basement membrane (GBM) and podocalyxin are essential for podocytemorphology. We provide evidence of functional interconnections between basement membranecomponents (collagen IV and laminin), the expression of podocalyxin and the morphology of humanglomerular epithelial cells (podocytes). We demonstrated that GBM and laminin, but not collagen IV,up-regulated the expression of podocalyxin. Scanning electron microscopy revealed that laminin induceda modified morphology of podocytes with process formation, which was more extensive in the presence ofGBM. Under high magnification, podocytes appeared ruffled. Using transmission electron microscopy weobserved that raised areas occurred in the basal cell surface. Furthermore, the presence ofanti-podocalyxin antibody increased the extent of adhesion and spreading of podocytes to both collagenIV and laminin, thus podocalyxin apparently inhibits cell-matrix interactions. We also performed adhesionand spreading assays on podocytes grown under increased glucose concentration (25 mM). Under theseconditions, the expression of podocalyxin was almost totally suppressed. The cells adhered and spread tobasement membrane components but there was no increase in the extent of adhesion and spreading inthe presence of anti-podocalyxin antibody, or ruffling of the cell edges. Additionally, in podocytesexpressing podocalyxin, the presence of anti-podocalyxin antibody partially reversed the inhibition ofadhesion to collagen IV provoked by anti-beta1 integrin antibody, thus podocalyxin should compete withbeta1-related cell adhesion. We suggest that the observed podocalyxin-mediated inhibition of binding tothe matrix could be in part responsible for the specialized conformation of the basal surface of podocytes.", "metadata": {}}
+{"_id": "13494853", "title": "", "text": "Mfold web server for nucleic acid folding and hybridization predictionThe abbreviated name, 'mfold webserver', describes a number of closely related software applications available on the World Wide Web(WWW) for the prediction of the secondary structure of single stranded nucleic acids. The objective of thisweb server is to provide easy access to RNA and DNA folding and hybridization software to the scientificcommunity at large. By making use of universally available web GUIs (Graphical User Interfaces), theserver circumvents the problem of portability of this software. Detailed output, in the form of structureplots with or without reliability information, single strand frequency plots and 'energy dot plots', areavailable for the folding of single sequences. A variety of 'bulk' servers give less information, but in ashorter time and for up to hundreds of sequences at once. The portal for the mfold web server ishttp://www.bioinfo.rpi.edu/applications/mfold. This URL will be referred to as 'MFOLDROOT'.", "metadata": {}}
+{"_id": "13496853", "title": "", "text": "Grip strength in healthy caucasian adults: reference values.PURPOSE The aim of this study was to updatereference data of handgrip strength for healthy adults of both genders spanning a wide age range and toanalyze possible factors of influence. METHODS Intraindividual and interindividual variations of gripstrength and their relation to several anthropometric factors were analyzed in a standardized manner for769 healthy adults (women, n = 403; men, n = 366) aged between 20 years and 95 years.Measurements were done in neutral position of arm, forearm, and wrist on setting II of a Baseline digitalhydraulic dynamometer (NexGen Ergonomics Inc. Quebec, Canada). RESULTS Mean strength was about41% less in women (right 29 kg; left 27 kg) than in men (right 49 kg; left 47 kg) resulting in a ratio ofleft to right hand slightly above .95 in both genders. During the course of life, hand strength developscomparably in both genders peaking at 35 years of age and decreasing continuously further on.Anthropometric variables such as forearm circumference and length, hand size, or body mass showed apositive correlation with grip strength. Body mass index, type of work, and hand dominance showed onlya partial positive correlation or no correlation with grip strength. Gender and age, followed by parametersrepresenting body length and obesity, were observed to have the highest predictive value for handgripstrength and were therefore entered into the generation of prediction equations. CONCLUSIONS Werecommend side adjustment of measured values for intraindividual comparison and inclusion ofinformation regarding anthropometric characteristics, as well as using gender- and age-adjustedreference values, whereas hand dominance can be neglected. The regression equations we generatedmight prove to be useful for clinicians or for those who use normative values within software to providemore accurate predictions of strength scores for specific applications.", "metadata": {}}
+{"_id": "13497630", "title": "", "text": "Association Between Biomarkers of Ovarian Reserve and Infertility Among Older Women of ReproductiveAgeImportance Despite lack of evidence of their utility, biomarkers of ovarian reserve are being promotedas potential markers of reproductive potential. Objective To determine the associations betweenbiomarkers of ovarian reserve and reproductive potential among women of late reproductive age. Design,Setting, and Participants Prospective time-to-pregnancy cohort study (2008 to date of last follow-up inMarch 2016) of women (N = 981) aged 30 to 44 years without a history of infertility who had been tryingto conceive for 3 months or less, recruited from the community in the Raleigh-Durham, North Carolina,area. Exposures Early-follicular-phase serum level of antimüllerian hormone (AMH), follicle-stimulatinghormone (FSH), and inhibin B and urinary level of FSH. Main Outcomes and Measures The primaryoutcomes were the cumulative probability of conception by 6 and 12 cycles of attempt and relativefecundability (probability of conception in a given menstrual cycle). Conception was defined as a positivepregnancy test result. Results A total of 750 women (mean age, 33.3 [SD, 3.2] years; 77% white; 36%overweight or obese) provided a blood and urine sample and were included in the analysis. Afteradjusting for age, body mass index, race, current smoking status, and recent hormonal contraceptiveuse, women with low AMH values (<0.7 ng/mL [n = 84]) did not have a significantly different predictedprobability of conceiving by 6 cycles of attempt (65%; 95% CI, 50%-75%) compared with women (n =579) with normal values (62%; 95% CI, 57%-66%) or by 12 cycles of attempt (84% [95% CI,70%-91%] vs 75% [95% CI, 70%-79%], respectively). Women with high serum FSH values (>10mIU/mL [n = 83]) did not have a significantly different predicted probability of conceiving after 6 cyclesof attempt (63%; 95% CI, 50%-73%) compared with women (n = 654) with normal values (62%; 95%CI, 57%-66%) or after 12 cycles of attempt (82% [95% CI, 70%-89%] vs 75% [95% CI, 70%-78%],respectively). Women with high urinary FSH values (>11.5 mIU/mg creatinine [n = 69]) did not have asignificantly different predicted probability of conceiving after 6 cycles of attempt (61%; 95% CI,46%-74%) compared with women (n = 660) with normal values (62%; 95% CI, 58%-66%) or after 12cycles of attempt (70% [95% CI, 54%-80%] vs 76% [95% CI, 72%-80%], respectively). Inhibin B levels(n = 737) were not associated with the probability of conceiving in a given cycle (hazard ratio per1-pg/mL increase, 0.999; 95% CI, 0.997-1.001). Conclusions and Relevance Among women aged 30 to44 years without a history of infertility who had been trying to conceive for 3 months or less, biomarkersindicating diminished ovarian reserve compared with normal ovarian reserve were not associated withreduced fertility. These findings do not support the use of urinary or blood follicle-stimulating hormonetests or antimüllerian hormone levels to assess natural fertility for women with these characteristics.", "metadata": {}}
+{"_id": "13509809", "title": "", "text": "Matrix-embedded osteocytes regulate mobilization of hematopoietic stem/progenitor cells.The bonemarrow (BM) niche comprises multiple cell types that regulate hematopoietic stem/progenitor cell (HSPC)migration out of the niche and into the circulation. Here, we demonstrate that osteocytes, the majorcellular component of mature bone, are regulators of HSPC egress. Granulocyte colony-stimulating factor(G-CSF), used clinically to mobilize HSPCs, induces changes in the morphology and gene expression ofthe osteocytic network that precedes changes in osteoblasts. This rapid response is likely under control ofthe sympathetic nervous system, since osteocytes express the β2-adrenergic receptor and surgicalsympathectomy prevents it. Mice with targeted ablation of osteocytes or a disrupted osteocyte networkhave comparable numbers of HSPCs in the BM but fail to mobilize HSPCs in response to G-CSF. Takentogether, these results indicate that the BM/bone niche interface is critically controlled from inside of thebone matrix and establish an important physiological role for skeletal tissues in hematopoietic function.", "metadata": {}}
+{"_id": "13513790", "title": "", "text": "Generation of Genetically Modified Mice by Oocyte Injection of Androgenetic Haploid Embryonic StemCellsHaploid cells are amenable for genetic analysis. Recent success in the derivation of mouse haploidembryonic stem cells (haESCs) via parthenogenesis has enabled genetic screening in mammalian cells.However, successful generation of live animals from these haESCs, which is needed to extend the geneticanalysis to the organism level, has not been achieved. Here, we report the derivation of haESCs fromandrogenetic blastocysts. These cells, designated as AG-haESCs, partially maintain paternal imprints,express classical ESC pluripotency markers, and contribute to various tissues, including the germline,upon injection into diploid blastocysts. Strikingly, live mice can be obtained upon injection of AG-haESCsinto MII oocytes, and these mice bear haESC-carried genetic traits and develop into fertile adults.Furthermore, gene targeting via homologous recombination is feasible in the AG-haESCs. Our resultsdemonstrate that AG-haESCs can be used as a genetically tractable fertilization agent for the productionof live animals via injection into oocytes.", "metadata": {}}
+{"_id": "13514898", "title": "", "text": "The impact of hydroxyethyl starches in cardiac surgery: a meta-analysisINTRODUCTION Recent studies inseptic patients showed that adverse effects of hydroxyethyl starches (HESs) possibly outweigh theirbenefits in severely impaired physiological haemostasis. It remains unclear whether this also applies topatient populations that are less vulnerable. In this meta-analysis, we evaluated the impact of variousHES generations on safety and efficacy endpoints in patients undergoing cardiac surgery. METHODS Wesearched the PubMed, Embase and Cochrane Central Register of Controlled Trials databases forrandomised controlled trials (RCTs) in the English or German language comparing the use of HES to anyother colloid or crystalloid during open heart surgery. RESULTS Blood loss and transfusion requirementswere higher for older starches with mean molecular weights more than 200 kDa compared to othervolume substitutes. In contrast, this effect was not observed with latest-generation tetrastarches(130/0.4), which performed even better when compared to albumin (blood loss of tetrastarch versusalbumin: standardised mean difference (SMD), -0.34; 95% CI, -0.63, -0.05; P = 0.02; versus gelatin:SMD, -0.06; 95% CI, -0.20, 0.08; P = 0.39; versus crystalloids: SMD, -0.05; 95% CI, -0.20, 0.10; P =0.54). Similar results were found for transfusion needs. Lengths of stay in the intensive care unit orhospital were significantly shorter with tetrastarches compared to gelatin (intensive care unit: SMD,-0.10; 95% CI, -0.15, -0.05; P = 0.0002) and crystalloids (hospital: SMD, -0.52; 95% CI, -0.90, -0.14; P= 0.007). CONCLUSIONS In this meta-analysis of RCTs, we could not identify safety issues withtetrastarches compared with other colloid or crystalloid solutions in terms of blood loss, transfusionrequirements or hospital length of stay in patients undergoing cardiac surgery. The safety data oncoagulation with older starches raise some issues that need to be addressed in future trials.", "metadata": {}}
+{"_id": "13515165", "title": "", "text": "Place of care in advanced cancer: a qualitative systematic literature review of patientpreferences.BACKGROUND It is commonly written that more patients wish to die at home than currentlyachieve this. However, the evidence for preferences for place of terminal care and death has not beensystematically reviewed. AIM To carry out a systematic literature review of the preferences for place ofcare and death among advanced cancer patients. METHOD Studies were identified using systematicdatabase searches of MEDLINE (1966-1999), PsychLit (1974-1999), and Bath Information Data Service(BIDS) (1981-1999). Studies were assessed and data extracted and synthesises following the NHSCentre for Reviews and Dissemination guidelines, grading studies according to design and rigor ofmethods. Studies of preferences in the general population and of groups including cancer patients and/ortheir caregivers were included. RESULTS Eighteen studies determining preferences in either the generalpopulation or groups including cancer patients were identified. Views were obtained prospectively andretrospectively from patients, the general population, families, and professionals. Respondents indicatedpreferences for home death (range 49%-100%), except one study of patients in the care of a continuingcare team in London where only 25%-29% of patients wanted a home death, and inpatient hospice wasthe most favored option. However, the response rate of this study was not known. Among the generalpublic there was a higher preference for inpatient hospice care among in people with recent experience ofa close friend or relative's death or dying. Where the views of patients, families, and professionals werecompared, all respondents broadly agreed although patients expressed the strongest home preferences.Only 2 of the studies provided longitudinal data, and 9 of the 18 had major deficits in design or reporting,such as poor or unknown response rate, unclear or unsystematic methods of eliciting preferences or othersample or measurement bias. However, sensitivity analysis of only the more robust and larger studies didnot alter the finding of a preference for home care at the end of life in over 50% of patients.CONCLUSIONS Home care is the most common preference, with inpatient hospice care as secondpreference in advanced illness. Meeting these preferences could be important outcomes for services.Study designs in this area need to be improved.", "metadata": {}}
+{"_id": "13519661", "title": "", "text": "Linkage Disequilibrium Mapping of       CHEK2: Common Variation and Breast Cancer RiskBackgroundCheckpoint kinase 2 (CHEK2) averts cancer development by promoting cell cycle arrest and activatingDNA repair in genetically damaged cells. Previous investigation has established a role for the CHEK2 genein breast cancer aetiology, but studies have largely been limited to the rare 1100delC mutation. Whethercommon polymorphisms in this gene influence breast cancer risk remains unknown. In this study, weaimed to assess the importance of common CHEK2 variants on population risk for breast cancer bycapturing the majority of diversity in the gene using haplotype tagging single nucleotide polymorphisms(tagSNPs). Methods and Findings We analyzed 14 common SNPs spanning 52 kilobases (kb) of theCHEK2 gene in 92 Swedish women. Coverage evaluation indicated that these typed SNPs would efficientlyconvey association signal also from untyped SNPs in the same region. Six of the 14 SNPs predicted wellboth the haplotypic and single SNP variations within CHEK2. We genotyped these six tagSNPs in 1,577postmenopausal breast cancer cases and 1,513 population controls, but found no convincing associationbetween any common CHEK2 haplotype and breast cancer risk. The 1100delC mutation was rare in ourSwedish population—0.7% in cases and 0.4% in controls— with a corresponding odds ratio for carriersversus noncarriers of 2.26 (95% confidence interval, 0.99–5.15). Estimates of the population frequencyand the odds ratio of 1100delC indicate that our sample is representative of a Northern Europeanpopulation.", "metadata": {}}
+{"_id": "13552682", "title": "", "text": "Decoding Mammalian Ribosome-mRNA States by Translational GTPase ComplexesIn eukaryotes, accurateprotein synthesis relies on a family of translational GTPases that pair with specific decoding factors todecipher the mRNA code on ribosomes. We present structures of the mammalian ribosome engaged withdecoding factor\u0000GTPase complexes representing intermediates of translation elongation(aminoacyl-tRNA\u0000eEF1A), termination (eRF1\u0000eRF3), and ribosome rescue (Pelota\u0000Hbs1l). Comparativeanalyses reveal that each decoding factor exploits the plasticity of the ribosomal decoding center todifferentially remodel ribosomal proteins and rRNA. This leads to varying degrees of large-scale ribosomemovements and implies distinct mechanisms for communicating information from the decoding center toeach GTPase. Additional structural snapshots of the translation termination pathway reveal theconformational changes that choreograph the accommodation of decoding factors into the peptidyltransferase center. Our results provide a structural framework for how different states of the mammalianribosome are selectively recognized by the appropriate decoding factor\u0000GTPase complex to ensuretranslational fidelity.", "metadata": {}}
+{"_id": "13573143", "title": "", "text": "Intestinal Cgi-58 Deficiency Reduces Postprandial Lipid AbsorptionComparative Gene Identification-58(CGI-58), a lipid droplet (LD)-associated protein, promotes intracellular triglyceride (TG) hydrolysis invitro. Mutations in human CGI-58 cause TG accumulation in numerous tissues including intestine.Enterocytes are thought not to store TG-rich LDs, but a fatty meal does induce temporary cytosolicaccumulation of LDs. Accumulated LDs are eventually cleared out, implying existence of TG hydrolyticmachinery in enterocytes. However, identities of proteins responsible for LD-TG hydrolysis remainunknown. Here we report that intestine-specific inactivation of CGI-58 in mice significantly reducespostprandial plasma TG concentrations and intestinal TG hydrolase activity, which is associated with a4-fold increase in intestinal TG content and large cytosolic LD accumulation in absorptive enterocytesduring the fasting state. Intestine-specific CGI-58 knockout mice also display mild yet significantdecreases in intestinal fatty acid absorption and oxidation. Surprisingly, inactivation of CGI-58 in intestinesignificantly raises plasma and intestinal cholesterol, and reduces hepatic cholesterol, without alteringintestinal cholesterol absorption and fecal neutral sterol excretion. In conclusion, intestinal CGI-58 isrequired for efficient postprandial lipoprotein-TG secretion and for maintaining hepatic and plasma lipidhomeostasis. Our animal model will serve as a valuable tool to further define how intestinal fatmetabolism influences the pathogenesis of metabolic disorders, such as obesity and type 2 diabetes.", "metadata": {}}
+{"_id": "13578199", "title": "", "text": "Transglutaminase 2 Undergoes a Large Conformational Change upon ActivationHuman transglutaminase2 (TG2), a member of a large family of enzymes that catalyze protein crosslinking, plays an importantrole in the extracellular matrix biology of many tissues and is implicated in the gluten-inducedpathogenesis of celiac sprue. Although vertebrate transglutaminases have been studied extensively, thusfar all structurally characterized members of this family have been crystallized in conformations withinaccessible active sites. We have trapped human TG2 in complex with an inhibitor that mimicsinflammatory gluten peptide substrates and have solved, at 2-A resolution, its x-ray crystal structure.The inhibitor stabilizes TG2 in an extended conformation that is dramatically different from earliertransglutaminase structures. The active site is exposed, revealing that catalysis takes place in a tunnel,bridged by two tryptophan residues that separate acyl-donor from acyl-acceptor and stabilize thetetrahedral reaction intermediates. Site-directed mutagenesis was used to investigate the acyl-acceptorside of the tunnel, yielding mutants with a marked increase in preference for hydrolysis overtransamidation. By providing the ability to visualize this activated conformer, our results create afoundation for understanding the catalytic as well as the non-catalytic roles of TG2 in biology, and fordissecting the process by which the autoantibody response to TG2 is induced in celiac sprue patients.", "metadata": {}}
+{"_id": "13580614", "title": "", "text": "Lactic acidosis in patients with diabetes treated with metformin.To the Editor: From May 1995, whenmetformin was introduced in the United States, through June 30, 1996, the Food and Drug Administration(FDA) received reports of lactic acidosis in 66 patients treated with metformin. In 47 patients, thediagnosis was confirmed on the basis of circulating lactate values (>5 mmol per liter), in accordance withestablished criteria for the diagnosis of lactic acidosis (Table 1).1,2 Of the 47 patients with confirmeddiagnoses, 43 had one or more risk factors for lactic acidosis. Thirty (64 percent) had preexisting cardiacdisease, of whom 18 had histories of congestive heart failure. . . .", "metadata": {}}
+{"_id": "13583521", "title": "", "text": "The Apaf-1 apoptosome induces formation of caspase-9 homo- and heterodimers with distinctactivitiesAccording to dogma, initiator caspases are activated through proximity-inducedhomodimerization, but some studies infer that during apoptosis caspase-9 may instead form aholoenzyme with the Apaf-1 apoptosome. Using several biochemical approaches, including a novelsite-specific crosslinking technique, we provide the first direct evidence that procaspase-9 homodimerizeswithin the apoptosome, markedly increasing its avidity for the complex and inducing selectiveintramolecular cleavage at Asp-315. Remarkably, however, procaspase-9 could also bind via its smallsubunit to the NOD domain in Apaf-1, resulting in the formation of a heterodimer that more efficientlyactivated procaspase-3. Following cleavage, the intersubunit linker (and associated conformationalchanges) in caspase-9-p35/p12 inhibited its ability to form homo- and heterodimers, but feedbackcleavage by caspase-3 at Asp-330 removed the linker entirely and partially restored activity tocaspase-9-p35/p10. Thus, the apoptosome mediates the formation of caspase-9 homo- andheterodimers, both of which are impacted by cleavage and contribute to its overall function.", "metadata": {}}
+{"_id": "13583615", "title": "", "text": "Repositioning of aurora B promoted by chiasmata ensures sister chromatid mono-orientation in meiosisI.During meiosis I, kinetochores of sister chromatids are juxtaposed or fused and mono-orient, whilehomologous chromosomes that are paired by chiasmata (bivalents) have to biorient. In the absence ofchiasmata, biorientation of sister chromatids (univalents), which carries a risk of aneuploidy, has beenoccasionally detected in several species, including humans. We show in fission yeast that biorientation offused sister kinetochores predominates during early prometaphase I. Without chiasmata, this undesirablebiorientation of univalents persists and eventually evades the spindle assembly checkpoint, provokingabnormal anaphase. When univalents are connected by chiasmata or by an artificial tether, thiserroneous attachment is converted to monopolar attachment and stabilized. This stabilization isapparently achieved by a chromosome configuration that brings kinetochores to the outer edge of thebivalent, while bringing Aurora B, a destabilizer of kinetochore-microtubule attachment, inward. Ourresults elucidate how chiasmata favor biorientation of bivalents over that of univalents at meiosis I.", "metadata": {}}
+{"_id": "13592721", "title": "", "text": "Biophysical Constraints Arising from Compositional Context in Synthetic Gene Networks.Synthetic geneexpression is highly sensitive to intragenic compositional context (promoter structure, spacing regionsbetween promoter and coding sequences, and ribosome binding sites). However, much less is knownabout the effects of intergenic compositional context (spatial arrangement and orientation of entire geneson DNA) on expression levels in synthetic gene networks. We compare expression of induced genesarranged in convergent, divergent, or tandem orientations. Induction of convergent genes yielded up to400% higher expression, greater ultrasensitivity, and dynamic range than divergent- or tandem-orientedgenes. Orientation affects gene expression whether one or both genes are induced. We postulate thattranscriptional interference in divergent and tandem genes, mediated by supercoiling, can explaindifferences in expression and validate this hypothesis through modeling and in vitro supercoilingrelaxation experiments. Treatment with gyrase abrogated intergenic context effects, bringing expressionlevels within 30% of each other. We rebuilt the toggle switch with convergent genes, taking advantage ofsupercoiling effects to improve threshold detection and switch stability.", "metadata": {}}
+{"_id": "13613916", "title": "", "text": "Glucose repression in Saccharomyces cerevisiaeGlucose is the primary source of energy for the buddingyeast Saccharomyces cerevisiae. Although yeast cells can utilize a wide range of carbon sources,presence of glucose suppresses molecular activities involved in the use of alternate carbon sources aswell as it represses respiration and gluconeogenesis. This dominant effect of glucose on yeast carbonmetabolism is coordinated by several signaling and metabolic interactions that mainly regulatetranscriptional activity but are also effective at post-transcriptional and post-translational levels. Thisreview describes effects of glucose repression on yeast carbon metabolism with a focus on roles of theSnf3/Rgt2 glucose-sensing pathway and Snf1 signal transduction in establishment and relief of glucoserepression.", "metadata": {}}
+{"_id": "13614794", "title": "", "text": "The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases.Thecyclin-dependent kinase Cdk2 associates with cyclins A, D, and E and has been implicated in the controlof the G1 to S phase transition in mammals. To identify potential Cdk2 regulators, we have employed animproved two-hybrid system to isolate human genes encoding Cdk-interacting proteins (Cips). CIP1encodes a novel 21 kd protein that is found in cyclin A, cyclin D1, cyclin E, and Cdk2 immunoprecipitates.p21CIP1 is a potent, tight-binding inhibitor of Cdks and can inhibit the phosphorylation of Rb by cyclinA-Cdk2, cyclin E-Cdk2, cyclin D1-Cdk4, and cyclin D2-Cdk4 complexes. Cotransfection experimentsindicate that CIP1 and SV40 T antigen function in a mutually antagonistic manner to control cell cycleprogression.", "metadata": {}}
+{"_id": "13618987", "title": "", "text": "Exploring the temporal structure of heterochronous sequences using TempEst (formerlyPath-O-Gen)Gene sequences sampled at different points in time can be used to infer molecularphylogenies on a natural timescale of months or years, provided that the sequences in question undergomeasurable amounts of evolutionary change between sampling times. Data sets with this property aretermed heterochronous and have become increasingly common in several fields of biology, most notablythe molecular epidemiology of rapidly evolving viruses. Here we introduce the cross-platform softwaretool, TempEst (formerly known as Path-O-Gen), for the visualization and analysis of temporally sampledsequence data. Given a molecular phylogeny and the dates of sampling for each sequence, TempEst usesan interactive regression approach to explore the association between genetic divergence through timeand sampling dates. TempEst can be used to (1) assess whether there is sufficient temporal signal in thedata to proceed with phylogenetic molecular clock analysis, and (2) identify sequences whose geneticdivergence and sampling date are incongruent. Examination of the latter can help identify data qualityproblems, including errors in data annotation, sample contamination, sequence recombination, oralignment error. We recommend that all users of the molecular clock models implemented in BEAST firstcheck their data using TempEst prior to analysis.", "metadata": {}}
+{"_id": "13619127", "title": "", "text": "Diabetes treatments and risk of amputation, blindness, severe kidney failure, hyperglycaemia, andhypoglycaemia: open cohort study in primary careOBJECTIVE To assess the risks of amputation,blindness, severe kidney failure, hyperglycaemia, and hypoglycaemia in patients with type 2 diabetesassociated with prescribed diabetes drugs, particularly newer agents including gliptins or glitazones(thiazolidinediones). DESIGN Open cohort study in primary care. SETTING 1243 practices contributingdata to the QResearch database in England. PARTICIPANTS 469,688 patients with type 2 diabetes aged25-84 years between 1 April 2007 and 31 January 2015. EXPOSURES Hypoglycaemic agents (glitazones,gliptins, metformin, sulphonylureas, insulin, and other) alone and in combination. MAIN OUTCOMEMEASURES First recorded diagnoses of amputation, blindness, severe kidney failure, hyperglycaemia, andhypoglycaemia recorded on patients' primary care, mortality, or hospital records. Cox models estimatedhazard ratios for diabetes treatments adjusting for potential confounders. RESULTS 21,308 (4.5%) and32,533 (6.9%) patients received prescriptions for glitazones and gliptins during follow-up, respectively.Compared with non-use, glitazones were associated with a decreased risk of blindness (adjusted hazardratio 0.71, 95% confidence interval 0.57 to 0.89; rate 14.4 per 10,000 person years of exposure) and anincreased risk of hypoglycaemia (1.22, 1.10 to 1.37; 65.1); gliptins were associated with a decreased riskof hypoglycaemia (0.86, 0.77 to 0.96; 45.8). Although the numbers of patients prescribed gliptinmonotherapy or glitazones monotherapy were relatively low, there were significantly increased risks ofsevere kidney failure compared with metformin monotherapy (adjusted hazard ratio 2.55, 95%confidence interval 1.13 to 5.74). We found significantly lower risks of hyperglycaemia among patientsprescribed dual therapy involving metformin with either gliptins (0.78, 0.62 to 0.97) or glitazones (0.60,0.45 to 0.80) compared with metformin monotherapy. Patients prescribed triple therapy with metformin,sulphonylureas, and either gliptins (adjusted hazard ratio 5.07, 95% confidence interval 4.28 to 6.00) orglitazones (6.32, 5.35 to 7.45) had significantly higher risks of hypoglycaemia than those prescribedmetformin monotherapy, but these risks were similar to those involving dual therapy with metformin andsulphonylureas (6.03, 5.47 to 6.63). Patients prescribed triple therapy with metformin, sulphonylureas,and glitazones had a significantly reduced risk of blindness compared with metformin monotherapy (0.67,0.48 to 0.94). CONCLUSIONS We have found lower risks of hyperglycaemia among patients prescribeddual therapy involving metformin with either gliptins or glitazones compared with metformin alone.Compared with metformin monotherapy, triple therapy with metformin, sulphonylureas, and eithergliptins or glitazones was associated with an increased risk of hypoglycaemia, which was similar to therisk for dual therapy with metformin and sulphonylureas. Compared with metformin monotherapy, tripletherapy with metformin, sulphonylureas, and glitazones was associated with a reduced risk of blindness.These results, while subject to residual confounding, could have implications for the prescribing ofhypoglycaemic drugs.", "metadata": {}}
+{"_id": "13621186", "title": "", "text": "Vertebrate rod photoreceptors express both BK and IK calcium-activated potassium channels, but only BKchannels are involved in receptor potential regulation.In salamander rods, Ca(2+)-activated K(+) current(I(KCa)) provides an effective \"clamp\" of the dark membrane potential to its normal resting level. By acombination of electrophysiological, pharmacological, and immunohistochemical approaches, we showthat salamander rods functionally express large-conductance Ca(2+)- and voltage-dependent potassium(BK) channel and intermediate-conductance Ca(2+)-dependent potassium (IK) channel, but notsmall-conductance Ca(2+)-dependent potassium channel (SK) subtypes. Application of 100 nMiberiotoxin and 100 nM clotrimazole reduced net I(KCa) to 36% and 63%, respectively, whereas thecurrent was unaffected by application of 1 microM apamin. Consistently, anti- SK1, -SK2, and -SK3antibodies were unable to stain rod photoreceptors, whereas both anti-BK and -SK4/ IK1 antibodiesheavily stained the ellipsoid region of the inner segments of the rods. Moreover, by using current-clampexperiments, it was clearly seen that the strong clamping effect of the total I(KCa) was lost when IbTx,but not CLTZ, was applied to the bath. This behavior strongly suggests that of BK and IK channels, onlythe former are responsible for the clamping effect on the photoreceptor membrane potential.", "metadata": {}}
+{"_id": "13624704", "title": "", "text": "Ondansetron reduces nausea and vomiting after paediatric adenotonsillectomy.The efficacy, safety andresource implications of a single intravenous dose of ondansetron (0.1 mg.kg-1, maximum 4 mg) wereassessed in a multinational, multicentre, randomized, double-blind, placebo-controlled trial of 427children aged 1-12 years, undergoing tonsillectomy with/without adenoidectomy. Emesis (retching and/orvomiting) and nausea were analysed separately. Significantly more ondansetron-treated children had noepisodes of emesis (127/212 (60%) vs 100/215 (47%); P = 0.004) and experienced no postoperativenausea (135/211 (64%) vs 108/213 (51%); P = 0.004) in the first 24 h. Ondansetron also reduced thenumber of emetic episodes (P < 0.001), the time to the first emetic episode (P < 0.001) and overallnausea severity (P = 0.003). Significantly fewer ondansetron-treated children were rescued or withdrawnfrom the study (5% vs 10%; P = 0.042). Fewer ondansetron-treated patients required nursingintervention (34% vs 45%; P = 0.007) and the average intervention time was significantly shorter (4.6vs 8.1 minutes; P = 0.001). Resources used to manage PONV were significantly reduced by ondansetron(43% vs 57%; P = 0.014).", "metadata": {}}
+{"_id": "13625993", "title": "", "text": "Assessing the cost effectiveness of using prognostic biomarkers with decision models: case study inprioritising patients waiting for coronary artery surgeryOBJECTIVE To determine the effectiveness andcost effectiveness of using information from circulating biomarkers to inform the prioritisation process ofpatients with stable angina awaiting coronary artery bypass graft surgery. DESIGN Decision analyticalmodel comparing four prioritisation strategies without biomarkers (no formal prioritisation, two urgencyscores, and a risk score) and three strategies based on a risk score using biomarkers: a routinelyassessed biomarker (estimated glomerular filtration rate), a novel biomarker (C reactive protein), orboth. The order in which to perform coronary artery bypass grafting in a cohort of patients wasdetermined by each prioritisation strategy, and mean lifetime costs and quality adjusted life years(QALYs) were compared. DATA SOURCES Swedish Coronary Angiography and Angioplasty Registry (9935patients with stable angina awaiting coronary artery bypass grafting and then followed up forcardiovascular events after the procedure for 3.8 years), and meta-analyses of prognostic effects(relative risks) of biomarkers. RESULTS The observed risk of cardiovascular events while on the waitinglist for coronary artery bypass grafting was 3 per 10,000 patients per day within the first 90 days (184events in 9935 patients). Using a cost effectiveness threshold of pound20,000- pound30,000(euro22,000-euro33,000; $32,000-$48,000) per additional QALY, a prioritisation strategy using a riskscore with estimated glomerular filtration rate was the most cost effective strategy (cost per additionalQALY was < pound410 compared with the Ontario urgency score). The impact on population health ofimplementing this strategy was 800 QALYs per 100,000 patients at an additional cost of pound 245,000to the National Health Service. The prioritisation strategy using a risk score with C reactive protein wasassociated with lower QALYs and higher costs compared with a risk score using estimated glomerularfiltration rate. CONCLUSION Evaluating the cost effectiveness of prognostic biomarkers is important evenwhen effects at an individual level are small. Formal prioritisation of patients awaiting coronary arterybypass grafting using a routinely assessed biomarker (estimated glomerular filtration rate) along withsimple, routinely collected clinical information was cost effective. Prioritisation strategies based on theprognostic information conferred by C reactive protein, which is not currently measured in this context, ora combination of C reactive protein and estimated glomerular filtration rate, is unlikely to be costeffective. The widespread practice of using only implicit or informal means of clinically ordering thewaiting list may be harmful and should be replaced with formal prioritisation approaches.", "metadata": {}}
+{"_id": "13636631", "title": "", "text": "Cytokine control of memory T-cell development and survivalEvidence has accumulated that cytokineshave a fundamental role in the differentiation of memory T cells. Here, we follow the CD8+ T cell frominitial activation to memory-cell generation, indicating the checkpoints at which cytokines determine thefate of the T cell. Members of the common cytokine-receptor γ-chain (γc)-cytokine family — in particular,interleukin-7 (IL-7) and IL-15 — act at each stage of the immune response to promote proliferation andsurvival. In this manner, a stable and protective, long-lived memory CD8+ T-cell pool can be propagatedand maintained.", "metadata": {}}
+{"_id": "13639330", "title": "", "text": "Histone Methylation-Dependent Mechanisms Impose Ligand Dependency for Gene Activation by NuclearReceptorsNuclear receptors undergo ligand-dependent conformational changes that are required forcorepressor-coactivator exchange, but whether there is an actual requirement for specific epigeneticlandmarks to impose ligand dependency for gene activation remains unknown. Here we report anunexpected and general strategy that is based on the requirement for specific cohorts of inhibitoryhistone methyltransferases (HMTs) to impose gene-specific gatekeeper functions that prevent unligandednuclear receptors and other classes of regulated transcription factors from binding to their target genepromoters and causing constitutive gene activation in the absence of stimulating signals. This strategy,based at least in part on an HMT-dependent inhibitory histone code, imposes a requirement for specifichistone demethylases, including LSD1, to permit ligand- and signal-dependent activation of regulatedgene expression. These events link an inhibitory methylation component of the histone code to a broadlyused strategy that circumvents pathological constitutive gene induction by physiologically regulatedtranscription factors.", "metadata": {}}
+{"_id": "13651792", "title": "", "text": "Human IRGM Regulates Autophagy and Its Cell-Autonomous Immunity Functions ThroughMitochondriaIRGM, a human immunity-related GTPase, confers autophagic defence against intracellularpathogens by an unknown mechanism. Here, we report an unexpected mode of IRGM action. IRGMdemonstrated differential affinity for the mitochondrial lipid cardiolipin, translocated to mitochondria,affected mitochondrial fission and induced autophagy. Mitochondrial fission was necessary for autophagiccontrol of intracellular mycobacteria by IRGM. IRGM influenced mitochondrial membrane polarization andcell death. Overexpression of IRGMd, but not IRGMb splice isoforms, caused mitochondrial depolarizationand autophagy-independent, but Bax/Bak-dependent, cell death. By acting on mitochondria, IRGMconfers autophagic protection or cell death, explaining IRGM action both in defence against tuberculosisand in the damaging inflammation caused by Crohn's disease.", "metadata": {}}
+{"_id": "13702924", "title": "", "text": "The Developmental Transcriptome of the Mosquito Aedes aegypti, an Invasive Species and MajorArbovirus VectorMosquitoes are vectors of a number of important human and animal diseases. Thedevelopment of novel vector control strategies requires a thorough understanding of mosquito biology. Tofacilitate this, we used RNA-seq to identify novel genes and provide the first high-resolution view of thetranscriptome throughout development and in response to blood feeding in a mosquito vector of humandisease, Aedes aegypti, the primary vector for Dengue and yellow fever. We characterized mRNAexpression at 34 distinct time points throughout Aedes development, including adult somatic andgermline tissues, by using polyA+ RNA-seq. We identify a total of 14,238 novel new transcribed regionscorresponding to 12,597 new loci, as well as many novel transcript isoforms of previously annotatedgenes. Altogether these results increase the annotated fraction of the transcribed genome into longpolyA+ RNAs by more than twofold. We also identified a number of patterns of shared gene expression,as well as genes and/or exons expressed sex-specifically or sex-differentially. Expression profiles of smallRNAs in ovaries, early embryos, testes, and adult male and female somatic tissues also were determined,resulting in the identification of 38 new Aedes-specific miRNAs, and ~291,000 small RNA new transcribedregions, many of which are likely to be endogenous small-interfering RNAs and Piwi-interacting RNAs.Genes of potential interest for transgene-based vector control strategies also are highlighted. Our datahave been incorporated into a user-friendly genome browser located at www. Aedes.caltech.edu, withrelevant links to Vectorbase (www.vectorbase.org).", "metadata": {}}
+{"_id": "13714201", "title": "", "text": "Gut microbial diversity is associated with lower arterial stiffness in womenAims The gut microbiomeinfluences metabolic syndrome (MetS) and inflammation and is therapeutically modifiable. Arterialstiffness is poorly correlated with most traditional risk factors. Our aim was to examine whether gutmicrobial composition is associated with arterial stiffness. Methods and results We assessed thecorrelation between carotid-femoral pulse wave velocity (PWV), a measure of arterial stiffness, and gutmicrobiome composition in 617 middle-aged women from the TwinsUK cohort with concurrent serummetabolomics data. Pulse wave velocity was negatively correlated with gut microbiome alpha diversity(Shannon index, Beta(SE)= -0.25(0.07), P = 1 × 10-4) after adjustment for covariates. We identifiedseven operational taxonomic units associated with PWV after adjusting for covariates and multipletesting-two belonging to the Ruminococcaceae family. Associations between microbe abundances,microbe diversity, and PWV remained significant after adjustment for levels of gut-derived metabolites(indolepropionate, trimethylamine oxide, and phenylacetylglutamine). We linearly combined thePWV-associated gut microbiome-derived variables and found that microbiome factors explained 8.3%(95% confidence interval 4.3-12.4%) of the variance in PWV. A formal mediation analysis revealed thatonly a small proportion (5.51%) of the total effect of the gut microbiome on PWV was mediated by insulinresistance and visceral fat, c-reactive protein, and cardiovascular risk factors after adjusting for age,body mass index, and mean arterial pressure. Conclusions Gut microbiome diversity is inverselyassociated with arterial stiffness in women. The effect of gut microbiome composition on PWV is onlyminimally mediated by MetS. This first human observation linking the gut microbiome to arterial stiffnesssuggests that targeting the microbiome may be a way to treat arterial ageing.", "metadata": {}}
+{"_id": "13717103", "title": "", "text": "ALS-FUS pathology revisited: singleton FUS mutations and an unusual case with both a FUS and TARDBPmutationINTRODUCTION Mutations in the FUS gene have been shown to be a rare cause of amyotrophiclateral sclerosis (ALS-FUS) and whilst well documented clinically and genetically there have beenrelatively few neuropathological studies. Recent work suggested a possible correlation betweenpathological features such as frequency of basophilic inclusions in neurons and rate of clinical decline,other studies have revealed a discrepancy between the upper motor neuron features detected clinicallyand the associated pathology. The purpose of this study was to describe the pathological featuresassociated with more recently discovered FUS mutations and reinvestigate those with well recognisedmutations in an attempt to correlate the pathology with mutation and/or clinical phenotype. The brainsand spinal cords of seven cases of ALS-FUS were examined neuropathologically, including cases with thenewly described p. K510E mutation and a case with both a known p. P525L mutation in the FUS gene anda truncating p. Y374X mutation in the TARDBP gene. RESULTS The neuropathology in all cases revealedbasophilic and FUS inclusions in the cord. The density and type of inclusions varied markedly betweencases, but did not allow a clear correlation with clinical progression. Only one case showed significantmotor cortical pathology despite the upper motor neuron clinical features being evident in 4 patients. Thecase with both a FUS and TARDBP mutation revealed FUS positive inclusions but no TDP-43 pathology.Instead there were unusual p62 positive, FUS negative neuronal and glial inclusions as well as dot-likeneurites. CONCLUSIONS The study confirms cases of ALS-FUS to be mainly a lower motor neuron diseaseand to have pathology that does not appear to neatly correlate with clinical features or genetics.Furthermore, the case with both a FUS and TARDBP mutation reveals an intriguing pathological profilewhich at least in part involves a very unusual staining pattern for the ubiquitin-binding protein p62.", "metadata": {}}
+{"_id": "13726379", "title": "", "text": "Coronary heart disease in south Asians overseas: a review.Coronary heart disease rates have beenreported in several parts of the world to be unusually high in people originating from the Indiansubcontinent. High coronary disease rates appear to be common to South Asian groups of differentgeographical origin, religion, and language. This presents a challenge to the understanding of coronaryheart disease: the high rates in South Asians are not explained on the basis of elevated serumcholesterol, smoking or hypertension. Low plasma HDL cholesterol, high plasma triglyceride levels andhigh prevalence of non-insulin-dependent diabetes have been consistently found in South Asiansoverseas: this probably reflects an underlying state of insulin resistance. Further studies are needed todetermine whether this metabolic disturbance can account for the high rates of coronary heart disease inSouth Asians, and to identify possibilities for prevention.", "metadata": {}}
+{"_id": "13732033", "title": "", "text": "A systematic review of parent and clinician views and perceptions that influence prescribing decisions inrelation to acute childhood infections in primary careOBJECTIVES To investigate the views of parents,clinicians, and children pertaining to prescribing decisions for acute childhood infection in primary care.METHODS A systematic review of qualitative studies. Meta-ethnographic methods were used, with datadrawn from the primary studies in an interpretive analysis. RESULTS A total of 15 studies met theinclusion criteria. The literature was dominated by concerns about antibiotic over-prescription. Children'sviews were not reported. Clinicians prescribed antibiotics when they felt pressured by parents or others(e.g. employers) to do so, when they believed there was a clear clinical indication, but also when they feltuncertain of clinical or social outcomes they prescribed \"just in case\". Parents wanted antibiotics whenthey felt they would improve the current illness, and when they felt pressure from daycare providers oremployers. Clinicians avoided antibiotics when they were concerned about adverse reactions or drugresistance, when certain they were not indicated, and when there was no perceived pressure fromparents. Parents also wished to avoid adverse effects of antibiotics, and did not want antibiotics whenthey would not relieve current symptoms. Some parents preferred to avoid medication altogether. Withinpaediatric consultations, parents sought a medical evaluation and decision. Primary care clinicians wantsatisfied parents and short consultations. CONCLUSIONS Antibiotic prescriptions for childhood infectionsin primary care often result from \"just in case\" prescribing. These findings suggest that interventionswhich reduce clinician uncertainty regarding social or clinical outcomes and provide strategies to meetparents' needs within a short consultation are most likely to reduce antibiotic prescribing.", "metadata": {}}
+{"_id": "13734012", "title": "", "text": "Prevalent abnormal prion protein in human appendixes after bovine spongiform encephalopathyepizootic: large scale surveyOBJECTIVES To carry out a further survey of archived appendix samples tounderstand better the differences between existing estimates of the prevalence of subclinical infectionwith prions after the bovine spongiform encephalopathy epizootic and to see whether a broader birthcohort was affected, and to understand better the implications for the management of blood and bloodproducts and for the handling of surgical instruments. DESIGN Irreversibly unlinked and anonymisedlarge scale survey of archived appendix samples. SETTING Archived appendix samples from thepathology departments of 41 UK hospitals participating in the earlier survey, and additional hospitals inregions with lower levels of participation in that survey. SAMPLE 32,441 archived appendix samples fixedin formalin and embedded in paraffin and tested for the presence of abnormal prion protein (PrP).RESULTS Of the 32,441 appendix samples 16 were positive for abnormal PrP, indicating an overallprevalence of 493 per million population (95% confidence interval 282 to 801 per million). Theprevalence in those born in 1941-60 (733 per million, 269 to 1596 per million) did not differ significantlyfrom those born between 1961 and 1985 (412 per million, 198 to 758 per million) and was similar in bothsexes and across the three broad geographical areas sampled. Genetic testing of the positive specimensfor the genotype at PRNP codon 129 revealed a high proportion that were valine homozygous comparedwith the frequency in the normal population, and in stark contrast with confirmed clinical cases of vCJD,all of which were methionine homozygous at PRNP codon 129. CONCLUSIONS This study corroboratesprevious studies and suggests a high prevalence of infection with abnormal PrP, indicating vCJD carrierstatus in the population compared with the 177 vCJD cases to date. These findings have importantimplications for the management of blood and blood products and for the handling of surgicalinstruments.", "metadata": {}}
+{"_id": "13757347", "title": "", "text": "Involvement of cortical fast-spiking parvalbumin-positive basket cells in epilepsy.GABAergic interneuronsof the parvalbumin-positive fast-spiking basket cells subtype (PV INs) are important regulators of corticalnetwork excitability and of gamma oscillations, involved in signal processing and cognition. Impaireddevelopment or function of PV INs has been associated with epilepsy in various animal models ofepilepsy, as well as in some genetic forms of epilepsy in humans. In this review, we provide an overviewof some of the experimental data linking PV INs dysfunction with epilepsy, focusing on disorders of thespecification, migration, maturation, synaptic function, or connectivity of PV INs. Furthermore, we reflecton the potential therapeutic use of cell-type specific stimulation of PV INs within active networks and onthe transplantation of PV INs precursors in the treatment of epilepsy and its comorbidities.", "metadata": {}}
+{"_id": "13759726", "title": "", "text": "Dynamic Gene Regulatory Networks of Human Myeloid Differentiation.The reconstruction of generegulatory networks underlying cell differentiation from high-throughput gene expression and chromatindata remains a challenge. Here, we derive dynamic gene regulatory networks for human myeloiddifferentiation using a 5-day time series of RNA-seq and ATAC-seq data. We profile HL-60 promyelocytesdifferentiating into macrophages, neutrophils, monocytes, and monocyte-derived macrophages. We find arapid response in the expression of key transcription factors and lineage markers that only regulate asubset of their targets at a given time, which is followed by chromatin accessibility changes that occurlater along with further gene expression changes. We observe differences between promyelocyte- andmonocyte-derived macrophages at both the transcriptional and chromatin landscape level, despite usingthe same differentiation stimulus, which suggest that the path taken by cells in the differentiationlandscape defines their end cell state. More generally, our approach of combining neighboring time pointsand replicates to achieve greater sequencing depth can efficiently infer footprint-based regulatorynetworks from long series data.", "metadata": {}}
+{"_id": "13760557", "title": "", "text": "Canonical transient receptor potential 5 channel in conjunction with Orai1 and STIM1 allows Sr2+ entry,optimal influx of Ca2+, and degranulation in a rat mast cell line.Degranulation of mast cells in responseto Ag or the calcium mobilizing agent, thapsigargin, is dependent on emptying of intracellular stores ofCa(2+) and the ensuing influx of external Ca(2+), also referred to as store-operated calcium entry.However, it is unlikely that the calcium release-activated calcium channel is the sole mechanism for theentry of Ca(2+) because Sr(2+) and other divalent cations also permeate and support degranulation instimulated mast cells. In this study we show that influx of Ca(2+) and Sr(2+) as well as degranulationare dependent on the presence of the canonical transient receptor potential (TRPC) channel proteinTRPC5, in addition to STIM1 and Orai1, as demonstrated by knock down of each of these proteins byinhibitory RNAs in a rat mast cell (RBL-2H3) line. Overexpression of STIM1 and Orai1, which are known tobe essential components of calcium release-activated calcium channel, allows entry of Ca(2+) but notSr(2+), whereas overexpression of STIM1 and TRPC5 allows entry of both Ca(2+) and Sr(2+). These andother observations suggest that the Sr(2+)-permeable TRPC5 associates with STIM1 and Orai1 in astoichiometric manner to enhance entry of Ca(2+) to generate a signal for degranulation.", "metadata": {}}
+{"_id": "13763195", "title": "", "text": "LincRNA-p21 suppresses target mRNA translation.Mammalian long intergenic noncoding RNAs (lincRNAs)are best known for modulating transcription. Here we report a posttranscriptional function forlincRNA-p21 as a modulator of translation. Association of the RNA-binding protein HuR with lincRNA-p21favored the recruitment of let-7/Ago2 to lincRNA-p21, leading to lower lincRNA-p21 stability. Underreduced HuR levels, lincRNA-p21 accumulated in human cervical carcinoma HeLa cells, increasing itsassociation with JUNB and CTNNB1 mRNAs and selectively lowering their translation. With elevated HuR,lincRNA-p21 levels declined, which in turn derepressed JunB and β-catenin translation and increased thelevels of these proteins. We propose that HuR controls translation of a subset of target mRNAs byinfluencing lincRNA-p21 levels. Our findings uncover a role for lincRNA as a posttranscriptional inhibitor oftranslation.", "metadata": {}}
+{"_id": "13764090", "title": "", "text": "Large intestine-targeted nanoparticle-releasing oral vaccine to control genitorectal viral infectionBothrectal and vaginal mucosal surfaces serve as transmission routes for pathogenic microorganisms.Vaccination through large intestinal mucosa, previously proven protective for both of these mucosal sitesin animal studies, can be achieved successfully by direct intracolorectal (i.c.r.) administration, but thisroute is clinically impractical. Oral vaccine delivery seems preferable but runs the risk of the vaccine'sdestruction in the upper gastrointestinal tract. Therefore, we designed a large intestine-targeted oraldelivery with pH-dependent microparticles containing vaccine nanoparticles, which induced colorectalimmunity in mice comparably to colorectal vaccination and protected against rectal and vaginal viralchallenge. Conversely, vaccine targeted to the small intestine induced only small intestinal immunity andprovided no rectal or vaginal protection, demonstrating functional compartmentalization within the gutmucosal immune system. Therefore, using this oral vaccine delivery system to target the large intestine,but not the small intestine, may represent a feasible new strategy for immune protection of rectal andvaginal mucosa.", "metadata": {}}
+{"_id": "13765757", "title": "", "text": "Timing of menarche and first full-term birth in relation to breast cancer risk.Ages at menarche and firstbirth are established risk factors for breast cancer. The interval between these ages may also affect risk,since the breast is more susceptible to carcinogenic insults during this period than during the parousperiod. However, few investigators have studied this relation. Using logistic regression, the authorsevaluated associations between the timing of reproductive events and breast cancer risk among 4,013cases and 4,069 controls enrolled in a multicenter, population-based US case-control study of White andAfrican-American women (1994-1998). For White, parous premenopausal and postmenopausal women,those who had an interval of > or =16 years between the ages of menarche and first birth had 1.5-fold(95% confidence interval (CI): 1.0, 2.2) and 1.4-fold (95% CI: 1.1, 1.8) increased risks of breast cancer,respectively, in comparison with those who had < or =5 years between these ages. Adjusting for age atfirst birth altered these risk estimates somewhat, to odds ratios of 1.5 (95% CI: 0.8, 2.9) and 1.0 (95%CI: 0.6, 1.5), respectively. These associations were stronger for lobular and hormone-receptor-positivetumors but were absent among premenopausal African-American women. The authors conclude that theinterval between age at menarche and age at first birth is associated with the risk of hormonally sensitivetypes of breast cancer, particularly among White women.", "metadata": {}}
+{"_id": "13768432", "title": "", "text": "Prognostic Value of Late Gadolinium Enhancement Cardiovascular Magnetic Resonance in CardiacAmyloidosisBACKGROUND The prognosis and treatment of the 2 main types of cardiac amyloidosis,immunoglobulin light chain (AL) and transthyretin (ATTR) amyloidosis, are substantially influenced bycardiac involvement. Cardiovascular magnetic resonance with late gadolinium enhancement (LGE) is areference standard for the diagnosis of cardiac amyloidosis, but its potential for stratifying risk isunknown. METHODS AND RESULTS Two hundred fifty prospectively recruited subjects, 122 patients withATTR amyloid, 9 asymptomatic mutation carriers, and 119 patients with AL amyloidosis, underwent LGEcardiovascular magnetic resonance. Subjects were followed up for a mean of 24±13 months. LGE wasperformed with phase-sensitive inversion recovery (PSIR) and without (magnitude only). These werecompared with extracellular volume measured with T1 mapping. PSIR was superior to magnitude-onlyinversion recovery LGE because PSIR always nulled the tissue (blood or myocardium) with the longest T1(least gadolinium). LGE was classified into 3 patterns: none, subendocardial, and transmural, which wereassociated with increasing amyloid burden as defined by extracellular volume (P<0.0001), withtransitions from none to subendocardial LGE at an extracellular volume of 0.40 to 0.43 (AL) and 0.39 to0.40 (ATTR) and to transmural at 0.48 to 0.55 (AL) and 0.47 to 0.59 (ATTR). Sixty-seven patients (27%)died. Transmural LGE predicted death (hazard ratio, 5.4; 95% confidence interval, 2.1-13.7; P<0.0001)and remained independent after adjustment for N-terminal pro-brain natriuretic peptide, ejectionfraction, stroke volume index, E/E', and left ventricular mass index (hazard ratio, 4.1; 95% confidenceinterval, 1.3-13.1; P<0.05). CONCLUSIONS There is a continuum of cardiac involvement in systemic ALand ATTR amyloidosis. Transmural LGE is determined reliably by PSIR and represents advanced cardiacamyloidosis. The PSIR technique provides incremental information on outcome even after adjustment forknown prognostic factors.", "metadata": {}}
+{"_id": "13770184", "title": "", "text": "Global, regional, and national comparative risk assessment of 79 behavioural, environmental andoccupational, and metabolic risks or clusters of risks, 1990–2015: a systematic analysis for the GlobalBurden of Disease Study 2015BACKGROUND The Global Burden of Diseases, Injuries, and Risk FactorsStudy 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributableburden of disease. By providing national and subnational assessments spanning the past 25 years, thisstudy can inform debates on the importance of addressing risks in context. METHODS We used thecomparative risk assessment framework developed for previous iterations of the Global Burden of DiseaseStudy to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure byage group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolicrisks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met WorldCancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk andexposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys,census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias,and incorporate covariates. We developed a metric that allows comparisons of exposure across riskfactors-the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level,we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposedtrends in attributable burden into contributions from population growth, population age structure, riskexposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to aSocio-demographic Index (SDI). FINDINGS Between 1990 and 2015, global exposure to unsafesanitation, household air pollution, childhood underweight, childhood stunting, and smoking eachdecreased by more than 25%. Global exposure for several occupational risks, high body-mass index(BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in2015 accounted for 57·8% (95% CI 56·6-58·8) of global deaths and 41·2% (39·8-42·8) of DALYs. In2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure(211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI(120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high totalcholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high insodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined formicronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household airpollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines.Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasmaglucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutritiondeclined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increasedwith SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed themost attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors forattributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers ofearly death and disability in much of sub-Saharan Africa. INTERPRETATION Declines in some keyenvironmental risks have contributed to declines in critical infectious diseases. Some risks appear to beinvariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and someoccupational exposures, contribute to rising burden from some conditions, but also provide opportunitiesfor intervention. Some highly preventable risks, such as smoking, remain major causes of attributableDALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that areincreasingly major contributors to global burden. FUNDING Bill & Melinda Gates Foundation.", "metadata": {}}
+{"_id": "13771184", "title": "", "text": "Human RecQ helicases in DNA repair, recombination, and replication.RecQ helicases are an importantfamily of genome surveillance proteins conserved from bacteria to humans. Each of the five human RecQhelicases plays critical roles in genome maintenance and stability, and the RecQ protein family membersare often referred to as guardians of the genome. The importance of these proteins in cellularhomeostasis is underscored by the fact that defects in BLM, WRN, and RECQL4 are linked to distinctheritable human disease syndromes. Each human RecQ helicase has a unique set of protein-interactingpartners, and these interactions dictate its specialized functions in genome maintenance, including DNArepair, recombination, replication, and transcription. Human RecQ helicases also interact with each other,and these interactions have significant impact on enzyme function. Future research goals in this fieldinclude a better understanding of the division of labor among the human RecQ helicases and learning howhuman RecQ helicases collaborate and cooperate to enhance genome stability.", "metadata": {}}
+{"_id": "13774178", "title": "", "text": "Metabolomics study of the therapeutic mechanism of Schisandra Chinensis lignans in diet-inducedhyperlipidemia miceBACKGROUND Schisandra, a globally distributed plant, has been widely applied forthe treatment of diseases such as hyperlipidemia, fatty liver and obesity in China. In the present work, arapid resolution liquid chromatography coupled with quadruple-time-of-flight mass spectrometry(RRLC-Q-TOF-MS)-based metabolomics was conducted to investigate the intervention effect ofSchisandra chinensis lignans (SCL) on hyperlipidemia mice induced by high-fat diet (HFD). METHODSHyperlipidemia mice were orally administered with SCL (100 mg/kg) once a day for 4 weeks. Serumbiochemistry assay of triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c)and high-density lipoprotein cholesterol (HDL-c) was conducted to confirm the treatment of SCL on lipidregulation. Metabolomics analysis on serum samples was carried out, and principal component analysis(PCA) and partial least squares-discriminant analysis (PLS-DA) were carried out for the patternrecognition and characteristic metabolites identification. The relative levels of critical regulatory factors ofliver lipid metabolism, sterol regulatory element-binding proteins (SREBPs) and its related geneexpressions were measured by quantitative real-time polymerase chain reaction (RT-PCR) forinvestigating the underlying mechanism. RESULTS Oral administration of SCL significantly decreased theserum levels of TC, TG and LDL-c and increased the serum level of HDL-c in the hyperlipidemia mice, andno effect of SCL on blood lipid levels was observed in control mice. Serum samples were scattered in thePCA scores plots in response to the control, HFD and SCL group. Totally, thirteen biomarkers wereidentified and nine of them were recovered to the normal levels after SCL treatment. Based on the KyotoEncyclopedia of Genes and Genomes (KEGG) pathways analysis, the anti-hyperlipidemia mechanisms ofSCL may be involved in the following metabolic pathways: tricarboxylic acid (TCA) cycle, synthesis ofketone body and cholesterol, choline metabolism and fatty acid metabolism. Meanwhile, SCL significantlyinhibited the mRNA expression level of hepatic lipogenesis genes such as SREBP-1c, fatty acid synthase(FAS) and acetyl-CoA carboxylase (ACC), and decreased the mRNA expression of liver X receptor α(LXRα). Moreover, SCL also significantly decreased the expression level of SREBP-2 and3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) in the liver of hyperlipidemia mice.CONCLUSION Anti-hyperlipidemia effect of SCL was confirmed by both serum biochemistry andmetabolomics analysis. The mechanism may be related to the down-regulation ofLXRα/SREBP-1c/FAS/ACC and SREBP2/HMGCR signaling pathways.", "metadata": {}}
+{"_id": "13777138", "title": "", "text": "Tet1 and Tet2 regulate 5-hydroxymethylcytosine production and cell lineage specification in mouseembryonic stem cells.TET family enzymes convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine(5hmC) in DNA. Here, we show that Tet1 and Tet2 are Oct4-regulated enzymes that together sustain5hmC in mouse embryonic stem cells (ESCs) and are induced concomitantly with 5hmC duringreprogramming of fibroblasts to induced pluripotent stem cells. ESCs depleted of Tet1 by RNAi showdiminished expression of the Nodal antagonist Lefty1 and display hyperactive Nodal signaling and skeweddifferentiation into the endoderm-mesoderm lineage in embryoid bodies in vitro. In Fgf4- andheparin-supplemented culture conditions, Tet1-depleted ESCs activate the trophoblast stem cell lineagedeterminant Elf5 and can colonize the placenta in midgestation embryo chimeras. Consistent with thesefindings, Tet1-depleted ESCs form aggressive hemorrhagic teratomas with increased endoderm, reducedneuroectoderm, and ectopic appearance of trophoblastic giant cells. Thus, 5hmC is an epigeneticmodification associated with the pluripotent state, and Tet1 functions to regulate the lineagedifferentiation potential of ESCs.", "metadata": {}}
+{"_id": "13777706", "title": "", "text": "Polycomb Associates Genome-wide with a Specific RNA Polymerase II Variant, and Regulates MetabolicGenes in ESCsPolycomb repressor complexes (PRCs) are important chromatin modifiers fundamentallyimplicated in pluripotency and cancer. Polycomb silencing in embryonic stem cells (ESCs) can beaccompanied by active chromatin and primed RNA polymerase II (RNAPII), but the relationship betweenPRCs and RNAPII remains unclear genome-wide. We mapped PRC repression markers and four RNAPIIstates in ESCs using ChIP-seq, and found that PRC targets exhibit a range of RNAPII variants. First,developmental PRC targets are bound by unproductive RNAPII (S5p(+)S7p(-)S2p(-)) genome-wide.Sequential ChIP, Ring1B depletion, and genome-wide correlations show that PRCs and RNAPII-S5pphysically bind to the same chromatin and functionally synergize. Second, we identify a cohort of genesmarked by PRC and elongating RNAPII (S5p(+)S7p(+)S2p(+)); they produce mRNA and protein, andtheir expression increases upon PRC1 knockdown. We show that this group of PRC targets switchesbetween active and PRC-repressed states within the ESC population, and that many have roles inmetabolism.", "metadata": {}}
+{"_id": "13778710", "title": "", "text": "Chemokine-like receptor 1 (CMKLR1) and chemokine (C-C motif) receptor-like 2 (CCRL2); twomultifunctional receptors with unusual properties.Chemokine-like receptor 1 (CMKLR1), also known asChemR23, and chemokine (C-C motif) receptor-like 2 (CCRL2) are 7-transmembrane receptors that werecloned in the late 1990s based on their homology to known G-protein-coupled receptors. They werepreviously orphan receptors without any known biological roles; however, recent studies identifiedligands for these receptors and their functions have begun to be unveiled. The plasma protein-derivedchemoattractant chemerin is a ligand for CMKLR1 and activation of CMKLR1 with chemerin induces themigration of macrophages and dendritic cells (DCs) in vitro, suggesting a proinflammatory role. However,in vivo studies using CMKLR-deficient mice suggest an anti-inflammatory role for this receptor, possiblydue to the recruitment of tolerogenic plasmacytoid DCs. Chemerin/CMKLR1 interaction also promotesadipogenesis and angiogenesis. The anti-inflammatory lipid mediator, resolving E1, is another CMKLR1ligand and it inhibits leukocyte infiltration and proinflammatory gene expression. These divergent resultssuggest that CMKLR1 is a multifunctional receptor. The chemokine CCL5 and CCL19 are reported to bindto CCRL2. Like Duffy antigen for chemokine receptor (DARC), D6 and CCX-CKR, CCRL2 does not signal,but it constitutively recycles, potentially reducing local concentration of CCL5 and CCL19 and subsequentimmune responses. Surprisingly, chemerin, a ligand for CMKLR1, is a ligand for CCRL2. CCRL2 bindschemerin and increases local chemerin concentration to efficiently present it to CMKLR1 on nearby cells,providing a link between CCRL2 and CMKLR1. Although these findings suggest an anti-inflammatory role,a recent study using CCRL2-deficient mice indicates a proinflammatory role; thus, CCRL2 may also bemultifunctional. Further studies using CMKLR1- or CCRL2-deficient mice are needed to further define therole of these receptors in immune responses and other cellular processes.", "metadata": {}}
+{"_id": "13779605", "title": "", "text": "Identification of vitronectin as an extrinsic inducer of cancer stem cell differentiation and tumorformation.There is mounting evidence that tumors are initiated by a rare subset of cells called cancerstem cells (CSCs). CSCs are generally quiescent, self-renew, form tumors at low numbers, and give riseto the heterogeneous cell types found within a tumor. CSCs isolated from multiple tumor typesdifferentiate both in vivo and in vitro when cultured in serum, yet the factors responsible for theirdifferentiation have not yet been identified. Here we show that vitronectin is the component of humanserum driving stem cell differentiation through an integrin alpha V beta 3-dependent mechanism. CSCscultured on vitronectin result in downregulation of stem cell genes, modulation of differentiation markers,and loss of beta-catenin nuclear localization. Blocking integrin alpha V beta 3 inhibits differentiation andsubsequently tumor formation. Thus, CSCs must be engaged by one or more extracellular signals todifferentiate and initiate tumor formation, defining a new axis for future novel therapies aimed at boththe extrinsic and intracellular pathways.", "metadata": {}}
+{"_id": "13780287", "title": "", "text": "STIM1 Is a Calcium Sensor Specialized for Digital SignalingWhen cells are activated by calcium-mobilizingagonists at low, physiological concentrations, the resulting calcium signals generally take the form ofrepetitive regenerative discharges of stored calcium, termed calcium oscillations [1]. These intracellularcalcium oscillations have long fascinated biologists as a mode of digitized intracellular signaling. Recentwork has highlighted the role of calcium influx as an essential component of calcium oscillations [2]. Thisinflux occurs through a process known as store-operated calcium entry, which is initiated by calciumsensor proteins, STIM1 and STIM2, in the endoplasmic reticulum [3]. STIM2 is activated by changes inendoplasmic reticulum calcium near the resting level, whereas a threshold of calcium depletion isrequired for STIM1 activation [4]. Here we show that, surprisingly, it is STIM1 and not STIM2 that isexclusively involved in calcium entry during calcium oscillations. The implication is that each oscillationproduces a transient drop in endoplasmic reticulum calcium and that this drop is sufficient to transientlyactivate STIM1. This transient activation of STIM1 can be observed in some cells by total internalreflection fluorescence microscopy. This arrangement nicely provides a clearly defined and unambiguoussignaling system, translating a digital calcium release signal into calcium influx that can signal todownstream effectors.", "metadata": {}}
+{"_id": "13782317", "title": "", "text": "Trends in the use of complementary health approaches among adults: United States,2002-2012.OBJECTIVE This report presents national estimates of the use of complementary healthapproaches among adults in the United States across three time points. Trends in the use of selectedcomplementary health approaches are compared for 2002, 2007, and 2012, and differences by selecteddemographic characteristics are also examined. METHODS Combined data from 88,962 adults aged 18and over collected as part of the 2002, 2007, and 2012 National Health Interview Survey were analyzedfor this report. Sample data were weighted to produce national estimates that are representative of thecivilian noninstitutionalized U.S. adult population. Differences between percentages were evaluated usingtwo-sided significance tests at the 0.05 level. RESULTS Although the use of individual approaches variedacross the three time points, nonvitamin, nonmineral dietary supplements remained the most popularcomplementary health approach used. The use of yoga, tai chi, and qi gong increased linearly across thethree time points; among these three approaches, yoga accounted for approximately 80% of theprevalence. The use of any complementary health approach also differed by selected sociodemographiccharacteristics. The most notable observed differences in use were by age and Hispanic or Latino originand race.", "metadata": {}}
+{"_id": "13790144", "title": "", "text": "Histone structure and nucleosome stability.Histone proteins play essential structural and functional rolesin the transition between active and inactive chromatin states. Although histones have a high degree ofconservation due to constraints to maintain the overall structure of the nucleosomal octameric core,variants have evolved to assume diverse roles in gene regulation and epigenetic silencing. Histonevariants, post-translational modifications and interactions with chromatin remodeling complexes influenceDNA replication, transcription, repair and recombination. The authors review recent findings on thestructure of chromatin that confirm previous interparticle interactions observed in crystal structures.", "metadata": {}}
+{"_id": "13791044", "title": "", "text": "Cerebral palsy among term and postterm births.CONTEXT Although preterm delivery is a well-establishedrisk factor for cerebral palsy (CP), preterm deliveries contribute only a minority of affected infants. Thereis little information on the relation of CP risk to gestational age in the term range, where most CP occurs.OBJECTIVE To determine whether timing of birth in the term and postterm period is associated with riskof CP. DESIGN, SETTING, AND PARTICIPANTS Population-based follow-up study using the Medical BirthRegistry of Norway to identify 1,682,441 singleton children born in the years 1967-2001 with agestational age of 37 through 44 weeks and no congenital anomalies. The cohort was followed up through2005 by linkage to other national registries. MAIN OUTCOME MEASURES Absolute and relative risk of CPfor children surviving to at least 4 years of age. RESULTS Of the cohort of term and postterm children,1938 were registered with CP in the National Insurance Scheme. Infants born at 40 weeks had the lowestrisk of CP, with a prevalence of 0.99/1000 (95% confidence interval [CI], 0.90-1.08). Risk for CP washigher with earlier or later delivery, with a prevalence at 37 weeks of 1.91/1000 (95% CI, 1.58-2.25) anda relative risk (RR) of 1.9 (95% CI, 1.6-2.4), a prevalence at 38 weeks of 1.25/1000 (95% CI, 1.07-1.42)and an RR of 1.3 (95% CI, 1.1-1.6), a prevalence at 42 weeks of 1.36/1000 (95% CI, 1.19-1.53) and anRR of 1.4 (95% CI, 1.2-1.6), and a prevalence after 42 weeks of 1.44 (95% CI, 1.15-1.72) and an RR of1.4 (95% CI, 1.1-1.8). These associations were even stronger in a subset with gestational age based onultrasound measurements: at 37 weeks the prevalence was 1.17/1000 (95% CI, 0.30-2.04) and therelative risk was 3.7 (95% CI, 1.5-9.1). At 42 weeks the prevalence was 0.85/1000 (95% CI, 0.33-1.38)and the relative risk was 2.4 (95% CI, 1.1-5.3). Adjustment for infant sex, maternal age, and varioussocioeconomic measures had little effect. CONCLUSION Compared with delivery at 40 weeks' gestation,delivery at 37 or 38 weeks or at 42 weeks or later was associated with an increased risk of CP.", "metadata": {}}
+{"_id": "13791206", "title": "", "text": "53BP1 Inhibits Homologous Recombination in Brca1-Deficient Cells by Blocking Resection of DNABreaksDefective DNA repair by homologous recombination (HR) is thought to be a major contributor totumorigenesis in individuals carrying Brca1 mutations. Here, we show that DNA breaks in Brca1-deficientcells are aberrantly joined into complex chromosome rearrangements by a process dependent on thenonhomologous end-joining (NHEJ) factors 53BP1 and DNA ligase 4. Loss of 53BP1 alleviateshypersensitivity of Brca1 mutant cells to PARP inhibition and restores error-free repair by HR.Mechanistically, 53BP1 deletion promotes ATM-dependent processing of broken DNA ends to producerecombinogenic single-stranded DNA competent for HR. In contrast, Lig4 deficiency does not rescue theHR defect in Brca1 mutant cells but prevents the joining of chromatid breaks into chromosomerearrangements. Our results illustrate that HR and NHEJ compete to process DNA breaks that arise duringDNA replication and that shifting the balance between these pathways can be exploited to selectivelyprotect or kill cells harboring Brca1 mutations.", "metadata": {}}
+{"_id": "13791788", "title": "", "text": "The genetics of Mexico recapitulates Native American substructure and affects biomedical traitsMexicoharbors great cultural and ethnic diversity, yet fine-scale patterns of human genome-wide variation fromthis region remain largely uncharacterized. We studied genomic variation within Mexico from over 1000individuals representing 20 indigenous and 11 mestizo populations. We found striking geneticstratification among indigenous populations within Mexico at varying degrees of geographic isolation.Some groups were as differentiated as Europeans are from East Asians. Pre-Columbian geneticsubstructure is recapitulated in the indigenous ancestry of admixed mestizo individuals across thecountry. Furthermore, two independently phenotyped cohorts of Mexicans and Mexican Americansshowed a significant association between subcontinental ancestry and lung function. Thus, accounting forfine-scale ancestry patterns is critical for medical and population genetic studies within Mexico, inMexican-descent populations, and likely in many other populations worldwide.", "metadata": {}}
+{"_id": "13794374", "title": "", "text": "COPI Complex Is a Regulator of Lipid HomeostasisLipid droplets are ubiquitous triglyceride and sterolester storage organelles required for energy storage homeostasis and biosynthesis. Although little isknown about lipid droplet formation and regulation, it is clear that members of the PAT (perilipin,adipocyte differentiation related protein, tail interacting protein of 47 kDa) protein family coat the dropletsurface and mediate interactions with lipases that remobilize the stored lipids. We identified keyDrosophila candidate genes for lipid droplet regulation by RNA interference (RNAi) screening with animage segmentation-based optical read-out system, and show that these regulatory functions areconserved in the mouse. Those include the vesicle-mediated Coat Protein Complex I (COPI) transportcomplex, which is required for limiting lipid storage. We found that COPI components regulate the PATprotein composition at the lipid droplet surface, and promote the association of adipocyte triglyceridelipase (ATGL) with the lipid droplet surface to mediate lipolysis. Two compounds known to inhibit COPIfunction, Exo1 and Brefeldin A, phenocopy COPI knockdowns. Furthermore, RNAi inhibition of ATGL andsimultaneous drug treatment indicate that COPI and ATGL function in the same pathway. These dataindicate that the COPI complex is an evolutionarily conserved regulator of lipid homeostasis, and highlightan interaction between vesicle transport systems and lipid droplets.", "metadata": {}}
+{"_id": "13798951", "title": "", "text": "Differentiation of effector CD4 T cell populations (*).CD4 T cells play critical roles in mediating adaptiveimmunity to a variety of pathogens. They are also involved in autoimmunity, asthma, and allergicresponses as well as in tumor immunity. During TCR activation in a particular cytokine milieu, naive CD4T cells may differentiate into one of several lineages of T helper (Th) cells, including Th1, Th2, Th17, andiTreg, as defined by their pattern of cytokine production and function. In this review, we summarize thediscovery, functions, and relationships among Th cells; the cytokine and signaling requirements for theirdevelopment; the networks of transcription factors involved in their differentiation; the epigeneticregulation of their key cytokines and transcription factors; and human diseases involving defective CD4 Tcell differentiation.", "metadata": {}}
+{"_id": "13801259", "title": "", "text": "Homocysteine and other thiols in plasma and urine: automated determination and sample stability.Wehave developed a modified version of our fully automated column-switching HPLC method for determiningtotal plasma homocysteine based on single-column (reversed-phase) separation. Homocysteine, cysteine,and cysteinylglycine in plasma (total concentrations), acid-precipitated plasma (non-protein-boundconcentrations), and urine can be determined. The derivatization and chromatography were performedautomatically by a sample processor. The successful separation of all thiol species (within 15 min) wasaccomplished by accurate adjustment of the pH of the mobile phase to 3.65 (plasma) or 3.50(acid-precipitated plasma, urine). Maximal fluorescence yield of cysteine, cysteinylglycine, and, to alesser degree, homocysteine was dependent on optimal concentrations of EDTA and dithioerythritolduring reduction (with NaBH4) and derivatization (with monobromobimane). The method is sensitive(detection limit approximately 0.05 pmol) and has a high degree of precision (CV < 5%). The sampleoutput is approximately 70 samples in 24 h. Serum and heparin plasma can also be analyzed. Hemolysisup to approximately 2.0 g/L of hemoglobin did not interfere with the analytical recovery of homocysteineor cysteine. Collection of blood, separation of plasma from whole blood, and acid precipitation must bestandardized to obtain reproducible thiol results. Our modifications and the standardization ofblood-sampling procedures have substantially improved the method and broadened its applications.", "metadata": {}}
+{"_id": "13814480", "title": "", "text": "Induced pluripotent stem cells in Alzheimer’s disease: applications for disease modeling andcell-replacement therapyAlzheimer's disease (AD) is the most common cause of dementia in those overthe age of 65. While a numerous of disease-causing genes and risk factors have been identified, the exactetiological mechanisms of AD are not yet completely understood, due to the inability to test theoreticalhypotheses on non-postmortem and patient-specific research systems. The use of recently developed andoptimized induced pluripotent stem cells (iPSCs) technology may provide a promising platform to createreliable models, not only for better understanding the etiopathological process of AD, but also for efficientanti-AD drugs screening. More importantly, human-sourced iPSCs may also provide a beneficial tool forcell-replacement therapy against AD. Although considerable progress has been achieved, a number ofkey challenges still require to be addressed in iPSCs research, including the identification of robustdisease phenotypes in AD modeling and the clinical availabilities of iPSCs-based cell-replacement therapyin human. In this review, we highlight recent progresses of iPSCs research and discuss the translationalchallenges of AD patients-derived iPSCs in disease modeling and cell-replacement therapy.", "metadata": {}}
+{"_id": "13823200", "title": "", "text": "Nitrite protects against morbidity and mortality associated with TNF- or LPS-induced shock in a solubleguanylate cyclase–dependent mannerNitrite (NO(2)(-)), previously viewed as a physiologically inertmetabolite and biomarker of the endogenous vasodilator NO, was recently identified as an importantbiological NO reservoir in vasculature and tissues, where it contributes to hypoxic signaling, vasodilation,and cytoprotection after ischemia-reperfusion injury. Reduction of nitrite to NO may occur enzymaticallyat low pH and oxygen tension by deoxyhemoglobin, deoxymyoglobin, xanthine oxidase, mitochondrialcomplexes, or NO synthase (NOS). We show that nitrite treatment, in sharp contrast with the worseningeffect of NOS inhibition, significantly attenuates hypothermia, mitochondrial damage, oxidative stress anddysfunction, tissue infarction, and mortality in a mouse shock model induced by a lethal tumor necrosisfactor challenge. Mechanistically, nitrite-dependent protection was not associated with inhibition ofmitochondrial complex I activity, as previously demonstrated for ischemia-reperfusion, but was largelyabolished in mice deficient for the soluble guanylate cyclase (sGC) alpha1 subunit, one of the principalintracellular NO receptors and signal transducers in the cardiovasculature. Nitrite could also provideprotection against toxicity induced by Gram-negative lipopolysaccharide, although higher doses wererequired. In conclusion, we show that nitrite can protect against toxicity in shock via sGC-dependentsignaling, which may include hypoxic vasodilation necessary to maintain microcirculation and organfunction, and cardioprotection.", "metadata": {}}
+{"_id": "13831558", "title": "", "text": "Mammographic density and the risk and detection of breast cancer.BACKGROUND Extensivemammographic density is associated with an increased risk of breast cancer and makes the detection ofcancer by mammography difficult, but the influence of density on risk according to method of cancerdetection is unknown. METHODS We carried out three nested case-control studies in screenedpopulations with 1112 matched case-control pairs. We examined the association of the measuredpercentage of density in the baseline mammogram with risk of breast cancer, according to method ofcancer detection, time since the initiation of screening, and age. RESULTS As compared with women withdensity in less than 10% of the mammogram, women with density in 75% or more had an increased riskof breast cancer (odds ratio, 4.7; 95% confidence interval [CI], 3.0 to 7.4), whether detected byscreening (odds ratio, 3.5; 95% CI, 2.0 to 6.2) or less than 12 months after a negative screeningexamination (odds ratio, 17.8; 95% CI, 4.8 to 65.9). Increased risk of breast cancer, whether detectedby screening or other means, persisted for at least 8 years after study entry and was greater in youngerthan in older women. For women younger than the median age of 56 years, 26% of all breast cancersand 50% of cancers detected less than 12 months after a negative screening test were attributable todensity in 50% or more of the mammogram. CONCLUSIONS Extensive mammographic density is stronglyassociated with the risk of breast cancer detected by screening or between screening tests. A substantialfraction of breast cancers can be attributed to this risk factor.", "metadata": {}}
+{"_id": "13831842", "title": "", "text": "Pooled analysis of prospective cohort studies on height, weight, and breast cancer risk.The associationbetween anthropometric indices and the risk of breast cancer was analyzed using pooled data from sevenprospective cohort studies. Together, these cohorts comprise 337,819 women and 4,385 incidentinvasive breast cancer cases. In multivariate analyses controlling for reproductive, dietary, and other riskfactors, the pooled relative risk (RR) of breast cancer per height increment of 5 cm was 1.02 (95%confidence interval (CI): 0.96, 1.10) in premenopausal women and 1.07 (95% CI: 1.03, 1.12) inpostmenopausal women. Body mass index (BMI) showed significant inverse and positive associationswith breast cancer among pre- and postmenopausal women, respectively; these associations werenonlinear. Compared with premenopausal women with a BMI of less than 21 kg/m2, women with a BMIexceeding 31 kg/m2 had an RR of 0.54 (95% CI: 0.34, 0.85). In postmenopausal women, the RRs didnot increase further when BMI exceeded 28 kg/m2; the RR for these women was 1.26 (95% CI: 1.09,1.46). The authors found little evidence for interaction with other breast cancer risk factors. Their dataindicate that height is an independent risk factor for postmenopausal breast cancer; in premenopausalwomen, this relation is less clear. The association between BMI and breast cancer varies by menopausalstatus. Weight control may reduce the risk among postmenopausal women.", "metadata": {}}
+{"_id": "13843341", "title": "", "text": "Cost effectiveness of ward based non-invasive ventilation for acute exacerbations of chronic obstructivepulmonary disease: economic analysis of randomised controlled trial.OBJECTIVE To evaluate the costeffectiveness of standard treatment with and without the addition of ward based non-invasive ventilationin patients admitted to hospital with an acute exacerbation of chronic obstructive pulmonary disease.DESIGN Incremental cost effectiveness analysis of a randomised controlled trial. SETTING Medical wardsin 14 hospitals in the United Kingdom. PARTICIPANTS The trial comprised 236 patients admitted tohospital with an acute exacerbation of chronic obstructive pulmonary disease and mild to moderateacidosis (pH 7.25-7.35) secondary to respiratory failure. The economic analysis compared the costs oftreatment that these patients received after randomisation. MAIN OUTCOME MEASURE Incremental costper in-hospital death. RESULTS 24/118 died in the group receiving standard treatment and 12/118 in thegroup receiving non-invasive ventilation (P=0.05). Allocation to the group receiving non-invasiveventilation was associated with a reduction in costs of 49362 pounds sterling (78741 dollars; 73109euros), mainly through reduced use of intensive care units. The incremental cost effectiveness ratio was-645 pounds sterling per death avoided (95% confidence interval -2310 pounds sterling to 386 poundssterling), indicating a dominant (more effective and less costly) strategy. Modelling of these dataindicates that a typical UK hospital providing a non-invasive ventilation service will avoid six deaths andthree to nine admissions to intensive care units per year, with an associated cost reduction of12000-53000 pounds sterling per year. CONCLUSIONS Non-invasive ventilation is a highly cost effectivetreatment that both reduced total costs and improved mortality in hospital.", "metadata": {}}
+{"_id": "13857083", "title": "", "text": "Persistent human papillomavirus infection and cervical neoplasia: a systematic review andmeta-analysis.Detection of persistent cervical carcinogenic human papillomavirus (HPV) DNA is used as amarker for cervical cancer risk in clinical trials. The authors performed a systematic review andmeta-analysis of the association between persistent HPV DNA and high-grade cervical intraepithelialneoplasia (CIN2-3), high-grade squamous intraepithelial lesions (HSIL), and invasive cervical cancer(together designated CIN2-3/HSIL+) to evaluate the robustness of HPV persistence for clinical use.MEDLINE and Current Contents were searched through January 30, 2006. Relative risks (RRs) werestratified by HPV comparison group. Of 2,035 abstracts, 41 studies were eligible for inclusion in themeta-analysis. Over 22,500 women were included in calculation of RRs for persistent HPV DNA detectionand cervical neoplasia. RRs ranged from 1.3 (95% confidence interval: 1.1, 1.5) to 813.0 (95%confidence interval: 168.2, 3,229.2) for CIN2-3/HSIL+ versus 12 months), wider testing intervals,CIN2-3/HSIL+, and use of an HPV-negative reference group were consistently associated with higherRRs. Thus, HPV persistence was consistently and strongly associated with CIN2-3/HSIL+, despite widevariation in definitions and study methods. The magnitude of association varied by duration ofpersistence and testing interval. Precise definition and standardization of HPV testing, samplingprocedure, and test interval are needed for reliable clinical testing. These findings validate HPVpersistence as a clinical marker and endpoint.", "metadata": {}}
+{"_id": "13867350", "title": "", "text": "Post-transcriptional Wnt Signaling Governs Epididymal Sperm MaturationThe canonical Wnt signalingpathway is of paramount importance in development and disease. An emergent question is whether theupstream cascade of the canonical Wnt pathway has physiologically relevant roles beyondβ-catenin-mediated transcription, which is difficult to study due to the pervasive role of this protein. Here,we show that transcriptionally silent spermatozoa respond to Wnt signals released from the epididymisand that mice mutant for the Wnt regulator Cyclin Y-like 1 are male sterile due to immotile andmalformed spermatozoa. Post-transcriptional Wnt signaling impacts spermatozoa through GSK3 by (1)reducing global protein poly-ubiquitination to maintain protein homeostasis; (2) inhibiting septin 4phosphorylation to establish a membrane diffusion barrier in the sperm tail; and (3) inhibiting proteinphosphatase 1 to initiate sperm motility. The results indicate that Wnt signaling orchestrates a richpost-transcriptional sperm maturation program and invite revisiting transcription-independent Wntsignaling in somatic cells as well.", "metadata": {}}
+{"_id": "13868795", "title": "", "text": "CD28 Costimulation: From Mechanism to Therapy.Ligation of the CD28 receptor on T cells provides acritical second signal alongside T cell receptor (TCR) ligation for naive T cell activation. Here, we discussthe expression, structure, and biochemistry of CD28 and its ligands. CD28 signals play a key role in manyT cell processes, including cytoskeletal remodeling, production of cytokines, survival, and differentiation.CD28 ligation leads to unique epigenetic, transcriptional, and post-translational changes in T cells thatcannot be recapitulated by TCR ligation alone. We discuss the function of CD28 and its ligands in botheffector and regulatory T cells. CD28 is critical for regulatory T cell survival and the maintenance ofimmune homeostasis. We outline the roles that CD28 and its family members play in human disease andwe review the clinical efficacy of drugs that block CD28 ligands. Despite the centrality of CD28 and itsfamily members and ligands to immune function, many aspects of CD28 biology remain unclear.Translation of a basic understanding of CD28 function into immunomodulatory therapeutics has beenuneven, with both successes and failures. Such real-world results might stem from multiple factors,including complex receptor-ligand interactions among CD28 family members, differences between themouse and human CD28 families, and cell-type specific roles of CD28 family members.", "metadata": {}}
+{"_id": "13870943", "title": "", "text": "Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on thediagnosis of multiple sclerosis.The International Panel on MS Diagnosis presents revised diagnosticcriteria for multiple sclerosis (MS). The focus remains on the objective demonstration of dissemination oflesions in both time and space. Magnetic resonance imaging is integrated with dinical and otherparaclinical diagnostic methods. The revised criteria facilitate the diagnosis of MS in patients with avariety of presentations, including \"monosymptomatic\" disease suggestive of MS, disease with a typicalrelapsing-remitting course, and disease with insidious progression, without clear attacks and remissions.Previously used terms such as \"clinically definite\" and \"probable MS\" are no longer recommended. Theoutcome of a diagnostic evaluation is either MS, \"possible MS\" (for those at risk for MS, but for whomdiagnostic evaluation is equivocal), or \"not MS. \"", "metadata": {}}
+{"_id": "13878124", "title": "", "text": "Regulation of radial glial survival by signals from the meninges.Radial glial cells (RGCs) in the developingcerebral cortex are progenitors for neurons and glia, and their processes serve as guideposts formigrating neurons. So far, it has remained unclear whether RGC processes also control the function ofRGCs more directly. Here, we show that RGC numbers and cortical size are reduced in mice lacking beta1integrins in RGCs. TUNEL stainings and time-lapse video recordings demonstrate that beta1-deficientRGCs processes detach from the meningeal basement membrane (BM) followed by apoptotic death ofRGCs. Apoptosis is also induced by surgical removal of the meninges. Finally, mice lacking the BMcomponents laminin alpha2 and alpha4 show defects in the attachment of RGC processes at themeninges, a reduction in cortical size, and enhanced apoptosis of RGC cells. Our findings demonstratethat attachment of RGC processes at the meninges is important for RGC survival and the control ofcortical size.", "metadata": {}}
+{"_id": "13878643", "title": "", "text": "The sterol regulatory element binding proteins are essential for the metabolic programming of effector Tcells and adaptive immunityNewly activated CD8(+) T cells reprogram their metabolism to meet theextraordinary biosynthetic demands of clonal expansion; however, the signals that mediate metabolicreprogramming remain poorly defined. Here we demonstrate an essential role for sterol regulatoryelement-binding proteins (SREBPs) in the acquisition of effector-cell metabolism. Without SREBPsignaling, CD8(+) T cells were unable to blast, which resulted in attenuated clonal expansion during viralinfection. Mechanistic studies indicated that SREBPs were essential for meeting the heightened lipidrequirements of membrane synthesis during blastogenesis. SREBPs were dispensable for homeostaticproliferation, which indicated a context-specific requirement for SREBPs in effector responses. Our studiesprovide insights into the molecular signals that underlie the metabolic reprogramming of CD8(+) T cellsduring the transition from quiescence to activation.", "metadata": {}}
+{"_id": "13882658", "title": "", "text": "Human contribution to the European heatwave of 2003The summer of 2003 was probably the hottest inEurope since at latest ad 1500, and unusually large numbers of heat-related deaths were reported inFrance, Germany and Italy. It is an ill-posed question whether the 2003 heatwave was caused, in asimple deterministic sense, by a modification of the external influences on climate—for example,increasing concentrations of greenhouse gases in the atmosphere—because almost any such weatherevent might have occurred by chance in an unmodified climate. However, it is possible to estimate byhow much human activities may have increased the risk of the occurrence of such a heatwave. Here weuse this conceptual framework to estimate the contribution of human-induced increases in atmosphericconcentrations of greenhouse gases and other pollutants to the risk of the occurrence of unusually highmean summer temperatures throughout a large region of continental Europe. Using a threshold for meansummer temperature that was exceeded in 2003, but in no other year since the start of the instrumentalrecord in 1851, we estimate it is very likely (confidence level >90%) that human influence has at leastdoubled the risk of a heatwave exceeding this threshold magnitude.", "metadata": {}}
+{"_id": "13883546", "title": "", "text": "Do Antidepressants Cure or Create Abnormal Brain States?The term antidepressant refers to a drug thathelps to rectify specific biological abnormalities that give rise to the symptoms of depression. Thisexemplifies what we have called the “disease-centred” model of psychotropic drug action [ 1]. Modelledon paradigmatic situations in general medicine—such as the use of insulin in diabetes, antibiotics ininfectious disease, chemotherapy in cancer—the disease-centred model suggests that antidepressantshelp restore normal functioning by acting on the neuropathology of depression or of depressivesymptoms. In contrast, we propose in this Essay that an alternative “drug-centred” model can betterexplain observed drug effects in psychiatric conditions. This drug-centred model suggests that instead ofrelieving a hypothetical biochemical abnormality, drugs themselves cause abnormal states, which maycoincidentally relieve psychiatric symptoms ( Table 1). Alcohol's disinhibiting effects may relievesymptoms of social phobia, but that does not imply that alcohol corrects a chemical imbalance underlyingsocial phobia. Sedation may lessen high arousal, present in many acute psychiatric situations. Drugs thatinduce indifference, such as neuroleptics or opiates, may help reduce the distress of acute psychoticsymptoms. Low-dose stimulants may help improve attention and concentration in the short term. Table1    Main Assumptions of Two Models of Psychotropic Drug Action The disease-centred model inpsychiatry leads researchers to infer antidepressant effects from patients' scores on symptom ratingscales presumed to assess the manifestations of the disease. The drug-centred model, on the other hand,suggests that physiological and subjective effects of drugs should be examined in their own right. Theseeffects include various forms of sedation, stimulation, and a plethora of biopsychological states.Depending on individual inclination and context (including a person's emotional state upon drugingestion), intoxication with some drugs produces euphoria or mood elevation. Because tolerancedevelops, however, euphoriant effects do not persist with long-term use. If antidepressants or any otherpsychotropic drugs could be shown to have mood-elevating effects that were long-term and notdiminished by being in a depressed emotional state, this would distinguish them from psychotropic drugsthat cause euphoria and might prove uniquely useful in depressed patients (see Sidebar).", "metadata": {}}
+{"_id": "13889430", "title": "", "text": "Cancer exosomes trigger fibroblast to myofibroblast differentiation.There is a growing interest in thecell-cell communication roles in cancer mediated by secreted vesicles termed exosomes. In this study, weexamined whether exosomes produced by cancer cells could transmit information to normal stromalfibroblasts and trigger a cellular response. We found that some cancer-derived exosomes could triggerelevated α-smooth muscle actin expression and other changes consistent with the process of fibroblastdifferentiation into myofibroblasts. We show that TGF-β is expressed at the exosome surface inassociation with the transmembrane proteoglycan betaglycan. Although existing in a latent state, thiscomplex was fully functional in eliciting SMAD-dependent signaling. Inhibiting either signaling orbetaglycan expression attenuated differentiation. While the kinetics and overall magnitude of theresponse were similar to that achieved with soluble TGF-β, we identified important qualitative differencesunique to the exosomal route of TGF-β delivery, as exemplified by a significant elevation in fibroblastFGF2 production. This hitherto unknown trigger for instigating cellular differentiation in a distinctivemanner has major implications for mechanisms underlying cancer-recruited stroma, fibrotic diseases, andwound-healing responses.", "metadata": {}}
+{"_id": "13889962", "title": "", "text": "A model of multiple myeloma: culture of 5T33 murine myeloma cells and evaluation of tumorigenicity inthe C57BL/KaLwRij mouse.The 5T33 multiple myeloma is one of a series of transplantable murinemyelomas arising spontaneously in C57BL/KaLwRij mice. This study describes the establishment andcharacterisation of the 5T33 murine myeloma in vitro as a cultured cell line in terms of its morphology,growth rate, expression of paraprotein (IgG2b) and tumorigenicity in syngeneic animals. The 5T33 cellline has been in continuous culture for over 10 months and has achieved more than passage 34. Inculture, 5T33 myeloma grows as single cells or in small clusters of loosely adherent cells on an adherentstromal cell layer. Maximum doubling time is approximately 25 h, and over 90% of the cells expresscytoplasmic IgG2b paraprotein. The cultured 5T33 myeloma cells are highly tumorigenic inC57BL/KaLwRij mice with as few as 500 cells inducing paralysis and death as early as day 36post-tumour inoculation. Kinetics of tumour development and detection of IgG2b paraprotein are dosedependent. Two weeks following intravenous inoculation of 5 x 10(5) cultured 5T33 myeloma cells,tumour cells were readily identified in the bone marrow. By 3 weeks post-tumour inoculation, 5T33myeloma cells were found in various tissues throughout the animal. Studies are now underway todetermine the sensitivity of this cell line to various therapeutic modalities.", "metadata": {}}
+{"_id": "13899137", "title": "", "text": "HIV Treatment as Prevention: Systematic Comparison of Mathematical Models of the Potential Impact ofAntiretroviral Therapy on HIV Incidence in South AfricaBACKGROUND Many mathematical models haveinvestigated the impact of expanding access to antiretroviral therapy (ART) on new HIV infections.Comparing results and conclusions across models is challenging because models have addressed slightlydifferent questions and have reported different outcome metrics. This study compares the predictions ofseveral mathematical models simulating the same ART intervention programmes to determine the extentto which models agree about the epidemiological impact of expanded ART. METHODS AND FINDINGSTwelve independent mathematical models evaluated a set of standardised ART intervention scenarios inSouth Africa and reported a common set of outputs. Intervention scenarios systematically varied the CD4count threshold for treatment eligibility, access to treatment, and programme retention. For a scenario inwhich 80% of HIV-infected individuals start treatment on average 1 y after their CD4 count drops below350 cells/µl and 85% remain on treatment after 3 y, the models projected that HIV incidence would be35% to 54% lower 8 y after the introduction of ART, compared to a counterfactual scenario in whichthere is no ART. More variation existed in the estimated long-term (38 y) reductions in incidence. Theimpact of optimistic interventions including immediate ART initiation varied widely across models,maintaining substantial uncertainty about the theoretical prospect for elimination of HIV from thepopulation using ART alone over the next four decades. The number of person-years of ART per infectionaverted over 8 y ranged between 5.8 and 18.7. Considering the actual scale-up of ART in South Africa,seven models estimated that current HIV incidence is 17% to 32% lower than it would have been in theabsence of ART. Differences between model assumptions about CD4 decline and HIV transmissibility overthe course of infection explained only a modest amount of the variation in model results. CONCLUSIONSMathematical models evaluating the impact of ART vary substantially in structure, complexity, andparameter choices, but all suggest that ART, at high levels of access and with high adherence, has thepotential to substantially reduce new HIV infections. There was broad agreement regarding theshort-term epidemiologic impact of ambitious treatment scale-up, but more variation in longer termprojections and in the efficiency with which treatment can reduce new infections. Differences betweenmodel predictions could not be explained by differences in model structure or parameterization that werehypothesized to affect intervention impact.", "metadata": {}}
+{"_id": "13900610", "title": "", "text": "Self-harm in prisons in England and Wales: an epidemiological study of prevalence, risk factors,clustering, and subsequent suicideBACKGROUND Self-harm and suicide are common in prisoners, yetrobust information on the full extent and characteristics of people at risk of self-harm is scant.Furthermore, understanding how frequently self-harm is followed by suicide, and in which prisoners thisprogression is most likely to happen, is important. We did a case-control study of all prisoners in Englandand Wales to ascertain the prevalence of self-harm in this population, associated risk factors, clusteringeffects, and risk of subsequent suicide after self-harm. METHODS Records of self-harm incidents in allprisons in England and Wales were gathered routinely between January, 2004, and December, 2009. Wedid a case-control comparison of prisoners who self-harmed and those who did not between January,2006, and December, 2009. We also used a Bayesian approach to look at clustering of people whoself-harmed. Prisoners who self-harmed and subsequently died by suicide in prison were compared withother inmates who self-harmed. FINDINGS 139,195 self-harm incidents were recorded in 26,510individual prisoners between 2004 and 2009; 5-6% of male prisoners and 20-24% of female inmatesself-harmed every year. Self-harm rates were more than ten times higher in female prisoners than inmale inmates. Repetition of self-harm was common, particularly in women and teenage girls, in whom asubgroup of 102 prisoners accounted for 17,307 episodes. In both sexes, self-harm was associated withyounger age, white ethnic origin, prison type, and a life sentence or being unsentenced; in femaleinmates, committing a violent offence against an individual was also a factor. Substantial evidence wasnoted of clustering in time and location of prisoners who self-harmed (adjusted intra-class correlation0·15, 95% CI 0·11-0·18). 109 subsequent suicides in prison were reported in individuals whoself-harmed; the risk was higher in those who self-harmed than in the general prison population, andmore than half the deaths occurred within a month of self-harm. Risk factors for suicide after self-harm inmale prisoners were older age and a previous self-harm incident of high or moderate lethality; in femaleinmates, a history of more than five self-harm incidents within a year was associated with subsequentsuicide. INTERPRETATION The burden of self-harm in prisoners is substantial, particularly in women.Self-harm in prison is associated with subsequent suicide in this setting. Prevention and treatment ofself-harm in prisoners is an essential component of suicide prevention in prisons. FUNDING WellcomeTrust, National Institute for Health Research, National Offender Management Service, and Department ofHealth.", "metadata": {}}
+{"_id": "13901073", "title": "", "text": "Elimination of HIV in South Africa through Expanded Access to Antiretroviral Therapy: A ModelComparison StudyBACKGROUND Expanded access to antiretroviral therapy (ART) using universal test andtreat (UTT) has been suggested as a strategy to eliminate HIV in South Africa within 7 y based on aninfluential mathematical modeling study. However, the underlying deterministic model was criticizedwidely, and other modeling studies did not always confirm the study's finding. The objective of our studyis to better understand the implications of different model structures and assumptions, so as to arrive atthe best possible predictions of the long-term impact of UTT and the possibility of elimination of HIV.METHODS AND FINDINGS We developed nine structurally different mathematical models of the SouthAfrican HIV epidemic in a stepwise approach of increasing complexity and realism. The simplest modelresembles the initial deterministic model, while the most comprehensive model is the stochasticmicrosimulation model STDSIM, which includes sexual networks and HIV stages with different degrees ofinfectiousness. We defined UTT as annual screening and immediate ART for all HIV-infected adults,starting at 13% in January 2012 and scaled up to 90% coverage by January 2019. All models predictelimination, yet those that capture more processes underlying the HIV transmission dynamics predictelimination at a later point in time, after 20 to 25 y. Importantly, the most comprehensive model predictsthat the current strategy of ART at CD4 count ≤350 cells/µl will also lead to elimination, albeit 10 y latercompared to UTT. Still, UTT remains cost-effective, as many additional life-years would be saved. Thestudy's major limitations are that elimination was defined as incidence below 1/1,000 person-years ratherthan 0% prevalence, and drug resistance was not modeled. CONCLUSIONS Our results confirm previouspredictions that the HIV epidemic in South Africa can be eliminated through universal testing andimmediate treatment at 90% coverage. However, more realistic models show that elimination is likely tooccur at a much later point in time than the initial model suggested. Also, UTT is a cost-effectiveintervention, but less cost-effective than previously predicted because the current South African ARTtreatment policy alone could already drive HIV into elimination. Please see later in the article for theEditors' Summary.", "metadata": {}}
+{"_id": "13902570", "title": "", "text": "Bile acid receptor TGR5 agonism induces NO production and reduces monocyte adhesion in vascularendothelial cells.OBJECTIVE TGR5 is a G-protein-coupled receptor for bile acids. So far, little is knownabout the function of TGR5 in vascular endothelial cells. APPROACH AND RESULTS In bovine aorticendothelial cells, treatment with a bile acid having a high affinity to TGR5, taurolithocholic acid (TLCA),significantly increased NO production. This effect was abolished by small interfering RNA-mediateddepletion of TGR5. TLCA-induced NO production was also observed in human umbilical vein endothelialcells measured via intracellular cGMP accumulation. TLCA increased endothelial NO synthase(ser1177)phosphorylation in human umbilical vein endothelial cells. This response was accompanied by increasedAkt(ser473) phosphorylation and intracellular Ca(2+). Inhibition of these signals significantly decreasedTLCA-induced NO production. We next examined whether TGR5-mediated NO production affectsinflammatory responses of endothelial cells. In human umbilical vein endothelial cells, TLCA significantlyreduced tumor necrosis factor-α-induced adhesion of monocytes, vascular cell adhesion molecule-1expression, and activation of nuclear factor-κB. TLCA also inhibited lipopolysaccharide-induced monocyteadhesion to mesenteric venules in vivo. These inhibitory effects of TLCA were abrogated by NO synthaseinhibition. CONCLUSIONS TGR5 agonism induces NO production via Akt activation and intracellularCa(2+) increase in vascular endothelial cells, and this function inhibits monocyte adhesion in response toinflammatory stimuli.", "metadata": {}}
+{"_id": "13903052", "title": "", "text": "Structural insights into calicivirus attachment and uncoating.The Caliciviridae family comprisespositive-sense RNA viruses of medical and veterinary significance. In humans, caliciviruses are a majorcause of acute gastroenteritis, while in animals respiratory illness, conjunctivitis, stomatitis, andhemorrhagic disease are documented. Investigation of virus-host interactions is limited by a lack ofculture systems for many viruses in this family. Feline calicivirus (FCV), a member of the Vesivirus genus,provides a tractable model, since it may be propagated in cell culture. Feline junctional adhesion molecule1 (fJAM-1) was recently identified as a functional receptor for FCV. We have analyzed the structure of thisvirus-receptor complex by cryo-electron microscopy and three-dimensional image reconstruction,combined with fitting of homology modeled high-resolution coordinates. We show that domain 1 offJAM-1 binds to the outer face of the P2 domain of the FCV capsid protein VP1, inducing conformationalchanges in the viral capsid. This study provides the first structural view of a native calicivirus-proteinreceptor complex and insights into the mechanisms of virus attachment and uncoating.", "metadata": {}}
+{"_id": "13905670", "title": "", "text": "Human SNP Links Differential Outcomes in Inflammatory and Infectious Disease to a FOXO3-RegulatedPathwayThe clinical course and eventual outcome, or prognosis, of complex diseases varies enormouslybetween affected individuals. This variability critically determines the impact a disease has on a patient'slife but is very poorly understood. Here, we exploit existing genome-wide association study data to gaininsight into the role of genetics in prognosis. We identify a noncoding polymorphism in FOXO3A(rs12212067: T > G) at which the minor (G) allele, despite not being associated with diseasesusceptibility, is associated with a milder course of Crohn's disease and rheumatoid arthritis and withincreased risk of severe malaria. Minor allele carriage is shown to limit inflammatory responses inmonocytes via a FOXO3-driven pathway, which through TGFβ1 reduces production of proinflammatorycytokines, including TNFα, and increases production of anti-inflammatory cytokines, including IL-10.Thus, we uncover a shared genetic contribution to prognosis in distinct diseases that operates via aFOXO3-driven pathway modulating inflammatory responses.", "metadata": {}}
+{"_id": "13906581", "title": "", "text": "Patient Outcomes with Teaching Versus Nonteaching Healthcare: A SystematicReviewBackground  Extensive debate exists in the healthcare community over whether outcomes ofmedical care at teaching hospitals and other healthcare units are better or worse than those at therespective nonteaching ones. Thus, our goal was to systematically evaluate the evidence pertaining tothis question. Methods and Findings  We reviewed all studies that compared teaching versus nonteachinghealthcare structures for mortality or any other patient outcome, regardless of health condition. Studieswere retrieved from PubMed, contact with experts, and literature cross-referencing. Data were extractedon setting, patients, data sources, author affiliations, definition of compared groups, types of diagnosesconsidered, adjusting covariates, and estimates of effect for mortality and for each other outcome.Overall, 132 eligible studies were identified, including 93 on mortality and 61 on other eligible outcomes(22 addressed both). Synthesis of the available adjusted estimates on mortality yielded a summaryrelative risk of 0.96 (95% confidence interval [CI], 0.93–1.00) for teaching versus nonteachinghealthcare structures and 1.04 (95% CI, 0.99–1.10) for minor teaching versus nonteaching ones. Therewas considerable heterogeneity between studies (I2 = 72% for the main analysis). Results were similarin studies using clinical and those using administrative databases. No differences were seen in the 14studies fully adjusting for volume/experience, severity, and comorbidity (relative risk 1.01). Smallerstudies did not differ in their results from larger studies. Differences were seen for some diagnoses (e.g.,significantly better survival for breast cancer and cerebrovascular accidents in teaching hospitals andsignificantly better survival from cholecystectomy in nonteaching hospitals), but these were small inmagnitude. Other outcomes were diverse, but typically teaching healthcare structures did not do betterthan nonteaching ones. Conclusions  The available data are limited by their nonrandomized design, butoverall they do not suggest that a healthcare facility's teaching status on its own markedly improves orworsens patient outcomes. Differences for specific diseases cannot be excluded, but are likely to besmall.", "metadata": {}}
+{"_id": "13906892", "title": "", "text": "DNA damage and Repair Modify DNA methylation and Chromatin Domain of the Targeted Locus:Mechanism of allele methylation polymorphismWe characterize the changes in chromatin structure, DNAmethylation and transcription during and after homologous DNA repair (HR). We find that HR modifies theDNA methylation pattern of the repaired segment. HR also alters local histone H3 methylation as wellchromatin structure by inducing DNA-chromatin loops connecting the 5' and 3' ends of the repaired gene.During a two-week period after repair, transcription-associated demethylation promoted by Base ExcisionRepair enzymes further modifies methylation of the repaired DNA. Subsequently, the repaired genesdisplay stable but diverse methylation profiles. These profiles govern the levels of expression in eachclone. Our data argue that DNA methylation and chromatin remodelling induced by HR may be a sourceof permanent variation of gene expression in somatic cells.", "metadata": {}}
+{"_id": "13907427", "title": "", "text": "DNA repair factor APLF is a histone chaperone.Poly(ADP-ribosyl)ation plays a major role in DNA repair,where it regulates chromatin relaxation as one of the critical events in the repair process. However, themolecular mechanism by which poly(ADP-ribose) modulates chromatin remains poorly understood. Herewe identify the poly(ADP-ribose)-regulated protein APLF as a DNA-damage-specific histone chaperone.APLF preferentially binds to the histone H3/H4 tetramer via its C-terminal acidic motif, which ishomologous to the motif conserved in the histone chaperones of the NAP1L family (NAP1L motif). Wefurther demonstrate that APLF exhibits histone chaperone activities in a manner that is dependent on itsacidic domain and that the NAP1L motif is critical for the repair capacity of APLF in vivo. Finally, weidentify structural analogs of APLF in lower eukaryotes with the ability to bind histones and localize to thesites of DNA-damage-induced poly(ADP-ribosyl)ation. Collectively, these findings define the involvementof histone chaperones in poly(ADP-ribose)-regulated DNA repair reactions.", "metadata": {}}
+{"_id": "13907928", "title": "", "text": "Regulation of sympathetic nerve activity during the cold pressor test in normotensive pregnant andnonpregnant women.Baseline neurovascular transduction is reduced in normotensive pregnancy;however, little is known about changes to neurovascular transduction during periods of heightenedsympathetic activation. We tested the hypothesis that, despite an exacerbated muscle sympathetic nerveactivity (microneurography) response to cold pressor stimulation, the blunting of neurovasculartransduction in normotensive pregnant women would result in similar changes in vascular resistance andmean arterial pressure (Finometer) relative to nonpregnant controls. Baseline neurovascular transductionwas reduced in pregnant women relative to controls when expressed as the quotient of both totalresistance and mean arterial pressure and sympathetic burst frequency (0.32±0.07 versus 0.58±0.16mm Hg/L/min/bursts/min, P<0.001 and 2.4±0.7 versus 3.6±0.8 mm Hg/bursts/min, P=0.001).Sympathetic activation was greater across all 3 minutes of cold pressor stimulation in the pregnantwomen relative to the nonpregnant controls. Peak sympathoexcitation was also greater in pregnant thanin nonpregnant women, whether expressed as sympathetic burst frequency (+17±13 versus +7±8bursts/min, P=0.049), burst incidence (+17±9 versus +6±11 bursts/100 hb, P=0.03), or total activity(+950±660 versus +363±414 arbitrary units, P=0.04). However, neurovascular transduction duringpeak cold pressor-induced sympathoexcitation remained blunted in pregnant women (0.25±0.11 versus0.45±0.08 mm Hg/L/min/bursts/min, P<0.001 and 1.9±1.0 versus 3.2±0.9 mm Hg/bursts/min,P=0.006). Therefore, mean arterial pressure (93±21 versus 99±6 mm Hg, P=0.4) and total peripheralresistance (12±3 versus 14±3 mm Hg/L/min) were not different between pregnant and nonpregnantwomen during peak sympathoexcitation. These data indicate that the third trimester of normotensivepregnancy is associated with reductions in neurovascular transduction, which result in the dissociation ofsympathetic outflow from hemodynamic outcomes, even during cold pressor-inducedsympathoexcitation.", "metadata": {}}
+{"_id": "13910150", "title": "", "text": "The Germ Cell Determinant Blimp1 Is Not Required for Derivation of Pluripotent Stem CellsBlimp1(Prdm1), the key determinant of primordial germ cells (PGCs), plays a combinatorial role with Prdm14during PGC specification from postimplantation epiblast cells. They together initiate epigeneticreprogramming in early germ cells toward an underlying pluripotent state, which is equivalent toembryonic stem cells (ESCs). Whereas Prdm14 alone can promote reprogramming and is important forthe propagation of the pluripotent state, it is not known whether Blimp1 is similarly involved. By using agenetic approach, we demonstrate that Blimp1 is dispensable for the derivation and maintenance of ESCsand postimplantation epiblast stem cells (epiSCs). Notably, Blimp1 is also dispensable for reprogrammingepiSCs to ESCs. Thus, although Blimp1 is obligatory for PGC specification, it is not required for thereversion of epiSCs to ESCs and for their maintenance thereafter. This study suggests thatreprogramming, including that of somatic cells to ESCs, may not entail an obligatory route through aBlimp1-positive PGC-like state.", "metadata": {}}
+{"_id": "13912224", "title": "", "text": "A Nexus for Gene Expression—Molecular Mechanisms of Spt5 and NusG in the Three Domains ofLifeEvolutionary related multisubunit RNA polymerases (RNAPs) transcribe the genomes of all livingorganisms. Whereas the core subunits of RNAPs are universally conserved in all three domains oflife-indicative of a common evolutionary descent-this only applies to one RNAP-associated transcriptionfactor-Spt5, also known as NusG in bacteria. All other factors that aid RNAP during the transcription cycleare specific for the individual domain or only conserved between archaea and eukaryotes. Spt5 and itsbacterial homologue NusG regulate gene expression in several ways by (i) modulating transcriptionprocessivity and promoter proximal pausing, (ii) coupling transcription and RNA processing or translation,and (iii) recruiting termination factors and thereby silencing laterally transferred DNA and protecting thegenome against double-stranded DNA breaks. This review discusses recent discoveries that identifySpt5-like factors as evolutionary conserved nexus for the regulation and coordination of the machineriesresponsible for information processing in the cell.", "metadata": {}}
+{"_id": "13914198", "title": "", "text": "Haplotype estimation using sequencing reads.High-throughput sequencing technologies produce shortsequence reads that can contain phase information if they span two or more heterozygote genotypes.This information is not routinely used by current methods that infer haplotypes from genotype data. Wehave extended the SHAPEIT2 method to use phase-informative sequencing reads to improve phasingaccuracy. Our model incorporates the read information in a probabilistic model through base qualityscores within each read. The method is primarily designed for high-coverage sequence data or data setsthat already have genotypes called. One important application is phasing of single samples sequenced athigh coverage for use in medical sequencing and studies of rare diseases. Our method can also useexisting panels of reference haplotypes. We tested the method by using a mother-father-child triosequenced at high-coverage by Illumina together with the low-coverage sequence data from the 1000Genomes Project (1000GP). We found that use of phase-informative reads increases the mean distancebetween switch errors by 22% from 274.4 kb to 328.6 kb. We also used male chromosome X haplotypesfrom the 1000GP samples to simulate sequencing reads with varying insert size, read length, and baseerror rate. When using short 100 bp paired-end reads, we found that using mixtures of insert sizesproduced the best results. When using longer reads with high error rates (5-20 kb read with 4%-15%error per base), phasing performance was substantially improved.", "metadata": {}}
+{"_id": "13914633", "title": "", "text": "Time and Money: The True Costs of Health Care Utilization for Patients Receiving \"Free\" HIV/TuberculosisCare and Treatment in Rural KwaZulu-Natal.BACKGROUND HIV and tuberculosis (TB) services areprovided free of charge in many sub-Saharan African countries, but patients still incur costs. METHODSPatient-exit interviews were conducted in primary health care clinics in rural South Africa withrepresentative samples of 200 HIV-infected patients enrolled in a pre-antiretroviral treatment (pre-ART)program, 300 patients receiving antiretroviral treatment (ART), and 300 patients receiving TB treatment.For each group, we calculated health expenditures across different spending categories, time spenttraveling to and using services, and how patients financed their spending. Associations between patientgroup and costs were assessed in multivariate regression models. RESULTS Total monthly healthexpenditures [1 USD = 7.3 South African Rand (ZAR)] were ZAR 171 [95% confidence interval (CI): 134to 207] for pre-ART, ZAR 164 (95% CI: 141 to 187) for ART, and ZAR 122 (95% CI: 105 to 140) for TBpatients (P = 0.01). Total monthly time costs (in hours) were 3.4 (95% CI: 3.3 to 3.5) for pre-ART, 5.0(95% CI: 4.7 to 5.3) for ART, and 3.2 (95% CI: 2.9 to 3.4) for TB patients (P < 0.01). Although overallpatient costs were similar across groups, pre-ART patients spent on average ZAR 29.2 more on traditionalhealers and ZAR 25.9 more on chemists and private doctors than ART patients, whereas ART patientsspent ZAR 34.0 more than pre-ART patients on transport to clinics (P < 0.05 for all results). Thirty-onepercent of pre-ART, 39% of ART, and 41% of TB patients borrowed money or sold assets to financehealth care. CONCLUSIONS Patients receiving nominally free care for HIV/TB face large private costs,commonly leading to financial distress. Subsidized transport, fewer clinic visits, and drug pick-up pointscloser to home could reduce costs for ART patients, potentially improving retention and adherence. Largeexpenditure on alternative care among pre-ART patients suggests that transitioning patients to ARTearlier, as under HIV treatment-as-prevention policies, may not substantially increase patients' financialburden.", "metadata": {}}
+{"_id": "13915464", "title": "", "text": "A new system for naming ribosomal proteins.A system for naming ribosomal proteins is described thatthe authors intend to use in the future. They urge others to adopt it. The objective is to eliminate theconfusion caused by the assignment of identical names to ribosomal proteins from different species thatare unrelated in structure and function. In the system proposed here, homologous ribosomal proteins areassigned the same name, regardless of species. It is designed so that new names are similar enough toold names to be easily recognized, but are written in a format that unambiguously identifies them as 'newsystem' names.", "metadata": {}}
+{"_id": "13916484", "title": "", "text": "COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in CancerCOSMIC(http://www.sanger.ac.uk/cosmic) curates comprehensive information on somatic mutations in humancancer. Release v48 (July 2010) describes over 136,000 coding mutations in almost 542,000 tumoursamples; of the 18,490 genes documented, 4803 (26%) have one or more mutations. Full scientificliterature curations are available on 83 major cancer genes and 49 fusion gene pairs (19 new cancergenes and 30 new fusion pairs this year) and this number is continually increasing. Key amongst these isTP53, now available through a collaboration with the IARC p53 database. In addition to data from theCancer Genome Project (CGP) at the Sanger Institute, UK, and The Cancer Genome Atlas project (TCGA),large systematic screens are also now curated. Major website upgrades now make these data much moremineable, with many new selection filters and graphics. A Biomart is now available allowing moreautomated data mining and integration with other biological databases. Annotation of genomic featureshas become a significant focus; COSMIC has begun curating full-genome resequencing experiments,developing new web pages, export formats and graphics styles. With all genomic information recentlyupdated to GRCh37, COSMIC integrates many diverse types of mutation information and is making muchcloser links with Ensembl and other data resources.", "metadata": {}}
+{"_id": "13916951", "title": "", "text": "Quantitative imaging assay for NF-κB nuclear translocation in primary human macrophagesQuantitativemeasurement of NF-kappaB nuclear translocation is an important research tool in cellular immunology.Established methodologies have a number of limitations, such as poor sensitivity, high cost ordependence on cell lines. Novel imaging methods to measure nuclear translocation of transcriptionallyactive components of NF-kappaB are being used but are also partly limited by the need for specialistimaging equipment or image analysis software. Herein we present a method for quantitative detection ofNF-kappaB rel A nuclear translocation, using immunofluorescence microscopy and the public domainimage analysis software ImageJ that can be easily adopted for cellular immunology research without theneed for specialist image analysis expertise and at low cost. The method presented here is validated bydemonstrating the time course and dose response of NF-kappaB nuclear translocation in primary humanmacrophages stimulated with LPS, and by comparison with a commercial NF-kappaB activation reportercell line.", "metadata": {}}
+{"_id": "13921526", "title": "", "text": "An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of thecerebral cortex.The major cell classes of the brain differ in their developmental processes, metabolism,signaling, and function. To better understand the functions and interactions of the cell types thatcomprise these classes, we acutely purified representative populations of neurons, astrocytes,oligodendrocyte precursor cells, newly formed oligodendrocytes, myelinating oligodendrocytes, microglia,endothelial cells, and pericytes from mouse cerebral cortex. We generated a transcriptome database forthese eight cell types by RNA sequencing and used a sensitive algorithm to detect alternative splicingevents in each cell type. Bioinformatic analyses identified thousands of new cell type-enriched genes andsplicing isoforms that will provide novel markers for cell identification, tools for genetic manipulation, andinsights into the biology of the brain. For example, our data provide clues as to how neurons andastrocytes differ in their ability to dynamically regulate glycolytic flux and lactate generation attributableto unique splicing of PKM2, the gene encoding the glycolytic enzyme pyruvate kinase. This dataset willprovide a powerful new resource for understanding the development and function of the brain. To ensurethe widespread distribution of these datasets, we have created a user-friendly website(http://web.stanford.edu/group/barres_lab/brain_rnaseq.html) that provides a platform for analyzingand comparing transciption and alternative splicing profiles for various cell classes in the brain.", "metadata": {}}
+{"_id": "13921783", "title": "", "text": "C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteinsAnexpanded GGGGCC repeat in C9orf72 is the most common genetic cause of frontotemporal dementia andamyotrophic lateral sclerosis. A fundamental question is whether toxicity is driven by the repeat RNAitself and/or by dipeptide repeat proteins generated by repeat-associated, non-ATG translation. Toaddress this question, we developed in vitro and in vivo models to dissect repeat RNA and dipeptiderepeat protein toxicity. Expression of pure repeats, but not stop codon–interrupted “RNA-only” repeats inDrosophila caused adult-onset neurodegeneration. Thus, expanded repeats promoted neurodegenerationthrough dipeptide repeat proteins. Expression of individual dipeptide repeat proteins with a non-GGGGCCRNA sequence revealed that both poly-(glycine-arginine) and poly-(proline-arginine) proteins causedneurodegeneration. These findings are consistent with a dual toxicity mechanism, whereby botharginine-rich proteins and repeat RNA contribute to C9orf72-mediated neurodegeneration.", "metadata": {}}
+{"_id": "13923069", "title": "", "text": "Targeted nanoparticles containing the proresolving peptide Ac2-26 protect against advancedatherosclerosis in hypercholesterolemic miceChronic, nonresolving inflammation is a critical factor in theclinical progression of advanced atherosclerotic lesions. In the normal inflammatory response, resolutionis mediated by several agonists, among which is the glucocorticoid-regulated protein called annexin A1.The proresolving actions of annexin A1, which are mediated through its receptor N-formyl peptidereceptor 2 (FPR2/ALX), can be mimicked by an amino-terminal peptide encompassing amino acids 2–26(Ac2-26). Collagen IV (Col IV)–targeted nanoparticles (NPs) containing Ac2-26 were evaluated for theirtherapeutic effect on chronic, advanced atherosclerosis in fat-fed Ldlr−/− mice. When administered tomice with preexisting lesions, Col IV–Ac2-26 NPs were targeted to lesions and led to a markedimprovement in key advanced plaque properties, including an increase in the protective collagen layeroverlying lesions (which was associated with a decrease in lesional collagenase activity), suppression ofoxidative stress, and a decrease in plaque necrosis. In mice lacking FPR2/ALX in myeloid cells, theseimprovements were not seen. Thus, administration of a resolution-mediating peptide in a targeted NPactivates its receptor on myeloid cells to stabilize advanced atherosclerotic lesions. These findingssupport the concept that defective inflammation resolution plays a role in advanced atherosclerosis, andsuggest a new form of therapy.", "metadata": {}}
+{"_id": "13923140", "title": "", "text": "Interleukin-2 gene variation impairs regulatory T cell function and causes autoimmunityAutoimmunediseases are thought to result from imbalances in normal immune physiology and regulation. Here, weshow that autoimmune disease susceptibility and resistance alleles on mouse chromosome 3 (Idd3)correlate with differential expression of the key immunoregulatory cytokine interleukin-2 (IL-2). In orderto test directly that an approximately twofold reduction in IL-2 underpins the Idd3-linked destabilizationof immune homeostasis, we show that engineered haplodeficiency of Il2 gene expression not onlyreduces T cell IL-2 production by twofold but also mimics the autoimmune dysregulatory effects of thenaturally occurring susceptibility alleles of Il2. Reduced IL-2 production achieved by either geneticmechanism correlates with reduced function of CD4+ CD25+ regulatory T cells, which are critical formaintaining immune homeostasis.", "metadata": {}}
+{"_id": "13931771", "title": "", "text": "GRSF1 Regulates RNA Processing in Mitochondrial RNA GranulesVarious specialized domains have beendescribed in the cytosol and the nucleus; however, little is known about compartmentalization within themitochondrial matrix. GRSF1 (G-rich sequence factor 1) is an RNA binding protein that was previouslyreported to localize in the cytosol. We found that an isoform of GRSF1 accumulates in discrete foci in themitochondrial matrix. These foci are composed of nascent mitochondrial RNA and also contain RNase P,an enzyme that participates in mitochondrial RNA processing. GRSF1 was found to interact with RNase Pand to be required for processing of both classical and tRNA-less RNA precursors. In its absence, cleavageof primary RNA transcripts is abnormal, leading to decreased expression of mitochondrially encodedproteins and mitochondrial dysfunction. Our findings suggest that the foci containing GRSF1 and RNase Pcorrespond to sites where primary RNA transcripts converge to be processed. We have termed theselarge ribonucleoprotein structures \"mitochondrial RNA granules. \"", "metadata": {}}
+{"_id": "13933299", "title": "", "text": "Midlife Serum Cholesterol and Increased Risk of Alzheimer’s and Vascular Dementia Three DecadesLaterAims: To investigate midlife cholesterol in relation to Alzheimer’s disease (AD) and vasculardementia (VaD) in a large multiethnic cohort of women and men. Methods: The Kaiser PermanenteNorthern California Medical Group (healthcare delivery organization) formed the database for this study.The 9,844 participants underwent detailed health evaluations during 1964–1973 at ages 40–45 years;they were still members of the health plan in 1994. AD and VaD were ascertained by medical recordsbetween 1 January 1994 and 1 June 2007. Cox proportional hazards models – adjusted for age,education, race/ethnic group, sex, midlife diabetes, hypertension, BMI and late-life stroke – wereconducted. Results: In total, 469 participants had AD and 127 had VaD. With desirable cholesterol levels(<200 mg/dl) as a reference, hazard ratios (HR) and 95% CI for AD were 1.23 (0.97–1.55) and 1.57(1.23–2.01) for borderline (200–239 mg/dl) and high cholesterol (≥240 mg/dl), respectively. HR and95% CI for VaD were 1.50 (1.01–2.23) for borderline and 1.26 (0.82–1.96) for high cholesterol. Furtheranalyses for AD (cholesterol quartiles, 1st quartile reference) indicated that cholesterol levels >220 mg/dlwere a significant risk factor: HR were 1.31 (1.01–1.71; 3rd quartile, 221–248 mg/dl) and 1.58(1.22–2.06; 4th quartile, 249–500 mg/dl). Conclusion: Midlife serum total cholesterol was associatedwith an increased risk of AD and VaD. Even moderately elevated cholesterol increased dementia risk.Dementia risk factors need to be addressed as early as midlife, before underlying disease(s) or symptomsappear.", "metadata": {}}
+{"_id": "13934676", "title": "", "text": "\"The contribution of chronic diseases to the prevalence of dependence among older people in LatinAmerica, China and India: a 10/66 Dementia Research Group population-based survey\"BACKGROUNDThe number of older people is set to increase dramatically worldwide. Demographic changes are likely toresult in the rise of age-related chronic diseases which largely contribute to years lived with a disabilityand future dependence. However dependence is much less studied although intrinsically linked todisability. We investigated the prevalence and correlates of dependence among older people from middleincome countries. METHODS A one-phase cross-sectional survey was carried out at 11 sites in sevencountries (urban sites in Cuba, Venezuela, and Dominican Republic, urban and rural sites in Peru, Mexico,China and India). All those aged 65 years and over living in geographically defined catchment areas wereeligible. In all, 15,022 interviews were completed with an informant interview for each participant. Thefull 10/66 Dementia Research Group survey protocol was applied, including ascertainment of depression,dementia, physical impairments and self-reported diagnoses. Dependence was interviewer-rated basedon a key informant's responses to a set of open-ended questions on the participant's needs for care. Weestimated the prevalence of dependence and the independent contribution of underlying healthconditions. Site-specific prevalence ratios were meta-analysed, and population attributable prevalencefractions (PAPF) calculated. RESULTS The prevalence of dependence increased with age at all sites, with atendency for the prevalence to be lower in men than in women. Age-standardised prevalence was lowerin all sites than in the USA. Other than in rural China, dementia made the largest independentcontribution to dependence, with a median PAPF of 34% (range 23%-59%). Other substantialcontributors were limb impairment (9%, 1%-46%), stroke (8%, 2%-17%), and depression (8%,1%-27%). CONCLUSION The demographic and health transitions will lead to large and rapid increases inthe numbers of dependent older people particularly in middle income countries (MIC). The prevention andcontrol of chronic neurological and neuropsychiatric diseases and the development of long-term carepolicies and plans should be urgent priorities.", "metadata": {}}
+{"_id": "13936152", "title": "", "text": "An actomyosin-based barrier inhibits cell mixing at compartmental boundaries in DrosophilaembryosPartitioning tissues into compartments that do not intermix is essential for the correctmorphogenesis of animal embryos and organs. Several hypotheses have been proposed to explaincompartmental cell sorting, mainly differential adhesion, but also regulation of the cytoskeleton or of cellproliferation. Nevertheless, the molecular and cellular mechanisms that keep cells apart at boundariesremain unclear. Here we demonstrate, in early Drosophila melanogaster embryos, that actomyosin-basedbarriers stop cells from invading neighbouring compartments. Our analysis shows that cells cantransiently invade neighbouring compartments, especially when they divide, but are then pushed backinto their compartment of origin. Actomyosin cytoskeletal components are enriched at compartmentalboundaries, forming cable-like structures when the epidermis is mitotically active. When MyoII(non-muscle myosin II) function is inhibited, including locally at the cable by chromophore-assisted laserinactivation (CALI), in live embryos, dividing cells are no longer pushed back, leading to compartmentalcell mixing. We propose that local regulation of actomyosin contractibility, rather than differentialadhesion, is the primary mechanism sorting cells at compartmental boundaries.", "metadata": {}}
+{"_id": "13938878", "title": "", "text": "Clinical algorithms for malaria diagnosis lack utility among people of different age groups.We conducted astudy to determine whether clinical algorithms would be useful in malaria diagnosis among people livingin an area of moderate malaria transmission within Kilifi District in Kenya. A total of 1602 people of allage groups participated. We took smears and recorded clinical signs and symptoms (prompted orspontaneous) of all those presenting to the study clinic with a history of fever. A malaria case was definedas a person presenting to the clinic with a history of fever and concurrent parasitaemia. A set of clinicalsigns and symptoms (algorithms) with the highest sensitivity and specificity for diagnosing a malaria casewas selected for the age groups </=5 years, 6-14 years and >/=15 years. These age-optimized derivedalgorithms were able to identify about 66% of the cases among those <15 years of age but only 23% ofcases among adults. Were these algorithms to be used as a basis for a decision on treatment amongthose presenting to the clinic, 16% of children </=5 years, 44% of those 6-14 years of age and 66% ofthe adults who had a history of fever and parasitaemia >/=5000 parasites/microl of blood would be senthome without treatment. Clinical algorithms therefore appear to have little utility in malaria diagnosis,performing even worse in the older age groups, where avoiding unnecessary use of anti-malarials wouldmake more drugs available to the really needy population of children under 5 years of age.", "metadata": {}}
+{"_id": "13940200", "title": "", "text": "Large-scale genetic fine mapping and genotype-phenotype associations implicate polymorphism in theIL2RA region in type 1 diabetesGenome-wide association studies are now identifying disease-associatedchromosome regions. However, even after convincing replication, the localization of the causal variant(s)requires comprehensive resequencing, extensive genotyping and statistical analyses in large sample setsleading to targeted functional studies. Here, we have localized the type 1 diabetes (T1D) association inthe interleukin 2 receptor alpha (IL2RA) gene region to two independent groups of SNPs, spanningoverlapping regions of 14 and 40 kb, encompassing IL2RA intron 1 and the 5′ regions of IL2RA andRBM17 (odds ratio = 2.04, 95% confidence interval = 1.70–2.45; P = 1.92 × 10−28; control frequency =0.635). Furthermore, we have associated IL2RA T1D susceptibility genotypes with lower circulating levelsof the biomarker, soluble IL-2RA (P = 6.28 × 10−28), suggesting that an inherited lower immuneresponsiveness predisposes to T1D.", "metadata": {}}
+{"_id": "13944805", "title": "", "text": "Maternal obesity epigenetically alters visceral fat progenitor cell properties in male offspring mice.KEYPOINTS Maternal obesity reduces adipogenic progenitor density in offspring adipose tissue. The ability ofadipose tissue expansion in the offspring of obese mothers is limited and is associated with metabolicdysfunction of adipose tissue when challenged with a high-fat diet. Maternal obesity induces DNAdemethylation in the promoter of zinc finger protein 423, which renders progenitor cells with a highadipogenic capacity. Maternal obesity demonstrates long-term effects on the adipogenic capacity ofprogenitor cells in offspring adipose tissue, demonstrating a developmental programming effect.ABSTRACT Maternal obesity (MO) programs offspring obesity and metabolic disorders, although theunderlying mechanisms remain poorly defined. Progenitor cells are the source of new adipocytes. Thepresent study aimed to test whether MO epigenetically predisposes adipocyte progenitors in the fat ofoffspring to adipogenic differentiation and subsequent depletion, which leads to a failure of adipose tissueplasticity under positive energy balance, contributing to adipose tissue metabolic dysfunction. C57BL/6female mice were fed either a control diet (10% energy from fat) or a high-fat diet (45% energy from fat)for 8 weeks before mating. Male offspring of control (Con) and obese (OB) dams were weaned onto aregular (Reg) or obesogenic (Obe) diet until 3 months of age. At weaning, male OB offspring had a higherexpression of Zinc finger protein 423 (zfp423), a key transcription factor in adipogenesis, as well as lowerDNA methylation of its promoter in progenitors of epididymal fat compared to Con offspring, which wascorrelated with enhanced adipogenic differentiation. At 3 months of age, progenitor density was 30.9 ±9.7% lower in OB/Obe compared to Con/Obe mice, accompanied by a limited expansion of the adipocytenumber when challenged with a high-energy diet. This difference was associated with lower DNAmethylation in the zfp423 promoter in the epididymal fat of OB/Obe offspring, which was correlated withgreater macrophage chemotactic protein-1 and hypoxia-inducible factor 1α expression. In summary, MOepigenetically limits the expansion capacity of offspring adipose tissue, providing an explanation for theadipose metabolic dysfunction of male offspring in the setting of MO.", "metadata": {}}
+{"_id": "13948920", "title": "", "text": "Quality Testing of Artemisinin-Based Antimalarial Drugs in Myanmar.Artemisinin-based combinationtherapies are the frontline treatment of Plasmodium falciparum malaria. The circulation of falsified andsubstandard artemisinin-based antimalarials in Southeast Asia has been a major predicament for themalaria elimination campaign. To provide an update of this situation, we purchased 153artemisinin-containing antimalarials, as convenience samples, in private drug stores from differentregions of Myanmar. The quality of these drugs in terms of their artemisinin derivative content was testedusing specific dipsticks for these artemisinin derivatives, as point-of-care devices. A subset of thesesamples was further tested by high-performance liquid chromatography (HPLC). This survey identifiedthat > 35% of the collected drugs were oral artesunate and artemether monotherapies. When tested withthe dipsticks, all but one sample passed the assays, indicating that the detected artemisinin derivativecontent corresponded approximately to the labeled contents. However, one artesunate injection samplewas found to contain no active ingredient at all by the dipstick assay and subsequent HPLC analysis. Thecontinued circulation of oral monotherapies and the description, for the first time, of falsified parenteralartesunate provides a worrisome picture of the antimalarial drug quality in Myanmar during the malariaelimination phase, a situation that deserves more oversight from regulatory authorities.", "metadata": {}}
+{"_id": "13949015", "title": "", "text": "LINE-1 Retrotransposition Activity in Human GenomesHighly active (i.e., \"hot\") long interspersedelement-1 (LINE-1 or L1) sequences comprise the bulk of retrotransposition activity in the humangenome; however, the abundance of hot L1s in the human population remains largely unexplored. Here,we used a fosmid-based, paired-end DNA sequencing strategy to identify 68 full-length L1s that aredifferentially present among individuals but are absent from the human genome reference sequence. Themajority of these L1s were highly active in a cultured cell retrotransposition assay. Genotyping 26elements revealed that two L1s are only found in Africa and that two more are absent from the H952subset of the Human Genome Diversity Panel. Therefore, these results suggest that hot L1s are moreabundant in the human population than previously appreciated, and that ongoing L1 retrotranspositioncontinues to be a major source of interindividual genetic variation.", "metadata": {}}
+{"_id": "13952658", "title": "", "text": "Immune cell promotion of metastasisMetastatic disease is the major cause of death from cancer, andimmunotherapy and chemotherapy have had limited success in reversing its progression. Data frommouse models suggest that the recruitment of immunosuppressive cells to tumours protects metastaticcancer cells from surveillance by killer cells, which nullifies the effects of immunotherapy and thusestablishes metastasis. Furthermore, in most cases, tumour-infiltrating immune cells differentiate intocells that promote each step of the metastatic cascade and thus are novel targets for therapy. In thisReview, we describe how tumour-infiltrating immune cells contribute to the metastatic cascade and wediscuss potential therapeutic strategies to target these cells.", "metadata": {}}
+{"_id": "13953762", "title": "", "text": "PICH: a DNA translocase specially adapted for processing anaphase bridge DNA.The Plk1-interactingcheckpoint helicase (PICH) protein localizes to ultrafine anaphase bridges (UFBs) in mitosis alongside acomplex of DNA repair proteins, including the Bloom's syndrome protein (BLM). However, very little isknown about the function of PICH or how it is recruited to UFBs. Using a combination of microfluidics,fluorescence microscopy, and optical tweezers, we have defined the properties of PICH in an in vitromodel of an anaphase bridge. We show that PICH binds with a remarkably high affinity to duplex DNA,resulting in ATP-dependent protein translocation and extension of the DNA. Most strikingly, the affinity ofPICH for binding DNA increases with tension-induced DNA stretching, which mimics the effect of themitotic spindle on a UFB. PICH binding also appears to diminish force-induced DNA melting. We propose amodel in which PICH recognizes and stabilizes DNA under tension during anaphase, thereby facilitatingthe resolution of entangled sister chromatids.", "metadata": {}}
+{"_id": "13955536", "title": "", "text": "The Dynamics of Genome-wide DNA Methylation Reprogramming in Mouse Primordial GermCellsGenome-wide DNA methylation reprogramming occurs in mouse primordial germ cells (PGCs) andpreimplantation embryos, but the precise dynamics and biological outcomes are largely unknown. Wehave carried out whole-genome bisulfite sequencing (BS-Seq) and RNA-Seq across key stages from E6.5epiblast to E16.5 PGCs. Global loss of methylation takes place during PGC expansion and migration withevidence for passive demethylation, but sequences that carry long-term epigenetic memory (imprints,CpG islands on the X chromosome, germline-specific genes) only become demethylated upon entry ofPGCs into the gonads. The transcriptional profile of PGCs is tightly controlled despite globalhypomethylation, with transient expression of the pluripotency network, suggesting that reprogrammingand pluripotency are inextricably linked. Our results provide a framework for the understanding of theepigenetic ground state of pluripotency in the germline.", "metadata": {}}
+{"_id": "13956305", "title": "", "text": "Major histocompatibility complex associations of ankylosing spondylitis are complex and involve furtherepistasis with ERAP1Ankylosing spondylitis (AS) is a common, highly heritable, inflammatory arthritis forwhich HLA-B*27 is the major genetic risk factor, although its role in the aetiology of AS remains elusive.To better understand the genetic basis of the MHC susceptibility loci, we genotyped 7,264 MHC SNPs in22,647 AS cases and controls of European descent. We impute SNPs, classical HLA alleles and amino-acidresidues within HLA proteins, and tested these for association to AS status. Here we show that in additionto effects due to HLA-B*27 alleles, several other HLA-B alleles also affect susceptibility. After controllingfor the associated haplotypes in HLA-B, we observe independent associations with variants in the HLA-A,HLA-DPB1 and HLA-DRB1 loci. We also demonstrate that the ERAP1 SNP rs30187 association is notrestricted only to carriers of HLA-B*27 but also found in HLA-B*40:01 carriers independently ofHLA-B*27 genotype.", "metadata": {}}
+{"_id": "13958154", "title": "", "text": "RNA sequencing identifies dysregulation of the human pancreatic islet transcriptome by the saturatedfatty acid palmitate.Pancreatic β-cell dysfunction and death are central in the pathogenesis of type 2diabetes (T2D). Saturated fatty acids cause β-cell failure and contribute to diabetes development ingenetically predisposed individuals. Here we used RNA sequencing to map transcripts expressed in fivepalmitate-treated human islet preparations, observing 1,325 modified genes. Palmitate induced fatty acidmetabolism and endoplasmic reticulum (ER) stress. Functional studies identified novel mediators ofadaptive ER stress signaling. Palmitate modified genes regulating ubiquitin and proteasome function,autophagy, and apoptosis. Inhibition of autophagic flux and lysosome function contributed to lipotoxicity.Palmitate inhibited transcription factors controlling β-cell phenotype, including PAX4 and GATA6.Fifty-nine T2D candidate genes were expressed in human islets, and 11 were modified by palmitate.Palmitate modified expression of 17 splicing factors and shifted alternative splicing of 3,525 transcripts.Ingenuity Pathway Analysis of modified transcripts and genes confirmed that top changed functionsrelated to cell death. Database for Annotation, Visualization and Integrated Discovery (DAVID) analysis oftranscription factor binding sites in palmitate-modified transcripts revealed a role for PAX4, GATA, andthe ER stress response regulators XBP1 and ATF6. This human islet transcriptome study identified novelmechanisms of palmitate-induced β-cell dysfunction and death. The data point to cross talk betweenmetabolic stress and candidate genes at the β-cell level.", "metadata": {}}
+{"_id": "13959707", "title": "", "text": "The Ratio of Monocytes to Lymphocytes in Peripheral Blood Correlates with Increased Susceptibility toClinical Malaria in Kenyan ChildrenBACKGROUND Plasmodium falciparum malaria remains a major causeof illness and death in sub-Saharan Africa. Young children bear the brunt of the disease and though olderchildren and adults suffer relatively fewer clinical attacks, they remain susceptible to asymptomatic P.falciparum infection. A better understanding of the host factors associated with immunity to clinicalmalaria and the ability to sustain asymptomatic P. falciparum infection will aid the development ofimproved strategies for disease prevention. METHODS AND FINDINGS Here we investigate whether fulldifferential blood counts can predict susceptibility to clinical malaria among Kenyan children sampled atfive annual cross-sectional surveys. We find that the ratio of monocytes to lymphocytes, measured inperipheral blood at the time of survey, directly correlates with risk of clinical malaria during follow-up.This association is evident among children with asymptomatic P. falciparum infection at the time the cellcounts are measured (Hazard ratio (HR)  =  2.7 (95% CI 1.42, 5.01, P  =  0.002) but not in thosewithout detectable parasitaemia (HR  =  1.0 (95% CI 0.74, 1.42, P  =  0.9). CONCLUSIONS We proposethat the monocyte to lymphocyte ratio, which is easily derived from routine full differential blood counts,reflects an individual's capacity to mount an effective immune response to P. falciparum infection.", "metadata": {}}
+{"_id": "13963620", "title": "", "text": "Dynamic analysis of filopodial interactions during the zippering phase of Drosophila dorsal closure.Dorsalclosure is a paradigm epithelial fusion episode that occurs late in Drosophila embryogenesis and leads tosealing of a midline hole by bonding of two opposing epithelial sheets. The leading edge epithelial cellsexpress filopodia and fusion is dependent on interdigitation of these filopodia to prime formation ofadhesions. Since the opposing epithelia are molecularly patterned there must exist some mechanism foraccurately aligning the two sheets across this fusion seam. To address this, we generated a fly in whichRFP-Moesin and GFP-Moesin are expressed in mutually exclusive stripes within each segment using theengrailed and patched promoters. We observe mutually exclusive interactions between the filopodia ofengrailed and patched cells. Interactions between filopodia from matching cells leads to formation oftethers between them, and these tethers can pull misaligned epithelial sheets into alignment. Filopodialmatching also occurs during repair of laser wounds in the ventral epithelium, and so this behaviour is notrestricted to leading edge cells during dorsal closure. Finally, we characterise the behaviour of apatched-expressing cell that we observe within the engrailed region of segments A1-A5, and provideevidence that this cell contributes to cell matching.", "metadata": {}}
+{"_id": "13964633", "title": "", "text": "Expression of Versican 3′-Untranslated Region Modulates Endogenous MicroRNA FunctionsBACKGROUNDMature microRNAs (miRNAs) are single-stranded RNAs that regulate post-transcriptional gene expression.In our previous study, we have shown that versican 3'UTR, a fragment of non-coding transcript, has theability to antagonize miR-199a-3p function thereby regulating expression of the matrix proteins versicanand fibronectin, and thus resulting in enhanced cell-cell adhesion and organ adhesion. However, theimpact of this non-coding fragment on tumorigenesis is yet to be determined. METHODS AND FINDINGSUsing computational prediction confirmed with in vitro and in vivo experiments, we report that theexpression of versican 3'UTR not only antagonizes miR-199a-3p but can also lower its steady stateexpression. We found that expression of versican 3'UTR in a mouse breast carcinoma cell line, 4T1,decreased miR-199a-3p levels. The decrease in miRNA activity consequently translated into differences intumor growth. Computational analysis indicated that both miR-199a-3p and miR-144 targeted a cell cycleregulator, Rb1. In addition, miR-144 and miR-136, which have also been shown to interact with versican3'UTR, was found to target PTEN. Expression of Rb1 and PTEN were up-regulated synergistically in vitroand in vivo, suggesting that the 3'UTR binds and modulates miRNA activities, freeing Rb1 and PTENmRNAs for translation. In tumor formation assays, cells transfected with the 3'UTR formed smallertumors compared with cells transfected with a control vector. CONCLUSION Our results demonstratedthat a 3'UTR fragment can be used to modulate miRNA functions. Our study also suggests that miRNAs inthe cancer cells are more susceptible to degradation, due to its interaction with a non-coding 3'UTR. Thisnon-coding component of mRNA may be used retrospectively to modulate miRNA activities.", "metadata": {}}
+{"_id": "13965483", "title": "", "text": "Prophylactic and therapeutic efficacy of the epitope vaccine CTB-UA against Helicobacter pylori infectionin a BALB/c mice modelEpitope vaccine based on the enzyme urease of Helicobacter pylori is a promisingoption for prophylactic and therapeutic vaccination against H. pylori infection. In our previous study, theepitope vaccine CTB-UA, which was composed of the mucosal adjuvant cholera toxin B subunit (CTB) andan epitope (UreA183–203) from the H. pylori urease A subunit (UreA) was constructed. This particularvaccine was shown to have good immunogenicity and immunoreactivity and could induce specificneutralizing antibodies, which exhibited effectively inhibitory effects on the enzymatic activity of H. pyloriurease. In this study, the prophylactic and therapeutic efficacy of the epitope vaccine CTB-UA wasevaluated in a BALB/c mice model. The experimental results indicated that oral prophylactic ortherapeutic immunization with CTB-UA significantly decreased H. pylori colonization compared with oralimmunization with PBS. The results also revealed that the protection was correlated with antigen-specificIgG, IgA, and mucosal secretory IgA antibody responses. CTB-UA may be a promising vaccine candidatefor the control of H. pylori infection.", "metadata": {}}
+{"_id": "13966946", "title": "", "text": "Spatial co-distribution of neglected tropical diseases in the east African great lakes region: revisiting thejustification for integrated control.OBJECTIVE To determine spatial patterns of co-endemicity ofschistosomiasis mansoni and the soil-transmitted helminths (STHs) Ascaris lumbricoides, Trichuristrichiura and hookworm in the Great Lakes region of East Africa, to help plan integrated neglected tropicaldisease programmes in this region. METHOD Parasitological surveys were conducted in Uganda,Tanzania, Kenya and Burundi in 28 213 children in 404 schools. Bayesian geostatistical models were usedto interpolate prevalence of these infections across the study area. Interpolated prevalence maps wereoverlaid to determine areas of co-endemicity. RESULTS In the Great Lakes region, prevalence was 18.1%for Schistosoma mansoni, 50.0% for hookworm, 6.8% for A. lumbricoides and 6.8% for T. trichiura.Hookworm infection was ubiquitous, whereas S. mansoni, A. lumbricoides and T. trichiura were highlyfocal. Most areas were endemic (prevalence >or=10%) or hyperendemic (prevalence >or=50%) for oneor more STHs, whereas endemic areas for schistosomiasis mansoni were restricted to foci adjacent largeperennial water bodies. CONCLUSION Because of the ubiquity of hookworm, treatment programmes arerequired for STH throughout the region but efficient schistosomiasis control should only be targeted atlimited high-risk areas. Therefore, integration of schistosomiasis with STH control is only indicated inlimited foci in East Africa.", "metadata": {}}
+{"_id": "13969173", "title": "", "text": "Direct conversion of patient fibroblasts demonstrates non-cell autonomous toxicity of astrocytes to motorneurons in familial and sporadic ALS.Amyotrophic lateral sclerosis (ALS) causes motor neurondegeneration, paralysis, and death. Accurate disease modeling, identifying disease mechanisms, anddeveloping therapeutics is urgently needed. We previously reported motor neuron toxicity throughpostmortem ALS spinal cord-derived astrocytes. However, these cells can only be harvested after death,and their expansion is limited. We now report a rapid, highly reproducible method to convert adult humanfibroblasts from living ALS patients to induced neuronal progenitor cells and subsequent differentiationinto astrocytes (i-astrocytes). Non-cell autonomous toxicity to motor neurons is found following cocultureof i-astrocytes from familial ALS patients with mutation in superoxide dismutase or hexanucleotideexpansion in C9orf72 (ORF 72 on chromosome 9) the two most frequent causes of ALS. Remarkably,i-astrocytes from sporadic ALS patients are as toxic as those with causative mutations, suggesting acommon mechanism. Easy production and expansion of i-astrocytes now enables rapid disease modelingand high-throughput drug screening to alleviate astrocyte-derived toxicity.", "metadata": {}}
+{"_id": "13980338", "title": "", "text": "Combined Single-Cell Functional and Gene Expression Analysis Resolves Heterogeneity within Stem CellPopulationsHeterogeneity within the self-renewal durability of adult hematopoietic stem cells (HSCs)challenges our understanding of the molecular framework underlying HSC function. Gene expressionstudies have been hampered by the presence of multiple HSC subtypes and contaminating non-HSCs inbulk HSC populations. To gain deeper insight into the gene expression program of murine HSCs, wecombined single-cell functional assays with flow cytometric index sorting and single-cell gene expressionassays. Through bioinformatic integration of these datasets, we designed an unbiased sorting strategythat separates non-HSCs away from HSCs, and single-cell transplantation experiments using the enrichedpopulation were combined with RNA-seq data to identify key molecules that associate with long-termdurable self-renewal, producing a single-cell molecular dataset that is linked to functional stem cellactivity. Finally, we demonstrated the broader applicability of this approach for linking key molecules withdefined cellular functions in another stem cell system.", "metadata": {}}
+{"_id": "13989491", "title": "", "text": "Acids: Structures, Properties, and Functions (University Science Books, Sausalito, CA, 2000).Humansexpressing a defective form of the transcription factor AIRE (autoimmune regulator) develop multiorganautoimmune disease. We used aire- deficient mice to test the hypothesis that this transcription factorregulates autoimmunity by promoting the ectopic expression of peripheral tissue- restricted antigens inmedullary epithelial cells of the thymus. This hypothesis proved correct. The mutant animals exhibited adefined profile of autoimmune diseases that depended on the absence of aire in stromal cells of thethymus. Aire-deficient thymic medullary epithelial cells showed a specific reduction in ectopictranscription of genes encoding peripheral antigens. These findings highlight the importance of thymicallyimposed \"central\" tolerance in controlling autoimmunity.", "metadata": {}}
+{"_id": "13992047", "title": "", "text": "Directed Actin Polymerization Is the Driving Force for Epithelial Cell–Cell AdhesionWe have found thatepithelial cells engage in a process of cadherin-mediated intercellular adhesion that utilizes calcium andactin polymerization in unexpected ways. Calcium stimulates filopodia, which penetrate and embed intoneighboring cells. E-cadherin complexes cluster at filopodia tips, generating a two-rowed zipper ofembedded puncta. Opposing cell surfaces are clamped by desmosomes, while vinculin, zyxin, VASP, andMena are recruited to adhesion zippers by a mechanism that requires alpha-catenin. Actin reorganizesand polymerizes to merge puncta into a single row and seal cell borders. In keratinocytes either null foralpha-catenin or blocked in VASP/Mena function, filopodia embed, but actin reorganization/polymerizationis prevented, and membranes cannot seal. Taken together, a dynamic mechanism for intercellularadhesion is unveiled involving calcium-activated filopodia penetration and VASP/Mena-dependent actinreorganization/polymerization.", "metadata": {}}
+{"_id": "14019636", "title": "", "text": "Ribosomal DNA copy number loss and sequence variation in cancerRibosomal DNA is one of the mostvariable regions in the human genome with respect to copy number. Despite the importance of rDNA forcellular function, we know virtually nothing about what governs its copy number, stability, and sequencein the mammalian genome due to challenges associated with mapping and analysis. We appliedcomputational and droplet digital PCR approaches to measure rDNA copy number in normal and cancerstates in human and mouse genomes. We find that copy number and sequence can change in cancergenomes. Counterintuitively, human cancer genomes show a loss of copies, accompanied by global copynumber co-variation. The sequence can also be more variable in the cancer genome. Cancer genomeswith lower copies have mutational evidence of mTOR hyperactivity. The PTEN phosphatase is a tumorsuppressor that is critical for genome stability and a negative regulator of the mTOR kinase pathway.Surprisingly, but consistent with the human cancer genomes, hematopoietic cancer stem cells from aPten-/- mouse model for leukemia have lower rDNA copy number than normal tissue, despite increasedproliferation, rRNA production, and protein synthesis. Loss of copies occurs early and is associated withhypersensitivity to DNA damage. Therefore, copy loss is a recurrent feature in cancers associated withmTOR activation. Ribosomal DNA copy number may be a simple and useful indicator of whether a cancerwill be sensitive to DNA damaging treatments.", "metadata": {}}
+{"_id": "14021596", "title": "", "text": "The association of Red cell distribution width and in-hospital mortality in older adults admitted to theemergency departmentBACKGROUND The objective of the study was to test the hypothesis that elevatedred cell distribution width (RDW) at admission increases the risk of mortality in older patients admitted tothe emergency department (ED). METHODS We performed a retrospective analysis of patients admittedto the ED between May 2013 and October 2013. We included patients who were older than 65 years whovisited the ED with any medical problems. Baseline RDW values were measured at the time of admissionto the ED. The primary outcome was all-cause in-hospital mortality. Multivariate logistic analysis wasperformed. RESULTS A total of 1,990 patients were finally included in this study. The mean age was 75years (SD 7), and 936 (47 %) subjects were male. The in-hospital mortality rate was 3.76 % (74patients). RDW values higher in non-survivors than in survivors (15.9 ± 2.5 vs. 13.8 ± 1.7, p < 0.001).Multivariate logistic analysis showed that RDW was associated with all-cause in-hospital mortality afteradjusting for other confounding factors. DISCUSSION RDW value at admission is an independentpredictor of all-cause in-hospital mortality among patients older than 65 years. After adjustment formultiple confounders, the all-cause in-hospital mortality rate increased by 21.8% for each 1% increase inRDW. CONCLUSION These results show that RDW at admission is associated with in-hospital mortalityamong patients older than 65. Thus, RDW at admission may represent a surrogate marker of diseaseseverity. We caution against using these findings to aid clinical decision-making process until they areexternally validated.", "metadata": {}}
+{"_id": "14050257", "title": "", "text": "Gene regulation by the act of long non-coding RNA transcriptionLong non-protein-coding RNAs (lncRNAs)are proposed to be the largest transcript class in the mouse and human transcriptomes. Two importantquestions are whether all lncRNAs are functional and how they could exert a function. Several lncRNAshave been shown to function through their product, but this is not the only possible mode of action. Inthis review we focus on a role for the process of lncRNA transcription, independent of the lncRNA product,in regulating protein-coding-gene activity in cis. We discuss examples where lncRNA transcription leads togene silencing or activation, and describe strategies to determine if the lncRNA product or itstranscription causes the regulatory effect.", "metadata": {}}
+{"_id": "14060030", "title": "", "text": "Life and death of cardiac stem cells: a paradigm shift in cardiac biology.The recognition that myocytemitosis occurs in the fetal, neonatal, adult, and hypertrophied heart and that a pool of primitive,undifferentiated cells is present in the myocardium has put forward a different view of the biology of theheart. The new paradigm suggests that myocyte formation is preserved during postnatal life, inadulthood or senescence, pointing to a remarkable growth reserve of the heart throughout the course oflife of the organism. This article reviews a large body of novel information, which has been obtained inthe last 2 decades, in favor of the notion that the mammalian heart has the inherent ability tocontinuously replace its parenchymal cells and that this unexpected characteristic has importantimplications in understanding myocardial homeostasis, cardiac aging, and tissue repair. The paradigmthat the heart is a postmitotic organ incapable of regenerating parenchymal cells was established in the1970s, and this dogma has profoundly conditioned basic and clinical research in cardiology for the last 3decades. On the basis of this paradigm, cardiomyocytes undergo cellular hypertrophy1,2 but cannot bereplaced either by entry into the cell cycle of a subpopulation of nonterminally differentiated myocytes orby activation of a pool of primitive cells that become committed to the myocyte lineage. The onlyresponse of cardiomyocytes to stress is hypertrophy and/or death. Therefore, a tremendous effort wasmade to identify the molecular mechanisms of myocyte hypertrophy and their genetic control. Asophisticated knowledge of various signaling pathways has been achieved, and our understanding of thebiology of hypertrophic myocyte growth has advanced markedly.3 An array of new technologies has beenintroduced that has led to a scientific revolution in terms of questions, approaches, and interpretation ofexperimental results. Despite this enormous progress in our understanding of basic mechanisms ofhypertrophy, however, very little …", "metadata": {}}
+{"_id": "14075252", "title": "", "text": "Paraneoplastic thrombocytosis: the secrets of tumor self-promotion.Paraneoplastic thrombocytosis isassociated with many solid tumors and often correlates with reduced survival. Recent studies suggestthat a pathogenic feed back loop may be operative between platelets and tumor cells, with reciprocalinteractions between tumor growth/metastasis and thrombocytosis/platelet activation. Specific molecularpathways have been identified in which tumors can stimulate platelet production and activation; activatedplatelets can, in turn, promote tumor growth and metastasis. Taken together, these findings provideexciting new potential targets for therapeutic intervention.", "metadata": {}}
+{"_id": "14079881", "title": "", "text": "Perceived age as clinically useful biomarker of ageing: cohort study.OBJECTIVE To determine whetherperceived age correlates with survival and important age related phenotypes. DESIGN Follow-up study,with survival of twins determined up to January 2008, by which time 675 (37%) had died. SETTINGPopulation based twin cohort in Denmark. PARTICIPANTS 20 nurses, 10 young men, and 11 older women(assessors); 1826 twins aged >or=70. MAIN OUTCOME MEASURES Assessors: perceived age of twinsfrom photographs. Twins: physical and cognitive tests and molecular biomarker of ageing (leucocytetelomere length). RESULTS For all three groups of assessors, perceived age was significantly associatedwith survival, even after adjustment for chronological age, sex, and rearing environment. Perceived agewas still significantly associated with survival after further adjustment for physical and cognitivefunctioning. The likelihood that the older looking twin of the pair died first increased with increasingdiscordance in perceived age within the twin pair-that is, the bigger the difference in perceived age withinthe pair, the more likely that the older looking twin died first. Twin analyses suggested that commongenetic factors influence both perceived age and survival. Perceived age, controlled for chronological ageand sex, also correlated significantly with physical and cognitive functioning as well as with leucocytetelomere length. CONCLUSION Perceived age-which is widely used by clinicians as a general indication ofa patient's health-is a robust biomarker of ageing that predicts survival among those aged >or=70 andcorrelates with important functional and molecular ageing phenotypes.", "metadata": {}}
+{"_id": "14082855", "title": "", "text": "Inflammatory Reaction as Determinant of Foreign Body Reaction Is an Early and Susceptible Event afterMesh ImplantationPURPOSE To investigate and relate the ultrashort-term and long-term courses ofdeterminants for foreign body reaction as biocompatibility predictors for meshes in an animal model.MATERIALS AND METHODS Three different meshes (TVT, UltraPro, and PVDF) were implanted in sheep.Native and plasma coated meshes were placed bilaterally: (a) interaperitoneally, (b) as fascia onlay, and(c) as muscle onlay (fascia sublay). At 5 min, 20 min, 60 min, and 120 min meshes were explanted andhistochemically investigated for inflammatory infiltrate, macrophage infiltration, vessel formation,myofibroblast invasion, and connective tissue accumulation. The results were related to long-term valuesover 24 months. RESULTS Macrophage invasion reached highest extents with up to 60% in short-termand decreased within 24 months to about 30%. Inflammatory infiltrate increased within the first 2 hours,the reached levels and the different extents and ranking among the investigated meshes remained stableduring long-term follow up. For myofibroblasts, connective tissue, and CD31+ cells, no activity wasdetected during the first 120 min. CONCLUSION The local inflammatory reaction is an early andsusceptible event after mesh implantation. It cannot be influenced by prior plasma coating and does notdepend on the localisation of implantation.", "metadata": {}}
+{"_id": "14083283", "title": "", "text": "Riesz pyramids for fast phase-based video magnificationWe present a new compact image pyramidrepresentation, the Riesz pyramid, that can be used for real-time phase-based motion magnification. Ournew representation is less overcomplete than even the smallest two orientation, octave-bandwidthcomplex steerable pyramid, and can be implemented using compact, efficient linear filters in the spatialdomain. Motion-magnified videos produced with this new representation are of comparable quality tothose produced with the complex steerable pyramid. When used with phase-based video magnification,the Riesz pyramid phase-shifts image features along only their dominant orientation rather than everyorientation like the complex steerable pyramid.", "metadata": {}}
+{"_id": "14092737", "title": "", "text": "Alpha-Synuclein Induces Lysosomal Rupture and Cathepsin Dependent Reactive Oxygen SpeciesFollowing Endocytosisα-synuclein dysregulation is a critical aspect of Parkinson's disease pathology.Recent studies have observed that α-synuclein aggregates are cytotoxic to cells in culture and that thistoxicity can be spread between cells. However, the molecular mechanisms governing this cytotoxicity andspread are poorly characterized. Recent studies of viruses and bacteria, which achieve their cytoplasmicentry by rupturing intracellular vesicles, have utilized the redistribution of galectin proteins as a tool tomeasure vesicle rupture by these organisms. Using this approach, we demonstrate that α-synucleinaggregates can induce the rupture of lysosomes following their endocytosis in neuronal cell lines. Thisrupture can be induced by the addition of α-synuclein aggregates directly into cells as well as bycell-to-cell transfer of α-synuclein. We also observe that lysosomal rupture by α-synuclein induces acathepsin B dependent increase in reactive oxygen species (ROS) in target cells. Finally, we observe thatα-synuclein aggregates can induce inflammasome activation in THP-1 cells. Lysosomal rupture is knownto induce mitochondrial dysfunction and inflammation, both of which are well established aspects ofParkinson's disease, thus connecting these aspects of Parkinson's disease to the propagation ofα-synuclein pathology in cells.", "metadata": {}}
+{"_id": "14103509", "title": "", "text": "Mechanistic Fracture Criteria For The Failure Of Human Cortical BoneA mechanistic understanding offracture in human bone is critical to predicting fracture risk associated with age and disease. Despiteextensive work, a mechanistic framework for describing how the microstructure affects the failure of boneis lacking. Although micromechanical models incorporating local failure criteria have been developed formetallic and ceramic materials, few such models exist for biological materials. In fact, there is no proof tosupport the widely held belief that fracture in bone is locally strain-controlled, as for example has beenshown for ductile fracture in metallic materials. In the present study, we provide such evidence through anovel series of experiments involving a double-notch-bend geometry, designed to shed light on thenature of the critical failure events in bone. We examine how the propagating crack interacts with thebone microstructure to provide some mechanistic understanding of fracture and to define how propertiesvary with orientation. It was found that fracture in human cortical bone is consistent withstrain-controlled failure, and the influence of microstructure can be described in terms of severaltoughening mechanisms. We provide estimates of the relative importance of these mechanisms, such asuncracked-ligament bridging.", "metadata": {}}
+{"_id": "14105446", "title": "", "text": "Inhibition of limb regeneration in the axolotl after treatment of the skin with actinomycin D.In thisexperiment actinomycin D was used to explore the action of the wound epidermis on underlying tissuesduring limb regeneration. In axolotl forelimbs the skin was removed from the elbow to the shoulder. Skinfrom the right limbs was soaked for three hours in actinomycin D (5.0 or 10.0 μg/ml 0.6% NaCl). Forcontrols, skin from left limbs was soaked in 0.6% NaCl for the same period of time. Each piece of skinwas orthotopically replanted, and both limbs were amputated through the treated skin, proximal to theelbow. After an initial healing period, the control limbs regenerated normally. Except for a slightly palercolor, limbs bearing actinomycin-treated skin were indistinguishable from the controls, both grossly andhistologically, during the first week following amputation. While the control limbs formed early blastemas,no grossly visible evidence of regeneration was apparent in the experimental limbs, but histologicallysome dedifferentiation was occurring. Normally three to four digits were seen in the control regeneratesbefore blastemas appeared on the experimental limbs. By 35–40 days blastemas had appeared on mostexperimental limbs. These developed very rapidly, and within a short time many of them had attainedlevels of development close to the controls. Actinomycin D temporarily suppresses formation of the apicalepidermal cap and the subsequent aggregation of dedifferentiated cells into a blastema. When the effectwears off, an apical cap forms and the dedifferentiated cells quickly organize into a blastema and begin todifferentiate.", "metadata": {}}
+{"_id": "14116046", "title": "", "text": "Retinoic acid-related orphan receptors α and γ: key regulators of lipid/glucose metabolism, inflammation,and insulin sensitivityRetinoic acid-related orphan receptors RORα and RORγ play a regulatory role inlipid/glucose homeostasis and various immune functions, and have been implicated in metabolicsyndrome and several inflammatory diseases. RORα-deficient mice are protected against age- anddiet-induced obesity, hepatosteatosis, and insulin resistance. The resistance to hepatosteatosis inRORα-deficient mice is related to the reduced expression of several genes regulating lipid synthesis,transport, and storage. Adipose tissue-associated inflammation, which plays a critical role in thedevelopment of insulin resistance, is considerably diminished in RORα-deficient mice as indicated by thereduced infiltration of M1 macrophages and decreased expression of many proinflammatory genes.Deficiency in RORγ also protects against diet-induced insulin resistance by a mechanism that appearsdifferent from that in RORα deficiency. Recent studies indicated that RORs provide an important linkbetween the circadian clock machinery and its regulation of metabolic genes and metabolic syndrome. Asligand-dependent transcription factors, RORs may provide novel therapeutic targets in the managementof obesity and associated metabolic diseases, including hepatosteatosis, adipose tissue-associatedinflammation, and insulin resistance.", "metadata": {}}
+{"_id": "14118484", "title": "", "text": "ERS/ESTS clinical guidelines on fitness for radical therapy in lung cancer patients (surgery andchemo-radiotherapy).A collaboration of multidisciplinary experts on the functional evaluation of lungcancer patients has been facilitated by the European Respiratory Society (ERS) and the European Societyof Thoracic Surgery (ESTS), in order to draw up recommendations and provide clinicians with clear,up-to-date guidelines on fitness for surgery and chemo-radiotherapy. The subject was divided intodifferent topics, which were then assigned to at least two experts. The authors searched the literatureaccording to their own strategies, with no central literature review being performed. The draft reportswritten by the experts on each topic were reviewed, discussed and voted on by the entire expert panel.The evidence supporting each recommendation was summarised, and graded as described by theScottish Intercollegiate Guidelines Network Grading Review Group. Clinical practice guidelines weregenerated and finalized in a functional algorithm for risk stratification of the lung resection candidates,emphasising cardiological evaluation, forced expiratory volume in 1 s, systematic carbon monoxide lungdiffusion capacity and exercise testing. Contrary to lung resection, for which the scientific evidences aremore robust, we were unable to recommend any specific test, cut-off value, or algorithm beforechemo-radiotherapy due to the lack of data. We recommend that lung cancer patients should bemanaged in specialised settings by multidisciplinary teams.", "metadata": {}}
+{"_id": "14119470", "title": "", "text": "The Ran GTPase regulates mitotic spindle assemblyRan is an abundant nuclear GTPase with a clear role innuclear transport during interphase but with roles in mitotic regulation that are less well understood. Thenucleotide-binding state of Ran is regulated by a GTPase activating protein, RanGAP1, and by a guaninenucleotide exchange factor, RCC1. Ran also interacts with a guanine nucleotide dissociation inhibitor,RanBP1. RanBP1 has a high affinity for GTP-bound Ran, and it acts as a cofactor for RanGAP1, increasingthe rate of GAP-mediated GTP hydrolysis on Ran approximately tenfold. RanBP1 levels oscillate during thecell cycle [4], and increased concentrations of RanBP1 prolong mitosis in mammalian cells and in Xenopusegg extracts (our unpublished observations). We investigated how increased concentrations of RanBP1disturb mitosis. We found that spindle assembly is dramatically disrupted when exogenous RanBP1 isadded to M phase Xenopus egg extracts. We present evidence that the role of Ran in spindle assembly isindependent of nuclear transport and is probably mediated through changes in microtubule dynamics.", "metadata": {}}
+{"_id": "14121786", "title": "", "text": "A summary of the effects of antihypertensive medications on measured blood pressure.BACKGROUNDEpidemiologic analysis of family data on blood pressure (BP) is often compromised by the effects ofantihypertensive medications. A review of numerous clinical trials that investigated the effects ofBP-lowering medications is summarized here. METHODS Published clinical trials, including 137 clinicaltrials with monodrug therapies and 28 clinical trials of combination drug therapies with a total of 11,739participants, were reviewed from PubMed. Six major classes/groups of antihypertensive medications werecategorized by ethnicity, including angiotensin-converting enzyme (ACE) inhibitors, alpha1-blockers,cardioselective beta-blockers (beta1-blockers), calcium channel blockers, thiazide and thiazide-likediuretics, and loop diuretics. RESULTS Using sitting or supine BP, for ethnic groups combined, monodrugtherapy with ACE inhibitors showed a weighted average effect of lowering the systolic and diastolic BP by12.5/9.5 mm Hg; alpha1-blockers by 15.5/11.7 mm Hg; beta1-blockers by 14.8/12.2 mm Hg; calciumchannel blockers by 15.3/10.5 mm Hg; thiazide diuretics by 15.3/9.8 mm Hg; and loop diuretics by15.8/8.2 mm Hg. However, ACE inhibitors, alpha1-blockers, and beta1-blockers were less effective inAfrican Americans than in non-African Americans, whereas calcium channel blockers, thiazide diuretics,and loop diuretics were more effective in African Americans than in non-African Americans. For two-drugcombination therapy with ethnic groups combined, the BP-lowering effect of the second medication, whencompared to its effect as monodrug therapy, was 84% and 65% for systolic and diastolic BP,respectively. CONCLUSIONS The BP-lowering effects reported here may be used to impute thepretreatment BP levels, which can improve the information content and hence the power of epidemiologicanalysis in studies where use of antihypertensive medications is a confounding factor in the BPmeasurements.", "metadata": {}}
+{"_id": "14128314", "title": "", "text": "Stem Cells and Early Lineage DevelopmentThe recent derivation of pluripotent stem cell lines from anumber of different sources, including reprogrammed adult somatic cells, raises the issue of thedevelopmental equivalence of these different pluripotent states. At least two different states representingthe epiblast progenitors in the blastocyst and the pluripotent progenitors of the later gastrulating embryohave been recognized. Understanding the initial developmental status of the different pluripotent lines iscritical for defining starting conditions for differentiation toward therapeutically relevant cell types.", "metadata": {}}
+{"_id": "14131683", "title": "", "text": "Divergent clonal evolution of castration resistant neuroendocrine prostate cancerAn increasinglyrecognized resistance mechanism to androgen receptor (AR)-directed therapy in prostate cancer involvesepithelial plasticity, in which tumor cells demonstrate low to absent AR expression and often haveneuroendocrine features. The etiology and molecular basis for this 'alternative' treatment-resistant cellstate remain incompletely understood. Here, by analyzing whole-exome sequencing data of metastaticbiopsies from patients, we observed substantial genomic overlap between castration-resistant tumorsthat were histologically characterized as prostate adenocarcinomas (CRPC-Adeno) and neuroendocrineprostate cancer (CRPC-NE); analysis of biopsy samples from the same individuals over time points to amodel most consistent with divergent clonal evolution. Genome-wide DNA methylation analysis revealedmarked epigenetic differences between CRPC-NE tumors and CRPC-Adeno, and also designated samplesof CRPC-Adeno with clinical features of AR independence as CRPC-NE, suggesting that epigeneticmodifiers may play a role in the induction and/or maintenance of this treatment-resistant state. Thisstudy supports the emergence of an alternative, 'AR-indifferent' cell state through divergent clonalevolution as a mechanism of treatment resistance in advanced prostate cancer.", "metadata": {}}
+{"_id": "14145440", "title": "", "text": "S-phase-promoting cyclin-dependent kinases prevent re-replication by inhibiting the transition ofreplication origins to a pre-replicative stateBACKGROUND DNA replication and mitosis are triggered byactivation of kinase complexes, each made up of a cyclin and a cyclin-dependent kinase (Cdk). It hadseemed possible that the association of Cdks with different classes of cyclins specifies whether S phase(replication) or M phase (mitosis) will occur. The recent finding that individual B-type cyclins (encoded bythe genes CLB1-CLB6) can have functions in both processes in the budding yeast Saccharomycescerevisiae casts doubt on this notion. RESULTS S. cerevisiae strains lacking C1b1-C1b4 undergo DNAreplication once but fail to enter mitosis. We have isolated mutations in two genes, SIM1 and SIM2 (SIM2is identical to SEC72), which allow such cells to undergo an extra round of DNA replication withoutmitosis. The Clb5 kinase, which promotes S phase, remains active during the G2-phase arrest of cells ofthe parental strain, but its activity declines rapidly in sim mutants. Increased expression of the CLB5gene prevents re-replication. Thus, a cyclin B-kinase that promotes DNA replication in G1-phase cells canprevent re-replication in G2-phase cells. Inactivation of C1b kinases by expression of the specificC1b-Cdk1 inhibitor p40SIC1 is sufficient to induce a prereplicative state at origins of replication in cellsblocked in G2/M phase by nocodazole. Re-activation of C1b-Cdk1 kinases induces a second round of DNAreplication. CONCLUSIONS We propose that S-phase-promoting cyclin B--Cdk complexes preventre-replication during S, G2 and M phases by inhibiting the transition of replication origins to apre-replicative state. This model can explain both why origins 'fire' only once per S phase and why Sphase is dependent on completion of the preceding M phase.", "metadata": {}}
+{"_id": "14149065", "title": "", "text": "E-cadherin engagement stimulates proliferation via Rac1E-cadherin has been linked to the suppression oftumor growth and the inhibition of cell proliferation in culture. We observed that progressively decreasingthe seeding density of normal rat kidney-52E (NRK-52E) or MCF-10A epithelial cells from confluence,indeed, released cells from growth arrest. Unexpectedly, a further decrease in seeding density so thatcells were isolated from neighboring cells decreased proliferation. Experiments using microengineeredsubstrates showed that E-cadherin engagement stimulated the peak in proliferation at intermediateseeding densities, and that the proliferation arrest at high densities did not involve E-cadherin, but ratherresulted from a crowding-dependent decrease in cell spreading against the underlying substrate. Rac1activity, which was induced by E-cadherin engagement specifically at intermediate seeding densities, wasrequired for the cadherin-stimulated proliferation, and the control of Rac1 activation by E-cadherin wasmediated by p120-catenin. Together, these findings demonstrate a stimulatory role for E-cadherin inproliferative regulation, and identify a simple mechanism by which cell–cell contact may trigger or inhibitepithelial cell proliferation in different settings.", "metadata": {}}
+{"_id": "14155726", "title": "", "text": "Structure of Actin-related protein 8 and its contribution to nucleosome bindingNuclear actin-relatedproteins (Arps) are subunits of several chromatin remodelers, but their molecular functions within thesecomplexes are unclear. We report the crystal structure of the INO80 complex subunit Arp8 in itsATP-bound form. Human Arp8 has several insertions in the conserved actin fold that explain its inabilityto polymerize. Most remarkably, one insertion wraps over the active site cleft and appears to rigidify thedomain architecture, while active site features shared with actin suggest an allosterically controlledATPase activity. Quantitative binding studies with nucleosomes and histone complexes reveal that Arp8and the Arp8-Arp4-actin-HSA sub-complex of INO80 strongly prefer nucleosomes and H3-H4 tetramersover H2A-H2B dimers, suggesting that Arp8 functions as a nucleosome recognition module. In contrast,Arp4 prefers free (H3-H4)(2) over nucleosomes and may serve remodelers through binding to(dis)assembly intermediates in the remodeling reaction.", "metadata": {}}
+{"_id": "14171859", "title": "", "text": "Regulation of β-Adrenergic Receptor Signaling by S-Nitrosylation of G-Protein-Coupled Receptor Kinase2beta-adrenergic receptors (beta-ARs), prototypic G-protein-coupled receptors (GPCRs), play a criticalrole in regulating numerous physiological processes. The GPCR kinases (GRKs) curtail G-protein signalingand target receptors for internalization. Nitric oxide (NO) and/or S-nitrosothiols (SNOs) can prevent theloss of beta-AR signaling in vivo, but the molecular details are unknown. Here we show in mice that SNOsincrease beta-AR expression and prevent agonist-stimulated receptor downregulation; and in cells, SNOsdecrease GRK2-mediated beta-AR phosphorylation and subsequent recruitment of beta-arrestin to thereceptor, resulting in the attenuation of receptor desensitization and internalization. In both cells andtissues, GRK2 is S-nitrosylated by SNOs as well as by NO synthases, and GRK2 S-nitrosylation increasesfollowing stimulation of multiple GPCRs with agonists. Cys340 of GRK2 is identified as a principal locus ofinhibition by S-nitrosylation. Our studies thus reveal a central molecular mechanism through which GPCRsignaling is regulated.", "metadata": {}}
+{"_id": "14174055", "title": "", "text": "Electroporation enables the efficient mRNA delivery into the mouse zygotes and facilitatesCRISPR/Cas9-based genome editingRecent use of the CRISPR/Cas9 system has dramatically reduced thetime required to produce mutant mice, but the involvement of a time-consuming microinjection step stillhampers its application for high-throughput genetic analysis. Here we developed a simple, highlyefficient, and large-scale genome editing method, in which the RNAs for the CRISPR/Cas9 system areelectroporated into zygotes rather than microinjected. We used this method to perform single-strandedoligodeoxynucleotide (ssODN)-mediated knock-in in mouse embryos. This method facilitates large-scalegenetic analysis in the mouse.", "metadata": {}}
+{"_id": "14178995", "title": "", "text": "SummaryThe genetic diseases Hutchinson-Gilford progeria syndrome (HGPS) and restrictive dermopathy(RD) arise from accumulation of farnesylated prelamin A because of defects in the lamin A maturationpathway. Both of these diseases exhibit symptoms that can be viewed as accelerated aging. Themechanism by which accumulation of farnesylated prelamin A leads to these accelerated agingphenotypes is not understood. Here we present evidence that in HGPS and RD fibroblasts, DNA damagecheckpoints are persistently activated because of the compromise in genomic integrity. Inactivation ofcheckpoint kinases Ataxia-telangiectasia-mutated (ATM) and ATR (ATM- and Rad3-related) in thesepatient cells can partially overcome their early replication arrest. Treatment of patient cells with a proteinfarnesyltransferase inhibitor (FTI) did not result in reduction of DNA double-strand breaks and damagecheckpoint signaling, although the treatment significantly reversed the aberrant shape of their nuclei.This suggests that DNA damage accumulation and aberrant nuclear morphology are independentphenotypes arising from prelamin A accumulation in these progeroid syndromes. Since DNA damageaccumulation is an important contributor to the symptoms of HGPS, our results call into question thepossibility of treatment of HGPS with FTIs alone.", "metadata": {}}
+{"_id": "14180217", "title": "", "text": "The Buccaneer software for automated model building. 1. Tracing protein chains.A new technique for theautomated tracing of protein chains in experimental electron-density maps is described. The techniquerelies on the repeated application of an oriented electron-density likelihood target function to identifylikely C(alpha) positions. This function is applied both in the location of a few promising ;seed' positionsin the map and to grow those initial C(alpha) positions into extended chain fragments. Techniques forassembling the chain fragments into an initial chain trace are discussed.", "metadata": {}}
+{"_id": "14180565", "title": "", "text": "Expression profile of genes modulated by Aloe emodin in human U87 glioblastoma cells.Glioblastoma, themost aggressive and malignant form of glioma, appears to be resistant to various chemotherapeuticagents. Hence, approaches have been intensively investigated to targeti specific molecular pathwaysinvolved in glioblastoma development and progression. Aloe emodin is believed to modulate theexpression of several genes in cancer cells. We aimed to understand the molecular mechanismsunderlying the therapeutic effect of Aloe emodin on gene expression profiles in the human U87glioblastoma cell line utilizing microarray technology. The gene expression analysis revealed that a totalof 8,226 gene alterations out of 28,869 genes were detected after treatment with 58.6 μg/ml for 24hours. Out of this total, 34 genes demonstrated statistically significant change (p<0.05) ranging from1.07 to 1.87 fold. The results revealed that 22 genes were up-regulated and 12 genes weredown-regulated in response to Aloe emodin treatment. These genes were then grouped into severalclusters based on their biological functions, revealing induction of expression of genes involved inapoptosis (programmed cell death) and tissue remodelling in U87 cells (p<0.01). Several genes withsignificant changes of the expression level e.g. SHARPIN, BCAP31, FIS1, RAC1 and TGM2 from theapoptotic cluster were confirmed by quantitative real-time PCR (qRT-PCR). These results could serve asguidance for further studies in order to discover molecular targets for the cancer therapy based on Aloeemodin treatment.", "metadata": {}}
+{"_id": "14185503", "title": "", "text": "The miniature genome of a carnivorous plant Genlisea aurea contains a low number of genes and shortnon-coding sequencesBACKGROUND Genlisea aurea (Lentibulariaceae) is a carnivorous plant withunusually small genome size - 63.6 Mb - one of the smallest known among higher plants. Data on thegenome sizes and the phylogeny of Genlisea suggest that this is a derived state within the genus. Thus,G. aurea is an excellent model organism for studying evolutionary mechanisms of genome contraction.RESULTS Here we report sequencing and de novo draft assembly of G. aurea genome. The assemblyconsists of 10,687 contigs of the total length of 43.4 Mb and includes 17,755 complete and partialprotein-coding genes. Its comparison with the genome of Mimulus guttatus, another representative ofhigher core Lamiales clade, reveals striking differences in gene content and length of non-coding regions.CONCLUSIONS Genome contraction was a complex process, which involved gene loss and reduction oflengths of introns and intergenic regions, but not intron loss. The gene loss is more frequent for thegenes that belong to multigenic families indicating that genetic redundancy is an important prerequisitefor genome size reduction.", "metadata": {}}
+{"_id": "14188138", "title": "", "text": "Abnormal Spine Morphology and Enhanced LTP in LIMK-1 Knockout MiceIn vitro studies indicate a role forthe LIM kinase family in the regulation of cofilin phosphorylation and actin dynamics. In addition,abnormal expression of LIMK-1 is associated with Williams syndrome, a mental disorder with profounddeficits in visuospatial cognition. However, the in vivo function of this family of kinases remains elusive.Using LIMK-1 knockout mice, we demonstrate a significant role for LIMK-1 in vivo in regulating cofilin andthe actin cytoskeleton. Furthermore, we show that the knockout mice exhibited significant abnormalitiesin spine morphology and in synaptic function, including enhanced hippocampal long-term potentiation.The knockout mice also showed altered fear responses and spatial learning. These results indicate thatLIMK-1 plays a critical role in dendritic spine morphogenesis and brain function.", "metadata": {}}
+{"_id": "14191255", "title": "", "text": "Wdr5 Mediates Self-Renewal and Reprogramming via the Embryonic Stem Cell Core TranscriptionalNetworkThe embryonic stem (ES) cell transcriptional and chromatin-modifying networks are critical forself-renewal maintenance. However, it remains unclear whether these networks functionally interact and,if so, what factors mediate such interactions. Here, we show that WD repeat domain 5 (Wdr5), a coremember of the mammalian Trithorax (trxG) complex, positively correlates with the undifferentiated stateand is a regulator of ES cell self-renewal. We demonstrate that Wdr5, an \"effector\" of H3K4 methylation,interacts with the pluripotency transcription factor Oct4. Genome-wide protein localization andtranscriptome analyses demonstrate overlapping gene regulatory functions between Oct4 and Wdr5. TheOct4-Sox2-Nanog circuitry and trxG cooperate in activating transcription of key self-renewal regulators,and furthermore, Wdr5 expression is required for the efficient formation of induced pluripotent stem (iPS)cells. We propose an integrated model of transcriptional and epigenetic control, mediated by select trxGmembers, for the maintenance of ES cell self-renewal and somatic cell reprogramming.", "metadata": {}}
+{"_id": "14192687", "title": "", "text": "Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improvesymptoms of rats with Parkinson's disease.The long-term goal of nuclear transfer or alternativereprogramming approaches is to create patient-specific donor cells for transplantation therapy, avoidingimmunorejection, a major complication in current transplantation medicine. It was recently shown thatthe four transcription factors Oct4, Sox2, Klf4, and c-Myc induce pluripotency in mouse fibroblasts.However, the therapeutic potential of induced pluripotent stem (iPS) cells for neural cell replacementstrategies remained unexplored. Here, we show that iPS cells can be efficiently differentiated into neuralprecursor cells, giving rise to neuronal and glial cell types in culture. Upon transplantation into the fetalmouse brain, the cells migrate into various brain regions and differentiate into glia and neurons, includingglutamatergic, GABAergic, and catecholaminergic subtypes. Electrophysiological recordings andmorphological analysis demonstrated that the grafted neurons had mature neuronal activity and werefunctionally integrated in the host brain. Furthermore, iPS cells were induced to differentiate intodopamine neurons of midbrain character and were able to improve behavior in a rat model of Parkinson'sdisease upon transplantation into the adult brain. We minimized the risk of tumor formation from thegrafted cells by separating contaminating pluripotent cells and committed neural cells usingfluorescence-activated cell sorting. Our results demonstrate the therapeutic potential of directlyreprogrammed fibroblasts for neuronal cell replacement in the animal model.", "metadata": {}}
+{"_id": "14195528", "title": "", "text": "Responses of primate frontal cortex neurons during natural vocal communication.The role of primatefrontal cortex in vocal communication and its significance in language evolution have a controversialhistory. While evidence indicates that vocalization processing occurs in ventrolateral prefrontal cortexneurons, vocal-motor activity has been conjectured to be primarily subcortical and suggestive of adistinctly different neural architecture from humans. Direct evidence of neural activity during naturalvocal communication is limited, as previous studies were performed in chair-restrained animals. Here werecorded the activity of single neurons across multiple regions of prefrontal and premotor cortex whilefreely moving marmosets engaged in a natural vocal behavior known as antiphonal calling. Our aim wasto test whether neurons in marmoset frontal cortex exhibited responses during vocal-signal processingand/or vocal-motor production in the context of active, natural communication. We observedmotor-related changes in single neuron activity during vocal production, but relatively weak sensoryresponses for vocalization processing during this natural behavior. Vocal-motor responses occurred bothprior to and during call production and were typically coupled to the timing of each vocalization pulse.Despite the relatively weak sensory responses a population classifier was able to distinguish betweenneural activity that occurred during presentations of vocalization stimuli that elicited an antiphonalresponse and those that did not. These findings are suggestive of the role that nonhuman primate frontalcortex neurons play in natural communication and provide an important foundation for more explicit testsof the functional contributions of these neocortical areas during vocal behaviors.", "metadata": {}}
+{"_id": "14198646", "title": "", "text": "Salt-inducible kinase 2 links transcriptional coactivator p300 phosphorylation to the prevention ofChREBP-dependent hepatic steatosis in mice.Obesity and type 2 diabetes are associated with increasedlipogenesis in the liver. This results in fat accumulation in hepatocytes, a condition known as hepaticsteatosis, which is a form of nonalcoholic fatty liver disease (NAFLD), the most common cause of liverdysfunction in the United States. Carbohydrate-responsive element-binding protein (ChREBP), atranscriptional activator of glycolytic and lipogenic genes, has emerged as a major player in thedevelopment of hepatic steatosis in mice. However, the molecular mechanisms enhancing itstranscriptional activity remain largely unknown. In this study, we have identified the histoneacetyltransferase (HAT) coactivator p300 and serine/threonine kinase salt-inducible kinase 2 (SIK2) askey upstream regulators of ChREBP activity. In cultured mouse hepatocytes, we showed thatglucose-activated p300 acetylated ChREBP on Lys672 and increased its transcriptional activity byenhancing its recruitment to its target gene promoters. SIK2 inhibited p300 HAT activity by directphosphorylation on Ser89, which in turn decreased ChREBP-mediated lipogenesis in hepatocytes andmice overexpressing SIK2. Moreover, both liver-specific SIK2 knockdown and p300 overexpressionresulted in hepatic steatosis, insulin resistance, and inflammation, phenotypes reversed by SIK2/p300co-overexpression. Finally, in mouse models of type 2 diabetes and obesity, low SIK2 activity wasassociated with increased p300 HAT activity, ChREBP hyperacetylation, and hepatic steatosis. Ourfindings suggest that inhibition of hepatic p300 activity may be beneficial for treating hepatic steatosis inobesity and type 2 diabetes and identify SIK2 activators and specific p300 inhibitors as potential targetsfor pharmaceutical intervention.", "metadata": {}}
+{"_id": "14205246", "title": "", "text": "A Role for NuSAP in Linking Microtubules to Mitotic ChromosomesThe spindle apparatus is a microtubule(MT)-based machinery that attaches to and segregates the chromosomes during mitosis and meiosis.Self-organization of the spindle around chromatin involves the assembly of MTs, their attachment to thechromosomes, and their organization into a bipolar array. One regulator of spindle self-organization isRanGTP. RanGTP is generated at chromatin and activates a set of soluble, Ran-regulated spindle factorssuch as TPX2, NuMA, and NuSAP . How the spindle factors direct and attach MTs to the chromosomes arekey open questions. Nucleolar and Spindle-Associated Protein (NuSAP) was recently identified as anessential MT-stabilizing and bundling protein that is enriched at the central part of the spindle . Here, weshow by biochemical reconstitution that NuSAP efficiently adsorbs to isolated chromatin and DNA and thatit can directly produce and retain high concentrations of MTs in the immediate vicinity of chromatin orDNA. Moreover, our data reveal that NuSAP-chromatin interaction is subject to Ran regulation and can besuppressed by Importin alpha (Impalpha) and Imp7. We propose that the presence of MT binding agentssuch as NuSAP, which can be directly immobilized on chromatin, are critical for targeting MT productionto vertebrate chromosomes during spindle self-organization.", "metadata": {}}
+{"_id": "14225271", "title": "", "text": "Molecular features of cellular reprogramming and developmentDifferentiating somatic cells areprogressively restricted to specialized functions during ontogeny, but they can be experimentally directedto form other cell types, including those with complete embryonic potential. Early nuclear reprogrammingmethods, such as somatic cell nuclear transfer (SCNT) and cell fusion, posed significant technical hurdlesto precise dissection of the regulatory programmes governing cell identity. However, the discovery ofreprogramming by ectopic expression of a defined set of transcription factors, known as directreprogramming, provided a tractable platform to uncover molecular characteristics of cellularspecification and differentiation, cell type stability and pluripotency. We discuss the control andmaintenance of cellular identity during developmental transitions as they have been studied using directreprogramming, with an emphasis on transcriptional and epigenetic regulation.", "metadata": {}}
+{"_id": "14240343", "title": "", "text": "Small molecule modifiers of circadian clocksCircadian clocks orchestrate 24-h oscillations of essentialphysiological and behavioral processes in response to daily environmental changes. These clocks areremarkably precise under constant conditions yet highly responsive to resetting signals. With themolecular composition of the core oscillator largely established, recent research has increasingly focusedon clock-modifying mechanisms/molecules. In particular, small molecule modifiers, intrinsic or extrinsic,are emerging as powerful tools for understanding basic clock biology as well as developing putativetherapeutic agents for clock-associated diseases. In this review, we will focus on synthetic compoundscapable of modifying the period, phase, or amplitude of circadian clocks, with particular emphasis on themammalian clock. We will discuss the potential of exploiting these small molecule modifiers in both basicand translational research.", "metadata": {}}
+{"_id": "14241418", "title": "", "text": "NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cellswith activating PI3K mutations.Phosphatidylinositol-3-kinase (PI3K) pathway deregulation is a commonevent in human cancer, either through inactivation of the tumor suppressor phosphatase and tensinhomologue deleted from chromosome 10 or activating mutations of p110-alpha. These hotspot mutationsresult in oncogenic activity of the enzyme and contribute to therapeutic resistance to the anti-HER2antibody trastuzumab. The PI3K pathway is, therefore, an attractive target for cancer therapy. We havestudied NVP-BEZ235, a dual inhibitor of the PI3K and the downstream mammalian target of rapamycin(mTOR). NVP-BEZ235 inhibited the activation of the downstream effectors Akt, S6 ribosomal protein, and4EBP1 in breast cancer cells. The antiproliferative activity of NVP-BEZ235 was superior to the allostericselective mTOR complex inhibitor everolimus in a panel of 21 cancer cell lines of different origin andmutation status. The described Akt activation due to mTOR inhibition was prevented by higher doses ofNVP-BEZ235. NVP-BEZ235 reversed the hyperactivation of the PI3K/mTOR pathway caused by theoncogenic mutations of p110-alpha, E545K, and H1047R, and inhibited the proliferation ofHER2-amplified BT474 cells exogenously expressing these mutations that render them resistant totrastuzumab. In trastuzumab-resistant BT474 H1047R breast cancer xenografts, NVP-BEZ235 inhibitedPI3K signaling and had potent antitumor activity. In treated animals, there was complete inhibition ofPI3K signaling in the skin at pharmacologically active doses, suggesting that skin may serve as surrogatetissue for pharmacodynamic studies. In summary, NVP-BEZ235 inhibits the PI3K/mTOR axis and resultsin antiproliferative and antitumoral activity in cancer cells with both wild-type and mutated p110-alpha.", "metadata": {}}
+{"_id": "14252892", "title": "", "text": "Pharmacokinetic, pharmacodynamic, and pharmacogenetic determinants of osteonecrosis in children withacute lymphoblastic leukemia.Osteonecrosis is a severe glucocorticoid-induced complication of acutelymphoblastic leukemia treatment. We prospectively screened children (n = 364) with magneticresonance imaging of hips and knees, regardless of symptoms; the cumulative incidence of any (grade1-4) versus symptomatic (grade 2-4) osteonecrosis was 71.8% versus 17.6%, respectively. Weinvestigated whether age, race, sex, acute lymphoblastic leukemia treatment arm, body mass, serumlipids, albumin and cortisol levels, dexamethasone pharmacokinetics, and genome-wide germline geneticpolymorphisms were associated with symptomatic osteonecrosis. Age more than 10 years (odds ratio, =4.85; 95% confidence interval, 2.5-9.2; P = .00001) and more intensive treatment (odds ratio = 2.5;95% confidence interval, 1.2-4.9; P = .011) were risk factors and included as covariates in all analyses.Lower albumin (P = .05) and elevated cholesterol (P = .02) associated with symptomatic osteonecrosis,and severe (grade 3 or 4) osteonecrosis was linked to poor dexamethasone clearance (P = .0005).Adjusting for clinical features, polymorphisms of ACP1 (eg, rs12714403, P = 1.9 × 10(-6), odds ratio =5.6; 95% confidence interval, 2.7-11.3), which regulates lipid levels and osteoblast differentiation, wereassociated with risk of osteonecrosis as well as with lower albumin and higher cholesterol. Overall, olderage, lower albumin, higher lipid levels, and dexamethasone exposure were associated with osteonecrosisand may be linked by inherited genomic variation.", "metadata": {}}
+{"_id": "14260013", "title": "", "text": "Prevention of Rectal SHIV Transmission in Macaques by Daily or Intermittent Prophylaxis withEmtricitabine and TenofovirBACKGROUND In the absence of an effective vaccine, HIV continues to spreadglobally, emphasizing the need for novel strategies to limit its transmission. Pre-exposure prophylaxis(PrEP) with antiretroviral drugs could prove to be an effective intervention strategy if highly efficaciousand cost-effective PrEP modalities are identified. We evaluated daily and intermittent PrEP regimens ofincreasing antiviral activity in a macaque model that closely resembles human transmission. METHODSAND FINDINGS We used a repeat-exposure macaque model with 14 weekly rectal virus challenges. Threedrug treatments were given once daily, each to a different group of six rhesus macaques. Group 1 wastreated subcutaneously with a human-equivalent dose of emtricitabine (FTC), group 2 received orally thehuman-equivalent dosing of both FTC and tenofovir-disoproxil fumarate (TDF), and group 3 receivedsubcutaneously a similar dosing of FTC and a higher dose of tenofovir. A fourth group of six rhesusmacaques (group 4) received intermittently a PrEP regimen similar to group 3 only 2 h before and 24 hafter each weekly virus challenge. Results were compared to 18 control macaques that did not receiveany drug treatment. The risk of infection in macaques treated in groups 1 and 2 was 3.8- and 7.8-foldlower than in untreated macaques (p = 0.02 and p = 0.008, respectively). All six macaques in group 3were protected. Breakthrough infections had blunted acute viremias; drug resistance was seen in two ofsix animals. All six animals in group 4 that received intermittent PrEP were protected. CONCLUSIONS Thismodel suggests that single drugs for daily PrEP can be protective but a combination of antiretroviral drugsmay be required to increase the level of protection. Short but potent intermittent PrEP can provideprotection comparable to that of daily PrEP in this SHIV/macaque model. These findings support PrEPtrials for HIV prevention in humans and identify promising PrEP modalities.", "metadata": {}}
+{"_id": "14275671", "title": "", "text": "Direct-coupling analysis of residue co-evolution captures native contacts across many protein familiesThesimilarity in the three-dimensional structures of homologous proteins imposes strong constraints on theirsequence variability. It has long been suggested that the resulting correlations among amino acidcompositions at different sequence positions can be exploited to infer spatial contacts within the tertiaryprotein structure. Crucial to this inference is the ability to disentangle direct and indirect correlations, asaccomplished by the recently introduced Direct Coupling Analysis (DCA) (Weigt et al. (2009) Proc NatlAcad Sci 106:67). Here we develop a computationally efficient implementation of DCA, which allows us toevaluate the accuracy of contact prediction by DCA for a large number of protein domains, based purelyon sequence information. DCA is shown to yield a large number of correctly predicted contacts,recapitulating the global structure of the contact map for the majority of the protein domains examined.Furthermore, our analysis captures clear signals beyond intra- domain residue contacts, arising, e.g.,from alternative protein conformations, ligand- mediated residue couplings, and inter-domain interactionsin protein oligomers. Our findings suggest that contacts predicted by DCA can be used as a reliable guideto facilitate computational predictions of alternative protein conformations, protein complex formation,and even the de novo prediction of protein domain structures, provided the existence of a large numberof homologous sequences which are being rapidly made available due to advances in genomesequencing.", "metadata": {}}
+{"_id": "14290854", "title": "", "text": "Variation in antibiotic prescribing and its impact on recovery in patients with acute cough in primary care:prospective study in 13 countries.OBJECTIVE To describe variation in antibiotic prescribing for acutecough in contrasting European settings and the impact on recovery. DESIGN Cross sectionalobservational study with clinicians from 14 primary care research networks in 13 European countries whorecorded symptoms on presentation and management. Patients followed up for 28 days with patientdiaries. SETTING Primary care. PARTICIPANTS Adults with a new or worsening cough or clinicalpresentation suggestive of lower respiratory tract infection. MAIN OUTCOME MEASURES Prescribing ofantibiotics by clinicians and total symptom severity scores over time. RESULTS 3402 patients wererecruited (clinicians completed a case report form for 99% (3368) of participants and 80% (2714)returned a symptom diary). Mean symptom severity scores at presentation ranged from 19 (scale range0 to 100) in networks based in Spain and Italy to 38 in the network based in Sweden. Antibioticprescribing by networks ranged from 20% to nearly 90% (53% overall), with wide variation in classes ofantibiotics prescribed. Amoxicillin was overall the most common antibiotic prescribed, but this rangedfrom 3% of antibiotics prescribed in the Norwegian network to 83% in the English network. Whilefluoroquinolones were not prescribed at all in three networks, they were prescribed for 18% in the Milannetwork. After adjustment for clinical presentation and demographics, considerable differences remainedin antibiotic prescribing, ranging from Norway (odds ratio 0.18, 95% confidence interval 0.11 to 0.30) toSlovakia (11.2, 6.20 to 20.27) compared with the overall mean (proportion prescribed: 0.53). The rate ofrecovery was similar for patients who were and were not prescribed antibiotics (coefficient -0.01, P<0.01)once clinical presentation was taken into account. CONCLUSIONS Variation in clinical presentation doesnot explain the considerable variation in antibiotic prescribing for acute cough in Europe. Variation inantibiotic prescribing is not associated with clinically important differences in recovery. TRIALREGISTRATION Clinicaltrials.gov NCT00353951.", "metadata": {}}
+{"_id": "14296612", "title": "", "text": "Dorsomorphin, a Selective Small Molecule Inhibitor of BMP Signaling, Promotes Cardiomyogenesis inEmbryonic Stem CellsBACKGROUND Pluripotent embryonic stem (ES) cells, which have the capacity togive rise to all tissue types in the body, show great promise as a versatile source of cells for regenerativetherapy. However, the basic mechanisms of lineage specification of pluripotent stem cells are largelyunknown, and generating sufficient quantities of desired cell types remains a formidable challenge. Smallmolecules, particularly those that modulate key developmental pathways like the bone morphogeneticprotein (BMP) signaling cascade, hold promise as tools to study in vitro lineage specification and to directdifferentiation of stem cells toward particular cell types. METHODOLOGY/ PRINCIPAL FINDINGS Wedescribe the use of dorsomorphin, a selective small molecule inhibitor of BMP signaling, to inducemyocardial differentiation in mouse ES cells. Cardiac induction is very robust, increasing the yield ofspontaneously beating cardiomyocytes by at least 20 fold. Dorsomorphin, unlike the endogenous BMPantagonist Noggin, robustly induces cardiomyogenesis when treatment is limited to the initial 24-hours ofES cell differentiation. Quantitative-PCR analyses of differentiating ES cells indicate that pharmacologicalinhibition of BMP signaling during the early critical stage promotes the development of the cardiomyocytelineage, but reduces the differentiation of endothelial, smooth muscle, and hematopoietic cells.CONCLUSIONS/ SIGNIFICANCE Administration of a selective small molecule BMP inhibitor during theinitial stages of ES cell differentiation substantially promotes the differentiation of primitive pluripotentcells toward the cardiomyocytic lineage, apparently at the expense of other mesodermal lineages. Smallmolecule modulators of developmental pathways like dorsomorphin could become versatilepharmacological tools for stem cell research and regenerative medicine.", "metadata": {}}
+{"_id": "14300799", "title": "", "text": "Cineradiography of Monkey Lip-Smacking Reveals Putative Precursors of Speech DynamicsA key featureof speech is its stereotypical 5 Hz rhythm. One theory posits that this rhythm evolved through themodification of rhythmic facial movements in ancestral primates. If the hypothesis has any validity, thena comparative approach may shed some light. We tested this idea by using cineradiography (X-raymovies) to characterize and quantify the internal dynamics of the macaque monkey vocal tract duringlip-smacking (a rhythmic facial expression) versus chewing. Previous human studies showed that speechmovements are faster than chewing movements, and the functional coordination between vocal tractstructures is different between the two behaviors. If rhythmic speech evolved through a rhythmicancestral facial movement, then one hypothesis is that monkey lip-smacking versus chewing should alsoexhibit these differences. We found that the lips, tongue, and hyoid move with a speech-like 5 Hz rhythmduring lip-smacking, but not during chewing. Most importantly, the functional coordination between thesestructures was distinct for each behavior. These data provide empirical support for the idea that thehuman speech rhythm evolved from the rhythmic facial expressions of ancestral primates.", "metadata": {}}
+{"_id": "14308244", "title": "", "text": "Interneuronal DISC1 regulates NRG1-ErbB4 signalling and excitatory-inhibitory synapse formation in themature cortex.Neuregulin-1 (NRG1) and its receptor ErbB4 influence several processes ofneurodevelopment, but the mechanisms regulating this signalling in the mature brain are not well known.DISC1 is a multifunctional scaffold protein that mediates many cellular processes. Here we present afunctional relationship between DISC1 and NRG1-ErbB4 signalling in mature cortical interneurons. By celltype-specific gene modulation in vitro and in vivo including in a mutant DISC1 mouse model, wedemonstrate that DISC1 inhibits NRG1-induced ErbB4 activation and signalling. This effect is likelymediated by competitive inhibition of binding of ErbB4 to PSD95. Finally, we show that interneuronalDISC1 affects NRG1-ErbB4-mediated phenotypes in the fast spiking interneuron-pyramidal neuron circuit.Post-mortem brain analyses and some genetic studies have reported interneuronal deficits andinvolvement of the DISC1, NRG1 and ErbB4 genes in schizophrenia, respectively. Our results suggest amechanism by which cross-talk between DISC1 and NRG1-ErbB4 signalling may contribute to thesedeficits.", "metadata": {}}
+{"_id": "14311986", "title": "", "text": "The Proto-Oncogene c-maf Is Responsible for Tissue-Specific Expression of Interleukin-4The molecularbasis for the distinctive cytokine expression of CD4+ T helper 1 (Th1) and T helper 2 (Th2) subsetsremains elusive. Here, we report that the proto-oncogene c-maf, a basic region/leucine zippertranscription factor, controls tissue-specific expression of IL-4. c-Maf is expressed in Th2 but not Th1clones and is induced during normal precursor cell differentiation along a Th2 but not Th1 lineage. c-Mafbinds to a c-Maf response element (MARE) in the proximal IL-4 promoter adjacent to a site footprinted byextracts from Th2 but not Th1 clones. Ectopic expression of c-Maf transactivates the IL-4 promoter in Th1cells, B cells, and nonlymphoid cells, a function that maps to the MARE and Th2-specific footprint.Furthermore, c-Maf acts in synergy with the nuclear factor of activated T cells (NF-ATp) to initiateendogeneous IL-4 production by B cells. Manipulation of c-Maf may alter Th subset ratios in humandisease.", "metadata": {}}
+{"_id": "14315749", "title": "", "text": "hClock gene expression in human colorectal carcinoma.In this study, we aimed to investigate changes inthe expression of human Clock (hClock), a gene at the core of the circadian gene family, in colorectalcarcinomas (CRCs) and to discuss the possible effects. Previous studies have revealed that the disruptionof circadian rhythms is one of the endogenous factors that contribute to the initiation and development ofCRCs. However, the underlying molecular changes to the circadian genes associated with CRCs have notbeen explored. Immunofluorescence and quantitative polymerase chain reaction (qPCR) analysis of thehCLOCK protein and gene expression were performed in 30 cases of CRC. The hCLOCK protein wasexpressed in all specimens obtained from 30 CRC patients. Higher levels of hCLOCK expression wereobserved in human CRC tissues compared with the paired non-cancerous tissues. hCLOCK expression wassignificantly higher in poorly differentiated, or late-stage, Dukes' grade tumors and in 64.3% of tumorcases with lymph node metastasis. The hClock gene was expressed in all specimens. A significantlyhigher expression of hClock was found in human CRC cases compared with paired non-cancerous tissues.There was a strong positive linear correlation between hClock gene expression and protein expression inhuman CRCs. A strong positive linear correlation was also found between hClock gene expression andARNT, HIF-1α and VEGF expression in human CRCs. There was no significant correlation between hClockand Bak, Bax, Bid, tumor necrosis factor receptor I (TNFR I) and TNFR II. The circadian gene hClock wasstably expressed in human colorectal mucosa and was important in regulating the expression ofdownstream clock-controlled genes. hCLOCK may interact with HIF-1α/ARNT and activate VEGF tostimulate tumor angiogenesis and metastasis.", "metadata": {}}
+{"_id": "14319754", "title": "", "text": "The Antiretroviral Therapy in Lower Income Countries (ART-LINC) Collaboration and ART CohortCollaboration (ART-CC) groups SummaryBACKGROUND Highly active antiretroviral therapy (HAART) isbeing scaled up in developing countries. We compared baseline characteristics and outcomes during thefirst year of HAART between HIV-1-infected patients in low-income and high-income settings. METHODS18 HAART programmes in Africa, Asia, and South America (low-income settings) and 12 HIV cohortstudies from Europe and North America (high-income settings) provided data for 4810 and 22,217,respectively, treatment-naïve adult patients starting HAART. All patients from high-income settings and2725 (57%) patients from low-income settings were actively followed-up and included in survivalanalyses. FINDINGS Compared with high-income countries, patients starting HAART in low-incomesettings had lower CD4 cell counts (median 108 cells per muL vs 234 cells per muL), were more likely tobe female (51%vs 25%), and more likely to start treatment with a non-nucleoside reverse transcriptaseinhibitor (NNRTI) (70%vs 23%). At 6 months, the median number of CD4 cells gained (106 cells per muLvs 103 cells per muL) and the percentage of patients reaching HIV-1 RNA levels lower than 500copies/mL (76%vs 77%) were similar. Mortality was higher in low-income settings (124 deaths during2236 person-years of follow-up) than in high-income settings (414 deaths during 20,532 person-years).The adjusted hazard ratio (HR) of mortality comparing low-income with high-income settings fell from 4.3(95% CI 1.6-11.8) during the first month to 1.5 (0.7-3.0) during months 7-12. The provision oftreatment free of charge in low-income settings was associated with lower mortality (adjusted HR 0.23;95% CI 0.08-0.61). INTERPRETATION Patients starting HAART in resource-poor settings have increasedmortality rates in the first months on therapy, compared with those in developed countries. Timelydiagnosis and assessment of treatment eligibility, coupled with free provision of HAART, might reduce thisexcess mortality.", "metadata": {}}
+{"_id": "14328288", "title": "", "text": "A family of phosphoinositide 3-kinases in Drosophila identifies a new mediator of signaltransductionBACKGROUND Mammalian phosphoinositide 3-kinases (PI 3-kinases) are involved inreceptor-mediated signal transduction and have been implicated in processes such as transformation andmitogenesis through their role in elevating cellular phosphatidylinositol (3,4,5)-trisphosphate.Additionally, a PI 3-kinase activity which generates phosphatidylinositol 3-phosphate has been shown tobe required for protein trafficking in yeast. RESULTS We have identified a family of three distinct PI3-kinases in Drosophila, using an approach based on the polymerase chain reaction to amplify a regioncorresponding to the conserved catalytic domain of PI 3-kinases. One of these family members,PI3K_92D, is closely related to the prototypical PI 3-kinase, p110 alpha; PI3K_59F is homologous toVps34p, whereas the third, PI3K_68D, is a novel PI 3-kinase which is widely expressed throughout theDrosophila life cycle. The PI3K_68D cDNA encodes a protein of 210 kDa, which lacks sequencesimplicated in linking p110 PI 3-kinases to p85 adaptor proteins, but contains an amino-terminalproline-rich sequence, which could bind to SH3 domains, and a carboxy-terminal C2 domain. Biochemicalanalyses demonstrate that PI3K_68D has a novel substrate specificity in vitro, restricted tophosphatidylinositol and phosphatidylinositol 4-phosphate, and is unable to phosphorylatephosphatidylinositol (4,5)-bisphosphate, the implied in vivo substrate for p110. CONCLUSIONS A familyof PI 3-kinases in Drosophila, including a novel class represented by PI3K_68D, is described. PI3K_68Dhas the potential to bind to signalling molecules containing SH3 domains, lacks p85-adaptor-bindingsequences, has a Ca(2+)-independent phospholipid-binding domain and displays a restricted in vitrosubstrate specificity, so it could define a novel signal transduction pathway.", "metadata": {}}
+{"_id": "14332945", "title": "", "text": "Mammalian RAD52 Functions in Break-Induced Replication Repair of Collapsed DNA ReplicationForksHuman cancers are characterized by the presence of oncogene-induced DNA replication stress(DRS), making them dependent on repair pathways such as break-induced replication (BIR) for damagedDNA replication forks. To better understand BIR, we performed a targeted siRNA screen for genes whosedepletion inhibited G1 to S phase progression when oncogenic cyclin E was overexpressed. RAD52, agene dispensable for normal development in mice, was among the top hits. In cells in which fork collapsewas induced by oncogenes or chemicals, the Rad52 protein localized to DRS foci. Depletion of Rad52 bysiRNA or knockout of the gene by CRISPR/Cas9 compromised restart of collapsed forks and led to DNAdamage in cells experiencing DRS. Furthermore, in cancer-prone, heterozygous APC mutant mice,homozygous deletion of the Rad52 gene suppressed tumor growth and prolonged lifespan. We thereforepropose that mammalian RAD52 facilitates repair of collapsed DNA replication forks in cancer cells.", "metadata": {}}
+{"_id": "14333540", "title": "", "text": "Neural crest cell lineage segregation in the mouse neural tube.Neural crest (NC) cells arise in the dorsalneural tube (NT) and migrate into the embryo to develop into many different cell types. A majorunresolved question is when and how the fate of NC cells is decided. There is widespread evidence formultipotential NC cells, whose fates are decided during or after migration. There is also some evidencethat the NC is already divided into subpopulations of discrete precursors within the NT. We haveinvestigated this question in the mouse embryo. We find that a subpopulation of cells on the mostdorsomedial aspect of the NT express the receptor tyrosine kinase Kit (previously known as c-kit),emigrate exclusively into the developing dermis, and then express definitive markers of the melanocytelineage. These are thus melanocyte progenitor cells. They are generated predominantly at themidbrain-hindbrain junction and cervical trunk, with significant numbers also in lower trunk. Other cellswithin the dorsal NT are Kit-, migrate ventrally, and, from embryonic day 9.5, express the neurotrophinreceptor p75. These cells most likely only give rise to ventral NC derivatives such as neurons and glia.The p75+ cells are located ventrolateral to the Kit+ cells in areas of the NT where these two cell types arefound. These data provide direct in vivo evidence for NC lineage segregation within the mouse neuraltube.", "metadata": {}}
+{"_id": "14337960", "title": "", "text": "How absolute is zero? An evaluation of historical and current definitions of malaria eliminationDecisions toeliminate malaria from all or part of a country involve a complex set of factors, and this complexity iscompounded by ambiguity surrounding some of the key terminology, most notably \"control\" and\"elimination. \" It is impossible to forecast resource and operational requirements accurately if endpointshave not been defined clearly, yet even during the Global Malaria Eradication Program, debate raged overthe precise definition of \"eradication. \" Analogous deliberations regarding the meaning of \"elimination\"and \"control\" are basically nonexistent today despite these terms' core importance to programmeplanning. To advance the contemporary debate about these issues, this paper presents a historical reviewof commonly used terms, including control, elimination, and eradication, to help contextualize currentunderstanding of these concepts. The review has been supported by analysis of the underlyingmathematical concepts on which these definitions are based through simple branching process modelsthat describe the proliferation of malaria cases following importation. Through this analysis, theimportance of pragmatic definitions that are useful for providing malaria control and eliminationprogrammes with a practical set of strategic milestones is emphasized, and it is argued that currentconceptions of elimination in particular fail to achieve these requirements. To provide all countries withprecise targets, new conceptual definitions are suggested to more precisely describe the old goals of\"control\" - here more exactly named \"controlled low-endemic malaria\" - and \"elimination. \" Additionally,it is argued that a third state, called \"controlled non-endemic malaria,\" is required to describe theepidemiological condition in which endemic transmission has been interrupted, but malaria resulting fromonwards transmission from imported infections continues to occur at a sufficiently high level thatelimination has not been achieved. Finally, guidelines are discussed for deriving the separate operationaldefinitions and metrics that will be required to make these concepts relevant, measurable, and achievablefor a particular environment.", "metadata": {}}
+{"_id": "14338915", "title": "", "text": "Fission Yeast Scm3: A CENP-A Receptor Required for Integrity of Subkinetochore ChromatinThemechanisms ensuring specific incorporation of CENP-A at centromeres are poorly understood. Mis16 andMis18 are required for CENP-A localization at centromeres and form a complex that is conserved fromfission yeast to human. Fission yeast sim1 mutants that alleviate kinetochore domain silencing aredefective in Scm3(Sp), the ortholog of budding yeast Scm3(Sc). Scm3(Sp) depends on Mis16/18 for itscentromere localization and like them is recruited to centromeres in late anaphase. Importantly,Scm3(Sp) coaffinity purifies with CENP-A(Cnp1) and associates with CENP-A(Cnp1) in vitro, yet localizesindependently of intact CENP-A(Cnp1) chromatin and is differentially released from chromatin. WhileScm3(Sc) has been proposed to form a unique hexameric nucleosome with CENP-A(Cse4) and histone H4at budding yeast point centromeres, we favor a model in which Scm3(Sp) acts as a CENP-A(Cnp1)receptor/assembly factor, cooperating with Mis16 and Mis18 to receive CENP-A(Cnp1) from the Sim3escort and mediate assembly of CENP-A(Cnp1) into subkinetochore chromatin.", "metadata": {}}
+{"_id": "14340571", "title": "", "text": "The Molecular Basis for Oat Intolerance in Patients with Celiac DiseaseBackground  Celiac disease is asmall intestinal inflammatory disorder characterized by malabsorption, nutrient deficiency, and a range ofclinical manifestations. It is caused by an inappropriate immune response to dietary gluten and is treatedwith a gluten-free diet. Recent feeding studies have indicated oats to be safe for celiac disease patients,and oats are now often included in the celiac disease diet. This study aimed to investigate whether oatintolerance exists in celiac disease and to characterize the cells and processes underlying this intolerance.Methods and Findings  We selected for study nine adults with celiac disease who had a history of oatsexposure. Four of the patients had clinical symptoms on an oats-containing diet, and three of these fourpatients had intestinal inflammation typical of celiac disease at the time of oats exposure. We establishedoats-avenin-specific and -reactive intestinal T-cell lines from these three patients, as well as from twoother patients who appeared to tolerate oats. The avenin-reactive T-cell lines recognized avenin peptidesin the context of HLA-DQ2. These peptides have sequences rich in proline and glutamine residues closelyresembling wheat gluten epitopes. Deamidation (glutamine\u0000glutamic acid conversion) by tissuetransglutaminase was involved in the avenin epitope formation. Conclusions  We conclude that someceliac disease patients have avenin-reactive mucosal T-cells that can cause mucosal inflammation. Oatintolerance may be a reason for villous atrophy and inflammation in patients with celiac disease who areeating oats but otherwise are adhering to a strict gluten-free diet. Clinical follow-up of celiac diseasepatients eating oats is advisable.", "metadata": {}}
+{"_id": "14361849", "title": "", "text": "A comparison of continuous and bi-level positive airway pressure non-invasive ventilation in patients withacute cardiogenic pulmonary oedema: a meta-analysisIntroductionWe conducted the present study toinvestigate the potential beneficial and adverse effects of continuous positive airway pressure (CPAP)compared with bi-level positive airway pressure (BiPAP) noninvasive ventilation in patients withcardiogenic pulmonary oedema. MethodWe included randomized controlled studies comparing CPAP andBiPAP treatment in patients with cardiogenic pulmonary oedema from the Cochrane Controlled TrialsRegister (2005 issue 3), and EMBASE and MEDLINE databases (1966 to 1 December 2005), withoutlanguage restriction. Two reviewers reviewed the quality of the studies and independently performed dataextraction. ResultsSeven randomized controlled studies, including a total of 290 patients with cardiogenicpulmonary oedema, were considered. The hospital mortality (relative risk [RR] 0.76, 95% confidenceinterval [CI] 0.32–1.78; P = 0.52; I2 = 0%) and risk for requiring invasive ventilation (RR 0.80, 95% CI0.33–1.94; P = 0.62; I2 = 0%) were not significantly different between patients treated with CPAP andthose treated with BiPAP. Stratifying studies that used either fixed or titrated pressure during BiPAPtreatment and studies involving patients with or without hypercapnia did not change the results. Theduration of noninvasive ventilation required until the pulmonary oedema resolved (weighted meandifference [WMD] in hours = 3.65, 95% CI -12.12 to +19.43; P = 0.65, I2 = 0%) and length of hospitalstay (WMD in days = -0.04, 95% CI -2.57 to +2.48; P = 0.97, I2 = 0%) were also not significantlydifferent between the two groups. Based on the limited data available, there was an insignificant trendtoward an increase in new onset acute myocardial infarction in patients treated with BiPAP (RR 2.10, 95%CI 0.91–4.84; P = 0.08; I2 = 25.3%).ConclusionBiPAP does not offer any significant clinical benefits overCPAP in patients with acute cardiogenic pulmonary oedema. Until a large randomized controlled trialshows significant clinical benefit and cost-effectiveness of BiPAP versus CPAP in patients with acutecardiogenic pulmonary oedema, the choice of modality will depend mainly on the equipment available.", "metadata": {}}
+{"_id": "14362678", "title": "", "text": "CaMKII induces permeability transition through Drp1 phosphorylation during chronic β-ARstimulationMitochondrial permeability transition pore (mPTP) is involved in cardiac dysfunction duringchronic β-adrenergic receptor (β-AR) stimulation. The mechanism by which chronic β-AR stimulationleads to mPTP openings is elusive. Here, we show that chronic administration of isoproterenol (ISO)persistently increases the frequency of mPTP openings followed by mitochondrial damage and cardiacdysfunction. Mechanistically, this effect is mediated by phosphorylation of mitochondrial fission protein,dynamin-related protein 1 (Drp1), by Ca2+/calmodulin-dependent kinase II (CaMKII) at a serine 616(S616) site. Mutating this phosphorylation site or inhibiting Drp1 activity blocks CaMKII- or ISO-inducedmPTP opening and myocyte death in vitro and rescues heart hypertrophy in vivo. In human failing hearts,Drp1 phosphorylation at S616 is increased. These results uncover a pathway downstream of chronic β-ARstimulation that links CaMKII, Drp1 and mPTP to bridge cytosolic stress signal with mitochondrialdysfunction in the heart.", "metadata": {}}
+{"_id": "14362780", "title": "", "text": "MicroRNA Response of Primary Human Macrophages to Arcobacter Butzleri InfectionThe role ofmicroRNAs (miRNAs) in infectious diseases is becoming more and more apparent, and the use of miRNAsas a diagnostic tool and their therapeutic application has become the major focus of investigation. Theaim of this study was to identify miRNAs involved in the immune signaling of macrophages in response toArcobacter (A.) butzleri infection, an emerging foodborne pathogen causing gastroenteritis. Therefore,primary human macrophages were isolated and infected, and miRNA expression was studied by means ofRNAseq. Analysis of the data revealed the expression of several miRNAs, which were previouslyassociated with bacterial infections such as miR-155, miR-125, and miR-212. They were shown to play akey role in Toll-like receptor signaling where they act as fine-tuners to establish a balanced immuneresponse. In addition, miRNAs which have yet not been identified during bacterial infections such asmiR-3613, miR-2116, miR-671, miR-30d, and miR-629 were differentially regulated in A.butzleri-infected cells. Targets of these miRNAs accumulated in pathways such as apoptosis andendocytosis - processes that might be involved in A. butzleri pathogenesis. Our study contributes newfindings about the interaction of A. butzleri with human innate immune cells helping to understandunderlying regulatory mechanisms in macrophages during infection.", "metadata": {}}
+{"_id": "14367469", "title": "", "text": "The circadian factor Period 2 modulates p53 stability and transcriptional activity in unstressed cellsHumanPeriod 2 (hPer2) is a transcriptional regulator at the core of the circadian clock mechanism that isresponsible for generating the negative feedback loop that sustains the clock. Its relevance to humandisease is underlined by alterations in its function that affect numerous biochemical and physiologicalprocesses. When absent, it results in the development of various cancers and an increase in the cell'ssusceptibility to genotoxic stress. Thus we sought to define a yet-uncharacterized checkpoint node inwhich circadian components integrate environmental stress signals to the DNA-damage response. Wefound that hPer2 binds the C-terminal half of human p53 (hp53) and forms a stable trimeric complex withhp53's negative regulator, Mdm2. We determined that hPer2 binding to hp53 prevents Mdm2 from beingubiquitinated and targeting hp53 by the proteasome. Down-regulation of hPer2 expression directly affectshp53 levels, whereas its overexpression influences both hp53 protein stability and transcription oftargeted genes. Overall our findings place hPer2 directly at the heart of the hp53-mediated response byensuring that basal levels of hp53 are available to precondition the cell when a rapid, hp53-mediated,transcriptional response is needed.", "metadata": {}}
+{"_id": "14376683", "title": "", "text": "Properties of Commelina yellow mottle virus's complete DNA sequence, genomic discontinuities andtranscript suggest that it is a pararetrovirus.The non-enveloped bacilliform viruses are the second groupof plant viruses known to possess a genome consisting of circular double-stranded DNA. We havecharacterized the viral transcript and determined the complete sequence of the genome of Commelinamellow mottle virus (CoYMV), a member of this group. Analysis of the viral transcript indicates that thevirus encodes a single terminally-redundant genome-length plus 120 nucleotide transcript. A fraction ofthe transcripts is polyadenylated, although the majority of the transcript is not polyadenylated. Analysisof the genome sequence indicates that the genome is 7489 bp in size and that the transcribed strandcontains three open reading frames capable of encoding proteins of 23, 15 and 216 kd. The function ofthe 25 and 15 kd proteins is unknown. Similarities between the 216 kd polypeptide and the cauliflowermosaic virus coat protein and protease/reverse transcriptase polyprotein suggest that the 216 kdpolypeptide is a polyprotein that is proteolytically processed to yield the virion coat protein, a protease,and replicase (reverse transcriptase and ribonuclease H). Each strand of the CoYMV genome isinterrupted by site-specific discontinuities. The locations of the 5'-ends of these discontinuities, and thepresence and location of a region on the CoYMV transcript capable of annealing with the 3'-end ofcytosolic initiator methionine tRNA are consistent with replication by reverse transcription. We havedemonstrated that a construct containing 1.3 CoYMV genomes is infective when introduced intoCommelina diffusa, the host for CoYMV, using Agrobacterium-mediated infection.", "metadata": {}}
+{"_id": "14380875", "title": "", "text": "The Glucocorticoid Receptor InhibitsGlucocorticoids repress NFkappaB-mediated activation ofproinflammatory genes such as interleukin-8 (IL-8) and ICAM-1. Our experiments suggest that theglucocorticoid receptor (GR) confers this effect by associating through protein-protein interactions withNFkappaB bound at each of these genes. That is, we show that the GR zinc binding region (ZBR), whichincludes the DNA binding and dimerization functions of the receptor, binds directly to the dimerizationdomain of the RelA subunit of NFkappaB in vitro and that the ZBR is sufficient to associate with RelAbound at NFkappaB response elements in vivo. Moreover, we demonstrate in vivo and in vitro that GRdoes not disrupt DNA binding by NFkappaB. In transient transfections, we found that the GR ligandbinding domain is essential for repression of NFkappaB but not for association with it and that GR canrepress an NFkappaB derivative bearing a heterologous activation domain. We used chromatinimmunoprecipitation assays in untransfected A549 cells to infer the mechanism by which the tethered GRrepresses NFkappaB-activated transcription. As expected, we found that the inflammatory signalTNFalpha stimulated preinitiation complex (PIC) assembly at the IL-8 and ICAM-1 promoters and that thelargest subunit of RNA polymerase II (pol II) in those complexes became phosphorylated at serines 2 and5 in its carboxy-terminal domain (CTD) heptapeptide repeats (YSPTSPS); these modifications arerequired for transcription initiation. Remarkably, GR did not inhibit PIC assembly under repressingconditions, but rather interfered with phosphorylation of serine 2 of the pol II CTD.", "metadata": {}}
+{"_id": "14386505", "title": "", "text": "Regulation of myeloid cell function through the CD200 receptor.Myeloid cells play pivotal roles in chronicinflammatory diseases through their broad proinflammatory, destructive, and remodeling capacities.CD200 is widely expressed on a variety of cell types, while the recently identified CD200R is expressed onmyeloid cells and T cells. CD200 deletion in vivo results in myeloid cell dysregulation and enhancedsusceptibility to autoimmune inflammation, suggesting that the CD200-CD200R interaction is involved inimmune suppression. We demonstrate in this study that CD200R agonists suppress mouse and humanmyeloid cell function in vitro, and also define a dose relationship between receptor expression and cellularinhibition. IFN-gamma- and IL-17-stimulated cytokine secretion from mouse peritoneal macrophages wasinhibited by CD200R engagement. Inhibitory effects were not universal, as LPS-stimulated responseswere unaffected. Inhibition of U937 cell cytokine production correlated with CD200R expression levels,and inhibition was only observed in low CD200R expressing cells, if the CD200R agonists were furthercross-linked. Tetanus toxoid-induced human PBMC IL-5 and IL-13 secretion was inhibited by CD200Ragonists. This inhibition was dependent upon cross-linking the CD200R on monocytes, but not oncross-linking the CD200R on CD4+ T cells. In all, we provide direct evidence that the CD200-CD200Rinteraction controls monocyte/macrophage function in both murine and human systems, furthersupporting the potential clinical application of CD200R agonists for the treatment of chronic inflammatorydiseases.", "metadata": {}}
+{"_id": "14390137", "title": "", "text": "Management of hepatitis C disease among VA patients with schizophrenia and substance usedisorders.OBJECTIVE Rates of hepatitis C (HCV) infection, testing, and treatment were compared amongpatients with schizophrenia, a substance use disorder, or co-occurring schizophrenia or schizoaffectivedisorder and a substance use disorder and a control group. METHODS Information about 293,445patients of the Northwest Veterans Healthcare Administration was obtained. RESULTS The substance usedisorder group constituted 13.6 percent of the sample; the schizophrenia group, 1.6 percent; and theco-occurring-disorders group, 1.4 percent. Respectively, these groups were approximately four, two, andsix times as likely as the control group to receive HCV testing and about seven, two, and eight times aslikely to be infected. The rate of interferon (IFN) therapy was significantly lower for the substance usegroup and the group with co-occurring disorders. However, the magnitude of the differences was notsubstantial, suggesting that these high-risk groups were not excluded from IFN therapy.", "metadata": {}}
+{"_id": "14395738", "title": "", "text": "Equity in adherence to antiretroviral therapy among economically vulnerable adolescents living with HIVin UgandaStudies from sub-Saharan Africa indicate that children made vulnerable by poverty have beendisproportionately affected by HIV with many exposed via mother-to-child transmission. For youth livingwith HIV, adherence to life-saving treatment regimens are likely to be affected by the complex set ofeconomic and social circumstances that challenge their families and also exacerbate health problems.Using baseline data from the National Institute of Child and Human Development (NICHD) fundedSuubi+Adherence study, we examined the extent to which individual and composite measures of equitypredict self-reported adherence among Ugandan adolescents aged 10-16 (n = 702) living with HIV.Results showed that greater asset ownership, specifically familial possession of seven or more tangibleassets, was associated with greater odds of self-reported adherence (OR 1.69, 95% CI: 1.00-2.85). Ouranalyses also indicated that distance to the nearest health clinic impacts youth's adherence to an ARVregimen. Youth who reported living nearest to a clinic were significantly more likely to report optimaladherence (OR 1.49, 95% CI: 0.92-2.40). Moreover, applying the composite equity scores, we found thatadolescents with greater economic advantage in ownership of household assets, financial savings, andcaregiver employment had higher odds of adherence by a factor of 1.70 (95% CI: 1.07-2.70). Thesefindings suggest that interventions addressing economic and social inequities may be beneficial toincrease antiretroviral therapy (ART) uptake among economically vulnerable youth, especially insub-Saharan Africa. This is one of the first studies to address the question of equity in adherence to ARTamong economically vulnerable youth with HIV.", "metadata": {}}
+{"_id": "14402338", "title": "", "text": "High-Resolution Phenotypic Profiling Defines Genes Essential for Mycobacterial Growth and CholesterolCatabolismThe pathways that comprise cellular metabolism are highly interconnected, and alterations inindividual enzymes can have far-reaching effects. As a result, global profiling methods that measure geneexpression are of limited value in predicting how the loss of an individual function will affect the cell. Inthis work, we employed a new method of global phenotypic profiling to directly define the genes requiredfor the growth of Mycobacterium tuberculosis. A combination of high-density mutagenesis anddeep-sequencing was used to characterize the composition of complex mutant libraries exposed todifferent conditions. This allowed the unambiguous identification of the genes that are essential for Mtb togrow in vitro, and proved to be a significant improvement over previous approaches. To further explorefunctions that are required for persistence in the host, we defined the pathways necessary for theutilization of cholesterol, a critical carbon source during infection. Few of the genes we identified hadpreviously been implicated in this adaptation by transcriptional profiling, and only a fraction wereencoded in the chromosomal region known to encode sterol catabolic functions. These genes comprise anunexpectedly large percentage of those previously shown to be required for bacterial growth in mousetissue. Thus, this single nutritional change accounts for a significant fraction of the adaption to the host.This work provides the most comprehensive genetic characterization of a sterol catabolic pathway todate, suggests putative roles for uncharacterized virulence genes, and precisely maps genes encodingpotential drug targets.", "metadata": {}}
+{"_id": "14405193", "title": "", "text": "Tyrosine phosphorylation regulates the endocytosis and surface expression of GluN3A-containing NMDAreceptors.Selective control of receptor trafficking provides a mechanism for remodeling the receptorcomposition of excitatory synapses, and thus supports synaptic transmission, plasticity, anddevelopment. GluN3A (formerly NR3A) is a nonconventional member of the NMDA receptor (NMDAR)subunit family, which endows NMDAR channels with low calcium permeability and reduced magnesiumsensitivity compared with NMDARs comprising only GluN1 and GluN2 subunits. Because of these specialproperties, GluN3A subunits act as a molecular brake to limit the plasticity and maturation of excitatorysynapses, pointing toward GluN3A removal as a critical step in the development of neuronal circuitry.However, the molecular signals mediating GluN3A endocytic removal remain unclear. Here we define anovel endocytic motif (YWL), which is located within the cytoplasmic C-terminal tail of GluN3A andmediates its binding to the clathrin adaptor AP2. Alanine mutations within the GluN3A endocytic motifinhibited clathrin-dependent internalization and led to accumulation of GluN3A-containing NMDARs at thecell surface, whereas mimicking phosphorylation of the tyrosine residue promoted internalization andreduced cell-surface expression as shown by immunocytochemical and electrophysiological approaches inrecombinant systems and rat neurons in primary culture. We further demonstrate that the tyrosineresidue is phosphorylated by Src family kinases, and that Src-activation limits surface GluN3A expressionin neurons. Together, our results identify a new molecular signal for GluN3A internalization that couplesthe functional surface expression of GluN3A-containing receptors to the phosphorylation state of GluN3Asubunits, and provides a molecular framework for the regulation of NMDAR subunit composition withimplications for synaptic plasticity and neurodevelopment.", "metadata": {}}
+{"_id": "14407673", "title": "", "text": "Myeloid-specific Krüppel-like factor 2 inactivation increases macrophage and neutrophil adhesion andpromotes atherosclerosis.RATIONALE Hemizygous deficiency of the transcription factor Krüppel-like factor2 (KLF2) has been shown previously to augment atherosclerosis in hypercholesterolemic mice. However,the cell type responsible for the increased atherosclerosis due to KLF2 deficiency has not been identified.This study examined the consequence of myeloid cell-specific KLF2 inactivation in atherosclerosis.METHODS AND RESULTS Cell-specific knockout mice were generated by Cre/loxP recombination.Macrophages isolated from myeloid-specific Klf2 knockout (myeKlf2(-/-)) mice were similar tomyeKlf2(+/+) macrophages in response to activation, polarization, and lipid accumulation. However, incomparison to myeKlf2(+/+) macrophages, myeKlf2(-/-) macrophages adhered more robustly toendothelial cells. Neutrophils from myeKlf2(-/-) mice also adhered more robustly to endothelial cells, andfewer myeKlf2(-/-) neutrophils survived in culture over a 24-hour period in comparison withmyeKlf2(+/+) neutrophils. When myeKlf2(-/-) mice were mated to Ldlr(-/-) mice and then fed a high fatand high cholesterol diet, significant increase in atherosclerosis was observed in the myeKlf2(-/-)Ldlr(-/-)mice compared with myeKlf2(+/+)Ldlr(-/-) littermates. The increased atherosclerosis inmyeKlf2(-/-)Ldlr(-/-) mice was associated with elevated presence of neutrophils and macrophages, withcorresponding increase of myeloperoxidase as well as chlorinated and nitrosylated tyrosine epitopes intheir lesion areas compared with myeKlf2(+/+)Ldlr(-/-) mice. CONCLUSIONS This study documents arole for myeloid KLF2 expression in modulating atherosclerosis. The increased neutrophil accumulationand atherosclerosis progression with myeloid-specific KLF2 deficiency also underscores the importance ofneutrophils in promoting vascular oxidative stress and atherosclerosis. Collectively, these results suggestthat elevating KLF2 expression may be a novel strategy for prevention and treatment of atherosclerosis.", "metadata": {}}
+{"_id": "14408200", "title": "", "text": "Epidemiology of Staphylococcus aureus blood and skin and soft tissue infections in the US military healthsystem, 2005-2010.CONTEXT Rates of hospital-onset methicillin-resistant Staphylococcus aureus (MRSA)infections are reported as decreasing, but recent rates of community-onset S. aureus infections are lessknown. OBJECTIVES To characterize the overall and annual incidence rates of community-onset andhospital-onset S. aureus bacteremia and skin and soft tissue infections (SSTIs) in a national health caresystem and to evaluate trends in the incidence rates of S. aureus bacteremia and SSTIs and theproportion due to MRSA. DESIGN, SETTING, AND PARTICIPANTS Observational study of all Departmentof Defense TRICARE beneficiaries from January 2005 through December 2010. Medical record databaseswere used to identify and classify all annual first-positive S. aureus blood and wound or abscess culturesas methicillin-susceptible S. aureus or MRSA, and as community-onset or hospital-onset infections(isolates collected >3 days after hospital admission). MAIN OUTCOME MEASURES Unadjusted incidencerates per 100,000 person-years of observation, the proportion of infections that was due to MRSA, andannual trends for 2005 through 2010 (examined using the Spearman rank correlation test or theMantel-Haenszel χ2 test for linear trend). RESULTS During 56 million person-years (nonactive duty: 47million person-years; active duty: 9 million person-years), there were 2643 blood and 80,281 wound orabscess annual first-positive S. aureus cultures. Annual incidence rates varied from 3.6 to 6.0 per100,000 person-years for S. aureus bacteremia and 122.7 to 168.9 per 100,000 person-years for S.aureus SSTIs. The annual incidence rates for community-onset MRSA bacteremia decreased from 1.7 per100,000 person-years (95% CI, 1.5-2.0 per 100,000 person-years) in 2005 to 1.2 per 100,000person-years (95% CI, 0.9-1.4 per 100,000 person-years) in 2010 (P = .005 for trend). The annualincidence rates for hospital-onset MRSA bacteremia also decreased from 0.7 per 100,000 person-years(95% CI, 0.6-0.9 per 100,000 person-years) in 2005 to 0.4 per 100,000 person-years (95% CI, 0.3-0.5per 100,000 person-years) in 2010 (P = .005 for trend). Concurrently, the proportion ofcommunity-onset SSTI due to MRSA peaked at 62% in 2006 before decreasing annually to 52% in 2010(P < .001 for trend). CONCLUSION In the Department of Defense population consisting of men andwomen of all ages from across the United States, the rates of both community-onset and hospital-onsetMRSA bacteremia decreased in parallel, while the proportion of community-onset SSTIs due to MRSA hasmore recently declined.", "metadata": {}}
+{"_id": "14419116", "title": "", "text": "Potentiation of NMDA currents by pituitary adenylate cyclase activating polypeptide in neonatal ratsympathetic preganglionic neurons.Whole cell patch-clamp recordings were made from sympatheticpreganglionic neurons (SPNs) in the intermediolateral cell column of thoracolumbar spinal cord slices of12- to 16-day-old rats, and the effects of pituitary adenylate cyclase activating polypeptide (PACAP)-38on N-methyl-D-aspartate (NMDA)- and kainate (KA)-induced inward currents were examined. PACAP, inconcentrations (10-30 nM) that caused no significant change of holding currents, reversibly increasedNMDA-induced currents but not KA-induced currents. At higher concentrations (>30 nM), the peptideproduced a sustained inward current. The potentiating effect of PACAP was nullified by prior incubation ofthe slices with the adenylate cyclase inhibitor MDL-12,330A (25 microM). Further, superfusing the sliceswith the membrane-permeable cyclic AMP analogue N6,2'-O-dibutyryladenosine 3':5'-cyclicmonophosphate (100-300 microM) in the presence of the phosphodiesterase inhibitor3-isobutyl-1-methylxanthine (700 microM) increased the NMDA currents. This result suggests that PACAPselectively increases NMDA-receptor-mediated responses in the rat SPNs, probably via acyclic-AMP-dependent mechanism, providing evidence that the peptide may be involved in synapticplasticity.", "metadata": {}}
+{"_id": "14434123", "title": "", "text": "Aberrant Expression of RCAN1 in Alzheimer’s Pathogenesis: A New Molecular Mechanism and a NovelDrug TargetAD, a devastating neurodegenerative disorder, is the most common cause of dementia in theelderly. Patients with AD are characterized by three hallmarks of neuropathology including neuritic plaquedeposition, neurofibrillary tangle formation, and neuronal loss. Growing evidences indicate thatdysregulation of regulator of calcineurin 1 (RCAN1) plays an important role in the pathogenesis of AD.Aberrant RCAN1 expression facilitates neuronal apoptosis and Tau hyperphosphorylation, leading toneuronal loss and neurofibrillary tangle formation. This review aims to describe the recent advances ofthe regulation of RCAN1 expression and its physiological functions. Moreover, the AD risk factors-inducedRCAN1 dysregulation and its role in promoting neuronal loss, synaptic impairments and neurofibrillarytangle formation are summarized. Furthermore, we provide an outlook into the effects of RCAN1dysregulation on APP processing, Aβ generation and neuritic plaque formation, and the possibleunderlying mechanisms, as well as the potential of targeting RCAN1 as a new therapeutic approach.", "metadata": {}}
+{"_id": "14437255", "title": "", "text": "Congruent Visual Speech Enhances Cortical Entrainment to Continuous Auditory Speech in Noise-FreeConditions.UNLABELLED Congruent audiovisual speech enhances our ability to comprehend a speaker,even in noise-free conditions. When incongruent auditory and visual information is presentedconcurrently, it can hinder a listener's perception and even cause him or her to perceive information thatwas not presented in either modality. Efforts to investigate the neural basis of these effects have oftenfocused on the special case of discrete audiovisual syllables that are spatially and temporally congruent,with less work done on the case of natural, continuous speech. Recent electrophysiological studies havedemonstrated that cortical response measures to continuous auditory speech can be easily obtained usingmultivariate analysis methods. Here, we apply such methods to the case of audiovisual speech and,importantly, present a novel framework for indexing multisensory integration in the context of continuousspeech. Specifically, we examine how the temporal and contextual congruency of ongoing audiovisualspeech affects the cortical encoding of the speech envelope in humans using electroencephalography. Wedemonstrate that the cortical representation of the speech envelope is enhanced by the presentation ofcongruent audiovisual speech in noise-free conditions. Furthermore, we show that this is likelyattributable to the contribution of neural generators that are not particularly active during unimodalstimulation and that it is most prominent at the temporal scale corresponding to syllabic rate (2-6 Hz).Finally, our data suggest that neural entrainment to the speech envelope is inhibited when the auditoryand visual streams are incongruent both temporally and contextually. SIGNIFICANCE STATEMENT Seeinga speaker's face as he or she talks can greatly help in understanding what the speaker is saying. This isbecause the speaker's facial movements relay information about what the speaker is saying, but also,importantly, when the speaker is saying it. Studying how the brain uses this timing relationship tocombine information from continuous auditory and visual speech has traditionally been methodologicallydifficult. Here we introduce a new approach for doing this using relatively inexpensive and noninvasivescalp recordings. Specifically, we show that the brain's representation of auditory speech is enhancedwhen the accompanying visual speech signal shares the same timing. Furthermore, we show that thisenhancement is most pronounced at a time scale that corresponds to mean syllable length.", "metadata": {}}
+{"_id": "14446279", "title": "", "text": "Telomere tethering at the nuclear periphery is essential for efficient DNA double strand break repair insubtelomeric regionIn the yeast Saccharomyces cerevisiae that lacks lamins, the nuclear pore complex(NPC) has been proposed to serve a role in chromatin organization. Here, using fluorescence microscopyin living cells, we show that nuclear pore proteins of the Nup84 core complex, Nup84p, Nup145Cp,Nup120p, and Nup133p, serve to anchor telomere XI-L at the nuclear periphery. The integrity of thiscomplex is shown to be required for repression of a URA3 gene inserted in the subtelomeric region of thischromosome end. Furthermore, altering the integrity of this complex decreases the efficiency of repair ofa DNA double-strand break (DSB) only when it is generated in the subtelomeric region, even though therepair machinery is functional. These effects are specific to the Nup84 complex. Our observations thusconfirm and extend the role played by the NPC, through the Nup84 complex, in the functionalorganization of chromatin. They also indicate that anchoring of telomeres is essential for efficient repairof DSBs occurring therein and is important for preserving genome integrity.", "metadata": {}}
+{"_id": "14460402", "title": "", "text": "p63 Regulates adult neural precursor and newly born neuron survival to control hippocampal-dependentBehavior.The molecular mechanisms that regulate adult neural precursor cell (NPC) survival, and thusmaintain adult neurogenesis, are not well defined. Here, we investigate the role of p63, a p53 familymember, in adult NPC function in mice. Conditional ablation of p63 in adult NPCs or p63haploinsufficiency led to reduced numbers of NPCs and newborn neurons in the neurogenic zones of thehippocampus and lateral ventricles and in the olfactory bulb. These reductions were attributable toenhanced apoptosis of NPCs and newborn neurons and were rescued by inhibition of caspase activity,p53, or the p53 apoptotic effector PUMA (p53-upregulated modulator of apoptosis). Moreover, thesecellular deficits were functionally important because they led to perturbations in hippocampus-dependentmemory formation. These results indicate that p63 regulates the numbers of adult NPCs and adult-bornneurons as well as neural stem cell-dependent cognitive functions, and that it does so, at least in part, byinhibiting p53-dependent cell death.", "metadata": {}}
+{"_id": "14461101", "title": "", "text": "Tyrosine-Phosphorylated Caveolin-1 Blocks Bacterial Uptake by Inducing Vav2-RhoA-MediatedCytoskeletal RearrangementsCertain bacterial adhesins appear to promote a pathogen's extracellularlifestyle rather than its entry into host cells. However, little is known about the stimuli elicited upon suchpathogen host-cell interactions. Here, we report that type IV pili (Tfp)-producing Neisseria gonorrhoeae(P(+)GC) induces an immediate recruitment of caveolin-1 (Cav1) in the host cell, which subsequentlyprevents bacterial internalization by triggering cytoskeletal rearrangements via downstreamphosphotyrosine signaling. A broad and unbiased analysis of potential interaction partners fortyrosine-phosphorylated Cav1 revealed a direct interaction with the Rho-family guanine nucleotideexchange factor Vav2. Both Vav2 and its substrate, the small GTPase RhoA, were found to play a directrole in the Cav1-mediated prevention of bacterial uptake. Our findings, which have been extended toenteropathogenic Escherichia coli, highlight how Tfp-producing bacteria avoid host cell uptake. Further,our data establish a mechanistic link between Cav1 phosphorylation and pathogen-induced cytoskeletonreorganization and advance our understanding of caveolin function.", "metadata": {}}
+{"_id": "14464451", "title": "", "text": "Effects of GC Bias in Next-Generation-Sequencing Data on De Novo GenomeAssemblyNext-generation-sequencing (NGS) has revolutionized the field of genome assembly because ofits much higher data throughput and much lower cost compared with traditional Sanger sequencing.However, NGS poses new computational challenges to de novo genome assembly. Among the challenges,GC bias in NGS data is known to aggravate genome assembly. However, it is not clear to what extent GCbias affects genome assembly in general. In this work, we conduct a systematic analysis on the effects ofGC bias on genome assembly. Our analyses reveal that GC bias only lowers assembly completeness whenthe degree of GC bias is above a threshold. At a strong GC bias, the assembly fragmentation due to GCbias can be explained by the low coverage of reads in the GC-poor or GC-rich regions of a genome. Thiseffect is observed for all the assemblers under study. Increasing the total amount of NGS data thusrescues the assembly fragmentation because of GC bias. However, the amount of data needed for a fullrescue depends on the distribution of GC contents. Both low and high coverage depths due to GC biaslower the accuracy of assembly. These pieces of information provide guidance toward a better de novogenome assembly in the presence of GC bias.", "metadata": {}}
+{"_id": "14471161", "title": "", "text": "Cancer inhibition through circadian reprogramming of tumor transcriptome with meal timing.Circadiandisruption accelerates cancer progression, whereas circadian reinforcement could halt it. Mice with P03pancreatic adenocarcinoma (n = 77) were synchronized and fed ad libitum (AL) or with meal timing (MT)from Zeitgeber time (ZT) 2 to ZT6 with normal or fat diet. Tumor gene expression profiling wasdetermined with DNA microarrays at endogenous circadian time (CT) 4 and CT16. Circadian mRNAexpression patterns were determined for clock genes Rev-erbalpha, Per2, and Bmal1, cellular stressgenes Hspa8 and Cirbp, and cyclin A2 gene Ccna2 in liver and tumor. The 24-hour patterns intelemetered rest-activity and body temperature and plasma corticosterone and insulin-like growthfactor-I (IGF-I) were assessed. We showed that MT inhibited cancer growth by approximately 40% ascompared with AL (P = 0.011) irrespective of calorie intake. Clock gene transcription remainedarrhythmic in tumors irrespective of feeding schedule or diet. Yet, MT upregulated or downregulated theexpression of 423 tumor genes, according to CT. Moreover, 36 genes involved in cellular stress, cellcycle, and metabolism were upregulated at one CT and downregulated 12 h apart. MT induced >10-foldcircadian expression of Hspa8, Cirbp, and Ccna2 in tumors. Corticosterone or IGF-I patterns played norole in tumor growth inhibition. In contrast, MT consistently doubled the circadian amplitude of bodytemperature. Peak and trough respectively corresponded to peak expressions of Hspa8 and Cirbp intumors. The reinforcement of the host circadian timing system with MT induced 24-hour rhythmicexpression of critical genes in clock-deficient tumors, which translated into cancer growth inhibition.Targeting circadian clocks represents a novel potential challenge for cancer therapeutics.", "metadata": {}}
+{"_id": "14474178", "title": "", "text": "Role of chicken melanoma differentiation-associated gene 5 in induction and activation of innate andadaptive immune responses to infectious bursal disease virus in cultured macrophagesThe objective ofthe present study was to determine if chicken melanoma-differentiation-associated gene 5 (MDA5)senses infectious bursal disease virus infection to induce innate immunity that bridges to adaptiveimmunity. During IBDV infection in HD11 cells, IBDV titers and RNA loads increased up to 3.4 × 107plaque-forming units (PFU)/mL and 1114 ng/µL, respectively, at 24 hours postinfection (hpi). IBDVinfection in HD11 cells induced significantly upregulated (p < 0.05) expression levels of chicken MDA5(59-fold), interferon-β (IFN-β) (693-fold), dsRNA-dependent protein kinase (PKR) (4-fold), 2’,5’-oligoadenylate synthetase (OAS) (286-fold), myxovirus resistance gene (Mx) (22-fold), interleukin-1β(IL-1β) (5-fold), IL-6 (146-fold), IL-8 (4-fold), IL-10 (4-fold), inducible nitric oxide synthase (iNOS)(15-fold), and major histocompatibility complex class I (MHC class I) (4-fold). Nitric oxide production inthe culture supernatants increased significantly (p < 0.05) up to 6.5 μM at 24 hpi. The expressed chMDA5and IBDV-derived dsRNA were localized in the cytoplasm of HD11 cells during IBDV infection.ChMDA5-knockdown HD11 cells had significantly higher (p < 0.05) IBDV RNA loads at 24 hpi andsignificantly lower (p < 0.05) nitric oxide production and expression levels of chicken MDA5, IFN-β, PKR,OAS, Mx, IL-1β, IL-6, IL-8, IL-12(p40), IL-18, IL-10, iNOS, MHC class I and CD86 at 24 hpi. In addition,chMDA5 overexpression in HD11 cells resulted in significantly reduced (p < 0.05) IBDV titers and RNAloads and significantly increased (p < 0.05) nitric oxide production at 16 and 24 hpi. It also resulted insignificantly higher (p < 0.05) expression levels of chicken MDA5, IFN-β, PKR, OAS, Mx, IL-1β, IL-6, IL-8,IL-12(p40), IL-10 and iNOS at 2 hpi. In conclusion, the results indicate that chMDA5 senses IBDVinfection in chicken macrophages, and this is associated with IBDV-induced expression of IFN-β andinitiation of an innate immune response that in turn activates the adaptive immune response and limitsIBDV replication.", "metadata": {}}
+{"_id": "14475235", "title": "", "text": "Age-Associated Sperm DNA Methylation Alterations: Possible Implications in Offspring DiseaseSusceptibilityRecent evidence demonstrates a role for paternal aging on offspring disease susceptibility. Itis well established that various neuropsychiatric disorders (schizophrenia, autism, etc.), trinucleotideexpansion associated diseases (myotonic dystrophy, Huntington's, etc.) and even some forms of cancerhave increased incidence in the offspring of older fathers. Despite strong epidemiological evidence thatthese alterations are more common in offspring sired by older fathers, in most cases the mechanismsthat drive these processes are unclear. However, it is commonly believed that epigenetics, andspecifically DNA methylation alterations, likely play a role. In this study we have investigated the impactof aging on DNA methylation in mature human sperm. Using a methylation array approach we evaluatedchanges to sperm DNA methylation patterns in 17 fertile donors by comparing the sperm methylome of 2samples collected from each individual 9-19 years apart. With this design we have identified 139 regionsthat are significantly and consistently hypomethylated with age and 8 regions that are significantlyhypermethylated with age. A representative subset of these alterations have been confirmed in anindependent cohort. A total of 117 genes are associated with these regions of methylation alterations(promoter or gene body). Intriguingly, a portion of the age-related changes in sperm DNA methylationare located at genes previously associated with schizophrenia and bipolar disorder. While our data doesnot establish a causative relationship, it does raise the possibility that the age-associated methylation ofthe candidate genes that we observe in sperm might contribute to the increased incidence ofneuropsychiatric and other disorders in the offspring of older males. However, further study is required todetermine whether, and to what extent, a causative relationship exists.", "metadata": {}}
+{"_id": "14479433", "title": "", "text": "Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasisNeonatalcholestasis is a potentially life-threatening condition requiring prompt diagnosis. Mutations in severaldifferent genes can cause progressive familial intrahepatic cholestasis, but known genes cannot accountfor all familial cases. Here we report four individuals from two unrelated families with neonatal cholestasisand mutations in NR1H4, which encodes the farnesoid X receptor (FXR), a bile acid-activated nuclearhormone receptor that regulates bile acid metabolism. Clinical features of severe, persistentNR1H4-related cholestasis include neonatal onset with rapid progression to end-stage liver disease,vitamin K-independent coagulopathy, low-to-normal serum gamma-glutamyl transferase activity,elevated serum alpha-fetoprotein and undetectable liver bile salt export pump (ABCB11) expression. Ourfindings demonstrate a pivotal function for FXR in bile acid homeostasis and liver protection.", "metadata": {}}
+{"_id": "14482051", "title": "", "text": "Phase II study of panobinostat in combination with bevacizumab for recurrent glioblastoma andanaplastic glioma.BACKGROUND Panobinostat is a histone deacetylase inhibitor with antineoplastic andantiangiogenic effects in glioma that may work synergistically with bevacizumab. We conducted amulticenter phase II trial of panobinostat combined with bevacizumab in patients with recurrenthigh-grade glioma (HGG). METHODS Patients with recurrent HGG were treated with oral panobinostat 30mg 3 times per week, every other week, in combination with bevacizumab 10 mg/kg every other week.The primary endpoint was a 6-month progression-fee survival (PFS6) rate for participants with recurrentglioblastoma (GBM). Patients with recurrent anaplastic glioma (AG) were evaluated as an exploratory armof the study. RESULTS At interim analysis, the GBM arm did not meet criteria for continued accrual, andthe GBM arm was closed. A total of 24 patients with GBM were accrued prior to closure. The PFS6 ratewas 30.4% (95%, CI 12.4%-50.7%), median PFS was 5 months (range, 3-9 months), and medianoverall survival (OS) was 9 months (range, 6-19 months). Accrual in the AG arm continued tocompletion, and a total of 15 patients were enrolled. The PFS6 rate was 46.7% (range, 21%-73%),median PFS was 7 months (range, 2-10 months), and median OS was 17 months (range, 5 months-27months). CONCLUSIONS This phase II study of panobinostat and bevacizumab in participants withrecurrent GBM did not meet criteria for continued accrual, and the GBM cohort of the study was closed.Although it was reasonably well tolerated, the addition of panobinostat to bevacizumab did notsignificantly improve PFS6 compared with historical controls of bevacizumab monotherapy in eithercohort.", "metadata": {}}
+{"_id": "14492339", "title": "", "text": "Blood monocytes consist of two principal subsets with distinct migratory propertiesPeripheral bloodmonocytes are a heterogeneous population of circulating leukocytes. Using a murine adoptive transfersystem to probe monocyte homing and differentiation in vivo, we identified two functional subsets amongmurine blood monocytes: a short-lived CX(3)CR1(lo)CCR2(+)Gr1(+) subset that is actively recruited toinflamed tissues and a CX(3)CR1(hi)CCR2(-)Gr1(-) subset characterized by CX(3)CR1-dependentrecruitment to noninflamed tissues. Both subsets have the potential to differentiate into dendritic cells invivo. The level of CX(3)CR1 expression also defines the two major human monocyte subsets, theCD14(+)CD16(-) and CD14(lo)CD16(+) monocytes, which share phenotype and homing potential withthe mouse subsets. These findings raise the potential for novel therapeutic strategies in inflammatorydiseases.", "metadata": {}}
+{"_id": "14492964", "title": "", "text": "The Spemann Organizer Signal noggin Binds and Inactivates Bone Morphogenetic Protein 4Signalsreleased by the Spemann organizer of the amphibian gastrula can directly induce neural tissue fromectoderm and can dorsalize ventral mesoderm to form muscle. The secreted polypeptide noggin mimicsthese activities and is expressed at the appropriate time and place to participate in the organizer signal.Neural induction and mesoderm dorsalization are antagonized by bone morphogenetic proteins (BMPs),which induce epidermis and ventral mesoderm instead. Here we report that noggin protein binds BMP4with high affinity and can abolish BMP4 activity by blocking binding to cognate cell-surface receptors.These data suggest that noggin secreted by the organizer patterns the embryo by interrupting BMPsignaling.", "metadata": {}}
+{"_id": "14496749", "title": "", "text": "A Conserved MST-FOXO Signaling Pathway Mediates Oxidative-Stress Responses and Extends LifeSpanOxidative stress influences cell survival and homeostasis, but the mechanisms underlying thebiological effects of oxidative stress remain to be elucidated. Here, we demonstrate that the proteinkinase MST1 mediates oxidative-stress-induced cell death in primary mammalian neurons by directlyactivating the FOXO transcription factors. MST1 phosphorylates FOXO proteins at a conserved site withinthe forkhead domain that disrupts their interaction with 14-3-3 proteins, promotes FOXO nucleartranslocation, and thereby induces cell death in neurons. We also extend the MST-FOXO signaling link tonematodes. Knockdown of the C. elegans MST1 ortholog CST-1 shortens life span and accelerates tissueaging, while overexpression of cst-1 promotes life span and delays aging. The cst-1-induced life-spanextension occurs in a daf-16-dependent manner. The identification of the FOXO transcription factors asmajor and evolutionarily conserved targets of MST1 suggests that MST kinases play important roles indiverse biological processes including cellular responses to oxidative stress and longevity.", "metadata": {}}
+{"_id": "14500725", "title": "", "text": "Physician Emigration from Sub-Saharan Africa to the United States: Analysis of the 2011 AMA PhysicianMasterfileBACKGROUND The large-scale emigration of physicians from sub-Saharan Africa (SSA) tohigh-income nations is a serious development concern. Our objective was to determine currentemigration trends of SSA physicians found in the physician workforce of the United States. METHODSAND FINDINGS We analyzed physician data from the World Health Organization (WHO) Global HealthWorkforce Statistics along with graduation and residency data from the 2011 American MedicalAssociation Physician Masterfile (AMA-PM) on physicians trained or born in SSA countries who currentlypractice in the US. We estimated emigration proportions, year of US entry, years of practice beforeemigration, and length of time in the US. According to the 2011 AMA-PM, 10,819 physicians were born ortrained in 28 SSA countries. Sixty-eight percent (n = 7,370) were SSA-trained, 20% (n = 2,126) wereUS-trained, and 12% (n = 1,323) were trained outside both SSA and the US. We estimated activephysicians (age ≤ 70 years) to represent 96% (n = 10,377) of the total. Migration trends amongSSA-trained physicians increased from 2002 to 2011 for all but one principal source country; theexception was South Africa whose physician migration to the US decreased by 8% (-156). The increase inlast-decade migration was >50% in Nigeria (+1,113) and Ghana (+243), >100% in Ethiopia (+274), and>200% (+244) in Sudan. Liberia was the most affected by migration to the US with 77% (n = 175) of itsestimated physicians in the 2011 AMA-PM. On average, SSA-trained physicians have been in the US for18 years. They practiced for 6.5 years before US entry, and nearly half emigrated during theimplementation years (1984-1999) of the structural adjustment programs. CONCLUSION Physicianemigration from SSA to the US is increasing for most SSA source countries. Unless far-reaching policiesare implemented by the US and SSA countries, the current emigration trends will persist, and the US willremain a leading destination for SSA physicians emigrating from the continent of greatest need. Pleasesee later in the article for the Editors' Summary.", "metadata": {}}
+{"_id": "14501880", "title": "", "text": "Kynurenic Acid Is a Nutritional Cue that Enables Behavioral PlasticityThe kynurenine pathway oftryptophan metabolism is involved in the pathogenesis of several brain diseases, but its physiologicalfunctions remain unclear. We report that kynurenic acid, a metabolite in this pathway, functions as aregulator of food-dependent behavioral plasticity in C. elegans. The experience of fasting in C. elegansalters a variety of behaviors, including feeding rate, when food is encountered post-fast. Levels ofneurally produced kynurenic acid are depleted by fasting, leading to activation ofNMDA-receptor-expressing interneurons and initiation of a neuropeptide-y-like signaling axis thatpromotes elevated feeding through enhanced serotonin release when animals re-encounter food. Uponrefeeding, kynurenic acid levels are eventually replenished, ending the elevated feeding period. Becausetryptophan is an essential amino acid, these findings suggest that a physiological role of kynurenic acid isin directly linking metabolism to activity of NMDA and serotonergic circuits, which regulate a broad rangeof behaviors and physiologies.", "metadata": {}}
+{"_id": "14530534", "title": "", "text": "Comprehensive Identification and Annotation of Cell Type-Specific and Ubiquitous CTCF-Binding Sites inthe Human GenomeChromatin insulators are DNA elements that regulate the level of gene expressioneither by preventing gene silencing through the maintenance of heterochromatin boundaries or bypreventing gene activation by blocking interactions between enhancers and promoters. CCCTC-bindingfactor (CTCF), a ubiquitously expressed 11-zinc-finger DNA-binding protein, is the only protein implicatedin the establishment of insulators in vertebrates. While CTCF has been implicated in diverse regulatoryfunctions, CTCF has only been studied in a limited number of cell types across human genome. Thus, it isnot clear whether the identified cell type-specific differences in CTCF-binding sites are functionallysignificant. Here, we identify and characterize cell type-specific and ubiquitous CTCF-binding sites in thehuman genome across 38 cell types designated by the Encyclopedia of DNA Elements (ENCODE)consortium. These cell type-specific and ubiquitous CTCF-binding sites show uniquely versatiletranscriptional functions and characteristic chromatin features. In addition, we confirm the insulatorbarrier function of CTCF-binding and explore the novel function of CTCF in DNA replication. These resultsrepresent a critical step toward the comprehensive and systematic understanding of CTCF-dependentinsulators and their versatile roles in the human genome.", "metadata": {}}
+{"_id": "14535322", "title": "", "text": "Experimental and Theoretical Approaches to Conscious ProcessingRecent experimental studies andtheoretical models have begun to address the challenge of establishing a causal link between subjectiveconscious experience and measurable neuronal activity. The present review focuses on the well-delimitedissue of how an external or internal piece of information goes beyond nonconscious processing and gainsaccess to conscious processing, a transition characterized by the existence of a reportable subjectiveexperience. Converging neuroimaging and neurophysiological data, acquired during minimal experimentalcontrasts between conscious and nonconscious processing, point to objective neural measures ofconscious access: late amplification of relevant sensory activity, long-distance cortico-corticalsynchronization at beta and gamma frequencies, and \"ignition\" of a large-scale prefronto-parietalnetwork. We compare these findings to current theoretical models of conscious processing, including theGlobal Neuronal Workspace (GNW) model according to which conscious access occurs when incominginformation is made globally available to multiple brain systems through a network of neurons withlong-range axons densely distributed in prefrontal, parieto-temporal, and cingulate cortices. The clinicalimplications of these results for general anesthesia, coma, vegetative state, and schizophrenia arediscussed.", "metadata": {}}
+{"_id": "14541844", "title": "", "text": "Reconstruction of the yeast Snf1 kinase regulatory network reveals its role as a global energyregulatorHighly conserved among eukaryotic cells, the AMP-activated kinase (AMPK) is a central regulatorof carbon metabolism. To map the complete network of interactions around AMPK in yeast (Snf1) and toevaluate the role of its regulatory subunit Snf4, we measured global mRNA, protein and metabolite levelsin wild type, Deltasnf1, Deltasnf4, and Deltasnf1Deltasnf4 knockout strains. Using four newly developedcomputational tools, including novel DOGMA sub-network analysis, we showed the benefits of three-levelome-data integration to uncover the global Snf1 kinase role in yeast. We for the first time identifiedSnf1's global regulation on gene and protein expression levels, and showed that yeast Snf1 has a farmore extensive function in controlling energy metabolism than reported earlier. Additionally, we identifiedcomplementary roles of Snf1 and Snf4. Similar to the function of AMPK in humans, our findings showedthat Snf1 is a low-energy checkpoint and that yeast can be used more extensively as a model system forstudying the molecular mechanisms underlying the global regulation of AMPK in mammals, failure ofwhich leads to metabolic diseases.", "metadata": {}}
+{"_id": "14544564", "title": "", "text": "Influence of Steroid Hormone Signaling on Life Span Control by Caenorhabditis elegans Insulin-LikeSignalingSterol-sensing nuclear receptors and insulin-like growth factor signaling play evolutionarilyconserved roles in the control of aging. In the nematode Caenorhabditis elegans, bile acid-like steroidhormones known as dafachronic acids (DAs) influence longevity by binding to and regulating the activityof the conserved nuclear receptor DAF-12, and the insulin receptor (InsR) ortholog DAF-2 controls lifespan by inhibiting the FoxO transcription factor DAF-16. How the DA/DAF-12 pathway interacts withDAF-2/InsR signaling to control life span is poorly understood. Here we specifically investigated the rolesof liganded and unliganded DAF-12 in life span control in the context of reduced DAF-2/InsR signaling. Inanimals with reduced daf-2/InsR activity, mutations that either reduce DA biosynthesis or fully abrogateDAF-12 activity shorten life span, suggesting that liganded DAF-12 promotes longevity. In animals withreduced DAF-2/InsR activity induced by daf-2/InsR RNAi, both liganded and unliganded DAF-12 promotelongevity. However, in daf-2/InsR mutants, liganded and unliganded DAF-12 act in opposition to controllife span. Thus, multiple DAF-12 activities influence life span in distinct ways in contexts of reducedDAF-2/InsR signaling. Our findings establish new roles for a conserved steroid signaling pathway in lifespan control and elucidate interactions among DA biosynthetic pathways, DAF-12, and DAF-2/InsRsignaling in aging.", "metadata": {}}
+{"_id": "14550841", "title": "", "text": "Asymmetric Cell Divisions Sustain Long-Term  Hematopoiesis from Single-sorted Human Fetal LiverCellsHematopoietic stem cells (HSCs) in adult marrow are believed to be derived from fetal liverprecursors. To study cell kinetics involved in long-term hematopoiesis, we studied single-sorted candidateHSCs from fetal liver that were cultured in the presence of a mixture of stimulatory cytokines. After 8–10d, the number of cells in primary cultures varied from 10,000 cells. Single cells in slow growing colonieswere recloned upon reaching a 100–200 cell stage. Strikingly, the number of cells in subclones variedwidely again. These results are indicative of asymmetric divisions in primitive hematopoietic cells in whichproliferative potential and cell cycle properties are unevenly distributed among daughter cells. Thecontinuous generation of functional heterogeneity among the clonal progeny of HSCs is in support ofintrinsic control of stem cell fate and provides a model for the long-term maintenance of hematopoiesis invitro and in vivo.", "metadata": {}}
+{"_id": "14555750", "title": "", "text": "Reprogramming factor expression initiates widespread targeted chromatin remodeling.Despite rapidprogress in characterizing transcription factor-driven reprogramming of somatic cells to an inducedpluripotent stem cell (iPSC) state, many mechanistic questions still remain. To gain insight into theearliest events in the reprogramming process, we systematically analyzed the transcriptional andepigenetic changes that occur during early factor induction after discrete numbers of divisions. Weobserved rapid, genome-wide changes in the euchromatic histone modification, H3K4me2, at more thana thousand loci including large subsets of pluripotency-related or developmentally regulated genepromoters and enhancers. In contrast, patterns of the repressive H3K27me3 modification remainedlargely unchanged except for focused depletion specifically at positions where H3K4 methylation isgained. These chromatin regulatory events precede transcriptional changes within the corresponding loci.Our data provide evidence for an early, organized, and population-wide epigenetic response to ectopicreprogramming factors that clarify the temporal order through which somatic identity is reset duringreprogramming.", "metadata": {}}
+{"_id": "14566771", "title": "", "text": "Stroke and migraine--the spectrum of cause and effect.The relationship of migraine and stroke iscomplex. Stroke may be coincidental with migraine but migraine may confer an increased risk of stroke inwomen under 45 years of age and possibly in men who have migraine with aura. Stroke may mimicmigraine but migraine syndromes may be symptomatic of underlying cerebrovascular disorders. Truemigraine-induced stroke is rare. The mechanisms of stroke induced during a migraine attack remain to bedetermined but probably involve an interaction between the dynamic shifts in cerebral blood flow andstroke risk factors.", "metadata": {}}
+{"_id": "14581009", "title": "", "text": "MicroRNA Regulation of Cbx7 Mediates a Switch of Polycomb Orthologs during ESC DifferentiationThePolycomb Group (PcG) of chromatin modifiers regulates pluripotency and differentiation. Mammaliangenomes encode multiple homologs of the Polycomb repressive complex 1 (PRC1) components, includingfive orthologs of the Drosophila Polycomb protein (Cbx2, Cbx4, Cbx6, Cbx7, and Cbx8). We haveidentified Cbx7 as the primary Polycomb ortholog of PRC1 complexes in embryonic stem cells (ESCs). Theexpression of Cbx7 is downregulated during ESC differentiation, preceding the upregulation of Cbx2,Cbx4, and Cbx8, which are directly repressed by Cbx7. Ectopic expression of Cbx7 inhibits differentiationand X chromosome inactivation and enhances ESC self-renewal. Conversely, Cbx7 knockdown inducesdifferentiation and derepresses lineage-specific markers. In a functional screen, we identified themiR-125 and miR-181 families as regulators of Cbx7 that are induced during ESC differentiation. Ectopicexpression of these miRNAs accelerates ESC differentiation via regulation of Cbx7. These observationsestablish a critical role for Cbx7 and its regulatory miRNAs in determining pluripotency.", "metadata": {}}
+{"_id": "14584755", "title": "", "text": "Differences in the Clinical Effects of Angiotensin-Converting Enzyme Inhibitors and Angiotensin ReceptorBlockers: A Critical Review of the EvidenceThe renin-angiotensin-aldosterone system plays a major rolein the pathophysiology of hypertension and closely related cardio- and cerebrovascular events. Althoughboth angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists (angiotensinreceptor blockers; ARBs) are equally important in the treatment of hypertension, according to the resultsof recent years, there might be substantial differences in their cardiovascular protective effects, andthese differences might be explained by our increasing knowledge of their non-overlapping mechanismsof action. The number of studies investigating how ACE inhibitors and ARB agents differ will certainly beincreasing in the future. ACE inhibitors are the safe therapeutic opportunity for hypertensive patients athigh risk, with a cardiological comorbidity.", "metadata": {}}
+{"_id": "14591894", "title": "", "text": "A talin-dependent LFA-1 focal zone is formed by rapidly migrating T lymphocytesCells such as fibroblastsand endothelial cells migrate through the coordinated responses of discrete integrin-containing focaladhesions and complexes. In contrast, little is known about the organization of integrins on the highlymotile T lymphocyte. We have investigated the distribution, activity, and cytoskeletal linkage of theintegrin lymphocyte function associated antigen-1 (LFA-1) on human T lymphocytes migrating onendothelial cells and on ligand intercellular adhesion molecule-1 (ICAM-1). The pattern of total LFA-1varies from low expression in the lamellipodia to high expression in the uropod. However, high affinity,clustered LFA-1 is restricted to a mid-cell zone that remains stable over time and over a range of ICAM-1densities. Talin is essential for the stability and formation of the LFA-1 zone. Disruption of thetalin–integrin link leads to loss of zone integrity and a substantial decrease in speed of migration onICAM-1. This adhesive structure, which differs from the previously described integrin-containingattachments displayed by many other cell types, we have termed the “focal zone. ”", "metadata": {}}
+{"_id": "14606752", "title": "", "text": "Tricyclic antidepressants and headaches: systematic review and meta-analysisOBJECTIVE To evaluate theefficacy and relative adverse effects of tricyclic antidepressants in the treatment of migraine,tension-type, and mixed headaches. DESIGN Meta-analysis. DATA SOURCES Medline, Embase, theCochrane Trials Registry, and PsycLIT. Studies reviewed Randomised trials of adults receiving tricyclics asonly treatment for a minimum of four weeks. DATA EXTRACTION Frequency of headaches (number ofheadache attacks for migraine and number of days with headache for tension-type headaches), intensityof headache, and headache index. RESULTS 37 studies met the inclusion criteria. Tricyclics significantlyreduced the number of days with tension-type headache and number of headache attacks from migrainethan placebo (average standardised mean difference -1.29, 95% confidence interval -2.18 to -0.39 and-0.70, -0.93 to -0.48) but not compared with selective serotonin reuptake inhibitors (-0.80, -2.63 to 0.02and -0.20, -0.60 to 0.19). The effect of tricyclics increased with longer duration of treatment (β=-0.11,95% confidence interval -0.63 to -0.15; P<0.0005). Tricyclics were also more likely to reduce theintensity of headaches by at least 50% than either placebo (tension-type: relative risk 1.41, 95%confidence interval 1.02 to 1.89; migraine: 1.80, 1.24 to 2.62) or selective serotonin reuptake inhibitors(1.73, 1.34 to 2.22 and 1.72, 1.15 to 2.55). Tricyclics were more likely to cause adverse effects thanplacebo (1.53, 95% confidence interval 1.11 to 2.12) and selective serotonin reuptake inhibitors (2.22,1.52 to 3.32), including dry mouth (P<0.0005 for both), drowsiness (P<0.0005 for both), and weightgain (P<0.001 for both), but did not increase dropout rates (placebo: 1.22, 0.83 to 1.80, selectiveserotonin reuptake inhibitors: 1.16, 0.81 to 2.97). CONCLUSIONS Tricyclic antidepressants are effectivein preventing migraine and tension-type headaches and are more effective than selective serotoninreuptake inhibitors, although with greater adverse effects. The effectiveness of tricyclics seems toincrease over time.", "metadata": {}}
+{"_id": "14610165", "title": "", "text": "Functional Consequences of Splicing of the Antisense Transcript COOLAIR on FLC TranscriptionAntisensetranscription is widespread in many genomes; however, how much is functional is hotly debated. We areinvestigating functionality of a set of long noncoding antisense transcripts, collectively called COOLAIR,produced at Arabidopsis FLOWERING LOCUS C (FLC). COOLAIR initiates just downstream of the majorsense transcript poly(A) site and terminates either early or extends into the FLC promoter region. Wenow show that splicing of COOLAIR is functionally important. This was revealed through analysis of ahypomorphic mutation in the core spliceosome component PRP8. The prp8 mutation perturbs acotranscriptional feedback mechanism linking COOLAIR processing to FLC gene body histonedemethylation and reduced FLC transcription. The importance of COOLAIR splicing in this repressionmechanism was confirmed by disrupting COOLAIR production and mutating the COOLAIR proximal spliceacceptor site. Our findings suggest that altered splicing of a long noncoding transcript can quantitativelymodulate gene expression through cotranscriptional coupling mechanisms.", "metadata": {}}
+{"_id": "14615911", "title": "", "text": "Nuclear Factor-\u0000B Affects Tumor Progression in a Mouse Model of Malignant Pleural EffusionWedeveloped a novel mouse model of malignant pleural effusion (MPE) by injecting Lewis lung cancer (LLC)cells directly into the pleural space of syngeneic C57B/6 mice. The pleural effusions in this model sharecommon cellular and biochemical features with human MPEs. Implantation and growth of pleural tumorstriggers a host inflammatory response characterized by a mixed inflammatory cell influx into the pleuralfluid. LLC cells exhibited high basal nuclear factor (NF)-κB activity in vitro and in vivo, which we used todrive expression of a NF-κB–dependent green fluorescent protein-firefly luciferase fusion reporterconstruct. NF-κB–dependent reporter expression allowed intravital tracing of pleural tumors. Inhibition ofNF-κB in LLC cells did not affect cell viability in culture; however, injection of LLC cells expressing adominant NF-κB inhibitor resulted in decreased tumor burden, decreased pleural effusion volume, anddecreased pleural effusion TNF-α levels. These studies indicate that tumor NF-κB a...", "metadata": {}}
+{"_id": "14626540", "title": "", "text": "A phase I study of PF-04449913, an oral hedgehog inhibitor, in patients with advanced solidtumors.PURPOSE To estimate the maximum tolerated dose (MTD) of single-agent PF-04449913, and toevaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity inpatients with advanced tumors. EXPERIMENTAL DESIGN A 3+3 design was used in this open-label,multicenter, phase I study and dose escalation/de-escalation applied until identification of the MTD.PF-04449913 was orally administered once daily in continuous 28-day treatment cycles. The startingdose was 80 mg. RESULTS A total of 23 patients were enrolled; 19 were evaluable for first-cycledose-limiting toxicity (DLT). The first-cycle DLT rate at the 640 mg dose level was 33.3%, and the MTDwas estimated to be 320 mg once daily. The recommended phase II dose was not determined.PF-04449913 was generally well tolerated at doses of 80 to 320 mg once daily. The most commontreatment-related adverse events (AE) were grade 1-2 dysgeusia, fatigue, decreased appetite, nausea,dizziness, dehydration, and diarrhea. Treatment-related grade 3 AEs only occurred in patients receivingPF-04449913 640 mg once daily. No treatment-related grade 4-5 AEs were reported. Pharmacokineticanalysis indicated a generally dose-proportional kinetics with biphasic elimination, supporting once-dailydosing. PF-04449913 modulated hedgehog signaling at the dose levels tested, as demonstrated by >80%downregulation of GLI1 expression in the skin of treated patients. Eight patients (34.8%) achieved stabledisease; none had complete or partial response. Three patients with disease progression at enrollmenthad prolonged disease stabilization (≥6 months). CONCLUSIONS The results obtained in this studysupport further evaluation of PF-04449913 in patients with advanced solid tumors.", "metadata": {}}
+{"_id": "14637235", "title": "", "text": "Histone levels are regulated by phosphorylation and ubiquitylation dependent proteolysisHistone levelsare tightly regulated to prevent harmful effects such as genomic instability and hypersensitivity toDNA-damaging agents due to the accumulation of these highly basic proteins when DNA replication slowsdown or stops. Although chromosomal histones are stable, excess (non-chromatin bound) histones arerapidly degraded in a Rad53 (radiation sensitive 53) kinase-dependent manner in Saccharomycescerevisiae. Here we demonstrate that excess histones associate with Rad53 in vivo and seem to undergomodifications such as tyrosine phosphorylation and polyubiquitylation, before their proteolysis by theproteasome. We have identified the Tyr 99 residue of histone H3 as being critical for the efficientubiquitylation and degradation of this histone. We have also identified the ubiquitin conjugating enzymes(E2) Ubc4 and Ubc5, as well as the ubiquitin ligase (E3) Tom1 (temperature dependent organization inmitotic nucleus 1), as enzymes involved in the ubiquitylation of excess histones. Regulated histoneproteolysis has major implications for the maintenance of epigenetic marks on chromatin, genomicstability and the packaging of sperm DNA.", "metadata": {}}
+{"_id": "14644164", "title": "", "text": "TLR-activated B cells suppress T cell-mediated autoimmunity.TLR sense microbial infections, and controlactivation of immune responses. Dendritic cells, macrophages, and B lymphocytes express TLR and theTLR-signaling adaptor protein MyD88. The impact of TLR-activated B cells on T cell-mediatedinflammation is unknown. In this study, we have used mice carrying B cell-restricted deficiencies inMyD88 or in distinct TLR to examine the impact of TLR-activated B cells on a T cell-mediated autoimmunedisease, experimental autoimmune encephalomyelitis (EAE). We demonstrate that TLR-signaling in Bcells suppresses inflammatory T cell responses (both Th1 and Th17), and stimulates recovery from EAE.Only certain TLR are required on B cells for resolution of EAE, and these are dispensable for diseaseinitiation, indicating that a category of TLR agonists preferentially triggers a suppressive function in Bcells and thereby limits autoimmune disease. The TLR agonists controlling the regulatory function of Bcells are provided by components of Mycobacterium tuberculosis present in the adjuvant. Thus, MyD88signaling in B cells antagonizes MyD88 signaling in other cells, which drives differentiation of Th17 cellsand is required for induction of EAE. Altogether, our data indicate that B cells link recognition of microbialproducts via TLR to suppression of a T cell-mediated autoimmune disease.", "metadata": {}}
+{"_id": "14647747", "title": "", "text": "Successful expansion of functional and stable regulatory T cells for immunotherapy in livertransplantationStrategies to prevent organ transplant rejection whilst minimizing long-termimmunosuppression are currently under intense investigation with regulatory T cells (Tregs) nearingclinical application. The clinical trial, ThRIL, recently commenced at King's College London, proposes touse Treg cell therapy to induce tolerance in liver transplant recipients, the success of which has thepotential to revolutionize the management of these patients and enable a future of drug-free transplants.This is the first report of the manufacture of clinical grade Tregs from prospective liver transplantrecipients via a CliniMACS-based GMP isolation technique and expanded using anti-CD3/CD28 beads, IL-2and rapamycin. We report the enrichment of a pure, stable population of Tregs (>95%CD4(+)CD25(+)FOXP3(+)), reaching adequate numbers for their clinical application. Our protocol provedsuccessful in, influencing the expansion of superior functional Tregs, as compared to freshly isolated cells,whilst also preventing their conversion to Th17 cells under pro-inflammatory conditions. We concludewith the manufacture of the final Treg product in the clinical research facility (CRF), a prerequisite for theclinical application of these cells. The data presented in this manuscript together with themuch-anticipated clinical results from ThRIL, will undoubtedly inform the improved management of theliver transplant recipient.", "metadata": {}}
+{"_id": "14652521", "title": "", "text": "A framework for improving microRNA prediction in non-human genomesThe prediction of novelpre-microRNA (miRNA) from genomic sequence has received considerable attention recently. However,the majority of studies have focused on the human genome. Previous studies have demonstrated thatsensitivity (correctly detecting true miRNA) is sustained when human-trained methods are applied toother species, however they have failed to report the dramatic drop in specificity (the ability to correctlyreject non-miRNA sequences) in non-human genomes. Considering the ratio of true miRNA sequences topseudo-miRNA sequences is on the order of 1:1000, such low specificity prevents the application of mostexisting tools to non-human genomes, as the number of false positives overwhelms the true predictions.We here introduce a framework (SMIRP) for creating species-specific miRNA prediction systems,leveraging sequence conservation and phylogenetic distance information. Substantial improvements inspecificity and precision are obtained for four non-human test species when our framework is applied tothree different prediction systems representing two types of classifiers (support vector machine andRandom Forest), based on three different feature sets, with both human-specific and taxon-wide trainingdata. The SMIRP framework is potentially applicable to all miRNA prediction systems and we expectsubstantial improvement in precision and specificity, while sustaining sensitivity, independent of themachine learning technique chosen.", "metadata": {}}
+{"_id": "14657344", "title": "", "text": "CD8 Cells of Patients with Diffuse Cutaneous Leishmaniasis Display Functional Exhaustion: The Latter IsReversed, In Vitro, by TLR2 AgonistsLeishmania mexicana (Lm) causes localized (LCL) and diffuse (DCL)cutaneous leishmaniasis. DCL patients have a poor cellular immune response leading to chronicity. It hasbeen proposed that CD8 T lymphocytes (CD8) play a crucial role in infection clearance, although the roleof CD8 cytotoxicity in disease control has not been elucidated. Lesions of DCL patients have been shownto harbor low numbers of CD8, as compared to patients with LCL, and leishmanicidal treatment restoresCD8 numbers. The marked response of CD8 towards Leishmania parasites led us to analyze possiblefunctional differences between CD8 from patients with LCL and DCL. We compared IFNγ production,antigen-specific proliferation, and cytotoxicity of CD8 purified from PBMC against autologousmacrophages (MO) infected with Leishmania mexicana (MOi). Additionally, we analyzed tissue biopsiesfrom both groups of patients for evidence of cytotoxicity associated with apoptotic cells in the lesions. Wefound that CD8 cell of DCL patients exhibited low cytotoxicity, low antigen-specific proliferation and lowIFNγ production when stimulated with MOi, as compared to LCL patients. Additionally, DCL patients hadsignificantly less TUNEL+ cells in their lesions. These characteristics are similar to cellular \"exhaustion\"described in chronic infections. We intended to restore the functional capacity of CD8 cells of DCL patientsby preincubating them with TLR2 agonists: Lm lipophosphoglycan (LPG) or Pam3Cys. Cytotoxicity againstMOi, antigen-specific proliferation and IFNγ production were restored with both stimuli, whereas PD-1 (amolecule associated with cellular exhaustion) expression, was reduced. Our work suggests that CD8response is associated with control of Lm infection in LCL patients and that chronic infection in DCLpatients leads to a state of CD8 functional exhaustion, which could facilitate disease spread. This is thefirst report that shows the presence of functionally exhausted CD8 T lymphocytes in DCL patients and,additionally, that pre-stimulation with TLR2 ligands can restore the effector mechanisms of CD8 Tlymphocytes from DCL patients against Leishmania mexicana-infected macrophages.", "metadata": {}}
+{"_id": "14658685", "title": "", "text": "Enhancer Evolution across 20 Mammalian SpeciesThe mammalian radiation has corresponded with rapidchanges in noncoding regions of the genome, but we lack a comprehensive understanding of regulatoryevolution in mammals. Here, we track the evolution of promoters and enhancers active in liver across 20mammalian species from six diverse orders by profiling genomic enrichment of H3K27 acetylation andH3K4 trimethylation. We report that rapid evolution of enhancers is a universal feature of mammaliangenomes. Most of the recently evolved enhancers arise from ancestral DNA exaptation, rather thanlineage-specific expansions of repeat elements. In contrast, almost all liver promoters are partially orfully conserved across these species. Our data further reveal that recently evolved enhancers can beassociated with genes under positive selection, demonstrating the power of this approach for annotatingregulatory adaptations in genomic sequences. These results provide important insight into the functionalgenetics underpinning mammalian regulatory evolution.", "metadata": {}}
+{"_id": "14663842", "title": "", "text": "IDH1 mutations alter citric acid cycle metabolism and increase dependence on oxidative mitochondrialmetabolism.Oncogenic mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) occur in several types ofcancer, but the metabolic consequences of these genetic changes are not fully understood. In this study,we performed (13)C metabolic flux analysis on a panel of isogenic cell lines containing heterozygousIDH1/2 mutations. We observed that under hypoxic conditions, IDH1-mutant cells exhibited increasedoxidative tricarboxylic acid metabolism along with decreased reductive glutamine metabolism, but notIDH2-mutant cells. However, selective inhibition of mutant IDH1 enzyme function could not reverse thedefect in reductive carboxylation activity. Furthermore, this metabolic reprogramming increased thesensitivity of IDH1-mutant cells to hypoxia or electron transport chain inhibition in vitro. Lastly,IDH1-mutant cells also grew poorly as subcutaneous xenografts within a hypoxic in vivomicroenvironment. Together, our results suggest therapeutic opportunities to exploit the metabolicvulnerabilities specific to IDH1 mutation.", "metadata": {}}
+{"_id": "14664424", "title": "", "text": "The assessment of the prognostic value of tumor markers and cytokines as SCCAg, CYFRA 21.1, IL-6,VEGF and sTNF receptors in patients with squamous cell cervical cancer, particularly with early stage ofthe diseaseThe aim of this study is to determine the prognostic value of tumor markers, as squamous cellcarcinoma antigen (SCCAg) and cytokeratin-19 fragment (CYFRA 21.1) and interleukin 6 (IL-6), vascularendothelial growth factor (VEGF), soluble tumor necrosis factor receptor I (sTNF RI), and sTNF RII inpatients with squamous cell carcinoma of the cervix. The subjects of analysis were 138 patients withstage I-IVA according to the International Federation of Gynecology and Obstetrics (FIGO) classification.The collected research material comes from one oncology center. During the 10 years of follow-up, 56relapses and 53 deaths were observed, and recurrent disease in early stage was confirmed in 45 % ofpatients. The pretreatment serum levels of SCCAg and CYFRA 21.1, and cytokines IL-6, VEGF, sTNF RI,and sTNF RII were determined in all patients. The probability of disease-free survival (DFS) and overallsurvival (OS) was evaluated using the log-rank test and the Cox regression model. Based on the ROCcurve analysis for patients with recurrence, the largest area under the curve was demonstrated forSCCAg and IL-6 and for patients who died, for SCCAg and VEGF. Cox analysis demonstrated thatindependent prognostic factor for DFS was only SCCAg and for OS cytokine IL-6 and SCCAg, but inpatients with early stage the prognostic value for DFS was VEGF, whereas IL-6 and CYFRA 21.1 for OS.Serum level of VEGF, CYFRA 21.1 and IL-6 before treatment in patients with early stage cervical cancerappears to be an important prognostic factor.", "metadata": {}}
+{"_id": "14672919", "title": "", "text": "Combination of platelet count and mean platelet volume (COP-MPV) predicts postoperative prognosis inboth resectable early and advanced stage esophageal squamous cell cancer patientsThe aim of this studyis to search the most powerful prognostic factor from routine blood test for esophageal squamous cellcancer (ESCC) patients. Multiple laboratory tests were evaluated including those reflecting red blood cellparameters (hemoglobin (Hb), mean corpuscular volume (MCV), mean corpuscular hemoglobinconcentration (MCHC), and red blood cell distribution width (RDW)), platelet morphological parameters(mean platelet volume (MPV) and platelet count (PLT)), blood coagulation status (D-dimer), and tumorbiomarker (CA19-9). Known inflammatory indices (NLR and PLR) were also calculated. A total of 468patients who were diagnosed with ESCC between December 2005 and December 2008 wereretrospectively analyzed in this study. By utilizing univariate and multivariate Cox proportional hazardanalyses, we found that PLT and MPV were significantly associated with overall survival (OS) anddisease-free survival (DFS) of ESCC patients, with optimal cutoff values of 212 and 10.6, respectively.Moreover, the combination of the preoperative PLT and MPV (COP-MPV) was calculated as follows:patients with both PLT (≥212 × 10(9) L(-1)) and MPV (≥10.6 fL) elevation were assigned a score of 2,and patients with one or neither were assigned a score of 1 and 0. The COP-MPV was an independentprognostic factor for OS (hazard ratio (HR) 0.378, 95 % confidence interval (CI) 0.241 to 0.593, P <0.001, 0/2) and DFS (HR 0.341, 95 % CI 0.218 to 0.534, P < 0.001, 0/2) in multivariate analyses. Insubgroup analyses for early (stages I and II) and locally (stage III) advanced stage patients, COP-MPVwas found significantly associated with OS and DFS in each group (P = 0.025 and P = 0.018 for OS and P= 0.029 and P = 0.002 for DFS). In conclusion, we considered that COP-MPV is a promising predictor forpostoperative survival in ESCC patients.", "metadata": {}}
+{"_id": "14682243", "title": "", "text": "Dementia incidence and mortality in middle-income countries, and associations with indicators ofcognitive reserve: a 10/66 Dementia Research Group population-based cohort studyBACKGROUNDResults of the few cohort studies from countries with low incomes or middle incomes suggest a lowerincidence of dementia than in high-income countries. We assessed incidence of dementia according tocriteria from the 10/66 Dementia Research Group and Diagnostic and Statistical Manual of MentalDisorders (DSM) IV, the effect of dementia at baseline on mortality, and the independent effects of age,sex, socioeconomic position, and indicators of cognitive reserve. METHODS We did a population-basedcohort study of all people aged 65 years and older living in urban sites in Cuba, the Dominican Republic,and Venezuela, and rural and urban sites in Peru, Mexico, and China, with ascertainment of incident10/66 and DSM-IV dementia 3-5 years after cohort inception. We used questionnaires to obtaininformation about age in years, sex, educational level, literacy, occupational attainment, and number ofhousehold assets. We obtained information about mortality from all sites. For participants who had died,we interviewed a friend or relative to ascertain the likelihood that they had dementia before death.FINDINGS 12,887 participants were interviewed at baseline. 11,718 were free of dementia, of whom8137 (69%) were reinterviewed, contributing 34,718 person-years of follow-up. Incidence for 10/66dementia varied between 18·2 and 30·4 per 1000 person-years, and were 1·4-2·7 times higher than werethose for DSM-IV dementia (9·9-15·7 per 1000 person-years). Mortality hazards were 1·56-5·69 timeshigher in individuals with dementia at baseline than in those who were dementia-free. Informant reportssuggested a high incidence of dementia before death; overall incidence might be 4-19% higher if thesedata were included. 10/66 dementia incidence was independently associated with increased age (HR1·67; 95% CI 1·56-1·79), female sex (0·72; 0·61-0·84), and low education (0·89; 0·81-0·97), but notwith occupational attainment (1·04; 0·95-1·13). INTERPRETATION Our results provide supportiveevidence for the cognitive reserve hypothesis, showing that in middle-income countries as in high-incomecountries, education, literacy, verbal fluency, and motor sequencing confer substantial protection againstthe onset of dementia. FUNDING Wellcome Trust Health Consequences of Population Change Programme,WHO, US Alzheimer's Association, FONACIT/ CDCH/ UCV.", "metadata": {}}
+{"_id": "14692646", "title": "", "text": "Regulation of immune responses by extracellular vesiclesExtracellular vesicles, including exosomes, aresmall membrane vesicles derived from multivesicular bodies or from the plasma membrane. Most, if notall, cell types release extracellular vesicles, which then enter the bodily fluids. These vesicles contain asubset of proteins, lipids and nucleic acids that are derived from the parent cell. It is thought thatextracellular vesicles have important roles in intercellular communication, both locally and systemically,as they transfer their contents, including proteins, lipids and RNAs, between cells. Extracellular vesiclesare involved in numerous physiological processes, and vesicles from both non-immune and immune cellshave important roles in immune regulation. Moreover, extracellular vesicle-based therapeutics are beingdeveloped and clinically tested for the treatment of inflammatory diseases, autoimmune disorders andcancer. Given the tremendous therapeutic potential of extracellular vesicles, this Review focuses on theirrole in modulating immune responses, as well as their potential therapeutic applications.", "metadata": {}}
+{"_id": "14700857", "title": "", "text": "Risk of cancer after low doses of ionising radiation: retrospective cohort study in 15countries.OBJECTIVES To provide direct estimates of risk of cancer after protracted low doses of ionisingradiation and to strengthen the scientific basis of radiation protection standards for environmental,occupational, and medical diagnostic exposures. DESIGN Multinational retrospective cohort study ofcancer mortality. SETTING Cohorts of workers in the nuclear industry in 15 countries. PARTICIPANTS 407391 workers individually monitored for external radiation with a total follow-up of 5.2 million personyears. MAIN OUTCOME MEASUREMENTS Estimates of excess relative risks per sievert (Sv) of radiationdose for mortality from cancers other than leukaemia and from leukaemia excluding chronic lymphocyticleukaemia, the main causes of death considered by radiation protection authorities. RESULTS The excessrelative risk for cancers other than leukaemia was 0.97 per Sv, 95% confidence interval 0.14 to 1.97.Analyses of causes of death related or unrelated to smoking indicate that, although confounding bysmoking may be present, it is unlikely to explain all of this increased risk. The excess relative risk forleukaemia excluding chronic lymphocytic leukaemia was 1.93 per Sv (< 0 to 8.47). On the basis of theseestimates, 1-2% of deaths from cancer among workers in this cohort may be attributable to radiation.CONCLUSIONS These estimates, from the largest study of nuclear workers ever conducted, are higherthan, but statistically compatible with, the risk estimates used for current radiation protection standards.The results suggest that there is a small excess risk of cancer, even at the low doses and dose ratestypically received by nuclear workers in this study.", "metadata": {}}
+{"_id": "14706752", "title": "", "text": "Gamma-Secretase Represents a Therapeutic Target for the Treatment of Invasive Glioma Mediated bythe p75 Neurotrophin ReceptorThe multifunctional signaling protein p75 neurotrophin receptor(p75(NTR)) is a central regulator and major contributor to the highly invasive nature of malignantgliomas. Here, we show that neurotrophin-dependent regulated intramembrane proteolysis (RIP) ofp75(NTR) is required for p75(NTR)-mediated glioma invasion, and identify a previously unnamed processfor targeted glioma therapy. Expression of cleavage-resistant chimeras of p75(NTR) or treatment ofanimals bearing p75(NTR)-positive intracranial tumors with clinically applicable gamma-secretaseinhibitors resulted in dramatically decreased glioma invasion and prolonged survival. Importantly,proteolytic processing of p75(NTR) was observed in p75(NTR)-positive patient tumor specimens and braintumor initiating cells. This work highlights the importance of p75(NTR) as a therapeutic target,suggesting that gamma-secretase inhibitors may have direct clinical application for the treatment ofmalignant glioma.", "metadata": {}}
+{"_id": "14711483", "title": "", "text": "Preliminary assessment of inhaled nitric oxide for acute vaso-occlusive crisis in pediatric patients withsickle cell disease.CONTEXT Vaso-occlusion is central to the painful crises and acute and chronic organdamage in sickle cell disease. Abnormal nitric oxide-dependent regulation of vascular tone, adhesion,platelet activation, and inflammation contributes to the pathophysiology of vaso-occlusion. Nitric oxidemay have promise as a mechanism-of-disease-based therapy for treatment of vaso-occlusion. OBJECTIVETo explore the efficacy and safety of inhaled nitric oxide (INO) for treatment of vaso-occlusive crisis inpediatric patients. DESIGN Prospective, double-blind, placebo-controlled, randomized clinical trial withenrollment between September 1999 and October 2001. SETTING Urban, tertiary care children's hospitalin the United States. PARTICIPANTS Twenty patients aged 10 to 21 years with sickle cell disease andsevere acute vaso-occlusive crisis. INTERVENTION Patients were randomly assigned to receive INO (80ppm with 21% final concentration of inspired oxygen; n = 10), or placebo (21% inspired oxygen; n = 10)for 4 hours. MAIN OUTCOME MEASURES Change in pain at 4 hours of inhalation compared withpreinhalation pain, measured on a 10-cm visual analog scale (VAS); secondary outcome measures werepain over 6 hours, parenteral narcotic use over 24 hours, duration of hospitalization, blood pressure,oxygen saturation, and methemoglobin concentration. RESULTS Preinhalation VAS pain scores weresimilar in the INO and placebo groups (P =.80). The decrease in VAS pain scores at 4 hours was 2.0 cmin the INO group and 1.2 cm in the placebo group (P =.37). Repeated-measures analysis of variance forhourly pain scores showed a 1-cm/h greater reduction in the INO group than the placebo group (P =.02).Morphine use over 6 hours was significantly less in the INO group (mean cumulative use, 0.29 vs 0.44mg/kg; P =.03) but was not different over 4 hours (0.26 vs 0.32 mg/kg; P =.21) or 24 hours (0.63 vs0.91 mg/kg; P =.15). Duration of hospitalization was 78 and 100 hours in the INO and placebo groups,respectively (P =.19). No INO toxicity was observed. CONCLUSIONS Results of this exploratory studysuggest that INO may be beneficial for acute vaso-occlusive crisis. These preliminary results warrantfurther investigation.", "metadata": {}}
+{"_id": "14717213", "title": "", "text": "Corresponding author:Over the years, methods of cytogenetic analysis evolved and became part ofroutine laboratory testing, providing valuable diagnostic and prognostic information in hematologicdisorders. Karyotypic aberrations contribute to the understanding of the molecular pathogenesis ofdisease and thereby to rational application of therapeutic modalities. Most of the progress in this fieldstems from the application of metaphase cytogenetics (MC), but recently, novel molecular technologieshave been introduced that complement MC and overcome many of the limitations of traditionalcytogenetics, including a need for cell culture. Whole genome scanning using comparative genomichybridization and single nucleotide polymorphism arrays (CGH-A; SNP-A) can be used for analysis ofsomatic or clonal unbalanced chromosomal defects. In SNP-A, the combination of copy number detectionand genotyping enables diagnosis of copy-neutral loss of heterozygosity, a lesion that cannot be detectedusing MC but may have important pathogenetic implications. Overall, whole genome scanning arrays,despite the drawback of an inability to detect balanced translocations, allow for discovery of chromosomaldefects in a higher proportion of patients with hematologic malignancies. Newly detected chromosomalaberrations, including somatic uniparental disomy, may lead to more precise prognostic schemes in manydiseases.", "metadata": {}}
+{"_id": "14717500", "title": "", "text": "Rare Variants Create Synthetic Genome-Wide AssociationsGenome-wide association studies (GWAS) havenow identified at least 2,000 common variants that appear associated with common diseases or relatedtraits (http://www.genome.gov/gwastudies), hundreds of which have been convincingly replicated. It isgenerally thought that the associated markers reflect the effect of a nearby common (minor allelefrequency >0.05) causal site, which is associated with the marker, leading to extensive resequencingefforts to find causal sites. We propose as an alternative explanation that variants much less commonthan the associated one may create \"synthetic associations\" by occurring, stochastically, more often inassociation with one of the alleles at the common site versus the other allele. Although syntheticassociations are an obvious theoretical possibility, they have never been systematically explored as apossible explanation for GWAS findings. Here, we use simple computer simulations to show the conditionsunder which such synthetic associations will arise and how they may be recognized. We show that theyare not only possible, but inevitable, and that under simple but reasonable genetic models, they are likelyto account for or contribute to many of the recently identified signals reported in genome-wideassociation studies. We also illustrate the behavior of synthetic associations in real datasets by showingthat rare causal mutations responsible for both hearing loss and sickle cell anemia create genome-widesignificant synthetic associations, in the latter case extending over a 2.5-Mb interval encompassingscores of \"blocks\" of associated variants. In conclusion, uncommon or rare genetic variants can easilycreate synthetic associations that are credited to common variants, and this possibility requires carefulconsideration in the interpretation and follow up of GWAS signals.", "metadata": {}}
+{"_id": "14719322", "title": "", "text": "Decoding of Cytoplasmic Ca2+ Oscillations through the Spatial Signature Drives GeneExpressionCytoplasmic Ca(2+) oscillations are a universal signaling mode that activates numerouscellular responses [1, 2]. Oscillations are considered the physiological mechanism of Ca(2+) signalingbecause they occur at low levels of stimulus intensity [3]. Ca(2+) oscillations are proposed to conveyinformation in their amplitude and frequency, leading to activation of specific downstream targets [4-6].Here, we report that the spatial Ca(2+) gradient within the oscillation is key. Ca(2+) oscillations in mastcells evoked over a range of agonist concentrations in the presence of external Ca(2+) wereindistinguishable from those in the absence of Ca(2+) when plasmalemmal Ca(2+) extrusion wassuppressed. Nevertheless, only oscillations with accompanying Ca(2+) entry through store-operatedCRAC channels triggered gene expression. Increased cytoplasmic Ca(2+) buffering prevented oscillationsbut not gene activation. Local Ca(2+) influx and not global Ca(2+) oscillations therefore drives geneexpression at physiological levels of stimulation. Rather than serving to maintain Ca(2+) oscillations byreplenishing stores, we suggest that the role of oscillations might be to activate CRAC channels, therebyensuring the generation of spatially restricted physiological Ca(2+) signals driving gene activation.Furthermore, we show that the spatial profile of a Ca(2+) oscillation provides a novel mechanismwhereby a pleiotropic messenger specifically activates gene expression.", "metadata": {}}
+{"_id": "14724693", "title": "", "text": "Effect of glucosamine on pain-related disability in patients with chronic low back pain and degenerativelumbar osteoarthritis: a randomized controlled trial.CONTEXT Chronic low back pain (LBP) withdegenerative lumbar osteoarthritis (OA) is widespread in the adult population. Although glucosamine isincreasingly used by patients with chronic LBP, little is known about its effect in this setting. OBJECTIVETo investigate the effect of glucosamine in patients with chronic LBP and degenerative lumbar OA.DESIGN, SETTING, AND PARTICIPANTS A double-blind, randomized, placebo-controlled trial conducted atOslo University Hospital Outpatient Clinic, Oslo, Norway, with 250 patients older than 25 years of agewith chronic LBP (>6 months) and degenerative lumbar OA. INTERVENTIONS Daily intake of 1500 mg oforal glucosamine (n = 125) or placebo (n = 125) for 6 months, with assessment of effect after the6-month intervention period and at 1 year (6 months postintervention). MAIN OUTCOME MEASURES Theprimary outcome was pain-related disability measured with the Roland Morris Disability Questionnaire(RMDQ). Secondary outcomes were numerical scores from pain-rating scales of patients at rest andduring activity, and the quality-of-life EuroQol-5 Dimensions (EQ-5D) instrument. Data collectionoccurred during the intervention period at baseline, 6 weeks, 3 and 6 months, and again 6 monthsfollowing the intervention at 1 year. Group differences were analyzed using linear mixed models analysis.RESULTS At baseline, mean RMDQ scores were 9.2 (95% confidence interval [CI], 8.4-10.0) forglucosamine and 9.7 (95% CI, 8.9-10.5) for the placebo group (P = .37). At 6 months, the mean RMDQscore was the same for the glucosamine and placebo groups (5.0; 95% CI, 4.2-5.8). At 1 year, the meanRMDQ scores were 4.8 (95% CI, 3.9-5.6) for glucosamine and 5.5 (95% CI, 4.7-6.4) for the placebogroup. No statistically significant difference in change between groups was found when assessed after the6-month intervention period and at 1 year: RMDQ (P = .72), LBP at rest (P = .91), LBP during activity (P= .97), and quality-of-life EQ-5D (P = .20). Mild adverse events were reported in 40 patients in theglucosamine group and 46 in the placebo group (P = .48). CONCLUSIONS Among patients with chronicLBP and degenerative lumbar OA, 6-month treatment with oral glucosamine compared with placebo didnot result in reduced pain-related disability after the 6-month intervention and after 1-year follow-up.TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00404079.", "metadata": {}}
+{"_id": "14726759", "title": "", "text": "Adult cervicocerebral artery dissection: a single-center study of 301 Finnish patients.BACKGROUND ANDPURPOSE There are only few small studies assessing potential risk factors, comorbidity, and prognosticfactors in adult spontaneous cervicocerebral artery dissection (CAD). METHODS We conducted aretrospective, hospital-based analysis on the prognostic factors and association of CAD with vascular riskfactors in 301 consecutive Finnish patients, diagnosed from 1994 to 2007. RESULTS Two thirds of thepatients were men (68%). Women were younger than men. Migraine (36% of all patients), especiallywith visual aura (63% of all migraineurs), and smoking were more common in patients with CADcompared with the general Finnish population. At 3 months, 247 (83%) patients reached a favorableoutcome. Occlusion of the dissected artery, internal carotid artery dissection (ICAD), and recent infectionin infarction patients were associated with a poorer outcome. ICAD patients had less often braininfarction, but the strokes they had were more severe. Seven (2.3%) patients died during the follow-up(mean 4.0 years, 1186 patient years). Six (2%) patients had verified CAD recurrence. CONCLUSIONSThis study provides evidence for the association of CAD with male sex, and possible association withsmoking and migraine. Occlusion of the dissected artery, ICAD, and infection appear to be associatedwith poorer outcome.", "metadata": {}}
+{"_id": "14729253", "title": "", "text": "Genetic variation and gastric cancer risk: a field synopsis and meta-analysis.BACKGROUND Data ongenetic susceptibility to sporadic gastric carcinoma have been published at a growing pace, but to date nocomprehensive overview and quantitative summary has been available. METHODS We conducted asystematic review and meta-analysis of the evidence on the association between DNA variation and riskof developing stomach cancer. To assess result credibility, summary evidence was graded according tothe Venice criteria and false positive report probability (FPRP) was calculated to further validate resultnoteworthiness. Meta-analysis was also conducted for subgroups, which were defined by ethnicity (Asianvs Caucasian), tumour histology (intestinal vs diffuse), tumour site (cardia vs non-cardia) andHelicobacter pylori infection status (positive vs negative). RESULTS Literature search identified 824eligible studies comprising 2 530 706 subjects (cases: 261 386 (10.3%)) and investigating 2841polymorphisms involving 952 distinct genes. Overall, we performed 456 primary and subgroupmeta-analyses on 156 variants involving 101 genes. We identified 11 variants significantly associatedwith disease risk and assessed to have a high level of summary evidence: MUC1 rs2070803 at 1q22(diffuse carcinoma subgroup), MTX1 rs2075570 at 1q22 (diffuse), PSCA rs2294008 at 8q24.2(non-cardia), PRKAA1 rs13361707 5p13 (non-cardia), PLCE1 rs2274223 10q23 (cardia), TGFBR2rs3087465 3p22 (Asian), PKLR rs3762272 1q22 (diffuse), PSCA rs2976392 (intestinal), GSTP1 rs169511q13 (Asian), CASP8 rs3834129 2q33 (mixed) and TNF rs1799724 6p21.3 (mixed), with the first ninevariants characterised by a low FPRP. We also identified polymorphisms with lower quality significantassociations (n=110). CONCLUSIONS We have identified several high-quality biomarkers of gastriccancer susceptibility. These data will form the backbone of an annually updated online resource that willbe integral to the study of gastric carcinoma genetics and may inform future screening programmes.", "metadata": {}}
+{"_id": "14753395", "title": "", "text": "Structure and function of the blood–brain barrierNeural signalling within the central nervous system(CNS) requires a highly controlled microenvironment. Cells at three key interfaces form barriers betweenthe blood and the CNS: the blood-brain barrier (BBB), blood-CSF barrier and the arachnoid barrier. TheBBB at the level of brain microvessel endothelium is the major site of blood-CNS exchange. The structureand function of the BBB is summarised, the physical barrier formed by the endothelial tight junctions, andthe transport barrier resulting from membrane transporters and vesicular mechanisms. The roles ofassociated cells are outlined, especially the endfeet of astrocytic glial cells, and pericytes and microglia.The embryonic development of the BBB, and changes in pathology are described. The BBB is subject toshort and long-term regulation, which may be disturbed in pathology. Any programme for drug discoveryor delivery, to target or avoid the CNS, needs to consider the special features of the BBB.", "metadata": {}}
+{"_id": "14767844", "title": "", "text": "Golli protein negatively regulates store depletion-induced calcium influx in T cells.Calcium influx is crucialfor T cell activation and differentiation. The detailed regulation of this process remains unclear. We reporthere that golli protein, an alternatively spliced product of the myelin basic protein gene, plays a criticalrole in regulating calcium influx in T cells. Golli-deficient T cells were hyperproliferative and showedenhanced calcium entry upon T cell receptor stimulation. We further found that golli regulates calciuminflux in T cells through the inhibition of the store depletion-induced calcium influx. Mutation of themyristoylation site on golli disrupted its association with the plasma membrane and reversed its inhibitoryaction on Ca2+ influx, indicating that membrane association of golli was essential for its inhibitory action.These results indicate that golli functions in a unique way to regulate T cell activation through amechanism involving the modulation of the calcium homeostasis.", "metadata": {}}
+{"_id": "14768471", "title": "", "text": "Extracellular vesicles derived from renal cancer stem cells induce a pro-tumorigenic phenotype inmesenchymal stromal cellsRenal carcinomas have been shown to contain a population of cancer stemcells (CSCs) that present self-renewing capacity and support tumor growth and metastasis. CSCs wereshown to secrete large amount of extracellular vesicles (EVs) that can transfer several molecules(proteins, lipids and nucleic acids) and induce epigenetic changes in target cells. Mesenchymal StromalCells (MSCs) are susceptible to tumor signalling and can be recruited to tumor regions. The precise role ofMSCs in tumor development is still under debate since both pro- and anti-tumorigenic effects have beenreported. In this study we analysed the participation of renal CSC-derived EVs in the interaction betweentumor and MSCs. We found that CSC-derived EVs promoted persistent phenotypical changes in MSCscharacterized by an increased expression of genes associated with cell migration (CXCR4, CXCR7), matrixremodeling (COL4A3), angiogenesis and tumor growth (IL-8, Osteopontin and Myeloperoxidase).EV-stimulated MSCs exhibited in vitro an enhancement of migration toward the tumor conditionedmedium. Moreover, EV-stimulated MSCs enhanced migration of renal tumor cells and induced vessel-likeformation. In vivo, EV-stimulated MSCs supported tumor development and vascularization, whenco-injected with renal tumor cells. In conclusion, CSC-derived EVs induced phenotypical changes in MSCsthat are associated with tumor growth.", "metadata": {}}
+{"_id": "14782049", "title": "", "text": "In vivo effect of chronic hypoxia on the neurochemical profile of the developing rat hippocampus.Thecognitive deficits observed in children with cyanotic congenital heart disease suggest involvement of thedeveloping hippocampus. Chronic postnatal hypoxia present during infancy in these children may play arole in these impairments. To understand the biochemical mechanisms of hippocampal injury in chronichypoxia, a neurochemical profile consisting of 15 metabolite concentrations and 2 metabolite ratios in thehippocampus was evaluated in a rat model of chronic postnatal hypoxia using in vivo 1H NMRspectroscopy at 9.4 T. Chronic hypoxia was induced by continuously exposing rats (n = 23) to 10% O2from postnatal day (P) 3 to P28. Fifteen metabolites were quantified from a volume of 9-11 microlcentered on the left hippocampus on P14, P21, and P28 and were compared with normoxic controls (n =14). The developmental trajectory of neurochemicals in chronic hypoxia was similar to that seen innormoxia. However, chronic hypoxia had an effect on the concentrations of the following neurochemicals:aspartate, creatine, phosphocreatine, GABA, glutamate, glutamine, glutathione, myoinositol,N-acetylaspartate (NAA), phosphorylethanolamine, and phosphocreatine/creatine (PCr/Cr) andglutamate/glutamine (Glu/Gln) ratios (P < 0.001 each, except glutamate, P = 0.04). The increasedPCr/Cr ratio is consistent with decreased brain energy consumption. Given the well-established linkbetween excitatory neurotransmission and brain energy metabolism, we postulate that elevatedglutamate, Glu/Gln ratio, and GABA indicate suppressed excitatory neurotransmission in anenergy-limited environment. Decreased NAA and phosphorylethanolamine suggest reduced neuronalintegrity and phospholipid metabolism. The altered hippocampal neurochemistry during its developmentmay underlie some of the cognitive deficits present in human infants at risk of chronic hypoxia.", "metadata": {}}
+{"_id": "14797520", "title": "", "text": "Noncoding Transcription by RNA Polymerase Pol IVb/Pol V Mediates Transcriptional Silencing ofOverlapping and Adjacent GenesNuclear transcription is not restricted to genes but occurs throughout theintergenic and noncoding space of eukaryotic genomes. The functional significance of this widespreadnoncoding transcription is mostly unknown. We show that Arabidopsis RNA polymerase IVb/Pol V, amultisubunit nuclear enzyme required for siRNA-mediated gene silencing of transposons and otherrepeats, transcribes intergenic and noncoding sequences, thereby facilitating heterochromatin formationand silencing of overlapping and adjacent genes. Pol IVb/Pol V transcription requires thechromatin-remodeling protein DRD1 but is independent of siRNA biogenesis. However, Pol IVb/Pol Vtranscription and siRNA production are both required to silence transposons, suggesting that Pol IVb/PolV generates RNAs or chromatin structures that serve as scaffolds for siRNA-mediatedheterochromatin-forming complexes. Pol IVb/Pol V function provides a solution to a paradox of epigeneticcontrol: the need for transcription in order to transcriptionally silence the same region.", "metadata": {}}
+{"_id": "14803797", "title": "", "text": "Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosisIntestinalmicrobiota metabolism of choline and phosphatidylcholine produces trimethylamine (TMA), which isfurther metabolized to a proatherogenic species, trimethylamine-N-oxide (TMAO). We demonstrate herethat metabolism by intestinal microbiota of dietary L-carnitine, a trimethylamine abundant in red meat,also produces TMAO and accelerates atherosclerosis in mice. Omnivorous human subjects produced moreTMAO than did vegans or vegetarians following ingestion of L-carnitine through a microbiota-dependentmechanism. The presence of specific bacterial taxa in human feces was associated with both plasmaTMAO concentration and dietary status. Plasma L-carnitine levels in subjects undergoing cardiacevaluation (n = 2,595) predicted increased risks for both prevalent cardiovascular disease (CVD) andincident major adverse cardiac events (myocardial infarction, stroke or death), but only among subjectswith concurrently high TMAO levels. Chronic dietary L-carnitine supplementation in mice altered cecalmicrobial composition, markedly enhanced synthesis of TMA and TMAO, and increased atherosclerosis,but this did not occur if intestinal microbiota was concurrently suppressed. In mice with an intactintestinal microbiota, dietary supplementation with TMAO or either carnitine or choline reduced in vivoreverse cholesterol transport. Intestinal microbiota may thus contribute to the well-established linkbetween high levels of red meat consumption and CVD risk.", "metadata": {}}
+{"_id": "14806256", "title": "", "text": "Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiencyvirus and the role of hepatitis C or B virus infection.CONTEXT Use of antiretroviral drugs, includingprotease inhibitors, for treatment of human immunodeficiency virus (HIV) infection has been anecdotallyassociated with hepatotoxicity, particularly in persons coinfected with hepatitis C or B virus. OBJECTIVESTo ascertain if incidence of severe hepatotoxicity during antiretroviral therapy is similar for allantiretroviral drug combinations, and to define the role of chronic viral hepatitis in its development.DESIGN Prospective cohort study. SETTING University-based urban HIV clinic. PATIENTS A total of 298patients who were prescribed new antiretroviral therapies between January 1996 and January 1998, 211(71%) of whom received protease inhibitors as part of combination therapy (median follow-up, 182 days)and 87 (29%) of whom received dual nucleoside analog regimens (median follow-up, 167 days). Chronichepatitis C and B virus infection was present in 154 (52%) and 8 (2.7%) patients, respectively. MAINOUTCOME MEASURE Severe hepatotoxicity, defined as a grade 3 or 4 change in levels of serum alanineaminotransferase and aspartate aminotransferase, evaluated before and during therapy. RESULTS Severehepatotoxicity was observed in 31 (10.4%) of 298 patients (95% confidence interval [CI], 7.2%-14.4%).Ritonavir use was associated with a higher incidence of toxicity (30%; 95% CI, 17.9% -44.6%).However, no significant difference was detected in hepatotoxicity incidence in other treatment groups, ie,nucleoside analogs (5.7%; 95% CI, 1.2%-12.9%), nelfinavir (5.9%; 95% CI, 1.2%-16.2%), saquinavir(5.9%; 95% CI, 0.15%-28.7%), and indinavir(6.8%; 95% CI, 3.0%-13.1 %). Although chronicviralhepatitis was associated with an increased risk of severe hepatotoxicity among patients prescribednonritonavir regimens (relative risk, 3.7; 95% CI, 1.0-11.8), most patients with chronic hepatitis C or Bvirus infection (88%) did not experience significant toxic effects. Rate of severe toxicity with use of anyprotease inhibitor in patients with hepatitis C infection was 12.2% (13/107; 95% CI, 6.6%-19.9%). Inmultivariate logistic regression, only ritonavir (adjusted odds ratio [AOR], 8.6; 95% CI, 3.0-24.6) and aCD4 cell count increase of more than 0.05 x 10(9)/L (AOR, 3.6; 95% CI, 1.0-12.9) were associated withsevere hepatotoxicity. No irreversible outcomes were seen in patients with severe hepatotoxicity.CONCLUSIONS Our data indicate that use of ritonavir may increase risk of severe hepatotoxicity.Although hepatotoxicity may be more common in persons with chronic viral hepatitis, these data do notsupport withholding protease inhibitor therapy from persons coinfected with hepatitis B or C virus.", "metadata": {}}
+{"_id": "14819804", "title": "", "text": "Mutations in the phosphatidylinositol-3-kinase pathway predict for antitumor activity of the inhibitorPX-866 whereas oncogenic Ras is a dominant predictor for resistance.The novelphosphatidylinositol-3-kinase (PI3K) inhibitor PX-866 was tested against 13 experimental human tumorxenografts derived from cell lines of various tissue origins. Mutant PI3K (PIK3CA) and loss of PTENactivity were sufficient, but not necessary, as predictors of sensitivity to the antitumor activity of the PI3Kinhibitor PX-866 in the presence of wild-type Ras, whereas mutant oncogenic Ras was a dominantdeterminant of resistance, even in tumors with coexisting mutations in PIK3CA. The level of activation ofPI3K signaling measured by tumor phosphorylated Ser(473)-Akt was insufficient to predict in vivoantitumor response to PX-866. Reverse-phase protein array revealed that the Ras-dependentdownstream targets c-Myc and cyclin B were elevated in cell lines resistant to PX-866 in vivo. Studiesusing an H-Ras construct to constitutively and preferentially activate the three best-defined downstreamtargets of Ras, i.e., Raf, RalGDS, and PI3K, showed that mutant Ras mediates resistance through itsability to use multiple pathways for tumorigenesis. The identification of Ras and downstream signalingpathways driving resistance to PI3K inhibition might serve as an important guide for patient selection asinhibitors enter clinical trials and for the development of rational combinations with other molecularlytargeted agents.", "metadata": {}}
+{"_id": "14823313", "title": "", "text": "Changing mortality patterns in East and West Germany and Poland. II: short-term trends duringtransition and in the 1990s.OBJECTIVES To examine trends in life expectancy at birth and age and causespecific patterns of mortality in the former German Democratic Republic (GDR) and Poland during politicaltransition and throughout the 1990s in both parts of Germany and in Poland. METHODS Decomposition oflife expectancy by age and cause of death. Changes in life expectancy during transition by cause of deathwere examined using data for 1988/89 and 1990/91 for the former GDR and Poland; examination of lifeexpectancy changes after transition were based on 1992-97 data for Germany and 1991-96 data forPoland. RESULTS In both the former GDR and Poland male life expectancy at birth declined by almost oneyear during transition, mainly attributable to rising death rates from external causes and circulatorydiseases. Female life expectancy in Poland deteriorated by 0.3 years, largely attributable to increasingcirculatory mortality among the old, while in East German female rising death rates in children and youngadults were nearly outbalanced by declining circulatory mortality among those over 70. Between 1991/92and 1996/97, male life expectancy at birth increased by 2.4 years in the former GDR, 1.2 years in oldFederal Republic, and 2.0 years in Poland (women: 2.3, 0.9, and 1.2 years). In East Germany andPoland, the overall improvement was largely attributable to falling mortality among men aged 40-64,while those over 65 contributed the largest proportion to life expectancy gains in women. The change indeaths among men aged 15-39 accounted for 0.4 of a year to life expectancy at birth in East Germanyand Poland, attributable largely to greater decreases from external causes. Among those over 40,absolute contributions to changing life expectancy were greater in the former GDR than in the other twoentities in both sexes, largely attributable to circulatory diseases. A persisting East-west life expectancygap in Germany of 2.1 years in men in 1997 was largely attributable to external causes, diseases of thedigestive system and circulatory diseases. Higher death rates from circulatory diseases among the elderlylargely explain the female life expectancy gap of approximately one year. CONCLUSIONS This studyprovides further insights into the health effects of political transition. Post-transition improvements in lifeexpectancy and mortality have been much steeper in East Germany compared with Poland. Changes indietary pattern and, in Germany, medical care may have been important factors in shapingpost-transition mortality trends.", "metadata": {}}
+{"_id": "14827874", "title": "", "text": "0021-972X/06/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 91(3):760–771 Printed inU.S.A. Copyright © 2006 by The Endocrine Society doi: 10.1210/jc.2005-1923 REVIEW: AromataseInhibitors for Ovulation InductionCONTEXT For the last 40 yr, the first line of treatment for anovulation ininfertile women has been clomiphene citrate (CC). CC is a safe, effective oral agent but is known to haverelatively common antiestrogenic endometrial and cervical mucous side effects that could preventpregnancy in the face of successful ovulation. In addition, there is a significant risk of multiple pregnancywith CC, compared with natural cycles. Because of these problems, we proposed the concept ofaromatase inhibition as a new method of ovulation induction that could avoid many of the adverse effectsof CC. The objective of this review was to describe the different physiological mechanisms of action for CCand aromatase inhibitors (AIs) and compare studies of efficacy for both agents for ovulation induction.EVIDENCE ACQUISITION We conducted a systematic review of all the published studies, both controlledand noncontrolled, comparing CC and AI treatment, either alone or in combination with gonadotropins,for ovulation induction or augmentation, identified through the Entrez-PubMed search engine. EVIDENCESYNTHESIS Because of the recent acceptance of the concept of using AIs for ovulation induction, fewcontrolled studies were identified, and the rest of the studies were pilot or preliminary comparisons.Based on these studies, it appears that AIs are as effective as CC in inducing ovulation, are devoid of anyantiestrogenic side effects, result in lower serum estrogen concentrations, and are associated with goodpregnancy rates with a lower incidence of multiple pregnancy than CC. When combined withgonadotropins for assisted reproductive technologies, AIs reduce the dose of FSH required for optimalfollicle recruitment and improve the response to FSH in poor responders. CONCLUSIONS Preliminaryevidence suggests that AIs may replace CC in the future because of similar efficacy with a reduced sideeffect profile. Although worldwide experience with AIs for ovulation induction is increasing, at present,definitive studies in the form of randomized controlled trials comparing CC with AIs are lacking.", "metadata": {}}
+{"_id": "14831629", "title": "", "text": "Patent ductus arteriosus: lack of evidence for common treatments.Patent ductus arteriosus (PDA) is acommon diagnosis among extremely premature infants, especially in those with lung disease. Treatmentsare often used to close the PDA. Despite nearly three decades of research, the question of whether thebenefits of treatments to prevent ductal patency or promote closure outweigh the risks of thesetreatments remains unanswered. The authors rarely use treatments designed to close the PDA. Thisarticle reviews three considerations in support of this restrained approach: rates of spontaneous closureof the ductus arteriosus; adverse effect of persistent ductal patency; and benefits and risks of treatmentsfor closure.", "metadata": {}}
+{"_id": "14834714", "title": "", "text": "Gene therapy of arthritis with TCR isolated from the inflamed paw.In recent years, the treatment ofautoimmune diseases has been significantly advanced by the use of biological agents. However, somebiologics are accompanied with severe side effects, including tuberculosis and other types of infection.There is thus a critical need for nonsystemic and lesion-specific methods of delivering these therapeuticagents. We attempted to treat a mouse model of arthritis by using T cells that expressed a regulatorymolecule and were specifically directed to the inflamed paw. To this end, we first identified the TCRalphabeta genes accumulating in the inflamed paw of mice with collagen-induced arthritis (CIA) by acombination of single-strand chain polymorphism analysis of TCR and single-cell sorting. We identified anexpanded clone B47 which is autoreactive but is not specific to type II collagen. In vivo, TCR genes fromB47-transduced T cells accumulated in the inflamed paw. Injection of cells cotransduced with the B47 andsoluble TNFRIg genes resulted in a significant suppression of CIA. The suppression was correlated withthe amount of TNFRIg transcripts in the hind paw, not with the serum concentrations of TNFRIg.Moreover, T cells cotransduced with the B47 and intracellular Foxp3 genes significantly suppressed CIAwith reductions in TNF-alpha, IL-17A, and IL-1beta expression and bone destruction. T cells cotransducedwith B47 and Foxp3 genes also suppressed the progression of established CIA. Therefore,immunosuppressive therapy with autoreactive TCR is a promising therapeutic strategy for arthritiswhether the TCRs are used to deliver either soluble or intracellular suppressive molecules.", "metadata": {}}
+{"_id": "14835068", "title": "", "text": "Melatonin: A Mitochondrial Targeting Molecule Involving Mitochondrial Protection and DynamicsMelatoninhas been speculated to be mainly synthesized by mitochondria. This speculation is supported by therecent discovery that aralkylamine N-acetyltransferase/serotonin N-acetyltransferase (AANAT/SNAT) islocalized in mitochondria of oocytes and the isolated mitochondria generate melatonin. We have alsospeculated that melatonin is a mitochondria-targeted antioxidant. It accumulates in mitochondria withhigh concentration against a concentration gradient. This is probably achieved by an active transportationvia mitochondrial melatonin transporter(s). Melatonin protects mitochondria by scavenging reactiveoxygen species (ROS), inhibiting the mitochondrial permeability transition pore (MPTP), and activatinguncoupling proteins (UCPs). Thus, melatonin maintains the optimal mitochondrial membrane potentialand preserves mitochondrial functions. In addition, mitochondrial biogenesis and dynamics is alsoregulated by melatonin. In most cases, melatonin reduces mitochondrial fission and elevates their fusion.Mitochondrial dynamics exhibit an oscillatory pattern which matches the melatonin circadian secretoryrhythm in pinealeocytes and probably in other cells. Recently, melatonin has been found to promotemitophagy and improve homeostasis of mitochondria.", "metadata": {}}
+{"_id": "14843502", "title": "", "text": "Self-reported health status and access to health services in a sample of prisoners in ItalyBACKGROUNDSelf-reported health status in underserved population of prisoners has not been extensively explored. Thepurposes of this cross-sectional study were to assess self-reported health, quality of life, and access tohealth services in a sample of male prisoners of Italy. METHODS A total of 908 prisoners received aself-administered anonymous questionnaire pertaining on demographic and detention characteristics,self-reported health status and quality of life, access to health services, lifestyles, and participation topreventive, social, and rehabilitation programs. A total of 650 prisoners agreed to participate in the studyand returned the questionnaire. RESULTS Respectively, 31.6% and 43.5% of prisoners reported a poorperceived health status and a poor quality of life, and 60% admitted that their health was worsened orgreatly worsened during the prison stay. Older age, lower education, psychiatric disorders, self-reportedhealth problems on prison entry, and suicide attempts within prison were significantly associated with aperceived worse health status. At the time of the questionnaire delivery, 30% of the prisonersself-reported a health problem present on prison entry and 82% present at the time of the survey. Mostfrequently reported health problems included dental health problems, arthritis or joint pain, eyeproblems, gastrointestinal diseases, emotional problems, and high blood pressure. On average, prisonersencountered general practitioners six times during the previous year, and the frequency of medicalencounters was significantly associated with older age, sentenced prisoners, psychiatric disorders, andself-reported health problems on prison entry. CONCLUSIONS The findings suggest that prisoners have aperceived poor health status, specific care needs and health promotion programs are seldom offered.Programs for correction of risk behaviour and prevention of long-term effects of incarceration onprisoners' health are strongly needed.", "metadata": {}}
+{"_id": "14848619", "title": "", "text": "BH3-only Protein Noxa Is a Mediator of Hypoxic Cell Death Induced by Hypoxia-inducible Factor1αHypoxia is a common cause of cell death and is implicated in many disease processes including strokeand chronic degenerative disorders. In response to hypoxia, cells express a variety of genes, which allowadaptation to altered metabolic demands, decreased oxygen demands, and the removal of irreversiblydamaged cells. Using polymerase chain reaction–based suppression subtractive hybridization to findgenes that are differentially expressed in hypoxia, we identified the BH3-only Bcl-2 family protein Noxa.Noxa is a candidate molecule mediating p53-induced apoptosis. We show that Noxa promoter respondsdirectly to hypoxia via hypoxia-inducible factor (HIF)-1α. Suppression of Noxa expression by antisenseoligonucleotides rescued cells from hypoxia-induced cell death and decreased infarction volumes in ananimal model of ischemia. Further, we show that reactive oxygen species and resultant cytochrome crelease participate in Noxa-mediated hypoxic cell death. Altogether, our results show that Noxa isinduced by HIF-1α and mediates hypoxic cell death.", "metadata": {}}
+{"_id": "14853989", "title": "", "text": "Neutrophil extracellular chromatin traps connect innate immune response to autoimmunityAutoantibodiesto DNA and histones (chromatin) are the defining antigen specificity in systemic lupus erythematosus(SLE) and related musculoskeletal disorders but the mechanisms responsible for their induction remainmysterious. That situation rapidly changed once neutrophil extracellular chromatin traps (NETs) werediscovered and observed to play a conserved role in innate immune responses to a broad variety ofmicrobial pathogens. At the center of an infectious process, neutrophils exert various antimicrobialdefenses, including the release of nuclear chromatin into the extracellular space. The externalized NETs, acomplex meshwork of nuclear chromatin and antimicrobial proteins, serve to immobilize and degrademicrobial pathogens. Here, we critically evaluate the evidence supporting NETs versus apoptotic bodies asa source for nuclear antigens in autoimmunity. We also discuss the possibility that NET chromatin formsan essential component of immune deposits in the pathogenesis of glomerulonephritis in SLE and otherautoimmune immune complex diseases.", "metadata": {}}
+{"_id": "14863011", "title": "", "text": "Bcl2 Regulation by the Melanocyte Master Regulator Mitf Modulates Lineage Survival and Melanoma CellViabilityKit/SCF signaling and Mitf-dependent transcription are both essential for melanocytedevelopment and pigmentation. To identify Mitf-dependent Kit transcriptional targets in primarymelanocytes, microarray studies were undertaken. Among identified targets was BCL2, whose germlinedeletion produces melanocyte loss and which exhibited phenotypic synergy with Mitf in mice. BCL2'sregulation by Mitf was verified in melanocytes and melanoma cells and by chromatin immunoprecipitationof the BCL2 promoter. Mitf also regulates BCL2 in osteoclasts, and both Mitf(mi/mi) and Bcl2(-/-) miceexhibit severe osteopetrosis. Disruption of Mitf in melanocytes or melanoma triggered profound apoptosissusceptible to rescue by BCL2 overexpression. Clinically, primary human melanoma expressionmicroarrays revealed tight nearest neighbor linkage for MITF and BCL2. This linkage helps explain thevital roles of both Mitf and Bcl2 in the melanocyte lineage and the well-known treatment resistance ofmelanoma.", "metadata": {}}
+{"_id": "14864285", "title": "", "text": "YOKO HONDA AND SHUJI HONDA 1Longevity is regulated by the daf-2 gene network in Caenorhabditiselegans. Mutations in the daf-2 gene, which encodes a member of the insulin receptor family, confer thelife extension (Age) phenotype and the constitutive dauer (a growth-arrested larval form specialized fordispersal) formation phenotype. The Age phenotype is mutually potentiated by two life extensionmutations in the daf-2 gene and the clk-1 gene, a homologue of yeast CAT5/COQ7 known to regulateubiquinone biosynthesis. In this study, we demonstrated that the daf-2 mutation also conferred anoxidative stress resistance (Oxr) phenotype, which was also enhanced by the clk-1 mutation. Similar tothe Age phenotype, the Oxr phenotype was regulated by the genetic pathway of insulin-like signalingfrom daf-2 to the daf-16 gene, a homologue of the HNF-3/forkhead transcription factor. These findingsled us to examine whether the insulin-like signaling pathway regulates the gene expression of antioxidantdefense enzymes. We found that the mRNA level of the sod-3 gene, which encodes Mn-superoxidedismutase (SOD), was much higher in daf-2 mutants than in the wild type. Moreover, the increased sod-3gene expression phenotype is regulated by the insulin-like signaling pathway. Although the clk-1 mutantitself did not display Oxr and the increased sod-3 expression phenotypes, the clk-1 mutation enhancedthem in the daf-2 mutant, suggesting that clk-1 is involved in longevity in two ways: clk-1 composes theoriginal clk-1 longevity program and the daf-2 longevity program. These observations suggest that thedaf-2 gene network controls longevity by regulating the Mn-SOD-associated antioxidant defense system.This system appears to play a role in efficient life maintenance at the dauer stage.", "metadata": {}}
+{"_id": "14865329", "title": "", "text": "Brown Fat and Browning for the Treatment of Obesity and Related Metabolic DisordersBrown fat is aspecialized fat depot that can increase energy expenditure and produce heat. After the recent discoveryof the presence of active brown fat in human adults and novel transcription factors controlling brownadipocyte differentiation, the field of the study of brown fat has gained great interest and is rapidlygrowing. Brown fat expansion and/or activation results in increased energy expenditure and a negativeenergy balance in mice and limits weight gain. Brown fat is also able to utilize blood glucose and lipid andresults in improved glucose metabolism and blood lipid independent of weight loss. Prolonged coldexposure and beta adrenergic agonists can induce browning of white adipose tissue. The inducible brownadipocyte, beige adipocyte evolving by thermogenic activation of white adipose tissue have differentorigin and molecular signature from classical brown adipocytes but share the characteristics of highmitochondria content, UCP1 expression and thermogenic capacity when activated. Increasing browningmay also be an efficient way to increase whole brown fat activity. Recent human studies have shownpossibilities that findings in mice can be reproduced in human, making brown fat a good candidate organto treat obesity and its related disorders.", "metadata": {}}
+{"_id": "14874811", "title": "", "text": "Hypoxia-induced energy stress regulates mRNA translation and cell growth.Oxygen (O2) deprivation, orhypoxia, has profound effects on cell metabolism and growth. Cells can adapt to low O2 in part throughactivation of hypoxia-inducible factor (HIF). We report here that hypoxia inhibits mRNA translation bysuppressing multiple key regulators, including eIF2alpha, eEF2, and the mammalian target of rapamycin(mTOR) effectors 4EBP1, p70S6K, and rpS6, independent of HIF. Hypoxia results in energy starvationand activation of the AMPK/TSC2/Rheb/mTOR pathway. Hypoxic AMP-activated protein kinase (AMPK)activation also leads to eEF2 inhibition. Moreover, hypoxic effects on cellular bioenergetics and mTORinhibition increase over time. Mutation of the TSC2 tumor suppressor gene confers a growth advantage tocells by repressing hypoxic mTOR inhibition and hypoxia-induced G1 arrest. Together, eIF2alpha, eEF2,and mTOR inhibition represent important HIF-independent mechanisms of energy conservation thatpromote survival under low O2 conditions.", "metadata": {}}
+{"_id": "14893425", "title": "", "text": "The dystonia-associated protein torsinA modulates synaptic vesicle recycling.The loss of a glutamic acidresidue in the AAA-ATPase (ATPases associated with diverse cellular activities) torsinA is responsible formost cases of early onset autosomal dominant primary dystonia. In this study, we found that snapin,which binds SNAP-25 (synaptosome-associated protein of 25,000 Da) and enhances the association ofthe SNARE complex with synaptotagmin, is an interacting partner for both wild type and mutant torsinA.Snapin co-localized with endogenous torsinA on dense core granules in PC12 cells and was recruited toperinuclear inclusions containing mutant DeltaE-torsinA in neuroblastoma SH-SY5Y cells. In view of theseobservations, synaptic vesicle recycling was analyzed using the lipophilic dye FM1-43 and an antibodydirected against an intravesicular epitope of synaptotagmin I. We found that overexpression of wild typetorsinA negatively affects synaptic vesicle endocytosis. Conversely, overexpression of DeltaE-torsinA inneuroblastoma cells increases FM1-43 uptake. Knockdown of snapin and/or torsinA using smallinterfering RNAs had a similar inhibitory effect on the exo-endocytic process. In addition, down-regulationof torsinA causes the persistence of synaptotagmin I on the plasma membrane, which closely resemblesthe effect observed by the overexpression of the DeltaE-torsinA mutant. Altogether, these findingssuggest that torsinA plays a role together with snapin in regulated exocytosis and that DeltaE-torsinAexerts its pathological effects through a loss of function mechanism. This may affect neuronal uptake ofneurotransmitters, such as dopamine, playing a role in the development of dystonic movements.", "metadata": {}}
+{"_id": "14893428", "title": "", "text": "In vivo electroporation in the embryonic mouse central nervous systemThis protocol describes a basicmethod for in vivo electroporation in the nervous system of embryonic mice. Delivery of electric pulsesfollowing microinjection of DNA into the brain ventricle or the spinal cord central canal enables efficienttransfection of genes into the nervous system. Transfection is facilitated by forceps-type electrodes,which hold the uterus and/or the yolk sac containing the embryo. More than ten embryos in a singlepregnant mouse can be operated on within 30 min. More than 90% of operated embryos survive andmore than 90% of these survivors express the transfected genes appropriately. Gene expression inneurons persists for a long time, even at postnatal stages, after electroporation. Thus, this method couldbe used to analyze roles of genes not only in embryonic development but also in higher order function ofthe nervous system, such as learning.", "metadata": {}}
+{"_id": "14915566", "title": "", "text": "Hierarchical phylogenetic models for analyzing multipartite sequence data.Debate exists over how toincorporate information from multipartite sequence data in phylogenetic analyses. Strict combined-dataapproaches argue for concatenation of all partitions and estimation of one evolutionary history,maximizing the explanatory power of the data. Consensus/independence approaches endorse a two-stepprocedure where partitions are analyzed independently and then a consensus is determined from themultiple results. Mixtures across the model space of a strict combined-data approach and a prioriindependent parameters are popular methods to integrate these methods. We propose an alternativemiddle ground by constructing a Bayesian hierarchical phylogenetic model. Our hierarchical frameworkenables researchers to pool information across data partitions to improve estimate precision in individualpartitions while permitting estimation and testing of tendencies in across-partition quantities. Suchacross-partition quantities include the distribution from which individual topologies relating the sequenceswithin a partition are drawn. We propose standard hierarchical priors on continuous evolutionaryparameters across partitions, while the structure on topologies varies depending on the researchproblem. We illustrate our model with three examples. We first explore the evolutionary history of theguinea pig (Cavia porcellus) using alignments of 13 mitochondrial genes. The hierarchical model returnssubstantially more precise continuous parameter estimates than an independent parameter approachwithout losing the salient features of the data. Second, we analyze the frequency of horizontal genetransfer using 50 prokaryotic genes. We assume an unknown species-level topology and allow individualgene topologies to differ from this with a small estimable probability. Simultaneously inferring the speciesand individual gene topologies returns a transfer frequency of 17%. We also examine HIV sequenceslongitudinally sampled from HIV+ patients. We ask whether posttreatment development of CCR5coreceptor virus represents concerted evolution from middisease CXCR4 virus or reemergence of initialinfecting CCR5 virus. The hierarchical model pools partitions from multiple unrelated patients byassuming that the topology for each patient is drawn from a multinomial distribution with unknownprobabilities. Preliminary results suggest evolution and not reemergence.", "metadata": {}}
+{"_id": "14920021", "title": "", "text": "Up-to-date catalogues of yeast protein complexesGold standard datasets on protein complexes are key toinferring and validating protein-protein interactions. Despite much progress in characterizing proteincomplexes in the yeast Saccharomyces cerevisiae, numerous researchers still use as reference themanually curated complexes catalogued by the Munich Information Center of Protein Sequencesdatabase. Although this catalogue has served the community extremely well, it no longer reflects thecurrent state of knowledge. Here, we report two catalogues of yeast protein complexes as results ofsystematic curation efforts. The first one, denoted as CYC2008, is a comprehensive catalogue of 408manually curated heteromeric protein complexes reliably backed by small-scale experiments reported inthe current literature. This catalogue represents an up-to-date reference set for biologists interested indiscovering protein interactions and protein complexes. The second catalogue, denoted as YHTP2008,comprises 400 high-throughput complexes annotated with current literature evidence. Among them, 262correspond, at least partially, to CYC2008 complexes. Evidence for interacting subunits is collected for 68complexes that have only partial or no overlap with CYC2008 complexes, whereas no literature evidencewas found for 100 complexes. Some of these partially supported and as yet unsupported complexes maybe interesting candidates for experimental follow up. Both catalogues are freely available at:http://wodaklab.org/cyc2008/.", "metadata": {}}
+{"_id": "14923462", "title": "", "text": "Synergistic Mechanisms of DNA Demethylation during Transition to Ground-State PluripotencyPluripotentstem cells (PSCs) occupy a spectrum of reversible molecular states ranging from a naive ground-state in2i, to metastable embryonic stem cells (ESCs) in serum, to lineage-primed epiblast stem cells (EpiSCs).To investigate the role of DNA methylation (5mC) across distinct pluripotent states, we mappedgenome-wide 5mC and 5-hydroxymethycytosine (5hmC) in multiple PSCs. Ground-state ESCs exhibit analtered distribution of 5mC and 5hmC at regulatory elements and dramatically lower absolute levelsrelative to ESCs in serum. By contrast, EpiSCs exhibit increased promoter 5mC coupled with reduced5hmC, which contributes to their developmental restriction. Switch to 2i triggers rapid onset of both theground-state gene expression program and global DNA demethylation. Mechanistically, repression of denovo methylases by PRDM14 drives DNA demethylation at slow kinetics, whereas TET1/TET2-mediated5hmC conversion enhances both the rate and extent of hypomethylation. These processes thus actsynergistically during transition to ground-state pluripotency to promote a robust hypomethylated state.", "metadata": {}}
+{"_id": "14924526", "title": "", "text": "Febrile seizures in the developing brain result in persistent modification of neuronal excitability in limbiccircuitsFebrile (fever-induced) seizures affect 3–5% of infants and young children. Despite the highincidence of febrile seizures, their contribution to the development of epilepsy later in life has remainedcontroversial. Combining a new rat model of complex febrile seizures and patch clamp techniques, wedetermined that hyperthermia-induced seizures in the immature rat cause a selective presynapticincrease in inhibitory synaptic transmission in the hippocampus that lasts into adulthood. The long-lastingnature of these potent alterations in synaptic communication after febrile seizures does not support theprevalent view of the 'benign' nature of early-life febrile convulsions.", "metadata": {}}
+{"_id": "14926162", "title": "", "text": "Identification of an allele of VAM3/SYP22 that confers a semi-dwarf phenotype in Arabidopsis thaliana.Theshort stem and midrib (ssm) mutants of Arabidopsis thaliana show both semi-dwarf and wavy leafphenotypes due to defects in the elongation of the stem internodes and leaves. Moreover, theseabnormalities cannot be recovered by exogenous phytohormones. ssm was originally identified as asingle recessive mutant of the ecotype Columbia (Col-0), but genetic crossing experiments have revealedthat this mutant phenotype is restored by another gene that is functional in the ecotype Landsberg erecta(Ler) and not in Col-0. Map-based cloning of the gene that is defective in ssm mutants has uncovered asmall deletion in the sixth intron of a gene encoding a syntaxin, VAM3/SYP22, which has been implicatedin vesicle transport to the vacuole. This mutation appears to cause a peptide insertion in the deducedVAM3/SYP22 polypeptide sequence due to defective splicing of the shortened sixth intron. Significantly,when compared with the wild-type Ler genome, the wild-type Col-0 genome has a single base pairdeletion causing a frameshift mutation in SYP23, a gene with the highest known homology toVAM3/SYP22. These findings suggest that VAM3/SYP22 and SYP23 have overlapping functions and thatthe vesicle transport mediated by these syntaxins is important for shoot morphogenesis.", "metadata": {}}
+{"_id": "14934137", "title": "", "text": "Class Ia MHC-deficient BALB/c mice generate CD8+ T cell-mediated protective immunity against Listeriamonocytogenes infection.CD8(+) T cells are required for protective immunity against intracellularpathogens such as Listeria monocytogenes. In this study, we used class Ia MHC-deficient mice, whichhave a severe reduction in circulating CD8(+) T cells, to determine the protective capacity of class IbMHC-restricted T cells during L. monocytogenes infection. The K(b-/-)D(b-/-) mutation was backcrossedonto a C.B10 (BALB/c congenic at H-2 locus with C57BL/10) background, because BALB/c mice are moresusceptible to Listeria infection than other commonly studied mouse strains such as C57BL/6. C.B10K(b-/-)D(b-/-) mice immunized with a sublethal dose of L. monocytogenes were fully protected against asubsequent lethal infection. Adoptive transfer of Listeria-immune splenocyte subsets into naiveK(b-/-)D(b-/-) mice indicated that CD8(+) T cells were the major component of this protective immuneresponse. A CD8(+) T cell line isolated from the spleen of a Listeria-infected class Ia MHC-deficientmouse was shown to specifically recognize Listeria-infected cells in vitro, as determined by IFN-gammasecretion and cytotoxicity assays. Adoptive transfer of this T cell line alone resulted in significantprotection against L. monocytogenes challenge. These results suggest that even a limited number of classIb MHC-restricted T cells are sufficient to generate the rapid recall response required for protectionagainst secondary infection with L. monocytogenes.", "metadata": {}}
+{"_id": "14938990", "title": "", "text": "Upregulated PD-1 Expression Is Associated with the Development of Systemic Lupus Erythematosus, butNot the PD-1.1 Allele of the PDCD1 GeneSystemic lupus erythematosus (SLE) is a multisystemautoimmune disease with complicated genetic inheritance. Programmed death 1 (PD-1), a negative T cellregulator to maintain peripheral tolerance, induces negative signals to T cells during interaction with itsligands and is therefore a candidate gene in the development of SLE. In order to examine whetherexpression levels of PD-1 contribute to the pathogenesis of SLE, 30 patients with SLE and 30 controlswere recruited and their PD-1 expression levels in peripheral blood mononuclear cells (PBMCs) weremeasured via flow cytometry and quantitative real-time-reverse transcription polymerase chain reaction(RT-PCR). Also, whether PD-1 expression levels are associated with the variant of the SNP rs36084323and the SLE Disease Activity Index (SLEDAI) was studied in this work. The PD-1 expression levels of SLEpatients were significantly increased compared with those of the healthy controls. The upregulated PD-1expression levels in SLE patients were greatly associated with SLEDAI scores. No significant differencewas found between PD-1 expression levels and SNP rs36084323. The results suggest that increasedexpression of PD-1 may correlate with the pathogenesis of SLE, upregulated PD-1 expression may be abiomarker for SLE diagnosis, and PD-1 inhibitor may be useful to SLE treatment.", "metadata": {}}
+{"_id": "14965508", "title": "", "text": "Endothelial cell membranes contain podocalyxin--the major sialoprotein of visceral glomerular epithelialcellsPodocalyxin is the major sialoprotein in the glycocalyx of glomerular podocytes. Here we report on itsextraglomerular localization, using a monospecific antibody which was obtained by affinity purification ofIgG on nitrocellulose transfers of glomerular podocalyxin. By indirect immunofluorescence, podocalyxinwas found in the blood vessels of several organs (lung, heart, kidney, small intestine, brain, pancreas,aorta, the periportal blood vessels in liver, and the central arteries of follicles of the spleen, but not in theendothelia that line the sinusoids of the latter organs). By immunoelectron microscopy--usingimmunogold conjugates in diffusion (\"pre-embedding\") and surface (\"postembedding\")procedures--podocalyxin was localized on the luminal membrane domain of endothelial cells, in a patchydistribution. The presence of podocalyxin was confirmed in SDS extracts of lung tissue byimmunoblotting. We conclude that (a) podocalyxin is a widespread component of endothelial plasmamembranes, (b) it is restricted to the luminal membrane domain, and (c) it is distributed unevenly on theendothelial cell surface.", "metadata": {}}
+{"_id": "14972169", "title": "", "text": "Teratogen-Induced Oxidative Stress Targets Glyceraldehyde-3-Phosphate Dehydrogenase in theOrganogenesis Stage Mouse EmbryoExposure during the organogenesis stage of the mouse embryo tothe model teratogen, hydroxyurea (HU), induces curly tail and limb malformations. Oxidative stresscontributes to the developmental toxicity of HU. Reactive oxygen species (ROS) interact withpolyunsaturated bilipid membranes to form α,β-unsaturated reactive aldehydes; 4-hydroxy-2-nonenal(4-HNE), one of the most cytotoxic of these aldehydes, covalently adducts with proteins, lipids, andnucleic acids. The goal of the current study is to determine if HU exposure of CD1 mice on gestation day 9generates region-specific 4-HNE-protein adducts in the embryo and to identify the proteins targeted. Theformation of 4-HNE-protein adducts was elevated in the caudal region of control embryos; HU exposurefurther increased 4-HNE-protein adduct formation in this area. Interestingly, three of the 4-HNE-modifiedproteins, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), glutamate oxaloacetate transaminase 2,and aldolase 1, A isoform, are involved in energy metabolism. The formation of 4-HNE-GAPDH proteinadducts reduced GAPDH enzymatic activity by 20% and attenuated lactate production by 40%.Furthermore, HU exposure induced the nuclear translocation of GAPDH in the caudal region of exposedembryos; this nuclear translocation may be associated with the reactivation of oxidized proteins involvedin DNA repair, such as apurinic/apyrimidinic endonuclease-1, and the stimulation of E1A-associated P300protein/creb-binding protein (p300/CBP) activity, initiating cell death in a p53-dependent pathway. Wepropose that GAPDH is a redox-sensitive target in the embryo and may play a role in a stress responseduring development.", "metadata": {}}
+{"_id": "14973286", "title": "", "text": "Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment inpatients with cancer and venous thrombosis.A small proportion of patients with deep vein thrombosisdevelop recurrent venous thromboembolic complications or bleeding during anticoagulant treatment.These complications may occur more frequently if these patients have concomitant cancer. Thisprospective follow-up study sought to determine whether in thrombosis patients those with cancer have ahigher risk for recurrent venous thromboembolism or bleeding during anticoagulant treatment than thosewithout cancer. Of the 842 included patients, 181 had known cancer at entry. The 12-month cumulativeincidence of recurrent thromboembolism in cancer patients was 20.7% (95% CI, 15.6%-25.8%) versus6.8% (95% CI, 3.9%- 9.7%) in patients without cancer, for a hazard ratio of 3.2 (95% CI, 1.9-5.4) The12-month cumulative incidence of major bleeding was 12.4% (95% CI, 6.5%-18.2%) in patients withcancer and 4.9% (95% CI, 2.5%-7.4%) in patients without cancer, for a hazard ratio of 2.2 (95% CI,1.2-4.1). Recurrence and bleeding were both related to cancer severity and occurred predominantlyduring the first month of anticoagulant therapy but could not be explained by sub- oroveranticoagulation. Cancer patients with venous thrombosis are more likely to develop recurrentthromboembolic complications and major bleeding during anticoagulant treatment than those withoutmalignancy. These risks correlate with the extent of cancer. Possibilities for improvement using thecurrent paradigms of anticoagulation seem limited and new treatment strategies should be developed.", "metadata": {}}
+{"_id": "15040589", "title": "", "text": "Fitting multilevel models in complex survey data with design weights: RecommendationsBACKGROUNDMultilevel models (MLM) offer complex survey data analysts a unique approach to understandingindividual and contextual determinants of public health. However, little summarized guidance exists withregard to fitting MLM in complex survey data with design weights. Simulation work suggests that analystsshould scale design weights using two methods and fit the MLM using unweighted and scaled-weighteddata. This article examines the performance of scaled-weighted and unweighted analyses across a varietyof MLM and software programs. METHODS Using data from the 2005-2006 National Survey of Childrenwith Special Health Care Needs (NS-CSHCN: n = 40,723) that collected data from children clusteredwithin states, I examine the performance of scaling methods across outcome type (categorical vs.continuous), model type (level-1, level-2, or combined), and software (Mplus, MLwiN, and GLLAMM).RESULTS Scaled weighted estimates and standard errors differed slightly from unweighted analyses,agreeing more with each other than with unweighted analyses. However, observed differences wereminimal and did not lead to different inferential conclusions. Likewise, results demonstrated minimaldifferences across software programs, increasing confidence in results and inferential conclusionsindependent of software choice. CONCLUSION If including design weights in MLM, analysts should scalethe weights and use software that properly includes the scaled weights in the estimation.", "metadata": {}}
+{"_id": "15041758", "title": "", "text": "Functional outcomes of multi-condition collaborative care and successful ageing: results of randomisedtrialOBJECTIVE To evaluate the effectiveness of integrated care for chronic physical diseases anddepression in reducing disability and improving quality of life. DESIGN A randomised controlled trial ofmulti-condition collaborative care for depression and poorly controlled diabetes and/or risk factors forcoronary heart disease compared with usual care among middle aged and elderly people   SETTINGFourteen primary care clinics in Seattle, Washington.   PARTICIPANTS Patients with diabetes or coronaryheart disease, or both, and blood pressure above 140/90 mm Hg, low density lipoprotein concentration>3.37 mmol/L, or glycated haemoglobin 8.5% or higher, and PHQ-9 depression scores of ≥ 10.INTERVENTION A 12 month intervention to improve depression, glycaemic control, blood pressure, andlipid control by integrating a \"treat to target\" programme for diabetes and risk factors for coronary heartdisease with collaborative care for depression. The intervention combined self management support,monitoring of disease control, and pharmacotherapy to control depression, hyperglycaemia,hypertension, and hyperlipidaemia. MAIN OUTCOME MEASURES Social role disability (Sheehan disabilityscale), global quality of life rating, and World Health Organization disability assessment schedule(WHODAS-2) scales to measure disabilities in activities of daily living (mobility, self care, householdmaintenance). RESULTS Of 214 patients enrolled (106 intervention and 108 usual care), disability andquality of life measures were obtained for 97 intervention patients at six months (92%) and 92 at 12months (87%), and for 96 usual care patients at six months (89%) and 92 at 12 months (85%).Improvements from baseline on the Sheehan disability scale (-0.9, 95% confidence interval -1.5 to -0.2;P = 0.006) and global quality of life rating (0.7, 0.2 to 1.2; P = 0.005) were significantly greater at sixand 12 months in patients in the intervention group. There was a trend toward greater improvement indisabilities in activities of daily living (-1.5, -3.3 to 0.4; P = 0.10). CONCLUSIONS Integrated care thatcovers chronic physical disease and comorbid depression can reduce social role disability and enhanceglobal quality of life. Trial registration Clinical Trials NCT00468676.", "metadata": {}}
+{"_id": "15048300", "title": "", "text": "A Comparison of Cost Effectiveness Using Data from Randomized Trials or Actual Clinical Practice:Selective Cox-2 Inhibitors as an ExampleBACKGROUND Data on absolute risks of outcomes and patternsof drug use in cost-effectiveness analyses are often based on randomised clinical trials (RCTs). Theobjective of this study was to evaluate the external validity of published cost-effectiveness studies bycomparing the data used in these studies (typically based on RCTs) to observational data from actualclinical practice. Selective Cox-2 inhibitors (coxibs) were used as an example. METHODS AND FINDINGSThe UK General Practice Research Database (GPRD) was used to estimate the exposure characteristicsand individual probabilities of upper gastrointestinal (GI) events during current exposure to nonsteroidalanti-inflammatory drugs (NSAIDs) or coxibs. A basic cost-effectiveness model was developed evaluatingtwo alternative strategies: prescription of a conventional NSAID or coxib. Outcomes included upper GIevents as recorded in GPRD and hospitalisation for upper GI events recorded in the national registry ofhospitalisations (Hospital Episode Statistics) linked to GPRD. Prescription costs were based on theprescribed number of tables as recorded in GPRD and the 2006 cost data from the British NationalFormulary. The study population included over 1 million patients prescribed conventional NSAIDs orcoxibs. Only a minority of patients used the drugs long-term and daily (34.5% of conventional NSAIDsand 44.2% of coxibs), whereas coxib RCTs required daily use for at least 6-9 months. The mean cost ofpreventing one upper GI event as recorded in GPRD was US$104k (ranging from US$64k with long-termdaily use to US$182k with intermittent use) and US$298k for hospitalizations. The mean costs (for GPRDevents) over calendar time were US$58k during 1990-1993 and US$174k during 2002-2005. Using RCTdata rather than GPRD data for event probabilities, the mean cost was US$16k with the VIGOR RCT andUS$20k with the CLASS RCT. CONCLUSIONS The published cost-effectiveness analyses of coxibs lackedexternal validity, did not represent patients in actual clinical practice, and should not have been used toinform prescribing policies. External validity should be an explicit requirement for cost-effectivenessanalyses.", "metadata": {}}
+{"_id": "15058155", "title": "", "text": "7α, 25-dihydroxycholesterol-mediated activation of EBI2 in immune regulation and diseasesEBI2, akaGPR183, is a G-couple receptor originally identified in 1993 as one of main genes induced in Burkitt'slymphoma cell line BL41 by Epstein-Barr virus (EBV) infection. After it was reported in 2009 that thereceptor played a key role in regulating B cell migration and responses, we initiated an effort in lookingfor its endogenous ligand. In 2011 we and another group reported the identification of 7α,25-dihydroxyxcholesterol (7α, 25-OHC), an oxysterol, as the likely physiological ligand of EBI2. A fewsubsequently published studies further elucidated how 7α, 25-OHC bound to EBI2, and how a gradient of7α, 25-OHC could be generated in vivo and regulated migration, activation, and functions of B cells, Tcells, dendritic cells (DCs), monocytes/macrophages, and astrocytes. The identification of 7α, 25-OHC asa G protein-coupled receptor ligand revealed a previously unknown signaling system of oxysterols, a classof molecules which exert profound biological functions. Dysregulation of the synthesis or functions ofthese molecules is believed to contribute to inflammation and autoimmune diseases, cardiovasculardiseases, neurodegenerative diseases, cancer as well as metabolic diseases such as diabetes, obesity,and dyslipidemia. Therefore EBI2 may represent a promising target for therapeutic interventions forhuman diseases.", "metadata": {}}
+{"_id": "15077696", "title": "", "text": "PrimPol Bypasses UV Photoproducts during Eukaryotic Chromosomal DNA ReplicationDNA damage canstall the DNA replication machinery, leading to genomic instability. Thus, numerous mechanisms exist tocomplete genome duplication in the absence of a pristine DNA template, but identification of the enzymesinvolved remains incomplete. Here, we establish that Primase-Polymerase (PrimPol; CCDC111), anarchaeal-eukaryotic primase (AEP) in eukaryotic cells, is involved in chromosomal DNA replication.PrimPol is required for replication fork progression on ultraviolet (UV) light-damaged DNA templates,possibly mediated by its ability to catalyze translesion synthesis (TLS) of these lesions. This PrimPol UVlesion bypass pathway is not epistatic with the Pol η-dependent pathway and, as a consequence, protectsxeroderma pigmentosum variant (XP-V) patient cells from UV-induced cytotoxicity. In addition, weestablish that PrimPol is also required for efficient replication fork progression during an unperturbed Sphase. These and other findings indicate that PrimPol is an important player in replication forkprogression in eukaryotic cells.", "metadata": {}}
+{"_id": "15081770", "title": "", "text": "The novel immunosuppressive enzyme IL4I1 is expressed by neoplastic cells of several B-cell lymphomasand by tumor-associated macrophagesWe previously reported a strong IL4I1 gene expression in primarymediastinal B-cell lymphoma (PMBL) and recently identified the protein as a secreted L-phenylalanineoxidase, physiologically expressed by myeloid cells, which inhibits T-cell proliferation in vitro. Here, weanalyzed the pattern of IL4I1 protein expression in 315 human lymphoid and non-lymphoid malignancies.Besides PMBL, IL4I1 expression in tumors was very frequent. IL4I1 was detected in tumor-associatedmacrophages from most of the tumors and in neoplastic cells from follicular lymphoma, classic andnodular lymphocyte predominant Hodgkin lymphomas and small lymphocytic lymphoma, three of whichare germinal center derived. IL4I1-positive tumor cells were also detected in rare cases of solid cancers,mainly mesothelioma. The enzymatic activity paralleled protein expression, suggesting that IL4I1 isfunctional in vivo. Depending on the tumor type, IL4I1 may impact on different infiltrating lymphocytepopulations with consequences on tumor evolution. In the particular case of follicular lymphoma cells,which are susceptible to antitumor cytotoxic T cells killing but depend on interactions with local T helpercells for survival, a high level of IL4I1 expression seems associated with the absence of bone marrowinvolvement and a better outcome. These findings plead for an evaluation of IL4I1 as a prognosis factor.", "metadata": {}}
+{"_id": "15113221", "title": "", "text": "Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumorsuppressor pathway activity.Pathway-specific therapy is the future of cancer management. The oncogenicphosphatidylinositol 3-kinase (PI3K) pathway is frequently activated in solid tumors; however, currently,no reliable test for PI3K pathway activation exists for human tumors. Taking advantage of theobservation that loss of PTEN, the negative regulator of PI3K, results in robust activation of this pathway,we developed and validated a microarray gene expression signature for immunohistochemistry(IHC)-detectable PTEN loss in breast cancer (BC). The most significant signature gene was PTEN itself,indicating that PTEN mRNA levels are the primary determinant of PTEN protein levels in BC. Some PTENIHC-positive BCs exhibited the signature of PTEN loss, which was associated to moderately reduced PTENmRNA levels cooperating with specific types of PIK3CA mutations and/or amplification of HER2. Thisdemonstrates that the signature is more sensitive than PTEN IHC for identifying tumors with pathwayactivation. In independent data sets of breast, prostate, and bladder carcinoma, prediction of pathwayactivity by the signature correlated significantly to poor patient outcome. Stathmin, encoded by thesignature gene STMN1, was an accurate IHC marker of the signature and had prognostic significance inBC. Stathmin was also pathway-pharmacodynamic in vitro and in vivo. Thus, the signature or itscomponents such as stathmin may be clinically useful tests for stratification of patients for anti-PI3Kpathway therapy and monitoring therapeutic efficacy. This study indicates that aberrant PI3K pathwaysignaling is strongly associated with metastasis and poor survival across carcinoma types, highlightingthe enormous potential impact on patient survival that pathway inhibition could achieve.", "metadata": {}}
+{"_id": "15121114", "title": "", "text": "Suppression of subtelomeric VSG switching by Trypanosoma brucei TRF requires its TTAGGGrepeat-binding activityTrypanosoma brucei causes human African trypanosomiasis and regularly switchesits major surface antigen, VSG, in the bloodstream of its mammalian host to evade the host immuneresponse. VSGs are expressed exclusively from subtelomeric loci, and we have previously shown thattelomere proteins TbTIF2 and TbRAP1 play important roles in VSG switching and VSG silencingregulation, respectively. We now discover that the telomere duplex DNA-binding factor, TbTRF, also playsa critical role in VSG switching regulation, as a transient depletion of TbTRF leads to significantly moreVSG switching events. We solved the NMR structure of the DNA-binding Myb domain of TbTRF, whichfolds into a canonical helix-loop-helix structure that is conserved to the Myb domains of mammalian TRFproteins. The TbTRF Myb domain tolerates well the bulky J base in T. brucei telomere DNA, and theDNA-binding affinity of TbTRF is not affected by the presence of J both in vitro and in vivo. In addition, wefind that point mutations in TbTRF Myb that significantly reduced its in vivo telomere DNA-binding affinityalso led to significantly increased VSG switching frequencies, indicating that the telomere DNA-bindingactivity is critical for TbTRF's role in VSG switching regulation.", "metadata": {}}
+{"_id": "15128866", "title": "", "text": "CD4+ T cell-mediated cytotoxicity eliminates primary tumor cells in metastatic melanoma through highMHC class II expression and can be enhanced by inhibitory receptor blockadeMetastatic melanoma is arapidly progressing disease with high mortality rate and limited treatment options. Immunotherapy basedon tumor-targeting cytotoxic T cell responses represents a promising strategy. To assist in itsdevelopment, we examined the possibility and efficacy of using CD4+ cytotoxic T cells. The regulatorymechanisms controlling CD4+ T cell-mediated cytotoxicity were also investigated. We found thatnaturally occurring granzyme B and perforin-expressing CD4+ cytotoxic T cells can be recovered frommetastatic melanoma patients at significantly elevated frequencies compared to those from healthycontrols. These CD4+ cytotoxic T cells were also capable of killing autologous tumor cells harvested frommetastatic melanoma, independent of CD8+ T cells or any other cell types. However, several restrictingfactors were observed. First, the cytolytic activity by CD4+ T cells required high MHC class II expressionon melanoma cells, which was not satisfied in a subset of melanomas. Second, the granzyme B andperforin release by activated CD4+ cytotoxic T cells was reduced after coculturing with autologousmelanoma cells, characterized by low LAMP-1 expression and low granzyme B and perforin secretion inthe supernatant. This suggested that inhibitory mechanisms were present to suppress CD4+ cytotoxic Tcells. Indeed, blockade of PD-1 and CTLA-4 had increased the cytolytic activity of CD4+ T cells but wasonly effective in MHC class II high but not MHC class II low melanomas. Together, our study showed thatCD4+ T cell-mediated cytotoxicity could eliminate primary melanoma cells but the efficacy depended onMHC class II expression.", "metadata": {}}
+{"_id": "15129362", "title": "", "text": "The epidemiology and iatrogenic transmission of hepatitis C virus in Egypt: a Bayesian coalescentapproach.Hepatitis C virus (HCV) is a leading cause of liver cancer and cirrhosis, and Egypt has possiblythe highest HCV prevalence worldwide. In this article we use a newly developed Bayesian inferenceframework to estimate the transmission dynamics of HCV in Egypt from sampled viral gene sequences,and to predict the public health impact of the virus. Our results indicate that the effective number of HCVinfections in Egypt underwent rapid exponential growth between 1930 and 1955. The timing and speed ofthis spread provides quantitative genetic evidence that the Egyptian HCV epidemic was initiated andpropagated by extensive antischistosomiasis injection campaigns. Although our results show that HCVtransmission has since decreased, we conclude that HCV is likely to remain prevalent in Egypt for severaldecades. Our combined population genetic and epidemiological analysis provides detailed estimates ofhistorical changes in Egyptian HCV prevalence. Because our results are consistent with a demographicscenario specified a priori, they also provide an objective test of inference methods based on thecoalescent process.", "metadata": {}}
+{"_id": "15135001", "title": "", "text": "Improving population representation through geographic health information systems: mapping theMURDOCK study.This paper highlights methods for using geospatial analysis to assess, enhance, andimprove recruitment efforts to ensure representativeness in study populations. We apply these methodsto the Measurement to Understand Reclassification of Disease of Cabarrus/Kannapolis (MURDOCK) study,a longitudinal population health study focused on the city of Kannapolis and Cabarrus County, NC.Although efforts have been made to recruit a participant registry that is representative of the 18 ZIP codecatchment region inclusive of Cabarrus County and Kannapolis, bias in such recruitment is inevitable.Participants in the MURDOCK study are geospatially referenced at entry, providing information that canbe used to monitor and guide recruitment efforts. MURDOCK participant population representativenesswas assessed using chi-squared tests to compare the MURDOCK population with 2010 Census data,relative to both the entire 18 ZIP code catchment area and for individual Census tracts. A logisticregression model was fit to characterize Census tracts with low recruitment, defined by fewer than 56participants from that tract. The distance to the site at which participants enrolled was calculated, andmedian distance to enrollment site was used in the logistic regression. Tracts with low recruitment ratescontained higher minority and younger populations, suggesting specific strategies for improvingrecruitment in these areas. Areal units farther away from enrollment sites were also not well-sampled,despite being in the specified study area, indicating that distance traveled to enrollment may be a barrier.These results have implications for targeting recruitment efforts and representative samples moregenerally, including in other population-based studies.", "metadata": {}}
+{"_id": "15153602", "title": "", "text": "Haplotype-based variant detection from short-read sequencingThe direct detection of haplotypes fromshort-read DNA sequencing data requires changes to existing small-variant detection methods. Here, wedevelop a Bayesian statistical framework which is capable of modeling multiallelic loci in sets ofindividuals with non-uniform copy number. We then describe our implementation of this framework in ahaplotype-based variant detector, FreeBayes.", "metadata": {}}
+{"_id": "15155862", "title": "", "text": "Longitudinal Genome-Wide Association of Cardiovascular Disease Risk Factors in the Bogalusa HeartStudyCardiovascular disease (CVD) is the leading cause of death worldwide. Recent genome-wideassociation (GWA) studies have pinpointed many loci associated with CVD risk factors in adults. It isunclear, however, if these loci predict trait levels at all ages, if they are associated with how a traitdevelops over time, or if they could be used to screen individuals who are pre-symptomatic to provide theopportunity for preventive measures before disease onset. We completed a genome-wide associationstudy on participants in the longitudinal Bogalusa Heart Study (BHS) and have characterized theassociation between genetic factors and the development of CVD risk factors from childhood toadulthood. We report 7 genome-wide significant associations involving CVD risk factors, two of whichhave been previously reported. Top regions were tested for replication in the Young Finns Study (YF) andtwo associations strongly replicated: rs247616 in CETP with HDL levels (combined P = 9.7 x 10(-24)),and rs445925 at APOE with LDL levels (combined P = 8.7 x 10(-19)). We show that SNPs previouslyidentified in adult cross-sectional studies tend to show age-independent effects in the BHS with effectsizes consistent with previous reports. Previously identified variants were associated with adult trait levelsabove and beyond those seen in childhood; however, variants with time-dependent effects were alsopromising predictors. This is the first GWA study to evaluate the role of common genetic variants in thedevelopment of CVD risk factors in children as they advance through adulthood and highlights the utilityof using longitudinal studies to identify genetic predictors of adult traits in children.", "metadata": {}}
+{"_id": "15176526", "title": "", "text": "Actin and serum response factor transduce physical cues from the microenvironment to regulateepidermal stem cell fate decisionsEpidermal homeostasis depends on a balance between stem cellrenewal and differentiation and is regulated by extrinsic signals from the extracellular matrix (ECM). Apowerful approach to analysing the pathways involved is to engineer single-cell microenvironments inwhich individual variables are precisely and quantitatively controlled. Here, we employ micropatternedsurfaces to identify the signalling pathways by which restricted ECM contact triggers human epidermalstem cells to initiate terminal differentiation. On small (20 μm diameter) circular islands, keratinocytesremained rounded, and differentiated at higher frequency than cells that could spread on large (50 μmdiameter) islands. Differentiation did not depend on ECM composition or density. Rather, the actincytoskeleton mediated shape-induced differentiation by regulating serum response factor (SRF)transcriptional activity. Knockdown of SRF or its co-factor MAL inhibited differentiation, whereasoverexpression of MAL stimulated SRF activity and involucrin expression. SRF target genes FOS and JUNBwere also required for differentiation: c-Fos mediated serum responsiveness, whereas JunB wasregulated by actin and MAL. Our findings demonstrate how biophysical cues are transduced intotranscriptional responses that determine epidermal cell fate.", "metadata": {}}
+{"_id": "15194125", "title": "", "text": "Reproducibility and automatic measurement of QT dispersion.This study investigated interobserver (twoobservers) and intrasubject (two measurements) reproducibility of QT dispersion from abnormalelectrocardiograms in patients with previous myocardial infarction, and compared a user-interactive withan automatic measurement system. Standard 12-lead electrocardiograms, recorded at 25 mm.s-1, wererandomly chosen from 70 patients following myocardial infarction. These were scanned into a personalcomputer, and specially designed software skeletonized and joined each image. The images were thenavailable for user-interactive (mouse and computer screen), or automatic measurements using aspecially designed algorithm. For all methods reproducibility of the RR interval was excellent (meanabsolute errors 3-4 ms, relative errors 0.3-0.5%). Reproducibility of the mean QT interval was good;intrasubject error was 6 ms (relative error 1.4%), interobserver error was 7 ms (1.8%), and observers'vs automatic measurement errors were 10 and 11 ms (2.5, 2.8%). However QTc dispersionmeasurements had large errors for all methods; intrasubject error was 12 ms (17.3%), interobservererror was 15 ms (22.1%), and observers' vs automatic measurement were errors 30 and 28 ms (35.4,31.9%). QT dispersion measurements rely on the most difficult to measure QT intervals, resulting in aproblem of reproducibility. Any automatic system must not only recognize common T wave morphologies,but also these more difficult T waves, if it is to be useful for measuring QT dispersion. The poorreproducibility of QT dispersion limits its role as a useful clinical tool, particularly as a predictor of events.", "metadata": {}}
+{"_id": "15215393", "title": "", "text": "Inhibition of LSD1 sensitizes glioblastoma cells to histone deacetylase inhibitors.Glioblastoma multiforme(GBM) is a particularly aggressive brain tumor and remains a clinically devastating disease. Despiteinnovative therapies for the treatment of GBM, there has been no significant increase in patient survivalover the past decade. Enzymes that control epigenetic alterations are of considerable interest as targetsfor cancer therapy because of their critical roles in cellular processes that lead to oncogenesis. Severalinhibitors of histone deacetylases (HDACs) have been developed and tested in GBM with moderatesuccess. We found that treatment of GBM cells with HDAC inhibitors caused the accumulation of histonemethylation, a modification removed by the lysine specific demethylase 1 (LSD1). This led us to examinethe effects of simultaneously inhibiting HDACs and LSD1 as a potential combination therapy. Weevaluated induction of apoptosis in GBM cell lines after combined inhibition of LSD1 and HDACs. LSD1was inhibited by targeted short hairpin RNA or pharmacological means and inhibition of HDACs wasachieved by treatment with either vorinostat or PCI-24781. Caspase-dependent apoptosis wassignificantly increased (>2-fold) in LSD1-knockdown GBM cells treated with HDAC inhibitors. Moreover,pharmacologically inhibiting LSD1 with the monoamine oxidase inhibitor tranylcypromine, in combinationwith HDAC inhibitors, led to synergistic apoptotic cell death in GBM cells; this did not occur in normalhuman astrocytes. Taken together, these results indicate that LSD1 and HDACs cooperate to regulate keypathways of cell death in GBM cell lines but not in normal counterparts, and they validate the combineduse of LSD1 and HDAC inhibitors as a therapeutic approach for GBM.", "metadata": {}}
+{"_id": "15237660", "title": "", "text": "Challenges for malaria elimination in Zanzibar: pyrethroid resistance in malaria vectors and poorperformance of long-lasting insecticide netsBACKGROUND Long-lasting insecticide treated nets (LLINs)and indoor residual house spraying (IRS) are the main interventions for the control of malaria vectors inZanzibar. The aim of the present study was to assess the susceptibility status of malaria vectors againstthe insecticides used for LLINs and IRS and to determine the durability and efficacy of LLINs on theisland. METHODS Mosquitoes were sampled from Pemba and Unguja islands in 2010-2011 for use in WHOsusceptibility tests. One hundred and fifty LLINs were collected from households on Unguja, their physicalstate was recorded and then tested for efficacy as well as total insecticide content. RESULTS Speciesidentification revealed that over 90% of the Anopheles gambiae complex was An. arabiensis with a smallnumber of An. gambiae s.s. and An. merus being present. Susceptibility tests showed that An. arabiensison Pemba was resistant to the pyrethroids used for LLINs and IRS. Mosquitoes from Unguja Island,however, were fully susceptible to all pyrethroids tested. A physical examination of 150 LLINs showedthat two thirds were damaged after only three years in use. All used nets had a significantly lower (p <0.001) mean permethrin concentration of 791.6 mg/m2 compared with 944.2 mg/m2 for new ones. Theirefficacy decreased significantly against both susceptible An. gambiae s.s. colony mosquitoes andwild-type mosquitoes from Pemba after just six washes (p < 0.001). CONCLUSION The sustainability ofthe gains achieved in malaria control in Zanzibar is seriously threatened by the resistance of malariavectors to pyrethroids and the short-lived efficacy of LLINs. This study has revealed that even inrelatively well-resourced and logistically manageable places like Zanzibar, malaria elimination is going tobe difficult to achieve with the current control measures.", "metadata": {}}
+{"_id": "15248287", "title": "", "text": "Proliferating cell nuclear antigen acts as a cytoplasmic platform controlling human neutrophilsurvivalNeutrophil apoptosis is a highly regulated process essential for inflammation resolution, themolecular mechanisms of which are only partially elucidated. In this study, we describe a survivalpathway controlled by proliferating cell nuclear antigen (PCNA), a nuclear factor involved in DNAreplication and repairing of proliferating cells. We show that mature neutrophils, despite their inability toproliferate, express high levels of PCNA exclusively in their cytosol and constitutively associated withprocaspases, presumably to prevent their activation. Notably, cytosolic PCNA abundance decreasedduring apoptosis, and increased during in vitro and in vivo exposure to the survival factor granulocytecolony-stimulating factor (G-CSF). Peptides derived from the cyclin-dependent kinase inhibitor p21,which compete with procaspases to bind PCNA, triggered neutrophil apoptosis thus demonstrating thatspecific modification of PCNA protein interactions affects neutrophil survival. Furthermore, PCNAoverexpression rendered neutrophil-differentiated PLB985 myeloid cells significantly more resistant toTNF-related apoptosis-inducing ligand- or gliotoxin-induced apoptosis. Conversely, a decrease in PCNAexpression after PCNA small interfering RNA transfection sensitized these cells to apoptosis. Finally, amutation in the PCNA interdomain-connecting loop, the binding site for many partners, significantlydecreased the PCNA-mediated antiapoptotic effect. These results identify PCNA as a regulator ofneutrophil lifespan, thereby highlighting a novel target to potentially modulate pathological inflammation.", "metadata": {}}
+{"_id": "15274349", "title": "", "text": "Development of the Human Infant Intestinal MicrobiotaAlmost immediately after a human being is born,so too is a new microbial ecosystem, one that resides in that person's gastrointestinal tract. Although it isa universal and integral part of human biology, the temporal progression of this process, the sources ofthe microbes that make up the ecosystem, how and why it varies from one infant to another, and howthe composition of this ecosystem influences human physiology, development, and disease are still poorlyunderstood. As a step toward systematically investigating these questions, we designed a microarray todetect and quantitate the small subunit ribosomal RNA (SSU rRNA) gene sequences of most currentlyrecognized species and taxonomic groups of bacteria. We used this microarray, along with sequencing ofcloned libraries of PCR-amplified SSU rDNA, to profile the microbial communities in an average of 26 stoolsamples each from 14 healthy, full-term human infants, including a pair of dizygotic twins, beginning withthe first stool after birth and continuing at defined intervals throughout the first year of life. Toinvestigate possible origins of the infant microbiota, we also profiled vaginal and milk samples from mostof the mothers, and stool samples from all of the mothers, most of the fathers, and two siblings. Thecomposition and temporal patterns of the microbial communities varied widely from baby to baby.Despite considerable temporal variation, the distinct features of each baby's microbial community wererecognizable for intervals of weeks to months. The strikingly parallel temporal patterns of the twinssuggested that incidental environmental exposures play a major role in determining the distinctivecharacteristics of the microbial community in each baby. By the end of the first year of life, theidiosyncratic microbial ecosystems in each baby, although still distinct, had converged toward a profilecharacteristic of the adult gastrointestinal tract.", "metadata": {}}
+{"_id": "15282056", "title": "", "text": "Combinatorial modulation of galP and glk gene expression for improved alternative glucoseutilizationPhosphoenolpyruvate (PEP) is an important precursor for anaerobic production of succinate andmalate. Although inactivating PEP/carbohydrate phosphotransferase systems (PTS) could increase PEPsupply, the resulting strain had a low glucose utilization rate. In order to improve anaerobic glucoseutilization rate for efficient production of succinate and malate, combinatorial modulation of galactosepermease (galP) and glucokinase (glk) gene expression was carried out in chromosome of an Escherichiacoli strain with inactivated PTS. Libraries of artificial regulatory parts, including promoter and messengerRNA stabilizing region (mRS), were firstly constructed in front of β-galactosidase gene (lacZ) in E. colichromosome through λ-Red recombination. Most regulatory parts selected from mRS library hadconstitutive strengths under different cultivation conditions. A convenient one-step recombination methodwas then used to modulate galP and glk gene expression with different regulatory parts. Glucoseutilization rates of strains modulated with either galP or glk all increased, and the rates had a positiverelation with expression strength of both genes. Combinatorial modulation had a synergistic effect onglucose utilization rate. The highest rate (1.64 g/L h) was tenfold higher than PTS− strain and 39%higher than the wild-type E. coli. These modulated strains could be used for efficient anaerobic productionof succinate and malate.", "metadata": {}}
+{"_id": "15286783", "title": "", "text": "Matrix eQTL: Ultra fast eQTL analysis via large matrix operationsExpression quantitative trait loci (eQTL)mapping aims to determine genomic regions that regulate gene transcription. Expression QTL is used tostudy the regulatory structure of normal tissues and to search for genetic factors in complex diseasessuch as cancer, diabetes, and cystic fibrosis. A modern eQTL dataset contains millions of SNPs andthousands of transcripts measured for hundreds of samples. This makes the analysis computationallycomplex as it involves independent testing for association for every transcript-SNP pair. The heavycomputational burden makes eQTL analysis less popular, often forces analysts to restrict their attentionto just a subset of transcripts and SNPs. As larger genotype and gene expression datasets becomeavailable, the demand for fast tools for eQTL analysis increases. We present a new method for fast eQTLanalysis via linear models, called Matrix eQTL. Matrix eQTL can model and test for association using bothlinear regression and ANOVA models. The models can include covariates to account for such factors aspopulation structure, gender, and clinical variables. It also supports testing of heteroscedastic models andmodels with correlated errors. In our experiment on large datasets Matrix eQTL was thousands of timesfaster than the existing popular software for QTL/eQTL analysis. Matrix eQTL is implemented as bothMatlab and R packages and thus can easily be run on Windows, Mac OS, and Linux systems. The softwareis freely available at the following address:http://www.bios.unc.edu/research/genomic_software/Matrix_eQTL", "metadata": {}}
+{"_id": "15305881", "title": "", "text": "The structure of DdrB from Deinococcus: a new fold for single-stranded DNA binding proteinsDeinococcusspp. are renowned for their amazing ability to recover rapidly from severe genomic fragmentation as aresult of exposure to extreme levels of ionizing radiation or desiccation. Despite having been originallycharacterized over 50 years ago, the mechanism underlying this remarkable repair process is still poorlyunderstood. Here, we report the 2.8 A structure of DdrB, a single-stranded DNA (ssDNA) binding proteinunique to Deinococcus spp. that is crucial for recovery following DNA damage. DdrB forms a pentamericring capable of binding single-stranded but not double-stranded DNA. Unexpectedly, the crystal structurereveals that DdrB comprises a novel fold that is structurally and topologically distinct from all othersingle-stranded binding (SSB) proteins characterized to date. The need for a unique ssDNA bindingfunction in response to severe damage, suggests a distinct role for DdrB which may encompass not onlystandard SSB protein function in protection of ssDNA, but also more specialized roles in proteinrecruitment or DNA architecture maintenance. Possible mechanisms of DdrB action in damage recoveryare discussed.", "metadata": {}}
+{"_id": "15319019", "title": "", "text": "N348I in the Connection Domain of HIV-1 Reverse Transcriptase Confers Zidovudine and NevirapineResistanceBackground The catalytically active 66-kDa subunit of the human immunodeficiency virus type1 (HIV-1) reverse transcriptase (RT) consists of DNA polymerase, connection, and ribonuclease H (RNaseH) domains. Almost all known RT inhibitor resistance mutations identified to date map to the polymerasedomain of the enzyme. However, the connection and RNase H domains are not routinely analysed inclinical samples and none of the genotyping assays available for patient management sequence the entireRT coding region. The British Columbia Centre for Excellence in HIV/AIDS (the Centre) genotypes clinicalisolates up to codon 400 in RT, and our retrospective statistical analyses of the Centre’s database haveidentified an N348I mutation in the RT connection domain in treatment-experienced individuals. Theobjective of this multidisciplinary study was to establish the in vivo relevance of this mutation and its rolein drug resistance. Methods and Findings The prevalence of N348I in clinical isolates, the time taken for itto emerge under selective drug pressure, and its association with changes in viral load, specific drugtreatment, and known drug resistance mutations was analysed from genotypes, viral loads, andtreatment histories from the Centre’s database. N348I increased in prevalence from below 1% in 368treatmentnao ¨ve individuals to 12.1% in 1,009 treatment-experienced patients (p ¼ 7.7 3 10 \u0000 12 ).N348I appeared early in therapy and was highly associated with thymidine analogue mutations (TAMs)M41L and T215Y/F (p , 0.001), the lamivudine resistance mutations M184V/I (p , 0.001), andnon-nucleoside RTI (NNRTI) resistance mutations K103N and Y181C/I (p , 0.001). The association withTAMs and NNRTI resistance mutations was consistent with the selection of N348I in patients treated withregimens that included both zidovudine and nevirapine (odds ratio 2.62, 95% confidence interval1.43–4.81). The appearance of N348I was associated with a significant increase in viral load (p , 0.001),which was as large as the viral load increases observed for any of the TAMs. However, this analysis didnot account for the simultaneous selection of other RT or protease inhibitor resistance mutations on viralload. To delineate the role of this mutation in RT inhibitor resistance, N348I was introduced into HIV-1molecular clones containing different genetic backbones. N348I decreased zidovudine susceptibility 2- to4-fold in the context of wildtype HIV-1 or when combined with TAMs. N348I also decreased susceptibilityto nevirapine (7.4fold) and efavirenz (2.5-fold) and significantly potentiated resistance to these drugswhen combined with K103N. Biochemical analyses of recombinant RT containing N348I providesupporting evidence for the role of this mutation in zidovudine and NNRTI resistance and give someinsight into the molecular mechanism of resistance. Conclusions", "metadata": {}}
+{"_id": "15322518", "title": "", "text": "Dual Targeting of PDGFRα and FGFR1 Displays Synergistic Efficacy in Malignant RhabdoidTumorsSubunits of the SWI/SNF chromatin remodeling complex are mutated in a significant proportion ofhuman cancers. Malignant rhabdoid tumors (MRTs) are lethal pediatric cancers characterized by adeficiency in the SWI/SNF subunit SMARCB1. Here, we employ an integrated molecular profiling andchemical biology approach to demonstrate that the receptor tyrosine kinases (RTKs) PDGFRα and FGFR1are coactivated in MRT cells and that dual blockade of these receptors has synergistic efficacy. Inhibitorcombinations targeting both receptors and the dual inhibitor ponatinib suppress the AKT and ERK1/2pathways leading to apoptosis. MRT cells that have acquired resistance to the PDGFRα inhibitor pazopanibare susceptible to FGFR inhibitors. We show that PDGFRα levels are regulated by SMARCB1 expression,and assessment of clinical specimens documents the expression of both PDGFRα and FGFR1 in rhabdoidtumor patients. Our findings support a therapeutic approach in cancers with SWI/SNF deficiencies byexploiting RTK coactivation dependencies.", "metadata": {}}
+{"_id": "15327601", "title": "", "text": "A nano-positioning system for macromolecular structural analysisVery often, the positions of flexibledomains within macromolecules as well as within macromolecular complexes cannot be determined bystandard structural biology methods. To overcome this problem, we developed a method that usesprobabilistic data analysis to combine single-molecule measurements with X-ray crystallography data.The method determines not only the most likely position of a fluorescent dye molecule attached to thedomain but also the complete three-dimensional probability distribution depicting the experimentaluncertainty. With this approach, single-pair fluorescence resonance energy transfer measurements cannow be used as a quantitative tool for investigating the position and dynamics of flexible domains withinmacromolecular complexes. We applied this method to find the position of the 5′ end of the nascent RNAexiting transcription elongation complexes of yeast (Saccharomyces cerevisiae) RNA polymerase II andstudied the influence of transcription factor IIB on the position of the RNA.", "metadata": {}}
+{"_id": "15335331", "title": "", "text": "Tumor-associated macrophages correlate with the clinicopathological features and poor outcomes viainducing epithelial to mesenchymal transition in oral squamous cell carcinomaBACKGROUND Bothtumor-associated macrophages (TAMs) and the epithelial to mesenchymal transition (EMT) of cancer cellsplay key roles in promoting tumor progression. However, whether TAMs could induce EMT in theprogression of oral squamous cell carcinoma (OSCC) remains undefined. RESULTS Here we detected theexpression of macrophages markers CD68 and CD163, epithelial marker E-cadherin and mesenchymalmarker vimentin in 127 OSCC patients by using semi-quantitative immunohistochemistry. CD68 andCD163 expression was not confined to the infiltrating TAMs, but also detected in cancer cells. The highnumber of CD68-positive macrophages was correlated with poor overall survival. Meanwhile, theexpression of CD163 both in macrophages and in cancer cells was associated with poor overall survivaland had a significant prognostic impact in OSCC. Importantly, the expression of CD163 in cancer cellshad a significant relationship with E-cadherin and vimentin. Furthermore, the incubation of TAMsconditioned medium resulted in a fibroblast-like appearance of cancer cells (HN4, HN6 and SCC9)together with the decreased/increased expression of E-cadherin/ vimentin, which were correlated withthe enhanced ability of migration and invasion. CONCLUSIONS Our results indicate that TAMs couldpromote the EMT of cancer cells, thereby leading to the progression of oral cancer.", "metadata": {}}
+{"_id": "15337254", "title": "", "text": "Geometric cues for directing the differentiation of mesenchymal stem cells.Significant efforts have beendirected to understanding the factors that influence the lineage commitment of stem cells. This paperdemonstrates that cell shape, independent of soluble factors, has a strong influence on the differentiationof human mesenchymal stem cells (MSCs) from bone marrow. When exposed to competing solubledifferentiation signals, cells cultured in rectangles with increasing aspect ratio and in shapes withpentagonal symmetry but with different subcellular curvature-and with each occupying the samearea-display different adipogenesis and osteogenesis profiles. The results reveal that geometric featuresthat increase actomyosin contractility promote osteogenesis and are consistent with in vivocharacteristics of the microenvironment of the differentiated cells. Cytoskeletal-disruptingpharmacological agents modulate shape-based trends in lineage commitment verifying the critical role offocal adhesion and myosin-generated contractility during differentiation. Microarray analysis and pathwayinhibition studies suggest that contractile cells promote osteogenesis by enhancing c-Jun N-terminalkinase (JNK) and extracellular related kinase (ERK1/2) activation in conjunction with elevatedwingless-type (Wnt) signaling. Taken together, this work points to the role that geometric shape cues canplay in orchestrating the mechanochemical signals and paracrine/autocrine factors that can direct MSCsto appropriate fates.", "metadata": {}}
+{"_id": "15347087", "title": "", "text": "Amyloid accumulation is a late event in sporadic Alzheimer's disease-like pathology in nontransgenicratsThe amyloid cascade hypothesis posits that deposition of the amyloid β (Aβ) peptide in the brain is akey event in the initiation of Alzheimer's disease (AD). Nonetheless, it now seems increasingly unlikelythat amyloid toxicity is the cause of sporadic AD, which leads to cognitive decline. Here, usingaccelerated-senescence nontransgenic OXYS rats, we confirmed that aggregation of Aβ is a later event inAD-like pathology. We showed that an age-dependent increase in the levels of Aβ\u0000\u0000\u0000\u0000 andextracellular Aβ deposits in the brain of OXYS rats occur later than do synaptic losses, neuronal celldeath, mitochondrial structural abnormalities, and hyperphosphorylation of the tau protein. We identifiedthe variants of the genes that are strongly associated with the risk of either late-onset or early-onset AD,including App, Apoe4, Bace1, Psen1, Psen2, and Picalm. We found that in OXYS rats nonsynonymousSNPs were located only in the genes Casp3 and Sorl1. Thus, we present proof that OXYS rats may be amodel of sporadic AD. It is possible that multiple age-associated pathological processes may precede thetoxic amyloid accumulation, which in turn triggers the final stage of the sporadic form of AD and becomesa hallmark event of the disease.", "metadata": {}}
+{"_id": "15360986", "title": "", "text": "Estimating low-density lipoprotein cholesterol by the Friedewald equation is adequate for classifyingpatients on the basis of nationally recommended cutpoints.We compared low-density lipoproteincholesterol (LDL) values obtained by the Friedewald formula--i.e., total cholesterol minus high-densitylipoprotein (HDL) cholesterol minus very-low-density lipoprotein (VLDL) cholesterol (estimated astriglyceride divided by 5)--with those obtained by lipoprotein fractionation, using 4736 specimens. Whentriglycerides were less than 2.0 g/L, greater than 90% of estimated LDL cholesterol values wereacceptable, within +/- 10% of measured values. At triglyceride concentrations of 2.0-4.0 g/L and 4.0-6.0g/L, only 72% and 39%, respectively, of the estimates were acceptable. LDL values derived from analternative formula, estimating VLDL as triglycerides divided by 6, were even less accurate. Nevertheless,the use of estimated LDL for risk classification based on the National Cholesterol Education Program AdultTreatment Panel cutpoints of 1.30 and 1.60 g/L was considered acceptable. At triglyceride concentrationsless than or equal to 5.0 g/L, 88% of classifications based on estimated LDL (using triglycerides dividedby 5) were concordant with those by measured LDL. Eleven percent of classifications were shifted acrossone cutpoint, evenly distributed between high and low. Fewer than 1% of classifications, all with Type IIIhyperlipoproteinemia, were misclassified two cutpoints high. Refinements in the estimation model did notsubstantially improve LDL estimation or concordance of risk classification.", "metadata": {}}
+{"_id": "15365719", "title": "", "text": "Conditional Kif3a ablation causes abnormal hedgehog signaling topography, growth plate dysfunction,and excessive bone and cartilage formation during mouse skeletogenesis.The motor protein Kif3a andprimary cilia regulate important developmental processes, but their roles in skeletogenesis remainill-defined. Here we created mice deficient in Kif3a in cartilage and focused on the cranial base andsynchondroses. Kif3a deficiency caused cranial base growth retardation and dysmorphogenesis, whichwere evident in neonatal animals by anatomical and micro-computed tomography (microCT) inspection.Kif3a deficiency also changed synchondrosis growth plate organization and function, and the severity ofthese changes increased over time. By postnatal day (P)7, mutant growth plates lacked typical zones ofchondrocyte proliferation and hypertrophy, and were instead composed of chondrocytes with an unusualphenotype characterized by strong collagen II (Col2a1) gene expression but barely detectable expressionof Indian hedgehog (Ihh), collagen X (Col10a1), Vegf (Vegfa), MMP-13 (Mmp13) and osterix (Sp7).Concurrently, unexpected developmental events occurred in perichondrial tissues, including excessiveintramembranous ossification all along the perichondrial border and the formation of ectopic cartilagemasses. Looking for possible culprits for these latter processes, we analyzed hedgehog signallingtopography and intensity by monitoring the expression of the hedgehog effectors Patched 1 and Gli1, andof the hedgehog-binding cell-surface component syndecan 3. Compared with controls, hedgehogsignaling was quite feeble within mutant growth plates as early as P0, but was actually higher and waswidespread all along mutant perichondrial tissues. Lastly, we studied postnatal mice deficient in Ihh incartilage; their cranial base defects only minimally resembled those in Kif3a-deficient mice. In summary,Kif3a and primary cilia make unique contributions to cranial base development and synchondrosis growthplate function. Their deficiency causes abnormal topography of hedgehog signaling, growth platedysfunction, and un-physiologic responses and processes in perichondrial tissues, including ectopiccartilage formation and excessive intramembranous ossification.", "metadata": {}}
+{"_id": "15381976", "title": "", "text": "Morin Attenuates Ovalbumin-Induced Airway Inflammation by Modulating Oxidative Stress-ResponsiveMAPK Signaling.Asthma is one of the most common inflammatory diseases characterized by airwayhyperresponsiveness, inflammation, and remodeling. Morin, an active ingredient obtained from Moraceaeplants, has been demonstrated to have promising anti-inflammatory activities in a range of disorders.However, its impacts on pulmonary diseases, particularly on asthma, have not been clarified. This studywas designed to investigate whether morin alleviates airway inflammation in chronic asthma with anemphasis on oxidative stress modulation. In vivo, ovalbumin- (OVA-) sensitized mice were administeredwith morin or dexamethasone before challenge. Bronchoalveolar lavage fluid (BALF) and lung tissueswere obtained to perform cell counts, histological analysis, and enzyme-linked immunosorbent assay. Invitro, human bronchial epithelial cells (BECs) were challenged by tumor necrosis factor alpha (TNF-α).The supernatant was collected for the detection of the proinflammatory proteins, and the cells werecollected for reactive oxygen species (ROS)/mitogen-activated protein kinase (MAPK) evaluations. Severeinflammatory responses and remodeling were observed in the airways of the OVA-sensitized mice.Treatment with morin dramatically attenuated the extensive trafficking of inflammatory cells into theBALF and inhibited their infiltration around the respiratory tracts and vessels. Morin administration alsosignificantly suppressed goblet cell hyperplasia and collagen deposition/fibrosis and dose-dependentlyinhibited the OVA-induced increases in IgE, TNF-α, interleukin- (IL-) 4, IL-13, matrixmetalloproteinase-9, and malondialdehyde. In human BECs challenged by TNF-α, the levels of proteinssuch as eotaxin-1, monocyte chemoattractant protein-1, IL-8 and intercellular adhesion molecule-1, wereconsistently significantly decreased by morin. Western blotting and the 2',7'-dichlorofluorescein assayrevealed that the increases in intracellular ROS and MAPK phosphorylation were abolished by morin,implying that ROS/MAPK signaling contributes to the relief of airway inflammation. Our findings indicatefor the first time that morin alleviates airway inflammation in chronic asthma, which probably occurs viathe oxidative stress-responsive MAPK pathway, highlighting a novel profile of morin as a potent agent forasthma management.", "metadata": {}}
+{"_id": "15405204", "title": "", "text": "Spontaneous autoimmunity prevented by thymic expression of a single self-antigenThe expression ofself-antigen in the thymus is believed to be responsible for the deletion of autoreactive T lymphocytes, acritical process in the maintenance of unresponsiveness to self. The Autoimmune regulator (Aire) gene,which is defective in the disorder autoimmune polyglandular syndrome type 1, has been shown topromote the thymic expression of self-antigens. A clear link, however, between specific thymicself-antigens and a single autoimmune phenotype in this model has been lacking. We show thatautoimmune eye disease in aire-deficient mice develops as a result of loss of thymic expression of asingle eye antigen, interphotoreceptor retinoid-binding protein (IRBP). In addition, lack of IRBPexpression solely in the thymus, even in the presence of aire expression, is sufficient to triggerspontaneous eye-specific autoimmunity. These results suggest that failure of thymic expression ofselective single self-antigens can be sufficient to cause organ-specific autoimmune disease, even inotherwise self-tolerant individuals.", "metadata": {}}
+{"_id": "15414628", "title": "", "text": "Preventing bacterial DNA release and absent in melanoma 2 inflammasome activation by a Legionellaeffector functioning in membrane trafficking.Legionella pneumophila, the causative agent of Legionnaires'pneumonia, resides in a distinct vacuole structure called Legionella-containing vacuole (LCV). The LCVresists fusion with the lysosome and permits efficient bacterial replication in host macrophages, whichrequires a Dot/Icm type IVB secretion system. Dot/Icm-translocated effector SdhA is critical for L.pneumophila intracellular growth and functions to prevent host cell death. Here, we show that theabsence of SdhA resulted in elevated caspase-1 activation and IL-1β secretion as well as macrophagepyroptosis during Legionella infection. These inflammasome activation phenotypes were independent ofthe established flagellin-NAIP5-NLRC4 axis, but relied on the DNA-sensing AIM2 inflammasome. Wefurther demonstrate that Legionella DNA was released into macrophage cytosol, and this effect wassignificantly exaggerated by the absence of SdhA. SdhA bears a functional Golgi-targeting GRIP domainthat is required for preventing AIM2 inflammasome activation. Ectopically expressed SdhA formed aunique ring-shape membrane structure, further indicating a role in membrane trafficking and maintainingLCV membrane integrity. Our data together suggest a possible link, mediated by the function of SdhA,between LCV trafficking/maturation and suppression of host innate immune detection.", "metadata": {}}
+{"_id": "15419873", "title": "", "text": "Cytosolic viral sensor RIG-I is a 5'-triphosphate-dependent translocase on double-stranded RNA.Retinoicacid inducible-gene I (RIG-I) is a cytosolic multidomain protein that detects viral RNA and elicits anantiviral immune response. Two N-terminal caspase activation and recruitment domains (CARDs)transmit the signal, and the regulatory domain prevents signaling in the absence of viral RNA.5'-triphosphate and double-stranded RNA (dsRNA) are two molecular patterns that enable RIG-I todiscriminate pathogenic from self-RNA. However, the function of the DExH box helicase domain that isalso required for activity is less clear. Using single-molecule protein-induced fluorescence enhancement,we discovered a robust adenosine 5'-triphosphate-powered dsRNA translocation activity of RIG-I. TheCARDs dramatically suppress translocation in the absence of 5'-triphosphate, and the activation by5'-triphosphate triggers RIG-I to translocate preferentially on dsRNA in cis. This functional integration oftwo RNA molecular patterns may provide a means to specifically sense and counteract replicating viruses.", "metadata": {}}
+{"_id": "15425958", "title": "", "text": "Human Cytomegalovirus-Encoded Interleukin-10 Homolog Inhibits Maturation of Dendritic Cells andAlters Their FunctionalityInterleukin-10 (IL-10) suppresses the maturation and cytokine production ofdendritic cells (DCs), key regulators of adaptive immunity, and prevents the activation and polarization ofnaïve T cells towards protective gamma interferon-producing effectors. We hypothesized that humancytomegalovirus (HCMV) utilizes its viral IL-10 homolog (cmvIL-10) to attenuate DC functionality,thereby subverting the efficient induction of antiviral immune responses. RNA and protein analysesdemonstrated that the cmvIL-10 gene was expressed with late gene kinetics. Treatment of immature DCs(iDCs) with supernatant from HCMV-infected cultures inhibited both the lipopolysaccharide-induced DCmaturation and proinflammatory cytokine production. These inhibitory effects were specifically mediatedthrough the IL-10 receptor and were not observed when DCs were treated with supernatant of cellsinfected with a cmvIL-10-knockout mutant. Incubation of iDCs with recombinant cmvIL-10 recapitulatedthe inhibition of maturation. Furthermore, cmvIL-10 had pronounced long-term effects on those DCs thatcould overcome this inhibition of maturation. It enhanced the migration of mature DCs (mDCs) towardsthe lymph node homing chemokine but greatly reduced their cytokine production. The inability of mDCsto secrete IL-12 was maintained, even when they were restimulated by the activated T-cell signal CD40ligand in the absence of cmvIL-10. Importantly, cmvIL-10 potentiates these anti-inflammatory effects, atleast partially, by inducing endogenous cellular IL-10 expression in DCs. Collectively, we show thatcmvIL-10 causes long-term functional alterations at all stages of DC activation.", "metadata": {}}
+{"_id": "15426878", "title": "", "text": "Model for unidirectional movement of axonemal and cytoplasmic dynein moleculesA model for theunidirectional movement of dynein is presented based on structural observations and biochemicalexperimental results available. In this model, the binding affinity of dynein for microtubule is independentof its nucleotide state and the change between strong and weak microtubule-binding is determinednaturally by the variation of relative orientation between the stalk and microtubule as the stalk rotatesfollowing nucleotide-state transition. Thus the enigmatic communication from the ATP binding site in theglobular domain to the far MT-binding site in the tip of the stalk, which is prerequisite in conventionalmodels, is not required. Using the present model, the previous experimental results such as the effect ofATP and ADP bindings on dissociation of dynein from microtubule, the processive movement ofsingle-headed axonemal dyneins at saturating ATP concentration, the load dependence of step size forthe processive movement of two-headed cytoplasmic dyneins and the dependence of stall force on ATPconcentration can be well explained.", "metadata": {}}
+{"_id": "15435343", "title": "", "text": "The inflammasome component NLRP3 impairs antitumor vaccine by enhancing the accumulation oftumor-associated myeloid-derived suppressor cells.The inflammasome is a proteolysis complex thatgenerates the active forms of the proinflammatory cytokines interleukin (IL)-1β and IL-18.Inflammasome activation is mediated by NLR proteins that respond to microbial and nonmicrobial stimuli.Among NLRs, NLRP3 senses the widest array of stimuli and enhances adaptive immunity. However, itsrole in antitumor immunity is unknown. Therefore, we evaluated the function of the NLRP3 inflammasomein the immune response using dendritic cell vaccination against the poorly immunogenic melanoma cellline B16-F10. Vaccination of Nlrp3(-/-) mice led to a relative 4-fold improvement in survival relative tocontrol animals. Immunity depended on CD8(+) T cells and exhibited immune specificity and memory.Increased vaccine efficacy in Nlrp3(-/-) hosts did not reflect differences in dendritic cells but ratherdifferences in myeloid-derived suppressor cells (MDSC). Although Nlrp3 was expressed in MDSCs, theabsence of Nlrp3 did not alter either their functional capacity to inhibit T cells or their presence inperipheral lymphoid tissues. Instead, the absence of Nlrp3 caused a 5-fold reduction in the number oftumor-associated MDSCs found in host mice. Adoptive transfer experiments also showed that Nlrp3(-/-)MDSCs were less efficient in reaching the tumor site. Depleting MDSCs with an anti-Gr-1 antibodyincreased the survival of tumor-bearing wild-type mice but not Nlrp3(-/-) mice. We concluded that Nlrp3was critical for accumulation of MDSCs in tumors and for inhibition of antitumor T-cell immunity afterdendritic cell vaccination. Our findings establish an unexpected role for Nlrp3 in impeding antitumorimmune responses, suggesting novel approaches to improve the response to antitumor vaccines bylimiting Nlrp3 signaling.", "metadata": {}}
+{"_id": "15462523", "title": "", "text": "Natural Killer Cells for Immunotherapy – Advantages of the NK-92 Cell Line over Blood NK CellsNaturalkiller (NK) cells are potent cytotoxic effector cells for cancer therapy and potentially for severe viralinfections. However, there are technical challenges to obtain sufficient numbers of functionally active NKcells from a patient's blood since they represent only 10% of the lymphocytes and are oftendysfunctional. The alternative is to obtain cells from a healthy donor, which requires depletion of theallogeneic T cells to prevent graft-versus-host reactions. Cytotoxic cell lines have been established frompatients with clonal NK-cell lymphoma. Those cells can be expanded in culture in the presence of IL-2.Except for the NK-92 cell line, though, none of the other six known NK cell lines has consistently andreproducibly shown high antitumor cytotoxicity. Only NK-92 cells can easily be genetically manipulated torecognize specific tumor antigens or to augment monoclonal antibody activity throughantibody-dependent cellular cytotoxicity. NK-92 is also the only cell line product that has been infusedinto patients with advanced cancer with clinical benefit and minimal side effects.", "metadata": {}}
+{"_id": "15472716", "title": "", "text": "Differential activation of DNA-PK based on DNA strand orientation and sequence biasDNA-PKcs and Kuare essential components of the complex that catalyzes non-homologous end joining (NHEJ) of DNAdouble-strand breaks (DSBs). Ku, a heterodimeric protein, binds to DNA ends and facilitates recruitmentof the catalytic subunit, DNA-PKcs. We have investigated the effect of DNA strand orientation andsequence bias on the activation of DNA-PK. In addition, we assessed the effect of the position and strandorientation of cisplatin adducts on kinase activation. A series of duplex DNA substrates with site-specificcisplatin–DNA adducts placed in three different orientations on the duplex DNA were prepared. Terminalbiotin modification and streptavidin (SA) blocking was employed to direct DNA-PK binding to theunblocked termini with a specific DNA strand orientation and cisplatin–DNA adduct position. DNA-PKkinase activity was measured and the results reveal that DNA strand orientation and sequence biasdramatically influence kinase activation, only a portion of which could be attributed to Ku-DNA bindingactivity. In addition, cisplatin–DNA adduct position resulted in differing degrees of inhibition depending ondistance from the terminus as well as strand orientation. These results highlight the importance of howlocal variations in DNA structure, chemistry and sequence influence DNA-PK activation and potentiallyNHEJ.", "metadata": {}}
+{"_id": "15473205", "title": "", "text": "Regulators of Trypanosoma brucei Cell Cycle Progression and Differentiation Identified Using aKinome-Wide RNAi ScreenThe African trypanosome, Trypanosoma brucei, maintains an integral linkbetween cell cycle regulation and differentiation during its intricate life cycle. Whilst extensive changes inphosphorylation have been documented between the mammalian bloodstream form and the insectprocyclic form, relatively little is known about the parasite's protein kinases (PKs) involved in the controlof cellular proliferation and differentiation. To address this, a T. brucei kinome-wide RNAi cell line librarywas generated, allowing independent inducible knockdown of each of the parasite's 190 predicted proteinkinases. Screening of this library using a cell viability assay identified ≥42 PKs that are required fornormal bloodstream form proliferation in culture. A secondary screen identified 24 PKs whoseRNAi-mediated depletion resulted in a variety of cell cycle defects including in G1/S, kinetoplastreplication/segregation, mitosis and cytokinesis, 15 of which are novel cell cycle regulators. A furtherscreen identified for the first time two PKs, named repressor of differentiation kinase (RDK1 and RDK2),depletion of which promoted bloodstream to procyclic form differentiation. RDK1 is amembrane-associated STE11-like PK, whilst RDK2 is a NEK PK that is essential for parasite proliferation.RDK1 acts in conjunction with the PTP1/PIP39 phosphatase cascade to block uncontrolled bloodstream toprocyclic form differentiation, whilst RDK2 is a PK whose depletion efficiently induces differentiation in theabsence of known triggers. Thus, the RNAi kinome library provides a valuable asset for functional analysisof cell signalling pathways in African trypanosomes as well as drug target identification and validation.", "metadata": {}}
+{"_id": "15476777", "title": "", "text": "Chemotherapy options in elderly and frail patients with metastatic colorectal cancer (MRC FOCUS2): anopen-label, randomised factorial trialBACKGROUND Elderly and frail patients with cancer, although oftentreated with chemotherapy, are under-represented in clinical trials. We designed FOCUS2 to investigatereduced-dose chemotherapy options and to seek objective predictors of outcome in frail patients withadvanced colorectal cancer. METHODS We undertook an open, 2 × 2 factorial trial in 61 UK centres forpatients with previously untreated advanced colorectal cancer who were considered unfit for full-dosechemotherapy. After comprehensive health assessment (CHA), patients were randomly assigned byminimisation to: 48-h intravenous fluorouracil with levofolinate (group A); oxaliplatin and fluorouracil(group B); capecitabine (group C); or oxaliplatin and capecitabine (group D). Treatment allocation wasnot masked. Starting doses were 80% of standard doses, with discretionary escalation to full dose after 6weeks. The two primary outcome measures were: addition of oxaliplatin ([A vs B] + [C vs D]), assessedwith progression-free survival (PFS); and substitution of fluorouracil with capecitabine ([A vs C] + [B vsD]), assessed by change from baseline to 12 weeks in global quality of life (QoL). Analysis was byintention to treat. Baseline clinical and CHA data were modelled against outcomes with a novel compositemeasure, overall treatment utility (OTU). This study is registered, number ISRCTN21221452. FINDINGS459 patients were randomly assigned (115 to each of groups A-C, 114 to group D). Factorial comparisonof addition of oxaliplatin versus no addition suggested some improvement in PFS, but the finding was notsignificant (median 5·8 months [IQR 3·3-7·5] vs 4·5 months [2·8-6·4]; hazard ratio 0·84, 95% CI0·69-1·01, p=0·07). Replacement of fluorouracil with capecitabine did not improve global QoL: 69 of 124(56%) patients receiving fluorouracil reported improvement in global QoL compared with 69 of 123(56%) receiving capecitabine. The risk of having any grade 3 or worse toxic effect was not significantlyincreased with oxaliplatin (83/219 [38%] vs 70/221 [32%]; p=0·17), but was higher with capecitabinethan with fluorouracil (88/222 [40%] vs 65/218 [30%]; p=0·03). In multivariable analysis, fewerbaseline symptoms (odds ratio 1·32, 95% CI 1·14-1·52), less widespread disease (1·51, 1·05-2·19), anduse of oxaliplatin (0·57, 0·39-0·82) were predictive of better OTU. INTERPRETATION FOCUS2 shows thatwith an appropriate design, including reduced starting doses of chemotherapy, frail and elderly patientscan participate in a randomised controlled trial. On balance, a combination including oxaliplatin waspreferable to single-agent fluoropyrimidines, although the primary endpoint of PFS was not met.Capecitabine did not improve QoL compared with fluorouracil. Comprehensive baseline assessment holdspromise as an objective predictor of treatment benefit. FUNDING Cancer Research UK and the MedicalResearch Council.", "metadata": {}}
+{"_id": "15478227", "title": "", "text": "Whole-genome sequencing of Oryza brachyantha reveals mechanisms underlying Oryza genomeevolutionThe wild species of the genus Oryza contain a largely untapped reservoir of agronomicallyimportant genes for rice improvement. Here we report the 261-Mb de novo assembled genome sequenceof Oryza brachyantha. Low activity of long-terminal repeat retrotransposons and massive internaldeletions of ancient long-terminal repeat elements lead to the compact genome of Oryza brachyantha.We model 32,038 protein-coding genes in the Oryza brachyantha genome, of which only 70% are locatedin collinear positions in comparison with the rice genome. Analysing breakpoints of non-collinear genessuggests that double-strand break repair through non-homologous end joining has an important role ingene movement and erosion of collinearity in the Oryza genomes. Transition of euchromatin toheterochromatin in the rice genome is accompanied by segmental and tandem duplications, furtherexpanded by transposable element insertions. The high-quality reference genome sequence of Oryzabrachyantha provides an important resource for functional and evolutionary studies in the genus Oryza.", "metadata": {}}
+{"_id": "15482274", "title": "", "text": "Ultrasound imaging for lumbar punctures and epidural catheterisations: systematic review andmeta-analysis.OBJECTIVE To determine whether ultrasound imaging can reduce the risk of failed lumbarpunctures or epidural catheterisations, when compared with standard palpation methods, and whetherultrasound imaging can reduce traumatic procedures, insertion attempts, and needle redirections.DESIGN Systematic review and meta-analysis of randomised controlled trials. DATA SOURCES OvidMedline, Embase, and Cochrane Central Register of Controlled Trials up to May 2012, without restrictionby language or publication status. REVIEW METHODS Randomised trials that compared ultrasoundimaging with standard methods (no imaging) in the performance of a lumbar puncture or epiduralcatheterisation were identified. RESULTS 14 studies with a total of 1334 patients were included (674patients assigned to the ultrasound group, 660 to the control group). Five studies evaluated lumbarpunctures and nine evaluated epidural catheterisations. Six of 624 procedures conducted in theultrasound group failed; 44 of 610 procedures in the control group failed. Ultrasound imaging reduced therisk of failed procedures (risk ratio 0.21 (95% confidence interval 0.10 to 0.43), P<0.001). Risk reductionwas similar when subgroup analysis was performed for lumbar punctures (risk ratio 0.19 (0.07 to 0.56),P=0.002) or epidural catheterisations (0.23 (0.09 to 0.60), P=0.003). Ultrasound imaging alsosignificantly reduced the risk of traumatic procedures (risk ratio 0.27 (0.11 to 0.67), P=0.005), thenumber of insertion attempts (mean difference -0.44 (-0.64 to -0.24), P<0.001), and the number ofneedle redirections (mean difference -1.00 (-1.24 to -0.75), P<0.001). CONCLUSIONS Ultrasoundimaging can reduce the risk of failed or traumatic lumbar punctures and epidural catheterisations, as wellas the number of needle insertions and redirections. Ultrasound may be a useful adjunct for theseprocedures.", "metadata": {}}
+{"_id": "15488881", "title": "", "text": "Guidance of B cells by the orphan G protein-coupled receptor EBI2 shapes humoral immuneresponses.Humoral immunity depends on both rapid and long-term antibody production against invadingpathogens. This is achieved by the generation of spatially distinct extrafollicular plasmablast and folliculargerminal center (GC) B cell populations, but the signals that guide responding B cells to these alternativecompartments have not been fully elucidated. Here, we show that expression of the orphan Gprotein-coupled receptor Epstein-Barr virus-induced gene 2 (EBI2, also known as GPR183) by activated Bcells was essential for their movement to extrafollicular sites and induction of early plasmablastresponses. Conversely, downregulation of EBI2 enabled B cells to access the center of follicles andpromoted efficient GC formation. EBI2 therefore provides a previously uncharacterized dimension to Bcell migration that is crucial for coordinating rapid versus long-term antibody responses.", "metadata": {}}
+{"_id": "15491308", "title": "", "text": "SIRT1 is required for long-term growth of human mesenchymal stem cellsHuman mesenchymal stemcells (MSCs) have therapeutic potential because of their ability to self-renew and differentiate intomultiple tissues. However, senescence often occurs in MSCs when they are cultured in vitro and themolecular mechanisms underlying this effect remain unclear. In this study, we found that NAD-dependentprotein deacetylase SIRT1 is differentially expressed in both human bone marrow-derived MSCs(B-MSCs) and adipose tissue-derived MSCs after increasing passages of cell culture. Using lentiviralshRNA we demonstrated that selective knockdown of SIRT1 in human MSCs at early passage slows downcell growth and accelerates cellular senescence. Conversely, overexpression of SIRT1 delays senescencein B-MSCs that have undergone prolonged in vitro culturing and the cells do not lose adipogenic andosteogenic potential. In addition, we found that the delayed accumulation of the protein p16 is involved inthe effect of SIRT1. However, resveratrol, which has been used as an activator of SIRT1 deacetylaseactivity, only transiently promotes proliferation of B-MSCs. Our findings will help us understand the roleof SIRT1 in the aging of normal diploid cells and may contribute to the prevention of human MSCssenescence thus benefiting MSCs-based tissue engineering and therapies.", "metadata": {}}
+{"_id": "15491404", "title": "", "text": "Rapid and persistent modulation of actin dynamics regulates postsynaptic reorganization underlyingbidirectional plasticityThe synapse is a highly organized cellular specialization whose structure andcomposition are reorganized, both positively and negatively, depending on the strength of input signals.The mechanisms orchestrating these changes are not well understood. A plausible locus for thereorganization of synapse components and structure is actin, because it serves as both cytoskeleton andscaffold for synapses and exists in a dynamic equilibrium between F-actin and G-actin that is modulatedbidirectionally by cellular signaling. Using a new FRET-based imaging technique to monitorF-actin/G-actin equilibrium, we show here that tetanic stimulation causes a rapid, persistent shift of actinequilibrium toward F-actin in the dendritic spines of rat hippocampal neurons. This enlarges the spinesand increases postsynaptic binding capacity. In contrast, prolonged low-frequency stimulation shifts theequilibrium toward G-actin, resulting in a loss of postsynaptic actin and of structure. This bidirectionalregulation of actin is actively involved in protein assembly and disassembly and provides a substrate forbidirectional synaptic plasticity.", "metadata": {}}
+{"_id": "15493354", "title": "", "text": "Sublime Microglia: Expanding Roles for the Guardians of the CNSRecent findings challenge the conceptthat microglia solely function in disease states in the central nervous system (CNS). Rather than simplyreacting to CNS injury, infection, or pathology, emerging lines of evidence indicate that microglia sculptthe structure of the CNS, refine neuronal circuitry and network connectivity, and contribute to plasticity.These physiological functions of microglia in the normal CNS begin during development and persist intomaturity. Here, we develop a conceptual framework for functions of microglia beyond neuroinflammationand discuss the rich repertoire of signaling and communication motifs in microglia that are critical both inpathology and for the normal physiology of the CNS.", "metadata": {}}
+{"_id": "15512462", "title": "", "text": "Cancer after pre-eclampsia: follow up of the Jerusalem perinatal study cohort.OBJECTIVE To compare theincidence of cancer among women with and without a history of pre-eclampsia. DESIGN Cohort study.SETTING Jerusalem perinatal study of women who delivered in three large hospitals in West Jerusalemduring 1964-76. PARTICIPANTS 37 033 women. MAIN OUTCOME MEASURES Age adjusted andmultivariable adjusted hazard ratios for cancer incidence for the entire cohort and for women who wereprimiparous at study entry. RESULTS Cancer developed in 91 women who had pre-eclampsia and 2204who did not (hazard ratio 1.27, 95% confidence interval 1.03 to 1.57). The risk of site specific cancerswas increased, particularly of the stomach, ovary epithelium, breast, and lung or larynx. The incidence ofcancer of the stomach, breast, ovary, kidney, and lung or larynx was increased in primiparous women atstudy entry who had a history pre-eclampsia. CONCLUSIONS A history of pre-eclampsia is associatedwith increases in overall risk of cancer and incidence at several sites. This may be explained byenvironmental and genetic factors common to the development of pre-eclampsia and cancer in thispopulation.", "metadata": {}}
+{"_id": "15521377", "title": "", "text": "Keeping your senescent cells under controlCellular senescence is a stable form of cell-cycle arrest whichis thought to limit the proliferative potential of premalignant cells [1]. The senescence phenotype wasinitially described by Hayflick and Moorhead in 1961 on human fibroblasts undergoing replicativeexhaustion in culture [2]. It has been shown that senescence can be triggered in different cell types inresponse to diverse forms of cellular damage or stress (for review see [1]). Importantly, whilesenescence was denounced as a tissue culture phenomenon for many years, recent in vivo studiesdemonstrated that cellular senescence represents a potent failsafe mechanism against tumorigenesis andcontributes to the cytotoxicity of certain anticancer agents (see for example [3-7]). Interestingly,senescent cells have also been observed in certain aged or damaged tissues and there is growingevidence that senescence checkpoints can affect the regenerative reserve of tissues and organismal aging[8-11]. However, senescence may also have positive effects on organ maintenance by limitingpathological responses to acute forms of injury such as fibrotic scarring in response to chemical inducedliver injury [12]. Over the past years it was also shown that senescent cells can communicate with theirenvironment by secreting a myriad of cytokines and growth factors. Interestingly, this \"senescenceassociated secretory phenotype (SASP)\" seems to be a double edged sword regarding tumor initiationand maintenance:    i)    On the one hand, it has been shown that the SASP can have pro-tumorigeniceffects. In an experimental system it was shown that senescent mesenchymal cells can enhance thetumorigenicity of surrounding breast cancer cells [13]. ii)    Similarly, it is possible that the SASPenhances selection of transformed cell clones in aged organ systems. It has been shown that loss ofproliferative competition of non-transformed cells can accelerate leukemogenesis [14]. It remains to beseen whether aberrant secretion of cytokines and growth factors by the SASP can accelerated thisprocess in aged and chronically damage organ systems. iii)    In contrast to its pro-tumorigenic aspect,the SASP could also have anti-tumor effects. A recent study showed that in a mosaic liver cancer mousemodel the activation of p53 induced senescence, an upregulation of inflammatory cytokines, andactivation of innate immune responses leading to tumour cell clearance [15]. iv)    In further support thatthe SASP could have anti-tumor activities, a series of recent papers showed that components of the SASPcan stabilize the senescence cell cycle arrest via an autoregulatory feedback loop [16,17] or inducesapoptosis of tumor cells [18]. In addition to its effects on tumorigenesis, the SASP could also influencetissue aging. Studies on aging telomere dysfunctional mice have provided direct experimental evidencefor an in vivo activation of the SASP in response to telomere dysfunction [19]. Interestingly, this in vivoSASP provoked alterations in stem cell differentiation (skewing of hematopoiesis towards reduction inlymphopoiesis and enhancement of myelopoiesis) that are also characteristic signs of human aging.Figure 1. Different cellular stresses can induce senescence including telomere shortening, DNA damage,and oncogene activation. Senescence of tumor cells ... In light of the many possible roles o the SASP inaging and carcinogenesis, it appears to be of utmost importance to decipher regulatory pathwayscontrolling the SASP. In a current publication, Bhaumik et al. have identified 2 microRNAs (miR-146a/b)that negatively regulate the secretion of IL-6 and IL-8 - two of the SASP [20]. The authors show thatthese microRNAs are up-regulated at late stages of senescence, many days after a permanent cell cyclearrest has been established. Interestingly, the inhibitory miRs are most strongly up-regulated insenescence of cell lines that show a strong SASP but not in cell lines characterized by a weak SASP. Theauthors propose a new concept indicating that miRs 146a and b function in a negative feedback looppreventing an over-activation of the SASP in senescent cells. The authors present some initial datasuggesting that activation of this negative feedback loop involves IL-1 receptor, IRAK-1, and NFκBsignalling leading to an up-regulation of miRs-146a and b. A direct proof that this proposed feedback loopsuppresses over-activation of the SASP remains to be demonstrated in future studies. The authors showthat blockage of IL-1-receptor signalling prevents both the up-regulation of miRs-146a and b as well asIl-6 secretion. To confirm their new concept, it would be important to show that a selective blockage ofmiRs-146a and b results in over-activation of the SASP. The work by Bhaumik et al. places mir-146a/b as", "metadata": {}}
+{"_id": "15535511", "title": "", "text": "Role for insulin signaling in catecholaminergic neurons in control of energy homeostasis.Dopaminergicmidbrain neurons integrate signals on food palatability and food-associated reward into the complexcontrol of energy homeostasis. To define the role of insulin receptor (IR) signaling in this circuitry, weinactivated IR signaling in tyrosine hydroxylase (Th)-expressing cells of mice (IR(ΔTh)). IR inactivation inTh-expressing cells of mice resulted in increased body weight, increased fat mass, and hyperphagia.While insulin acutely stimulated firing frequency in 50% of dopaminergic VTA/SN neurons, this responsewas abolished in IR(ΔTh) mice. Moreover, these mice exhibited an altered response to cocaine underfood-restricted conditions. Taken together, these data provide in vivo evidence for a critical role of insulinsignaling in catecholaminergic neurons to control food intake and energy homeostasis.", "metadata": {}}
+{"_id": "15541119", "title": "", "text": "[New guidelines to evaluate the response to treatment in solid tumors].Anticancer agents go through aprocess by which their antitumor activity, on the basis of the amount of tumor shrinkage they couldgenerate, has been investigated. In the late 1970s, the International Union Against Cancer and the WorldHealth Organization (WHO) introduced specific criteria for the codification of tumor response evaluation.In 1994, several organizations involved in clinical cancer research joined together to undertake thereview of these response evaluation criteria on the basis of their experience and knowledge. After severalyears of intensive discussions, new guidelines are ready and will replace the previous WHO criteria. Inparallel to this initiative, one of the participating groups developed a model by which response rates couldbe derived from unidimensional measurement of tumor lesions instead of the usual bidimensionalapproach. This new concept has been largely validated by the Response Evaluation Criteria in SolidTumors (Recist) Group and integrated into the present guidelines. This special article provides somephilosophic background to clarify the various purposes of response evaluation. It proposes a model bywhich a combined assessment of all existing lesions, characterized by target lesion (to be measured) andnontarget lesions, is used to extrapolate an overall response to treatment. Methods of assessing tumorlesions are better codified. All other aspects of response evaluation have been discussed, reviewed, andamended whenever suitable.", "metadata": {}}
+{"_id": "15548965", "title": "", "text": "Structural Rearrangements of NR1/NR2A NMDA Receptors during Allosteric InhibitionIonotropicglutamate receptor (iGluR) subunits contain a large N-terminal domain (NTD) that precedes theagonist-binding domain (ABD) and participates in subunit oligomerization. In NMDA receptors (NMDARs),the NTDs of NR2A and NR2B subunits also form binding sites for the endogenous inhibitor Zn(2+) ion.Although these allosteric sites have been characterized in detail, the molecular mechanisms by which theNTDs communicate with the rest of the receptor to promote its inhibition remain unknown. Here, weidentify the ABD dimer interface as a major structural determinant that permits coupling between theNTDs and the channel gate. The strength of this interface also controls proton inhibition, another form ofallosteric modulation of NMDARs. Conformational rearrangements at the ABD dimer interface thus appearto be a key mechanism conserved in all iGluR subfamilies, but have evolved to fulfill different functions:fast desensitization at AMPA and kainate receptors, allosteric inhibition at NMDARs.", "metadata": {}}
+{"_id": "15551129", "title": "", "text": "The role of iron in Mycobacterium smegmatis biofilm formation: the exochelin siderophore is essential inlimiting iron conditions for biofilm formation but not for planktonic growthMany species of mycobacteriaform structured biofilm communities at liquid–air interfaces and on solid surfaces. Full development ofMycobacterium smegmatis biofilms requires addition of supplemental iron above 1 μM ferrous sulphate,although addition of iron is not needed for planktonic growth. Microarray analysis of the M. smegmatistranscriptome shows that iron-responsive genes – especially those involved in siderophore synthesis andiron uptake – are strongly induced during biofilm formation reflecting a response to iron deprivation, evenwhen 2 μM iron is present. The acquisition of iron under these conditions is specifically dependent on theexochelin synthesis and uptake pathways, and the strong defect of an iron–exochelin uptake mutantsuggests a regulatory role of iron in the transition to biofilm growth. In contrast, although the expressionof mycobactin and iron ABC transport operons is highly upregulated during biofilm formation, mutants inthese systems form normal biofilms in low-iron (2 μM) conditions. A close correlation between ironavailability and matrix-associated fatty acids implies a possible metabolic role in the late stages of biofilmmaturation, in addition to the early regulatory role. M. smegmatis surface motility is similarly dependenton iron availability, requiring both supplemental iron and the exochelin pathway to acquire it.", "metadata": {}}
+{"_id": "15559582", "title": "", "text": "Plasma lipids and prolactin in patients with breast cancer.In a comparative study of pre- andpostmenopausal women with benign and malignant breast disease, a number of differences wereobserved in circulating plasma prolactin and lipid concentrations. Plasma lipids, phospholipids,triglycerides, cholesterol and free fatty acids were all higher in blood obtained from breast cancer patientsprior to surgery. HDL-Cholesterol levels were significantly lower in these patients. These differencesremained when the patient groups were sub-divided according to menopausal status. Plasma prolactinconcentrations were also found to be higher in cancer compared with non-cancer patients, this effectbeing more marked in premenopausal than in postmenopausal patients. Premenopausal patients withinvasive or poorly differentiated disease had significantly higher prolactin levels than those withnon-invasive disease. No correlations were found between plasma prolactin and any of the lipid fractions.", "metadata": {}}
+{"_id": "15561961", "title": "", "text": "expression by oxidized linoleicHypercholesterolemia is associated with impairments inendothelium-dependent vascular relaxations. Paradoxically, endothelial production of nitrogen oxides isincreased in early stages of hypercholesterolemia. Prior work has shown that oxidized low densitylipoprotein (LDL) has both stimulatory and inhibitory effects on endothelial nitric oxide synthaseexpression (eNOS) and has focused on lysophosphatidyl choline (LPC) as a component of oxidized LDLwhich may modulate this effect. Another biologically active component of oxidized LDL is13-hydroperoxyoctadecadienoic acid (13-HPODE), an oxidized form of linoleic acid. The purpose of thisstudy was to determine the effect of HPODE on the expression of eNOS in bovine aortic endothelial cells(BAECs). Twenty four hour treatment of endothelial cells with HPODE caused a dose-dependent increasein eNOS mRNA levels as assessed by Northern analysis. The time response studies show that HPODEtreatment significantly increased eNOS mRNA levels at 12 and 24 h. Concomitant with the increase ineNOS mRNA levels, 20 microM HPODE treatment significantly increased eNOS protein content andenzyme activity. Nuclear run-on studies indicated that the rate of transcription of eNOS gene wassignificantly elevated 4 h after HPODE treatment when compared to control cultures. Also, actinomycin Dstudies demonstrated that the half-life of eNOS mRNA was increased from 6 h to 12 h by HPODEtreatment. Thus, HPODE-induced up-regulation of eNOS expression is mediated by both transcriptionaland posttranscriptional mechanisms. These observations suggest that endothelial cells may attempt tocompensate for oxidative injury by increasing expression of eNOS in early stages ofhypercholesterolemia.", "metadata": {}}
+{"_id": "15563864", "title": "", "text": "Specific killing of multiple myeloma cells by (-)-epigallocatechin-3-gallate extracted from green tea:biologic activity and therapeutic implications.Epigallocatechin-3-gallate (EGCG), a polyphenol extractedfrom green tea, is an antioxidant with chemopreventive and chemotherapeutic actions. Based on itsability to modulate growth factor-mediated cell proliferation, we evaluated its efficacy in multiplemyeloma (MM). EGCG induced both dose- and time-dependent growth arrest and subsequent apoptoticcell death in MM cell lines including IL-6-dependent cells and primary patient cells, without significanteffect on the growth of peripheral blood mononuclear cells (PBMCs) and normal fibroblasts. Treatmentwith EGCG also led to significant apoptosis in human myeloma cells grown as tumors in SCID mice. EGCGinteracts with the 67-kDa laminin receptor 1 (LR1), which is significantly elevated in myeloma cell linesand patient samples relative to normal PBMCs. RNAi-mediated inhibition of LR1 resulted in abrogation ofEGCG-induced apoptosis in myeloma cells, indicating that LR1 plays an important role in mediating EGCGactivity in MM while sparing PBMCs. Evaluation of changes in gene expression profile indicates that EGCGtreatment activates distinct pathways of growth arrest and apoptosis in MM cells by inducing theexpression of death-associated protein kinase 2, the initiators and mediators of deathreceptor-dependent apoptosis (Fas ligand, Fas, and caspase 4), p53-like proteins (p73, p63), positiveregulators of apoptosis and NF-kappaB activation (CARD10, CARD14), and cyclin-dependent kinaseinhibitors (p16 and p18). Expression of related genes at the protein level were also confirmed by Westernblot analysis. These data demonstrate potent and specific antimyeloma activity of EGCG and provide therationale for its clinical evaluation.", "metadata": {}}
+{"_id": "15570691", "title": "", "text": "Pharmacologic inhibition of cyclin-dependent kinases 4 and 6 arrests the growth of glioblastomamultiforme intracranial xenografts.Activation of cyclin-dependent kinases 4 and 6 (cdk4/6) occurs in themajority of glioblastoma multiforme (GBM) tumors, and represents a promising molecular target for thedevelopment of small molecule inhibitors. In the current study, we investigated the moleculardeterminants and in vivo response of diverse GBM cell lines and xenografts to PD-0332991, acdk4/6-specific inhibitor. In vitro testing of PD-0332991 against a panel of GBM cell lines revealed apotent G(1) cell cycle arrest and induction of senescence in each of 16 retinoblastoma protein(Rb)-proficient cell lines regardless of other genetic lesions, whereas 5 cell lines with homozygousinactivation of Rb were completely resistant to treatment. Short hairpin RNA depletion of Rb expressionconferred resistance of GBM cells to PD-0332991, further demonstrating a requirement of Rb forsensitivity to cdk4/6 inhibition. PD-0332991 was found to efficiently cross the blood-brain barrier andproved highly effective in suppressing the growth of intracranial GBM xenograft tumors, including thosethat had recurred after initial therapy with temozolomide. Remarkably, no mice receiving PD-0332991died as a result of disease progression while on therapy. Additionally, the combination of PD-0332991and radiation therapy resulted in significantly increased survival benefit compared with either therapyalone. In total, our results support clinical trial evaluation of PD-0332991 against newly diagnosed as wellas recurrent GBM, and indicate that Rb status is the primary determinant of potential benefit from thistherapy.", "metadata": {}}
+{"_id": "15570962", "title": "", "text": "Choosing Haplotype-Tagging SNPS Based on Unphased Genotype Data Using a Preliminary Sample ofUnrelated Subjects with an Example from the Multiethnic Cohort StudyWe describe an approach forpicking haplotype-tagging single nucleotide polymorphisms (htSNPs) that is presently being taken in twolarge nested case-control studies within a multiethnic cohort (MEC), which are engaged in a search forassociations between risk of prostate and breast cancer and common genetic variations in candidategenes. Based on a preliminary sample of 70 control subjects chosen at random from each of the 5 ethnicgroups in the MEC we estimate haplotype frequencies using a variant of the Excoffier-Slatkin E-Malgorithm after genotyping a high density of SNPs selected every 3–5 kb in and surrounding a candidategene. In order to evaluate the performance of a candidate set of htSNPS (which will be genotyped in themuch larger case-control sample) we treat the haplotype frequencies estimate above as known, and carryout a formal calculation of the uncertainty of the number of copies of common haplotypes carried by anindividual, summarizing this calculation as a coefficient of determination, R2h. A candidate set of htSNPSof a given size is chosen so as to maximize the minimum value of R2h over the common haplotypes, h.", "metadata": {}}
+{"_id": "15578265", "title": "", "text": "A model for the role of gut bacteria in the development of autoimmunity for type 1 diabetesSeveral linesof evidence suggest a role for the gut microbiome in type 1 diabetes. Treating diabetes-prone rodentswith probiotics or antibiotics prevents the development of the disorder. Diabetes-prone rodents also havea distinctly different gut microbiome compared with healthy rodents. Recent studies in children with ahigh genetic risk for type 1 diabetes demonstrate significant differences in the gut microbiome betweenchildren who develop autoimmunity for the disease and those who remain healthy. However, thedifferences in microbiome composition between autoimmune and healthy children are not consistentacross all studies because of the strong environmental influences on microbiome composition, particularlydiet and geography. Controlling confounding factors of microbiome composition uncovers bacterialassociations with disease. For example, in a human cohort from a single Finnish city where geography isconfined, a strong association between one dominant bacterial species, Bacteroides dorei, and type 1diabetes was discovered (Davis-Richardson et al. Front Microbiol 2014;5:678). Beyond this, recent DNAmethylation analyses suggest that a thorough epigenetic analysis of the gut microbiome may bewarranted. These studies suggest a testable model whereby a diet high in fat and gluten and low inresistant starch may be the primary driver of gut dysbiosis. This dysbiosis may cause a lack of butyrateproduction by gut bacteria, which, in turn, leads to the development of a permeable gut followed byautoimmunity. The bacterial community responsible for these changes in butyrate production may varyaround the world, but bacteria of the genus Bacteroides are thought to play a key role.", "metadata": {}}
+{"_id": "15588516", "title": "", "text": "METHODS AND RESULTSCytoscape is an open source software project for integrating biomolecularinteraction networks with high-throughput expression data and other molecular states into a unifiedconceptual framework. Although applicable to any system of molecular components and interactions,Cytoscape is most powerful when used in conjunction with large databases of protein-protein,protein-DNA, and genetic interactions that are increasingly available for humans and model organisms.Cytoscape's software Core provides basic functionality to layout and query the network; to visuallyintegrate the network with expression profiles, phenotypes, and other molecular states; and to link thenetwork to databases of functional annotations. The Core is extensible through a straightforward plug-inarchitecture, allowing rapid development of additional computational analyses and features. Several casestudies of Cytoscape plug-ins are surveyed, including a search for interaction pathways correlating withchanges in gene expression, a study of protein complexes involved in cellular recovery to DNA damage,inference of a combined physical/functional interaction network for Halobacterium, and an interface todetailed stochastic/kinetic gene regulatory models.", "metadata": {}}
+{"_id": "15590539", "title": "", "text": "Dual Regulation of miRNA Biogenesis Generates Target Specificity in Neurotrophin-Induced ProteinSynthesisControl of translation is a fundamental source of regulation in gene expression. The induction ofprotein synthesis by brain-derived neurotrophic factor (BDNF) critically contributes to enduringmodifications of synaptic function, but how BDNF selectively affects only a minority of expressed mRNAsis poorly understood. We report that BDNF rapidly elevates Dicer, increasing mature miRNA levels andinducing RNA processing bodies in neurons. BDNF also rapidly induces Lin28, causing selective loss ofLin28-regulated miRNAs and a corresponding upregulation in translation of their target mRNAs. Bindingsites for Lin28-regulated miRNAs are necessary and sufficient to confer BDNF responsiveness to atranscript. Lin28 deficiency, or expression of a Lin28-resistant Let-7 precursor miRNA, inhibits BDNFtranslation specificity and BDNF-dependent dendrite arborization. Our data establish that specificity inBDNF-regulated translation depends upon a two-part posttranscriptional control of miRNA biogenesis thatgenerally enhances mRNA repression in association with GW182 while selectively derepressing andincreasing translation of specific mRNAs.", "metadata": {}}
+{"_id": "15593561", "title": "", "text": "A Viral microRNA Cluster Strongly Potentiates the Transforming Properties of a HumanHerpesvirusEpstein-Barr virus (EBV), an oncogenic human herpesvirus, induces cell proliferation afterinfection of resting B lymphocytes, its reservoir in vivo. The viral latent proteins are necessary forpermanent B cell growth, but it is unknown whether they are sufficient. EBV was recently found to encodemicroRNAs (miRNAs) that are expressed in infected B cells and in some EBV-associated lymphomas. EBVmiRNAs are grouped into two clusters located either adjacent to the BHRF1 gene or in introns containedwithin the viral BART transcripts. To understand the role of the BHRF1 miRNA cluster, we haveconstructed a virus mutant that lacks all its three members (Δ123) and a revertant virus. Here we showthat the B cell transforming capacity of the Δ123 EBV mutant is reduced by more than 20-fold, relative towild type or revertant viruses. B cells exposed to the knock-out virus displayed slower growth, andexhibited a two-fold reduction in the percentage of cells entering the cell cycle S phase. Furthermore,they displayed higher latent gene expression levels and latent protein production than their wild typecounterparts. Therefore, the BHRF1 miRNAs accelerate B cell expansion at lower latent gene expressionlevels. Thus, this miRNA cluster simultaneously enhances expansion of the virus reservoir and reducesthe viral antigenic load, two features that have the potential to facilitate persistence of the virus in theinfected host. Thus, the EBV BHRF1 miRNAs may represent new therapeutic targets for the treatment ofsome EBV-associated lymphomas.", "metadata": {}}
+{"_id": "15600979", "title": "", "text": "EMSY overexpression disrupts the BRCA2/RAD51 pathway in the DNA-damage response: implications forchromosomal instability/recombination syndromes as checkpoint diseasesEMSY links the BRCA2 pathwayto sporadic breast/ovarian cancer. It encodes a nuclear protein that binds to the BRCA2 N-terminaldomain implicated in chromatin/transcription regulation, but when sporadically amplified/overexpressed,increased EMSY level represses BRCA2 transactivation potential and induces chromosomal instability,mimicking the activity of BRCA2 mutations in the development of hereditary breast/ovarian cancer. Inaddition to chromatin/transcription regulation, EMSY may also play a role in the DNA-damage response,suggested by its ability to localize at chromatin sites of DNA damage/repair. This implies that EMSYoverexpression may also repress BRCA2 in DNA-damage replication/checkpoint and recombination/repair,coordinated processes that also require its interacting proteins: PALB2, the partner and localizer ofBRCA2; RPA, replication/checkpoint protein A; and RAD51, the inseparable recombination/repair enzyme.Here, using a well-characterized recombination/repair assay system, we demonstrate that a slightincrease in EMSY level can indeed repress these two processes independently of transcriptionalinterference/repression. Since EMSY, RPA and PALB2 all bind to the same BRCA2 region, these findingsfurther support a scenario wherein: (a) EMSY amplification may mimic BRCA2 deficiency, at least byoverriding RPA and PALB2, crippling the BRCA2/RAD51 complex at DNA-damage andreplication/transcription sites; and (b) BRCA2/RAD51 may coordinate these processes by employing atleast EMSY, PALB2 and RPA. We extensively discuss the molecular details of how this can happen toascertain its implications for a novel recombination mechanism apparently conceived as checkpoint ratherthan a DNA repair system for cell division, survival, death, and human diseases, including the tissuespecificity of cancer predisposition, which may renew our thinking about targeted therapy and prevention.", "metadata": {}}
+{"_id": "15615957", "title": "", "text": "Original ArticleUNLABELLED Fruit and vegetable consumption has been inversely associated with the riskof chronic diseases including cancer and cardiovascular disease, with the beneficial effects attributed to avariety of protective antioxidants, carotenoids and phytonutrients. The objective of the present study wasto determine the effect of supplementation with dehydrated concentrates from mixed fruit and vegetablejuices (Juice Plus+R) on serum antioxidant and folate status, plasma homocysteine levels and markersfor oxidative stress and DNA damage. Japanese subjects (n=60; age 27.8 yrs; BMI 22.1) were recruitedto participate in a double-blind placebo controlled study and were randomized into 2 groups of 30,matched for sex, age, BMI and smoking status (39 males, 22 smokers; 21 females, 13 smokers).Subjects were given encapsulated supplements containing mixed fruit and vegetable juice concentratesor a matching placebo for 28 days, with blood and urine samples collected at baseline, day 14 and day 28for analytical testing. Compared with the placebo, 28 day supplementation significantly increased theconcentration of serum beta-carotene 528% (p<0.0001), lycopene 80.2% (p<0.0005), and alphatocopherol 39.5% (p<0.0001). Serum folate increased 174.3% (p<0.0001) and correlated with adecrease in plasma homocysteine of -19.9% (p<0.03). Compared with baseline, measures of oxidativestress decreased with serum lipid peroxides declining -10.5% (p<0.02) and urine 8OHdG decreasing-21.1% (p<0.02). Evaluation of data from smokers only (n=17) after 28 days of active supplementationshowed comparable changes. CONCLUSION In the absence of dietary modification, supplementation withthe fruit and vegetable juice concentrate capsules proved to be a highly bioavailable source ofphytonutrients. Important antioxidants were elevated to desirable levels associated with decreased risk ofdisease while markers of oxidative stress were reduced, and folate status improved with a concomitantdecrease in homocysteine, and these benefits occurred to a similar extent in smokers when compared tonon-smokers.", "metadata": {}}
+{"_id": "15617300", "title": "", "text": "NCBI GEO: archive for functional genomics data sets—updateThe Gene Expression Omnibus (GEO,http://www.ncbi.nlm.nih.gov/geo/) is an international public repository for high-throughput microarrayand next-generation sequence functional genomic data sets submitted by the research community. Theresource supports archiving of raw data, processed data and metadata which are indexed, cross-linkedand searchable. All data are freely available for download in a variety of formats. GEO also providesseveral web-based tools and strategies to assist users to query, analyse and visualize data. This articlereports current status and recent database developments, including the release of GEO2R, an R-basedweb application that helps users analyse GEO data.", "metadata": {}}
+{"_id": "15617866", "title": "", "text": "Viral Paratransgenesis in the Malaria Vector Anopheles gambiaeParatransgenesis, the geneticmanipulation of insect symbiotic microorganisms, is being considered as a potential method to controlvector-borne diseases such as malaria. The feasibility of paratransgenic malaria control has beenhampered by the lack of candidate symbiotic microorganisms for the major vector Anopheles gambiae. Inother systems, densonucleosis viruses (DNVs) are attractive agents for viral paratransgenesis becausethey infect important vector insects, can be genetically manipulated and are transmitted to subsequentgenerations. However, An. gambiae has been shown to be refractory to DNV dissemination. Wediscovered, cloned and characterized the first known DNV (AgDNV) capable of infection and disseminationin An. gambiae. We developed a flexible AgDNV-based expression vector to express any gene of interestin An. gambiae using a two-plasmid helper-transducer system. To demonstrate proof-of-concept of theviral paratransgenesis strategy, we used this system to transduce expression of an exogenous gene(enhanced green fluorescent protein; EGFP) in An. gambiae mosquitoes. Wild-type and EGFP-transducingAgDNV virions were highly infectious to An. gambiae larvae, disseminated to and expressed EGFP inepidemiologically relevant adult tissues such as midgut, fat body and ovaries and were transmitted tosubsequent mosquito generations. These proof-of-principle data suggest that AgDNV could be used aspart of a paratransgenic malaria control strategy by transduction of anti-Plasmodium peptides orinsect-specific toxins in Anopheles mosquitoes. AgDNV will also be extremely valuable as an effective andeasy-to-use laboratory tool for transient gene expression or RNAi in An. gambiae.", "metadata": {}}
+{"_id": "15635366", "title": "", "text": "The polycomb group protein L3mbtl2 assembles an atypical PRC1-family complex that is essential inpluripotent stem cells and early development.L3mbtl2 has been implicated in transcriptional repressionand chromatin compaction but its biological function has not been defined. Here we show that disruptionof L3mbtl2 results in embryonic lethality with failure of gastrulation. This correlates with compromisedproliferation and abnormal differentiation of L3mbtl2(-/-) embryonic stem (ES) cells. L3mbtl2 regulatesgenes by recruiting a Polycomb Repressive Complex1 (PRC1)-related complex, resembling the previouslydescribed E2F6-complex, and including G9A, Hdac1, and Ring1b. The presence of L3mbtl2 at targetgenes is associated with H3K9 dimethylation, low histone acetylation, and H2AK119 ubiquitination, butthe latter is neither dependent on L3mbtl2 nor sufficient for repression. Genome-wide studies revealedthat the L3mbtl2-dependent complex predominantly regulates genes not bound by canonical PRC1 andPRC2. However, some developmental regulators are repressed by the combined activity of all threecomplexes. Together, we have uncovered a highly selective, essential role for an atypical PRC1-familycomplex in ES cells and early development.", "metadata": {}}
+{"_id": "15648443", "title": "", "text": "Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from theCAPP2 randomised controlled trialBACKGROUND Observational studies report reduced colorectal cancer inregular aspirin consumers. Randomised controlled trials have shown reduced risk of adenomas but nonehave employed prevention of colorectal cancer as a primary endpoint. The CAPP2 trial aimed toinvestigate the antineoplastic effects of aspirin and a resistant starch in carriers of Lynch syndrome, themajor form of hereditary colorectal cancer; we now report long-term follow-up of participants randomlyassigned to aspirin or placebo. METHODS In the CAPP2 randomised trial, carriers of Lynch syndrome wererandomly assigned in a two-by-two factorial design to 600 mg aspirin or aspirin placebo or 30 g resistantstarch or starch placebo, for up to 4 years. Randomisation was in blocks of 16 with provision for optionalsingle-agent randomisation and extended postintervention double-blind follow-up; participants andinvestigators were masked to treatment allocation. The primary endpoint was development of colorectalcancer. Analysis was by intention to treat and per protocol. This trial is registered, ISRCTN59521990.RESULTS 861 participants were randomly assigned to aspirin or aspirin placebo. At a mean follow-up of55·7 months, 48 participants had developed 53 primary colorectal cancers (18 of 427 randomly assignedto aspirin, 30 of 434 to aspirin placebo). Intention-to-treat analysis of time to first colorectal cancershowed a hazard ratio (HR) of 0·63 (95% CI 0·35-1·13, p=0·12). Poisson regression taking account ofmultiple primary events gave an incidence rate ratio (IRR) of 0·56 (95% CI 0·32-0·99, p=0·05). Forparticipants completing 2 years of intervention (258 aspirin, 250 aspirin placebo), per-protocol analysisyielded an HR of 0·41 (0·19-0·86, p=0·02) and an IRR of 0·37 (0·18-0·78, p=0·008). No data for adverseevents were available postintervention; during the intervention, adverse events did not differ betweenaspirin and placebo groups. INTERPRETATION 600 mg aspirin per day for a mean of 25 monthssubstantially reduced cancer incidence after 55·7 months in carriers of hereditary colorectal cancer.Further studies are needed to establish the optimum dose and duration of aspirin treatment. FUNDINGEuropean Union; Cancer Research UK; Bayer Corporation; National Starch and Chemical Co; UK MedicalResearch Council; Newcastle Hospitals trustees; Cancer Council of Victoria Australia; THRIPP SouthAfrica; The Finnish Cancer Foundation; SIAK Switzerland; Bayer Pharma.", "metadata": {}}
+{"_id": "15655418", "title": "", "text": "Drosophila CPEB Orb2A Mediates Memory Independent of Its RNA-Binding DomainLong-term memoryand synaptic plasticity are thought to require the synthesis of new proteins at activated synapses. TheCPEB family of RNA binding proteins, including Drosophila Orb2, has been implicated in this process. Theprecise mechanism by which these molecules regulate memory formation is however poorly understood.We used gene targeting and site-specific transgenesis to specifically modify the endogenous orb2 gene inorder to investigate its role in long-term memory formation. We show that the Orb2A and Orb2Bisoforms, while both essential, have distinct functions in memory formation. These two isoforms havecommon glutamine-rich and RNA-binding domains, yet Orb2A uniquely requires the former and Orb2Bthe latter. We further show that Orb2A induces Orb2 complexes in a manner dependent upon both itsglutamine-rich region and neuronal activity. We propose that Orb2B acts as a conventional CPEB toregulate transport and/or translation of specific mRNAs, whereas Orb2A acts in an unconventionalmanner to form stable Orb2 complexes that are essential for memory to persist.", "metadata": {}}
+{"_id": "15657779", "title": "", "text": "Functional hemichannels in astrocytes: a novel mechanism of glutamate release.Little is known about theexpression and possible functions of unopposed gap junction hemichannels in the brain. Emergingevidence suggests that gap junction hemichannels can act as stand-alone functional channels inastrocytes. With immunocytochemistry, dye uptake, and HPLC measurements, we show that astrocytes invitro express functional hemichannels that can mediate robust efflux of glutamate and aspartate.Functional hemichannels were confirmed by passage of extracellular lucifer yellow (LY) into astrocytes innominal divalent cation-free solution (DCFS) and the ability to block this passage with gap junctionblocking agents. Glutamate/aspartate release (or LY loading) in DCFS was blocked by multivalent cations(Ca2+, Ba2+, Sr2+, Mg2+, and La3+) and by gap junction blocking agents (carbenoxolone, octanol,heptanol, flufenamic acid, and 18alpha-glycyrrhetinic acid) with affinities close to those reported forblockade of gap junction intercellular communication. Glutamate efflux via hemichannels was alsoaccompanied by greatly reduced glutamate uptake. Glutamate release in DCFS, however, was notsignificantly mediated by reversal of the glutamate transporter: release did not saturate and was notblocked by glutamate transporter blockers. Control experiments in DCFS precluded glutamate release byvolume-sensitive anion channels, P2X7 purinergic receptor pores, or general purinergic receptoractivation. Blocking intracellular Ca2+ mobilization by BAPTA-AM or thapsigargin did not inhibit glutamaterelease in DCFS. Divalent cation removal also induced glutamate release from intact CNS white matter(acutely isolated optic nerve) that was blocked by carbenoxolone, suggesting the existence of functionalhemichannels in situ. Our results indicated that astrocyte hemichannels could influence CNS levels ofextracellular glutamate with implications for normal and pathological brain function.", "metadata": {}}
+{"_id": "15659108", "title": "", "text": "Human Rad52 binds and wraps single-stranded DNA and mediates annealing via two hRad52–ssDNAcomplexesRad52 promotes the annealing of complementary strands of DNA bound by replication proteinA (RPA) during discrete repair pathways. Here, we used a fluorescence resonance energy transfer (FRET)between two fluorescent dyes incorporated into DNA substrates to probe the mechanism by which humanRad52 (hRad52) interacts with and mediates annealing of ssDNA-hRPA complexes. Human Rad52 boundssDNA or ssDNA-hRPA complex in two, concentration-dependent modes. At low hRad52 concentrations,ssDNA was wrapped around the circumference of the protein ring, while at higher protein concentrations,ssDNA was stretched between multiple hRad52 rings. Annealing by hRad52 occurred most efficientlywhen each complementary DNA strand or each ssDNA-hRPA complex was bound by hRad52 in a wrappedconfiguration, suggesting homology search and annealing occur via two hRad52-ssDNA complexes. Incontrast to the wild type protein, hRad52(RQK/AAA) and hRad52(1-212) mutants with impaired ability tobind hRPA protein competed with hRPA for binding to ssDNA and failed to counteract hRPA-mediatedduplex destabilization highlighting the importance of hRad52-hRPA interactions in promoting efficientDNA annealing.", "metadata": {}}
+{"_id": "15663829", "title": "", "text": "Mendelian Randomization Study of B-Type Natriuretic Peptide and Type 2 Diabetes: Evidence of CausalAssociation from Population StudiesBACKGROUND Genetic and epidemiological evidence suggests aninverse association between B-type natriuretic peptide (BNP) levels in blood and risk of type 2 diabetes(T2D), but the prospective association of BNP with T2D is uncertain, and it is unclear whether theassociation is confounded. METHODS AND FINDINGS We analysed the association between levels of theN-terminal fragment of pro-BNP (NT-pro-BNP) in blood and risk of incident T2D in a prospectivecase-cohort study and genotyped the variant rs198389 within the BNP locus in three T2D case-controlstudies. We combined our results with existing data in a meta-analysis of 11 case-control studies. Using aMendelian randomization approach, we compared the observed association between rs198389 and T2D tothat expected from the NT-pro-BNP level to T2D association and the NT-pro-BNP difference per C allele ofrs198389. In participants of our case-cohort study who were free of T2D and cardiovascular disease atbaseline, we observed a 21% (95% CI 3%-36%) decreased risk of incident T2D per one standarddeviation (SD) higher log-transformed NT-pro-BNP levels in analysis adjusted for age, sex, body massindex, systolic blood pressure, smoking, family history of T2D, history of hypertension, and levels oftriglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol. The associationbetween rs198389 and T2D observed in case-control studies (odds ratio = 0.94 per C allele, 95% CI0.91-0.97) was similar to that expected (0.96, 0.93-0.98) based on the pooled estimate for thelog-NT-pro-BNP level to T2D association derived from a meta-analysis of our study and published data(hazard ratio = 0.82 per SD, 0.74-0.90) and the difference in NT-pro-BNP levels (0.22 SD, 0.15-0.29) perC allele of rs198389. No significant associations were observed between the rs198389 genotype andpotential confounders. CONCLUSIONS Our results provide evidence for a potential causal role of the BNPsystem in the aetiology of T2D. Further studies are needed to investigate the mechanisms underlying thisassociation and possibilities for preventive interventions. Please see later in the article for the Editors'Summary.", "metadata": {}}
+{"_id": "15669393", "title": "", "text": "brain organizationTransient activation of estrogen receptors (ER) in the developing brain during a limitedperinatal \"window of time\" is recognized as a key mechanism of defeminization of neural control ofreproductive function and sexual behavior. Two major ER isoforms, alpha and beta, are present in neuralcircuits that govern ovarian cycle and sexual behavior. Using highly selective ER agonists, this studyprovides the first evidence for distinct contribution of individual ER isoforms to the process of estrogendependent defeminization. Neonatal activation of the ERalpha in female rats resulted in abrogation ofcyclic ovarian activity and female sexual behavior in adulthood. These effects are associated withmale-like alterations in the morphology of the anteroventral periventricular (AVPV) and sexuallydimorphic nucleus of the preoptic area (SDN-POA), as well as refractoriness to estrogen-mediatedinduction of sexual receptivity. Exposure to an ERbeta-selective agonist induced persistent estrus and hada strong defeminizing effect on the hypothalamic gonadotropin \"surge generator\" AVPV. However,neonatal ERbeta activation failed to alter female sexual behavior, responsiveness to estrogens andmorphometric features of the behaviorally relevant SDN-POA. Thus, although co-present in several brainregions involved in the control of female reproductive function, ER isoforms convey different, andprobably not synergistic, chemical signals in the course of neonatal sex-specific brain organization.", "metadata": {}}
+{"_id": "15670968", "title": "", "text": "Thresholds for the cost–effectiveness of interventions: alternative approachesMany countries use thecost-effectiveness thresholds recommended by the World Health Organization's Choosing Interventionsthat are Cost-Effective project (WHO-CHOICE) when evaluating health interventions. This project sets thethreshold for cost-effectiveness as the cost of the intervention per disability-adjusted life-year (DALY)averted less than three times the country's annual gross domestic product (GDP) per capita. Highlycost-effective interventions are defined as meeting a threshold per DALY averted of once the annual GDPper capita. We argue that reliance on these thresholds reduces the value of cost-effectiveness analysesand makes such analyses too blunt to be useful for most decision-making in the field of public health. Useof these thresholds has little theoretical justification, skirts the difficult but necessary ranking of therelative values of locally-applicable interventions and omits any consideration of what is truly affordable.The WHO-CHOICE thresholds set such a low bar for cost-effectiveness that very few interventions withevidence of efficacy can be ruled out. The thresholds have little value in assessing the trade-offs thatdecision-makers must confront. We present alternative approaches for applying cost-effectiveness criteriato choices in the allocation of health-care resources.", "metadata": {}}
+{"_id": "15678772", "title": "", "text": "Effect of low doses of ionising radiation in infancy on cognitive function in adulthood: Swedish populationbased cohort study.OBJECTIVE To determine whether exposure to low doses of ionising radiation ininfancy affects cognitive function in adulthood. DESIGN Population based cohort study. SETTING Sweden.PARTICIPANTS 3094 men who had received radiation for cutaneous haemangioma before age 18 monthsduring 1930-59. MAIN OUTCOME MEASURES Radiation dose to frontal and posterior parts of the brain,and association between dose and intellectual capacity at age 18 or 19 years based on cognitive tests(learning ability, logical reasoning, spatial recognition) and high school attendance. RESULTS Theproportion of boys who attended high school decreased with increasing doses of radiation to both thefrontal and the posterior parts of the brain from about 32% among those not exposed to around 17% inthose who received > 250 mGy. For the frontal dose, the multivariate odds ratio was 0.47 (95%confidence interval 0.26 to 0.85, P for trend 0.0003) and for the posterior dose it was 0.59 (0.23 to 1.47,0.0005). A negative dose-response relation was also evident for the three cognitive tests for learningability and logical reasoning but not for the test of spatial recognition. CONCLUSIONS Low doses ofionising radiation to the brain in infancy influence cognitive abilities in adulthood.", "metadata": {}}
+{"_id": "15685921", "title": "", "text": "Differential effects of charybdotoxin on the activity of retinal ganglion cells in the dark- and light-adaptedmouse retinaPatch-clamp recordings were made from retinal ganglion cells in the mouse retina. Underdark adaptation, blockage of BK(Ca) channels increases the spontaneous excitatory postsynaptic currents(EPSCs) and light-evoked On-EPSCs, while it decreases the light-evoked Off inhibitory postsynapticcurrents (IPSCs). However, under light adaptation it decreases the light-evoked On-EPSCs, thespontaneous IPSCs and the light-evoked On- and Off-IPSCs. Blockage of BK(Ca) channels significantlyaltered the outputs of RGCs by changing their light-evoked responses into a bursting pattern andincreasing the light-evoked depolarization of the membrane potentials, while it did not significantlychange the peak firing rates of light-evoked responses.", "metadata": {}}
+{"_id": "15692098", "title": "", "text": "Hutchinson-Gilford progeria syndrome: review of the phenotypeHutchinson-Gilford progeria syndrome(HGPS) is a rare but well known entity characterized by extreme short stature, low body weight, earlyloss of hair, lipodystrophy, scleroderma, decreased joint mobility, osteolysis, and facial features thatresemble aged persons. Cardiovascular compromise leads to early demise. Cognitive development isnormal. Data on 10 of our own cases and 132 cases from literature are presented. The incidence in thelast century in the Netherlands was 1:4,000,000. Sex ratio was 1.2:1. Main first symptoms were failureto thrive (55%), hair loss (40%), skin problems (28%), and lipodystrophy (20%). Mean age at diagnosiswas 2.9 years. Growth in weight was more disturbed than growth in height, and growth delay startedalready prenatally. Mean height > 13 years was 109.0 cm, mean weight was 14.5 kg. Osteolysis waswide-spread but not expressed, except in the viscerocranium, and remained limited to membranousformed bone. Lipodystrophy is generalized, only intra-abdominal fat depositions remain present.Cardiovascular problems are extremely variable, both in age of onset and nature. Stroke and coronarydysfunctioning are most frequent. Pathologic findings in coronaries and aorta resemble sometimes thefindings in elderly persons, but can also be much more limited. Loss of smooth muscle cells seems themost important finding. Mean age of demise was 12.6 years. Patients can be subdivided in patients withclassical HGPS, which follows an autosomal dominant pattern of inheritance, (almost) all casesrepresenting spontaneous mutations, and in non-classical progeria, in whom growth can be less retarded,scalp hair remains present for a longer time, lipodystrophy is more slowly progressive, osteolysis is moreexpressed except in the face, and survival well into adulthood is not uncommon. Pattern of inheritance ofnon-classical progeria is most probably autosomal recessive. The cause of HGPS is an abnormally formedLamin A, either directly by a mutated LMNA gene, or through abnormal posttranslational processing(ZMPSTE24 gene mutations). Of 34 LMNA mutations found in progeria patients, there were 26 classical p.G608G mutations (76%). Pathogenesis is most likely to follow several different pathways. Potentialtherapeutic strategies are developed along these lines and include RNA interference techniques andinhibition of the dominant-negative influence of abnormally formed Lamin A on polymerization withnormally formed Lamin A.", "metadata": {}}
+{"_id": "15707049", "title": "", "text": "Identification of an autoantigen demonstrates a link between interstitial lung disease and a defect incentral tolerance.Interstitial lung disease (ILD) is a common manifestation of systemic autoimmunitycharacterized by progressive inflammation or scarring of the lungs. Patients who develop thesecomplications can exhibit significantly impaired gas exchange that may result in hypoxemia, pulmonaryhypertension, and even death. Unfortunately, little is understood about how these diseases arise,including the role of specific defects in immune tolerance. Another key question is whether autoimmuneresponses targeting the lung parenchyma are critical to ILD pathogenesis, including that of isolatedidiopathic forms. We show that a specific defect in central tolerance brought about by mutations in theautoimmune regulator gene (Aire) leads to an autoreactive T cell response to a lung antigen namedvomeromodulin and the development of ILD. We found that a human patient and mice with defects inAire develop similar lung pathology, demonstrating that the AIRE-deficient model of autoimmunity is asuitable translational system in which to unravel fundamental mechanisms of ILD pathogenesis.", "metadata": {}}
+{"_id": "15716328", "title": "", "text": "In vivo role of ER-associated peptidase activity in tailoring peptides for presentation by MHC class Ia andclass Ib moleculesEndoplasmic reticulum (ER)-associated aminopeptidase (ERAP)1 has been implicated inthe final proteolytic processing of peptides presented by major histocompatibility complex (MHC) class Imolecules. To evaluate the in vivo role of ERAP1, we have generated ERAP1-deficient mice. Cell surfaceexpression of the class Ia molecules H-2Kb and H-2Db and of the class Ib molecule Qa-2 was significantlyreduced in these animals. Although cells from mutant animals exhibited reduced capacity to presentseveral self- and foreign antigens to Kb-, Db-, or Qa-1b–restricted CD8+ cytotoxic T cells, presentation ofsome antigens was unaffected or significantly enhanced. Consistent with these findings, mice generateddefective CD8+ T cell responses against class I–presented antigens. These findings reveal an important invivo role of ER-associated peptidase activity in tailoring peptides for presentation by MHC class Ia andclass Ib molecules.", "metadata": {}}
+{"_id": "15721252", "title": "", "text": "PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminalestrogen receptor-positive human breast cancer cell lines in vitroINTRODUCTION Alterations in cell cycleregulators have been implicated in human malignancies including breast cancer. PD 0332991 is an orallyactive, highly selective inhibitor of the cyclin D kinases (CDK)4 and CDK6 with ability to blockretinoblastoma (Rb) phosphorylation in the low nanomolar range. To identify predictors of response, wedetermined the in vitro sensitivity to PD 0332991 across a panel of molecularly characterized humanbreast cancer cell lines. METHODS Forty-seven human breast cancer and immortalized cell linesrepresenting the known molecular subgroups of breast cancer were treated with PD 0332991 todetermine IC50 values. These data were analyzed against baseline gene expression data to identifygenes associated with PD 0332991 response. RESULTS Cell lines representing luminal estrogenreceptor-positive (ER+) subtype (including those that are HER2 amplified) were most sensitive to growthinhibition by PD 0332991 while nonluminal/basal subtypes were most resistant. Analysis of varianceidentified 450 differentially expressed genes between sensitive and resistant cells. pRb and cyclin D1were elevated and CDKN2A (p16) was decreased in the most sensitive lines. Cell cycle analysis showedG0/G1 arrest in sensitive cell lines and Western blot analysis demonstrated that Rb phosphorylation isblocked in sensitive lines but not resistant lines. PD 0332991 was synergistic with tamoxifen andtrastuzumab in ER+ and HER2-amplified cell lines, respectively. PD 0332991 enhanced sensitivity totamoxifen in cell lines with conditioned resistance to ER blockade. CONCLUSIONS These studies suggest arole for CDK4/6 inhibition in some breast cancers and identify criteria for patient selection in clinicalstudies of PD 0332991", "metadata": {}}
+{"_id": "15727984", "title": "", "text": "Identification of secreted proteins that mediate cell-cell interactions in an in vitro model of the lungcancer microenvironment.Non-small cell lung cancer (NSCLC) cells with somatic mutations in K-rasrecruit to the tumor a variety of cell types (hereafter collectively termed \"stromal cells\") that can promoteor inhibit tumorigenesis by mechanisms that have not been fully elucidated. Here, we postulated thatstromal cells in the tumor microenvironment alter the tumor cell secretome, including those proteinsrequired for tumor growth and dissemination, and we developed an in vitro model to test this hypothesis.Coculturing a murine K-ras mutant lung adenocarcinoma cell line (LKR-13) with a murine lung stromalcell (macrophage, endothelial cell, or fibroblast) enhanced stromal cell migration, induced endothelialtube formation, increased LKR-13 cell proliferation, and regulated the secretion of proteins involved inangiogenesis, inflammation, cell proliferation, and epithelial-to-mesenchymal transition. Among theseproteins, CXCL1 has been reported to promote NSCLC development, whereas interleukin-18 (IL-18) hasan undefined role. Genetic and pharmacologic strategies to inhibit CXCL1 and IL-18 revealed that stromalcell migration, LKR-13 cell proliferation, and LKR-13 cell tumorigenicity required one or both of theseproteins. We conclude that stromal cells enhanced LKR-13 cell tumorigenicity partly through their effectson the secretome of LKR-13 cells. Strategies to inhibit tumor/stromal cell interactions may be useful astherapeutic approaches in NSCLC patients.", "metadata": {}}
+{"_id": "15728433", "title": "", "text": "Tightrope act: autophagy in stem cell renewal, differentiation, proliferation, and agingAutophagy is aconstitutive lysosomal catabolic pathway that degrades damaged organelles and protein aggregates.Stem cells are characterized by self-renewal, pluripotency, and quiescence; their long life span, limitedcapacity to dilute cellular waste and spent organelles due to quiescence, along with their requirement forremodeling in order to differentiate, all suggest that they require autophagy more than other cell types.Here, we review the current literature on the role of autophagy in embryonic and adult stem cells,including hematopoietic, mesenchymal, and neuronal stem cells, highlighting the diverse and contrastingroles autophagy plays in their biology. Furthermore, we review the few studies on stem cells, lysosomalactivity, and autophagy. Novel techniques to detect autophagy in primary cells are required to studyautophagy in different stem cell types. These will help to elucidate the importance of autophagy in stemcells during transplantation, a promising therapeutic approach for many diseases.", "metadata": {}}
+{"_id": "15778034", "title": "", "text": "Variant Histone H2A.Z Is Globally Localized to the Promoters of Inactive Yeast Genes and RegulatesNucleosome PositioningH2A.Z is an evolutionary conserved histone variant involved in transcriptionalregulation, antisilencing, silencing, and genome stability. The mechanism(s) by which H2A.Z regulatesthese various biological functions remains poorly defined, in part due to the lack of knowledge regardingits physical location along chromosomes and the bearing it has in regulating chromatin structure. Here wemapped H2A.Z across the yeast genome at an approximately 300-bp resolution, using chromatinimmunoprecipitation combined with tiling microarrays. We have identified 4,862 small regions—typicallyone or two nucleosomes wide—decorated with H2A.Z. Those “Z loci” are predominantly found withinspecific nucleosomes in the promoter of inactive genes all across the genome. Furthermore, we haveshown that H2A.Z can regulate nucleosome positioning at the GAL1 promoter. Within HZAD domains, theregions where H2A.Z shows an antisilencing function, H2A.Z is localized in a wider pattern, suggestingthat the variant histone regulates a silencing and transcriptional activation via different mechanisms. Ourdata suggest that the incorporation of H2A.Z into specific promoter-bound nucleosomes configureschromatin structure to poise genes for transcriptional activation. The relevance of these findings to highereukaryotes is discussed.", "metadata": {}}
+{"_id": "15780826", "title": "", "text": "Collective trauma in northern Sri Lanka: a qualitative psychosocial-ecological studyBACKGROUNDComplex situations that follow war and natural disasters have a psychosocial impact on not only theindividual but also on the family, community and society. Just as the mental health effects on theindividual psyche can result in non pathological distress as well as a variety of psychiatric disorders;massive and widespread trauma and loss can impact on family and social processes causing changes atthe family, community and societal levels. METHOD This qualitative, ecological study is a naturalistic,psychosocial ethnography in Northern Sri Lanka, while actively involved in psychosocial and communitymental health programmes among the Tamil community. Participatory observation, key informantinterviews and focus group discussion with community level relief and rehabilitation workers andgovernment and non-governmental officials were used to gather data. The effects on the community ofthe chronic, man-made disaster, war, in Northern Sri Lanka were compared with the contexts foundbefore the war and after the tsunami. RESULTS Fundamental changes in the functioning of the family andthe community were observed. While the changes after the tsunami were not so prominent, the chronicwar situation caused more fundamental social transformations. At the family level, the dynamics of singleparent families, lack of trust among members, and changes in significant relationships, and child rearingpractices were seen. Communities tended to be more dependent, passive, silent, without leadership,mistrustful, and suspicious. Additional adverse effects included the breakdown in traditional structures,institutions and familiar ways of life, and deterioration in social norms and ethics. A variety of communitylevel interventions were tried. CONCLUSION Exposure to conflict, war and disaster situations impact onfundamental family and community dynamics resulting in changes at a collective level. Relief,rehabilitation and development programmes to be effective will need to address the problem of collectivetrauma, particularly using integrated multi-level approaches.", "metadata": {}}
+{"_id": "15790930", "title": "", "text": "Guidelines for the selection of highly effective siRNA sequences for mammalian and chick RNAinterference.In the present study, the relationship between short interfering RNA (siRNA) sequence andRNA interference (RNAi) effect was extensively analyzed using 62 targets of four exogenous and twoendogenous genes and three mammalian and Drosophila cells. We present the rules that may governsiRNA sequence preference and in accordance with which highly effective siRNAs essential for systematicmammalian functional genomics can be readily designed. These rules indicate that siRNAs whichsimultaneously satisfy all four of the following sequence conditions are capable of inducing highlyeffective gene silencing in mammalian cells: (i) A/U at the 5' end of the antisense strand; (ii) G/C at the5' end of the sense strand; (iii) at least five A/U residues in the 5' terminal one-third of the antisensestrand; and (iv) the absence of any GC stretch of more than 9 nt in length. siRNAs opposite in featureswith respect to the first three conditions give rise to little or no gene silencing in mammalian cells.Essentially the same rules for siRNA sequence preference were found applicable to DNA-based RNAi inmammalian cells and in ovo RNAi using chick embryos. In contrast to mammalian and chick cells, littlesiRNA sequence preference could be detected in Drosophila in vivo RNAi.", "metadata": {}}
+{"_id": "15795880", "title": "", "text": "Overview of the CCP4 suite and current developmentsThe CCP4 (Collaborative Computational Project,Number 4) software suite is a collection of programs and associated data and software libraries which canbe used for macromolecular structure determination by X-ray crystallography. The suite is designed to beflexible, allowing users a number of methods of achieving their aims. The programs are from a widevariety of sources but are connected by a common infrastructure provided by standard file formats, dataobjects and graphical interfaces. Structure solution by macromolecular crystallography is becomingincreasingly automated and the CCP4 suite includes several automation pipelines. After giving a briefdescription of the evolution of CCP4 over the last 30 years, an overview of the current suite is given.While detailed descriptions are given in the accompanying articles, here it is shown how the individualprograms contribute to a complete software package.", "metadata": {}}
+{"_id": "15803282", "title": "", "text": "Histone Demethylase Expression Enhances Human Somatic Cell Nuclear Transfer Efficiency and PromotesDerivation of Pluripotent Stem Cells.The extremely low efficiency of human embryonic stem cell (hESC)derivation using somatic cell nuclear transfer (SCNT) limits its potential application. Blastocyst formationfrom human SCNT embryos occurs at a low rate and with only some oocyte donors. We previouslyshowed in mice that reduction of histone H3 lysine 9 trimethylation (H3K9me3) through ectopicexpression of the H3K9me3 demethylase Kdm4d greatly improves SCNT embryo development. Here weshow that overexpression of a related H3K9me3 demethylase KDM4A improves human SCNT, and that,as in mice, H3K9me3 in the human somatic cell genome is an SCNT reprogramming barrier.Overexpression of KDM4A significantly improves the blastocyst formation rate in human SCNT embryosby facilitating transcriptional reprogramming, allowing efficient derivation of SCNT-derived ESCs usingadult Age-related Macular Degeneration (AMD) patient somatic nuclei donors. This conserved mechanisticinsight has potential applications for improving SCNT in a variety of contexts, including regenerativemedicine.", "metadata": {}}
+{"_id": "15816729", "title": "", "text": "Interface Contractility between Differently Fated Cells Drives Cell Elimination and Cyst FormationAlthoughcellular tumor-suppression mechanisms are widely studied, little is known about mechanisms that act atthe level of tissues to suppress the occurrence of aberrant cells in epithelia. We find that ectopicexpression of transcription factors that specify cell fates causes abnormal epithelial cysts in Drosophilaimaginal discs. Cysts do not form cell autonomously but result from the juxtaposition of two cellpopulations with divergent fates. Juxtaposition of wild-type and aberrantly specified cells inducesenrichment of actomyosin at their entire shared interface, both at adherens junctions as well as alongbasolateral interfaces. Experimental validation of 3D vertex model simulations demonstrates thatenhanced interface contractility is sufficient to explain many morphogenetic behaviors, which depend oncell cluster size. These range from cyst formation by intermediate-sized clusters to segregation of largecell populations by formation of smooth boundaries or apical constriction in small groups of cells. Inaddition, we find that single cells experiencing lateral interface contractility are eliminated from tissues byapoptosis. Cysts, which disrupt epithelial continuity, form when elimination of single, aberrantly specifiedcells fails and cells proliferate to intermediate cell cluster sizes. Thus, increased interface contractilityfunctions as error correction mechanism eliminating single aberrant cells from tissues, but failure leads tothe formation of large, potentially disease-promoting cysts. Our results provide a novel perspective onmorphogenetic mechanisms, which arise from cell-fate heterogeneities within tissues and maintain ordisrupt epithelial homeostasis.", "metadata": {}}
+{"_id": "15830352", "title": "", "text": "Resonating circadian clocks enhance fitness in cyanobacteria.In some organisms longevity, growth, anddevelopmental rate are improved when they are maintained on a light/dark cycle, the period of which\"resonates\" optimally with the period of the endogenous circadian clock. However, to our knowledge nostudies have demonstrated that reproductive fitness per se is improved by resonance between theendogenous clock and the environmental cycle. We tested the adaptive significance of circadianprogramming by measuring the relative fitness under competition between various strains ofcyanobacteria expressing different circadian periods. Strains that had a circadian period similar to that ofthe light/dark cycle were favored under competition in a manner that indicates the action of softselection.", "metadata": {}}
+{"_id": "15832146", "title": "", "text": "Stromal Fibroblasts Present in Invasive Human Breast Carcinomas Promote Tumor Growth andAngiogenesis through Elevated SDF-1/CXCL12 SecretionFibroblasts often constitute the majority of thestromal cells within a breast carcinoma, yet the functional contributions of these cells to tumorigenesisare poorly understood. Using a coimplantation tumor xenograft model, we demonstrate thatcarcinoma-associated fibroblasts (CAFs) extracted from human breast carcinomas promote the growth ofadmixed breast carcinoma cells significantly more than do normal mammary fibroblasts derived from thesame patients. The CAFs, which exhibit the traits of myofibroblasts, play a central role in promoting thegrowth of tumor cells through their ability to secrete stromal cell-derived factor 1 (SDF-1); CAFs promoteangiogenesis by recruiting endothelial progenitor cells (EPCs) into carcinomas, an effect mediated in partby SDF-1. CAF-secreted SDF-1 also stimulates tumor growth directly, acting through the cognatereceptor, CXCR4, which is expressed by carcinoma cells. Our findings indicate that fibroblasts withininvasive breast carcinomas contribute to tumor promotion in large part through the secretion of SDF-1.", "metadata": {}}
+{"_id": "15833835", "title": "", "text": "Embryonic Origin of Postnatal Neural Stem CellsAdult neural stem/progenitor (B1) cells within the walls ofthe lateral ventricles generate different types of neurons for the olfactory bulb (OB). The location of B1cells determines the types of OB neurons they generate. Here we show that the majority of mouse B1 cellprecursors are produced between embryonic days (E) 13.5 and 15.5 and remain largely quiescent untilthey become reactivated postnatally. Using a retroviral library carrying over 100,000 genetic tags, wefound that B1 cells share a common progenitor with embryonic cells of the cortex, striatum, and septum,but this lineage relationship is lost before E15.5. The regional specification of B1 cells is evident as earlyas E11.5 and is spatially linked to the production of neurons that populate different areas of the forebrain.This study reveals an early embryonic regional specification of postnatal neural stem cells and the lineagerelationship between them and embryonic progenitor cells.", "metadata": {}}
+{"_id": "15836115", "title": "", "text": "The Opa1-Dependent Mitochondrial Cristae Remodeling Pathway Controls Atrophic, Apoptotic, andIschemic Tissue DamageMitochondrial morphological and ultrastructural changes occur during apoptosisand autophagy, but whether they are relevant in vivo for tissue response to damage is unclear. Here weinvestigate the role of the optic atrophy 1 (OPA1)-dependent cristae remodeling pathway in vivo andprovide evidence that it regulates the response of multiple tissues to apoptotic, necrotic, and atrophicstimuli. Genetic inhibition of the cristae remodeling pathway in vivo does not affect development, butprotects mice from denervation-induced muscular atrophy, ischemic heart and brain damage, as well ashepatocellular apoptosis. Mechanistically, OPA1-dependent mitochondrial cristae stabilization increasesmitochondrial respiratory efficiency and blunts mitochondrial dysfunction, cytochrome c release, andreactive oxygen species production. Our results indicate that the OPA1-dependent cristae remodelingpathway is a fundamental, targetable determinant of tissue damage in vivo.", "metadata": {}}
+{"_id": "15856466", "title": "", "text": "First Proposal of Minimum Information About a Cellular Assay for Regenerative Medicine: Advances instem cell research have triggered scores of studies in regenerative medicine in a large number ofinstitutions and companies around the world. However, reproducibility and data exchange amonglaboratories or cell banks are constrained by the lack of a standardized format for experiments. Toenhance information flow in stem cell and derivative cell research, here we propose a minimuminformation standard to describe cellular assay data to facilitate practical regenerative medicine. Basedon the existing Minimum Information About a Cellular Assay, we developed Minimum Information About aCellular Assay for Regenerative Medicine (MIACARM), which allows for the description of advancedcellular experiments with defined taxonomy of human cell types. By using controlled terms, such asontologies, MIACARM will provide a platform for cellular assay data exchange among cell banks orregistries that have been established at more than 20 sites in the world. SIGNIFICANCE Currently, thereare more than 20 human cell information storage sites around the world. However, reproducibility anddata exchange among different laboratories or cell information providers are usually inadequate ornonexistent because of the lack of a standardized format for experiments. This study, which is the fruit ofcollaborative work by scientists at stem cell banks and cellular information registries worldwide, includingthose in the U.S., the U.K., Europe, and Japan, proposes new minimum information guidelines, MinimumInformation About a Cellular Assay for Regenerative Medicine (MIACARM), for cellular assay datadeposition. MIACARM is intended to promote data exchange and facilitation of practical regenerativemedicine.", "metadata": {}}
+{"_id": "15868816", "title": "", "text": "The PAR proteins: fundamental players in animal cell polarization.The par genes were discovered ingenetic screens for regulators of cytoplasmic partitioning in the early embryo of C. elegans, and encodesix different proteins required for asymmetric cell division by the worm zygote. Some of the PAR proteinsare localized asymmetrically and form physical complexes with one another. Strikingly, the PAR proteinshave been found to regulate cell polarization in many different contexts in diverse animals, suggestingthey form part of an ancient and fundamental mechanism for cell polarization. Although the picture ofhow the PAR proteins function remains incomplete, cell biology and biochemistry are beginning to explainhow PAR proteins polarize cells.", "metadata": {}}
+{"_id": "15879544", "title": "", "text": "Prions Adhere to Soil Minerals and Remain InfectiousAn unidentified environmental reservoir of infectivitycontributes to the natural transmission of prion diseases (transmissible spongiform encephalopathies[TSEs]) in sheep, deer, and elk. Prion infectivity may enter soil environments via shedding from diseasedanimals and decomposition of infected carcasses. Burial of TSE-infected cattle, sheep, and deer as ameans of disposal has resulted in unintentional introduction of prions into subsurface environments. Weexamined the potential for soil to serve as a TSE reservoir by studying the interaction of thedisease-associated prion protein (PrPSc) with common soil minerals. In this study, we demonstratedsubstantial PrPSc adsorption to two clay minerals, quartz, and four whole soil samples. We quantified thePrPSc-binding capacities of each mineral. Furthermore, we observed that PrPSc desorbed frommontmorillonite clay was cleaved at an N-terminal site and the interaction between PrPSc and Mte wasstrong, making desorption of the protein difficult. Despite cleavage and avid binding, PrPSc bound to Mteremained infectious. Results from our study suggest that PrPSc released into soil environments may bepreserved in a bioavailable form, perpetuating prion disease epizootics and exposing other species to theinfectious agent.", "metadata": {}}
+{"_id": "15879931", "title": "", "text": "Regulated Accumulation of Desmosterol Integrates Macrophage Lipid Metabolism and InflammatoryResponsesInflammation and macrophage foam cells are characteristic features of atherosclerotic lesions,but the mechanisms linking cholesterol accumulation to inflammation and LXR-dependent responsepathways are poorly understood. To investigate this relationship, we utilized lipidomic and transcriptomicmethods to evaluate the effect of diet and LDL receptor genotype on macrophage foam cell formationwithin the peritoneal cavities of mice. Foam cell formation was associated with significant changes inhundreds of lipid species and unexpected suppression, rather than activation, of inflammatory geneexpression. We provide evidence that regulated accumulation of desmosterol underlies many of thehomeostatic responses, including activation of LXR target genes, inhibition of SREBP target genes,selective reprogramming of fatty acid metabolism, and suppression of inflammatory-response genes,observed in macrophage foam cells. These observations suggest that macrophage activation inatherosclerotic lesions results from extrinsic, proinflammatory signals generated within the artery wallthat suppress homeostatic and anti-inflammatory functions of desmosterol.", "metadata": {}}
+{"_id": "15889329", "title": "", "text": "A JOURNAL OF NEUROLOGYBrain glial cells, five times more prevalent than neurons, have recentlyreceived attention for their potential involvement in epileptic seizures. Microglia and astrocytes,associated with inflammatory innate immune responses, are responsible for surveillance of brain damagethat frequently results in seizures. Thus, an intriguing suggestion has been put forward that seizures maybe facilitated and perhaps triggered by brain immune responses. Indeed, recent evidence stronglyimplicates innate immune responses in lowering seizure threshold in experimental models of epilepsy,yet, there is no proof that they can play an independent role in initiating seizures in vivo. Here, we showthat cortical innate immune responses alone produce profound increases of brain excitability resulting infocal seizures. We found that cortical application of lipopolysaccharide, binding to toll-like receptor 4(TLR4), triples evoked field potential amplitudes and produces focal epileptiform discharges. These effectsare prevented by pre-application of interleukin-1 receptor antagonist. Our results demonstrate how theinnate immune response may participate in acute seizures, increasing neuronal excitability throughinterleukin-1 release in response to TLR4 detection of the danger signals associated with infections of thecentral nervous system and with brain injury. These results suggest an important role of innate immunityin epileptogenesis and focus on glial inhibition, through pharmacological blockade of TLR4 and thepro-inflammatory mediators released by activated glia, in the study and treatment of seizure disorders inhumans.", "metadata": {}}
+{"_id": "15893330", "title": "", "text": "Sequential domain assembly of ribosomal protein S3 drives 40S subunit maturation.Eukaryotic ribosomesassemble by association of ribosomal RNA with ribosomal proteins into nuclear precursor particles, whichundergo a complex maturation pathway coordinated by non-ribosomal assembly factors. Here, weprovide functional insights into how successive structural re-arrangements in ribosomal protein S3promote maturation of the 40S ribosomal subunit. We show that S3 dimerizes and is imported into thenucleus with its N-domain in a rotated conformation and associated with the chaperone Yar1. Initialassembly of S3 with 40S precursors occurs via its C-domain, while the N-domain protrudes from the 40Ssurface. Yar1 is replaced by the assembly factor Ltv1, thereby fixing the S3 N-domain in the rotatedorientation and preventing its 40S association. Finally, Ltv1 release, triggered by phosphorylation, andflipping of the S3 N-domain into its final position results in the stable integration of S3. Such a stepwiseassembly may represent a new paradigm for the incorporation of ribosomal proteins.", "metadata": {}}
+{"_id": "15907458", "title": "", "text": "Assaying proliferation and differentiation capacity of stem cells using disaggregated adult mouseepidermisIn this protocol, we describe how to isolate keratinocytes from adult mouse epidermis,fractionate them into different sub-populations on the basis of cell surface markers and examine theirfunction in an in vivo skin reconstitution assay with disaggregated neonatal dermal cells. We also describehow the isolated keratinocytes can be subjected to clonal analysis in vitro and in vivo and how to enrichfor hair follicle-inducing dermal papilla cells in the dermal preparation. Using these approaches, it ispossible to compare the capacity of different populations of adult epidermal stem cells to proliferate andto generate progeny that differentiate along the different epidermal lineages. Isolating, fractionating andgrafting cells for the skin reconstitution assay is normally spread over 2 d. Clonal growth in culture isassessed after 14 d, while evaluation of the grafts is carried out after 4–5 weeks.", "metadata": {}}
+{"_id": "15913433", "title": "", "text": "Telomerase-negative immortalized human cells contain a novel type of promyelocytic leukemia (PML)body.Telomerase-negative immortalized human cells maintain their telomeres by a mechanism known asalternative lengthening of telomeres (ALT). We report here that ALT cells contain a novel promyelocyticleukemia (PML) body (ALT-associated PML body, APB). APBs are large donut-shaped nuclear structurescontaining PML protein, telomeric DNA, and the telomere binding proteins human telomere repeat bindingfactors 1 and 2. Immunostaining showed that APBs also contain replication factor A, RAD51, and RAD52,proteins involved in DNA synthesis and recombination. During immortalization, APBs appeared at exactlythe same time as activation of ALT. APBs were found in ALT tumors and cell lines but not in mortal cellstrains or in telomerase-positive cell lines or tumors.", "metadata": {}}
+{"_id": "15925931", "title": "", "text": "Prediction of coronary artery disease by a systemic atherosclerosis score index derived from whole-bodyMR angiographyBACKGROUND Whole-body magnetic resonance angiography (WB-MRA) has shown itspotential for the non-invasive assessment of nearly the entire arterial vasculature within oneexamination. Since the presence of extra-cardiac atherosclerosis is associated with an increased risk ofcoronary events, our goal was to establish the relationship between WB-MRA findings, including asystemic atherosclerosis score index, and the presence of significant coronary artery disease (CAD).METHODS WB-MRA was performed on a 1.5T scanner in 50 patients scheduled to undergo electivecardiac catheterization for suspected CAD. In each patient, 40 extra-cardiac vessel segments wereevaluated and assigned scores according to their luminal narrowing. The atherosclerosis score index(ASI) was generated as the ratio of summed scores to analyzable segments. RESULTS ASI was higher inpatients with significant (> 50% stenosis) CAD (n = 27) vs. patients without CAD (n = 22; 1.56 vs. 1.28,p = 0.004). ASI correlated with PROCAM (R = 0.57, p < 0.001) and Framingham (R = 0.36, p = 0.01)risk scores as estimates of the 10-year risk of coronary events. A ROC derived ASI of > 1.54 predictedsignificant CAD with a sensitivity of 59%, specificity of 86% and a positive predictive value of 84%.Logistic regression revealed ASI > 1.54 as the strongest independent predictor for CAD with a 11-foldincrease in likelihood to suffer from significant coronary disease. On the contrary, while 15/27 (55%) ofpatients with CAD exhibited at least one extra-cardiac stenosis > 50%, only 3/22 (14%) of those patientswithout CAD did (p = 0.003). The likelihood for an extra-cardiac stenosis when CAD is present differedbetween vascular territories and ranged from 15% for a carotid stenosis to 44% for a stenosis in thelower extremities. CONCLUSION This study provides important new evidence for the close association ofextra-cardiac and coronary atherosclerosis. The novel findings that a WB-MRA derived systemicatherosclerosis score index is not only associated with established cardiovascular risk scores but is alsopredictive of significant CAD suggest its potential prognostic implications and underline the importance toscreen for coronary disease in patients with extra-cardiac manifestations of atherosclerosis.", "metadata": {}}
+{"_id": "15926408", "title": "", "text": "Analysis of re-replication from deregulated origin licensing by DNA fiber spreadingA major challenge eachhuman cell-division cycle is to ensure that DNA replication origins do not initiate more than once, aphenomenon known as re-replication. Acute deregulation of replication control ultimately causesextensive DNA damage, cell-cycle checkpoint activation and cell death whereas moderate deregulationpromotes genome instability and tumorigenesis. In the absence of detectable increases in cellular DNAcontent however, it has been difficult to directly demonstrate re-replication or to determine if the abilityto re-replicate is restricted to a particular cell-cycle phase. Using an adaptation of DNA fiber spreading wereport the direct detection of re-replication on single DNA molecules from human chromosomes. Usingthis method we demonstrate substantial re-replication within 1 h of S phase entry in cells overproducingthe replication factor, Cdt1. Moreover, a comparison of the HeLa cancer cell line to untransformedfibroblasts suggests that HeLa cells produce replication signals consistent with low-level re-replication inotherwise unperturbed cell cycles. Re-replication after depletion of the Cdt1 inhibitor, geminin, in anuntransformed fibroblast cell line is undetectable by standard assays but readily quantifiable by DNA fiberspreading analysis. Direct evaluation of re-replicated DNA molecules will promote increasedunderstanding of events that promote or perturb genome stability.", "metadata": {}}
+{"_id": "15928989", "title": "", "text": "Liver receptor homolog-1 is essential for pregnancySuccessful pregnancy requires coordination of anarray of signals and factors from multiple tissues. One such element, liver receptor homolog-1 (Lrh-1), isan orphan nuclear receptor that regulates metabolism and hormone synthesis. It is strongly expressed ingranulosa cells of ovarian follicles and in the corpus luteum of rodents and humans. Germline ablation ofNr5a2 (also called Lrh-1), the gene coding for Lrh-1, in mice is embryonically lethal at gastrulation.Depletion of Lrh-1 in the ovarian follicle shows that it regulates genes required for both steroid synthesisand ovulation. To study the effects of Lrh-1 on mouse gestation, we genetically disrupted its expressionin the corpus luteum, resulting in luteal insufficiency. Hormone replacement permitted embryoimplantation but was followed by gestational failure with impaired endometrial decidualization,compromised placental formation, fetal growth retardation and fetal death. Lrh-1 is also expressed in themouse and human endometrium, and in a primary culture of human endometrial stromal cells, reductionof NR5A2 transcript abundance by RNA interference abrogated decidualization. These findings show thatLrh-1 is necessary for maintenance of the corpus luteum, for promotion of decidualization and forformation of the placenta. It therefore has multiple, indispensible roles in establishing and sustainingpregnancy.", "metadata": {}}
+{"_id": "15945975", "title": "", "text": "Transcriptional Signature and Memory Retention of Human-Induced Pluripotent Stem CellsGeneticreprogramming of somatic cells to a pluripotent state (induced pluripotent stem cells or iPSCs) byover-expression of specific genes has been accomplished using mouse and human cells. However, it isstill unclear how similar human iPSCs are to human Embryonic Stem Cells (hESCs). Here, we describe thetranscriptional profile of human iPSCs generated without viral vectors or genomic insertions, revealingthat these cells are in general similar to hESCs but with significant differences. For the generation ofhuman iPSCs without viral vectors or genomic insertions, pluripotent factors Oct4 and Nanog were clonedin episomal vectors and transfected into human fetal neural progenitor cells. The transient expression ofthese two factors, or from Oct4 alone, resulted in efficient generation of human iPSCs. Thereprogramming strategy described here revealed a potential transcriptional signature for human iPSCsyet retaining the gene expression of donor cells in human reprogrammed cells free of viral and transgeneinterference. Moreover, the episomal reprogramming strategy represents a safe way to generate humaniPSCs for clinical purposes and basic research.", "metadata": {}}
+{"_id": "15946643", "title": "", "text": "A CXCL1 Paracrine Network Links Cancer Chemoresistance and MetastasisMetastasis andchemoresistance in cancer are linked phenomena, but the molecular basis for this link is unknown. Weuncovered a network of paracrine signals between carcinoma, myeloid, and endothelial cells that drivesboth processes in breast cancer. Cancer cells that overexpress CXCL1 and 2 by transcriptionalhyperactivation or 4q21 amplification are primed for survival in metastatic sites. CXCL1/2 attractCD11b(+)Gr1(+) myeloid cells into the tumor, which produce chemokines including S100A8/9 thatenhance cancer cell survival. Although chemotherapeutic agents kill cancer cells, these treatments triggera parallel stromal reaction leading to TNF-α production by endothelial and other stromal cells. TNF-α viaNF-kB heightens the CXCL1/2 expression in cancer cells, thus amplifying the CXCL1/2-S100A8/9 loop andcausing chemoresistance. CXCR2 blockers break this cycle, augmenting the efficacy of chemotherapyagainst breast tumors and particularly against metastasis. This network of endothelial-carcinoma-myeloidsignaling interactions provides a mechanism linking chemoresistance and metastasis, with opportunitiesfor intervention.", "metadata": {}}
+{"_id": "15948830", "title": "", "text": "Prophylaxis of postoperative vomiting in children undergoing tonsillectomy: a systematic review andmeta-analysis.Postoperative vomiting (POV) remains one of the commonest causes of significantmorbidity after tonsillectomy in children. A variety of prophylactic anti-emetic interventions have beenreported, but there has only been a limited systematic review in this patient group. A systematic searchwas performed by using Cochrane Controlled Trials Register, MEDLINE and EMBASE to identifydouble-blind, randomized, placebo-controlled trials of prophylactic anti-emetic interventions in childrenundergoing tonsillectomy, with or without adenoidectomy. The outcome of interest was POV in the first24 h. Summary estimates of the effect of each prophylactic anti-emetic strategy were derived using fixedeffect meta-analysis. Where appropriate, dose-response effects were estimated using logistic regressionand 22 articles were identified. Good evidence was found for the prophylactic anti-emetic effect ofdexamethasone [odds ratio (OR) 0.23, 95% CI 0.16-0.33], and the serotinergic antagonists ondansetron(OR 0.36, 95% CI 0.29-0.46), granisetron (OR 0.11, 95% CI 0.06-0.19), tropisetron (OR 0.15, 95% CI0.06-0.35) and dolasetron (OR 0.25, 95% CI 0.1-0.59). Metoclopramide was also found to be efficacious(OR 0.51, 95% CI 0.34-0.77). There is not sufficient evidence to suggest that dimenhydrinate,perphenazine or droperidol, in the doses studied, are efficacious, nor were gastric aspiration oracupuncture. In conclusion, dexamethasone and the anti-serotinergic agents appear to be the mosteffective agents for the prophylaxis for POV in children undergoing tonsillectomy.", "metadata": {}}
+{"_id": "15953181", "title": "", "text": "A method of comparing the areas under receiver operating characteristic curves derived from the samecases.Receiver operating characteristic (ROC) curves are used to describe and compare the performanceof diagnostic technology and diagnostic algorithms. This paper refines the statistical comparison of theareas under two ROC curves derived from the same set of patients by taking into account the correlationbetween the areas that is induced by the paired nature of the data. The correspondence between the areaunder an ROC curve and the Wilcoxon statistic is used and underlying Gaussian distributions (binormal)are assumed to provide a table that converts the observed correlations in paired ratings of images into acorrelation between the two ROC areas. This between-area correlation can be used to reduce thestandard error (uncertainty) about the observed difference in areas. This correction for pairing, analogousto that used in the paired t-test, can produce a considerable increase in the statistical sensitivity (power)of the comparison. For studies involving multiple readers, this method provides a measure of acomponent of the sampling variation that is otherwise difficult to obtain.", "metadata": {}}
+{"_id": "15955172", "title": "", "text": "Transient inactivation of Rb and ARF yields regenerative cells from postmitotic mammalian muscle.Anoutstanding biological question is why tissue regeneration in mammals is limited, whereas urodeleamphibians and teleost fish regenerate major structures, largely by cell cycle reentry. Upon inactivationof Rb, proliferation of postmitotic urodele skeletal muscle is induced, whereas in mammalian muscle thismechanism does not exist. We postulated that a tumor suppressor present in mammals but absent inregenerative vertebrates, the Ink4a product ARF (alternative reading frame), is a regenerationsuppressor. Concomitant inactivation of Arf and Rb led to mammalian muscle cell cycle reentry, loss ofdifferentiation properties, and upregulation of cytokinetic machinery. Single postmitotic myocytes wereisolated by laser micro-dissection-catapulting, and transient suppression of Arf and Rb yielded myoblastcolonies that retained the ability to differentiate and fuse into myofibers upon transplantation in vivo.These results show that differentiation of mammalian cells is reversed by inactivation of Arf and Rb andsupport the hypothesis that Arf evolved at the expense of regeneration.", "metadata": {}}
+{"_id": "15960670", "title": "", "text": "CENP-B Controls Centromere Formation Depending on the Chromatin ContextThe centromere is achromatin region that serves as the spindle attachment point and directs accurate inheritance ofeukaryotic chromosomes during cell divisions. However, the mechanism by which the centromereassembles and stabilizes at a specific genomic region is not clear. The de novo formation of ahuman/mammalian artificial chromosome (HAC/MAC) with a functional centromere assembly requires thepresence of alpha-satellite DNA containing binding motifs for the centromeric CENP-B protein. Wedemonstrate here that de novo centromere assembly on HAC/MAC is dependent on CENP-B. In contrast,centromere formation is suppressed in cells expressing CENP-B when alpha-satellite DNA was integratedinto a chromosomal site. Remarkably, on those integration sites CENP-B enhances histone H3-K9trimethylation and DNA methylation, thereby stimulating heterochromatin formation. Thus, we proposethat CENP-B plays a dual role in centromere formation, ensuring de novo formation on DNA lacking afunctional centromere but preventing the formation of excess centromeres on chromosomes.", "metadata": {}}
+{"_id": "15966318", "title": "", "text": "Improved tools for biological sequence comparison.We have developed three computer programs forcomparisons of protein and DNA sequences. They can be used to search sequence data bases, evaluatesimilarity scores, and identify periodic structures based on local sequence similarity. The FASTA programis a more sensitive derivative of the FASTP program, which can be used to search protein or DNAsequence data bases and can compare a protein sequence to a DNA sequence data base by translatingthe DNA data base as it is searched. FASTA includes an additional step in the calculation of the initialpairwise similarity score that allows multiple regions of similarity to be joined to increase the score ofrelated sequences. The RDF2 program can be used to evaluate the significance of similarity scores usinga shuffling method that preserves local sequence composition. The LFASTA program can display all theregions of local similarity between two sequences with scores greater than a threshold, using the samescoring parameters and a similar alignment algorithm; these local similarities can be displayed as a\"graphic matrix\" plot or as individual alignments. In addition, these programs have been generalized toallow comparison of DNA or protein sequences based on a variety of alternative scoring matrices.", "metadata": {}}
+{"_id": "15968271", "title": "", "text": "The adverse consequences of unmet need among older persons living in the community: dual-eligibleversus Medicare-only beneficiaries.OBJECTIVE Our objective is to estimate and compare the prevalenceof selected adverse consequences associated with unmet need for assistance among a socioeconomicallyand medically vulnerable subgroup of the older adult population, those who are dually eligible forMedicare and Medicaid, with those eligible for Medicare only. METHOD Using data from the NationalHealth and Aging Trends Study (NHATS), a representative survey of the older Medicare population, wecalculated the prevalence of disability-related need for assistance with self-care, household tasks, andmobility activities and the prevalence of adverse consequences of unmet need by dually eligible andMedicare only status. RESULTS Over 2 million community-dwelling older persons experienced an adverseconsequence due to unmet need for assistance with self-care (e.g., soiled their clothes), over 2 millionexperienced adverse consequences due to unmet need for assistance with household tasks (e.g., wentwithout groceries), and over 3 million persons experienced at least one adverse consequence of unmetneed for assistance with mobility-related activities (e.g., had to stay in bed) in the month prior to theNHATS interview. Dually eligible persons experienced higher rates of 6 of the 11 adverse consequencesstudied and were more likely to have at least one adverse consequence in all 3 domains than others.DISCUSSION Several care models are emerging with the goal of integrating medical care, behavioralhealth, and long-term services for the dual eligible population. Indicators of adverse consequences ofunmet need could be used to monitor the quality and adequacy of such care systems.", "metadata": {}}
+{"_id": "15969637", "title": "", "text": "Supplementary information: ‘MesoRD User’s Guide ’ and otherUNLABELLED MesoRD is a tool forstochastic simulation of chemical reactions and diffusion. In particular, it is an implementation of the nextsubvolume method, which is an exact method to simulate the Markov process corresponding to thereaction-diffusion master equation. AVAILABILITY MesoRD is free software, written in C++ and licensedunder the GNU general public license (GPL). MesoRD runs on Linux, Mac OS X, NetBSD, Solaris andWindows XP. It can be downloaded from http://mesord.sourceforge.net. CONTACT johan.elf@icm.uu.se;johan.hattne@embl-hamburg.de   SUPPLEMENTARY INFORMATION 'MesoRD User's Guide' and otherdocuments are available at http://mesord.sourceforge.net.", "metadata": {}}
+{"_id": "15972906", "title": "", "text": "Functional anatomy of T cell activation and synapse formation.T cell activation and function require astructured engagement of antigen-presenting cells. These cell contacts are characterized by two distinctdynamics in vivo: transient contacts resulting from promigratory junctions called immunological kinapsesor prolonged contacts from stable junctions called immunological synapses. Kinapses operate in thesteady state to allow referencing to self-peptide-MHC (pMHC) and searching for pathogen-derived pMHC.Synapses are induced by T cell receptor (TCR) interactions with agonist pMHC under specific conditionsand correlate with robust immune responses that generate effector and memory T cells. High-resolutionimaging has revealed that the synapse is highly coordinated, integrating cell adhesion, TCR recognition ofpMHC complexes, and an array of activating and inhibitory ligands to promote or prevent T cell signaling.In this review, we examine the molecular components, geometry, and timing underlying kinapses andsynapses. We integrate recent molecular and physiological data to provide a synthesis and suggest waysforward.", "metadata": {}}
+{"_id": "15975146", "title": "", "text": "Modulation of Replicative Lifespan in Cryptococcus neoformans: Implications for VirulenceThe fungalpathogen, Cryptococcus neoformans, has been shown to undergo replicative aging. Old cells arecharacterized by advanced generational age and phenotypic changes that appear to mediate enhancedresistance to host and antifungal-based killing. As a consequence of this age-associated resilience, oldcells accumulate during chronic infection. Based on these findings, we hypothesized that shifting thegenerational age of a pathogenic yeast population would alter its vulnerability to the host and affect itsvirulence. SIR2 is a well-conserved histone deacetylase, and a pivotal target for the development ofanti-aging drugs. We tested its effect on C. neoformans' replicative lifespan (RLS). First, a mutant C.neoformans strain (sir2Δ) was generated, and confirmed a predicted shortened RLS in sir2Δ cellsconsistent with its known role in aging. Next, RLS analysis showed that treatment of C. neoformans withSir2p-agonists resulted in a significantly prolonged RLS, whereas treatment with a Sir2p-antagonistshortened RLS. RLS modulating effects were dependent on SIR2 and not observed in sir2Δ cells. BecauseSIR2 loss resulted in a slightly impaired fitness, effects of genetic RLS modulation on virulence could notbe compared with wild type cells. Instead we chose to chemically modulate RLS, and investigated theeffect of Sir2p modulating drugs on C. neoformans cells in a Galleria mellonella infection model.Consistent with our hypothesis that shifts in the generational age of the infecting yeast population altersits vulnerability to host cells, we observed decreased virulence of C. neoformans in the Galleria host whenRLS was prolonged by treatment with Sir2p agonists. In contrast, treatment with a Sir2p antagonist,which shortens RLS enhanced virulence in Galleria. In addition, combination of Sir2p agonists withantifungal therapy enhanced the antifungal's effect. Importantly, no difference in virulence was observedwith drug treatment when sir2Δ cells were used for infection, which confirmed target specificity and ruledout non-specific effects of the drugs on the Galleria host. Thus, this study suggests that RLS modulatingdrugs, such as Sir2p agonists, shift lifespan and vulnerability of the fungal population, and should befurther investigated as a potential class of novel antifungal drug targets that can enhance antifungalefficacy.", "metadata": {}}
+{"_id": "15981174", "title": "", "text": "Pf4-Cre transgenic mice allow the generation of lineage-restricted gene knockouts for studyingmegakaryocyte and platelet function in vivo.To generate transgenic mice that express Cre-recombinaseexclusively in the megakaryocytic lineage, we modified a mouse bacterial artificial chromosome (BAC)clone by homologous recombination and replaced the first exon of the platelet factor 4 (Pf4), also calledCXCL4, with a codon-improved Cre cDNA. Several strains expressing the transgene were obtained andone strain, Q3, was studied in detail. Crossing Q3 mice with the ROSA26-lacZ reporter strain showed thatCre-recombinase activity was confined to megakaryocytes. These results were further verified by crossingthe Q3 mice with a strain containing loxP-flanked integrin beta1. Excision of this conditional allele inmegakaryocytes was complete at the DNA level, and platelets were virtually devoid of the integrin beta1protein. The Pf4-Cre transgenic strain will be a valuable tool to study megakaryopoiesis, plateletformation, and platelet function.", "metadata": {}}
+{"_id": "15983148", "title": "", "text": "LIN-44/Wnt Directs Dendrite Outgrowth through LIN-17/Frizzled in C. elegans NeuronsNervous systemfunction requires proper development of two functional and morphological domains of neurons, axons anddendrites. Although both these domains are equally important for signal transmission, our understandingof dendrite development remains relatively poor. Here, we show that in C. elegans the Wnt ligand,LIN-44, and its Frizzled receptor, LIN-17, regulate dendrite development of the PQR oxygen sensoryneuron. In lin-44 and lin-17 mutants, PQR dendrites fail to form, display stunted growth, or aremisrouted. Manipulation of temporal and spatial expression of LIN-44, combined with cell-ablationexperiments, indicates that this molecule is patterned during embryogenesis and acts as an attractive cueto define the site from which the dendrite emerges. Genetic interaction between lin-44 and lin-17suggests that the LIN-44 signal is transmitted through the LIN-17 receptor, which acts cell autonomouslyin PQR. Furthermore, we provide evidence that LIN-17 interacts with another Wnt molecule, EGL-20, andfunctions in parallel to MIG-1/Frizzled in this process. Taken together, our results reveal a crucial role forWnt and Frizzled molecules in regulating dendrite development in vivo.", "metadata": {}}
+{"_id": "15983982", "title": "", "text": "Why do general practitioners prescribe antibiotics for upper respiratory tract infections to meet patientexpectations: a mixed methods studyOBJECTIVES To describe the role patient expectations play ingeneral practitioners (GPs) antibiotic prescribing for upper respiratory tract infections (URTI). METHODSConcurrent explanatory mixed methods approach using a cross-sectional survey and semistructuredinterviews. SETTINGS Primary care GPs in Australia. PARTICIPANTS 584 GPs (response rate of 23.6%)completed the cross-sectional survey. 32 GPs were interviewed individually. OUTCOME MEASUREPrescribing of antibiotics for URTI. RESULTS More than half the GP respondents to the survey in Australiaself-reported that they would prescribe antibiotics for an URTI to meet patient expectations. Ourqualitative findings suggest that 'patient expectations' may be the main reason given for inappropriateprescribing, but it is an all-encompassing phrase that includes other reasons. These include limited time,poor doctor-patient communication and diagnostic uncertainty. We have identified three role archetypesto explain the behaviour of GPs in reference to antibiotic prescribing for URTIs. The main themesemerging from the qualitative component was that many GPs did not think that antibiotic prescribing inprimary care was responsible for the development of antibiotic resistance nor that their individualprescribing would make any difference in light of other bigger issues like hospital prescribing orveterinary use. For them, there were negligible negative consequences from their inappropriateprescribing. CONCLUSIONS There is a need to increase awareness of the scope and magnitude ofantibiotic resistance and the role primary care prescribing plays, and of the contribution of individualprescribing decisions to the problem of antibiotic resistance.", "metadata": {}}
+{"_id": "15984735", "title": "", "text": "Migraine and cardiovascular disease: systematic review and meta-analysis.OBJECTIVE To evaluate theassociation between migraine and cardiovascular disease, including stroke, myocardial infarction, anddeath due to cardiovascular disease. DESIGN Systematic review and meta-analysis. DATA SOURCESElectronic databases (PubMed, Embase, Cochrane Library) and reference lists of included studies andreviews published until January 2009. Selection criteria Case-control and cohort studies investigating theassociation between any migraine or specific migraine subtypes and cardiovascular disease. Reviewmethods Two investigators independently assessed eligibility of identified studies in a two step approach.Disagreements were resolved by consensus. Studies were grouped according to a priori categories onmigraine and cardiovascular disease. DATA EXTRACTION Two investigators extracted data. Pooledrelative risks and 95% confidence intervals were calculated. RESULTS Studies were heterogeneous forparticipant characteristics and definition of cardiovascular disease. Nine studies investigated theassociation between any migraine and ischaemic stroke (pooled relative risk 1.73, 95% confidenceinterval 1.31 to 2.29). Additional analyses indicated a significantly higher risk among people who hadmigraine with aura (2.16, 1.53 to 3.03) compared with people who had migraine without aura (1.23, 0.90to 1.69; meta-regression for aura status P=0.02). Furthermore, results suggested a greater risk amongwomen (2.08, 1.13 to 3.84) compared with men (1.37, 0.89 to 2.11). Age less than 45 years, smoking,and oral contraceptive use further increased the risk. Eight studies investigated the association betweenmigraine and myocardial infarction (1.12, 0.95 to 1.32) and five between migraine and death due tocardiovascular disease (1.03, 0.79 to 1.34). Only one study investigated the association between womenwho had migraine with aura and myocardial infarction and death due to cardiovascular disease, showinga twofold increased risk. CONCLUSION Migraine is associated with a twofold increased risk of ischaemicstroke, which is only apparent among people who have migraine with aura. Our results also suggest ahigher risk among women and risk was further magnified for people with migraine who were aged lessthan 45, smokers, and women who used oral contraceptives. We did not find an overall associationbetween any migraine and myocardial infarction or death due to cardiovascular disease. Too few studiesare available to reliably evaluate the impact of modifying factors, such as migraine aura, on theseassociations.", "metadata": {}}
+{"_id": "15997009", "title": "", "text": "Effect of Duration and Intermittency of Rifampin on Tuberculosis Treatment Outcomes: A SystematicReview and Meta-AnalysisBACKGROUND Treatment regimens for active tuberculosis (TB) that areintermittent, or use rifampin during only the initial phase, offer practical advantages, but their efficacyhas been questioned. We conducted a systematic review of treatment regimens for active TB, to assessthe effect of duration and intermittency of rifampin use on TB treatment outcomes. METHODS ANDFINDINGS PubMed, Embase, and the Cochrane CENTRAL database for clinical trials were searched forrandomized controlled trials, published in English, French, or Spanish, between 1965 and June 2008.Selected studies utilized standardized treatment with rifampin-containing regimens. Studies reportedbacteriologically confirmed failure and/or relapse in previously untreated patients with bacteriologicallyconfirmed pulmonary TB. Pooled cumulative incidences of treatment outcomes and association with riskfactors were computed with stratified random effects meta-analyses. Meta-regression was performedusing a negative binomial regression model. A total of 57 trials with 312 arms and 21,472 participantswere included in the analysis. Regimens utilizing rifampin only for the first 1-2 mo had significantly higherrates of failure, relapse, and acquired drug resistance, as compared to regimens that used rifampin for 6mo. This was particularly evident when there was initial drug resistance to isoniazid, streptomycin, orboth. On the other hand, there was little evidence of difference in failure or relapse with daily orintermittent schedules of treatment administration, although there was insufficient published evidence ofthe efficacy of twice-weekly rifampin administration throughout therapy. CONCLUSIONS TB treatmentoutcomes were significantly worse with shorter duration of rifampin, or with initial drug resistance toisoniazid and/or streptomycin. Treatment outcomes were similar with all intermittent schedulesevaluated, but there is insufficient evidence to support administration of treatment twice weeklythroughout therapy.", "metadata": {}}
+{"_id": "16016673", "title": "", "text": "A novel set of DNA methylation markers in urine sediments for sensitive/specific detection of bladdercancer.PURPOSE This study aims to provide a better set of DNA methylation markers in urine sedimentsfor sensitive and specific detection of bladder cancer. EXPERIMENTAL DESIGN Fifty-nine tumor-associatedgenes were profiled in three bladder cancer cell lines, a small cohort of cancer biopsies and urinesediments by methylation-specific PCR. Twenty-one candidate genes were then profiled in urinesediments from 132 bladder cancer patients (8 cases for stage 0a; 68 cases for stage I; 50 cases forstage II; 4 cases for stages III; and 2 cases for stage IV), 23 age-matched patients with noncancerousurinary lesions, 6 neurologic diseases, and 7 healthy volunteers. RESULTS Despite six incidences of fourgenes reported in 3 of 23 noncancerous urinary lesion patients analyzed, cancer-specifichypermethylation in urine sediments were reported for 15 genes (P < 0.05). Methylation assessment ofan 11-gene set (SALL3, CFTR, ABCC6, HPR1, RASSF1A, MT1A, RUNX3, ITGA4, BCL2, ALX4, MYOD1,DRM, CDH13, BMP3B, CCNA1, RPRM, MINT1, and BRCA1) confirmed the existing diagnosis of 121 among132 bladder cancer cases (sensitivity, 91.7%) with 87% accuracy. Significantly, more than 75% of stage0a and 88% of stage I disease were detected, indicating its value in the early diagnosis of bladder cancer.Interestingly, the cluster of reported methylation markers used in the U.S. bladder cancers is distinctlydifferent from that identified in this study, suggesting a possible epigenetic disparity between theAmerican and Chinese cases. CONCLUSIONS Methylation profiling of an 11-gene set in urine sedimentsprovides a sensitive and specific detection of bladder cancer.", "metadata": {}}
+{"_id": "16056410", "title": "", "text": "Posttranslational Acetylation of α-Tubulin Constrains Protofilament Number in NativeMicrotubulesBACKGROUND Microtubules are built from linear polymers of α-β tubulin dimers(protofilaments) that form a tubular quinary structure. Microtubules assembled from purified tubulin invitro contain between 10 and 16 protofilaments; however, such structural polymorphisms are not foundin cells. This discrepancy implies that factors other than tubulin constrain microtubule protofilamentnumber, but the nature of these constraints is unknown. RESULTS Here, we show that acetylation ofMEC-12 α-tubulin constrains protofilament number in C. elegans touch receptor neurons (TRNs). Whereasthe sensory dendrite of wild-type TRNs is packed with a cross-linked bundle of long, 15-protofilamentmicrotubules, mec-17;atat-2 mutants lacking α-tubulin acetyltransferase activity have shortmicrotubules, rampant lattice defects, and variable protofilament number both between and withinmicrotubules. All-atom molecular dynamics simulations suggest a model in which acetylation of lysine 40promotes the formation of interprotofilament salt bridges, stabilizing lateral interactions betweenprotofilaments and constraining quinary structure to produce stable, structurally uniform microtubules invivo. CONCLUSIONS Acetylation of α-tubulin is an essential constraint on protofilament number in vivo.We propose a structural model in which this posttranslational modification promotes the formation oflateral salt bridges that fine-tune the association between adjacent protofilaments and enable theformation of uniform microtubule populations in vivo.", "metadata": {}}
+{"_id": "16056514", "title": "", "text": "A KEY ROLE FOR OREXIN IN PANIC ANXIETYPanic disorder is a severe anxiety disorder with recurrent,debilitating panic attacks. In individuals with panic disorder there is evidence of decreased centralgamma-aminobutyric acid (GABA) activity as well as marked increases in autonomic and respiratoryresponses after intravenous infusions of hypertonic sodium lactate. In a rat model of panic disorder,chronic inhibition of GABA synthesis in the dorsomedial-perifornical hypothalamus of rats producesanxiety-like states and a similar vulnerability to sodium lactate-induced cardioexcitatory responses. Thedorsomedial-perifornical hypothalamus is enriched in neurons containing orexin (ORX, also known ashypocretin), which have a crucial role in arousal, vigilance and central autonomic mobilization, all ofwhich are key components of panic. Here we show that activation of ORX-synthesizing neurons isnecessary for developing a panic-prone state in the rat panic model, and either silencing of thehypothalamic gene encoding ORX (Hcrt) with RNAi or systemic ORX-1 receptor antagonists blocks thepanic responses. Moreover, we show that human subjects with panic anxiety have elevated levels of ORXin the cerebrospinal fluid compared to subjects without panic anxiety. Taken together, our results suggestthat the ORX system may be involved in the pathophysiology of panic anxiety and that ORX antagonistsconstitute a potential new treatment strategy for panic disorder.", "metadata": {}}
+{"_id": "16057926", "title": "", "text": "Local Increases in Mechanical Tension Shape Compartment Boundaries by Biasing CellIntercalationsMechanical forces play important roles during tissue organization in developing animals.Many tissues are organized into adjacent, nonmixing groups of cells termed compartments. Boundariesbetween compartments display a straight morphology and are associated with signaling centers that areimportant for tissue growth and patterning. Local increases in mechanical tension at cell junctions alongcompartment boundaries have recently been shown to prevent cell mixing and to maintain straightboundaries. The cellular mechanisms by which local increases in mechanical tension prevent cell mixingat compartment boundaries, however, remain poorly understood. Here, we have used live imaging andquantitative image analysis to determine cellular dynamics at and near the anteroposterior compartmentboundaries of the Drosophila pupal abdominal epidermis. We show that cell mixing within compartmentsinvolves multiple cell intercalations. Frequency and orientation of cell intercalations are unchanged alongthe compartment boundaries; rather, an asymmetry in the shrinkage of junctions during intercalation isbiased, resulting in cell rearrangements that suppress cell mixing. Simulations of tissue growth show thatlocal increases in mechanical tension can account for this bias in junctional shrinkage. We conclude thatlocal increases in mechanical tension maintain cell populations separate by influencing junctionalrearrangements during cell intercalation.", "metadata": {}}
+{"_id": "16058322", "title": "", "text": "MDA5 and PTPN2, two candidate genes for type 1 diabetes, modify pancreatic β-cell responses to theviral by-product double-stranded RNAbeta-Cell destruction in type 1 diabetes (T1D) is at least in partconsequence of a 'dialog' between beta-cells and immune system. This dialog may be affected by theindividual's genetic background. We presently evaluated whether modulation of MDA5 and PTPN2, twocandidate genes for T1D, affects beta-cell responses to double-stranded RNA (dsRNA), a by-product ofviral replication. These genes were selected following comparison between known candidate genes forT1D and genes expressed in pancreatic beta-cells, as identified in previous array analysis. INS-1E cellsand primary fluorescence-activated cell sorting-purified rat beta-cells were transfected with smallinterference RNAs (siRNAs) targeting MDA5 or PTPN2 and subsequently exposed to intracellular syntheticdsRNA (polyinosinic-polycitidilic acid-PIC). Real-time RT-PCR, western blot and viability assays wereperformed to characterize gene/protein expression and viability. PIC increased MDA5 and PTPN2 mRNAexpression, which was inhibited by the specific siRNAs. PIC triggered apoptosis in INS-1E and primarybeta-cells and this was augmented by PTPN2 knockdown (KD), although inhibition of MDA5 did notmodify PIC-induced apoptosis. In contrast, MDA5 silencing decreased PIC-induced cytokine andchemokine expression, although inhibition of PTPN2 induced minor or no changes in these inflammatorymediators. These findings indicate that changes in MDA5 and PTPN2 expression modify beta-cellresponses to dsRNA. MDA5 regulates inflammatory signals, whereas PTPN2 may function as a defencemechanism against pro-apoptotic signals generated by dsRNA. These two candidate genes for T1D maythus modulate beta-cell apoptosis and/or local release of inflammatory mediators in the course of a viralinfection by acting, at least in part, at the pancreatic beta-cell level.", "metadata": {}}
+{"_id": "16066726", "title": "", "text": "Tumor necrosis factor signaling mediates resistance to mycobacteria by inhibiting bacterial growth andmacrophage death.Tumor necrosis factor (TNF), a key effector in controlling tuberculosis, is thought toexert protection by directing formation of granulomas, organized aggregates of macrophages and otherimmune cells. Loss of TNF signaling causes progression of tuberculosis in humans, and the increasedmortality of Mycobacterium tuberculosis-infected mice is associated with disorganized necroticgranulomas, although the precise roles of TNF signaling preceding this endpoint remain undefined. Wemonitored transparent Mycobacterium marinum-infected zebrafish live to conduct a stepwise dissection ofhow TNF signaling operates in mycobacterial pathogenesis. We found that loss of TNF signaling causedincreased mortality even when only innate immunity was operant. In the absence of TNF, intracellularbacterial growth and granuloma formation were accelerated and was followed by necrotic death ofoverladen macrophages and granuloma breakdown. Thus, TNF is not required for tuberculous granulomaformation, but maintains granuloma integrity indirectly by restricting mycobacterial growth withinmacrophages and preventing their necrosis.", "metadata": {}}
+{"_id": "16086778", "title": "", "text": "Loss of negative regulation by Numb over Notch is relevant to human breast carcinogenesisThe biologicalantagonism between Notch and Numb controls the proliferative/differentiative balance in developmentand homeostasis. Although altered Notch signaling has been linked to human diseases, including cancer,evidence for a substantial involvement of Notch in human tumors has remained elusive. Here, we showthat Numb-mediated control on Notch signaling is lost in \u000050% of human mammary carcinomas, due tospecific Numb ubiquitination and proteasomal degradation. Mechanistically, Numb operates as anoncosuppressor, as its ectopic expression in Numb-negative, but not in Numb-positive, tumor cellsinhibits proliferation. Increased Notch signaling is observed in Numb-negative tumors, but reverts tobasal levels after enforced expression of Numb. Conversely, Numb silencing increases Notch signaling innormal breast cells and in Numb-positive breast tumors. Finally, growth suppression of Numb-negative,but not Numb-positive, breast tumors can be achieved by pharmacological inhibition of Notch. Thus, theNumb/Notch biological antagonism is relevant to the homeostasis of the normal mammary parenchymaand its subversion contributes to human mammary carcinogenesis.", "metadata": {}}
+{"_id": "16090672", "title": "", "text": "Cortical Dynein Controls Microtubule Dynamics to Generate Pulling Forces that Position MicrotubuleAstersDynein at the cortex contributes to microtubule-based positioning processes such as spindlepositioning during embryonic cell division and centrosome positioning during fibroblast migration. Toinvestigate how cortical dynein interacts with microtubule ends to generate force and how this functionalassociation impacts positioning, we have reconstituted the 'cortical' interaction between dynein anddynamic microtubule ends in an in vitro system using microfabricated barriers. We show thatbarrier-attached dynein captures microtubule ends, inhibits growth, and triggers microtubulecatastrophes, thereby controlling microtubule length. The subsequent interaction with shrinkingmicrotubule ends generates pulling forces up to several pN. By combining experiments in microchamberswith a theoretical description of aster mechanics, we show that dynein-mediated pulling forces lead to thereliable centering of microtubule asters in simple confining geometries. Our results demonstrate theintrinsic ability of cortical microtubule-dynein interactions to regulate microtubule dynamics and drivepositioning processes in living cells.", "metadata": {}}
+{"_id": "16098747", "title": "", "text": "Breast cancer risk factors in relation to breast density (United States)Evaluate known breast cancer riskfactors in relation to breast density. We examined factors in relation to breast density in 144,018 NewHampshire (NH) women with at least one mammogram recorded in a statewide mammography registry.Mammographic breast density was measured by radiologists using the BI-RADS classification; risk factorsof interest were obtained from patient intake forms and questionnaires. Initial analyses showed a stronginverse influence of age and body mass index (BMI) on breast density. In addition, women with late ageat menarche, late age at first birth, premenopausal women, and those currently using hormone therapy(HT) tended to have higher breast density, while those with greater parity tended to have less densebreasts. Analyses stratified on age and BMI suggested interactions, which were formally assessed in amultivariable model. The impact of current HT use, relative to nonuse, differed across age groups, withan inverse association in younger women, and a positive association in older women (p < 0.0001 for theinteraction). The positive effects of age at menarche and age at first birth, and the inverse influence ofparity were less apparent in women with low BMI than in those with high BMI (p = 0.04, p < 0.0001 andp = 0.01, respectively, for the interactions). We also noted stronger positive effects for age at first birthin postmenopausal women (p = 0.004 for the interaction). The multivariable model indicated a slightpositive influence of family history of breast cancer. The influence of age at menarche and reproductivefactors on breast density is less evident in women with high BMI. Density is reduced in young womenusing HT, but increased in HT users of age 50 or more.", "metadata": {}}
+{"_id": "16108876", "title": "", "text": "Perspective: repression of competition and the evolution of cooperation.Repression of competition withingroups joins kin selection as the second major force in the history of life shaping the evolution ofcooperation. When opportunities for competition against neighbors are limited within groups, individualscan increase their own success only by enhancing the efficiency and productivity of their group. Thus,characters that repress competition within groups promote cooperation and enhance group success. Leighfirst expressed this idea in the context of fair meiosis, in which each chromosome has an equal chance oftransmission via gametes. Randomized success means that each part of the genome can increase its ownsuccess only by enhancing the total number of progeny and thus increasing the success of the group.Alexander used this insight about repression of competition in fair meiosis to develop his theories for theevolution of human sociality. Alexander argued that human social structures spread when they represscompetition within groups and promote successful group-against-group competition. Buss introduced anew example with his suggestion that metazoan success depended on repression of competition betweencellular lineages. Maynard Smith synthesized different lines of thought on repression of competition. Inthis paper, I develop simple mathematical models to illustrate the main processes by which repression ofcompetition evolves. With the concepts made clear, I then explain the history of the idea. I finish bysummarizing many new developments in this subject and the most promising lines for future study.", "metadata": {}}
+{"_id": "16119973", "title": "", "text": "ArticleIBD is characterized by uncontrolled immune responses in inflamed mucosa, with dominance ofIL-17-producing cells and deficiency of Treg cells. The aim of this study was to explore the effect andmechanisms of RA, the ligand of RARalpha, on immune responses in human and murine colitis. Colonicbiopsies from patients with UC were cultured and treated with RA as the agonist of RARalpha or LE135 asthe antagonist of RARalpha. Expressions of IL-17 and FOXP3 were detected by immunohistochemistry.Murine colitis was induced by intrarectal administration with TNBS at Day 1. Mice were then i.p.-treatedwith RA or LE135 daily for 7 days. Cytokine levels in the cultures of mouse LPMCs were measured.Expressions of FOXP3 and IL-17 in colon tissues or MLN were detected by immunohistological analysis.Body weight and colon inflammation were evaluated. RA treatment up-regulated FOXP3 expression anddown-regulated IL-17 expression in colon biopsies of patients and in colon tissues and MLN of mice withcolitis compared with controls. LPMCs from RA-treated mice produced lower levels of proinflammatorycytokines (TNF-alpha, IL-1beta, IL-17) but more regulatory cytokines (IL-10, TGF-beta) compared withthat of untreated mice. LE135 showed the opposite effect of RA. Furthermore, RA amelioratedTNBS-induced colitis in a dose-dependent manner, as seen by improved body weight and coloninflammation. RA down-regulates colon inflammatory responses in patients with IBD in vitro and inmurine colitis in vivo, representing a potential therapeutic approach in IBD treatment.", "metadata": {}}
+{"_id": "16120395", "title": "", "text": "Multiple RNA surveillance pathways limit aberrant expression of iron uptake mRNAs and prevent irontoxicity in S. cerevisiae.Tight regulation of the expression of mRNAs encoding iron uptake proteins isessential to control iron homeostasis and avoid intracellular iron toxicity. We show that many mRNAsencoding iron uptake or iron mobilization proteins are expressed in iron-replete conditions in the absenceof the S. cerevisiae RNase III ortholog Rnt1p or of the nuclear exosome component Rrp6p. Extendedforms of these mRNAs accumulate in the absence of Rnt1p or of the 5'-->3' exonucleases Xrn1p andRat1p, showing that multiple degradative pathways contribute to the surveillance of aberrant forms ofthese transcripts. RNase III-deficient cells are hypersensitive to high iron concentrations, suggesting thatRnt1p-mediated RNA surveillance is required to prevent iron toxicity. These results show that RNAsurveillance through multiple ribonucleolytic pathways plays a role in iron homeostasis in yeast to avoidthe potentially toxic effects of the expression of the iron starvation response in iron-replete conditions.", "metadata": {}}
+{"_id": "16128711", "title": "", "text": "Differential regulation of adherens junction dynamics during apical-basal polarization.Adherens junctions(AJs) in epithelial cells are constantly turning over to modulate adhesion properties under variousphysiological and developmental contexts, but how such AJ dynamics are regulated during theapical-basal polarization of primary epithelia remains unclear. Here, we used new and geneticallyvalidated GFP markers of Drosophila E-cadherin (DE-cadherin, hereafter referred to as DE-Cad) andβ-catenin (Armadillo, Arm) to quantitatively assay the in vivo dynamics of biosynthetic turnover andmembrane redistribution by fluorescence recovery after photobleaching (FRAP) assays. Our data showedthat membrane DE-Cad and Arm in AJs of polarizing epithelial cells had much faster biosynthetic turnoverthan in polarized cells. Fast biosynthetic turnover of membrane DE-Cad is independent of actin- anddynamin-based trafficking, but is microtubule-dependent. Furthermore, Arm in AJs of polarizing cellsshowed a faster and diffusion-based membrane redistribution that was both quantitatively andqualitatively different from the slower and exchange-based DE-Cad membrane distribution, indicatingthat the association of Arm with DE-Cad is more dynamic in polarizing cells, and only becomes stable inpolarized epithelial cells. Consistently, biochemical assays showed that the binding of Arm to DE-Cad isweaker in polarizing cells than in polarized cells. Our data revealed that the molecular interactionbetween DE-Cad and Arm is modulated during apical-basal polarization, suggesting a new mechanismthat might be crucial for establishing apical-basal polarity through regulating the AJ dynamics.", "metadata": {}}
+{"_id": "16167746", "title": "", "text": "Phylogenetic analysis of mRNA polyadenylation sites reveals a role of transposable elements in evolutionof the 3′-end of genesmRNA polyadenylation is an essential step for the maturation of almost alleukaryotic mRNAs, and is tightly coupled with termination of transcription in defining the 3'-end of genes.Large numbers of human and mouse genes harbor alternative polyadenylation sites [poly(A) sites] thatlead to mRNA variants containing different 3'-untranslated regions (UTRs) and/or encoding distinctprotein sequences. Here, we examined the conservation and divergence of different types of alternativepoly(A) sites across human, mouse, rat and chicken. We found that the 3'-most poly(A) sites tend to bemore conserved than upstream ones, whereas poly(A) sites located upstream of the 3'-most exon, alsotermed intronic poly(A) sites, tend to be much less conserved. Genes with longer evolutionary history aremore likely to have alternative polyadenylation, suggesting gain of poly(A) sites through evolution. Wealso found that nonconserved poly(A) sites are associated with transposable elements (TEs) to a muchgreater extent than conserved ones, albeit less frequently utilized. Different classes of TEs have differentcharacteristics in their association with poly(A) sites via exaptation of TE sequences into polyadenylationelements. Our results establish a conservation pattern for alternative poly(A) sites in several vertebratespecies, and indicate that the 3'-end of genes can be dynamically modified by TEs through evolution.", "metadata": {}}
+{"_id": "16172576", "title": "", "text": "Inter- and Intra-Host Viral Diversity in a Large Seasonal DENV2 OutbreakBACKGROUND High geneticdiversity at both inter- and intra-host level are hallmarks of RNA viruses due to the error-prone nature oftheir genome replication. Several groups have evaluated the extent of viral variability using different RNAvirus deep sequencing methods. Although much of this effort has been dedicated to pathogens that causechronic infections in humans, few studies investigated arthropod-borne, acute viral infections. METHODSAND PRINCIPAL FINDINGS We deep sequenced the complete genome of ten DENV2 isolates fromrepresentative classical and severe cases sampled in a large outbreak in Brazil using two differentapproaches. Analysis of the consensus genomes confirmed the larger extent of the 2010 epidemic incomparison to a previous epidemic caused by the same viruses in another city two years before (geneticdistance = 0.002 and 0.0008 respectively). Analysis of viral populations within the host revealed a highlevel of conservation. After excluding homopolymer regions of 454/Roche generated sequences, we found10 to 44 variable sites per genome population at a frequency of >1%, resulting in very low intra-hostgenetic diversity. While up to 60% of all variable sites at intra-host level were non-synonymous changes,only 10% of inter-host variability resulted from non-synonymous mutations, indicative of purifyingselection at the population level. CONCLUSIONS AND SIGNIFICANCE Despite the error-prone nature ofRNA-dependent RNA-polymerase, dengue viruses maintain low levels of intra-host variability.", "metadata": {}}
+{"_id": "16180601", "title": "", "text": "Serum Soluble Corin Deficiency Predicts Major Disability within 3 Months after Acute StrokeOBJECTIVESerum soluble corin has been associated with stroke. However, whether it is associated with strokeprognosis has not yet been studied. Therefore, we aimed to study the association of serum soluble corinwith risk of poor outcomes within 3 months after stroke. METHODS We followed 522 stroke patients for 3months to identify major disability, death and vascular events. Serum soluble corin was measured atbaseline for all participants. Logistic regression was used to examine the associations of baseline serumsoluble corin with outcomes of stroke, adjusting for age, sex, baseline NIHSS score, hours from onset tohospitalization, smoking, drinking, hypertension, diabetes, coronary heart disease, atrial fibrillation,family history of stroke, and stroke subtype. RESULTS Patients with high corin had a significantly lowercrude risk for the composite outcome of major disability or death (OR = 0.64, 95%CI: 0.43-0.96) thanpatients with low corin (the lowest tertile). After adjustment for age and baseline NIHSS score, patientswith high corin still had a significantly lower risk for the composite outcome of major disability or death(OR = 0.60, 95%CI: 0.36-0.99). This association became bottom line significant after additionallyadjusting for other conventional factors (OR = 0.61, P = 0.058). No association was found betweenserum soluble corin and other composite outcomes. CONCLUSION Serum soluble corin deficiencypredicted risk for major disability within 3 months after stroke, independent of baseline neurologicaldeficient. Our results may indicate a probable role of corin in stroke prognosis.", "metadata": {}}
+{"_id": "16201748", "title": "", "text": "Altered PTEN expression; a diagnostic marker for differentiating normal, hyperplastic and neoplasticendometriumBACKGROUND Different molecular alterations have been described in endometrioidendometrial carcinoma (EECA). Among them the most frequently altered is loss of the PTEN protein, atumor suppressor gene. The purpose of this study was to evaluate the expression pattern of PTEN gene innormal, hyperplastic and neoplastic endometrium. METHODS In a study in a referral gynecologic hospitalin Tehran, Iran, immunohistochemical (IHC) evaluation of PTEN was performed on 87 consecutivespecimens to the following three groups; group A- normal proliferative endometrium(n = 29); group B-hyperplastic endometrium [including simple hyperplasia without atypia(n = 21) and complex hyperplasiawith atypia (n = 8)] and group C- EECA(n = 29). Immunostaining of cells was analyzed by arbitraryquantitative methods according to both slide's area staining and intensity of color reaction. RESULTSPTEN immunoreactivity was present in all normal proliferative endometrium, all simple hyperplasia, 75%of atypical complex hyperplasia and in 48% of EECA (P < 0.001). The intensity of PTEN reaction wassignificantly higher in group with proliferative endometrium than hyperplastic endometrium and EECA (P< 0.001). CONCLUSION PTEN expression was significantly higher in cyclical endometrium than in atypicalhyperplasia and endometrioid carcinoma.", "metadata": {}}
+{"_id": "16204011", "title": "", "text": "Care Seeking for Neonatal Illness in Low- and Middle-Income Countries: A SystematicReviewBACKGROUND Despite recent achievements to reduce child mortality, neonatal deaths continue toremain high, accounting for 41% of all deaths in children under five years of age worldwide, of which over90% occur in low- and middle-income countries (LMICs). Infections are a leading cause of death andlimitations in care seeking for ill neonates contribute to high mortality rates. As estimates forcare-seeking behaviors in LMICs have not been studied, this review describes care seeking for neonatalillnesses in LMICs, with particular attention to type of care sought. METHODS AND FINDINGS Weconducted a systematic literature review of studies that reported the proportion of caregivers that soughtcare for ill or suspected ill neonates in LMICs. The initial search yielded 784 studies, of which 22 studiesdescribed relevant data from community household surveys, facility-based surveys, and interventiontrials. The majority of studies were from South Asia (n = 17/22), set in rural areas (n = 17/22), andpublished within the last 4 years (n = 18/22). Of the 9,098 neonates who were ill or suspected to be ill,4,320 caregivers sought some type of care, including care from a health facility (n = 370) or provider (n= 1,813). Care seeking ranged between 10% and 100% among caregivers with a median of 59%. Careseeking from a health care provider yielded a similar range and median, while care seeking at a healthcare facility ranged between 1% and 100%, with a median of 20%. Care-seeking estimates were limitedby the few studies conducted in urban settings and regions other than South Asia. There was a lack ofconsistency regarding illness, care-seeking, and care provider definitions. CONCLUSIONS There is apaucity of data regarding newborn care-seeking behaviors; in South Asia, care seeking is low for newbornillness, especially in terms of care sought from health care facilities and medically trained providers.There is a need for representative data to describe care-seeking patterns in different geographic regionsand better understand mechanisms to enhance care seeking during this vulnerable time period.", "metadata": {}}
+{"_id": "16208091", "title": "", "text": "Synaptic Incorporation of AMPA Receptors during LTP Is Controlled by a PKC Phosphorylation Site onGluR1Incorporation of GluR1-containing AMPA receptors into synapses is essential to several forms ofneural plasticity, including long-term potentiation (LTP). Numerous signaling pathways that trigger thisprocess have been identified, but the direct modifications of GluR1 that control its incorporation intosynapses are unclear. Here, we show that phosphorylation of GluR1 by PKC at a highly conserved serine818 residue is increased during LTP and critical for LTP expression. GluR1 is phosphorylated by PKC atthis site in vitro and in vivo. In addition, acute phosphorylation at GluR1 S818 by PKC, as well as aphosphomimetic mutation, promotes GluR1 synaptic incorporation. Conversely, preventing GluR1 S818phosphorylation reduces LTP and blocks PKC-driven synaptic incorporation of GluR1. We conclude thatthe phosphorylation of GluR1 S818 by PKC is a critical event in the plasticity-driven synaptic incorporationof AMPA receptors.", "metadata": {}}
+{"_id": "16217855", "title": "", "text": "The Bloom's syndrome helicase promotes the annealing of complementary single-stranded DNATheproduct of the gene mutated in Bloom's syndrome, BLM, is a 3′–5′ DNA helicase belonging to the highlyconserved RecQ family. In addition to a conventional DNA strand separation activity, BLM catalyzes boththe disruption of non-B-form DNA, such as G-quadruplexes, and the branch migration of Hollidayjunctions. Here, we have characterized a new activity for BLM: the promotion of single-stranded DNA(ssDNA) annealing. This activity does not require Mg2+, is inhibited by ssDNA binding proteins and ATP,and is dependent on DNA length. Through analysis of various truncation mutants of BLM, we show thatthe C-terminal domain is essential for strand annealing and identify a 60 amino acid stretch of thisdomain as being important for both ssDNA binding and strand annealing. We present a model in whichthe ssDNA annealing activity of BLM facilitates its role in the processing of DNA intermediates that ariseduring repair of damaged replication forks.", "metadata": {}}
+{"_id": "16232581", "title": "", "text": "Bayesian selection of continuous-time Markov chain evolutionary models.We develop a reversible jumpMarkov chain Monte Carlo approach to estimating the posterior distribution of phylogenies based onaligned DNA/RNA sequences under several hierarchical evolutionary models. Using a proper, yetnontruncated and uninformative prior, we demonstrate the advantages of the Bayesian approach tohypothesis testing and estimation in phylogenetics by comparing different models for the infinitesimalrates of change among nucleotides, for the number of rate classes, and for the relationships amongbranch lengths. We compare the relative probabilities of these models and the appropriateness of amolecular clock using Bayes factors. Our most general model, first proposed by Tamura and Nei,parameterizes the infinitesimal change probabilities among nucleotides (A, G, C, T/U) into sixparameters, consisting of three parameters for the nucleotide stationary distribution, two rate parametersfor nucleotide transitions, and another parameter for nucleotide transversions. Nested models include theHasegawa, Kishino, and Yano model with equal transition rates and the Kimura model with a uniformstationary distribution and equal transition rates. To illustrate our methods, we examine simulated data,16S rRNA sequences from 15 contemporary eubacteria, halobacteria, eocytes, and eukaryotes, 9primates, and the entire HIV genome of 11 isolates. We find that the Kimura model is too restrictive, thatthe Hasegawa, Kishino, and Yano model can be rejected for some data sets, that there is evidence formore than one rate class and a molecular clock among similar taxa, and that a molecular clock can berejected for more distantly related taxa.", "metadata": {}}
+{"_id": "16233471", "title": "", "text": "The intersection between aging and cardiovascular disease.The average lifespan of humans is increasing,and with it the percentage of people entering the 65 and older age group is growing rapidly and willcontinue to do so in the next 20 years. Within this age group, cardiovascular disease will remain theleading cause of death, and the cost associated with treatment will continue to increase. Aging is aninevitable part of life and unfortunately poses the largest risk factor for cardiovascular disease. Althoughnumerous studies in the cardiovascular field have considered both young and aged humans, there are stillmany unanswered questions as to how the genetic pathways that regulate aging in model organismsinfluence cardiovascular aging. Likewise, in the molecular biology of aging field, few studies fully assessthe role of these aging pathways in cardiovascular health. Fortunately, this gap is beginning to close, andthese two fields are merging together. We provide an overview of some of the key genes involved inregulating lifespan and health span, including sirtuins, AMP-activated protein kinase, mammalian targetof rapamycin, and insulin-like growth factor 1 and their roles regulating cardiovascular health. We thendiscuss a series of review articles that will appear in succession and provide a more comprehensiveanalysis of studies carried out linking genes of aging and cardiovascular health, and perspectives offuture directions of these two intimately linked fields.", "metadata": {}}
+{"_id": "16237005", "title": "", "text": "Single-RNA counting reveals alternative modes of gene expression in yeastProper execution oftranscriptional programs is a key requirement of gene expression regulation, demanding accurate controlof timing and amplitude. How precisely the transcription machinery fulfills this task is not known. Usingan in situ hybridization approach that detects single mRNA molecules, we measured mRNA abundanceand transcriptional activity within single Saccharomyces cerevisiae cells. We found that expression levelsfor particular genes are higher than initially reported and can vary substantially among cells. However,variability for most constitutively expressed genes is unexpectedly small. Combining single-transcriptmeasurements with computational modeling indicates that low expression variation is achieved bytranscribing genes using single transcription-initiation events that are clearly separated in time, ratherthan by transcriptional bursts. In contrast, PDR5, a gene regulated by the transcription coactivatorcomplex SAGA, is expressed using transcription bursts, resulting in larger variation. These data directlydemonstrate the existence of multiple expression modes used to modulate the transcriptome.", "metadata": {}}
+{"_id": "16242975", "title": "", "text": "A complete landscape of post-transcriptional modifications in mammalian mitochondrial tRNAsInmammalian mitochondria, 22 species of tRNAs encoded in mitochondrial DNA play crucial roles in thetranslation of 13 essential subunits of the respiratory chain complexes involved in oxidativephosphorylation. Following transcription, mitochondrial tRNAs are modified by nuclear-encodedtRNA-modifying enzymes. These modifications are required for the proper functioning of mitochondrialtRNAs (mt tRNAs), and the absence of these modifications can cause pathological consequences. To date,however, the information available about these modifications has been incomplete. To address this issue,we isolated all 22 species of mt tRNAs from bovine liver and comprehensively determined thepost-transcriptional modifications in each tRNA by mass spectrometry. Here, we describe the primarystructures with post-transcriptional modifications of seven species of mt tRNAs which were previouslyuncharacterized, and provide revised information regarding base modifications in five other mt tRNAs. Inthe complete set of bovine mt tRNAs, we found 15 species of modified nucleosides at 118 positions(7.48% of total bases). This result provides insight into the molecular mechanisms underlying thedecoding system in mammalian mitochondria and enables prediction of candidate tRNA-modifyingenzymes responsible for each modification of mt tRNAs.", "metadata": {}}
+{"_id": "16252863", "title": "", "text": "Preventing coronary heart disease: B vitamins and homocysteine.The list of preventable and reversiblerisk factors for atherosclerotic cardiovascular disease continues to grow. Cigarette smoking, high bloodpressure, physical inactivity, elevated cholesterol, underlying lipoprotein abnormalities, lipoprotein(a),diabetes, overweight, male gender, and age are well-established risk factors. During the 1990s, therehave been many reports associating elevated plasma homocysteine levels with arterioscleroticcardiovascular disease and consistent evidence that dietary and supplemental folic acid can reducehomocysteine levels.1 2   The article by Robinson and colleagues3 in this issue of Circulation presentsfurther evidence of the importance of homocysteine and suggestive evidence that plasma folate andplasma pyrixodal-l-phosphate (vitamin B6) are protective factors. Their study is part of the EuropeanConcerted Action Project,4 which examined 750 patients younger than age 60 with diagnoses within theprevious 12 months of coronary, cerebrovascular, or peripheral vascular disease and 800 healthy controlsubjects. The patient groups were young (47 years for cases and 44 years for control subjects) andheterogeneous, with nonfatal clinical events or symptoms of arteriosclerotic cardiovascular diseasesupported by ECG, angiographic, or Doppler evidence; the study involved 19 centers in nine Europeancountries. Men in the highest quintile for fasting total homocysteine (tHcy), compared with the remainderof the population, had an estimated relative risk of 2.2 (95% confidence interval [CI], 1.6 to 2.9), with astriking dose-response relationship and a more-than-multiplicative interaction with cigarette smoking andhigh blood pressure on vascular disease risk4 ; the corresponding estimated relative risk for coronaryheart disease was similar (2.0; 95% CI 1.6 to 2.8). (tHcy is the sum of homocysteine and homocysteinylmoieties of oxidized disulfides, homocystine, and cysteine- homocysteine. ) Robinson and colleagues3examined three B vitamins in detail to determine their effects on fasting and post–methionine-loadingtHcy levels and any independent effects on cardiovascular disease …", "metadata": {}}
+{"_id": "16256507", "title": "", "text": "Relationship between serum parathyroid hormone levels, vitamin D sufficiency, and calciumintake.CONTEXT Adequate vitamin D status for optimum bone health has received increased recognitionin recent years; however, the ideal intake is not known. Serum 25-hydroxyvitamin D is the generallyaccepted indicator of vitamin D status, but no universal reference level has been reached. OBJECTIVE Toinvestigate the relative importance of high calcium intake and serum 25-hydroxyvitamin D for calciumhomeostasis, as determined by serum intact parathyroid hormone (PTH). DESIGN, SETTING, ANDPARTICIPANTS Cross-sectional study of 2310 healthy Icelandic adults who were divided equally into 3age groups (30-45 years, 50-65 years, or 70-85 years) and recruited from February 2001 to January2003. They were administered a semi-quantitative food frequency questionnaire, which assessed vitaminD and calcium intake. Participants were further divided into groups according to calcium intake (<800mg/d, 800-1200 mg/d, and >1200 mg/d) and serum 25-hydroxyvitamin D level (<10 ng/mL, 10-18ng/mL, and >18 ng/mL). MAIN OUTCOME MEASURE Serum intact PTH as determined by calcium intakeand vitamin D.   RESULTS A total of 944 healthy participants completed all parts of the study. Afteradjusting for relevant factors, serum PTH was lowest in the group with a serum 25-hydroxyvitamin Dlevel of more than 18 ng/mL but highest in the group with a serum 25-hydroxyvitamin D level of lessthan 10 ng/mL. At the low serum 25-hydroxyvitamin D level (<10 ng/mL), calcium intake of less than800 mg/d vs more than 1200 mg/d was significantly associated with higher serum PTH (P = .04); and ata calcium intake of more than 1200 mg/d, there was a significant difference between the lowest andhighest vitamin D groups (P = .04). CONCLUSIONS As long as vitamin D status is ensured, calcium intakelevels of more than 800 mg/d may be unnecessary for maintaining calcium metabolism. Vitamin Dsupplements are necessary for adequate vitamin D status in northern climates.", "metadata": {}}
+{"_id": "16267205", "title": "", "text": "Sex-specific effects of the DAF-12 steroid receptor on aging in Caenorhabditis elegans.Sex differences inlongevity and aging are seen throughout the animal kingdom. These are likely to result, in part, from sexdifferences in endocrinology. In the nematode Caenorhabditis elegans, males are the longer-lived sex.Here we explore the possibility that sex differences in insulin/insulin-like growth factor 1 (IGF-1) andsteroid endocrinology contribute to this sex difference in aging by studying C. elegans populations inliquid culture. We report that in hermaphrodite populations, mutational loss of the DAF-12 steroidreceptor affected life span as in previous plate-culture studies: mutant longevity is suppressed in a weakdaf-2 insulin/IGF-1 receptor mutant but enhanced in a stronger daf-2 mutant. However, in males,mutation of daf-12 had little effect on aging in either weak or strong daf-2 mutants. Moreover, whilemutation of daf-12 marginally reduced life span in daf-2(+) hermaphrodites, as in plate-culturedpopulations, it did not in daf-2(+) males. These results could imply that in C. elegans, as in mammals,sex differences in steroid endocrinology contribute to sex differences in aging.", "metadata": {}}
+{"_id": "16270577", "title": "", "text": "Nonclassical binding of formylated peptide in crystal structure of the MHC class lb molecule H2-M3H2-M3is a class Ib MHC molecule of the mouse with a 10(4)-fold preference for binding N-formylated peptides.To elucidate the basis of this unusual specificity, we expressed and crystallized a soluble form of M3 witha formylated nonamer peptide, fMYFINILTL, and determined the structure by X-ray crystallography. M3,refined at 2.1 A resolution, resembles class la MHC molecules in its overall structure, but differs in thepeptide-binding groove. The A pocket, which usually accommodates the free N-terminus of a boundpeptide, is closed, and the peptide is shifted one residue, such that the P1 side chain is lodged in the Bpocket. The formyl group is coordinated by His-9 and a bound water on the floor of the groove.", "metadata": {}}
+{"_id": "16280642", "title": "", "text": "Sequential signals toward podosome formation in NIH-src cellsPodosomes (also termed invadopodia incancer cells) are actin-rich adhesion structures with matrix degradation activity that develop in variouscell types. Despite their significant physiological importance, the molecular mechanism of podosomeformation is largely unknown. In this study, we investigated the molecular mechanisms of podosomeformation. The expression of various phosphoinositide-binding domains revealed that the podosomes inSrc-transformed NIH3T3 (NIH-src) cells are enriched with PtdIns(3,4)P2, suggesting an important role ofthis phosphoinositide in podosome formation. Live-cell imaging analysis revealed that Src-expressionstimulated podosome formation at focal adhesions of NIH3T3 cells after PtdIns(3,4)P2 accumulation. Theadaptor protein Tks5/FISH, which is essential for podosome formation, was found to form a complex withGrb2 at adhesion sites in an Src-dependent manner. Further, it was found that N-WASP bound all SH3domains of Tks5/FISH, which facilitated circular podosome formation. These results indicate thataugmentation of the N-WASP-Arp2/3 signal was accomplished on the platform of Tks5/FISH-Grb2complex at focal adhesions, which is stabilized by PtdIns(3,4)P2.", "metadata": {}}
+{"_id": "16284655", "title": "", "text": "Forebrain engraftment by human glial progenitor cells enhances synaptic plasticity and learning in adultmice.Human astrocytes are larger and more complex than those of infraprimate mammals, suggestingthat their role in neural processing has expanded with evolution. To assess the cell-autonomous andspecies-selective properties of human glia, we engrafted human glial progenitor cells (GPCs) intoneonatal immunodeficient mice. Upon maturation, the recipient brains exhibited large numbers and highproportions of both human glial progenitors and astrocytes. The engrafted human glia weregap-junction-coupled to host astroglia, yet retained the size and pleomorphism of hominid astroglia, andpropagated Ca2+ signals 3-fold faster than their hosts. Long-term potentiation (LTP) was sharplyenhanced in the human glial chimeric mice, as was their learning, as assessed by Barnes mazenavigation, object-location memory, and both contextual and tone fear conditioning. Mice allografted withmurine GPCs showed no enhancement of either LTP or learning. These findings indicate that human gliadifferentially enhance both activity-dependent plasticity and learning in mice.", "metadata": {}}
+{"_id": "16287725", "title": "", "text": "Reprogramming of human fibroblasts to pluripotency with lineage specifiers.Since the initial discoverythat OCT4, SOX2, KLF4, and c-MYC overexpression sufficed for the induction of pluripotency in somaticcells, methodologies replacing the original factors have enhanced our understanding of thereprogramming process. However, unlike in mouse, OCT4 has not been replaced successfully duringreprogramming of human cells. Here we report on a strategy to accomplish this replacement. Through acombination of transcriptome and bioinformatic analysis we have identified factors previouslycharacterized as being lineage specifiers that are able to replace OCT4 and SOX2 in the reprogramming ofhuman fibroblasts. Our results show that it is possible to replace OCT4 and SOX2 simultaneously withalternative lineage specifiers in the reprogramming of human cells. At a broader level, they also support amodel in which counteracting lineage specification networks underlies the induction of pluripotency.", "metadata": {}}
+{"_id": "16319097", "title": "", "text": "Mechanisms of endocytosis.Endocytic mechanisms control the lipid and protein composition of the plasmamembrane, thereby regulating how cells interact with their environments. Here, we review what is knownabout mammalian endocytic mechanisms, with focus on the cellular proteins that control these events.We discuss the well-studied clathrin-mediated endocytic mechanisms and dissect endocytic pathwaysthat proceed independently of clathrin. These clathrin-independent pathways include the CLIC/GEECendocytic pathway, arf6-dependent endocytosis, flotillin-dependent endocytosis, macropinocytosis,circular doral ruffles, phagocytosis, and trans-endocytosis. We also critically review the role of caveolaeand caveolin1 in endocytosis. We highlight the roles of lipids, membrane curvature-modulating proteins,small G proteins, actin, and dynamin in endocytic pathways. We discuss the functional relevance ofdistinct endocytic pathways and emphasize the importance of studying these pathways to understandhuman disease processes.", "metadata": {}}
+{"_id": "16322674", "title": "", "text": "Birth Size and Breast Cancer Risk: Re-analysis of Individual Participant Data from 32StudiesBACKGROUND Birth size, perhaps a proxy for prenatal environment, might be a correlate ofsubsequent breast cancer risk, but findings from epidemiological studies have been inconsistent. Were-analysed individual participant data from published and unpublished studies to obtain more preciseestimates of the magnitude and shape of the birth size-breast cancer association. METHODS ANDFINDINGS Studies were identified through computer-assisted and manual searches, and personalcommunication with investigators. Individual participant data from 32 studies, comprising 22,058 breastcancer cases, were obtained. Random effect models were used, if appropriate, to combine study-specificestimates of effect. Birth weight was positively associated with breast cancer risk in studies based onbirth records (pooled relative risk [RR] per one standard deviation [SD] [= 0.5 kg] increment in birthweight: 1.06; 95% confidence interval [CI] 1.02-1.09) and parental recall when the participants werechildren (1.02; 95% CI 0.99-1.05), but not in those based on adult self-reports, or maternal recall duringthe woman's adulthood (0.98; 95% CI 0.95-1.01) (p for heterogeneity between data sources = 0.003).Relative to women who weighed 3.000-3.499 kg, the risk was 0.96 (CI 0.80-1.16) in those who weighed< 2.500 kg, and 1.12 (95% CI 1.00-1.25) in those who weighed > or = 4.000 kg (p for linear trend =0.001) in birth record data. Birth length and head circumference from birth records were also positivelyassociated with breast cancer risk (pooled RR per one SD increment: 1.06 [95% CI 1.03-1.10] and 1.09[95% CI 1.03-1.15], respectively). Simultaneous adjustment for these three birth size variables showedthat length was the strongest independent predictor of risk. The birth size effects did not appear to beconfounded or mediated by established breast cancer risk factors and were not modified by age ormenopausal status. The cumulative incidence of breast cancer per 100 women by age 80 y in the studypopulations was estimated to be 10.0, 10.0, 10.4, and 11.5 in those who were, respectively, in thebottom, second, third, and top fourths of the birth length distribution. CONCLUSIONS This pooled analysisof individual participant data is consistent with birth size, and in particular birth length, being anindependent correlate of breast cancer risk in adulthood.", "metadata": {}}
+{"_id": "16346504", "title": "", "text": "LncRNA-GAS5 induces PTEN expression through inhibiting miR-103 in endometrial cancercellsBACKGROUND Growth arrest-specific 5 (GAS5) was reported to be implicated and aberrantly expressin multiple cancers. However, the expression and mechanism of action of GAS5 were largely poorunderstood in endometrial carcinoma. RESULTS According to the result of real-time reverse-transcriptasepolymerase chain reaction (RT-PCR) and flow cytometry analysis, we identified that GAS5 wasdown-regulated in endometrial cancer cells and stimulated the apoptosis of endometrial cancer cells. Toinvestigate the expression of GAS5, PTEN and miR-103, RT-PCR was performed. And we found that theexpression of PTEN was up-regulated when endometrial cancer cells overexpressed GAS5. The predictionof bioinformatics online revealed that GAS5 could bind to miR-103, which was further found to beregulated by GAS5. Finally, we found that miR-103 mimic could decrease the mRNA and protein levels ofPTEN through luciferase reporter assay and western blotting, and GAS5 plasmid may reverse thisregulation effect in endometrial cancer cells. CONCLUSION In summary, we demonstrate that GAS5 actsas an tumor suppressor lncRNA in endometrial cancer. Through inhibiting the expression of miR-103,GAS5 significantly enhanced the expression of PTEN to promote cancer cell apoptosis, and, thus, could bean important mediator in the pathogenesis of endometrial cancer.", "metadata": {}}
+{"_id": "16355392", "title": "", "text": "Modification of kidney barrier function by the urokinase receptorPodocyte dysfunction, represented byfoot process effacement and proteinuria, is often the starting point for progressive kidney disease.Therapies aimed at the cellular level of the disease are currently not available. Here we show thatinduction of urokinase receptor (uPAR) signaling in podocytes leads to foot process effacement andurinary protein loss via a mechanism that includes lipid-dependent activation of αvβ3 integrin. Micelacking uPAR (Plaur−/−) are protected from lipopolysaccharide (LPS)-mediated proteinuria but developdisease after expression of a constitutively active β3 integrin. Gene transfer studies reveal a prerequisitefor uPAR expression in podocytes, but not in endothelial cells, for the development of LPS-mediatedproteinuria. Mechanistically, uPAR is required to activate αvβ3 integrin in podocytes, promoting cellmotility and activation of the small GTPases Cdc42 and Rac1. Blockade of αvβ3 integrin reduces podocytemotility in vitro and lowers proteinuria in mice. Our findings show a physiological role for uPAR signalingin the regulation of kidney permeability.", "metadata": {}}
+{"_id": "16361581", "title": "", "text": "Jagged1-induced Notch signaling drives proliferation of multiple myeloma cells.Notch receptors expressedon hematopoietic stem cells interact with their ligands on bone marrow stromal cells and thereby controlcell fate decisions and survival. We recently demonstrated that Notch signaling is involved in proliferationand survival of B cell-derived tumor cells of classic Hodgkin disease and described a novel mechanism forthe oncogenic capacity of Notch. In this study we investigated whether Notch signaling is involved in thetight interactions between neoplastic plasma cells and their bone marrow microenvironment, which areessential for tumor cell growth in multiple myeloma (MM). Here we demonstrate that Notch receptors andtheir ligand Jagged1 are highly expressed in cultured and primary MM cells, whereas nonneoplasticcounterparts show low to undetectable levels of Notch. Functional data indicate that ligand-induced Notchsignaling is a growth factor for MM cells and suggest that these interactions contribute tomyelomagenesis in vivo.", "metadata": {}}
+{"_id": "16364639", "title": "", "text": "An Extensive MicroRNA-Mediated Network of RNA-RNA Interactions Regulates Established OncogenicPathways in GlioblastomaBy analyzing gene expression data in glioblastoma in combination with matchedmicroRNA profiles, we have uncovered a posttranscriptional regulation layer of surprising magnitude,comprising more than 248,000 microRNA (miR)-mediated interactions. These include \u00007,000 geneswhose transcripts act as miR \"sponges\" and 148 genes that act through alternative, nonspongeinteractions. Biochemical analyses in cell lines confirmed that this network regulates established driversof tumor initiation and subtype implementation, including PTEN, PDGFRA, RB1, VEGFA, STAT3, andRUNX1, suggesting that these interactions mediate crosstalk between canonical oncogenic pathways.siRNA silencing of 13 miR-mediated PTEN regulators, whose locus deletions are predictive of PTENexpression variability, was sufficient to downregulate PTEN in a 3'UTR-dependent manner and to increasetumor cell growth rates. Thus, miR-mediated interactions provide a mechanistic, experimentally validatedrationale for the loss of PTEN expression in a large number of glioma samples with an intact PTEN locus.", "metadata": {}}
+{"_id": "16375102", "title": "", "text": "Direct reprogramming of mouse fibroblasts to neural progenitors.The simple yet powerful technique ofinduced pluripotency may eventually supply a wide range of differentiated cells for cell therapy and drugdevelopment. However, making the appropriate cells via induced pluripotent stem cells (iPSCs) requiresreprogramming of somatic cells and subsequent redifferentiation. Given how arduous and lengthy thisprocess can be, we sought to determine whether it might be possible to convert somatic cells intolineage-specific stem/progenitor cells of another germ layer in one step, bypassing the intermediatepluripotent stage. Here we show that transient induction of the four reprogramming factors (Oct4, Sox2,Klf4, and c-Myc) can efficiently transdifferentiate fibroblasts into functional neural stem/progenitor cells(NPCs) with appropriate signaling inputs. Compared with induced neurons (or iN cells, which are directlyconverted from fibroblasts), transdifferentiated NPCs have the distinct advantage of being expandable invitro and retaining the ability to give rise to multiple neuronal subtypes and glial cells. Our results providea unique paradigm for iPSC-factor-based reprogramming by demonstrating that it can be readily modifiedto serve as a general platform for transdifferentiation.", "metadata": {}}
+{"_id": "16389141", "title": "", "text": "Tissue-Specific Knockout of the Insulin Receptor in Pancreatic β Cells Creates an Insulin Secretory DefectSimilar to that in Type 2 DiabetesDysfunction of the pancreatic beta cell is an important defect in thepathogenesis of type 2 diabetes, although its exact relationship to the insulin resistance is unclear. Todetermine whether insulin signaling has a functional role in the beta cell we have used the Cre-loxPsystem to specifically inactivate the insulin receptor gene in the beta cells. The resultant mice exhibit aselective loss of insulin secretion in response to glucose and a progressive impairment of glucosetolerance. These data indicate an important functional role for the insulin receptor in glucose sensing bythe pancreatic beta cell and suggest that defects in insulin signaling at the level of the beta cell maycontribute to the observed alterations in insulin secretion in type 2 diabetes.", "metadata": {}}
+{"_id": "16390264", "title": "", "text": "Social variations in access to hospital care for patients with colorectal, breast, and lung cancer between1999 and 2006: retrospective analysis of hospital episode statisticsOBJECTIVES To determine the extentto which type of hospital admission (emergency compared with elective) and surgical procedure varied bysocioeconomic circumstances, age, sex, and year of admission for colorectal, breast, and lung cancer.DESIGN Repeated cross sectional study with data from individual patients, 1 April 1999 to 31 March2006. SETTING Hospital episode statistics (HES) dataset. PARTICIPANTS 564 821 patients aged 50 andover admitted with a diagnosis of colorectal, breast, or lung cancer. MAIN OUTCOME MEASURESProportion of patients admitted as emergencies, and the proportion receiving the recommended surgicaltreatment. RESULTS Patients from deprived areas, older people, and women were more likely to beadmitted as emergencies. For example, the adjusted odds ratio for patients with breast cancer in theleast compared with most deprived fifth of deprivation was 0.63 (95% confidence interval 0.60 to 0.66)and the adjusted odds ratio for patients with lung cancer aged 80-89 compared with those aged 50-59was 3.13 (2.93 to 3.34). There were some improvements in disparities between age groups but not forpatients living in deprived areas over time. Patients from deprived areas were less likely to receivepreferred procedures for rectal, breast, and lung cancer. These findings did not improve with time. Forexample, 67.4% (3529/5237) of patients in the most deprived fifth of deprivation had anterior resectionfor rectal cancer compared with 75.5% (4497/5959) of patients in the least deprived fifth (1.34, 1.22 to1.47). Over half (54.0%, 11 256/20 849) of patients in the most deprived fifth of deprivation had breastconserving surgery compared with 63.7% (18 445/28 960) of patients in the least deprived fifth (1.21,1.16 to 1.26). Men were less likely than women to undergo anterior resection and lung cancer resectionand older people were less likely to receive breast conserving surgery and lung cancer resection. Forexample, the adjusted odds ratio for lung cancer patients aged 80-89 compared with those aged 50-59was 0.52 (0.46 to 0.59). Conclusions Despite the implementation of the NHS Cancer Plan, social factorsstill strongly influence access to and the provision of care.", "metadata": {}}
+{"_id": "16398049", "title": "", "text": "Identification of Gene Positioning Factors Using High-Throughput Imaging MappingGenomes are arrangednon-randomly in the 3D space of the cell nucleus. Here, we have developed HIPMap, a high-precision,high-throughput, automated fluorescent in situ hybridization imaging pipeline, for mapping of the spatiallocation of genome regions at large scale. High-throughput imaging position mapping (HIPMap) enabledan unbiased siRNA screen for factors involved in genome organization in human cells. We identify 50cellular factors required for proper positioning of a set of functionally diverse genomic loci. Positioningfactors include chromatin remodelers, histone modifiers, and nuclear envelope and pore proteins.Components of the replication and post-replication chromatin re-assembly machinery are prominentlyrepresented among positioning factors, and timely progression of cells through replication, but notmitosis, is required for correct gene positioning. Our results establish a method for the large-scalemapping of genome locations and have led to the identification of a compendium of cellular factorsinvolved in spatial genome organization.", "metadata": {}}
+{"_id": "16398827", "title": "", "text": "Astrocyte-Mediated Distributed Plasticity at Hypothalamic Glutamate SynapsesAfferent activity can inducefast, feed-forward changes in synaptic efficacy that are synapse specific. Using combinedelectrophysiology, caged molecule photolysis, and Ca(2+) imaging, we describe a plasticity in which therecruitment of astrocytes in response to afferent activity causes a fast and feed-forward, yet distributedincrease in the amplitude of quantal synaptic currents at multiple glutamate synapses on magnocellularneurosecretory cells in the hypothalamic paraventricular nucleus. The plasticity is largely multiplicative,consistent with a proportional increase or \"scaling\" in the strength of all synapses on the neuron. Thiseffect requires a metabotropic glutamate receptor-mediated rise in Ca(2+) in the astrocyte processessurrounding the neuron and the release of the gliotransmitter ATP, which acts on postsynaptic purinergicreceptors. These data provide evidence for a form of distributed synaptic plasticity that is feed-forward,expressed quickly, and mediated by the synaptic activation of neighboring astrocytes.", "metadata": {}}
+{"_id": "16422880", "title": "", "text": "Effect of smoking reduction on lung cancer risk.CONTEXT Many smokers are unable or unwilling tocompletely quit smoking. A proposed means of harm reduction is to reduce the number of cigarettessmoked per day. However, it is not clear whether this strategy decreases the risk for tobacco-relateddiseases. OBJECTIVE To assess the effects of smoking reduction on lung cancer incidence. DESIGN,SETTING, AND PARTICIPANTS Observational population-based cohort study with up to 31 years offollow-up from the Copenhagen Centre for Prospective Population Studies, which administrates data from3 longitudinal studies conducted in Copenhagen and suburbs, the Copenhagen City Heart Study, theCopenhagen Male Study, and the Glostrup Population Studies, Denmark. Participants were 11,151 menand 8563 women (N = 19,714) aged 20 to 93 years, who attended 2 consecutive examinations with a 5-to 10-year interval between 1964 and 1988. Participants underwent a physical examination andcompleted self-filled questionnaires about lifestyle habits. The study population was divided into 6 groupsaccording to smoking habits: continued heavy smokers (> or =15 cigarettes/d), reducers (reduced from> or =15 cigarettes/d by minimum of 50% without quitting), continued light smokers (1-14 cigarettes/d),quitters (stopped between first and second examination), stable ex-smokers, and never smokers. MAINOUTCOME MEASURE Incident primary lung cancer cases assessed by record linkage with the NationalCancer Registry until December 31, 2003. RESULTS There were 864 incident lung cancers duringfollow-up. Using Cox regression, the adjusted hazard ratio (HR) for lung cancer in reducers was 0.73(95% confidence interval [CI], 0.54-0.98) compared with persistent heavy smokers. The HR for lightsmokers was 0.44 (95% CI, 0.35-0.56); for quitters, HR 0.50 (95% CI, 0.36-0.69), for stableex-smokers, HR 0.17 (95% CI, 0.13-0.23), and for never smokers, HR 0.09 (95% CI, 0.06-0.13).CONCLUSION Among individuals who smoke 15 or more cigarettes per day, smoking reduction by 50%significantly reduces the risk of lung cancer.", "metadata": {}}
+{"_id": "16427454", "title": "", "text": "Facilities for macromolecular crystallography at the Helmholtz-Zentrum BerlinThree macromolecularcrystallography (MX) beamlines at the Helmholtz-Zentrum Berlin (HZB) are available for the regional,national and international structural biology user community. The state-of-the-art synchrotron beamlinesfor MX BL14.1, BL14.2 and BL14.3 are located within the low-β section of the BESSY II electron storagering. All beamlines are fed from a superconducting 7 T wavelength-shifter insertion device. BL14.1 andBL14.2 are energy tunable in the range 5-16 keV, while BL14.3 is a fixed-energy side station operated at13.8 keV. All three beamlines are equipped with CCD detectors. BL14.1 and BL14.2 are in regular useroperation providing about 200 beam days per year and about 600 user shifts to approximately 50research groups across Europe. BL14.3 has initially been used as a test facility and was brought intoregular user mode operation during the year 2010. BL14.1 has recently been upgraded with amicrodiffractometer including a mini-κ goniometer and an automated sample changer. Additional userfacilities include office space adjacent to the beamlines, a sample preparation laboratory, a biologylaboratory (safety level 1) and high-end computing resources. In this article the instrumentation of thebeamlines is described, and a summary of the experimental possibilities of the beamlines and theprovided ancillary equipment for the user community is given.", "metadata": {}}
+{"_id": "16461149", "title": "", "text": "PHENIX: a comprehensive Python-based system for macromolecular structure solutionMacromolecularX-ray crystallography is routinely applied to understand biological processes at a molecular level.However, significant time and effort are still required to solve and complete many of these structuresbecause of the need for manual interpretation of complex numerical data using many software packagesand the repeated use of interactive three-dimensional graphics. PHENIX has been developed to provide acomprehensive system for macromolecular crystallographic structure solution with an emphasis on theautomation of all procedures. This has relied on the development of algorithms that minimize or eliminatesubjective input, the development of algorithms that automate procedures that are traditionallyperformed by hand and, finally, the development of a framework that allows a tight integration betweenthe algorithms.", "metadata": {}}
+{"_id": "16465895", "title": "", "text": "Telomeric 3′ Overhangs Derive from Resection by Exo1 and Apollo and Fill-In by POT1b-Associated CSTA3' overhang is critical for the protection and maintenance of mammalian telomeres, but its synthesismust be regulated to avoid excessive resection of the 5' end, which could cause telomere shortening.How this balance is achieved in mammals has not been resolved. Here, we determine the mechanism for3' overhang synthesis in mouse cells by evaluating changes in telomeric overhangs throughout the cellcycle and at leading- and lagging-end telomeres. Apollo, a nuclease bound to the shelterin subunit TRF2,initiates formation of the 3' overhang at leading-, but not lagging-end telomeres. Hyperresection byApollo is blocked at both ends by the shelterin protein POT1b. Exo1 extensively resects both telomereends, generating transient long 3' overhangs in S/G2. CST/AAF, a DNA polα.primase accessory factor,binds POT1b and shortens the extended overhangs produced by Exo1, likely through fill-in synthesis. 3'overhang formation is thus a multistep, shelterin-controlled process, ensuring functional telomericoverhangs at chromosome ends.", "metadata": {}}
+{"_id": "16472469", "title": "", "text": "Targeting BRCA1 and BRCA2 Deficiencies with G-Quadruplex-Interacting CompoundsG-quadruplex(G4)-forming genomic sequences, including telomeres, represent natural replication fork barriers. Stalledreplication forks can be stabilized and restarted by homologous recombination (HR), which also repairsDNA double-strand breaks (DSBs) arising at collapsed forks. We have previously shown that HR facilitatestelomere replication. Here, we demonstrate that the replication efficiency of guanine-rich (G-rich)telomeric repeats is decreased significantly in cells lacking HR. Treatment with the G4-stabilizingcompound pyridostatin (PDS) increases telomere fragility in BRCA2-deficient cells, suggesting that G4formation drives telomere instability. Remarkably, PDS reduces proliferation of HR-defective cells byinducing DSB accumulation, checkpoint activation, and deregulated G2/M progression and by enhancingthe replication defect intrinsic to HR deficiency. PDS toxicity extends to HR-defective cells that haveacquired olaparib resistance through loss of 53BP1 or REV7. Altogether, these results highlight thetherapeutic potential of G4-stabilizing drugs to selectively eliminate HR-compromised cells and tumors,including those resistant to PARP inhibition.", "metadata": {}}
+{"_id": "16488405", "title": "", "text": "Downloaded fromPhysical activity induces a subclinical inflammatory response, mediated in part byleukocytes, and manifested by elevated concentrations of circulating proinflammatory cytokines,including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α). However, the source of thecytokines that appear during exercise remains unknown. In this study, we examined exercise-inducedchanges in plasma cytokine concentrations and their corresponding mRNA expression in peripheral bloodmononuclear cells. Ten healthy [peak oxygen uptake = 48.8 ± 6.5 (SD) ml · kg−1 · min−1] butuntrained men [age = 25 ± 5 (SD) yr] undertook 3 h of exercise (cycling and inclined walking) at60–65% peak oxygen uptake. Circulating leukocyte subset counts were elevated during and 2 hpostexercise but returned to normal within 24 h. Plasma concentrations of IL-1β, IL-6, and TNF-α peakedat the end of exercise and remained elevated at 2 h (IL-6) and up to 24 h (IL-1β and TNF-α)postexercise. Cytokine gene expression in circulating mononucl...", "metadata": {}}
+{"_id": "16494316", "title": "", "text": "Receptor tyrosine kinases endocytosis in endothelium: biology and signaling.Receptor tyrosine kinasesare involved in regulation of key processes in endothelial biology, including proliferation, migration, andangiogenesis. It is now generally accepted that receptor tyrosine kinase signaling occurs intracellularlyand on the plasma membrane, although many important details remain to be worked out. Endocytosisand subsequent intracellular trafficking spatiotemporally regulate receptor tyrosine kinase signaling,whereas signaling endosomes provide a platform for the compartmentalization of signaling events. Thisreview summarizes recent advances in our understanding of endothelial receptor tyrosine kinaseendocytosis and signaling using vascular endothelial growth factor receptor-2 as a paradigm.", "metadata": {}}
+{"_id": "16495649", "title": "", "text": "Ethnographic study of incidence and severity of intravenous drug errors.OBJECTIVES To determine theincidence and clinical importance of errors in the preparation and administration of intravenous drugs andthe stages of the process in which errors occur. DESIGN Prospective ethnographic study using disguisedobservation. PARTICIPANTS Nurses who prepared and administered intravenous drugs. SETTING 10wards in a teaching and non-teaching hospital in the United Kingdom. MAIN OUTCOME MEASURESNumber, type, and clinical importance of errors. RESULTS 249 errors were identified. At least one erroroccurred in 212 out of 430 intravenous drug doses (49%, 95% confidence interval 45% to 54%). Threedoses (1%) had potentially severe errors, 126 (29%) potentially moderate errors, and 83 (19%)potentially minor errors. Most errors occurred when giving bolus doses or making up drugs that requiredmultiple step preparation. CONCLUSIONS The rate of intravenous drug errors was high. Although mosterrors would cause only short term adverse effects, a few could have been serious. A combination ofreducing the amount of preparation on the ward, training, and technology to administer slow bolus doseswould probably have the greatest effect on error rates.", "metadata": {}}
+{"_id": "16510361", "title": "", "text": "Feature Selection with the Boruta PackageThis article describes a R package Boruta, implementing anovel feature selection algorithm for finding emph{all relevant variables}. The algorithm is designed as awrapper around a Random Forest classification algorithm. It iteratively removes the features which areproved by a statistical test to be less relevant than random probes. The Boruta package provides aconvenient interface to the algorithm. The short description of the algorithm and examples of itsapplication are presented.", "metadata": {}}
+{"_id": "16511863", "title": "", "text": "Integrin-linked kinase expression is elevated in human cardiac hypertrophy and induces hypertrophy intransgenic mice.BACKGROUND Although numerous signaling pathways are known to be activated inexperimental cardiac hypertrophy, the molecular basis of the hypertrophic response inherent in humanheart diseases remains largely unknown. Integrin-linked kinase (ILK) is a multifunctional protein kinasethat physically links beta-integrins with the actin cytoskeleton, suggesting a potential mechanoreceptorrole. METHODS AND RESULTS Here, we show a marked increase in ILK protein levels in hypertrophicventricles of patients with congenital and acquired outflow tract obstruction. This increase in ILK wasassociated with activation of the Rho family guanine triphosphatases, Rac1 and Cdc42, and knownhypertrophic signaling kinases, including extracellular signal-related kinases (ERK1/2) and p70 S6 kinase.Transgenic mice with cardiac-specific expression of a constitutively active ILK (ILK(S343D)) or wild-typeILK (ILK(WT)) exhibited a compensated ventricular hypertrophic phenotype and displayed an activationprofile of guanine triphosphatases and downstream protein kinases concordant with that seen in humanhypertrophy. In contrast, transgenic mice with cardiomyocyte-restricted expression of a kinase-inactiveILK (ILK(R211A)) were unable to mount a compensatory hypertrophic response to angiotensin II in vivo.CONCLUSIONS Taken together, these results identify ILK-regulated signaling as a broadly adaptivehypertrophic response mechanism relevant to a wide range of clinical heart disease.", "metadata": {}}
+{"_id": "16527698", "title": "", "text": "Functional and molecular defects of pancreatic islets in human type 2 diabetes.To shed further light onthe primary alterations of insulin secretion in type 2 diabetes and the possible mechanisms involved, westudied several functional and molecular properties of islets isolated from the pancreata of 13 type 2diabetic and 13 matched nondiabetic cadaveric organ donors. Glucose-stimulated insulin secretion fromtype 2 diabetic islets was significantly lower than from control islets, whereas arginine- andglibenclamide-stimulated insulin release was less markedly affected. The defects were accompanied byreduced mRNA expression of GLUT1 and -2 and glucokinase and by diminished glucose oxidation. Inaddition, AMP-activated protein kinase activation was reduced. Furthermore, the expression of insulinwas decreased, and that of pancreatic duodenal homeobox-1 (PDX-1) and forkhead box O1 (Foxo-1) wasincreased. Nitrotyrosine and 8-hydroxy-2'-deoxyguanosine concentrations, markers of oxidative stress,were significantly higher in type 2 diabetic than control islets, and they were correlated with the degree ofglucose-stimulated insulin release impairment. Accordingly, 24-h exposure to glutathione significantlyimproved glucose-stimulated insulin release and decreased nitrotyrosine concentration, with partialrecovery of insulin mRNA expression. These results provide direct evidence that the defects of insulinsecretion in type 2 diabetic islets are associated with multiple islet cell alterations. Most importantly, thecurrent study shows that the functional impairment of type 2 diabetic islets can be, at least in part,reversible. In this regard, it is suggested that reducing islet cell oxidative stress is a potential target ofhuman type 2 diabetes therapy.", "metadata": {}}
+{"_id": "16532419", "title": "", "text": "Induction of stem-like cells with malignant properties by chronic exposure of human lung epithelial cellsto single-walled carbon nanotubesBACKGROUND Carbon nanotubes (CNT) hold great promise to createnew and better products for commercial and biomedical applications, but their long-term adverse healtheffects are a major concern. The objective of this study was to address human lung cancer risksassociated with chronic pulmonary exposure to single-walled (SW) CNT through the fundamentalunderstanding of cellular and molecular processes leading to carcinogenesis. We hypothesized that theacquisition of cancer stem cells (CSC), a subpopulation that drive tumor initiation and progression, maycontribute to CNT carcinogenesis. METHODS Non-tumorigenic human lung epithelial cells were chronicallyexposed to well-dispersed SWCNT for a period of 6 months at the physiologically relevant concentrationof 0.02 μg/cm2 surface area dose. Chronic SWCNT-exposed cells were evaluated for the presence ofCSC-like cells under CSC-selective conditions of tumor spheres and side population (SP). CSC-like cellswere isolated using fluorescence-activated cell sorting and were assessed for aggressive behaviors,including acquired apoptosis resistance and increased cell migration and invasion in vitro, andtumor-initiating capability in vivo. Non-small cell lung cancer cells served as a positive control. RESULTSWe demonstrated for the first time the existence of CSC-like cells in all clones of chronic SWCNT-exposedlung epithelial cells. These CSC-like cells, in contrary to their non-CSC counterpart, possessed allbiological features of lung CSC that are central to irreversible malignant transformation, self-renewal,aggressive cancer behaviors, and in vivo tumorigenesis. These cells also displayed aberrant stem cellmarkers, notably Nanog, SOX-2, SOX-17 and E-cadherin. Restored expression of tumor suppressor p53abrogated CSC properties of CSC-like cells. Furthermore, we identified specific stem cell surface markersCD24low and CD133high that are associated with SWCNT-induced CSC formation and tumorigenesis.CONCLUSIONS Our findings provide new and compelling evidence for the acquisition of CSC-like cellsinduced by chronic SWCNT exposure, which are likely to be a major driving force for SWCNTtumorigenesis. Thus, our study supports prudent adoption of prevention strategies and implementation ofexposure control for SWCNT. We also suggest that the detection of CSC and associated surface markersmay provide an effective screening tool for prediction of the carcinogenic potential of SWCNT and relatednanoparticles.", "metadata": {}}
+{"_id": "16541762", "title": "", "text": "Reprogramming factor stoichiometry influences the epigenetic state and biological properties of inducedpluripotent stem cells.We compared two genetically highly defined transgenic systems to identifyparameters affecting reprogramming of somatic cells to a pluripotent state. Our results demonstrate thatthe level and stoichiometry of reprogramming factors during the reprogramming process stronglyinfluence the resulting pluripotency of iPS cells. High expression of Oct4 and Klf4 combined with lowerexpression of c-Myc and Sox2 produced iPS cells that efficiently generated \"all-iPSC mice\" by tetraploid(4n) complementation, maintained normal imprinting at the Dlk1-Dio3 locus, and did not create micewith tumors. Loss of imprinting (LOI) at the Dlk1-Dio3 locus did not strictly correlate with reducedpluripotency though the efficiency of generating \"all-iPSC mice\" was diminished. Our data indicate thatstoichiometry of reprogramming factors can influence epigenetic and biological properties of iPS cells.This concept complicates efforts to define a \"generic\" epigenetic state of iPSCs and ESCs and should beconsidered when comparing different iPS and ES cell lines.", "metadata": {}}
+{"_id": "16546131", "title": "", "text": "Activator protein-1 (AP-1) DNA binding activity is induced by hydroxyurea in organogenesis stage mouseembryosHydroxyurea is a potent teratogen; free radical scavengers or antioxidants reduce itsteratogenicity. Activator Protein-1 (AP-1) and NF-kappaB are redox-sensitive transcription factors withimportant roles in normal development and the stress response. This study was designed to determine ifexposure to teratogenic doses of hydroxyurea induces oxidative stress and alters gene expression byactivating these transcription factors. Pregnant mice were treated with saline or hydroxyurea (400, 500,or 600 mg/kg) on gestation day 9 (GD 9) and killed either on GD 9, 0.5, 3, or 6 h after treatment, toassess oxidative stress and transcription factor activities, or on GD 18, to assess fetal development.Exposure to 400 mg/kg hydroxyurea did not affect the progeny, whereas exposure to 500 or 600 mg/kgresulted in dose-dependent increases in fetal resorptions and malformations, including curly tails,abnormal limbs (oligodactyly, hemimelia, and amelia), and short ribs. Hydroxyurea did not induceoxidative stress, as assessed by the ratio of oxidized to reduced glutathione, nor did it alter NF-kappaBDNA binding activity in the GD 9 conceptus. In contrast, exposure to hydroxyurea at any dose increasedAP-1 DNA binding activity in embryos and yolk sacs 0.5 or 3 h after treatment. Hydroxyurea-inducedc-Fos heterodimer activity in the embryo peaked 3-4-fold above control at 3 h and remained elevated by6 h; in contrast, the activity of c-Jun dimers was not altered by drug exposure. A dramatic andregion-specific increase in c-Fos immunoreactivity was found in hydroxyurea-treated embryos. Theinduction of AP-1 DNA binding activity by hydroxyurea represents an early, sensitive marker of theembryonic response to insult.", "metadata": {}}
+{"_id": "16550075", "title": "", "text": "BCL-6 represses genes that function in lymphocyte differentiation, inflammation, and cell cyclecontrol.BCL-6, a transcriptional repressor frequently translocated in lymphomas, regulates germinalcenter B cell differentiation and inflammation. DNA microarray screening identified genes repressed byBCL-6, including many lymphocyte activation genes, suggesting that BCL-6 modulates B cell receptorsignals. BCL-6 repression of two chemokine genes, MIP-1alpha and IP-10, may also attenuateinflammatory responses. Blimp-1, another BCL-6 target, is important for plasmacytic differentiation.Since BCL-6 expression is silenced in plasma cells, repression of blimp-1 by BCL-6 may controlplasmacytic differentiation. Indeed, inhibition of BCL-6 function initiated changes indicative of plasmacyticdifferentiation, including decreased expression of c-Myc and increased expression of the cell cycleinhibitor p27kip1. These data suggest that malignant transformation by BCL-6 involves inhibition ofdifferentiation and enhanced proliferation.", "metadata": {}}
+{"_id": "16557565", "title": "", "text": "Local, Efflux-Dependent Auxin Gradients as a Common Module for Plant Organ FormationPlants,compared to animals, exhibit an amazing adaptability and plasticity in their development. This is largelydependent on the ability of plants to form new organs, such as lateral roots, leaves, and flowers duringpostembryonic development. Organ primordia develop from founder cell populations into organs bycoordinated cell division and differentiation. Here, we show that organ formation in Arabidopsis involvesdynamic gradients of the signaling molecule auxin with maxima at the primordia tips. These gradients aremediated by cellular efflux requiring asymmetrically localized PIN proteins, which represent a functionallyredundant network for auxin distribution in both aerial and underground organs. PIN1 polar localizationundergoes a dynamic rearrangement, which correlates with establishment of auxin gradients andprimordium development. Our results suggest that PIN-dependent, local auxin gradients represent acommon module for formation of all plant organs, regardless of their mature morphology ordevelopmental origin.", "metadata": {}}
+{"_id": "16562534", "title": "", "text": "Drosophila MICAL regulates myofilament organization and synaptic structureThe overall size andstructure of a synaptic terminal is an important determinant of its function. In a large-scale mutagenesisscreen, designed to identify Drosophila mutants with abnormally structured neuromuscular junctions(NMJs), we discovered mutations in Drosophila mical, a conserved gene encoding a multi-domain proteinwith a N-terminal monooxygenase domain. In mical mutants, synaptic boutons do not sprout normallyover the muscle surface and tend to form clusters along synaptic branches and at nerve entry sites.Consistent with high expression of MICAL in somatic muscles, immunohistochemical stainings reveal thatthe subcellular localization and architecture of contractile muscle filaments are dramatically disturbed inmical mutants. Instead of being integrated into a regular sarcomeric pattern, actin and myosin filamentsare disorganized and accumulate beneath the plasmamembrane. Whereas contractile elements arestrongly deranged, the proposed organizer of sarcomeric structure, D-Titin, is much less affected.Transgenic expression of interfering RNA molecules demonstrates that MICAL is required in muscles forthe higher order arrangement of myofilaments. Ultrastructural analysis confirms that myosin-rich thickfilaments enter submembranous regions and interfere with synaptic development, indicating that thedisorganized myofilaments may cause the synaptic growth phenotype. As a model, we suggest that thefilamentous network around synaptic boutons restrains the spreading of synaptic branches.", "metadata": {}}
+{"_id": "16572581", "title": "", "text": "Viral Infection of Engrafted Human Islets Leads to DiabetesType 1 diabetes (T1D) is characterized by thedestruction of the insulin-producing β-cells of pancreatic islets. Genetic and environmental factors bothcontribute to T1D development. Viral infection with enteroviruses is a suspected trigger for T1D, but acausal role remains unproven and controversial. Studies in animals are problematic because ofspecies-specific differences in host cell susceptibility and immune responses to candidate viral pathogenssuch as coxsackievirus B (CVB). In order to resolve the controversial role of viruses in human T1D, wedeveloped a viral infection model in immunodeficient mice bearing human islet grafts. Hyperglycemia wasinduced in mice by specific ablation of native β-cells. Human islets, which are naturally susceptible to CVBinfection, were transplanted to restore normoglycemia. Transplanted mice were infected with CVB4 andmonitored for hyperglycemia. Forty-seven percent of CVB4-infected mice developed hyperglycemia.Human islet grafts from infected mice contained viral RNA, expressed viral protein, and had reducedinsulin levels compared with grafts from uninfected mice. Human-specific gene expression profiles ingrafts from infected mice revealed the induction of multiple interferon-stimulated genes. Thus, humanislets can become severely dysfunctional with diminished insulin production after CVB infection of β-cells,resulting in diabetes.", "metadata": {}}
+{"_id": "16605494", "title": "", "text": "MicroRNA-22 (miR-22) Overexpression Is Neuroprotective via General Anti-Apoptotic Effects and Mayalso Target Specific Huntington’s Disease-Related MechanismsBACKGROUND Whereas many causes andmechanisms of neurodegenerative diseases have been identified, very few therapeutic strategies haveemerged in parallel. One possible explanation is that successful treatment strategy may requiresimultaneous targeting of more than one molecule of pathway. A new therapeutic approach to haveemerged recently is the engagement of microRNAs (miRNAs), which affords the opportunity to targetmultiple cellular pathways simultaneously using a single sequence. METHODOLOGY/PRINCIPAL FINDINGSWe identified miR-22 as a potentially neuroprotective miRNA based on its predicted regulation of severaltargets implicated in Huntington's disease (histone deacetylase 4 (HDAC4), REST corepresor 1 (Rcor1)and regulator of G-protein signaling 2 (Rgs2)) and its diminished expression in Huntington's andAlzheimer's disease brains. We then tested the hypothesis that increasing cellular levels of miRNA-22would achieve neuroprotection in in vitro models of neurodegeneration. As predicted, overexpression ofmiR-22 inhibited neurodegeneration in primary striatal and cortical cultures exposed to a mutated humanhuntingtin fragment (Htt171-82Q). Overexpression of miR-22 also decreased neurodegeneration inprimary neuronal cultures exposed to 3-nitropropionic acid (3-NP), a mitochondrial complex II/IIIinhibitor. In addition, miR-22 improved neuronal viability in an in vitro model of brain aging. Themechanisms underlying the effects of miR-22 included a reduction in caspase activation, consistent withmiR-22's targeting the pro-apoptotic activities of mitogen-activated protein kinase 14/p38 (MAPK14/p38)and tumor protein p53-inducible nuclear protein 1 (Tp53inp1). Moreover, HD-specific effects comprisednot only targeting HDAC4, Rcor1 and Rgs2 mRNAs, but also decreasing focal accumulation of mutantHtt-positive foci, which occurred via an unknown mechanism. CONCLUSIONS These data show thatmiR-22 has multipartite anti-neurodegenerative activities including the inhibition of apoptosis and thetargeting of mRNAs implicated in the etiology of HD. These results motivate additional studies to evaluatethe feasibility and therapeutic efficacy of manipulating miR-22 in vivo.", "metadata": {}}
+{"_id": "16625620", "title": "", "text": "Research in cardiovascular care: a position statement of the Council on Cardiovascular Nursing and AlliedProfessionals of the European Society of Cardiology.To deliver optimal patient care, evidence-based careis advocated and research is needed to support health care staff of all disciplines in deciding whichoptions to use in their daily practice. Due to the increasing complexity of cardiac care across the life spanof patients combined with the increasing opportunities and challenges in multidisciplinary research, theScience Committee of the Council on Cardiovascular Nursing and Allied Professionals (CCNAP) recognisedthe need for a position statement to guide researchers, policymakers and funding bodies to contribute tothe advancement of the body of knowledge that is needed to further improve cardiovascular care. In thispaper, knowledge gaps in current research related to cardiovascular patient care are identified, upcomingchallenges are explored and recommendations for future research are given.", "metadata": {}}
+{"_id": "16626264", "title": "", "text": "Genome-Wide Dynamics of Htz1, a Histone H2A Variant that Poises Repressed/Basal Promoters forActivation through Histone LossHistone variants help specialize chromatin regions; however, their impacton transcriptional regulation is largely unknown. Here, we determined the genome-wide localization anddynamics of Htz1, the yeast histone H2A variant. Htz1 localizes to hundreds of repressed/basal Pol IIpromoters and prefers TATA-less promoters. Specific Htz1 deposition requires the SWR1 complex, whichlargely colocalizes with Htz1. Htz1 occupancy correlates with particular histone modifications, and Htz1deposition is partially reliant on Gcn5 (a histone acetyltransferase) and Bdf1, an SWR1 complex memberthat binds acetylated histones. Changes in growth conditions cause a striking redistribution of Htz1 fromactivated to repressed/basal promoters. Furthermore, Htz1 promotes full gene activation but does notgenerally impact repression. Importantly, Htz1 releases from purified chromatin in vitro under conditionswhere H2A and H3 remain associated. We suggest that Htz1-bearing nucleosomes are deposited atrepressed/basal promoters but facilitate activation through their susceptibility to loss, thereby helping toexpose promoter DNA.", "metadata": {}}
+{"_id": "16626846", "title": "", "text": "Metagenomic analysis of microbial consortium from natural crude oil that seeps into the marineecosystem offshore Southern CaliforniaCrude oils can be major contaminants of the marine ecosystemand microorganisms play a significant role in the degradation of its main constituents. To increase ourunderstanding of the microbial hydrocarbon degradation process in the marine ecosystem, we collectedcrude oil from an active seep area located in the Santa Barbara Channel (SBC) and generated a total ofabout 52 Gb of raw metagenomic sequence data. The assembled data comprised ~500 Mb, representing~1.1 million genes derived primarily from chemolithoautotrophic bacteria. Members of Oceanospirillales,a bacterial order belonging to the Deltaproteobacteria, recruited less than 2% of the assembled geneswithin the SBC metagenome. In contrast, the microbial community associated with the oil plume thatdeveloped in the aftermath of the Deepwater Horizon (DWH) blowout in 2010, was dominated byOceanospirillales, which comprised more than 60% of the metagenomic data generated from the DWH oilplume. This suggests that Oceanospirillales might play a less significant role in the microbially mediatedhydrocarbon conversion within the SBC seep oil compared to the DWH plume oil. We hypothesize thatthis difference results from the SBC oil seep being mostly anaerobic, while the DWH oil plume is aerobic.Within the Archaea, the phylum Euryarchaeota, recruited more than 95% of the assembled archaealsequences from the SBC oil seep metagenome, with more than 50% of the sequences assigned tomembers of the orders Methanomicrobiales and Methanosarcinales. These orders contain organismscapable of anaerobic methanogenesis and methane oxidation (AOM) and we hypothesize that theseorders - and their metabolic capabilities - may be fundamental to the ecology of the SBC oil seep.", "metadata": {}}
+{"_id": "16627684", "title": "", "text": "Hmga2 Promotes Neural Stem Cell Self-Renewal in Young but Not Old Mice by Reducing p16Ink4a andp19Arf ExpressionStem cells persist throughout life in diverse tissues by undergoing self-renewingdivisions. Self-renewal capacity declines with age, partly because of increasing expression of the tumorsuppressor p16(Ink4a). We discovered that the Hmga2 transcriptional regulator is highly expressed infetal neural stem cells but that expression declines with age. This decrease is partly caused by theincreasing expression of let-7b microRNA, which is known to target HMGA2. Hmga2-deficient mice showreduced stem cell numbers and self-renewal throughout the central and peripheral nervous systems offetal and young-adult mice but not old-adult mice. Furthermore, p16(Ink4a) and p19(Arf) expressionwere increased in Hmga2-deficient fetal and young-adult stem cells, and deletion of p16(Ink4a) and/orp19(Arf) partially restored self-renewal capacity. let-7b overexpression reduced Hmga2 and increasedp16(Ink4a)/p19(Arf) expression. Hmga2 thus promotes fetal and young-adult stem cell self-renewal bydecreasing p16(Ink4a)/p19(Arf) expression. Changes in let-7 and Hmga2 expression during agingcontribute to the decline in neural stem cell function.", "metadata": {}}
+{"_id": "16630060", "title": "", "text": "Genotoxic Stress Abrogates Renewal of Melanocyte Stem Cells by Triggering Their DifferentiationSomaticstem cell depletion due to the accumulation of DNA damage has been implicated in the appearance ofaging-related phenotypes. Hair graying, a typical sign of aging in mammals, is caused by the incompletemaintenance of melanocyte stem cells (MSCs) with age. Here, we report that irreparable DNA damage, ascaused by ionizing radiation, abrogates renewal of MSCs in mice. Surprisingly, the DNA-damage responsetriggers MSC differentiation into mature melanocytes in the niche, rather than inducing their apoptosis orsenescence. The resulting MSC depletion leads to irreversible hair graying. Furthermore, deficiency ofAtaxia-telangiectasia mutated (ATM), a central transducer kinase of the DNA-damage response,sensitizes MSCs to ectopic differentiation, demonstrating that the kinase protects MSCs from theirpremature differentiation by functioning as a \"stemness checkpoint\" to maintain the stem cell quality andquantity.", "metadata": {}}
+{"_id": "16630996", "title": "", "text": "Gemcitabine chemoresistance and molecular markers associated with gemcitabine transport andmetabolism in human pancreatic cancer cellsTo identify predictive molecular markers for gemcitabineresistance, we investigated changes in the expression of four genes associated with gemcitabinetransport and metabolism during the development of acquired gemcitabine resistance of pancreaticcancer cell lines. The expression levels of human equilibrative nucleoside transporter-1 (hENT1),deoxycytidine kinase (dCK), RRM1, and RRM2 mRNA were analysed by real-time light cycler-PCR invarious subclones during the development of acquired resistance to gemcitabine. Real-time lightcycler-PCR demonstrated that the expression levels of either RRM1 or RRM2 progressively increasedduring the development of gemcitabine resistance. Expression of dCK was slightly increased in cellsresistant to lower concentrations of gemcitabine, but was decreased below the undetectable level inhigher concentration-resistant subclones. Expression of hENT1 was increased in the development ofgemcitabine resistance. As acquired resistance to gemcitabine seems to correlate with the balance ofthese four factors, we calculated the ratio of hENT1 × dCK/RRM1 × RRM2 gene expression ingemcitabine-resistant subclones. The ratio of gene expression decreased progressively with developmentof acquired resistance in gemcitabine-resistant subclones. Furthermore, the expression ratio significantlycorrelated with gemcitabine sensitivity in eight pancreatic cancer cell lines, whereas no single geneexpression level correlated with the sensitivity. These results suggest that the sensitivity of pancreaticcancer cells to gemcitabine is determined by the ratio of four factors involved in gemcitabine transportand metabolism. The ratio of the four gene expression levels correlates with acquiredgemcitabine-resistance in pancreatic cancer cells, and may be useful as a predictive marker for theefficacy of gemcitabine therapy in pancreatic cancer patients.", "metadata": {}}
+{"_id": "16644043", "title": "", "text": "The DNA Damage Machinery and Homologous Recombination Pathway Act Consecutively to ProtectHuman TelomeresTelomeres protect chromosome ends from being detected as lesions and fromtriggering DNA damage checkpoints. Paradoxically, telomere function depends on checkpoint proteinssuch as ATM and ATR, but a molecular model explaining this seemingly contradictory relationship hasbeen missing so far. Here we show that the DNA damage machinery acts on telomeres in at least twoindependent steps. First, the ATR-dependent machinery is recruited to telomeres before telomerereplication is completed, likely in response to single-stranded DNA resulting from replication fork stalling.Second, after replication, telomeres attract ATM and the homologous recombination (HR) machinery. Invivo and in vitro results suggest that the HR machinery is required for formation of a telomere-specificstructure at chromosome ends after replication. Our results suggest that telomere ends need to berecognized as DNA damage to complete end replication and to acquire a structure that is essential forfunction.", "metadata": {}}
+{"_id": "16660256", "title": "", "text": "Sprouty1 Regulates Reversible Quiescence of a Self-Renewing Adult Muscle Stem Cell Pool duringRegenerationSatellite cells are skeletal muscle stem cells capable of self-renewal and differentiation aftertransplantation, but whether they contribute to endogenous muscle fiber repair has been unclear. Thetranscription factor Pax7 marks satellite cells and is critical for establishing the adult satellite cell pool. Byusing a lineage tracing approach, we show that after injury, quiescent adult Pax7(+) cells enter the cellcycle; a subpopulation returns to quiescence to replenish the satellite cell compartment, while otherscontribute to muscle fiber formation. We demonstrate that Sprouty1 (Spry1), a receptor tyrosine kinasesignaling inhibitor, is expressed in quiescent Pax7(+) satellite cells in uninjured muscle, downregulated inproliferating myogenic cells after injury, and reinduced as Pax7(+) cells re-enter quiescence. We showthat Spry1 is required for the return to quiescence and homeostasis of the satellite cell pool during repair.Our results therefore define a role for Spry1 in adult muscle stem cell biology and tissue repair.", "metadata": {}}
+{"_id": "16669757", "title": "", "text": "Mechanosensitivity in the enteric nervous systemThe enteric nervous system (ENS) autonomouslycontrols gut muscle activity. Mechanosensitive enteric neurons (MEN) initiate reflex activity by respondingto mechanical deformation of the gastrointestinal wall. MEN throughout the gut primarily respond tocompression or stretch rather than to shear force. Some MEN are multimodal as they respond tocompression and stretch. Depending on the region up to 60% of the entire ENS population responds tomechanical stress. MEN fire action potentials after mechanical stimulation of processes or soma althoughthey are more sensitive to process deformation. There are at least two populations of MEN based on theirsensitivity to different modalities of mechanical stress and on their firing pattern. (1) Rapidly, slowly andultra-slowly adapting neurons which encode compressive forces. (2) Ultra-slowly adaptingstretch-sensitive neurons encoding tensile forces. Rapid adaptation of firing is typically observed aftercompressive force while slow adaptation or ongoing spike discharge occurs often during tensile stress(stretch). All MEN have some common properties: they receive synaptic input, are low fidelitymechanoreceptors and are multifunctional in that some serve interneuronal others even motor functions.Consequently, MEN possess processes with mechanosensitive as well as efferent functions. This raisesthe intriguing hypothesis that MEN sense and control muscle activity at the same time as servo-feedbackloop. The mechanosensitive channel(s) or receptor(s) expressed by the different MEN populations areunknown. Future concepts have to incorporate compressive and tensile-sensitive MEN into neural circuitsthat controls muscle activity. They may interact to control various forms of a particular motor pattern orregulate different motor patterns independently from each other.", "metadata": {}}
+{"_id": "16686383", "title": "", "text": "Phosphorylation of centromeric histone H3 variant regulates chromosome segregation in SaccharomycescerevisiaeThe centromeric histone H3 variant (CenH3) is essential for chromosome segregation ineukaryotes. We identify posttranslational modifications of Saccharomyces cerevisiae CenH3, Cse4.Functional characterization of cse4 phosphorylation mutants shows growth and chromosome segregationdefects when combined with kinetochore mutants okp1 and ame1. Using a phosphoserine-specificantibody, we show that the association of phosphorylated Cse4 with centromeres increases in response todefective microtubule attachment or reduced cohesion. We determine that evolutionarily conservedIpl1/Aurora B contributes to phosphorylation of Cse4, as levels of phosphorylated Cse4 are reduced atcentromeres in ipl1 strains in vivo, and in vitro assays show phosphorylation of Cse4 by Ipl1. Consistentwith these results, we observe that a phosphomimetic cse4-4SD mutant suppresses thetemperature-sensitive growth of ipl1-2 and Ipl1 substrate mutants dam1 spc34 and ndc80, which aredefective for chromosome biorientation. Furthermore, cell biology approaches using a green fluorescentprotein-labeled chromosome show that cse4-4SD suppresses chromosome segregation defects in dam1spc34 strains. On the basis of these results, we propose that phosphorylation of Cse4 destabilizesdefective kinetochores to promote biorientation and ensure faithful chromosome segregation. Takentogether, our results provide a detailed analysis, in vivo and in vitro, of Cse4 phosphorylation and its rolein promoting faithful chromosome segregation.", "metadata": {}}
+{"_id": "16691520", "title": "", "text": "Genome-wide analysis of estrogen receptor binding sitesThe estrogen receptor is the mastertranscriptional regulator of breast cancer phenotype and the archetype of a molecular therapeutic target.We mapped all estrogen receptor and RNA polymerase II binding sites on a genome-wide scale,identifying the authentic cis binding sites and target genes, in breast cancer cells. Combining this uniqueresource with gene expression data demonstrates distinct temporal mechanisms of estrogen-mediatedgene regulation, particularly in the case of estrogen-suppressed genes. Furthermore, this resource hasallowed the identification of cis-regulatory sites in previously unexplored regions of the genome and thecooperating transcription factors underlying estrogen signaling in breast cancer.", "metadata": {}}
+{"_id": "16693950", "title": "", "text": "Replicative aging in yeast: the means to the end.Progress in aging research is now rapid, andsurprisingly, studies in a single-celled eukaryote are a driving force. The genetic modulators of replicativelife span in yeast are being identified, the molecular events that accompany aging are being discovered,and the extent to which longevity pathways are conserved between yeast and multicellular eukaryotes isbeing tested. In this review, we provide a brief retrospective view on the development of yeast as amodel for aging and then turn to recent discoveries that have pushed aging research into novel directionsand also linked aging in yeast to well-developed hypotheses in mammals. Although the question of whatcauses aging still cannot be answered definitively, that day may be rapidly approaching.", "metadata": {}}
+{"_id": "16701509", "title": "", "text": "Serum high-density lipoprotein cholesterol, metabolic profile, and breast cancer risk.BACKGROUND Theprevalence of metabolic syndrome (obesity, glucose intolerance, low serum high-density lipoproteincholesterol [HDL-C], high serum triglycerides, hypertension) is high and increasing in parallel with anincreasing breast cancer incidence worldwide. HDL-C represents an important aspect of the syndrome,yet its role in breast cancer is still undefined. METHODS In two population-based screening surveysduring 1977-1983 and 1985-1987, serum HDL-C was assayed enzymatically among 38,823 Norwegianwomen aged 17-54 years at entry. Height, weight, blood pressure, serum lipids, fat and energy intake,physical activity, parity, oral contraceptive use, hormone therapy use, alcohol intake, and tobacco usewere also assessed. We used Cox proportional hazards modeling to estimate the relative risk (RR) ofbreast cancer associated with serum HDL-C levels and to adjust for potential confounding variables. Weperformed stratified analyses to evaluate effect modification by body mass index (BMI) and menopausalstatus. All statistical tests were two-sided. RESULTS During a median follow-up of 17.2 years, weidentified 708 cases of invasive breast cancer. In multivariable analysis, the risk of postmenopausalbreast cancer was inversely related to quartile of HDL-C (P(trend) =.02). Among women with HDL-Cabove 1.64 mmol/L (highest quartile) versus below 1.20 mmol/L (lowest quartile), the relative risk was0.75 (95% confidence interval [CI] = 0.58 to 0.97). The HDL-C association was confined to women in theheavier subgroup (BMI > or =25 kg/m2), for whom the relative risk of postmenopausal breast cancer inthose with HDL-C above 1.64 mmol/L versus below 1.20 mmol/L was 0.43 (95% CI = 0.28 to 0.67;P(trend)<.001; P(interaction) =.001). CONCLUSION Low HDL-C, as part of the metabolic syndrome, isassociated with increased postmenopausal breast cancer risk.", "metadata": {}}
+{"_id": "16705338", "title": "", "text": "Prediction of Chemical-Protein Interactions Network with Weighted Network-Based InferenceMethodChemical-protein interaction (CPI) is the central topic of target identification and drug discovery.However, large scale determination of CPI is a big challenge for in vitro or in vivo experiments, while insilico prediction shows great advantages due to low cost and high accuracy. On the basis of our previousdrug-target interaction prediction via network-based inference (NBI) method, we further developed node-and edge-weighted NBI methods for CPI prediction here. Two comprehensive CPI bipartite networksextracted from ChEMBL database were used to evaluate the methods, one containing 17,111 CPI pairsbetween 4,741 compounds and 97 G protein-coupled receptors, the other including 13,648 CPI pairsbetween 2,827 compounds and 206 kinases. The range of the area under receiver operatingcharacteristic curves was 0.73 to 0.83 for the external validation sets, which confirmed the reliability ofthe prediction. The weak-interaction hypothesis in CPI network was identified by the edge-weighted NBImethod. Moreover, to validate the methods, several candidate targets were predicted for five approveddrugs, namely imatinib, dasatinib, sertindole, olanzapine and ziprasidone. The molecular hypotheses andexperimental evidence for these predictions were further provided. These results confirmed that ourmethods have potential values in understanding molecular basis of drug polypharmacology and would behelpful for drug repositioning.", "metadata": {}}
+{"_id": "16712164", "title": "", "text": "Exploiting the yeast stress-activated signaling network to inform on stress biology and diseasesignalingHealthy cells utilize intricate systems to monitor their environment and mount robust responsesin the event of cellular stress. Whether stress arises from external insults or defects due to mutation anddisease, cells must be able to respond precisely to mount the appropriate defenses. Multi-faceted stressresponses are generally coupled with arrest of growth and cell-cycle progression, which both limits thetransmission of damaged materials and serves to reallocate limited cellular resources toward defense.Therefore, stress defense versus rapid growth represent competing interests in the cell. How eukaryoticcells set the balance between defense versus proliferation, and in particular knowledge of the regulatorynetworks that control this decision, are poorly understood. In this perspective, we expand upon ourrecent work inferring the stress-activated signaling network in budding yeast, which captures pathwayscontrolling stress defense and regulators of growth and cell-cycle progression. We highlight similaritiesbetween the yeast and mammalian stress responses and explore how stress-activated signaling networksin yeast can inform on signaling defects in human cancers.", "metadata": {}}
+{"_id": "16728949", "title": "", "text": "Cell Stem Cell Review FoxO Transcription Factors and Stem Cell Homeostasis: Insights from theHematopoietic SystemThe forkhead O (FoxO) family of transcription factors participates in diversephysiologic processes, including induction of cell-cycle arrest, stress resistance, differentiation, apoptosis,and metabolism. Several recent studies indicate that FoxO-dependent signaling is required for long-termregenerative potential of the hematopoietic stem cell (HSC) compartment through regulation of HSCresponse to physiologic oxidative stress, quiescence, and survival. These observations link FoxO functionin mammalian systems with the evolutionarily conserved role of FoxO in promotion of stress resistanceand longevity in lower phylogenetic systems. Furthermore, these findings have implications for aging inhigher organisms and in malignant stem cell biology, and suggest that FoxOs may play an important rolein the maintenance and integrity of stem cell compartments in a broad spectrum of tissues.", "metadata": {}}
+{"_id": "16732790", "title": "", "text": "A Teratocarcinoma-Like Human Embryonic Stem Cell (hESC) Line and Four hESC Lines Reveal PotentiallyOncogenic Genomic ChangesThe first Swiss human embryonic stem cell (hESC) line, CH-ES1, has shownfeatures of a malignant cell line. It originated from the only single blastomere that survivedcryopreservation of an embryo, and it more closely resembles teratocarcinoma lines than other hESClines with respect to its abnormal karyotype and its formation of invasive tumors when injected into SCIDmice. The aim of this study was to characterize the molecular basis of the oncogenicity of CH-ES1 cells,we looked for abnormal chromosomal copy number (by array Comparative Genomic Hybridization, aCGH)and single nucleotide polymorphisms (SNPs). To see how unique these changes were, we compared theseresults to data collected from the 2102Ep teratocarcinoma line and four hESC lines (H1, HS293, HS401and SIVF-02) which displayed normal G-banding result. We identified genomic gains and losses inCH-ES1, including gains in areas containing several oncogenes. These features are similar to thoseobserved in teratocarcinomas, and this explains the high malignancy. The CH-ES1 line was trisomic forchromosomes 1, 9, 12, 17, 19, 20 and X. Also the karyotypically (based on G-banding) normal hESC lineswere also found to have several genomic changes that involved genes with known roles in cancer. Thelargest changes were found in the H1 line at passage number 56, when large 5 Mb duplications inchromosomes 1q32.2 and 22q12.2 were detected, but the losses and gains were seen already at passage22. These changes found in the other lines highlight the importance of assessing the acquisition ofgenetic changes by hESCs before their use in regenerative medicine applications. They also point to thepossibility that the acquisition of genetic changes by ESCs in culture may be used to explore certainaspects of the mechanisms regulating oncogenesis.", "metadata": {}}
+{"_id": "16734530", "title": "", "text": "The Association between Single-Nucleotide Polymorphisms of ORAI1 Gene and Breast Cancer in aTaiwanese PopulationBACKGROUND Breast cancer is the most common malignancy in women. There isincreasing evidence suggesting that ORAI1, components of store-operated calcium channel, play a pivotalrole in breast cancer progression and metastasis. METHODS A total of 384 female patients with breastcancer were included in this study. We selected five representative tagging ORAI1 SNPs from HapMapdatabase with minimum allele frequency (MAF) >10%. Genotyping was performed using TaqMan allelicdiscrimination assay. Chi-square (χ²) test was used to analyze statistical differences among control andpatient groups in genotype and allelic frequencies. RESULTS Two of the ORAI1 SNPs (rs12320939 andrs12313273) were associated with estrogen receptors positive in breast cancer patients under therecessive model. When the Bonferroni correction was performed, the significance still existed. In addition,rs12320939 also associated with the lymph nodal involvement. CONCLUSION We showed that geneticpolymorphisms of ORAI1 associated strongly with lymph nodal involvement and estrogen receptors (ERs)positive breast cancer patients in a Taiwanese population.", "metadata": {}}
+{"_id": "16736872", "title": "", "text": "Noninvasive Imaging beyond the Diffraction Limit of 3D Dynamics in Thickly FluorescentSpecimensOptical imaging of the dynamics of living specimens involves tradeoffs between spatialresolution, temporal resolution, and phototoxicity, made more difficult in three dimensions. Here,however, we report that rapid three-dimensional (3D) dynamics can be studied beyond the diffractionlimit in thick or densely fluorescent living specimens over many time points by combining ultrathin planarillumination produced by scanned Bessel beams with super-resolution structured illumination microscopy.We demonstrate in vivo karyotyping of chromosomes during mitosis and identify different dynamics forthe actin cytoskeleton at the dorsal and ventral surfaces of fibroblasts. Compared to spinning diskconfocal microscopy, we demonstrate substantially reduced photodamage when imaging rapidmorphological changes in D. discoideum cells, as well as improved contrast and resolution at depth withindeveloping C. elegans embryos. Bessel beam structured plane illumination thus promises new insightsinto complex biological phenomena that require 4D subcellular spatiotemporal detail in either a single ormulticellular context.", "metadata": {}}
+{"_id": "16736883", "title": "", "text": "The Ndc80 Kinetochore Complex Forms Load-Bearing Attachments to Dynamic Microtubule Tips viaBiased DiffusionKinetochores couple chromosomes to the assembling and disassembling tips ofmicrotubules, a dynamic behavior that is fundamental to mitosis in all eukaryotes but poorly understood.Genetic, biochemical, and structural studies implicate the Ndc80 complex as a direct point of contactbetween kinetochores and microtubules, but these approaches provide only a static view. Here, usingtechniques for manipulating and tracking individual molecules in vitro, we demonstrate that the Ndc80complex is capable of forming the dynamic, load-bearing attachments to assembling and disassemblingtips required for coupling in vivo. We also establish that Ndc80-based coupling likely occurs through abiased diffusion mechanism and that this activity is conserved from yeast to humans. Our findingsdemonstrate how an ensemble of Ndc80 complexes may provide the combination of plasticity andstrength that allows kinetochores to maintain load-bearing tip attachments during both microtubuleassembly and disassembly.", "metadata": {}}
+{"_id": "16737163", "title": "", "text": "Myelin oligodendrocyte glycoprotein antibodies are associated with a non-MS course inchildrenOBJECTIVE To determine whether myelin oligodendrocyte glycoprotein antibodies (MOG-Abs)were predictive of a demyelination phenotype in children presenting with acquired demyelinatingsyndrome (ADS). METHOD Sixty-five children with a first episode of ADS (12 acute disseminatedencephalomyelitis, 24 optic neuritis, 18 transverse myelitis, 11 other clinically isolated syndrome) wereidentified from 2 national demyelination programs in the United Kingdom and France. Acute serumsamples were tested for MOG-Abs by cell-based assay. Antibodies were used to predict diagnosis ofmultiple sclerosis (MS) at 1 year. RESULTS Twenty-three of 65 (35%) children had MOG-Abs.Antibody-positive and antibody-negative patients were not clinically different at presentation, butidentification of MOG-Abs predicted a non-MS course at 1-year follow-up: only 2/23 (9%)MOG-Ab-positive patients were diagnosed with MS compared to 16/42 (38%) MOG-Ab-negative patients(p = 0.019, Fisher exact test). Antibody positivity at outset was a useful predictor for a non-MS diseasecourse, with a positive predictive value of 91% (95% confidence interval [CI] 72-99), negative predictivevalue of 38% (95% CI 24-54), positive likelihood ratio of 4.02 (CI 1.0-15.4), and odds ratio of 6.5 (CI1.3-31.3). CONCLUSIONS MOG-Abs are found at presentation in 35% of patients with childhood ADS,across a range of demyelinating disorders. Antibody positivity can be useful in predicting a non-MSdisease course at onset.", "metadata": {}}
+{"_id": "16737210", "title": "", "text": "Kidney paired donation and optimizing the use of live donor organs.CONTEXT Blood type and crossmatchincompatibility will exclude at least one third of patients in need from receiving a live donor kidneytransplant. Kidney paired donation (KPD) offers incompatible donor/recipient pairs the opportunity tomatch for compatible transplants. Despite its increasing popularity, very few transplants have resultedfrom KPD. OBJECTIVE To determine the potential impact of improved matching schemes on the numberand quality of transplants achievable with KPD. DESIGN, SETTING, AND POPULATION We developed amodel that simulates pools of incompatible donor/recipient pairs. We designed a mathematicallyverifiable optimized matching algorithm and compared it with the scheme currently used in some centersand regions. Simulated patients from the general community with characteristics drawn from distributionsdescribing end-stage renal disease patients eligible for renal transplantation and their willing and eligiblelive donors. MAIN OUTCOME MEASURES Number of kidneys matched, HLA mismatch of matched kidneys,and number of grafts surviving 5 years after transplantation. RESULTS A national optimized matchingalgorithm would result in more transplants (47.7% vs 42.0%, P<.001), better HLA concordance (3.0 vs4.5 mismatched antigens; P<.001), more grafts surviving at 5 years (34.9% vs 28.7%; P<.001), and areduction in the number of pairs required to travel (2.9% vs 18.4%; P<.001) when compared with anextension of the currently used first-accept scheme to a national level. Furthermore, highly sensitizedpatients would benefit 6-fold from a national optimized scheme (2.3% vs 14.1% successfully matched;P<.001). Even if only 7% of patients awaiting kidney transplantation participated in an optimized nationalKPD program, the health care system could save as much as $750 million. CONCLUSIONS Thecombination of a national KPD program and a mathematically optimized matching algorithm yields morematches with lower HLA disparity. Optimized matching affords patients the flexibility of customizing theirmatching priorities and the security of knowing that the greatest number of high-quality matches will befound and distributed equitably.", "metadata": {}}
+{"_id": "16745747", "title": "", "text": "Genetic Interaction between Mutations in c-Myb and the KIX Domains of CBP and p300 Affects MultipleBlood Cell Lineages and Influences Both Gene Activation and RepressionAdult blood cell production ordefinitive hematopoiesis requires the transcription factor c-Myb. The closely related KAT3 histoneacetyltransferases CBP (CREBBP) and p300 (EP300) bind c-Myb through their KIX domains and micehomozygous for a p300 KIX domain mutation exhibit multiple blood defects. Perplexingly, micehomozygous for the same KIX domain mutation in CBP have normal blood. Here we test the hypothesisthat the CBP KIX domain contributes subordinately to hematopoiesis via a genetic interaction with c-Myb.We assessed hematopoiesis in mice bearing compound mutations of c-Myb and/or the KIX domains ofCBP and p300, and measured the effect of KIX domain mutations on c-Myb-dependent gene expression.We found that in the context of a p300 KIX mutation, the CBP KIX domain mutation affects platelets, Bcells, T cells, and red cells. Gene interaction (epistasis) analysis provides mechanistic evidence that blooddefects in KIX mutant mice are consistent with reduced c-Myb and KIX interaction. Lastly, wedemonstrated that the CBP and p300 KIX domains contribute to both c-Myb-dependent gene activationand repression. Together these results suggest that the KIX domains of CBP, and especially p300, areprincipal mediators of c-Myb-dependent gene activation and repression that is required for definitivehematopoiesis.", "metadata": {}}
+{"_id": "16760369", "title": "", "text": "Comparative determinants of 4-year cardiovascular event rates in stable outpatients at risk of or withatherothrombosis.CONTEXT Clinicians and trialists have difficulty with identifying which patients arehighest risk for cardiovascular events. Prior ischemic events, polyvascular disease, and diabetes mellitushave all been identified as predictors of ischemic events, but their comparative contributions to futurerisk remain unclear. OBJECTIVE To categorize the risk of cardiovascular events in stable outpatients withvarious initial manifestations of atherothrombosis using simple clinical descriptors. DESIGN, SETTING,AND PATIENTS Outpatients with coronary artery disease, cerebrovascular disease, or peripheral arterialdisease or with multiple risk factors for atherothrombosis were enrolled in the global Reduction ofAtherothrombosis for Continued Health (REACH) Registry and were followed up for as long as 4 years.Patients from 3647 centers in 29 countries were enrolled between 2003 and 2004 and followed up until2008. Final database lock was in April 2009. MAIN OUTCOME MEASURES Rates of cardiovascular death,myocardial infarction, and stroke. RESULTS A total of 45,227 patients with baseline data were included inthis 4-year analysis. During the follow-up period, a total of 5481 patients experienced at least 1 event,including 2315 with cardiovascular death, 1228 with myocardial infarction, 1898 with stroke, and 40 withboth a myocardial infarction and stroke on the same day. Among patients with atherothrombosis, thosewith a prior history of ischemic events at baseline (n = 21,890) had the highest rate of subsequentischemic events (18.3%; 95% confidence interval [CI], 17.4%-19.1%); patients with stable coronary,cerebrovascular, or peripheral artery disease (n = 15,264) had a lower risk (12.2%; 95% CI,11.4%-12.9%); and patients without established atherothrombosis but with risk factors only (n = 8073)had the lowest risk (9.1%; 95% CI, 8.3%-9.9%) (P < .001 for all comparisons). In addition, inmultivariable modeling, the presence of diabetes (hazard ratio [HR], 1.44; 95% CI, 1.36-1.53; P < .001),an ischemic event in the previous year (HR, 1.71; 95% CI, 1.57-1.85; P < .001), and polyvasculardisease (HR, 1.99; 95% CI, 1.78-2.24; P < .001) each were associated with a significantly higher risk ofthe primary end point. CONCLUSION Clinical descriptors can assist clinicians in identifying high-riskpatients within the broad range of risk for outpatients with atherothrombosis.", "metadata": {}}
+{"_id": "16787954", "title": "", "text": "The association between sterilizing activity and drug distribution into tuberculosis lesionsFinding newtreatment-shortening antibiotics to improve cure rates and curb the alarming emergence of drugresistance is the major objective of tuberculosis (TB) drug development. Using a matrix-assisted laserdesorption/ionization (MALDI) mass spectrometry imaging suite in a biosafety containment facility, weshow that the key sterilizing drugs rifampicin and pyrazinamide efficiently penetrate the sites of TBinfection in lung lesions. Rifampicin even accumulates in necrotic caseum, a critical lesion site wherepersisting tubercle bacilli reside. In contrast, moxifloxacin, which is active in vitro against a subpopulationof Mycobacterium tuberculosis that persists in specific niches under drug pressure and has achievedtreatment shortening in mice, does not diffuse well in caseum, concordant with its failure to shortentherapy in recent clinical trials. We suggest that such differential spatial distribution and kinetics ofaccumulation in lesions may create temporal and spatial windows of monotherapy in specific niches,allowing the gradual development of multidrug-resistant TB. We propose an alternative working model toprioritize new antibiotic regimens based on quantitative and spatial distribution of TB drugs in the majorlesion types found in human lungs. The finding that lesion penetration may contribute to treatmentoutcome has wide implications for TB.", "metadata": {}}
+{"_id": "16790253", "title": "", "text": "Notch signaling: cell fate control and signal integration in development.Notch signaling defines anevolutionarily ancient cell interaction mechanism, which plays a fundamental role in metazoandevelopment. Signals exchanged between neighboring cells through the Notch receptor can amplify andconsolidate molecular differences, which eventually dictate cell fates. Thus, Notch signals control howcells respond to intrinsic or extrinsic developmental cues that are necessary to unfold specificdevelopmental programs. Notch activity affects the implementation of differentiation, proliferation, andapoptotic programs, providing a general developmental tool to influence organ formation andmorphogenesis.", "metadata": {}}
+{"_id": "16806763", "title": "", "text": "A long non-coding RNA signature to improve prognosis prediction of colorectal cancerIncreasing evidencesuggests long non-coding RNAs (lncRNAs) are frequently aberrantly expressed in cancers, however, fewrelated lncRNA signatures have been established for prediction of cancer prognosis. We aimed to developa lncRNA signature to improve prognosis prediction of colorectal cancer (CRC). Using a lncRNA-miningapproach, we performed lncRNA expression profiling in large CRC cohorts from Gene Expression Ominus(GEO), including GSE39582 test series(N=436), internal validation series (N=117); and two independentvalidation series GSE14333 (N=197) and GSE17536(N=145). We established a set of six lncRNAs thatwere significantly correlated with the disease free survival (DFS) in the test series. Based on thissix-lncRNA signature, the test series patients could be classified into high-risk and low-risk subgroupswith significantly different DFS (HR=2.670; P<0.0001). The prognostic value of this six-lncRNA signaturewas confirmed in the internal validation series and another two independent CRC sets. Gene setenrichment analysis (GSEA) analysis suggested that risk score positively correlated with several cancermetastasis related pathways. Functional experiments demonstrated three dysregulated lncRNAs,AK123657, BX648207 and BX649059 were required for efficient invasion and proliferation suppression inCRC cell lines. Our results might provide an efficient classification tool for clinical prognosis evaluation ofCRC.", "metadata": {}}
+{"_id": "16812091", "title": "", "text": "Clinical use of bone densitometry: scientific review.CONTEXT Osteoporosis causes substantial morbidityand costs $13.8 billion annually in the United States. Measurement of bone mass by densitometry is aprimary part of diagnosing osteoporosis and deciding a preventive treatment course. Bone mineraldensitometry has become more widely available and commonly used in practice. OBJECTIVE To reviewevidence about the value of various clinical applications of bone densitometry. DATA SOURCES AMEDLINE search was performed to update previous meta-analyses of the relationship between variousmeasurements of bone density and risk of vertebral and hip fracture. We used data from the prospectiveStudy of Osteoporotic Fractures to estimate risk of fracture from bone density and age in postmenopausalwomen. STUDY SELECTION AND DATA EXTRACTION When available, meta-analyses and systematicreviews are emphasized in the review. DATA SYNTHESIS Bone mineral density (BMD) predicts fractureand can be used in combination with age to estimate absolute risk of fractures in postmenopausal whitewomen. Hip BMD predicts hip fracture more strongly than other measurements of BMD. There areinsufficient data to translate BMD results into risk of fracture for men and nonwhite women. The benefitsof treatments to prevent fractures depend on BMD: women with osteoporosis have a greater risk offractures and greater benefit from treatments than women without osteoporosis. CONCLUSIONSGuidelines based on systematic reviews and a cost-effectiveness analysis have suggested that it isworthwhile to measure BMD in white women older than 65 years and perhaps to use risk factors to selectyounger postmenopausal women for densitometry. Other potential clinical applications of BMD that havenot yet been adequately studied include screening men or nonwhite women, monitoring BMD in patientsreceiving treatment, and using BMD to identify patients who should be evaluated for secondary causes ofosteoporosis.", "metadata": {}}
+{"_id": "16826810", "title": "", "text": "Vascular Calcifying Progenitor Cells Possess Bidirectional Differentiation PotentialsVascular calcification isan advanced feature of atherosclerosis for which no effective therapy is available. To investigate themodulation or reversal of calcification, we identified calcifying progenitor cells and investigated theircalcifying/decalcifying potentials. Cells from the aortas of mice were sorted into four groups using Sca-1and PDGFRα markers. Sca-1(+) (Sca-1(+)/PDGFRα(+) and Sca-1(+)/PDGFRα(-)) progenitor cellsexhibited greater osteoblastic differentiation potentials than Sca-1(-) (Sca-1(-)/PDGFRα(+) andSca-1(-)/PDGFRα(-)) progenitor cells. Among Sca-1(+) progenitor populations, Sca-1(+)/PDGFRα(-) cellspossessed bidirectional differentiation potentials towards both osteoblastic and osteoclastic lineages,whereas Sca-1(+)/PDGFRα(+) cells differentiated into an osteoblastic lineage unidirectionally. Whentreated with a peroxisome proliferator activated receptor γ (PPARγ) agonist, Sca-1(+)/PDGFRα(-) cellspreferentially differentiated into osteoclast-like cells. Sca-1(+) progenitor cells in the artery originatedfrom the bone marrow (BM) and could be clonally expanded. Vessel-resident BM-derived Sca-1(+)calcifying progenitor cells displayed nonhematopoietic, mesenchymal characteristics. To evaluate themodulation of in vivo calcification, we established models of ectopic and atherosclerotic calcification.Computed tomography indicated that Sca-1(+) progenitor cells increased the volume and calcium scoresof ectopic calcification. However, Sca-1(+)/PDGFRα(-) cells treated with a PPARγ agonist decreased boneformation 2-fold compared with untreated cells. Systemic infusion of Sca-1(+)/PDGFRα(-) cells intoApoe(-/-) mice increased the severity of calcified atherosclerotic plaques. However, Sca-1(+)/PDGFRα(-)cells in which PPARγ was activated displayed markedly decreased plaque severity. Immunofluorescentstaining indicated that Sca-1(+)/PDGFRα(-) cells mainly expressed osteocalcin; however, activation ofPPARγ triggered receptor activator for nuclear factor-κB (RANK) expression, indicating their bidirectionalfate in vivo. These findings suggest that a subtype of BM-derived and vessel-resident progenitor cellsoffer a therapeutic target for the prevention of vascular calcification and that PPARγ activation may be anoption to reverse calcification.", "metadata": {}}
+{"_id": "16839245", "title": "", "text": "Physiological relevance of cell cycle kinases.The basic biology of the cell division cycle and its control byprotein kinases was originally studied through genetic and biochemical studies in yeast and other modelorganisms. The major regulatory mechanisms identified in this pioneer work are conserved in mammals.However, recent studies in different cell types or genetic models are now providing a new perspective onthe function of these major cell cycle regulators in different tissues. Here, we review the physiologicalrelevance of mammalian cell cycle kinases such as cyclin-dependent kinases (Cdks), Aurora and Polo-likekinases, and mitotic checkpoint regulators (Bub1, BubR1, and Mps1) as well as other less-studiedenzymes such as Cdc7, Nek proteins, or Mastl and their implications in development, tissue homeostasis,and human disease. Among these functions, the control of self-renewal or asymmetric cell division instem/progenitor cells and the ability to regenerate injured tissues is a central issue in current research. Inaddition, many of these proteins play previously unexpected roles in metabolism, cardiovascular function,or neuron biology. The modulation of their enzymatic activity may therefore have multiple therapeuticbenefits in human disease.", "metadata": {}}
+{"_id": "16853734", "title": "", "text": "Matrix Metalloproteinase 1 Is Necessary for the Migration of Human Bone Marrow-Derived MesenchymalStem Cells Toward Human GliomaHuman mesenchymal stem cells (MSCs) have increasingly been used ascellular vectors for the delivery of therapeutic genes to tumors. However, the precise mechanism ofmobilization remains poorly defined. In this study, MSCs that expressed similar cell surface markers andexhibited multilineage differentiation potentials were isolated from various donors. Interestingly, differentMSC isolates displayed differential migration ability toward human glioma cells. We hypothesized thatdistinct molecular signals may be involved in the varied tumor tropisms exhibited by different MSCisolates. To test this hypothesis, gene expression profiles of tumor-trophic MSCs were compared withthose of non-tumor-trophic MSCs. Among the various differentially regulated genes, matrixmetalloproteinase one (MMP1) gene expression and its protein activities were enhanced by 27-fold and21-fold, respectively, in highly migrating MSCs compared with poorly migrating MSCs. By contrast, therewas no change in the transcriptional levels of other MMPs. Functional inactivation of MMP1 abrogated themigratory potential of MSCs toward glioma-conditioned medium. Conversely, the nonmigratoryphenotype of poorly migrating MSC could be rescued in the presence of either recombinant MMP1 orconditioned medium from the highly migrating MSCs. Ectopic expression of MMP1 in these poorlymigrating cells also rendered the cells responsive to the signaling cues from the glioma cells in vivo.However, blocking the interaction of MMP1 and its cognate receptor PAR1 effectively diminished themigratory ability of MSCs. Taken together, this study provides, for the first time, supporting evidence thatMMP1 is critically involved in the migration capacity of MSCs, acting through the MMP1/PAR1 axis.", "metadata": {}}
+{"_id": "16855829", "title": "", "text": "Bullying in school: are short pupils at risk? Questionnaire study in a cohort.Bullying is still prevalent inschools and is clearly stressful for victims. 1 2 It may also have undesirable consequences for bullies,with antisocial behaviour persisting into adulthood. Victims are generally reported to be weaker than thebullies. 2 3 This would suggest that very short pupils are more likely to be victims and less likely to be theaggressors. The Wessex growth study allowed us to examine the prevalence of bullying, as experiencedor perpetrated by pupils of different heights. Ninety two short normal adolescents who had been belowthe third centile for height at school entry4 and 117 controls matched for age and sex completed abullying questionnaire, derived from work by Whitney and Smith.5 There were no refusals or anysignificant differences in sex or social class between the groups. Mean age (range) was 14.7 (13.4-15.7)years. Mean height SD scores were: short pupils −1.90 (−3.53 to −0.01), controls 0.31 (−1.41 …", "metadata": {}}
+{"_id": "16863359", "title": "", "text": "Inflammasome-induced IL-1β secretion in microglia is characterized by delayed kinetics and is onlypartially dependent on inflammatory caspases.Inflammasomes are multiprotein complexes that linkpathogen recognition and cellular stress to the processing of the proinflammatory cytokine interleukin-1β(IL-1β). Whereas inflammasome-mediated activation is heavily studied in hematopoietic macrophagesand dendritic cells, much less is known about microglia, resident tissue macrophages of the brain thatoriginate from a distinct progenitor. To directly compare inflammasome-mediated activation in differenttypes of macrophages, we isolated primary microglia and hematopoietic macrophages from adult, healthyrhesus macaques. We analyzed the expression profile of NOD (nucleotide-binding oligomerizationdomain)-like receptors, adaptor proteins, and caspases and characterized inflammasome activation andregulation in detail. We here demonstrate that primary microglia can respond to the same innate stimulias hematopoietic macrophages. However, microglial responses are more persistent due to lack ofnegative regulation on pro-IL-1β expression. In addition, we show that while caspase 1, 4, and 5activation is pivotal for inflammasome-induced IL-1β secretion by hematopoietic macrophages, microglialsecretion of IL-1β is only partially dependent on these inflammatory caspases. These results identify keycell type-specific differences that may aid the development of strategies to modulate innate immuneresponses in the brain.", "metadata": {}}
+{"_id": "16882895", "title": "", "text": "microRNA-29a suppresses cell proliferation by targeting SPARC in hepatocellular carcinoma.In thepresent study, we constructed a lentivirus vector encoding the miR-29a             precursor andestablished two stably infected cell lines, PLC-29a and 97L-29a. The overexpression of miR-29a wasconfirmed by TaqMan RT-PCR and significantly             suppressed the growth of the hepatocellularcarcinoma cell lines MHCC-97L and             PLC. Dual-luciferase reporter assays indicated that the SPARCmRNA 3'UTR was directly             targeted by miR-29a since the mutated 3'UTR was not affected.Silencing SPARC             expression by RNAi knockdown resulted in a similar effect as miR-29aoverexpression             on hepatocellular carcinoma (HCC) cell growth regulation. Anti-miR-29aoligonucleotides             (AMOs) upregulated the levels of SPARC in the HCC cells. The phosphorylationof             AKT/mTOR downstream of SPARC was inhibited in miR-29a-overexpressing HCC cells. Wefurther examined and compared the expression levels of miR-29a in HCC tissues             and thecorresponding nearby non-cancerous liver tissues of 110 patients with             HCC by qRT-PCR, andsignificantly lower expression of miR-29a was observed in             the tissues affected by HCC. Ourfindings demonstrate that the expression of miR-29a             is important in the regulation of theSPARC-AKT pathway and HCC growth.", "metadata": {}}
+{"_id": "16905344", "title": "", "text": "Another Barrier to Regeneration in the CNS: Activated Macrophages Induce Extensive Retraction ofDystrophic Axons through Direct Physical InteractionsInjured axons of the adult CNS undergo lengthyretraction from the initial site of axotomy after spinal cord injury. Macrophage infiltration correlatesspatiotemporally with this deleterious phenomenon, but the direct involvement of these inflammatorycells has not been demonstrated. In the present study, we examined the role of macrophages in axonalretraction within the dorsal columns after spinal cord injury in vivo and found that retraction occurredbetween days 2 and 28 after lesion and that the ends of injured axons were associated with ED-1+ cells.Clodronate liposome-mediated depletion of infiltrating macrophages resulted in a significant reduction inaxonal retraction; however, we saw no evidence of regeneration. We used time-lapse imaging of adultdorsal root ganglion neurons in an in vitro model of the glial scar to examine macrophage-axoninteractions and observed that adhesive contacts and considerable physical interplay betweenmacrophages and dystrophic axons led to extensive axonal retraction. The induction of retraction wasdependent on both the growth state of the axon and the activation state of the macrophage. Onlydystrophic adult axons were susceptible to macrophage \"attack. \" Unlike intrinsically active cell linemacrophages, both primary macrophages and microglia required activation to induce axonal retraction.Contact with astrocytes had no deleterious effect on adult dystrophic axons, suggesting that the inductionof extensive retraction was specific to phagocytic cells. Our data are the first to indicate a direct role ofactivated macrophages in axonal retraction by physical cell-cell interactions with injured axons.", "metadata": {}}
+{"_id": "16927286", "title": "", "text": "Large-Scale Movements of IF3 and tRNA during Bacterial Translation InitiationIn bacterial translationalinitiation, three initiation factors (IFs 1-3) enable the selection of initiator tRNA and the start codon in theP site of the 30S ribosomal subunit. Here, we report 11 single-particle cryo-electron microscopy (cryoEM)reconstructions of the complex of bacterial 30S subunit with initiator tRNA, mRNA, and IFs 1-3,representing different steps along the initiation pathway. IF1 provides key anchoring points for IF2 andIF3, thereby enhancing their activities. IF2 positions a domain in an extended conformation appropriatefor capturing the formylmethionyl moiety charged on tRNA. IF3 and tRNA undergo large conformationalchanges to facilitate the accommodation of the formylmethionyl-tRNA (fMet-tRNA(fMet)) into the P sitefor start codon recognition.", "metadata": {}}
+{"_id": "16929739", "title": "", "text": "Corresponding Author:In higher eukaryotes, introns are spliced out of protein-coding mRNAs by thespliceosome, a massive complex comprising five non-coding RNAs (ncRNAs) and about 200 proteins. Bycomparing the differences between spliceosomal proteins from many basal eukaryotic lineages, it ispossible to infer properties of the splicing system in the last common ancestor of extant eukaryotes, theeukaryotic ancestor. We begin with the hypothesis that, similar to intron length (that appears to haveincreased in multicellular eukaryotes), the spliceosome has increased in complexity throughouteukaryotic evolution. However, examination of the distribution of spliceosomal components indicates thatnot only was a spliceosome present in the eukaryotic ancestor but it also contained most of the keycomponents found in today's eukaryotes. All the small nuclear ribonucleoproteins (snRNPs) proteincomponents are likely to have been present, as well as many splicing-related proteins. Both major andtrans-splicing are likely to have been present, and the spliceosome had already formed links with othercellular processes such as transcription and capping. However, there is no evidence as yet to suggest thatminor (U12-dependent) splicing was present in the eukaryotic ancestor. Although the last commonancestor of extant eukaryotes appears to show much of the molecular complexity seen today, we do not,from this work, infer anything of the properties of the earlier \"first eukaryote. \"", "metadata": {}}
+{"_id": "16939583", "title": "", "text": "2D and 3D Stem Cell Models of Primate Cortical Development Identify Species-Specific Differences inProgenitor Behavior Contributing to Brain Size.Variation in cerebral cortex size and complexity is thoughtto contribute to differences in cognitive ability between humans and other animals. Here we comparecortical progenitor cell output in humans and three nonhuman primates using directed differentiation ofpluripotent stem cells (PSCs) in adherent two-dimensional (2D) and organoid three-dimensional (3D)culture systems. Clonal lineage analysis showed that primate cortical progenitors proliferate for aprotracted period of time, during which they generate early-born neurons, in contrast to rodents, wherethis expansion phase largely ceases before neurogenesis begins. The extent of this additional corticalprogenitor expansion differs among primates, leading to differences in the number of neurons generatedby each progenitor cell. We found that this mechanism for controlling cortical size is regulated cellautonomously in culture, suggesting that primate cerebral cortex size is regulated at least in part at thelevel of individual cortical progenitor cell clonal output.", "metadata": {}}
+{"_id": "16962732", "title": "", "text": "Multicolor “DiOlistic” Labeling of the Nervous System Using Lipophilic Dye CombinationsWe describe atechnique for rapid labeling of a large number of cells in the nervous system with many different colors.By delivering lipophilic dye-coated particles to neuronal preparations with a \"gene gun,\" individualneurons and glia whose membranes are contacted by the particles are quickly labeled. Using particlesthat are each coated with different combinations of various lipophilic dyes, many cells within a complexneuronal network can be simultaneously labeled with a wide variety of colors. This approach is mosteffective in living material but also labels previously fixed material. In living material, labeled neuronscontinue to show normal synaptic responses and undergo dendritic remodeling. This technique is thususeful for studying structural plasticity of neuronal circuits in living preparations. In addition, theGolgi-like labeling of neurons with many different colors provides a novel way to study neuronalconnectivity.", "metadata": {}}
+{"_id": "16963081", "title": "", "text": "A DNA test to sex most birds.Birds are difficult to sex. Nestlings rarely show sex-linked morphology andwe estimate that adult females appear identical to males in over 50% of the world's bird species. Thisproblem can hinder both evolutionary studies and human-assisted breeding of birds. DNA-based sexidentification provides a solution. We describe a test based on two conserved CHD(chromo-helicase-DNA-binding) genes that are located on the avian sex chromosomes of all birds, withthe possible exception of the ratites (ostriches, etc.; Struthioniformes). The CHD-W gene is located onthe W chromosome; therefore it is unique to females. The other gene, CHD-Z, is found on the Zchromosome and therefore occurs in both sexes (female, ZW; male, ZZ). The test employs PCR with asingle set of primers. It amplifies homologous sections of both genes and incorporates introns whoselengths usually differ. When examined on a gel there is a single CHD-Z band in males but females have asecond, distinctive CHD-W band.", "metadata": {}}
+{"_id": "16964262", "title": "", "text": "Evidence that Embryonic Neurons Regulate the Onset of Cortical Gliogenesis via Cardiotrophin-1Precursorcells of the embryonic cortex sequentially generate neurons and then glial cells, but the mechanismsregulating this neurogenic-to-gliogenic transition are unclear. Using cortical precursor cultures, whichtemporally mimic this in vivo differentiation pattern, we demonstrate that cortical neurons synthesize andsecrete the neurotrophic cytokine cardiotrophin-1, which activates the gp130-JAK-STAT pathway and isessential for the timed genesis of astrocytes in vitro. Our data indicate that a similar phenomenon alsooccurs in vivo. In utero electroporation of neurotrophic cytokines in the environment of embryonic corticalprecursors causes premature gliogenesis, while acute perturbation of gp130 in cortical precursors delaysthe normal timed appearance of astrocytes. Moreover, the neonatal cardiotrophin-1-/- cortex containsfewer astrocytes. Together, these results describe a neural feedback mechanism; newly born neuronsproduce cardiotrophin-1, which instructs multipotent cortical precursors to generate astrocytes, therebyensuring that gliogenesis does not occur until neurogenesis is largely complete.", "metadata": {}}
+{"_id": "16966326", "title": "", "text": "The Inhibition of TDP-43 Mitochondrial Localization Blocks Its Neuronal ToxicityGenetic mutations in TARDNA-binding protein 43 (TARDBP, also known as TDP-43) cause amyotrophic lateral sclerosis (ALS), andan increase in the presence of TDP-43 (encoded by TARDBP) in the cytoplasm is a prominenthistopathological feature of degenerating neurons in various neurodegenerative diseases. However, themolecular mechanisms by which TDP-43 contributes to ALS pathophysiology remain elusive. Here wehave found that TDP-43 accumulates in the mitochondria of neurons in subjects with ALS orfrontotemporal dementia (FTD). Disease-associated mutations increase TDP-43 mitochondriallocalization. In mitochondria, wild-type (WT) and mutant TDP-43 preferentially bindmitochondria-transcribed messenger RNAs (mRNAs) encoding respiratory complex I subunits ND3 andND6, impair their expression and specifically cause complex I disassembly. The suppression of TDP-43mitochondrial localization abolishes WT and mutant TDP-43-induced mitochondrial dysfunction andneuronal loss, and improves phenotypes of transgenic mutant TDP-43 mice. Thus, our studies linkTDP-43 toxicity directly to mitochondrial bioenergetics and propose the targeting of TDP-43 mitochondriallocalization as a promising therapeutic approach for neurodegeneration.", "metadata": {}}
+{"_id": "16979690", "title": "", "text": "Effect on the quality of peer review of blinding reviewers and asking them to sign their reports: arandomized controlled trial.CONTEXT Anxiety about bias, lack of accountability, and poor quality of peerreview has led to questions about the imbalance in anonymity between reviewers and authors.OBJECTIVE To evaluate the effect on the quality of peer review of blinding reviewers to the authors'identities and requiring reviewers to sign their reports. DESIGN Randomized controlled trial. SETTING Ageneral medical journal. PARTICIPANTS A total of 420 reviewers from the journal's database.INTERVENTION We modified a paper accepted for publication introducing 8 areas of weakness. Reviewerswere randomly allocated to 5 groups. Groups 1 and 2 received manuscripts from which the authors'names and affiliations had been removed, while groups 3 and 4 were aware of the authors' identities.Groups 1 and 3 were asked to sign their reports, while groups 2 and 4 were asked to return their reportsunsigned. The fifth group was sent the paper in the usual manner of the journal, with authors' identitiesrevealed and a request to comment anonymously. Group 5 differed from group 4 only in that its memberswere unaware that they were taking part in a study. MAIN OUTCOME MEASURE The number ofweaknesses in the paper that were commented on by the reviewers. RESULTS Reports were receivedfrom 221 reviewers (53%). The mean number of weaknesses commented on was 2 (1.7, 2.1, 1.8, and1.9 for groups 1, 2, 3, and 4 and 5 combined, respectively). There were no statistically significantdifferences between groups in their performance. Reviewers who were blinded to authors' dentities wereless likely to recommend rejection than those who were aware of the authors' identities (odds ratio, 0.5;95% confidence interval, 0.3-1.0). CONCLUSIONS Neither blinding reviewers to the authors and origin ofthe paper nor requiring them to sign their reports had any effect on rate of detection of errors. Suchmeasures are unlikely to improve the quality of peer review reports.", "metadata": {}}
+{"_id": "16980892", "title": "", "text": "2001. Comparison of three management strategies for patients with atypical squamous cells ofundetermined significance. Baseline results from a randomized trialBACKGROUND More than 2 millionU.S. women receive an equivocal cervical cytologic diagnosis (atypical squamous cells of undeterminedsignificance [ASCUS]) each year. Effective colposcopy triage strategies are needed to identify theminority of women who have clinically significant disease while avoiding excessive follow-up evaluationfor others. METHODS The ASCUS/LSIL (i.e., low-grade squamous intraepithelial lesion) Triage Study(ALTS) is a multicenter, randomized trial comparing the sensitivity and specificity of the following threemanagement strategies to detect cervical intraepithelial neoplasia grade 3 (CIN3): 1) immediatecolposcopy (considered to be the reference standard), 2) triage to colposcopy based on humanpapillomavirus (HPV) results from Hybrid Capture 2(TM) (HC 2) and thin-layer cytology results, or 3)triage based on cytology results alone. This article summarizes the cross-sectional enrollment results for3488 women with a referral diagnosis of ASCUS. All statistical tests are two-sided. RESULTS Amongparticipants with ASCUS, the underlying prevalence of histologically confirmed CIN3 was 5.1%.Sensitivity to detect CIN3 or above by testing for cancer-associated HPV DNA was 96.3% (95%confidence interval [CI] = 91.6% to 98.8%), with 56.1% of women referred to colposcopy. Sensitivity ofa single repeat cytology specimen with a triage threshold of HSIL or above was 44.1% (95% CI = 35.6%to 52.9%), with 6.9% referred. Sensitivity of a lower cytology triage threshold of ASCUS or above was85.3% (95% CI = 78.2% to 90.8%), with 58.6% referred. CONCLUSIONS HC 2 testing forcancer-associated HPV DNA is a viable option in the management of women with ASCUS. It has greatersensitivity to detect CIN3 or above and specificity comparable to a single additional cytologic testindicating ASCUS or above.", "metadata": {}}
+{"_id": "16999023", "title": "", "text": "Cell Stem Cell Article In Vivo Fate Analysis Reveals the Multipotent and Self-Renewal Capacities of Sox2 +Neural Stem Cells in the Adult HippocampusTo characterize the properties of adult neural stem cells(NSCs), we generated and analyzed Sox2-GFP transgenic mice. Sox2-GFP cells in the subgranular zone(SGZ) express markers specific for progenitors, but they represent two morphologically distinctpopulations that differ in proliferation levels. Lentivirus- and retrovirus-mediated fate-tracing studiesshowed that Sox2+ cells in the SGZ have potential to give rise to neurons and astrocytes, revealing theirmultipotency at the population as well as at a single-cell level. A subpopulation of Sox2+ cells gives riseto cells that retain Sox2, highlighting Sox2+ cells as a primary source for adult NSCs. In response tomitotic signals, increased proliferation of Sox2+ cells is coupled with the generation of Sox2+ NSCs aswell as neuronal precursors. An asymmetric contribution of Sox2+ NSCs may play an important role inmaintaining the constant size of the NSC pool and producing newly born neurons during adultneurogenesis.", "metadata": {}}
+{"_id": "17000834", "title": "", "text": "Past exposure to sun, skin phenotype, and risk of multiple sclerosis: case-control study.OBJECTIVE Toexamine whether past high sun exposure is associated with a reduced risk of multiple sclerosis. DESIGNPopulation based case-control study. SETTING Tasmania, latitudes 41-3 degrees S.   PARTICIPANTS 136cases with multiple sclerosis and 272 controls randomly drawn from the community and matched on sexand year of birth. MAIN OUTCOME MEASURE Multiple sclerosis defined by both clinical and magneticresonance imaging criteria. RESULTS Higher sun exposure when aged 6-15 years (average 2-3 hours ormore a day in summer during weekends and holidays) was associated with a decreased risk of multiplesclerosis (adjusted odds ratio 0.31, 95% confidence interval 0.16 to 0.59). Higher exposure in winterseemed more important than higher exposure in summer. Greater actinic damage was also independentlyassociated with a decreased risk of multiple sclerosis (0.32, 0.11 to 0.88 for grades 4-6 disease). Adose-response relation was observed between multiple sclerosis and decreasing sun exposure when aged6-15 years and with actinic damage. CONCLUSION Higher sun exposure during childhood and earlyadolescence is associated with a reduced risk of multiple sclerosis. Insufficient ultraviolet radiation maytherefore influence the development of multiple sclerosis.", "metadata": {}}
+{"_id": "17017465", "title": "", "text": "Endocytic Trafficking of Rac Is Required for the Spatial Restriction of Signaling in Cell MigrationThe smallGTPases, Rab5 and Rac, are essential for endocytosis and actin remodeling, respectively. Coordination ofthese processes is critical to achieve spatial restriction of intracellular signaling, which is essential for avariety of polarized functions. Here, we show that clathrin- and Rab5-mediated endocytosis are requiredfor the activation of Rac induced by motogenic stimuli. Rac activation occurs on early endosomes, wherethe RacGEF Tiam1 is also recruited. Subsequent recycling of Rac to the plasma membrane ensureslocalized signaling, leading to the formation of actin-based migratory protrusions. Thus, membranetrafficking of Rac is required for the spatial resolution of Rac-dependent motogenic signals. We furtherdemonstrate that a Rab5-to-Rac circuitry controls the morphology of motile mammalian tumor cells andprimordial germinal cells during zebrafish development, suggesting that this circuitry is relevant for theregulation of migratory programs in various cells, in both in vitro settings and whole organisms.", "metadata": {}}
+{"_id": "17021845", "title": "", "text": "Significance of stem cell marker Nanog gene in the diagnosis and prognosis of lung cancerThe aim of thepresent study was to analyze the stem cell marker, Nanog gene, for the diagnosis and prognosis of lungcancer cases, and to study its application in the diagnosis of lung cancer. In total, 100 patients diagnosedwith lung cancer between April, 2013 and May, 2015 were included in the present study. The patientswere randomly divided into group A (lung cancer) and group B (squamous cell lung carcinoma). RT-PCRwas used to detect the cancer and adjacent tissues, and Nanog gene expression was detected in groups Aand B in cells. The results showed that, analysis of Nanog gene expression in the two groups of patientsvaried to different degrees. There was no significant difference between the two groups with regard toage, gender, disease stage and lymph node metastasis. Nanog gene expression in patients withcarcinoma were significantly higher than that in the adjacent tissues (p<0.05). By contrast, differentiatedand well-differentiated carcinoma tissue showed a significantly higher Nanog gene expression than poorlydifferentiated and undifferentiated carcinoma (p<0.05). The expression of Nanog in normal cells wassignificantly higher than that in normal lung tissues and benign lesions in lung cancer stem cells. Nanogwas highly expressed in CD44+ cells, and Nanog expression in lung cancer stem cells was significantlyhigher (p<0.05). In conclusion, for groups A (lung cancer) and B (squamous cell lung carcinoma) theNanog gene expression was significantly higher. The data of the present study show that the patientswith stage III and IV lung cancer had a higher Nanog gene expression. In addition, there was a higherexpression of Nanog in lung cancer patients. By contrast, a lower degree of cell differentiation wasassociated with strong Nanog gene expression in lung cancer.", "metadata": {}}
+{"_id": "17023584", "title": "", "text": "Current knowledge and future directions of TLR and NOD signaling in sepsisThe incidence of sepsis isincreasing over time, along with an increased risk of dying from the condition. Sepsis care costs billionsannually in the United States. Death from sepsis is understood to be a complex process, driven by a lackof normal immune homeostatic functions and excessive production of proinflammatory cytokines, whichleads to multi-organ failure. The Toll-like receptor (TLR) family, one of whose members was initiallydiscovered in Drosophila, performs an important role in the recognition of microbial pathogens. Thesepattern recognition receptors (PRRs), upon sensing invading microorganisms, activate intracellular signaltransduction pathways. NOD signaling is also involved in the recognition of bacteria and actssynergistically with the TLR family in initiating an efficient immune response for the eradication ofinvading microbial pathogens. TLRs and NOD1/NOD2 respond to different pathogen-associated molecularpatterns (PAMPs). Modulation of both TLR and NOD signaling is an area of research that has promptedmuch excitement and debate as a therapeutic strategy in the management of sepsis. Molecules targetingTLR and NOD signaling pathways exist but regrettably thus far none have proven efficacy from clinicaltrials.", "metadata": {}}
+{"_id": "17049436", "title": "", "text": "Concentration Sensing by the Moving Nucleus in Cell Fate Determination: A Computational AnalysisDuringdevelopment of the vertebrate neuroepithelium, the nucleus in neural progenitor cells (NPCs) moves fromthe apex toward the base and returns to the apex (called interkinetic nuclear migration) at which pointthe cell divides. The fate of the resulting daughter cells is thought to depend on the sampling by themoving nucleus of a spatial concentration profile of the cytoplasmic Notch intracellular domain (NICD).However, the nucleus executes complex stochastic motions including random waiting and back and forthmotions, which can expose the nucleus to randomly varying levels of cytoplasmic NICD. How nuclearposition can determine daughter cell fate despite the stochastic nature of nuclear migration is not clear.Here we derived a mathematical model for reaction, diffusion, and nuclear accumulation of NICD in NPCsduring interkinetic nuclear migration (INM). Using experimentally measured trajectory-dependentprobabilities of nuclear turning, nuclear waiting times and average nuclear speeds in NPCs in thedeveloping zebrafish retina, we performed stochastic simulations to compute the nucleartrajectory-dependent probabilities of NPC differentiation. Comparison with experimentally measurednuclear NICD concentrations and trajectory-dependent probabilities of differentiation allowed estimationof the NICD cytoplasmic gradient. Spatially polarized production of NICD, rapid NICD cytoplasmicconsumption and the time-averaging effect of nuclear import/export kinetics are sufficient to explain theexperimentally observed differentiation probabilities. Our computational studies lend quantitative supportto the feasibility of the nuclear concentration-sensing mechanism for NPC fate determination in zebrafishretina.", "metadata": {}}
+{"_id": "17050065", "title": "", "text": "Odorant-specific adaptation pathways generate olfactory plasticity in C. elegansFollowing prolongedexposure to an odorant, C. elegans exhibits a diminished response to the odorant for several hours. Thisolfactory adaptation is odorant selective; animals can adapt independently to different odorants sensedby a single pair of olfactory neurons, the AWC neurons. The mechanism of olfactory adaptation isgenetically complex, with different genes required for adaptation to different odorants. Animals mutantfor the gene adp-1 fail to adapt to a subset of AWC-sensed odorants; adp-1 affects a calcium-dependentprocess required for adaptation. Mutations in another gene, osm-9, affect adaptation to a different butoverlapping subset of AWC-sensed odorants. Mutations in adp-1 and osm-9 do not diminish the ability ofunadapted animals to respond to odorants, indicating that odorant sensation and odorant adaptation aredistinct processes.", "metadata": {}}
+{"_id": "17055665", "title": "", "text": "Genome-wide dFOXO targets and topology of the transcriptomic response to stress and insulinsignallingFoxO transcription factors, inhibited by insulin/insulin-like growth factor signalling (IIS), arecrucial players in numerous organismal processes including lifespan. Using genomic tools, we uncoverover 700 direct dFOXO targets in adult female Drosophila. dFOXO is directly required for transcription ofseveral IIS components and interacting pathways, such as TOR, in the wild-type fly. The genomiclocations occupied by dFOXO in adults are different from those observed in larvae or cultured cells. Theselocations remain unchanged upon activation by stresses or reduced IIS, but the binding is increased andadditional targets activated upon genetic reduction in IIS. We identify the part of the IIS transcriptionalresponse directly controlled by dFOXO and the indirect effects and show that parts of the transcriptionalresponse to IIS reduction do not require dfoxo. Promoter analyses revealed GATA and other forkheadfactors as candidate mediators of the indirect and dfoxo-independent effects. We demonstrategenome-wide evolutionary conservation of dFOXO targets between the fly and the worm Caenorhabditiselegans, enriched for a second tier of regulators including the dHR96/daf-12 nuclear hormone receptor.", "metadata": {}}
+{"_id": "17077004", "title": "", "text": "Stable partnership and progression to AIDS or death in HIV infected patients receiving highly activeantiretroviral therapy: Swiss HIV cohort study.OBJECTIVES To explore the association between a stablepartnership and clinical outcome in HIV infected patients receiving highly active antiretroviral therapy(HAART). DESIGN Prospective cohort study of adults with HIV (Swiss HIV cohort study). SETTING Sevenoutpatient clinics throughout Switzerland. PARTICIPANTS The 3736 patients in the cohort who startedHAART before 2002 (median age 36 years, 29% female, median follow up 3.6 years). MAIN OUTCOMEMEASURES Time to AIDS or death (primary endpoint), death alone, increases in CD4 cell count of at least50 and 100 above baseline, optimal viral suppression (a viral load below 400 copies/ml), and viralrebound. RESULTS During follow up 2985 (80%) participants reported a stable partnership on at leastone occasion. When starting HAART, 52% (545/1042) of participants reported a stable partnership; afterfive years of follow up 46% (190/412) of participants reported a stable partnership. In an analysisstratified by previous antiretroviral therapy and clinical stage when starting HAART (US Centers forDisease Control and Prevention group A, B, or C), the adjusted hazard ratio for progression to AIDS ordeath was 0.79 (95% confidence interval 0.63 to 0.98) for participants with a stable partnershipcompared with those without. Adjusted hazards ratios for other endpoints were 0.59 (0.44 to 0.79) forprogression to death, 1.15 (1.06 to 1.24) for an increase in CD4 cells of 100 counts/microl or more, and1.06 (0.98 to 1.14) for optimal viral suppression. CONCLUSIONS A stable partnership is associated with aslower rate of progression to AIDS or death in HIV infected patients receiving HAART.", "metadata": {}}
+{"_id": "17081238", "title": "", "text": "Specific deficit of the ON response in visual transmission by targeted disruption of the mGIuR6geneTaking advantage of the restricted expression of metabotropic glutamate receptor subtype 6(mGluR6) in retinal ON bipolar cells, we generated knockout mice lacking mGluR6 expression. Thehomozygous mutant mice showed a loss of ON responses but unchanged OFF responses to light. Themutant mice displayed no obvious changes in retinal cell organization nor in the projection of optic fibersto the brain. Furthermore, the mGluR6-deficient mice showed visual behavioral responses to lightstimulation as examined by shuttle box avoidance behavior experiments using light exposure as aconditioned stimulus. The results demonstrate that mGluR6 is essential in synaptic transmission to theON bipolar cell and that the OFF response provides an important means for transmitting visualinformation.", "metadata": {}}
+{"_id": "17088791", "title": "", "text": "Common BRCA1 variants and susceptibility to breast and ovarian cancer in the general population.Mostmultiple case families of young onset breast cancer and ovarian cancer are thought to be due to highlypenetrant mutations in the predisposing genes BRCA1 and BRCA2. However, these mutations areuncommon in the population and they probably account for only a few percent of all breast cancerincidence. A much larger fraction of breast cancer might, in principle, be due to common variants whichconfer more modest individual risks. There are several common polymorphisms in the BRCA1 gene whichgenerate amino acid substitutions. We have examined the frequency of four of these polymorphisms:Gln356Arg, Pro871Leu, Glu1038Gly and Ser1613Gly in large series of breast and ovarian cancer casesand matched controls. Due to strong linkage disequilibrium, these four sites generate only threehaplotypes with a frequency > 1.3%. The most common haplotypes, defined by the allelesGln356Pro871Glu1038Ser1613 and Gln356Leu871Gly1038Gly1613, have frequencies of 0.57 and 0.32respectively, and these frequencies do not differ significantly between patient and control groups. Thusthe most common polymorphisms of the BRCA1 gene do not make a significant contribution to breast orovarian cancer risk. However, our data suggest that the Arg356 allele may have a different genotypedistribution in breast cancer patients from that in controls (Arg356 homozygotes are more frequent in thecontrol groups, P = 0.01), indicating that it may be protective against breast cancer. If this finding can beconfirmed, it may provide an insight into the structural features of the BRCA1 protein that are importantfor its function.", "metadata": {}}
+{"_id": "17097974", "title": "", "text": "Exercise causes a tissue-specific change of NO production in the kidney and lung.Nitric oxide (NO) isproduced in the vascular endothelium and is a potent vasodilator substance that participates in theregulation of local vascular tone. Exercise causes peculiar changes in systemic and regional blood flow,i.e., an increase of systemic blood flow and a redistribution of local tissue blood flow, by which the bloodflow is greatly increased in the working muscles, whereas it is decreased in some organs such as thekidney and intestine. Thus we hypothesized that exercise causes a tissue-specific change of NOproduction in some internal organs. We studied whether exercise affects expression of NO synthase(NOS) mRNA and protein, NOS activity, and tissue level of nitrite/nitrate (stable end products of NO) inthe kidneys (in which blood flow during exercise is decreased) and lungs (in which blood flow duringexercise is increased with the increase of cardiac output) of rat. Rats ran on a treadmill for 45 min at aspeed of 25 m/min. Immediately after this exercise, kidneys and lungs were quickly removed. Controlrats remained at rest during this 45-min period. Expression of endothelial NOS (eNOS) mRNA in thekidneys was markedly lower in exercise rats than in control rats, whereas that in the lungs wassignificantly higher in exercise rats than in control rats. Western blot analysis confirmed down- andupregulation of eNOS protein in the kidney and lung, respectively, after exercise. On the other hand,neither expression of neuronal NOS (nNOS) mRNA and nNOS protein nor inducible NOS (iNOS) mRNAand iNOS protein in the kidneys and lungs differed between exercise and control rats. NOS activity in thekidney was significantly lower in exercise rats than in control rats, whereas that in the lung wassignificantly higher in exercise rats than in control rats. On the other hand, the iNOS activity in thekidneys and lungs did not differ between exercise rats and control rats. Tissue nitrite/nitrate level in thekidneys was markedly lower in exercise rats, whereas that in the lungs was significantly higher inexercise rats. The present results show that production of NO is markedly and tissue-specifically changedin the kidney and lung by exercise.", "metadata": {}}
+{"_id": "17101262", "title": "", "text": "Ballistic labeling and dynamic imaging of astrocytes in organotypic hippocampal sliceculturesProtoplasmic astrocytes in mammalian CNS tissues in vivo have a highly complex 3D morphology,but in dissociated cell cultures they often assume a flattened, fibroblast-like morphology bearing only afew, simple processes. By fluorescent labeling and confocal reconstruction we show that many astrocytesin organotypic hippocampal slice cultures exhibit a more native complex cytoarchitecture. Althoughastrocytes at the surface of slice cultures show a reactive form with several thick glial fibrillary acidicprotein (GFAP)-positive processes, astrocytes situated in deeper portions of tissue slices retain a highlycomplex 3D morphology with many fine spine- or veil-like protrusions. Dozens of astrocytes can belabeled in single slice cultures by gene gun-mediated ballistic delivery of gold or tungsten particlescarrying cDNAs (Biolistics), lipophilic dyes (DiOlistics), or fluorescent intracellular calcium indicators(Calistics). Expression of a membrane-targeted form of eGFP (Lck-GFP) is superior to soluble eGFP forresolving fine astrocytic processes. Time-lapse confocal imaging of Lck-GFP transfected astrocytes or\"calistically\" labeled astrocytes show structural remodeling and calcium transients, respectively. Thisapproach provides an in vitro system for investigating the functional architecture, development anddynamic remodeling of astrocytes and their relationships to neurons and glia in live mammalian braintissues.", "metadata": {}}
+{"_id": "17119869", "title": "", "text": "A bipotential precursor population for pancreas and liver within the embryonic endoderm.The pancreasemerges independently from dorsal and ventral domains of embryonic gut endoderm. Gene inactivationexperiments in mice have identified factors required for dorsal pancreas development, but factors thatinitiate the ventral pancreas have remained elusive. In this study, we investigated the hypothesis that theemergence of the ventral pancreas is related to the emergence of the liver. We find that the liver andventral pancreas are specified at the same time and in the same general domain of cells. Using embryotissue explantation experiments, we find that the default fate of the ventral foregut endoderm is toactivate the pancreas gene program. FGF signalling from the cardiac mesoderm diverts this endoderm toexpress genes for liver instead of those for pancreas. No evidence was found to indicate that the cell typechoice for pancreas or liver involves a selection for growth or viability. Cardiac mesoderm or FGF inducesthe local expression of sonic hedgehog, which in turn is inhibitory to pancreas but not to liver. Thebipotential precursor cell population for pancreas and liver in embryonic development and its fateselection by FGF has features that appear to be recapitulated in the adult pancreas and are reflected inthe evolution of these organs.", "metadata": {}}
+{"_id": "17123316", "title": "", "text": "ErbB4-neuregulin signaling modulates synapse development and dendritic arborization through distinctmechanisms.Perturbations in neuregulin-1 (NRG1)/ErbB4 function have been associated withschizophrenia. Affected patients exhibit altered levels of these proteins and display hypofunction ofglutamatergic synapses as well as altered neuronal circuitry. However, the role of NRG1/ErbB4 inregulating synapse maturation and neuronal process formation has not been extensively examined. Herewe demonstrate that ErbB4 is expressed in inhibitory interneurons at both excitatory and inhibitorypostsynaptic sites. Overexpression of ErbB4 postsynaptically enhances size but not number ofpresynaptic inputs. Conversely, knockdown of ErbB4 using shRNA decreases the size of presynapticinputs, demonstrating a specific role for endogenous ErbB4 in synapse maturation. Using ErbB4 mutantconstructs, we demonstrate that ErbB4-mediated synapse maturation requires its extracellular domain,whereas its tyrosine kinase activity is dispensable for this process. We also demonstrate that depletion ofErbB4 decreases the number of primary neurites and that stimulation of ErbB4 using a soluble form ofNRG1 results in exuberant dendritic arborization through activation of the tyrosine kinase domain ofErbB4 and the phosphoinositide 3-kinase pathway. These findings demonstrate that NRG1/ErbB4signaling differentially regulates synapse maturation and dendritic morphology via two distinctmechanisms involving trans-synaptic signaling and tyrosine kinase activity, respectively.", "metadata": {}}
+{"_id": "17123657", "title": "", "text": "Dynamic Helix Interactions in Transmembrane SignalingStudying how protein transmembrane domainstransmit signals across membranes is beset by unique challenges. Here, we discuss the circumstancesthat have led to success and reflect on what has been learned from these examples. Such efforts suggestthat some of the most interesting properties of transmembrane helix interactions may be the leastamenable to study by current techniques.", "metadata": {}}
+{"_id": "17124832", "title": "", "text": "Association between smoking and risk of bladder cancer among men and women.CONTEXT Previousstudies indicate that the population attributable risk (PAR) of bladder cancer for tobacco smoking is 50%to 65% in men and 20% to 30% in women and that current cigarette smoking triples bladder cancer riskrelative to never smoking. During the last 30 years, incidence rates have remained stable in the UnitedStates in men (123.8 per 100,000 person-years to 142.2 per 100,000 person-years) and women (32.5per 100,000 person-years to 33.2 per 100,000 person-years); however, changing smoking prevalenceand cigarette composition warrant revisiting risk estimates for smoking and bladder cancer. OBJECTIVETo evaluate the association between tobacco smoking and bladder cancer. DESIGN, SETTING, ANDPARTICIPANTS Men (n = 281,394) and women (n = 186,134) of the National Institutes of Health-AARP(NIH-AARP) Diet and Health Study cohort completed a lifestyle questionnaire and were followed upbetween October 25, 1995, and December 31, 2006. Previous prospective cohort studies of smoking andincident bladder cancer were identified by systematic review and relative risks were estimated fromfixed-effects models with heterogeneity assessed by the I(2) statistic. MAIN OUTCOME MEASURESHazard ratios (HRs), PARs, and number needed to harm (NNH). RESULTS During 4,518,941 person-yearsof follow-up, incident bladder cancer occurred in 3896 men (144.0 per 100,000 person-years) and 627women (34.5 per 100,000 person-years). Former smokers (119.8 per 100,000 person-years; HR, 2.22;95% confidence interval [CI], 2.03-2.44; NNH, 1250) and current smokers (177.3 per 100,000person-years; HR, 4.06; 95% CI, 3.66-4.50; NNH, 727) had higher risks of bladder cancer than neversmokers (39.8 per 100,000 person-years). In contrast, the summary risk estimate for current smoking in7 previous studies (initiated between 1963 and 1987) was 2.94 (95% CI, 2.45-3.54; I(2) = 0.0%). ThePAR for ever smoking in our study was 0.50 (95% CI, 0.45-0.54) in men and 0.52 (95% CI, 0.45-0.59) inwomen. CONCLUSION Compared with a pooled estimate of US data from cohorts initiated between 1963and 1987, relative risks for smoking in the more recent NIH-AARP Diet and Health Study cohort werehigher, with PARs for women comparable with those for men.", "metadata": {}}
+{"_id": "17150648", "title": "", "text": "Leptin regulates glutamate and glucose transporters in hypothalamic astrocytes.Glial cells perform criticalfunctions that alter the metabolism and activity of neurons, and there is increasing interest in their role inappetite and energy balance. Leptin, a key regulator of appetite and metabolism, has previously beenreported to influence glial structural proteins and morphology. Here, we demonstrate that metabolicstatus and leptin also modify astrocyte-specific glutamate and glucose transporters, indicating thatmetabolic signals influence synaptic efficacy and glucose uptake and, ultimately, neuronal function. Wefound that basal and glucose-stimulated electrical activity of hypothalamic proopiomelanocortin (POMC)neurons in mice were altered in the offspring of mothers fed a high-fat diet. In adulthood, increased bodyweight and fasting also altered the expression of glucose and glutamate transporters. These resultsdemonstrate that whole-organism metabolism alters hypothalamic glial cell activity and suggest thatthese cells play an important role in the pathology of obesity.", "metadata": {}}
+{"_id": "17163294", "title": "", "text": "Metabolic phenotyping of human blood plasma: a powerful tool to discriminate between cancertypes?BACKGROUND Accumulating evidence has shown that cancer cell metabolism differs from that ofnormal cells. However, up to now it is not clear whether different cancer types are characterized by aspecific metabolite profile. Therefore, this study aims to evaluate whether the plasma metabolicphenotype allows to discriminate between lung and breast cancer. PATIENTS AND METHODS The protonnuclear magnetic resonance spectrum of plasma is divided into 110 integration regions, representing themetabolic phenotype. These integration regions reflect the relative metabolite concentrations and wereused to train a classification model in discriminating between 80 female breast cancer patients and 54female lung cancer patients, all with an adenocarcinoma. The validity of the model was examined bypermutation testing and by classifying an independent validation cohort of 60 female breast cancerpatients and 81 male lung cancer patients, all with an adenocarcinoma. RESULTS The model allows toclassify 99% of the breast cancer patients and 93% of the lung cancer patients correctly with an areaunder the curve (AUC) of 0.96 and can be validated in the independent cohort with a sensitivity of 89%, aspecificity of 82% and an AUC of 0.94. Decreased levels of sphingomyelin and phosphatidylcholine(phospholipids with choline head group) and phospholipids with short, unsaturated fatty acid chains nextto increased levels of phospholipids with long, saturated fatty acid chains seem to indicate that cellmembranes of lung tumors are more rigid and less sensitive to lipid peroxidation. The otherdiscriminating metabolites are pointing to a more pronounced response of the body to the Warburg effectfor lung cancer. CONCLUSION Metabolic phenotyping of plasma allows to discriminate between lung andbreast cancer, indicating that the metabolite profile reflects more than a general cancer marker.CLINICAL TRIAL REGISTRATION NUMBER NCT02362776.", "metadata": {}}
+{"_id": "17168045", "title": "", "text": "Direct in vivo assessment of microcirculatory dysfunction in severe falciparum malaria.BACKGROUND Thisstudy sought to describe and quantify microcirculatory changes in the mucosal surfaces of patients withsevere malaria, by direct in vivo observation using orthogonal polarization spectral (OPS) imaging.METHODS The microcirculation in the rectal mucosa of adult patients with severe malaria was assessedby use of OPS imaging, at admission and then daily. Comparison groups comprised patients withuncomplicated falciparum malaria, patients with bacterial sepsis, and healthy individuals. RESULTSErythrocyte velocities were measured directly in 43 adult patients with severe falciparum malaria, ofwhom 20 died. Microcirculatory blood flow was markedly disturbed, with heterogeneous obstruction thatwas proportional to severity of disease. Blocked capillaries were found in 29 patients (67%) and wereassociated with concurrent hyperdynamic blood flow (erythrocyte velocity, >750 mm/s) in adjacentvessels in 27 patients (93%). The proportion of blocked capillaries correlated with the base deficit inplasma and with the concentration of lactate. Abnormalities disappeared when the patients recovered. Inhealthy individuals and in patients with uncomplicated malaria or sepsis, no stagnant erythrocytes weredetected, and, in patients with sepsis, hyperdynamic blood flow was prominent. CONCLUSION Patientswith severe falciparum malaria show extensive microvascular obstruction that is proportional to theseverity of the disease. This finding underscores the prominent role that microvascular obstruction playsin the pathophysiology of severe malaria and illustrates the fundamental difference between themicrovascular pathophysiology of malaria and that of bacterial sepsis.", "metadata": {}}
+{"_id": "17173492", "title": "", "text": "Multiple archaeal groups mediate methane oxidation in anoxic cold seep sediments.No microorganismcapable of anaerobic growth on methane as the sole carbon source has yet been cultivated.Consequently, information about these microbes has been inferred from geochemical and microbiologicalobservations of field samples. Stable isotope analysis of lipid biomarkers and rRNA gene surveys haveimplicated specific microbes in the anaerobic oxidation of methane (AOM). Here we use combinedfluorescent in situ hybridization and secondary ion mass spectrometry analyses, to identify anaerobicmethanotrophs in marine methane-seep sediments. The results provide direct evidence for theinvolvement of at least two distinct archaeal groups (ANME-1 and ANME-2) in AOM at methane seeps.Although both archaeal groups often occurred in direct physical association with bacteria, they also wereobserved as monospecific aggregations and as single cells. The ANME-1 archaeal group more frequentlyexisted in monospecific aggregations or as single filaments, apparently without a bacterial partner.Bacteria associated with both archaeal groups included, but were not limited to, close relatives ofDesulfosarcina species. Isotopic analyses suggest that monospecific archaeal cells and cell aggregateswere active in anaerobic methanotrophy, as were multispecies consortia. In total, the data indicate thatthe microbial species and biotic interactions mediating anaerobic methanotrophy are diverse andcomplex. The data also clearly show that highly structured ANME-2/Desulfosarcina consortia are not thesole entities responsible for AOM at marine methane seeps. Other microbial groups, including ANME-1archaea, are capable of anaerobic methane consumption either as single cells, in monospecificaggregates, or in multispecies consortia.", "metadata": {}}
+{"_id": "17188921", "title": "", "text": "N-cadherin in the spotlight of cell-cell adhesion, differentiation, embryogenesis, invasion andsignalling.Cell migration is a process which is essential during embryonic development, throughout adultlife and in some pathological conditions. Cadherins, and more specifically the neural cell adhesionmolecule N-cadherin, play an important role in migration. In embryogenesis, N-cadherin is the keymolecule during gastrulation and neural crest development. N-cadherin mediated contacts activateseveral pathways like Rho GTPases and function in tyrosine kinase signalling (for example via thefibroblast growth factor receptor). In cancer, cadherins control the balance between suppression andpromotion of invasion. E-cadherin functions as an invasion suppressor and is downregulated in mostcarcinomas, while N-cadherin, as an invasion promoter, is frequently upregulated. Expression ofN-cadherin in epithelial cells induces changes in morphology to a fibroblastic phenotype, rendering thecells more motile and invasive. However in some cancers, like osteosarcoma, N-cadherin may behave asa tumour suppressor. N-cadherin can have multiple functions: promoting adhesion or induction ofmigration dependent on the cellular context.", "metadata": {}}
+{"_id": "17194716", "title": "", "text": "Role of fascin in filopodial protrusionIn this study, the mechanisms of actin-bundling in filopodia wereexamined. Analysis of cellular localization of known actin cross-linking proteins in mouse melanomaB16F1 cells revealed that fascin was specifically localized along the entire length of all filopodia, whereasother actin cross-linkers were not. RNA interference of fascin reduced the number of filopodia, andremaining filopodia had abnormal morphology with wavy and loosely bundled actin organization.Dephosphorylation of serine 39 likely determined cellular filopodia frequency. The constitutively activefascin mutant S39A increased the number and length of filopodia, whereas the inactive fascin mutantS39E reduced filopodia frequency. Fluorescence recovery after photobleaching of GFP-tagged wild-typeand S39A fascin showed that dephosphorylated fascin underwent rapid cycles of association to anddissociation from actin filaments in filopodia, with t1/2 < 10 s. We propose that fascin is a key specificactin cross-linker, providing stiffness for filopodial bundles, and that its dynamic behavior allows forefficient coordination between elongation and bundling of filopodial actin filaments.", "metadata": {}}
+{"_id": "17195001", "title": "", "text": "TOR Signaling in Growth and MetabolismThe target of rapamycin (TOR) is a conserved Ser/Thr kinasethat regulates cell growth and metabolism in response to environmental cues. Here, highlightingcontributions from studies in model organisms, we review mammalian TOR complexes and the signalingbranches they mediate. TOR is part of two distinct multiprotein complexes, TOR complex 1 (TORC1),which is sensitive to rapamycin, and TORC2, which is not. The physiological consequences of mammalianTORC1 dysregulation suggest that inhibitors of mammalian TOR may be useful in the treatment ofcancer, cardiovascular disease, autoimmunity, and metabolic disorders.", "metadata": {}}
+{"_id": "17208742", "title": "", "text": "Self-Organization of the Escherichia coli Chemotaxis Network Imaged with Super-Resolution LightMicroscopyThe Escherichia coli chemotaxis network is a model system for biological signal processing. InE. coli, transmembrane receptors responsible for signal transduction assemble into large clusterscontaining several thousand proteins. These sensory clusters have been observed at cell poles and futuredivision sites. Despite extensive study, it remains unclear how chemotaxis clusters form, what controlscluster size and density, and how the cellular location of clusters is robustly maintained in growing anddividing cells. Here, we use photoactivated localization microscopy (PALM) to map the cellular locations ofthree proteins central to bacterial chemotaxis (the Tar receptor, CheY, and CheW) with a precision of 15nm. We find that cluster sizes are approximately exponentially distributed, with no characteristic clustersize. One-third of Tar receptors are part of smaller lateral clusters and not of the large polar clusters.Analysis of the relative cellular locations of 1.1 million individual proteins (from 326 cells) suggests thatclusters form via stochastic self-assembly. The super-resolution PALM maps of E. coli receptors supportthe notion that stochastic self-assembly can create and maintain approximately periodic structures inbiological membranes, without direct cytoskeletal involvement or active transport.", "metadata": {}}
+{"_id": "17209919", "title": "", "text": "Ciliary Extracellular Vesicles: Txt Msg OrganellesCilia are sensory organelles that protrude from cellsurfaces to monitor the surrounding environment. In addition to its role as sensory receiver, the ciliumalso releases extracellular vesicles (EVs). The release of sub-micron sized EVs is a conserved form ofintercellular communication used by all three kingdoms of life. These extracellular organelles playimportant roles in both short and long range signaling between donor and target cells and may coordinatesystemic responses within an organism in normal and diseased states. EV shedding from ciliated cells andEV–cilia interactions are evolutionarily conserved phenomena, yet remarkably little is known about therelationship between the cilia and EVs and the fundamental biology of EVs. Studies in the modelorganisms Chlamydomonas and Caenorhabditis elegans have begun to shed light on ciliary EVs.Chlamydomonas EVs are shed from tips of flagella and are bioactive. Caenorhabditis elegans EVs areshed and released by ciliated sensory neurons in an intraflagellar transport-dependent manner.Caenorhabditis elegans EVs play a role in modulating animal-to-animal communication, and this EVbioactivity is dependent on EV cargo content. Some ciliary pathologies, or ciliopathies, are associatedwith abnormal EV shedding or with abnormal cilia–EV interactions. Until the 21st century, both cilia andEVs were ignored as vestigial or cellular junk. As research interest in these two organelles continues togain momentum, we envision a new field of cell biology emerging. Here, we propose that the cilium is adedicated organelle for EV biogenesis and EV reception. We will also discuss possible mechanisms bywhich EVs exert bioactivity and explain how what is learned in model organisms regarding EV biogenesisand function may provide insight to human ciliopathies.", "metadata": {}}
+{"_id": "17223891", "title": "", "text": "The NOD-like receptor NLRP12 attenuates colon inflammation and tumorigenesis.NLRP12 is a member ofthe intracellular Nod-like receptor (NLR) family that has been suggested to downregulate the productionof inflammatory cytokines, but its physiological role in regulating inflammation has not beencharacterized. We analyzed mice deficient in Nlrp12 to study its role in inflammatory diseases such ascolitis and colorectal tumorigenesis. We show that Nlrp12-deficient mice are highly susceptible to coloninflammation and tumorigenesis, which is associated with increased production of inflammatorycytokines, chemokines, and tumorigenic factors. Enhanced colon inflammation and colorectal tumordevelopment in Nlrp12-deficient mice are due to a failure to dampen NF-κB and ERK activation inmacrophages. These results reveal a critical role for NLRP12 in maintaining intestinal homeostasis andproviding protection against colorectal tumorigenesis.", "metadata": {}}
+{"_id": "17231273", "title": "", "text": "Ionic mechanism of ouabain-induced concurrent apoptosis and necrosis in individual cultured corticalneuronsEnergy deficiency and dysfunction of the Na+, K+-ATPase are common consequences of manypathological insults. The nature and mechanism of cell injury induced by impaired Na+, K+-ATPase,however, are not well defined. We used cultured cortical neurons to examine the hypothesis that blockingthe Na+, K+-ATPase induces apoptosis by depleting cellular K+ and, concurrently, induces necrotic injuryin the same cells by increasing intracellular Ca2+ and Na+. The Na+, K+-ATPase inhibitor ouabaininduced concentration-dependent neuronal death. Ouabain triggered transient neuronal cell swellingfollowed by cell shrinkage, accompanied by intracellular Ca2+ and Na+ increase, K+ decrease,cytochrome c release, caspase-3 activation, and DNA laddering. Electron microscopy revealed thecoexistence of ultrastructural features of both apoptosis and necrosis in individual cells. The caspaseinhibitor Z-Val-Ala-Asp(OMe)-fluoromethyl ketone (Z-VAD-FMK) blocked >50% of ouabain-inducedneuronal death. Potassium channel blockers or high K+ medium, but not Ca2+ channel blockade,prevented cytochrome c release, caspase activation, and DNA damage. Blocking of K+, Ca2+, or Na+channels or high K+ medium each attenuated the ouabain-induced cell death; combined inhibition of K+channels and Ca2+ or Na+ channels resulted in additional protection. Moreover, coapplication ofZ-VAD-FMK and nifedipine produced virtually complete neuroprotection. These results suggest that theneuronal death associated with Na+, K+-pump failure consists of concurrent apoptotic and necroticcomponents, mediated by intracellular depletion of K+ and accumulation of Ca2+ and Na+, respectively.The ouabain-induced hybrid death may represent a distinct form of cell death related to the brain injuryof inadequate energy supply and disrupted ion homeostasis.", "metadata": {}}
+{"_id": "17236106", "title": "", "text": "Potential consequences of replacing a retail alcohol monopoly with a private licence system: results fromSweden.AIM To examine the potential effects of replacing the Swedish alcohol retail system with a privatelicensing system on alcohol consumption and alcohol-related harm. DESIGN Two possible scenarios wereanalysed: (1) replacing the current alcohol retail monopoly with private licensed stores that specialize inalcohol sales or (2) making all alcohol available in grocery stores. We utilized a multiplicative model thatprojected effects of changes in a set of key factors including hours of sale, retail prices, promotion andadvertising and outlet density. Next, we estimated the effect of the projected consumption increase on aset of harm indicators. Values for the model parameters were obtained from the research literature.MEASUREMENTS Measures of alcohol-related harm included explicitly alcohol-related mortality, accidentmortality, suicide, homicide, assaults, drinking driving and sickness absence. FINDINGS According to theprojections, scenario 1 yields a consumption increase of 17% (1.4 litres/capita), which in turn wouldcause an additional 770 deaths, 8500 assaults, 2700 drinking driving offences and 4.5 million sick daysper year. The corresponding figures for scenario 2 are a consumption increase of 37.4% (3.1litres/capita) leading to an additional annual toll of 2000 deaths, 20 000 assaults, 6600 drinking drivingoffences and 11.1 million days of sick leave. CONCLUSIONS Projections based on the research literaturesuggest that privatization of the Swedish alcohol retail market would significantly increase alcoholconsumption and alcohol-related harm.", "metadata": {}}
+{"_id": "17240457", "title": "", "text": "A comprehensive genomic binding map of gene and chromatin regulatory proteins inSaccharomyces.Hundreds of different proteins regulate and implement transcription in Saccharomyces.Yet their interrelationships have not been investigated on a comprehensive scale. Here we determinedthe genome-wide binding locations of 200 transcription-related proteins, under normal and acuteheat-shock conditions. This study distinguishes binding between distal versus proximal promoter regionsas well as the 3' ends of genes for nearly all mRNA and tRNA genes. This study reveals (1) a greaterdiversity and specialization of regulation associated with the SAGA transcription pathway compared to theTFIID pathway, (2) new regulators enriched at tRNA genes, (3) a global co-occupancy network of>20,000 unique regulator combinations that show a high degree of regulatory interconnections amonglowly expressed genes, (4) regulators of the SAGA pathway located largely distal to the core promoterand regulators of the TFIID pathway located proximally, and (5) distinct mobilization of SAGA- versusTFIID-linked regulators during acute heat shock.", "metadata": {}}
+{"_id": "17271462", "title": "", "text": "Tie2/Angiopoietin-1 Signaling Regulates Hematopoietic Stem Cell Quiescence in the Bone MarrowNicheThe quiescent state is thought to be an indispensable property for the maintenance ofhematopoietic stem cells (HSCs). Interaction of HSCs with their particular microenvironments, known asthe stem cell niches, is critical for adult hematopoiesis in the bone marrow (BM). Here, we demonstratethat HSCs expressing the receptor tyrosine kinase Tie2 are quiescent and antiapoptotic, and comprise aside-population (SP) of HSCs, which adhere to osteoblasts (OBs) in the BM niche. The interaction of Tie2with its ligand Angiopoietin-1 (Ang-1) induced cobblestone formation of HSCs in vitro and maintained invivo long-term repopulating activity of HSCs. Furthermore, Ang-1 enhanced the ability of HSCs tobecome quiescent and induced adhesion to bone, resulting in protection of the HSC compartment frommyelosuppressive stress. These data suggest that the Tie2/Ang-1 signaling pathway plays a critical rolein the maintenance of HSCs in a quiescent state in the BM niche.", "metadata": {}}
+{"_id": "17324544", "title": "", "text": "Thirty-One Novel Biomarkers as Predictors for Clinically Incident DiabetesBACKGROUND The prevalenceof diabetes is increasing in all industrialized countries and its prevention has become a public healthpriority. However, the predictors of diabetes risk are insufficiently understood. We evaluated, whether 31novel biomarkers could help to predict the risk of incident diabetes. METHODS AND FINDINGS Thebiomarkers were evaluated primarily in the FINRISK97 cohort (n = 7,827; 417 cases of clinically incidentdiabetes during the follow-up). The findings were replicated in the Health 2000 cohort (n = 4,977; 179cases of clinically incident diabetes during the follow-up). We used Cox proportional hazards models tocalculate the relative risk of diabetes, after adjusting for the classic risk factors, separately for eachbiomarker. Next, we assessed the discriminatory ability of single biomarkers using receiver operatingcharacteristic curves and C-statistics, integrated discrimination improvement (IDI) and netreclassification improvement (NRI). Finally, we derived a biomarker score in the FINRISK97 cohort andvalidated it in the Health 2000 cohort. A score consisting of adiponectin, apolipoprotein B, C-reactiveprotein and ferritin almost doubled the relative risk of diabetes in the validation cohort (HR per onestandard deviation increase 1.88, p = 2.8 e-5). It also improved discrimination of the model (IDI =0.0149, p<0.0001) and reclassification of diabetes risk (NRI = 11.8%, p = 0.006). Gender-specificanalyses suggested that the best score differed between men and women. Among men, the best resultswere obtained with the score of four biomarkers: adiponectin, apolipoprotein B, ferritin and interleukin-1receptor antagonist, which gave an NRI of 25.4% (p<0.0001). Among women, the best score includedadiponectin, apolipoprotein B, C-reactive protein and insulin. It gave an NRI of 13.6% (p = 0.041).CONCLUSIONS We identified novel biomarkers that were associated with the risk of clinically incidentdiabetes over and above the classic risk factors. This gives new insights into the pathogenesis of diabetesand may help with targeting prevention and treatment.", "metadata": {}}
+{"_id": "17327939", "title": "", "text": "Exploiting lymphatic transport and complement activation in nanoparticle vaccinesAntigen targeting andadjuvancy schemes that respectively facilitate delivery of antigen to dendritic cells and elicit theiractivation have been explored in vaccine development. Here we investigate whether nanoparticles can beused as a vaccine platform by targeting lymph node–residing dendritic cells via interstitial flow andactivating these cells by in situ complement activation. After intradermal injection, interstitial flowtransported ultra-small nanoparticles (25 nm) highly efficiently into lymphatic capillaries and theirdraining lymph nodes, targeting half of the lymph node–residing dendritic cells, whereas 100-nmnanoparticles were only 10% as efficient. The surface chemistry of these nanoparticles activated thecomplement cascade, generating a danger signal in situ and potently activating dendritic cells. Usingnanoparticles conjugated to the model antigen ovalbumin, we demonstrate generation of humoral andcellular immunity in mice in a size- and complement-dependent manner.", "metadata": {}}
+{"_id": "17333231", "title": "", "text": "The sheddase ADAM10 is a potent modulator of prion diseaseThe prion protein (PrP(C)) is highlyexpressed in the nervous system and critically involved in prion diseases where it misfolds intopathogenic PrP(Sc). Moreover, it has been suggested as a receptor mediating neurotoxicity in commonneurodegenerative proteinopathies such as Alzheimer's disease. PrP(C) is shed at the plasma membraneby the metalloprotease ADAM10, yet the impact of this on prion disease remains enigmatic. Employingconditional knockout mice, we show that depletion of ADAM10 in forebrain neurons leads toposttranslational increase of PrP(C) levels. Upon prion infection of these mice, clinical, biochemical, andmorphological data reveal that lack of ADAM10 significantly reduces incubation times and increasesPrP(Sc) formation. In contrast, spatiotemporal analysis indicates that absence of shedding impairs spreadof prion pathology. Our data support a dual role for ADAM10-mediated shedding and highlight the role ofproteolytic processing in prion disease.", "metadata": {}}
+{"_id": "17338543", "title": "", "text": "High-affinity zinc inhibition of NMDA NR1-NR2A receptorsMicromolar concentrations of extracellular Zn2+are known to antagonize native NMDA receptors via a dual mechanism involving both avoltage-independent and a voltage-dependent inhibition. We have tried to evaluate the relativeimportance of these two effects and their subunit specificity on recombinant NMDA receptors expressed inHEK 293 cells and Xenopus oocytes. The comparison of NR1a-NR2A and NR1a-NR2B receptors shows thatthe voltage-dependent inhibition is similar in both types of receptors but that the voltage-independentinhibition occurs at much lower Zn2+ concentrations in NR1a-NR2A receptors (IC50 in the nanomolarrange) than in NR1a-NR2B receptors (IC50 in the micromolar range). The high affinity of the effectobserved with NR1a-NR2A receptors was found to be attributable mostly to the slow dissociation of Zn2+from its binding site. By analyzing the effects of Zn2+ on varied combinations of NR1 (NR1a or NR1b)and NR2 (NR2A, NR2B, NR2C), we show that both the NR1 and the NR2 subunits contribute to thevoltage-independent Zn2+ inhibition. We have observed further that under control conditions, i.e., inzero nominal Zn2+ solutions, the addition of low concentrations of heavy metal chelators markedlypotentiates the responses of NR1a-NR2A receptors, but not of NR1a-NR2B receptors. This result suggeststhat traces of a heavy metal (probably Zn2+) contaminate standard solutions and tonically inhibitNR1a-NR2A receptors. Chelation of a contaminant metal also could account for the rapid NR2Asubunit-specific potentiations produced by reducing compounds like DTT or glutathione.", "metadata": {}}
+{"_id": "17368516", "title": "", "text": "PrimPol, an Archaic Primase/Polymerase Operating in Human CellsWe describe a second primase inhuman cells, PrimPol, which has the ability to start DNA chains with deoxynucleotides unlike regularprimases, which use exclusively ribonucleotides. Moreover, PrimPol is also a DNA polymerase tailored tobypass the most common oxidative lesions in DNA, such as abasic sites and 8-oxoguanine. Subcellularfractionation and immunodetection studies indicated that PrimPol is present in both nuclear andmitochondrial DNA compartments. PrimPol activity is detectable in mitochondrial lysates from human andmouse cells but is absent from mitochondria derived from PRIMPOL knockout mice. PRIMPOL genesilencing or ablation in human and mouse cells impaired mitochondrial DNA replication. On the basis ofthe synergy observed with replicative DNA polymerases Polγ and Polε, PrimPol is proposed to facilitatereplication fork progression by acting as a translesion DNA polymerase or as a specific DNA primasereinitiating downstream of lesions that block synthesis during both mitochondrial and nuclear DNAreplication.", "metadata": {}}
+{"_id": "17374970", "title": "", "text": "Predictors of Attrition and Academic Success of Medical Students: A 30-Year Retrospective StudyAIM Todetermine attrition and predictors of academic success among medical students at University of Split,Croatia. METHODS We analysed academic records of 2054 students enrolled during 1979-2008 period.RESULTS We found that 26% (533/2054) of enrolled students did not graduate. The most commonreasons for attrition were 'personal' (36.4%), transfer to another medical school (35.6%), and dismissaldue to unsatisfactory academic record (21.2%). Grade point average (GPA) and study duration ofattrition students were significantly associated with parental education. There were 1126 graduates, 395men and 731 women. Their average graduation GPA was 3.67±0.53 and study duration 7.6±2.44 years.During 5-year curriculum only 6.4% (42/654) of students graduated in time, and 55% (240/472) ofstudents graduated in time after curriculum was extended to 6 years. Variables predicting whether astudent will graduate or not were high school grades, entrance exam score and year of enrollment.Significant predictors of graduation grades were high school grades and entrance exam score. Entranceexam score predicted length of studying. CONCLUSION Preadmission academic qualifications and year ofenrollment predict academic success in medical school. More attention should be devoted to highattrition.", "metadata": {}}
+{"_id": "17388232", "title": "", "text": "Mechanical regulation of cell function with geometrically modulated elastomeric substratesWe report theestablishment of a library of micromolded elastomeric micropost arrays to modulate substrate rigidityindependently of effects on adhesive and other material surface properties. We demonstrated thatmicropost rigidity impacts cell morphology, focal adhesions, cytoskeletal contractility and stem celldifferentiation. Furthermore, early changes in cytoskeletal contractility predicted later stem cell fatedecisions in single cells.", "metadata": {}}
+{"_id": "17402386", "title": "", "text": "THE EMBO JOURNALGlutamate-gated ion channels (ionotropic glutamate receptors, iGluRs) sense theextracellular milieu via an extensive extracellular portion, comprised of two clamshell-shaped segments.The distal, N-terminal domain (NTD) has allosteric potential in NMDA-type iGluRs, which has not beenascribed to the analogous domain in AMPA receptors (AMPARs). In this study, we present new structuraldata uncovering dynamic properties of the GluA2 and GluA3 AMPAR NTDs. GluA3 features a zipped-opendimer interface with unconstrained lower clamshell lobes, reminiscent of metabotropic GluRs (mGluRs).The resulting labile interface supports interprotomer rotations, which can be transmitted to downstreamreceptor segments. Normal mode analysis reveals two dominant mechanisms of AMPAR NTD motion:intraprotomer clamshell motions and interprotomer counter-rotations, as well as accessibleinterconversion between AMPAR and mGluR conformations. In addition, we detect electron density for apotential ligand in the GluA2 interlobe cleft, which may trigger lobe motions. Together, these datasupport a dynamic role for the AMPAR NTDs, which widens the allosteric landscape of the receptor andcould provide a novel target for ligand development.", "metadata": {}}
+{"_id": "17412260", "title": "", "text": "A complex secretory program orchestrated by the inflammasome controls paracrinesenescenceOncogene-induced senescence (OIS) is crucial for tumour suppression. Senescent cellsimplement a complex pro-inflammatory response termed the senescence-associated secretory phenotype(SASP). The SASP reinforces senescence, activates immune surveillance and paradoxically also haspro-tumorigenic properties. Here, we present evidence that the SASP can also induce paracrinesenescence in normal cells both in culture and in human and mouse models of OIS in vivo. Couplingquantitative proteomics with small-molecule screens, we identified multiple SASP components mediatingparacrine senescence, including TGF-β family ligands, VEGF, CCL2 and CCL20. Amongst them, TGF-βligands play a major role by regulating p15(INK4b) and p21(CIP1). Expression of the SASP is controlledby inflammasome-mediated IL-1 signalling. The inflammasome and IL-1 signalling are activated insenescent cells and IL-1α expression can reproduce SASP activation, resulting in senescence. Our resultsdemonstrate that the SASP can cause paracrine senescence and impact on tumour suppression andsenescence in vivo.", "metadata": {}}
+{"_id": "17415081", "title": "", "text": "Prospective Study of One Million Deaths in India: Rationale, Design, and Validation ResultsOver 75% ofthe annual estimated 9.5 million deaths in India occur in the home, and the large majority of these do nothave a certified cause. India and other developing countries urgently need reliable quantification of thecauses of death. They also need better epidemiological evidence about the relevance of physical (such asblood pressure and obesity), behavioral (such as smoking, alcohol, HIV-1 risk taking, and immunizationhistory), and biological (such as blood lipids and gene polymorphisms) measurements to thedevelopment of disease in individuals or disease rates in populations. This report here is on the rationale,design, and implementation of the world’s largest prospective study of the causes and correlates ofmortality. Nearly 14 million people in 2.4 million nationally representative Indian households will bemonitored (for vital status and, if dead, the causes of death through a well-validated verbal autopsy (VA)instrument. be addressed. This study will reliably document not only the underlying cause of child andadult deaths but also key risk factors (behavioral, physical, environmental, and eventually, genetic). Itoffers a globally replicable model for reliably estimating cause-specific mortality using VA and strengthensIndia’s flagship mortality monitoring system. Despite the misclassification that is still expected, thenew cause-of-death data will be substantially better than that available previously.[PLoS Medicine,February 2006.]", "metadata": {}}
+{"_id": "17416520", "title": "", "text": "Genome-wide identification of genes directly regulated by the pleiotropic transcription factor Spx inBacillus subtilisThe transcriptional regulator Spx plays a key role in maintaining the redox homeostasis ofBacillus subtilis cells exposed to disulfide stress. Defects in Spx were previously shown to lead todifferential expression of numerous genes but direct and indirect regulatory effects could not bedistinguished. Here we identified 283 discrete chromosomal sites potentially bound by the Spx-RNApolymerase (Spx-RNAP) complex using chromatin immunoprecipitation of Spx. Three quarters of thesesites were located near Sigma(A)-dependent promoters, and upon diamide treatment, the fraction of theSpx-RNAP complex increased in parallel with the number and occupancy of DNA sites. Correlation ofSpx-RNAP-binding sites with gene differential expression in wild-type and Δspx strains exposed or not todiamide revealed that 144 transcription units comprising 275 genes were potentially under direct Spxregulation. Spx-controlled promoters exhibited an extended -35 box in which nucleotide composition atthe -43/-44 positions strongly correlated with observed activation. In vitro transcription confirmedactivation by oxidized Spx of seven newly identified promoters, of which one was also activated byreduced Spx. Our study globally characterized the Spx regulatory network, revealing its role in the basalexpression of some genes and its complex interplay with other stress responses.", "metadata": {}}
+{"_id": "17421851", "title": "", "text": "Expression of interleukin-18 in human atherosclerotic plaques and relation to plaqueinstability.BACKGROUND Interleukin (IL)-18 is a potent proinflammatory cytokine with potentialatherogenic properties. Its expression and role in atherosclerosis, however, are unknown. METHODS ANDRESULTS In the present study, we examined stable and unstable human carotid atherosclerotic plaquesretrieved by endarterectomy for the presence of IL-18 using reverse transcription-polymerase chainreaction (PCR), Western blot, and immunohistochemical techniques. IL-18 was highly expressed in theatherosclerotic plaques compared with control normal arteries and was localized mainly in plaquemacrophages. IL-18 receptor was also upregulated in plaque macrophages and endothelial cells,suggesting potential biological effects. To examine the role of IL-18 in atherosclerosis, we determined therelation between IL-18 mRNA expression and signs of plaque instability using real-time quantitative PCR.Interestingly, significantly higher levels of IL-18 mRNA were found in symptomatic (unstable) plaquesthan asymptomatic (stable) plaques (P<0.01). CONCLUSIONS These results suggest, for the first time, amajor role for IL-18 in atherosclerotic plaque destabilization leading to acute ischemic syndromes.", "metadata": {}}
+{"_id": "17422777", "title": "", "text": "US-SOMO HPLC-SAXS module: dealing with capillary fouling and extraction of pure component patternsfrom poorly resolved SEC-SAXS dataSize-exclusion chromatography coupled with SAXS (small-angleX-ray scattering), often performed using a flow-through capillary, should allow direct collection ofmonodisperse sample data. However, capillary fouling issues and non-baseline-resolved peaks canhamper its efficacy. The UltraScan solution modeler (US-SOMO) HPLC-SAXS (high-performance liquidchromatography coupled with SAXS) module provides a comprehensive framework to analyze such data,starting with a simple linear baseline correction and symmetrical Gaussian decomposition tools [Brookes,Pérez, Cardinali, Profumo, Vachette & Rocco (2013 \u0000). J. Appl. Cryst.46, 1823-1833]. In addition toseveral new features, substantial improvements to both routines have now been implemented,comprising the evaluation of outcomes by advanced statistical tools. The novel integralbaseline-correction procedure is based on the more sound assumption that the effect of capillary foulingon scattering increases monotonically with the intensity scattered by the material within the X-ray beam.Overlapping peaks, often skewed because of sample interaction with the column matrix, can now beaccurately decomposed using non-symmetrical modified Gaussian functions. As an example, the case of apolydisperse solution of aldolase is analyzed: from heavily convoluted peaks, individual SAXS profiles oftetramers, octamers and dodecamers are extracted and reliably modeled.", "metadata": {}}
+{"_id": "17433284", "title": "", "text": "Determination of Malaria Epidemiological Status in Iran’s Malarious Areas as Baseline Information forImplementation of Malaria Elimination Program in IranBACKGROUND According to willingness of theMinistry of Health, Iran and presence of appropriate conditions for disease elimination, national malariacontrol program decided to conduct a research to clarify malaria status in 2007 and to provide requiredinformation to perform the elimination program. This review is comprised of the basis of national malariaelimination program in vision of 2025, which was started in 2010. METHODS In this descriptive study,data were analyzed by applications of different variables at district level. All districts in the three southeastern provinces, in which malaria has local transmission, were considered. Malaria cases has beendetermined and studied based on the national malaria surveillance system. RESULTS Since vivax malariais predominant in Sistan & Baluchestan Province, number of vivax cases is equal to malaria positive casesapproximately. The important point is that Nikshahr contains the maximum number of local vivax casesin this province and the maximum number of falciparum cases is reported from Sarbaz district. Among alldistricts of Hormozgan Province, no case of autochthonous falciparum was detected except in Bandar Jaskand one case in Minab. There was no case of autochthonous falciparum in Kerman Province, except inKahnoj and Ghale Ganj that each of them had one case in 2007. CONCLUSION It appears that the reportof locally transmitted cases in Iran is increasing over the past few years, before starting malariaelimination plan. Since the Afghan refugees started to return to their own country so the main source ofreporting of imported malaria cases reduced and local cases would be demonstrated more clearly.", "metadata": {}}
+{"_id": "17438862", "title": "", "text": "Local neuroinflammation and the progression of Alzheimer’s diseasePostmortem immunohistochemicalstudies have revealed a state of chronic inflammation limited to lesioned areas of brain in Alzheimer’sdisease. Some key actors in this inflammation are activated microglia (brain macrophages), proteins ofthe classical complement cascade, the pentraxins, cytokines, and chemokines. The inflammation does notinvolve the adaptive immune system or peripheral organs, but is rather due to the phylogenetically mucholder innate immune system, which appears to operate in most tissues of the body. Chronic inflammationcan damage host tissue and the brain may be particularly vulnerable because of the postmitotic nature ofneurons. Many of the inflammatory mediators have been shown to be locally produced and selectivelyelevated in affected regions of Alzheimer’s brain. Moreover, studies of tissue in such degenerativeprocesses as atherosclerosis and infarcted heart suggest a similar local innate immune reaction may beimportant in such conditions. Much epidemiological and limited clinical evidence suggests thatnonsteroidal anti-inflammatory drugs may impede the onset and slow the progression of Alzheimer’sdisease. But these drugs strike at the periphery of the inflammatory reaction. Much better results mightbe obtained if drugs were found that could inhibit the activation of microglia or the complement system inbrain, and combinations of drugs aimed at different inflammatory targets might be much more effectivethan single agents.", "metadata": {}}
+{"_id": "17447653", "title": "", "text": "BLAST+: architecture and applicationsBACKGROUND Sequence similarity searching is a very importantbioinformatics task. While Basic Local Alignment Search Tool (BLAST) outperforms exact methodsthrough its use of heuristics, the speed of the current BLAST software is suboptimal for very long queriesor database sequences. There are also some shortcomings in the user-interface of the currentcommand-line applications. RESULTS We describe features and improvements of rewritten BLASTsoftware and introduce new command-line applications. Long query sequences are broken into chunks forprocessing, in some cases leading to dramatically shorter run times. For long database sequences, it ispossible to retrieve only the relevant parts of the sequence, reducing CPU time and memory usage forsearches of short queries against databases of contigs or chromosomes. The program can now retrievemasking information for database sequences from the BLAST databases. A new modular software librarycan now access subject sequence data from arbitrary data sources. We introduce several new features,including strategy files that allow a user to save and reuse their favorite set of options. The strategy filescan be uploaded to and downloaded from the NCBI BLAST web site. CONCLUSION The new BLASTcommand-line applications, compared to the current BLAST tools, demonstrate substantial speedimprovements for long queries as well as chromosome length database sequences. We have alsoimproved the user interface of the command-line applications.", "metadata": {}}
+{"_id": "17450673", "title": "", "text": "Intrauterine environments and breast cancer risk: meta-analysis and systematic reviewINTRODUCTIONVarious perinatal factors, including birth weight, birth order, maternal age, gestational age, twin status,and parental smoking, have been postulated to affect breast cancer risk in daughters by altering thehormonal environment of the developing fetal mammary glands. Despite ample biologic plausibility,epidemiologic studies to date have yielded conflicting results. We investigated the associations betweenperinatal factors and subsequent breast cancer risk through meta-analyses. METHODS We reviewedbreast cancer studies published from January 1966 to February 2007 that included data on birth weight,birth order, maternal age, gestational age, twin status, and maternal or paternal smoking. Meta-analysesusing random effect models were employed to summarize the results. RESULTS We found that heavierbirth weights were associated with increased breast cancer risk, with studies involving five categories ofbirth weight identifying odds ratios (ORs) of 1.24 (95% confidence interval [CI] 1.04 to 1.48) for 4,000 gor more and 1.15 (95% CI 1.04 to 1.26) for 3,500 g to 3,999 g, relative to a birth weight of 2,500 to2,599 g. These studies provided no support for a J-shaped relationship of birthweight to risk. Support foran association with birthweight was also derived from studies based on three birth weight categories (OR1.15 [95% CI 1.01 to 1.31] for > or =4,000 g relative to <3,000 g) and two birth weight categories (OR1.09 [95% CI 1.02 to 1.18] for > or =3,000 g relative to <3,000 g). Women born to older mothers andtwins were also at some increased risk, but the results were heterogeneous across studies andpublication years. Birth order, prematurity, and maternal smoking were unrelated to breast cancer risk.CONCLUSION Our findings provide some support for the hypothesis that in utero exposures reflective ofhigher endogenous hormone levels could affect risk for development of breast cancer in adulthood.", "metadata": {}}
+{"_id": "17454301", "title": "", "text": "Epidemiologic studies on Dengue in Santiago de Cuba, 1997.A small, isolated outbreak of denguehemorrhagic fever/dengue shock syndrome (DHF/DSS) due to dengue virus type 2 (DEN-2) wasdocumented in Santiago de Cuba on the island of Cuba beginning in January 1997. There were 205DHF/DSS cases, all in persons older than age 15 years. All but three had evidence of a prior dengueinfection, with the only known opportunity being the islandwide dengue virus type 1 (DEN-1) epidemic of1977-1979. Virtually complete clinical and laboratory surveillance of overt disease was achieved. FromDecember 1997 to January 1998, a random, age-stratified serum sample was obtained from 1,151persons in 40 residential clusters in Santiago. Sera were tested for DEN-1 and DEN-2 neutralizingantibodies. The prevalence of DEN-2 antibodies in children age 15 years and under, born after the 1981DEN-2 epidemic, was taken as the 1997 DEN-2 infection rate. This was adjusted slightly to accommodateobserved cases, resulting in an estimated infection rate of 4.3%. Dengue fever and DHF/DSS attack rateswere calculated from estimated total primary and secondary DEN-2 infections. Only 3% of 13,116primary infections were overt. The DHF/DSS attack rate for adults of all ages was 420 per 10,000secondary DEN-2 infections.", "metadata": {}}
+{"_id": "17462437", "title": "", "text": "Prognostic and Predictive Value of KRAS Mutations in Advanced Non-Small Cell Lung CancerClinicalimplications of KRAS mutations in advanced non-small cell lung cancer remain unclear. Weretrospectively evaluated the prognostic and predictive value of KRAS mutations in patients withadvanced NSCLC. Among 484 patients with available results for both KRAS and EGFR mutations, 39 (8%)had KRAS and 182 (38%) EGFR mutations, with two cases having both mutations. The median overallsurvivals for patients with KRAS mutations, EGFR mutations, or both wild types were 7.7, 38.0, and 15.0months, respectively (P<0.001). The KRAS mutation was an independent poor prognostic factor in themultivariate analysis (hazard ratio = 2.6, 95% CI: 1.8-3.7). Response rates and progression-free survival(PFS) for the pemetrexed-based regimen in the KRAS mutation group were 14% and 2.1 months, inferiorto those (28% and 3.9 months) in the KRAS wild type group. KRAS mutation tended to be associatedwith inferior treatment outcomes after gemcitabine-based chemotherapy, while there was no differenceregarding taxane-based regimen. Although the clinical outcomes to EGFR tyrosine kinase inhibitors (TKIs)seemed to be better in patients with KRAS wild type than those with KRAS mutations, there was nostatistical difference in response rates and PFS according to KRAS mutation status when EGFR mutationstatus was considered. Two patients with both KRAS and EGFR mutations showed partial response toEGFR TKIs. Although G12D mutation appeared more frequently in never smokers, there was no differencein clinical outcomes according to KRAS genotypes. These results suggested KRAS mutations have anindependent prognostic value but a limited predictive role for EGFR TKIs or cytotoxic chemotherapy inadvanced NSCLC.", "metadata": {}}
+{"_id": "17463469", "title": "", "text": "A Heteroskedasticity-Consistent Covariance Matrix Estimator And A Direct Test For HeteroskedasticityThispaper presents a parameter covariance matrix estimator which is consistent even when the disturbancesof a linear regression model are heteroskedastic. This estimator does not depend on a formal model ofthe structure of the heteroskedasticity. By comparing the elements of the new estimator to those of theusual covariance estimator, one obtains a direct test for heteroskedasticity, since in the absence ofheteroskedasticity, the two estimators will be approximately equal, but will generally diverge otherwise.The test has an appealing least squares interpretation.", "metadata": {}}
+{"_id": "17463549", "title": "", "text": "Two Subsets of Naive T Helper Cells with Distinct T Cell Receptor Excision Circle Content in Human AdultPeripheral BloodDuring ageing thymic function declines and is unable to meet the demand for peripheralT helper (Th) cell replenishment. Therefore, population maintenance of naive Th cells must be at leastpartly peripherally based. Such peripheral postthymic expansion of recent thymic emigrants (RTEs)during ageing consequently should lead to loss or dilution of T cell receptor excision circles (TRECs) froma subset of naive T cells. We have identified two subsets of naive Th cells in human adult peripheral bloodcharacterized by a striking unequal content of TRECs, indicating different peripheral proliferativehistories. TRECs are highly enriched in peripheral naive CD45RA+ Th cells coexpressing CD31 comparedwith peripheral naive CD45RA+ Th cells lacking CD31 expression, in which TRECs can hardly be detected.Furthermore we show that CD31−CD45RA+ Th cells account for increasing percentages of the naiveperipheral Th cell pool during ageing but retain phenotypic and functional features of naive Th cells. AsCD31 is lost upon T cell receptor (TCR) engagement in vitro, we hypothesize that TCR triggering is aprerequisite for homeostatically driven peripheral postthymic expansion of human naive RTEs. Wedescribe here the identification of peripherally expanded naive Th cells in human adult bloodcharacterized by the loss of CD31 expression and a highly reduced TREC content.", "metadata": {}}
+{"_id": "17464771", "title": "", "text": "A Role for the Vacuolating Cytotoxin, VacA, in Colonization and Helicobacter pylori–Induced Metaplasia inthe StomachCarriage of Helicobacter pylori strains producing more active (s1/i1) forms of VacA isstrongly associated with gastric adenocarcinoma. To our knowledge, we are the first to determine effectsof different polymorphic forms of VacA on inflammation and metaplasia in the mouse stomach. Bacteriaproducing the less active s2/i2 form of VacA colonized mice more efficiently than mutants null for VacA orproducing more active forms of it, providing the first evidence of a positive role for the minimally actives2/i2 toxin. Strains producing more active toxin forms induced more severe and extensive metaplasia andinflammation in the mouse stomach than strains producing weakly active (s2/i2) toxin. We also examinedthe association in humans, controlling for cagPAI status. In human gastric biopsy specimens, the vacA i1allele was strongly associated with precancerous intestinal metaplasia, with almost complete absence ofintestinal metaplasia in subjects infected with i2-type strains, even in a vacA s1, cagA(+) background.", "metadata": {}}
+{"_id": "17482507", "title": "", "text": "Systematic review of role of bisphosphonates on skeletal morbidity in metastatic cancer.OBJECTIVE Toreview the evidence for the use of bisphosphonates to reduce skeletal morbidity in cancer patients withbone metastases. DATA SOURCES Electronic databases, scanning reference lists, and consultation withexperts and pharmaceutical companies. Foreign language papers were included. STUDY SELECTIONIncluded trials were randomised controlled trials of patients with malignant disease and bone metastaseswho were treated with oral or intravenous bisphosphonate compared with another bisphosphonate,placebo, or standard care. All trials measured at least one outcome of skeletal morbidity. RESULTS 95articles were identified; 30 studies fulfilled inclusion criteria. In studies that lasted > or = 6 months,compared with placebo bisphosphonates significantly reduced the odds ratio for fractures (vertebral 0.69,95% confidence interval 0.57 to 0.84, P < 0.0001; non-vertebral 0.65, 0.54 to 0.79, P < 0.0001;combined 0.65, 0.55 to 0.78, P < 0.0001), radiotherapy (0.67, 0.57 to 0.79, P < 0.0001), andhypercalcaemia (0.54, 0.36 to 0.81, P = 0.003) but not for orthopaedic surgery (0.70, 0.46 to 1.05, P =0.086) or spinal cord compression (0.71, 0.47 to 1.08, P = 0.113). The reduction in orthopaedic surgerywas significant in studies that lasted over a year (0.59, 0.39 to 0.88, P = 0.009). Use of bisphosphonatessignificantly increased time to first skeletal related event but did not increase survival. Subanalysesshowed that most evidence supports use of intravenous aminobisphosphonates. CONCLUSIONS In peoplewith metastatic bone disease bisphosphonates significantly decrease skeletal morbidity, except for spinalcord compression and increased time to first skeletal related event. Treatment should start when bonemetastases are diagnosed and continue until it is no longer clinically relevant.", "metadata": {}}
+{"_id": "17506075", "title": "", "text": "Rodent Models of Depression: Neurotrophic and Neuroinflammatory BiomarkersRodent models are anindispensable tool for studying etiology and progress of depression. Since interrelated systems ofneurotrophic factors and cytokines comprise major regulatory mechanisms controlling normal brainplasticity, impairments of these systems form the basis for development of cerebral pathologies, includingmental diseases. The present review focuses on the numerous experimental rodent models of depressioninduced by different stress factors (exteroceptive and interoceptive) during early life (including prenatalperiod) or adulthood, giving emphasis to the data on the changes of neurotrophic factors andneuroinflammatory indices in the brain. These parameters are closely related to behavioraldepression-like symptoms and impairments of neuronal plasticity and are both gender- andgenotype-dependent. Stress-related changes in expression of neurotrophins and cytokines in rodent brainare region-specific. Some contradictory data reported by different groups may be a consequence ofdifferences of stress paradigms or their realization in different laboratories. Like all experimental models,stress-induced depression-like conditions are experimental simplification of clinical depression states;however, they are suitable for understanding the involvement of neurotrophic factors and cytokines in thepathogenesis of the disease-a goal unachievable in the clinical reality. These major regulatory systemsmay be important targets for therapeutic measures as well as for development of drugs for treatment ofdepression states.", "metadata": {}}
+{"_id": "17518195", "title": "", "text": "The docking domain of histone H2A is required for H1 binding and RSC-mediated nucleosomeremodelingHistone variants within the H2A family show high divergences in their C-terminal regions. Inthis work, we have studied how these divergences and in particular, how a part of the H2ACOOH-terminus, the docking domain, is implicated in both structural and functional properties of thenucleosome. Using biochemical methods in combination with Atomic Force Microscopy and ElectronCryo-Microscopy, we show that the H2A-docking domain is a key structural feature within thenucleosome. Deletion of this domain or replacement with the incomplete docking domain from the variantH2A.Bbd results in significant structural alterations in the nucleosome, including an increase in overallaccessibility to nucleases, un-wrapping of \u000010 bp of DNA from each end of the nucleosome andassociated changes in the entry/exit angle of DNA ends. These structural alterations are associated with areduced ability of the chromatin remodeler RSC to both remodel and mobilize the nucleosomes. Linkerhistone H1 binding is also abrogated in nucleosomes containing the incomplete docking domain ofH2A.Bbd. Our data illustrate the unique role of the H2A-docking domain in coordinating thestructural-functional aspects of the nucleosome properties. Moreover, our data suggest that incorporationof a 'defective' docking domain may be a primary structural role of H2A.Bbd in chromatin.", "metadata": {}}
+{"_id": "17539488", "title": "", "text": "Regulation of poly(A) site choice of several yeast mRNAsSeveral yeast genes produce multiple transcriptswith different 3'-ends. Of these, four genes are known to produce truncated transcripts that end withinthe coding sequence of longer transcripts: CBP1 , AEP2 / ATP13 , RNA14 and SIR1 . It has been shownthat the level of the truncated CBP1 transcript increases during the switch to respiratory growth whilethat of the full-length transcript decreases. To determine whether this phenomenon is unique to CBP1 ,northern analysis was used to determine whether the levels of other truncated transcripts are regulatedsimilarly by carbon source. The levels of the shortest transcripts of AEP2 / ATP13 and RNA14 increasedduring respiration while the shortest SIR1 transcript remained constant. However, two longer SIR1transcripts were regulated reciprocally by carbon source. Mapping the 3'-ends of each transcript bysequencing partial cDNA clones revealed multiple 3'-ends for each transcript. Examination of thesequences surrounding the 3'-ends of the induced transcripts failed to identify a consensus sequence butdid reveal weak putative 3'-end formation signals in all of the transcripts. Similarly, no consensussequence was found when the sequences surrounding the 3'-ends of the longest transcripts werecompared, but again weak putative 3'-end formation signals were identified. These data are suggestive ofcarbon source regulation of alternative poly(A) site choice in yeast.", "metadata": {}}
+{"_id": "17544977", "title": "", "text": "Circular RNA and miR-7 in cancer.MicroRNAs (miRNA) play important roles in fine-tuning gene expressionand are often deregulated in cancer. The identification of competing endogenous RNA and circular RNA(circRNA) as important regulators of miRNA activity underscores the increasing complexity ofncRNA-mediated regulatory networks. Particularly, the recently identified circular RNA, ciRS-7, which actsas a designated miR-7 inhibitor/sponge, has conceptually changed the mechanistic understanding ofmiRNA networks. As miR-7 modulates the expression of several oncogenes, disclosing the regulation ofmiR-7 activity will likely advance the understanding of various cancer etiologies. Here, we review thecurrent knowledge about the ciRS-7/miR-7 axis in cancer-related pathways and discuss possible modelsexplaining the relevance of coexpressing miR-7 along with a circRNA inhibitor.", "metadata": {}}
+{"_id": "17546486", "title": "", "text": "Angiotensin II Evokes Angiogenic Signals within Skeletal Muscle through Co-ordinated Effects on SkeletalMyocytes and Endothelial CellsSkeletal muscle overload induces the expression of angiogenic factors suchas vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP)-2, leading to newcapillary growth. We found that the overload-induced increase in angiogenesis, as well as increases inVEGF, MMP-2 and MT1-MMP transcripts were abrogated in muscle VEGF KO mice, highlighting the criticalrole of myocyte-derived VEGF in controlling this process. The upstream mediators that contribute tooverload-induced expression of VEGF have yet to be ascertained. We found that muscle overloadincreased angiotensinogen expression, a precursor of angiotensin (Ang) II, and that Ang II signalingplayed an important role in basal VEGF production in C2C12 cells. Furthermore, matrix-bound VEGFreleased from myoblasts induced the activation of endothelial cells, as evidenced by elevated endothelialcell phospho-p38 levels. We also found that exogenous Ang II elevates VEGF expression, as well asMMP-2 transcript levels in C2C12 myotubes. Interestingly, these responses also were observed in skeletalmuscle endothelial cells in response to Ang II treatment, indicating that these cells also can responddirectly to the stimulus. The involvement of Ang II in muscle overload-induced angiogenesis wasassessed. We found that blockade of AT1R-dependent Ang II signaling using losartan did not attenuatecapillary growth. Surprisingly, increased levels of VEGF protein were detected in overloaded muscle fromlosartan-treated rats. Similarly, we observed elevated VEGF production in cultured endothelial cellstreated with losartan alone or in combination with Ang II. These studies conclusively establish therequirement for muscle derived VEGF in overload-induced angiogenesis and highlight a role for Ang II inbasal VEGF production in skeletal muscle. However, while Ang II signaling is activated following overloadand plays a role in muscle VEGF production, inhibition of this pathway is not sufficient to haltoverload-induced angiogenesis, indicating that AT1-independent signals maintain VEGF production inlosartan-treated muscle.", "metadata": {}}
+{"_id": "17553026", "title": "", "text": "A specific loop in human DNA polymerase mu allows switching between creative and DNA-instructedsynthesisHuman DNA polymerase mu (Polμ) is a family X member that has terminal transferase activitybut, in spite of a non-orthodox selection of the template information, displays its maximal catalyticefficiency in DNA-templated reactions. As terminal deoxynucleotidyl transferase (TdT), Polμ has a specificloop (loop1) that could provide this enzyme with its terminal transferase activity. When loop1 wasdeleted, human Polμ lacked TdT activity but improved DNA-binding and DNA template-dependentpolymerization. Interestingly, when loop1 from TdT was inserted in Polμ (substituting its cognate loop1),the resulting chimaera displayed TdT activity, preferentially inserting dGTP residues, but had a stronglyreduced template-dependent polymerization activity. Therefore, a specialized loop in Polμ, that couldadopt alternative conformations, appears to provide this enzyme with a dual capacity: (i) templateindependency to create new DNA information, in which loop1 would have an active role by acting as a‘pseudotemplate’; (ii) template-dependent polymerization, in which loop1 must allow binding of thetemplate strand. Recent in vivo and in vitro data suggest that such a dual capacity could beadvantageous to resolve microhomology-mediated end-joining reactions.", "metadata": {}}
+{"_id": "17587795", "title": "", "text": "Dnmt1-Independent CG Methylation Contributes to Nucleosome Positioning in Diverse EukaryotesDnmt1epigenetically propagates symmetrical CG methylation in many eukaryotes. Their genomes are typicallydepleted of CG dinucleotides because of imperfect repair of deaminated methylcytosines. Here, weextensively survey diverse species lacking Dnmt1 and show that, surprisingly, symmetrical CGmethylation is nonetheless frequently present and catalyzed by a different DNA methyltransferase family,Dnmt5. Numerous Dnmt5-containing organisms that diverged more than a billion years ago exhibitclustered methylation, specifically in nucleosome linkers. Clustered methylation occurs at unprecedenteddensities and directly disfavors nucleosomes, contributing to nucleosome positioning between clusters.Dense methylation is enabled by a regime of genomic sequence evolution that enriches CG dinucleotidesand drives the highest CG frequencies known. Species with linker methylation have small,transcriptionally active nuclei that approach the physical limits of chromatin compaction. These featuresconstitute a previously unappreciated genome architecture, in which dense methylation influencesnucleosome positions, likely facilitating nuclear processes under extreme spatial constraints.", "metadata": {}}
+{"_id": "17591478", "title": "", "text": "The Immunogenicity and Safety of the Live-attenuated SA 14-14-2 Japanese Encephalitis Vaccine Givenwith a Two-dose Primary Schedule in ChildrenEffective and tolerable vaccination is an essential strategyto prevent Japanese encephalitis (JE) in endemic areas. Although the live attenuated SA 14-14-2 JEvaccine (LAJEV) has been widely used since its introduction, the systemic data of LAJEV was very rarelyavailable in Korea. We conducted the open-label, prospective cohort study to assess the immunogenicityand safety of this vaccine. Ninety subjects were enrolled, and LAJEV in a 2-dose primary series was givenwith a 12-month interval. Neutralizing antibody titers were measured before and after each vaccination,and active monitoring for adverse events was performed. After the first dose, 91.1% of subjects hadseroprotection with a geometric mean titer (GMT) of 40.9. Seroprotection rate after the second dose was97%, and GMT showed an increase of 6.5-fold. Most adverse events following immunization wereself-limited, and no serious adverse events were reported until 42 days after each dose. The 2-doseadministration of LAJEV in the primary immunization schedule appeared to be highly immunogenic andsafe.", "metadata": {}}
+{"_id": "17601006", "title": "", "text": "Centrosome-dependent asymmetric inheritance of the midbody ring in Drosophila germline stem celldivisionMany stem cells, including Drosophila germline stem cells (GSCs), divide asymmetrically,producing one stem cell and one differentiating daughter. Cytokinesis is often asymmetric, in that onlyone daughter cell inherits the midbody ring (MR) upon completion of abscission even in apparentlysymmetrically dividing cells. However, whether the asymmetry in cytokinesis correlates with cell fate orhas functional relevance has been poorly explored. Here we show that the MR is asymmetricallysegregated during GSC divisions in a centrosome age-dependent manner: male GSCs, which inherit themother centrosome, exclude the MR, whereas female GSCs, which we here show inherit the daughtercentrosome, inherit the MR. We further show that stem cell identity correlates with the mode of MRinheritance. Together our data suggest that the MR does not inherently dictate stem cell identity,although its stereotypical inheritance is under the control of stemness and potentially provides a platformfor asymmetric segregation of certain factors.", "metadata": {}}
+{"_id": "17625068", "title": "", "text": "Penile Curvature Incidence in Hypospadias: Can It Be Determined?The aim was to retrospectivelydetermine the real incidence of congenital penile curvature in various forms of hypospadias, in order toindicate intraoperative assessment and correction of curvature. We analyzed 842 patients withhypospadias who underwent surgery from 2003 to 2010, classified into two groups. First group wasintraoperatively checked for curvature as a routine procedure, while a curvature in the second group wasassessed mostly in severe hypospadias. Results are analyzed using Fisher's and chi-square tests. In total,238 cases (28.3%) of associated curvature were confirmed. Curvature was significantly more frequent inthe first group, regarding hypospadias in general (P < 0.01), as well as distal (P < 0.05) and midshaftforms (P < 0.01). Penile curvature is common figure in hypospadias, including distal types. Intraoperativetesting for associated curvature should be considered as a routine procedure in hypospadias repair.", "metadata": {}}
+{"_id": "17626822", "title": "", "text": "Home birth and barriers to referring women with obstetric complications to hospitals: a mixed-methodsstudy in Zahedan, southeastern IranBACKGROUND One factor that contributes to high maternal mortalityin developing countries is the delayed use of Emergency Obstetric-Care (EmOC) facilities. The objectiveof this study was to determine the factors that hinder midwives and parturient women from usinghospitals when complications occur during home birth in Sistan and Baluchestan province, Iran, where23% of all deliveries take place in non- hospital settings. METHODS In the study and data management,a mixed-methods approach was used. In the quantitative phase, we compared the existing health-sectordata with World Health Organization (WHO) standards for the availability and use of EmOC services. Thequalitative phase included collection and analysis of interviews with midwives and traditional birthattendants and twenty-one in-depth interviews with mothers. The data collected in this phase weremanaged according to the principles of qualitative data analysis. RESULTS The findings demonstrate thatthree distinct factors lead to indecisiveness and delay in the use of EmOC by the midwives and mothersstudied. Socio-cultural and familial reasons compel some women to choose to give birth at home and tohesitate seeking professional emergency care for delivery complications. Apprehension about beinginsulted by physicians, the necessity of protecting their professional integrity in front of patients and aninability to persuade their patients lead to an over-insistence by midwives on completing deliveries at themothers' homes and a reluctance to refer their patients to hospitals. The low quality and expense ofEmOC and the mothers' lack of health insurance also contribute to delays in referral. CONCLUSIONSWomen who choose to give birth at home accept the risk that complications may arise. Training midwivesand persuading mothers and significant others who make decisions about the value of referring women tohospitals at the onset of life-threatening complications are central factors to increasing the use ofavailable hospitals. The hospitals must be safe, comfortable and attractive environments for parturitionand should give appropriate consideration to the ethical and cultural concerns of the women. Appropriatemanagement of financial and insurance-related issues can help midwives and mothers make a rationaldecision when complications arise.", "metadata": {}}
+{"_id": "17628888", "title": "", "text": "ATPase-Dependent Control of the Mms21 SUMO Ligase during DNA RepairModification of proteins bySUMO is essential for the maintenance of genome integrity. During DNA replication, the Mms21-branch ofthe SUMO pathway counteracts recombination intermediates at damaged replication forks, thusfacilitating sister chromatid disjunction. The Mms21 SUMO ligase docks to the arm region of the Smc5protein in the Smc5/6 complex; together, they cooperate during recombinational DNA repair. Yet how theactivity of the SUMO ligase is controlled remains unknown. Here we show that the SUMO ligase and thechromosome disjunction functions of Mms21 depend on its docking to an intact and active Smc5/6complex, indicating that the Smc5/6-Mms21 complex operates as a large SUMO ligase in vivo. In spite ofthe physical distance separating the E3 and the nucleotide-binding domains in Smc5/6,Mms21-dependent sumoylation requires binding of ATP to Smc5, a step that is part of the ligasemechanism that assists Ubc9 function. The communication is enabled by the presence of a conserveddisruption in the coiled coil domain of Smc5, pointing to potential conformational changes for SUMOligase activation. In accordance, scanning force microscopy of the Smc5-Mms21 heterodimer shows thatthe molecule is physically remodeled in an ATP-dependent manner. Our results demonstrate that theATP-binding activity of the Smc5/6 complex is coordinated with its SUMO ligase, through the coiled coildomain of Smc5 and the physical remodeling of the molecule, to promote sumoylation and chromosomedisjunction during DNA repair.", "metadata": {}}
+{"_id": "17631671", "title": "", "text": "Cadherins in brain morphogenesis and wiring.Cadherins are Ca(2+)-dependent cell-cell adhesionmolecules that play critical roles in animal morphogenesis. Various cadherin-related molecules have alsobeen identified, which show diverse functions, not only for the regulation of cell adhesion but also for thatof cell proliferation and planar cell polarity. During the past decade, understanding of the roles of thesemolecules in the nervous system has significantly progressed. They are important not only for thedevelopment of the nervous system but also for its functions and, in turn, for neural disorders. In thisreview, we discuss the roles of cadherins and related molecules in neural development and function in thevertebrate brain.", "metadata": {}}
+{"_id": "17648235", "title": "", "text": "Autocrine WNT signaling contributes to breast cancer cell proliferation via the canonical WNT pathway andEGFR transactivationDe-regulation of the wingless and integration site growth factor (WNT) signalingpathway via mutations in APC and Axin, proteins that target β-catenin for destruction, have been linkedto various types of human cancer. These genetic alterations rarely, if ever, are observed in breasttumors. However, various lines of evidence suggest that WNT signaling may also be de-regulated inbreast cancer. Most breast tumors show hypermethylation of the promoter region of secretedFrizzled-related protein 1 (sFRP1), a negative WNT pathway regulator, leading to downregulation of itsexpression. As a consequence, WNT signaling is enhanced and may contribute to proliferation of humanbreast tumor cells. We previously demonstrated that, in addition to the canonical WNT/β-cateninpathway, WNT signaling activates the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway inmouse mammary epithelial cells via epidermal growth factor receptor (EGFR) transactivation. Using theWNT modulator sFRP1 and short interfering RNA-mediated Dishevelled (DVL) knockdown, we interferedwith autocrine WNT signaling at the ligand-receptor level. The impact on proliferation was measured bycell counting, YOPRO, and the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide)assay; β-catenin, EGFR, ERK1/2 activation, and PARP (poly [ADP-ribose]polymerase) cleavages wereassessed by Western blotting after treatment of human breast cancer cell lines with conditioned media,purified proteins, small-molecule inhibitors, or blocking antibodies. Phospho-DVL and stabilized β-cateninare present in many breast tumor cell lines, indicating autocrine WNT signaling activity. Interfering withthis loop decreases active β-catenin levels, lowers ERK1/2 activity, blocks proliferation, and inducesapoptosis in MDA-MB-231, BT474, SkBr3, JIMT-1, and MCF-7 cells. The effects of WNT signaling aremediated partly by EGFR transactivation in human breast cancer cells in a metalloprotease- andSrc-dependent manner. Furthermore, Wnt1 rescues estrogen receptor-positive (ER+) breast cancer cellsfrom the anti-proliferative effects of 4-hydroxytamoxifen (4-HT) and this activity can be blocked by anEGFR tyrosine kinase inhibitor. Our data show that interference with autocrine WNT signaling in humanbreast cancer reduces proliferation and survival of human breast cancer cells and rescues ER+ tumorcells from 4-HT by activation of the canonical WNT pathway and EGFR transactivation. These findingssuggest that interference with WNT signaling at the ligand-receptor level in combination with othertargeted therapies may improve the efficiency of breast cancer treatments.", "metadata": {}}
+{"_id": "17656445", "title": "", "text": "Alternative Markers of Hyperglycemia and Risk of DiabetesOBJECTIVE Fructosamine, glycated albumin,and 1,5-anhydroglucitol (1,5-AG) are of interest for monitoring short-term glycemic control in patientswith diabetes; however, their associations with diabetes risk are uncharacterized. RESEARCH DESIGNAND METHODS We used Cox proportional hazards models to examine the associations of fructosamine,glycated albumin, and 1,5-AG with incident diabetes in 1,299 participants, from the Atherosclerosis Riskin Communities (ARIC) Study (2005-2006), who had no history of diagnosed diabetes at baseline.Incident diabetes was self-reported during annual telephone calls. RESULTS There were 119 new cases ofdiabetes during a median follow-up of 3.3 years. When compared with the lowest quartile, the fourthquartiles of fructosamine and glycated albumin were significantly associated with diabetes risk (hazardratio [HR] 3.99 [95% CI 1.93-8.28] and 5.22 [2.49-10.94], respectively). The fourth quartile of 1,5-AGwas associated with a significantly lower diabetes risk (0.27 [0.14-0.55]). Associations were attenuatedbut still significant after adjustment for hemoglobin A(1c) (A1C) or fasting glucose. CONCLUSIONSFructosamine, glycated albumin, and 1,5-AG were associated with the subsequent development ofdiabetes independently of baseline A1C and fasting glucose. Our results suggest these alternativebiomarkers may be useful in identifying persons at risk for diabetes.", "metadata": {}}
+{"_id": "17671145", "title": "", "text": "ROR-γ drives androgen receptor expression and represents a therapeutic target in castration-resistantprostate cancerThe androgen receptor (AR) is overexpressed and hyperactivated in humancastration-resistant prostate cancer (CRPC). However, the determinants of AR overexpression in CRPCare poorly defined. Here we show that retinoic acid receptor-related orphan receptor γ (ROR-γ) isoverexpressed and amplified in metastatic CRPC tumors, and that ROR-γ drives AR expression in thetumors. ROR-γ recruits nuclear receptor coactivator 1 and 3 (NCOA1 and NCOA3, also known as SRC-1and SRC-3) to an AR-ROR response element (RORE) to stimulate AR gene transcription. ROR-γantagonists suppress the expression of both AR and its variant AR-V7 in prostate cancer (PCa) cell linesand tumors. ROR-γ antagonists also markedly diminish genome-wide AR binding, H3K27ac abundanceand expression of the AR target gene network. Finally, ROR-γ antagonists suppressed tumor growth inmultiple AR-expressing, but not AR-negative, xenograft PCa models, and they effectively sensitized CRPCtumors to enzalutamide, without overt toxicity, in mice. Taken together, these results establish ROR-γ asa key player in CRPC by acting upstream of AR and as a potential therapeutic target for advanced PCa.", "metadata": {}}
+{"_id": "17676273", "title": "", "text": "affy--analysis of Affymetrix GeneChip data at the probe level.MOTIVATION The processing of theAffymetrix GeneChip data has been a recent focus for data analysts. Alternatives to the originalprocedure have been proposed and some of these new methods are widely used. RESULTS The affypackage is an R package of functions and classes for the analysis of oligonucleotide arrays manufacturedby Affymetrix. The package is currently in its second release, affy provides the user with extremeflexibility when carrying out an analysis and make it possible to access and manipulate probe intensitydata. In this paper, we present the main classes and functions in the package and demonstrate how theycan be used to process probe-level data. We also demonstrate the importance of probe-level analysiswhen using the Affymetrix GeneChip platform.", "metadata": {}}
+{"_id": "17682477", "title": "", "text": "Inducible caspase-9 suicide gene controls adverse effects from alloreplete T cells after haploidenticalstem cell transplantation.To test the feasibility of a single T-cell manipulation to eliminate alloreactivitywhile sparing antiviral and antitumor T cells, we infused 12 haploidentical hematopoietic stem celltransplant patients with increasing numbers of alloreplete haploidentical T cells expressing the induciblecaspase 9 suicide gene (iC9-T cells). We determined whether the iC9-T cells produced immunereconstitution and if any resultant graft-versus-host disease (GVHD) could be controlled byadministration of a chemical inducer of dimerization (CID; AP1903/Rimiducid). All patients receiving>10(4) alloreplete iC9-T lymphocytes per kilogram achieved rapid reconstitution of immune responsestoward 5 major pathogenic viruses and concomitant control of active infections. Four patients received asingle AP1903 dose. CID infusion eliminated 85% to 95% of circulating CD3(+)CD19(+) T cells within 30minutes, with no recurrence of GVHD within 90 days. In one patient, symptoms and signs ofGVHD-associated cytokine release syndrome (CRS-hyperpyrexia, high levels of proinflammatorycytokines, and rash) resolved within 2 hours of AP1903 infusion. One patient with varicella zoster virusmeningitis and acute GVHD had iC9-T cells present in the cerebrospinal fluid, which were reduced by>90% after CID. Notably, virus-specific T cells recovered even after AP1903 administration and continuedto protect against infection. Hence, alloreplete iC9-T cells can reconstitute immunity posttransplant andadministration of CID can eliminate them from both peripheral blood and the central nervous system(CNS), leading to rapid resolution of GVHD and CRS. The approach may therefore be useful for the rapidand effective treatment of toxicities associated with infusion of engineered T lymphocytes. This trial wasregistered at www.clinicaltrials.gov as #NCT01494103.", "metadata": {}}
+{"_id": "17685207", "title": "", "text": "Clonal analysis of epiblast fate during germ layer formation in the mouse embryo.The fate of cells in theepiblast at prestreak and early primitive streak stages has been studied by injecting horseradishperoxidase (HRP) into single cells in situ of 6.7-day mouse embryos and identifying the labelleddescendants at midstreak to neural plate stages after one day of culture. Ectoderm was composed ofdescendants of epiblast progenitors that had been located in the embryonic axis anterior to the primitivestreak. Embryonic mesoderm was derived from all areas of the epiblast except the distal tip and theadjacent region anterior to it: the most anterior mesoderm cells originated posteriorly, traversing theprimitive streak early; labelled cells in the posterior part of the streak at the neural plate stage werederived from extreme anterior axial and paraxial epiblast progenitors; head process cells were derivedfrom epiblast at or near the anterior end of the primitive streak. Endoderm descendants were mostfrequently derived from a region that included, but extended beyond, the region producing the headprocess: descendants of epiblast were present in endoderm by the midstreak stage, as well as at laterstages. Yolk sac and amnion mesoderm developed from posterolateral and posterior epiblast. Theresulting fate map is essentially the same as those of the chick and urodele and indicates that, despitegeometrical differences, topological fate relationships are conserved among these vertebrates. Clonaldescendants were not necessarily confined to a single germ layer or to extraembryonic mesoderm,indicating that these lineages are not separated at the beginning of gastrulation. The embryonic axislengthened up to the neural plate stage by (1) elongation of the primitive streak through progressiveincorporation of the expanding lateral and initially more anterior regions of epiblast and, (2) expansion ofthe region of epiblast immediately cranial to the anterior end of the primitive streak. The populationdoubling time of labelled cells was 7.5 h; a calculated 43% were in, or had completed, a 4th cell cycle,and no statistically significant regional differences in the number of descendants were found. This clonalanalysis also showed that (1) growth in the epiblast was noncoherent and in most regions anisotropic anddirected towards the primitive streak and (2) the midline did not act as a barrier to clonal spread, eitherin the epiblast in the anterior half of the axis or in the primitive streak. These results taken together withthe fate map indicate that, while individual cells in the epiblast sheet behave independently with respectto their neighbours, morphogenetic movement during germ layer formation is coordinated in thepopulation as a whole.", "metadata": {}}
+{"_id": "17691617", "title": "", "text": "Effects of a High-Intensity Functional Exercise Program on Dependence in Activities of Daily Living andBalance in Older Adults with DementiaOBJECTIVES To investigate the effects of a high-intensity functionalexercise program on independence in activities of daily living (ADLs) and balance in older people withdementia and whether exercise effects differed between dementia types. DESIGN Cluster-randomizedcontrolled trial: Umeå Dementia and Exercise (UMDEX) study. SETTING Residential care facilities, Umeå,Sweden. PARTICIPANTS Individuals aged 65 and older with a dementia diagnosis, a Mini-Mental StateExamination score of 10 or greater, and dependence in ADLs (N=186). INTERVENTION Ninety-threeparticipants each were allocated to the high-intensity functional exercise program, comprising lower limbstrength and balance exercises, and 93 to a seated control activity. MEASUREMENTS Blinded assessorsmeasured ADL independence using the Functional Independence Measure (FIM) and Barthel Index (BI)and balance using the Berg Balance Scale (BBS) at baseline and 4 (directly after intervention completion)and 7 months. RESULTS Linear mixed models showed no between-group effect on ADL independence at 4(FIM=1.3, 95% confidence interval (CI)=-1.6-4.3; BI=0.6, 95% CI=-0.2-1.4) or 7 (FIM=0.8, 95%CI=-2.2-3.8; BI=0.6, 95% CI=-0.3-1.4) months. A significant between-group effect on balance favoringexercise was observed at 4 months (BBS=4.2, 95% CI=1.8-6.6). In interaction analyses, exercise effectsdiffered significantly between dementia types. Positive between-group exercise effects were found inparticipants with non-Alzheimer's dementia according to the FIM at 7 months and BI and BBS at 4 and 7months. CONCLUSION In older people with mild to moderate dementia living in residential care facilities,a 4-month high-intensity functional exercise program appears to slow decline in ADL independence andimprove balance, albeit only in participants with non-Alzheimer's dementia.", "metadata": {}}
+{"_id": "17693849", "title": "", "text": "Effect of Health Literacy on Quality of Life amongst Patients with Ischaemic Heart Disease in AustralianGeneral PracticeBACKGROUND Appropriate understanding of health information by patients withcardiovascular disease (CVD) is fundamental for better management of risk factors and improvedmorbidity, which can also benefit their quality of life. OBJECTIVES To assess the relationship betweenhealth literacy and health-related quality of life (HRQoL) in patients with ischaemic heart disease (IHD),and to investigate the role of sociodemographic and clinical variables as possible confounders. METHODSCross-sectional study of patients with IHD recruited from a stratified sample of general practices in twoAustralian states (Queensland and South Australia) between 2007 and 2009. Health literacy wasmeasured using a validated questionnaire and classified as inadequate, marginal, or adequate. Physicaland mental components of HRQoL were assessed using the Medical Outcomes Study Short Form (SF12)questionnaire. Analyses were adjusted for confounders (sociodemographic variables, clinical history ofIHD, number of CVD comorbidities, and CVD risk factors) using multiple linear regression. RESULTS Atotal sample of 587 patients with IHD (mean age 72.0±8.4 years) was evaluated: 76.8% males, 84.2%retired or pensioner, and 51.4% with up to secondary educational level. Health literacy showed a mean of39.6±6.7 points, with 14.3% (95%CI 11.8-17.3) classified as inadequate. Scores of the physicalcomponent of HRQoL were 39.6 (95%CI 37.1-42.1), 42.1 (95%CI 40.8-43.3) and 44.8 (95%CI43.3-46.2) for inadequate, marginal, and adequate health literacy, respectively (p-value for trend =0.001). This association persisted after adjustment for confounders. Health literacy was not associatedwith the mental component of HRQoL (p-value = 0.482). Advanced age, lower educational level,disadvantaged socioeconomic position, and a larger number of CVD comorbidities adversely affectedboth, health literacy and HRQoL.   CONCLUSION Inadequate health literacy is a contributing factor topoor physical functioning in patients with IHD. Increasing health literacy may improve HRQoL and reducethe impact of IHD among patients with this chronic CVD.", "metadata": {}}
+{"_id": "17695748", "title": "", "text": "inTransglutaminase 2 (TGase 2) is a Ca+2-dependent enzyme that catalyzes both intracellular andextracellular cross-linking reactions by transamidation of specific glutamine residues. TGase 2 is known tobe involved in the membrane-mediated events required for glucose-stimulated insulin release from thepancreatic beta cells. Here we show that targeted disruption of TGase 2 impairs glucose-stimulatedinsulin secretion. TGase 2-/- mice show glucose intolerance after intraperitoneal glucose loading. TGase2-/- mice manifest a tendency to develop hypoglycemia after administration of exogenous insulin as aconsequence of enhanced insulin receptor substrate 2 (IRS-2) phosphorylation. We suggest that theincreased peripheral sensitivity to insulin partially compensates for the defective secretion in this animalmodel. TGase 2-/- mouse phenotype resembles that of the maturity-onset diabetes of young (MODY)patients. In the course of screening for human TGase 2 gene in Italian subjects with the clinical featuresof MODY, we detected a missense mutation (N333S) in the active site of the enzyme. Collectively, theseresults identify TGase 2 as a potential candidate gene in type 2 diabetes.", "metadata": {}}
+{"_id": "17702490", "title": "", "text": "Chromatin structure and gene expression programs of human embryonic and induced pluripotent stemcells.Knowledge of both the global chromatin structure and the gene expression programs of humanembryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) should provide a robust means toassess whether the genomes of these cells have similar pluripotent states. Recent studies have suggestedthat ESCs and iPSCs represent different pluripotent states with substantially different gene expressionprofiles. We describe here a comparison of global chromatin structure and gene expression data for apanel of human ESCs and iPSCs. Genome-wide maps of nucleosomes with histone H3K4me3 andH3K27me3 modifications indicate that there is little difference between ESCs and iPSCs with respect tothese marks. Gene expression profiles confirm that the transcriptional programs of ESCs and iPSCs showvery few consistent differences. Although some variation in chromatin structure and gene expression wasobserved in these cell lines, these variations did not serve to distinguish ESCs from iPSCs.", "metadata": {}}
+{"_id": "17708753", "title": "", "text": "Myeloid Cells Expressing VEGF and Arginase-1 Following Uptake of Damaged Retinal Pigment EpitheliumSuggests Potential Mechanism That Drives the Onset of Choroidal Angiogenesis in MiceWhilst datarecognise both myeloid cell accumulation during choroidal neovascularisation (CNV) as well ascomplement activation, none of the data has presented a clear explanation for the angiogenic drive thatpromotes pathological angiogenesis. One possibility that is a pre-eminent drive is a specific and earlyconditioning and activation of the myeloid cell infiltrate. Using a laser-induced CNV murine model, wehave identified that disruption of retinal pigment epithelium (RPE) and Bruch's membrane resulted in anearly recruitment of macrophages derived from monocytes and microglia, prior to angiogenesis andcontemporaneous with lesional complement activation. Early recruited CD11b(+) cells expressed adefinitive gene signature of selective inflammatory mediators particularly a pronounced Arg-1 expression.Accumulating macrophages from retina and peripheral blood were activated at the site of injury,displaying enhanced VEGF expression, and notably prior to exaggerated VEGF expression from RPE, orearliest stages of angiogenesis. All of these initial events, including distinct VEGF (+) Arg-1(+) myeloidcells, subsided when CNV was established and at the time RPE-VEGF expression was maximal. Depletionof inflammatory CCR2-positive monocytes confirmed origin of infiltrating monocyte Arg-1 expression, asfollowing depletion Arg-1 signal was lost and CNV suppressed. Furthermore, our in vitro data supported amyeloid cell uptake of damaged RPE or its derivatives as a mechanism generating VEGF (+) Arg-1(+)phenotype in vivo. Our results reveal a potential early driver initiating angiogenesis via myeloid-derivedVEGF drive following uptake of damaged RPE and deliver an explanation of why CNV develops during anyof the stages of macular degeneration and can be explored further for therapeutic gain.", "metadata": {}}
+{"_id": "17717391", "title": "", "text": "Monitoring Tumorigenesis and Senescence In Vivo with a p16INK4a-Luciferase ModelMonitoring cancerand aging in vivo remains experimentally challenging. Here, we describe a luciferase knockin mouse(p16(LUC)), which faithfully reports expression of p16(INK4a), a tumor suppressor and aging biomarker.Lifelong assessment of luminescence in p16(+/LUC) mice revealed an exponential increase with aging,which was highly variable in a cohort of contemporaneously housed, syngeneic mice. Expression ofp16(INK4a) with aging did not predict cancer development, suggesting that the accumulation ofsenescent cells is not a principal determinant of cancer-related death. In 14 of 14 tested tumor models,expression of p16(LUC) was focally activated by early neoplastic events, enabling visualization of tumorswith sensitivity exceeding other imaging modalities. Activation of p16(INK4a) was noted in the emergingneoplasm and surrounding stromal cells. This work suggests that p16(INK4a) activation is a characteristicof all emerging cancers, making the p16(LUC) allele a sensitive, unbiased reporter of neoplastictransformation.", "metadata": {}}
+{"_id": "17731780", "title": "", "text": "The Bacteroides sp. 3_1_23 Pif1 protein is a multifunctional helicaseScPif1 DNA helicase is theprototypical member of a 5'-to-3' helicase superfamily conserved from bacteria to human and playsvarious roles in the maintenance of genomic homeostasis. While many studies have been performed witheukaryotic Pif1 helicases, including yeast and human Pif1 proteins, the potential functions andbiochemical properties of prokaryotic Pif1 helicases remain largely unknown. Here, we report theexpression, purification and biochemical analysis of Pif1 helicase from Bacteroides sp. 3_1_23 (BsPif1).BsPif1 binds to a large panel of DNA substrates and, in particular, efficiently unwinds partial duplex DNAswith 5'-overhang, fork-like substrates, D-loop and flap-like substrates, suggesting that BsPif1 may act atstalled DNA replication forks and enhance Okazaki fragment maturation. Like its eukaryotic homologues,BsPif1 resolves R-loop structures and unwinds DNA-RNA hybrids. Furthermore, BsPif1 efficiently unfoldsG-quadruplexes and disrupts nucleoprotein complexes. Altogether, these results highlight thatprokaryotic Pif1 helicases may resolve common issues that arise during DNA transactions. Interestingly,we found that BsPif1 is different from yeast Pif1, but resembles more human Pif1 with regard to substratespecificity, helicase activity and mode of action. These findings are discussed in the context of thepossible functions of prokaryotic Pif1 helicases in vivo.", "metadata": {}}
+{"_id": "17741440", "title": "", "text": "Netting neutrophils in autoimmune small-vessel vasculitisSmall-vessel vasculitis (SVV) is a chronicautoinflammatory condition linked to antineutrophil cytoplasm autoantibodies (ANCAs). Here we showthat chromatin fibers, so-called neutrophil extracellular traps (NETs), are released by ANCA-stimulatedneutrophils and contain the targeted autoantigens proteinase-3 (PR3) and myeloperoxidase (MPO).Deposition of NETs in inflamed kidneys and circulating MPO-DNA complexes suggest that NET formationtriggers vasculitis and promotes the autoimmune response against neutrophil components in individualswith SVV.", "metadata": {}}
+{"_id": "17755060", "title": "", "text": "Control of Nutrient Stress-Induced Metabolic Reprogramming by PKCζ in TumorigenesisTumor cells havehigh-energetic and anabolic needs and are known to adapt their metabolism to be able to survive andkeep proliferating under conditions of nutrient stress. We show that PKCζ deficiency promotes theplasticity necessary for cancer cells to reprogram their metabolism to utilize glutamine through the serinebiosynthetic pathway in the absence of glucose. PKCζ represses the expression of two key enzymes of thepathway, PHGDH and PSAT1, and phosphorylates PHGDH at key residues to inhibit its enzymatic activity.Interestingly, the loss of PKCζ in mice results in enhanced intestinal tumorigenesis and increased levels ofthese two metabolic enzymes, whereas patients with low levels of PKCζ have a poor prognosis.Furthermore, PKCζ and caspase-3 activities are correlated with PHGDH levels in human intestinal tumors.Taken together, this demonstrates that PKCζ is a critical metabolic tumor suppressor in mouse andhuman cancer.", "metadata": {}}
+{"_id": "17768946", "title": "", "text": "XRCC4's interaction with XLF is required for coding (but not signal) end joiningXRCC4 and XLF arestructurally related proteins important for DNA Ligase IV function. XRCC4 forms a tight complex with DNALigase IV while XLF interacts directly with XRCC4. Both XRCC4 and XLF form homodimers that canpolymerize as heterotypic filaments independently of DNA Ligase IV. Emerging structural and in vitrobiochemical data suggest that XRCC4 and XLF together generate a filamentous structure that promotesbridging between DNA molecules. Here, we show that ablating XRCC4's affinity for XLF results in DNArepair deficits including a surprising deficit in VDJ coding, but not signal end joining. These data areconsistent with a model whereby XRCC4/XLF complexes hold DNA ends together--stringently required forcoding end joining, but dispensable for signal end joining. Finally, DNA-PK phosphorylation of XRCC4/XLFcomplexes disrupt DNA bridging in vitro, suggesting a regulatory role for DNA-PK's phosphorylation ofXRCC4/XLF complexes.", "metadata": {}}
+{"_id": "17775228", "title": "", "text": "Loss of imprinting in colorectal cancer linked to hypomethylation of H19 and IGF2.Epigenetic alterationsin human cancers include global DNA hypomethylation,gene hypomethylation and promoterhypermethylation, and loss of imprinting (LOI) of the insulin-like growth factor-II gene (IGF2). Amechanism for LOI described previously is hypermethylation of a differentially methylated region (DMR)upstream of the H19 gene, allowing activation of the normally silent maternal allele of IGF2. Here weshow that this mechanism does not apply to colorectal cancers, which show hypomethylation of the H19DMR as well as a DMR upstream of exon 3 of IGF2. This hypomethylation is found in both colorectalcancers and normal mucosa from the same patients, and in cell lines with somatic cell knockout of DNAmethyltransferases DNMT1 and DNMT3B. These data suggest that hypomethylation is a mechanism forLOI, that the popular IGF2-H19 enhancer competition model for IGF2 imprinting does not apply to thehuman colon, and that an alternative model for LOI would involve a transcriptional repressor acting onthe normally silent maternal allele of IGF2.", "metadata": {}}
+{"_id": "17779800", "title": "", "text": "Management of patients with sore throats in relation to guidelines: An interview study inSwedenOBJECTIVE To explore how a group of Swedish general practitioners (GPs) manage patients witha sore throat in relation to current guidelines as expressed in interviews. DESIGN Qualitative contentanalysis was used to analyse semi-structured interviews. SETTING Swedish primary care. SUBJECTS Astrategic sample of 25 GPs. MAIN OUTCOME MEASURES Perceived management of sore throat patients.RESULTS It was found that nine of the interviewed GPs were adherent to current guidelines for sorethroat and 16 were non-adherent. The two groups differed in terms of guideline knowledge, which wasshared within the team for adherent GPs while idiosyncratic knowledge dominated for the non-adherentGPs. Adherent GPs had no or low concerns for bacterial infections and differential diagnosis whilstnon-adherent GPs believed that in patients with a sore throat any bacterial infection should be identifiedand treated with antibiotics. Patient history and examination was mainly targeted by adherent GPs whilstfor non-adherent GPs it was often redundant. Non-adherent GPs reported problems getting patients toabstain from antibiotics, whilst no such problems were reported in adherent GPs. CONCLUSION Thisinterview study of sore throat management in a strategically sampled group of Swedish GPs showed thatwhile two-thirds were non-adherent and had a liberal attitude to antibiotics one-third were guidelineadherent with a restricted view on antibiotics. Non-adherent GPs revealed significant knowledge gaps.Adherent GPs had discussed guidelines within the primary care team while non-adherent GPs had not.Guideline implementation thus seemed to be promoted by knowledge shared in team discussions.", "metadata": {}}
+{"_id": "17805221", "title": "", "text": "Catch and release: how do kinetochores hook the right microtubules during mitosis?Sport fishermen keeptension on their lines to prevent hooked fish from releasing. A molecular version of this angler's trick,operating at kinetochores, ensures accuracy during mitosis: the mitotic spindle attaches randomly tochromosomes and then correctly bioriented attachments are stabilized due to the tension exerted onthem by opposing microtubules. Incorrect attachments, which lack tension, are unstable and releasequickly, allowing another chance for biorientation. Stabilization of molecular interactions by tension alsooccurs in other physiological contexts, such as cell adhesion, motility, hemostasis, and tissuemorphogenesis. Here, we review models for the stabilization of kinetochore attachments with an eyetoward emerging models for other force-activated systems. Although attention in the mitosis field hasfocused mainly on one kinase-based mechanism, multiple mechanisms may act together to stabilizeproperly bioriented kinetochores and some principles governing other tension-sensitive systems may alsoapply to kinetochores.", "metadata": {}}
+{"_id": "17814815", "title": "", "text": "Label-free in vivo imaging of myelinated axons in health and disease with spectral confocal reflectancemicroscopyWe report a newly developed technique for high-resolution in vivo imaging of myelinatedaxons in the brain, spinal cord and peripheral nerve that requires no fluorescent labeling. This method,based on spectral confocal reflectance microscopy (SCoRe), uses a conventional laser-scanning confocalsystem to generate images by merging the simultaneously reflected signals from multiple lasers ofdifferent wavelengths. Striking color patterns unique to individual myelinated fibers are generated thatfacilitate their tracing in dense axonal areas. These patterns highlight nodes of Ranvier andSchmidt-Lanterman incisures and can be used to detect various myelin pathologies. Using SCoRe wecarried out chronic brain imaging up to 400 μm deep, capturing de novo myelination of mouse corticalaxons in vivo. We also established the feasibility of imaging myelinated axons in the human cerebralcortex. SCoRe adds a powerful component to the evolving toolbox for imaging myelination in livinganimals and potentially in humans.", "metadata": {}}
+{"_id": "17821387", "title": "", "text": "Applicability of current staging/categorization of α-synuclein pathology and their clinical relevanceInParkinson's disease (PD) and dementia with Lewy bodies (DLB) alpha-synuclein (alphaS) pathology isseen that displays a predictable topographic distribution. There are two staging/categorization systems,i.e. Braak's and McKeith's, currently in use for the assessment of alphaS pathology. The aim of thesediagnostic strategies in pathology is, in addition to assess the stage/severity of pathology, to assess theprobabilities of the related clinical symptomatology i.e. dementia and extrapyramidal symptoms (EPS).Herein, we assessed the applicability of these two staging/categorization systems and the frequency ofdementia and EPS in a cohort of 226 alphaS-positive-subjects. These subject were selected from a largeautopsy sample (n = 1,720), irrespective of the clinical presentation, based on the detection ofalphaS-immunoreactivity (IR) in one of the most vulnerable nuclei; in the dorsal motor nucleus of vagus,substantia nigra and basal forebrain. The frequency of alphaS-IR lesions in this large cohort was 14%(248 out of 1,720). If applicable, each of the 226 subjects with all required material available wasassigned a neuropathological stage/category of PD/DLB and finally the neuropathological data wasanalyzed in relation to dementia and EPS. 83% of subjects showed a distribution pattern of alphaS-IRthat was compatible with the current staging/categorization systems. Around 55% of subjects withwidespread alphaS pathology (Braak's PD stages 5-6) lacked clinical signs of dementia or EPS. Similarly,in respect to those subjects that fulfilled the McKeith criteria for diffuse neocortical category anddisplaying only mild concomitant Alzheimer's disease-related pathology, only 48% were demented and54% displayed EPS. It is noteworthy that some subjects (17%) deviated from the suggestedcaudo-rostral propagation suggesting alternative routes of progression, perhaps due to concomitantdiseases and genetic predisposition. In conclusion, our results do indeed confirm that currentstaging/categorization systems can readily be applied to most of the subjects with alphaS pathology.However, finding that around half of the subjects with abundant alphaS pathology remain neurologicallyintact is intriguing and raises the question whether we do assess the actual disease process.", "metadata": {}}
+{"_id": "17829012", "title": "", "text": "Batf is important for IL-4 expression in T follicular helper cellsApart from T helper (Th)-2 cells, T follicularhelper (Tfh) cells are a major class of IL-4-producing T cells, required for regulation of type 2 humoralimmunity; however, transcriptional control of IL-4 production in Tfh cells remains mainly unknown. Here,we show that the basic leucine zipper transcription factor ATF-like, Batf is important for IL-4 expression inTfh cells rather than in canonical Th2 cells. Functionally, Batf in cooperation with interferon regulatoryfactor (IRF) 4 along with Stat3 and Stat6 trigger IL-4 production in Tfh cells by directly binding to andactivation of the CNS2 region in the IL-4 locus. In addition, Batf-to-c-Maf signalling is an importantdeterminant of IL-4 expression in Tfh cells. Batf deficiency impairs the generation of IL-4-producing Tfhcells that results in protection against allergic asthma. Our results thus indicate a positive role of Batf inpromoting the generation of pro-allergic IL-4-producing Tfh cells.", "metadata": {}}
+{"_id": "17844478", "title": "", "text": "Autocrine VEGF Signaling Synergizes with EGFR in Tumor Cells to Promote Epithelial CancerDevelopmentIt is established that tumor cell-derived VEGF acts on endothelial cells to promoteangiogenesis and tumor growth. Here, we demonstrate that in K5-SOS-dependent mouse skin tumors,autocrine VEGF is required for tumor cell proliferation in a cell-autonomous andangiogenesis-independent manner. VEGF is upregulated in SOS-expressing tumors, and its deletion inepidermal cells delays tumorigenesis by suppressing angiogenesis and tumor cell proliferation.Epidermis-specific Flt1 deletion also impairs tumorigenesis and proliferation. Surprisingly, completetumor inhibition occurs in the absence of VEGF in EGFR mutant mice, demonstrating that VEGFR andEGFR synergize in neoplastic cells to promote tumor growth. Mechanistically, K5-SOS upregulates VEGF,Flt1, and Neuropilin-1 in an Erk-dependent manner, thereby activating an autocrine proliferation loop,whereas EGFR prevents tumor cells from apoptosis. Moreover, Flt1 is upregulated in human SCC, and itsinhibition in SCC cells impairs proliferation. Thus, in addition to regulating angiogenesis, VEGF has to beconsidered as a potent growth factor for epidermal tumors.", "metadata": {}}
+{"_id": "17876040", "title": "", "text": "Discovery and development of the Polo-like kinase inhibitor volasertib in cancer therapyOwing to theirintegral involvement in cell cycle regulation, the Polo-like kinase (Plk) family, particularly Plk1, hasemerged as an attractive therapeutic target in oncology. In recent years, several Plk1 inhibitors havebeen developed, with some agents showing encouraging results in early-phase clinical trials. This reviewfocuses on volasertib (BI 6727; an investigational agent), a potent and selective Plk inhibitor. Volasertibhas shown promising activity in various cancer cell lines and xenograft models of human cancer. Trialsperformed to date suggest that volasertib has clinical efficacy in a range of malignancies, with the mostpromising results seen in patients with acute myeloid leukemia (AML). Encouragingly, recent phase IIdata have demonstrated that volasertib combined with low-dose cytarabine (LDAC) was associated withhigher response rates and improved event-free survival than LDAC alone in patients with previouslyuntreated AML. Based on these observations, and its presumably manageable safety profile, volasertib iscurrently in phase III development as a potential treatment for patients with AML who are ineligible forintensive remission induction therapy. Given that many patients with AML are of an older age and frail,this constitutes an area of major unmet need. In this review, we discuss the biologic rationale for Plk1inhibitors in cancer, the clinical development of volasertib to date in solid tumors and AML, and the futureidentification of biomarkers that might predict response to volasertib and help determine the role of thisagent in the clinic.", "metadata": {}}
+{"_id": "17877537", "title": "", "text": "Babies driving robots: self-generated mobility in very young infantsSelf-generated mobility vialocomotion is a key for the cognitive, social and motor development of young infants. For certain childrenwith special needs, self-generated mobility is only attained via assistive technology such as a powerwheelchair. Up until recently, infants under 24 months of age were not considered candidates for trainingin power mobility. Recent work in our labs and others suggest that younger infants can utilize theirreaching and grasping ability to learn power mobility. This interdisciplinary study combines our previouswork in motor development and learning in infants with special needs, and the application of robottechnology for rehabilitation to determine whether young infants without structured training, would drivea mobile robot, and if so, to determine how their driving would change over multiple sessions. The twoinfants that were seen for the most sessions were the focus of this pilot study. Both infants increasedtheir total session time, percentage of session time spent driving, and total path length. These resultssuggest that, without training, young infants will independently move themselves using a mobile robot.These results provide the foundation for training studies to advance the self-generated mobility in younginfants with special needs. Our future studies will explore the multiple training and technologycombinations to reduce the barriers to exploration via self-generated mobility, and advance the generaldevelopment of infants with special needs.", "metadata": {}}
+{"_id": "17897801", "title": "", "text": "Effects of Abciximab on the architecture of platelet-rich clots in patients with acute myocardial infarctionundergoing primary coronary intervention.BACKGROUND Abciximab plus aspirin improves the TIMI 3 flowrate of the infarct-related artery in patients treated with either percutaneous coronary intervention orthrombolysis. The present study investigated whether the reperfusion efficacy of abciximab relates tomodifications of clot architecture in patients admitted for acute myocardial infarction (AMI). METHODSAND RESULTS A total of 23 AMI patients in the Abciximab before Direct angioplasty and stenting inMyocardial Infarction Regarding Acute and Long term follow-up (ADMIRAL) trial received, in adouble-blind fashion, either abciximab (n=13) or placebo (n=10) before primary stenting. Viscoelastic (G'in dyne/cm(2)) and morphological (mean platelet aggregate surface area [SAG] in micrometer(2))indexes of ex vivo platelet-rich clots (PRC) were assessed in a double-blind fashion before and after thebolus administration of abciximab or placebo. G' and SAG reflect the mechanical and morphologicalimpact of activated platelets on the PRC fibrin network, respectively. Abciximab administration reduced G'by 63% (P=0.0001) and SAG by 65% (P=0.0007), and no effect was seen in the placebo group. Theseabciximab-related changes increased fibrin exposure as a consequence of the platelet-aggregate surfacereduction and may have improved endogenous fibrinolysis. These effects were identified in all patients,independent of previous heparin administration. CONCLUSIONS Abciximab dramatically reduces plateletaggregate size and increases the fibrin accessibility of ex vivo PRC in AMI patients. These modificationscould participate in the better coronary artery patency observed with abciximab.", "metadata": {}}
+{"_id": "17911973", "title": "", "text": "Natural Mutagenesis of Human Genomes by Endogenous RetrotransposonsTwo abundant classes ofmobile elements, namely Alu and L1 elements, continue to generate new retrotransposon insertions inhuman genomes. Estimates suggest that these elements have generated millions of new germlineinsertions in individual human genomes worldwide. Unfortunately, current technologies are not capable ofdetecting most of these young insertions, and the true extent of germline mutagenesis by endogenoushuman retrotransposons has been difficult to examine. Here, we describe technologies for detecting theseyoung retrotransposon insertions and demonstrate that such insertions indeed are abundant in humanpopulations. We also found that new somatic L1 insertions occur at high frequencies in human lungcancer genomes. Genome-wide analysis suggests that altered DNA methylation may be responsible forthe high levels of L1 mobilization observed in these tumors. Our data indicate that transposon-mediatedmutagenesis is extensive in human genomes and is likely to have a major impact on human biology anddiseases.", "metadata": {}}
+{"_id": "17914395", "title": "", "text": "Knowledge of young African American adults about heart disease: a cross-sectional surveyBACKGROUNDAfrican Americans have higher rates of cardiovascular disease (CVD) mortality than other ethnic groups.Young adults are prime targets for intervention strategies to prevent and reduce disease risk. The studypurpose was to determine the level of knowledge of lifestyle risk factors for CVD among young AfricanAmerican adults in Phoenix. The results will be used to guide the development of CVD outreach programstargeted to this population. The Health Belief Model was used as a conceptual framework. METHODS Aconvenience sample of 172 African American men and women aged 18-26 years completed aquestionnaire adapted from the American Heart Association national surveys. Descriptive statistics werecompared by age, gender, education level, and health status variables including BMI, smoking status,and physical activity. RESULTS Some aspects of heart-disease were well known among young adultAfrican Americans. Knowledge of certain other important risk factors (menopause) and preventivebehaviors (eating fewer animal products), however, was more variable and inconsistent among therespondents. Differences in knowledge of individual variables was greater by education level than bygender overall. Predictors of a summary CVD knowledge score included higher education, female gender,and high self-efficacy (adjusted R2 = 0.158, p < .001). Predictors of self-efficacy in changing CVD riskwere higher education and perceived low risk of CVD (adjusted R2 = 0.064, p < .001), but thesecharacteristics explained only 6% of the variance. CONCLUSIONS Evaluation of baseline knowledge ofCVD is essential before designing and implementing health promotion programs. Existing strengths andweaknesses in knowledge can guide tailoring of programs to be more effective. Further research wouldhelp to identify the range of other characteristics that determine knowledge and risk perception.", "metadata": {}}
+{"_id": "17917408", "title": "", "text": "Recent insights into the role of Notch signaling in tumorigenesisMembers of the Notch family oftransmembrane receptors play an important role in cell fate determination. Over the past decade, a rolefor Notch in the pathogenesis of hematologic and solid malignancies has become apparent. Numerouscellular functions and microenvironmental cues associated with tumorigenesis are modulated by Notchsignaling, including proliferation, apoptosis, adhesion, epithelial-to-mesenchymal transition, andangiogenesis. It is becoming increasingly evident that Notch signaling can be both oncogenic and tumorsuppressive. This review highlights recent findings regarding the molecular and functional aspects ofNotch-mediated neoplastic transformation. In addition, cellular mechanisms that potentially explain thecomplex role of Notch in tumorigenesis are discussed.", "metadata": {}}
+{"_id": "17919731", "title": "", "text": "BRIEFINGS IN FUNCTIONAL GENOMICS AND PROTEOMICS. VOL 5. NO 3. 209^221doi:10.1093/bfgp/ell028 Histone acetylation in gene regulationGenetic information is packaged in thehighly dynamic nucleoprotein structure called chromatin. Many biological processes are regulated viapost-translational modifications of key proteins. Acetylation of lysine residues at the N-terminal histonetails is one of the most studied covalent modifications influencing gene regulation in eukaryotic cells. Thisreview focuses on the role of enzymes involved in controlling both histone and non-histone proteinsacetylation levels in the cell, with particular emphasis on their effects on cancer.", "metadata": {}}
+{"_id": "17925632", "title": "", "text": "Efficacy of monthly tafenoquine for prophylaxis of Plasmodium vivax and multidrug-resistant P.falciparum malaria.We assessed monthly doses of tafenoquine for preventing Plasmodium vivax andmultidrug-resistant P. falciparum malaria. In a randomized, double-blind, placebo-controlled study, 205Thai soldiers received either a loading dose of tafenoquine 400 mg (base) daily for 3 days, followed bysingle monthly 400-mg doses (n = 104), or placebo (n = 101), for up to 5 consecutive months. Involunteers completing follow-up (96 tafenoquine and 91 placebo recipients), there were 22 P. vivax, 8 P.falciparum, and 1 mixed infection. All infections except 1 P. vivax occurred in placebo recipients, givingtafenoquine a protective efficacy of 97% for all malaria (95% confidence interval [CI], 82%-99%), 96%for P. vivax malaria (95% CI, 76%-99%), and 100% for P. falciparum malaria (95% CI, 60%-100%).Monthly tafenoquine was safe, well tolerated, and highly effective in preventing P. vivax andmultidrug-resistant P. falciparum malaria in Thai soldiers during 6 months of prophylaxis.", "metadata": {}}
+{"_id": "17930286", "title": "", "text": "Headache, migraine, and structural brain lesions and function: population based Epidemiology of VascularAgeing-MRI studyOBJECTIVE To evaluate the association of overall and specific headaches with volume ofwhite matter hyperintensities, brain infarcts, and cognition. DESIGN Population based, cross sectionalstudy. SETTING Epidemiology of Vascular Ageing study, Nantes, France. PARTICIPANTS 780 participants(mean age 69, 58.5% women) with detailed headache assessment. MAIN OUTCOME MEASURES Brainscans were evaluated for volume of white matter hyperintensities (by fully automated imagingprocessing) and for classification of infarcts (by visual reading with a standardised assessment grid).Cognitive function was assessed by a battery of tests including the mini-mental state examination.RESULTS 163 (20.9%) participants reported a history of severe headache and 116 had migraine, ofwhom 17 (14.7%) reported aura symptoms. An association was found between any history of severeheadache and increasing volume of white matter hyperintensities. The adjusted odds ratio of being in thehighest third for total volume of white matter hyperintensities was 2.0 (95% confidence interval 1.3 to3.1, P for trend 0.002) for participants with any history of severe headache when compared withparticipants without severe headache being in the lowest third. The association pattern was similar for allheadache types. Migraine with aura was the only headache type strongly associated with volume of deepwhite matter hyperintensities (highest third odds ratio 12.4, 1.6 to 99.4, P for trend 0.005) and withbrain infarcts (3.4, 1.2 to 9.3). The location of infarcts was predominantly outside the cerebellum andbrain stem. Evidence was lacking for cognitive impairment for any headache type with or without brainlesions. CONCLUSIONS In this population based study, any history of severe headache was associatedwith an increased volume of white matter hyperintensities. Migraine with aura was the only headachetype associated with brain infarcts. Evidence that headache of any type by itself or in combination withbrain lesions was associated with cognitive impairment was lacking.", "metadata": {}}
+{"_id": "17933691", "title": "", "text": "Characterization of adipocytes derived from fibro/adipogenic progenitors resident in human skeletalmuscleA population of fibro/adipogenic but non-myogenic progenitors located between skeletal musclefibers was recently discovered. The aim of this study was to determine the extent to which theseprogenitors differentiate into fully functional adipocytes. The characterization of muscleprogenitor-derived adipocytes is a central issue in understanding muscle homeostasis. They areconsidered as being the cellular origin of intermuscular adipose tissue that develops in severalpathophysiological situations. Here fibro/adipogenic progenitors were isolated from a panel of 15 humanmuscle biopsies on the basis of the specific cell-surface immunophenotype CD15+/PDGFRα+CD56-. Thisallowed investigations of their differentiation into adipocytes and the cellular functions of terminallydifferentiated adipocytes. Adipogenic differentiation was found to be regulated by the same effectors asthose regulating differentiation of progenitors derived from white subcutaneous adipose tissue. Similarly,basic adipocyte functions, such as triglyceride synthesis and lipolysis occurred at levels similar to thoseobserved with subcutaneous adipose tissue progenitor-derived adipocytes. However, muscleprogenitor-derived adipocytes were found to be insensitive to insulin-induced glucose uptake, inassociation with the impairment of phosphorylation of key insulin-signaling effectors. Our findingsindicate that muscle adipogenic progenitors give rise to bona fide white adipocytes that have theunexpected feature of being insulin-resistant.", "metadata": {}}
+{"_id": "17934082", "title": "", "text": "Membrane lipids in invadopodia and podosomes: Key structures for cancer invasion andmetastasisInvadopodia are extracellular matrix (ECM)-degrading protrusions formed by invasive cancercells. Podosomes are structures functionally similar to invadopodia that are found inoncogene-transformed fibroblasts and monocyte-derived cells, including macrophages and osteoclasts.These structures are thought to play important roles in the pericellular remodeling of ECM during cancerinvasion and metastasis. Much effort has been directed toward identification of the molecular componentsand regulators of invadopodia/podosomes, which could be therapeutic targets in the treatment ofmalignant cancers. However, it remains largely unknown how these components are assembled intoinvadopodia/podosomes and how the assembly process is spatially and temporally regulated. This reviewwill summarize recent progress on the molecular mechanisms of invadopodia/podosome formation, withstrong emphasis on the roles of lipid rafts and phosphoinositides.", "metadata": {}}
+{"_id": "17934603", "title": "", "text": "CCR2 and CXCR4 regulate peripheral blood monocyte pharmacodynamics and link to efficacy inexperimental autoimmune encephalomyelitisBACKGROUND CCR2 plays a key role in regulating monocytetrafficking to sites of inflammation and therefore has been the focus of much interest as a target forinflammatory disease. METHODS Here we examined the effects of CCR2 blockade with a potent smallmolecule antagonist to determine the pharmacodynamic consequences on the peripheral blood monocytecompartment in the context of acute and chronic inflammatory processes. RESULTS We demonstrate thatCCR2 antagonism in vivo led to a rapid decrease in the number of circulating Ly6Chi monocytes and thatthis decrease was largely due to the CXCR4-dependent sequestration of these cells in the bone marrow,providing pharmacological evidence for a mechanism by which monocyte dynamics are regulated in vivo.CCR2 antagonism led to an accumulation of circulating CCL2 and CCL7 levels in the blood, indicating arole for CCR2 in regulating the levels of its ligands under homeostatic conditions. Finally, we show thatthe pharmacodynamic changes due to CCR2 antagonism were apparent after chronic dosing in mouseexperimental autoimmune encephalomyelitis, a model in which CCR2 blockade demonstrated a dramaticreduction in disease severity, manifest in a reduced accumulation of monocytes and other cells in theCNS. CONCLUSION CCR2 antagonism in vivo has tractable pharmacodynamic effects that can be used toalign target engagement with biologic effects on disease activity.", "metadata": {}}
+{"_id": "17939443", "title": "", "text": "Displacement of a DNA binding protein by Dda helicaseBacteriophage T4 Dda helicase has recently beenshown to be active as a monomer for unwinding of short duplex oligonucleotides and for displacingstreptavidin from 3′-biotinylated oligonucleotides. However, its activity for streptavidin displacement andDNA unwinding has been shown to increase as the number of Dda molecules bound to the substratemolecule increases. A substrate was designed to address the ability of Dda to displace DNA bindingproteins. A DNA binding site for the Escherichia coli trp repressor was introduced into an oligonucleotidesubstrate for Dda helicase containing single-stranded overhang. Here we show that a Dda monomer isinsufficient to displace the E.coli trp repressor from dsDNA under single turnover conditions, although thesubstrate is unwound and the repressor displaced when the single-stranded overhang is long enough toaccommodate two Dda molecules. The quantity of product formed increases when the substrate is able toaccommodate more than two Dda molecules. These results indicate that multiple Dda molecules act todisplace DNA binding proteins in a manner that correlates with the DNA unwinding activity andstreptavidin displacement activity. We suggest a cooperative inchworm model to describe the activities ofDda helicase.", "metadata": {}}
+{"_id": "17945638", "title": "", "text": "Control of Developmental Regulators by Polycomb in Human Embryonic Stem CellsPolycomb groupproteins are essential for early development in metazoans, but their contributions to human developmentare not well understood. We have mapped the Polycomb Repressive Complex 2 (PRC2) subunit SUZ12across the entire nonrepeat portion of the genome in human embryonic stem (ES) cells. We found thatSUZ12 is distributed across large portions of over two hundred genes encoding key developmentalregulators. These genes are occupied by nucleosomes trimethylated at histone H3K27, aretranscriptionally repressed, and contain some of the most highly conserved noncoding elements in thegenome. We found that PRC2 target genes are preferentially activated during ES cell differentiation andthat the ES cell regulators OCT4, SOX2, and NANOG cooccupy a significant subset of these genes. Theseresults indicate that PRC2 occupies a special set of developmental genes in ES cells that must berepressed to maintain pluripotency and that are poised for activation during ES cell differentiation.", "metadata": {}}
+{"_id": "17967608", "title": "", "text": "PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular trapsNeutrophilstrap and kill bacteria by forming highly decondensed chromatin structures, termed neutrophilextracellular traps (NETs). We previously reported that histone hypercitrullination catalyzed bypeptidylarginine deiminase 4 (PAD4) correlates with chromatin decondensation during NET formation.However, the role of PAD4 in NET-mediated bacterial trapping and killing has not been tested. Here, weuse PAD4 knockout mice to show that PAD4 is essential for NET-mediated antibacterial function. UnlikePAD4(+/+) neutrophils, PAD4(-/-) neutrophils cannot form NETs after stimulation with chemokines orincubation with bacteria, and are deficient in bacterial killing by NETs. In a mouse infectious diseasemodel of necrotizing fasciitis, PAD4(-/-) mice are more susceptible to bacterial infection than PAD4(+/+)mice due to a lack of NET formation. Moreover, we found that citrullination decreased the bacterial killingactivity of histones and nucleosomes, which suggests that PAD4 mainly plays a role in chromatindecondensation to form NETs instead of increasing histone-mediated bacterial killing. Our results define arole for histone hypercitrullination in innate immunity during bacterial infection.", "metadata": {}}
+{"_id": "17973161", "title": "", "text": "Human ‘brite / beige’ adipocytes develop from capillary networks and their implantation improvesmetabolic homeostasis in miceUncoupling protein 1 (UCP1) is highly expressed in brown adipose tissue,where it generates heat by uncoupling electron transport from ATP production. UCP1 is also found outsideclassical brown adipose tissue depots, in adipocytes that are termed 'brite' (brown-in-white) or 'beige'. Inhumans, the presence of brite or beige (brite/beige) adipocytes is correlated with a lean, metabolicallyhealthy phenotype, but whether a causal relationship exists is not clear. Here we report that humanbrite/beige adipocyte progenitors proliferate in response to pro-angiogenic factors, in association withexpanding capillary networks. Adipocytes formed from these progenitors transform in response toadenylate cyclase activation from being UCP1 negative to being UCP1 positive, which is a defining featureof the beige/brite phenotype, while displaying uncoupled respiration. When implanted into normalchow-fed, or into high-fat diet (HFD)-fed, glucose-intolerant NOD-scid IL2rg(null) (NSG) mice, brite/beigeadipocytes activated in vitro enhance systemic glucose tolerance. These adipocytes expressneuroendocrine and secreted factors, including the pro-protein convertase PCSK1, which is stronglyassociated with human obesity. Pro-angiogenic conditions therefore drive the proliferation of humanbeige/brite adipocyte progenitors, and activated beige/brite adipocytes can affect systemic glucosehomeostasis, potentially through a neuroendocrine mechanism.", "metadata": {}}
+{"_id": "17973630", "title": "", "text": "Mindfulness meditation and improvement in sleep quality and daytime impairment among older adultswith sleep disturbances: a randomized clinical trial.IMPORTANCE Sleep disturbances are most prevalentamong older adults and often go untreated. Treatment options for sleep disturbances remain limited, andthere is a need for community-accessible programs that can improve sleep. OBJECTIVE To determine theefficacy of a mind-body medicine intervention, called mindfulness meditation, to promote sleep quality inolder adults with moderate sleep disturbances. DESIGN, SETTING, AND PARTICIPANTS Randomizedclinical trial with 2 parallel groups conducted from January 1 to December 31, 2012, at a medicalresearch center among an older adult sample (mean [SD] age, 66.3 [7.4] years) with moderate sleepdisturbances (Pittsburgh Sleep Quality Index [PSQI] >5). INTERVENTIONS A standardized mindfulawareness practices (MAPs) intervention (n = 24) or a sleep hygiene education (SHE) intervention (n =25) was randomized to participants, who received a 6-week intervention (2 hours per week) withassigned homework. MAIN OUTCOMES AND MEASURES The study was powered to detect between-groupdifferences in moderate sleep disturbance measured via the PSQI at postintervention. Secondaryoutcomes pertained to sleep-related daytime impairment and included validated measures of insomniasymptoms, depression, anxiety, stress, and fatigue, as well as inflammatory signaling via nuclear factor(NF)-κB.   RESULTS Using an intent-to-treat analysis, participants in the MAPs group showed significantimprovement relative to those in the SHE group on the PSQI. With the MAPs intervention, the mean (SD)PSQIs were 10.2 (1.7) at baseline and 7.4 (1.9) at postintervention. With the SHE intervention, the mean(SD) PSQIs were 10.2 (1.8) at baseline and 9.1 (2.0) at postintervention. The between-group meandifference was 1.8 (95% CI, 0.6-2.9), with an effect size of 0.89. The MAPs group showed significantimprovement relative to the SHE group on secondary health outcomes of insomnia symptoms, depressionsymptoms, fatigue interference, and fatigue severity (P < .05 for all). Between-group differences werenot observed for anxiety, stress, or NF-κB, although NF-κB concentrations significantly declined over timein both groups (P < .05). CONCLUSIONS AND RELEVANCE The use of a community-accessible MAPsintervention resulted in improvements in sleep quality at immediate postintervention, which was superiorto a highly structured SHE intervention. Formalized mindfulness-based interventions have clinicalimportance by possibly serving to remediate sleep problems among older adults in the short term, andthis effect appears to carry over into reducing sleep-related daytime impairment that has implications forquality of life. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01534338.", "metadata": {}}
+{"_id": "17991818", "title": "", "text": "THE ORIGIN AND DIFFERENTIATION OF MICROGLIAL CELLS DURING DEVELOPMENTSome authors claimthat microglia originate from the neuroepithelium, although most now believe that microglial cells are ofmesodermal origin, and probably belong to the monocyte/macrophage cell line. These cells must enterthe developing central nervous system (CNS) from the blood stream, the ventricular space or themeninges. Afterward microglial cells are distributed more or less homogeneously through the entirenervous parenchyma. Stereotyped patterns of migration have been recognized during development, inwhich long-distance tangential migration precedes radial migration of individual cells. Microglial cellsmoving through the nervous parenchyma are ameboid microglia, which apparently differentiate intoramified microglia after reaching their definitive location. This is supported by the presence of cellsshowing intermediate features between those of ameboid and ramified microglia. The factors that controlthe invasion of the nervous parenchyma, migration within the developing CNS and differentiation ofmicroglial cells are not well known. These phenomena apparently depend on environmental factors suchas soluble or cell-surface bound molecules and components of the extracellular matrix. Microglial cellswithin the developing CNS are involved in clearing cell debris and withdrawing misdirected or transitoryaxons, and presumably support cell survival and neurite growth.", "metadata": {}}
+{"_id": "17997584", "title": "", "text": "Integrin αvβ8-Mediated TGF-β Activation by Effector Regulatory T Cells Is Essential for Suppression ofT-Cell-Mediated InflammationRegulatory T (Treg) cells play a pivotal role in suppressing self-harmful Tcell responses, but how Treg cells mediate suppression to maintain immune homeostasis and limitresponses during inflammation is unclear. Here we show that effector Treg cells express high amounts ofthe integrin αvβ8, which enables them to activate latent transforming growth factor-β (TGF-β).Treg-cell-specific deletion of integrin αvβ8 did not result in a spontaneous inflammatory phenotype,suggesting that this pathway is not important in Treg-cell-mediated maintenance of immunehomeostasis. However, Treg cells lacking expression of integrin αvβ8 were unable to suppress pathogenicT cell responses during active inflammation. Thus, our results identify a mechanism by which Treg cellssuppress exuberant immune responses, highlighting a key role for effector Treg-cell-mediated activationof latent TGF-β in suppression of self-harmful T cell responses during active inflammation.", "metadata": {}}
+{"_id": "18025240", "title": "", "text": "Effects of treatment for intestinal helminth infection on growth and cognitive performance in children:systematic review of randomised trials.OBJECTIVE To summarise the effects of anthelmintic drugtreatment on growth and cognitive performance in children. DATA SOURCES Electronic databases:Cochrane Infectious Diseases Group controlled trial register, Cochrane controlled trials register, Embase,and Medline. Citations of all identified trials. Contact with the World Health Organization and fieldresearchers. REVIEW METHODS Systematic review of randomised controlled trials in children aged 1-16that compared anthelmintic treatment with placebo or no treatment. Assessment of validity and dataabstraction conducted independently by two reviewers. MAIN OUTCOME MEASURES Growth and cognitiveperformance. RESULTS Thirty randomised controlled trials in more than 15 000 children were identified.Effects on mean weight were unremarkable, and heterogeneity was evident in the results. There weresome positive effects on mean weight change in the trials reporting this outcome: after a single dose (anyanthelmintic) the pooled estimates were 0.24 kg (95% confidence interval 0.15 kg to 0. 32 kg; fixedeffects model assumed) and 0.38 kg (0.01 kg to 0.77 kg; random effects model assumed). Results fromtrials of multiple doses showed mean weight change in up to one year of follow up of 0.10 kg (0.04 kg to0.17 kg; fixed effects) or 0.15 kg (0.00 to 0.30; random effects). At more than one year of follow up,mean weight change was 0.12 kg (-0.02 kg to 0.26 kg; fixed effects) and 0.43 (-0.61 to 1. 47; randomeffects). Results from studies of cognitive performance were inconclusive. CONCLUSIONS There is somelimited evidence that routine treatment of children in areas where helminths are common has effects onweight gain, but this is not consistent between trials. There is insufficient evidence as to whether thisintervention improves cognitive performance.", "metadata": {}}
+{"_id": "18027063", "title": "", "text": "Choosing appropriate substitution models for the phylogenetic analysis of protein-codingsequences.Although phylogenetic inference of protein-coding sequences continues to dominate theliterature, few analyses incorporate evolutionary models that consider the genetic code. This problem isexacerbated by the exclusion of codon-based models from commonly employed model selectiontechniques, presumably due to the computational cost associated with codon models. We investigated anefficient alternative to standard nucleotide substitution models, in which codon position (CP) isincorporated into the model. We determined the most appropriate model for alignments of 177 RNA virusgenes and 106 yeast genes, using 11 substitution models including one codon model and four CP models.The majority of analyzed gene alignments are best described by CP substitution models, rather than bystandard nucleotide models, and without the computational cost of full codon models. These results havesignificant implications for phylogenetic inference of coding sequences as they make it clear thatsubstitution models incorporating CPs not only are a computationally realistic alternative to standardmodels but may also frequently be statistically superior.", "metadata": {}}
+{"_id": "18037805", "title": "", "text": "Polycomb Proteins Remain Bound to Chromatin and DNA during DNA Replication In VitroThetranscriptional status of a gene can be maintained through multiple rounds of cell division duringdevelopment. This epigenetic effect is believed to reflect heritable changes in chromatin folding andhistone modifications or variants at target genes, but little is known about how these chromatin featuresare inherited through cell division. A particular challenge for maintaining transcription states is DNAreplication, which disrupts or dilutes chromatin-associated proteins and histone modifications. PRC1-classPolycomb group protein complexes are essential for development and are thought to heritably silencetranscription by altering chromatin folding and histone modifications. It is not known whether thesecomplexes and their effects are maintained during DNA replication or subsequently re-established. Wefind that when PRC1-class Polycomb complex-bound chromatin or DNA is replicated in vitro, Polycombcomplexes remain bound to replicated templates. Retention of Polycomb proteins through DNA replicationmay contribute to maintenance of transcriptional silencing through cell division.", "metadata": {}}
+{"_id": "18038250", "title": "", "text": "Control of CNS Cell-Fate Decisions by SHP-2 and Its Dysregulation in Noonan SyndromeWithin thedeveloping mammalian CNS, growth factors direct multipotent precursors to generate neurons versusglia, a process that if perturbed might lead to neural dysfunction. In this regard, genetic mutationsresulting in constitutive activation of the protein tyrosine phosphatase SHP-2 cause Noonan Syndrome(NS), which is associated with learning disabilities and mental retardation. Here, we demonstrate thatgenetic knockdown of SHP-2 in cultured cortical precursors or in the embryonic cortex inhibited basalneurogenesis and caused enhanced and precocious astrocyte formation. Conversely, expression of an NSSHP-2 mutant promoted neurogenesis and inhibited astrogenesis. Neural cell-fate decisions weresimilarly perturbed in a mouse knockin model that phenocopies human NS. Thus, SHP-2 instructsprecursors to make neurons and not astrocytes during the neurogenic period, and perturbations in therelative ratios of these two cell types upon constitutive SHP-2 activation may contribute to the cognitiveimpairments in NS patients.", "metadata": {}}
+{"_id": "18038955", "title": "", "text": "Global Regulation of H2A.Z Localization by the INO80 Chromatin-Remodeling Enzyme Is Essential forGenome IntegrityINO80 is an evolutionarily conserved, ATP-dependent chromatin-remodeling enzymethat plays roles in transcription, DNA repair, and replication. Here, we show that yeast INO80 facilitatesthese diverse processes at least in part by controlling genome-wide distribution of the histone variantH2A.Z. In the absence of INO80, H2A.Z nucleosomes are mislocalized, and H2A.Z levels at promotersshow reduced responsiveness to transcriptional changes, suggesting that INO80 controls H2A.Zdynamics. Additionally, we demonstrate that INO80 has a histone-exchange activity in which the enzymecan replace nucleosomal H2A.Z/H2B with free H2A/H2B dimers. Genetic interactions between ino80 andhtz1 support a model in which INO80 catalyzes the removal of unacetylated H2A.Z from chromatin as amechanism to promote genome stability.", "metadata": {}}
+{"_id": "18041692", "title": "", "text": "Rho GTPase signalling in cell migrationCells migrate in multiple different ways depending on theirenvironment, which includes the extracellular matrix composition, interactions with other cells, andchemical stimuli. For all types of cell migration, Rho GTPases play a central role, although the relativecontribution of each Rho GTPase depends on the environment and cell type. Here, I review recentadvances in our understanding of how Rho GTPases contribute to different types of migration, comparinglamellipodium-driven versus bleb-driven migration modes. I also describe how cells migrate across theendothelium. In addition to Rho, Rac and Cdc42, which are well known to regulate migration, I discussthe roles of other less-well characterized members of the Rho family.", "metadata": {}}
+{"_id": "18042803", "title": "", "text": "A Novel Adaptor Protein Orchestrates Receptor Patterning and Cytoskeletal Polarity in T-CellContactsRecognition of antigen by T cells requires the formation of a specialized junction between the Tcell and the antigen-presenting cell. This junction is generated by the recruitment and the exclusion ofspecific proteins from the contact area. The mechanisms that regulate these events are unknown. Herewe demonstrate that ligand engagement of the adhesion molecule, CD2, initiates a process of proteinsegregation, CD2 clustering, and cytoskeletal polarization. Although protein segregation was notdependent on the cytoplasmic domain of CD2, CD2 clustering and cytoskeletal polarization required aninteraction of the CD2 cytoplasmic domain with a novel SH3-containing protein. This novel protein, calledCD2AP, is likely to facilitate receptor patterning in the contact area by linking specific adhesion receptorsto the cytoskeleton.", "metadata": {}}
+{"_id": "18062308", "title": "", "text": "Operable non-small cell lung cancer diagnosed by transpleural techniques : do they affect relapse andprognosis?STUDY OBJECTIVE We assessed whether transpleural methods for diagnosing peripheral lungcancer, such as needle aspiration or tumor excision, affect relapse and prognosis, because thesetechniques have potential to spread malignant cells from the tumor. DESIGN A retrospective study.SETTING National referral hospital. PATIENTS We reviewed 239 patients who underwent surgery between1990 and 1998 and for whom non-small cell lung cancer (NSCLC) of < 3 cm in maximum diameter wascompletely resected. The duration of postoperative follow-up ranged from 12 to 105 months, with amedian period of 45 months. INTERVENTIONS We defined the transbronchial method as using abronchoscope, and the transpleural method as using needle aspiration cytology or tumor excision.Dichotomous variables included gender, histologic type of squamous cell carcinoma or other type ofcarcinoma, pathologic stage, and whether the diagnostic method was the transbronchial type only(first-line method) or the transpleural type (second-line method). RESULTS NSCLC was diagnosed in 45patients by the transpleural technique and in 194 patients by the transbronchial technique. There were nosignificant statistical differences in age of patients, gender, histologic type, pathologic stage, and tumorsize. There were 42 relapses, 7 in the transpleural technique group and 35 in the transbronchialtechnique group (p = 0.90). Of the 7 patients in the transpleural group, there were 4 distant metastasisand 3 local relapses; of the 35 patients in the transbronchial group, there were 20 distant metastasis and15 local relapses (p = 0.99). Pleural carcinomatosis occurred in none of the 45 patients in thetranspleural group and in 1 case (0.5%) in the 194 patients in the transbronchial group (p = 0.99).Patients in the transpleural group had a statistically better 5-year survival rate than patients in thetransbronchial group (79.4% vs 60.3%, p = 0.04). This is also confirmed as an independent prognosticfactor in a multivariate analysis. CONCLUSIONS Transpleural methods seem to be an advisable way todiagnose operable lung cancer that is difficult to diagnose using bronchoscopy, because these methodsdid not affect relapse and prognosis in the patients in our study.", "metadata": {}}
+{"_id": "18064113", "title": "", "text": "Characterization of the adipocyte cellular lineage in vivoMature adipocytes are generated through theproliferation and differentiation of precursor cells. Our previous studies identified adipocyte progenitors inwhite adipose tissue (WAT) as Lin(-):CD29(+):CD34(+):Sca-1(+):CD24(+) (CD24(+)) cells that arecapable of generating functional WAT (ref.  ). Here, we employ several Cre recombinase mouse models toidentify the adipocyte cellular lineage in vivo. Although it has been proposed that white adipocytes arederived from endothelial and haematopoietic lineages, we find that neither of these lineages label whiteadipocytes. However, platelet-derived growth factor receptor α (PdgfRα)-Cre trace labels all whiteadipocytes. Analysis of WAT from PdgfRα-Cre reporter mice identifies CD24(+) andLin(-):CD29(+):CD34(+):Sca-1(+): CD24(-) (CD24(-)) cells as adipocyte precursors. We show thatCD24(+) cells generate the CD24(-) population in vivo and the CD24(-) cells express late markers ofadipogenesis. From these data we propose a model where the CD24(+) adipocyte progenitors becomefurther committed to the adipocyte lineage as CD24 expression is lost, generating CD24(-) preadipocytes.This characterization of the adipocyte cellular lineage will facilitate the study of the mechanisms thatregulate WAT formation in vivo and WAT mass expansion in obesity.", "metadata": {}}
+{"_id": "18074797", "title": "", "text": "Reducing Plasmodium falciparum Malaria Transmission in Africa: A Model-Based Evaluation ofIntervention StrategiesBACKGROUND Over the past decade malaria intervention coverage has beenscaled up across Africa. However, it remains unclear what overall reduction in transmission is achievableusing currently available tools. METHODS AND FINDINGS We developed an individual-based simulationmodel for Plasmodium falciparum transmission in an African context incorporating the three major vectorspecies (Anopheles gambiae s.s., An. arabiensis, and An. funestus) with parameters obtained by fitting toparasite prevalence data from 34 transmission settings across Africa. We incorporated the effect of theswitch to artemisinin-combination therapy (ACT) and increasing coverage of long-lasting insecticidetreated nets (LLINs) from the year 2000 onwards. We then explored the impact on transmission ofcontinued roll-out of LLINs, additional rounds of indoor residual spraying (IRS), mass screening andtreatment (MSAT), and a future RTS,S/AS01 vaccine in six representative settings with varyingtransmission intensity (as summarized by the annual entomological inoculation rate, EIR: 1 setting withlow, 3 with moderate, and 2 with high EIRs), vector-species combinations, and patterns of seasonality. Inall settings we considered a realistic target of 80% coverage of interventions. In the low-transmissionsetting (EIR approximately 3 ibppy [infectious bites per person per year]), LLINs have the potential toreduce malaria transmission to low levels (<1% parasite prevalence in all age-groups) provided usagelevels are high and sustained. In two of the moderate-transmission settings (EIR approximately 43 and81 ibppy), additional rounds of IRS with DDT coupled with MSAT could drive parasite prevalence below a1% threshold. However, in the third (EIR = 46) with An. arabiensis prevailing, these interventions areinsufficient to reach this threshold. In both high-transmission settings (EIR approximately 586 and 675ibppy), either unrealistically high coverage levels (>90%) or novel tools and/or substantial socialimprovements will be required, although considerable reductions in prevalence can be achieved withexisting tools and realistic coverage levels. CONCLUSIONS Interventions using current tools can result inmajor reductions in P. falciparum malaria transmission and the associated disease burden in Africa.Reduction to the 1% parasite prevalence threshold is possible in low- to moderate-transmission settingswhen vectors are primarily endophilic (indoor-resting), provided a comprehensive and sustainedintervention program is achieved through roll-out of interventions. In high-transmission settings andthose in which vectors are mainly exophilic (outdoor-resting), additional new tools that target exophagic(outdoor-biting), exophilic, and partly zoophagic mosquitoes will be required.", "metadata": {}}
+{"_id": "18078750", "title": "", "text": "Golgi Export of the Kir2.1 Channel Is Driven by a Trafficking Signal Located within Its TertiaryStructureMechanisms that are responsible for sorting newly synthesized proteins for traffic to the cellsurface from the Golgi are poorly understood. Here, we show that the potassium channel Kir2.1,mutations in which are associated with Andersen-Tawil syndrome, is selected as cargo into Golgi exportcarriers in an unusual signal-dependent manner. Unlike conventional trafficking signals, which aretypically comprised of short linear peptide sequences, Golgi exit of Kir2.1 is dictated by residues that areembedded within the confluence of two separate domains. This signal patch forms a recognition site forinteraction with the AP1 adaptor complex, thereby marking Kir2.1 for incorporation into clathrin-coatedvesicles at the trans-Golgi. The identification of a trafficking signal in the tertiary structure of Kir2.1reveals a quality control step that couples protein conformation to Golgi export and provides molecularinsight into how mutations in Kir2.1 arrest the channels at the Golgi.", "metadata": {}}
+{"_id": "18084826", "title": "", "text": "Characteristics of Body Fat, Body Fat Percentage and Other Body Composition for Koreans from KNHANESIVAccurate measurement of fat mass has become increasingly important with the increasing incidence ofobesity. We assessed fat and muscle mass of Koreans with the Korea National Health and NutritionExamination Survey IV (KNHANES IV). We studied 10,456 subjects (aged 20 to 85 yr; 4,476 men, 5,980women). Fat and muscle mass were measured by dual-energy x-ray absorptiometry. Reference values ofbody compositions were obtained using the LMS method. The fat mass index (FMI, body fatmass/height(2); kg/m(2)) of Korean men did not correlate with age (P = 0.452), but those of Koreanwomen (P < 0.001) did. The ratio of percentage of fat in the trunk and legs was positively related withage in both the genders. The appendicular lean mass/height(2) (kg/m(2)) of Korean men was negativelyrelated to age (P < 0.001). In women, this ratio increased with age (P < 0.001). When we definedobesity according to the FMI classification, the rates of obesity were 6.1% (FMI > 9 kg/m(2)) in men and2.7% (FMI > 13 kg/m(2)) in women. It is concluded that the muscle mass decreases and obesityincreases with aging in Korean men, whereas both fat mass and obesity increase with aging in Koreanwomen.", "metadata": {}}
+{"_id": "18098290", "title": "", "text": "The Evolution of Dominance in Sporophytic Self-Incompatibility Systems. II. Mate Availability andRecombinationSporophytic self-incompatibility (SSI) is a self-pollen recognition system that enforcesoutcrossing in plants. Recognition in SSI systems is typically controlled by a complex locus (5-locus) withseparate genes that determine pollen and stigma specificity. Experimental studies show that S-alleles canbe dominant, recessive, or codominant, and that the dominance level of a given S-allele can depend uponwhether pollen or stigma specificity is examined. Here and in the companion paper by Llaurens andcolleagues, the evolution of dominance in single-locus SSI is explored using numerical models andsimulation. Particular attention is directed at factors that can cause S-allele dominance to differ in pollenversus stigma. The effect of recombination between the S-locus and modifier locus is also examined. Themodels predict that limitation in the number of compatible mates is required for the evolution of S-alleledominance in the stigma but not in the pollen. Tight linkage between the S-locus and modifier promotesthe evolution of S-allele dominance hierarchies. Model results are interpreted with respect to publishedinformation on the molecular basis of dominance in SSI systems, and reported S-allele dominancerelationships in a variety of species. These studies show that dominant S-alleles are more common in thepollen than in the stigma, a pattern that when interpreted in light of model predictions, suggests thatmate limitation may be relatively infrequent in natural populations with SSI.", "metadata": {}}
+{"_id": "18104691", "title": "", "text": "Neurological outcomes of animal models of uterine artery ligation and relevance to human intrauterinegrowth restriction: a systematic reviewAIM This review explores the molecular, neurological, andbehavioural outcomes in animal models of uterine artery ligation. We analyse the relevance of this type ofmodel to the pathological and functional phenotypes that are consistent with cerebral palsy and itsdevelopmental comorbidities in humans. METHOD A literature search of the PubMed database wasconducted for research using the uterine artery ligation model published between 1990 and 2013. Fromthe studies included, any relevant neuroanatomical and behavioural deficits were then summarized fromeach document and used for further analysis. RESULTS There were 25 papers that met the criteriaincluded for review, and several outcomes were summarized from the results of these papers. Fetuseswith growth restriction demonstrated a gradient of reduced body weight with a relative sparing of brainmass. There was a significant reduction in the size of the somatosensory cortex, hippocampus, andcorpus callosum. The motor cortex appeared to be spared of identifiable deficits. Apoptotic proteins wereupregulated, while those important to neuronal survival, growth, and differentiation were downregulated.Neuronal apoptosis and astrogliosis occurred diffusely throughout the brain regions. White matter injuryinvolved oligodendrocyte precursor maturation arrest, hypomyelination, and an aberrant organization ofexisting myelin. Animals with growth restriction demonstrated deficits in gait, memory, objectrecognition, and spatial processing. INTERPRETATION This review concludes that neuronal death, whitematter injury, motor abnormalities, and cognitive deficits are important outcomes of uterine arteryligation in animal models. Therefore, this is a clinically relevant type of model, as these findings resembledeficits in human cerebral palsy.", "metadata": {}}
+{"_id": "18111172", "title": "", "text": "The fidelity of the ligation step determines how ends are resolved during Nonhomologous endjoiningNonhomologous end joining (NHEJ) can effectively resolve chromosome breaks despite diverse endstructures; however, it is unclear how the steps employed for resolution are determined. We sought toaddress this question by analysing cellular NHEJ of ends with systematically mispaired and damagedtermini. We show NHEJ is uniquely proficient at bypassing subtle terminal mispairs and radiomimeticdamage by direct ligation. Nevertheless, bypass ability varies widely, with increases in mispair severitygradually reducing bypass products from 85 to 6%. End-processing by nucleases and polymerases isincreased to compensate, although paths with the fewest number of steps to generate a substratesuitable for ligation are favoured. Thus, both the frequency and nature of end processing are tailored tomeet the needs of the ligation step. We propose a model where the ligase organizes all steps during NHEJwithin the stable paired-end complex to limit end processing and associated errors.", "metadata": {}}
+{"_id": "18126445", "title": "", "text": "Laminin-based cell adhesion anchors microtubule plus ends to the epithelial cell basal cortex throughLL5α/βLL5beta has been identified as a microtubule-anchoring factor that attaches EB1/CLIP-associatingprotein (CLASP)-bound microtubule plus ends to the cell cortex. In this study, we show that LL5beta andits homologue LL5alpha (LL5s) colocalize with autocrine laminin-5 and its receptors, integrinsalpha3beta1 and alpha6beta4, at the basal side of fully polarized epithelial sheets. Depletion of bothlaminin receptor integrins abolishes the cortical localization of LL5s, whereas LL5 depletion reduces theamount of integrin alpha3 at the basal cell cortex. Activation of integrin alpha3 is sufficient to initiate LL5accumulation at the cell cortex. LL5s form a complex with the cytoplasmic tails of these integrins, buttheir interaction might be indirect. Analysis of the three-dimensional distribution of microtubule growthby visualizing EB1-GFP in epithelial sheets in combination with RNA interference reveals that LL5s arerequired to maintain the density of growing microtubules selectively at the basal cortex. These findingsreveal that signaling from laminin-integrin associations attaches microtubule plus ends to the epithelialbasal cell cortex.", "metadata": {}}
+{"_id": "18144189", "title": "", "text": "DNA topoisomerases: structure, function, and mechanism.DNA topoisomerases solve the topologicalproblems associated with DNA replication, transcription, recombination, and chromatin remodeling byintroducing temporary single- or double-strand breaks in the DNA. In addition, these enzymes fine-tunethe steady-state level of DNA supercoiling both to facilitate protein interactions with the DNA and toprevent excessive supercoiling that is deleterious. In recent years, the crystal structures of a number oftopoisomerase fragments, representing nearly all the known classes of enzymes, have been solved.These structures provide remarkable insights into the mechanisms of these enzymes and complementprevious conclusions based on biochemical analyses. Surprisingly, despite little or no sequence homology,both type IA and type IIA topoisomerases from prokaryotes and the type IIA enzymes from eukaryotesshare structural folds that appear to reflect functional motifs within critical regions of the enzymes. Thetype IB enzymes are structurally distinct from all other known topoisomerases but are similar to a class ofenzymes referred to as tyrosine recombinases. The structural themes common to all topoisomerasesinclude hinged clamps that open and close to bind DNA, the presence of DNA binding cavities fortemporary storage of DNA segments, and the coupling of protein conformational changes to DNA rotationor DNA movement. For the type II topoisomerases, the binding and hydrolysis of ATP further modulateconformational changes in the enzymes to effect changes in DNA topology.", "metadata": {}}
+{"_id": "18153456", "title": "", "text": "Pilot testing of dipsticks as point-of-care assays for rapid diagnosis of poor-quality artemisinin drugs inendemic settingsBACKGROUND Good-quality artemisinin drugs are essential for malaria treatment, butincreasing prevalence of poor-quality artemisinin drugs in many endemic countries hinders effectivemanagement of malaria cases. METHODS To develop a point-of-care assay for rapid identification ofcounterfeit and substandard artemisinin drugs for resource-limited areas, we used specific monoclonalantibodies against artesunate and artemether, and developed prototypes of lateral flow dipstick assays.In this pilot test, we evaluated the feasibility of these dipsticks under different endemic settings and theirperformance in the hands of untrained personnel. RESULTS The results showed that the dipstick tests canbe successfully performed by different investigators with the included instruction sheet. None of theartemether and artesunate drugs collected from public pharmacies in different endemic countries failedthe test. CONCLUSION It is possible that the simple dipstick assays, with future optimization of testconditions and sensitivity, can be used as a qualitative and semi-quantitative assay for rapid screening ofcounterfeit artemisinin drugs in endemic settings.", "metadata": {}}
+{"_id": "18174210", "title": "", "text": "Increased Microerythrocyte Count in Homozygous α+-Thalassaemia Contributes to Protection againstSevere Malarial AnaemiaBACKGROUND The heritable haemoglobinopathy alpha(+)-thalassaemia iscaused by the reduced synthesis of alpha-globin chains that form part of normal adult haemoglobin (Hb).Individuals homozygous for alpha(+)-thalassaemia have microcytosis and an increased erythrocytecount. Alpha(+)-thalassaemia homozygosity confers considerable protection against severe malaria,including severe malarial anaemia (SMA) (Hb concentration < 50 g/l), but does not influence parasitecount. We tested the hypothesis that the erythrocyte indices associated with alpha(+)-thalassaemiahomozygosity provide a haematological benefit during acute malaria. METHODS AND FINDINGS Datafrom children living on the north coast of Papua New Guinea who had participated in a case-control studyof the protection afforded by alpha(+)-thalassaemia against severe malaria were reanalysed to assessthe genotype-specific reduction in erythrocyte count and Hb levels associated with acute malarial disease.We observed a reduction in median erythrocyte count of approximately 1.5 x 10(12)/l in all children withacute falciparum malaria relative to values in community children (p < 0.001). We developed a simplemathematical model of the linear relationship between Hb concentration and erythrocyte count. Thismodel predicted that children homozygous for alpha(+)-thalassaemia lose less Hb than children of normalgenotype for a reduction in erythrocyte count of >1.1 x 10(12)/l as a result of the reduced mean cell Hbin homozygous alpha(+)-thalassaemia. In addition, children homozygous for alpha(+)-thalassaemiarequire a 10% greater reduction in erythrocyte count than children of normal genotype (p = 0.02) for Hbconcentration to fall to 50 g/l, the cutoff for SMA. We estimated that the haematological profile in childrenhomozygous for alpha(+)-thalassaemia reduces the risk of SMA during acute malaria compared tochildren of normal genotype (relative risk 0.52; 95% confidence interval [CI] 0.24-1.12, p = 0.09).CONCLUSIONS The increased erythrocyte count and microcytosis in children homozygous foralpha(+)-thalassaemia may contribute substantially to their protection against SMA. A lowerconcentration of Hb per erythrocyte and a larger population of erythrocytes may be a biologicallyadvantageous strategy against the significant reduction in erythrocyte count that occurs during acuteinfection with the malaria parasite Plasmodium falciparum. This haematological profile may reduce therisk of anaemia by other Plasmodium species, as well as other causes of anaemia. Other hostpolymorphisms that induce an increased erythrocyte count and microcytosis may confer a similaradvantage.", "metadata": {}}
+{"_id": "18188022", "title": "", "text": "Construction of Escherichia coli K-12 in-frame, single-gene knockout mutants: the Keio collectionWe havesystematically made a set of precisely defined, single\u0000gene deletions of all nonessential genes inEscherichia coli K\u000012. Open\u0000reading frame coding regions were replaced with a kanamycin cassetteflanked by FLP recognition target sites by using a one\u0000step method for inactivation of chromosomalgenes and primers designed to create in\u0000frame deletions upon excision of the resistance cassette. Of4288 genes targeted, mutants were obtained for 3985. To alleviate problems encountered inhigh\u0000throughput studies, two independent mutants were saved for every deleted gene. Thesemutants—the ‘Keio collection’—provide a new resource not only for systematic analyses of unknown genefunctions and gene regulatory networks but also for genome\u0000wide testing of mutational effects in acommon strain background, E . coli K\u000012 BW25113. We were unable to disrupt 303 genes, including 37of unknown function, which are candidates for essential genes. Distribution is being handled viaGenoBase (http://ecoli.aist\u0000nara.ac.jp/).", "metadata": {}}
+{"_id": "18190552", "title": "", "text": "Validated RealTime reverse transcriptase PCR methods for the diagnosis and pathotyping of Eurasian H7avian influenza virusesBACKGROUND Avian influenza (AI) caused by H7 AI viruses (AIVs) of both lowpathogenicity (LP) and high pathogenicity (HP) are notifiable poultry diseases. OBJECTIVES Design andvalidate two RealTime reverse transcriptase polymerase chain reactions (RRT PCRs) for Eurasian H7 AIVdetection and pathotyping. METHODS The H7 RRT PCRs amplified within the (i) HA2 and (ii) cleavage siteCS regions of the haemagglutinin gene. Both were validated against 65 H7 AIVs, 57 non-H7 AIVs and 259poultry swabs in comparison to M gene (AI generic) RRT PCR and virus isolation (VI). An additional 38swabs and 20 tissue specimens extended validation against M gene RRT PCR. RESULTS Both H7 RRTPCRs amplified all 61 Eurasian lineage H7 AIVs and none of 57 non-H7 AIVs. A total of 297 poultry swabswere used to determine diagnostic sensitivity and specificity relative to M gene RRT PCR, sensitivity was95.4% and 64.6% for the HA2 and CS RRT PCRs respectively, and specificity 97.9% and 99.6%respectively. The H7 HA2 RRT PCR was more sensitive than VI. This was emphasized by analysis of 37swabs from turkeys infected experimentally with HPAI H7N1 virus sampled at 24 hours post-inoculationand LPAI H7N1 chicken infections sampled at 40-64 hours. Although less sensitive, usefulness of the H7CS RRT PCR was confirmed by the correct molecular pathotyping for all 61 Eurasian lineage H7 AIVstested. CONCLUSIONS The high sensitivity of H7 HA2 RRT PCR confirms its suitability for use in poultrysurveillance and disease diagnosis. H7 CS RRT PCR provides an opportunity for rapid pathotyping of H7AIVs.", "metadata": {}}
+{"_id": "18199839", "title": "", "text": "Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82studiesBACKGROUND Persistent inflammation has been proposed to contribute to various stages in thepathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstreaminflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, westudied a functional genetic variant known to affect IL6R signalling. METHODS In a collaborativemeta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional riskfactors and inflammation biomarkers in 125,222 participants. We also compared the frequency ofAsp358Ala in 51,441 patients with coronary heart disease and in 136,226 controls. To gain insight intopossible mechanisms, we assessed Asp358Ala in relation to localised gene expression and topostlipopolysaccharide stimulation of interleukin 6. FINDINGS The minor allele frequency of Asp358Alawas 39%. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity,dysglycaemia, or smoking (p value for association per minor allele ≥0·04 for each). By contrast, for everycopy of 358Ala inherited, mean concentration of IL6R increased by 34·3% (95% CI 30·4-38·2) and ofinterleukin 6 by 14·6% (10·7-18·4), and mean concentration of C-reactive protein was reduced by 7·5%(5·9-9·1) and of fibrinogen by 1·0% (0·7-1·3). For every copy of 358Ala inherited, risk of coronary heartdisease was reduced by 3·4% (1·8-5·0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6production in monocytes. INTERPRETATION Large-scale human genetic and biomarker data areconsistent with a causal association between IL6R-related pathways and coronary heart disease.FUNDING British Heart Foundation; UK Medical Research Council; UK National Institute of HealthResearch, Cambridge Biomedical Research Centre; BUPA Foundation.", "metadata": {}}
+{"_id": "18207615", "title": "", "text": "Plasma exosomes can deliver exogenous short interfering RNA to monocytes and lymphocytesDespite thepromise of RNA interference (RNAi) and its potential, e.g. for use in cancer therapy, several technicalobstacles must first be overcome. The major hurdle of RNAi-based therapeutics is to deliver nucleic acidsacross the cell's plasma membrane. This study demonstrates that exosome vesicles derived from humanscan deliver short interfering RNA (siRNA) to human mononuclear blood cells. Exosomes are nano-sizedvesicles of endocytic origin that are involved in cell-to-cell communication, i.e. antigen presentation,tolerance development and shuttle RNA (mainly mRNA and microRNA). Having tested different strategies,an optimized method (electroporation) was used to introduce siRNA into human exosomes of variousorigins. Plasma exosomes (exosomes from peripheral blood) were used as gene delivery vector (GDV) totransport exogenous siRNA to human blood cells. The vesicles effectively delivered the administeredsiRNA into monocytes and lymphocytes, causing selective gene silencing of mitogen-activated proteinkinase 1. These data suggest that human exosomes can be used as a GDV to provide cells withheterologous nucleic acids such as therapeutic siRNAs.", "metadata": {}}
+{"_id": "18218379", "title": "", "text": "Quantitative analysis of tumor-derived methylated p16INK4a sequences in plasma, serum, and bloodcells of hepatocellular carcinoma patients.PURPOSE AND EXPERIMENTAL DESIGN Using real-timequantitative methylation-specific PCR (RTQ-MSP), we quantified methylated p16INK4a sequences anddetermined the fractional concentrations of circulating tumor DNA in plasma, serum, and peripheral bloodcells collected preoperatively, intraoperatively, and postoperatively from 49 patients with hepatocellularcarcinoma (HCC). RESULTS RTQ-MSP was sufficiently sensitive to detect down to 10 genome-equivalentsof methylated p16INK4a sequences. Quantitative MSP data were expressed in terms of the methylationindex, which was the percentage of bisulfite converted unmethylated and methylated p16INK4asequences that consisted of methylated p16INK4a sequences. Quantities of methylated p16INK4asequences were detected in peripheral circulation of 80% (23 of 29) of HCC patients. No significantdifference was seen in the detectability and concentrations of methylated p16INK4a sequences (range:10-4046 genome-equivalents/ml) between preoperative plasma and serum samples from HCC patients.Preoperatively, the p16INK4a methylation indices ranged from 0.2 to 100% and from 0.012 to 0.075% inthe patients' plasma and buffy coat samples, respectively. After surgical resection, the median p16INK4amethylation indices in plasma and buffy coat concordantly decreased 12- and 15-fold, respectively. Theseresults demonstrated the clinical usefulness and effectiveness of peripheral blood RTQ-MSP for detectingand monitoring HCC after treatment. Furthermore, none of the intraoperative plasma samples and onlytwo of the intraoperative buffy coat samples were p16INK4a methylation positive. CONCLUSIONSQuantification of epigenetic changes in peripheral blood by RTQ-MSP is useful for the detection andmonitoring of HCC.", "metadata": {}}
+{"_id": "18231257", "title": "", "text": "Dynamic control of excitatory synapse development by a Rac1 GEF/GAP regulatory complex.The smallGTPase Rac1 orchestrates actin-dependent remodeling essential for numerous cellular processesincluding synapse development. While precise spatiotemporal regulation of Rac1 is necessary for itsfunction, little is known about the mechanisms that enable Rac1 activators (GEFs) and inhibitors (GAPs)to act in concert to regulate Rac1 signaling. Here, we identify a regulatory complex composed of aRac-GEF (Tiam1) and a Rac-GAP (Bcr) that cooperate to control excitatory synapse development.Disruption of Bcr function within this complex increases Rac1 activity and dendritic spine remodeling,resulting in excessive synaptic growth that is rescued by Tiam1 inhibition. Notably, EphB receptors utilizethe Tiam1-Bcr complex to control synaptogenesis. Following EphB activation, Tiam1 inducesRac1-dependent spine formation, whereas Bcr prevents Rac1-mediated receptor internalization,promoting spine growth over retraction. The finding that a Rac-specific GEF/GAP complex is required tomaintain optimal levels of Rac1 signaling provides an important insight into the regulation of smallGTPases.", "metadata": {}}
+{"_id": "18231807", "title": "", "text": "4-1BB Costimulation Ameliorates T Cell Exhaustion Induced by Tonic Signaling of Chimeric AntigenReceptorsChimeric antigen receptors (CARs) targeting CD19 have mediated dramatic antitumorresponses in hematologic malignancies, but tumor regression has rarely occurred using CARs targetingother antigens. It remains unknown whether the impressive effects of CD19 CARs relate to greatersusceptibility of hematologic malignancies to CAR therapies, or superior functionality of the CD19 CARitself. We show that tonic CAR CD3-ζ phosphorylation, triggered by antigen-independent clustering ofCAR single-chain variable fragments, can induce early exhaustion of CAR T cells that limits antitumorefficacy. Such activation is present to varying degrees in all CARs studied, except the highly effectiveCD19 CAR. We further determine that CD28 costimulation augments, whereas 4-1BB costimulationreduces, exhaustion induced by persistent CAR signaling. Our results provide biological explanations forthe antitumor effects of CD19 CARs and for the observations that CD19 CAR T cells incorporating the4-1BB costimulatory domain are more persistent than those incorporating CD28 in clinical trials.", "metadata": {}}
+{"_id": "18236313", "title": "", "text": "Ultrafast Evolution and Loss of CRISPRs Following a Host Shift in a Novel Wildlife Pathogen, MycoplasmagallisepticumMeasureable rates of genome evolution are well documented in human pathogens but areless well understood in bacterial pathogens in the wild, particularly during and after host switches.Mycoplasma gallisepticum (MG) is a pathogenic bacterium that has evolved predominantly in poultry andrecently jumped to wild house finches (Carpodacus mexicanus), a common North American songbird. Forthe first time we characterize the genome and measure rates of genome evolution in House Finch isolatesof MG, as well as in poultry outgroups. Using whole-genome sequences of 12 House Finch isolates acrossa 13-year serial sample and an additional four newly sequenced poultry strains, we estimate a nucleotidediversity in House Finch isolates of only \u00002% of ancestral poultry strains and a nucleotide substitutionrate of 0.8-1.2×10(-5) per site per year both in poultry and in House Finches, an exceptionally fast raterivaling some of the highest estimates reported thus far for bacteria. We also found high diversity andcomplete turnover of CRISPR arrays in poultry MG strains prior to the switch to the House Finch host, butafter the invasion of House Finches there is progressive loss of CRISPR repeat diversity, and recruitmentof novel CRISPR repeats ceases. Recent (2007) House Finch MG strains retain only \u000050% of the CRISPRrepertoire founding (1994-95) strains and have lost the CRISPR-associated genes required for CRISPRfunction. Our results suggest that genome evolution in bacterial pathogens of wild birds can be extremelyrapid and in this case is accompanied by apparent functional loss of CRISPRs.", "metadata": {}}
+{"_id": "18237384", "title": "", "text": "Inducing Tumor Immunity through the Selective Engagement of Activating Fcγ Receptors on DendriticCellsInduction of tumor-specific immunity requires that dendritic cells (DCs) efficiently capture andpresent tumor antigens to result in the expansion and activation of tumor-specific cytotoxic T cells. Thetransition from antigen capture to T cell stimulation requires a maturation signal; in its absencetolerance, rather than immunity may develop. While immune complexes (ICs) are able to enhanceantigen capture, they can be poor at inducing DC maturation, naive T cell activation and protectiveimmunity. We now demonstrate that interfering with the inhibitory signal delivered by FcγRIIB on DCsconverts ICs to potent maturation agents and results in T cell activation. Applying this approach toimmunization with DCs pulsed ex-vivo with ICs, we have generated antigen-specific CD8+ T cells in vivoand achieved efficient protective immunity in a murine melanoma model. These data imply that ICs maynormally function to maintain tolerance through the binding to inhibitory FcγRs on DCs, but they can beconverted to potent immunogenic stimuli by selective engagement of activating FcγRs. This mechanismsuggests a novel approach to the development of tumor vaccines.", "metadata": {}}
+{"_id": "18256197", "title": "", "text": "Homocysteine and the risk of ischemic stroke in a triethnic cohort: the NOrthern MAnhattanStudy.BACKGROUND AND PURPOSE The level of total homocysteine (tHcy) that confers a risk of ischemicstroke is unsettled, and no prospective cohort studies have included sufficient elderly minority subjects.We investigated the association between mild to moderate fasting tHcy level and the incidence ofischemic stroke, myocardial infarction, and vascular death in a multiethnic prospective study. METHODSA population-based cohort was followed for vascular events (stroke, myocardial infarction, and vasculardeath). Baseline values of tHcy and methylmalonic acid were measured among 2939 subjects (mean age,69+/-10; 61% women, 53% Hispanics, 24% blacks, and 20% whites). Cox proportional models wereused to calculate hazard ratios (HRs) and 95% CIs in tHcy categories after adjusting for age, race,education, renal insufficiency, B12 deficiency, and other risk factors. RESULTS The adjusted HR for a tHcylevel > or =15 micromol/L compared with <10 micromol/L was greatest for vascular death (HR=6.04;95% CI, 3.44 to 10.60), followed by combined vascular events (HR=2.27; 95% CI, 1.51 to 3.43),ischemic stroke (HR=2.01; 95% CI, 1.00 to 4.05), and nonvascular death (HR=2.02; 95% CI, 1.31 to3.14). Mild to moderate elevations of tHcy of 10 to 15 micromol/L were not significantly predictive ofischemic stroke, but increased the risk of vascular death (2.27; 95% CI, 1.44 to 3.60) and combinedvascular events (1.42; 95% CI, 1.06 to 1.88). The effect of tHcy was stronger among whites andHispanics, but not a significant risk factor for blacks. CONCLUSIONS Total Hcy elevations above 15micromol/L are an independent risk factor for ischemic stroke, whereas mild elevations of tHcy of 10 to15 micromol/L are less predictive. The vascular effects of tHcy are greatest among whites and Hispanics,and less among blacks.", "metadata": {}}
+{"_id": "18261004", "title": "", "text": "Expression and purification of recombinant methylated HBHA in Mycobacterium smegmatis.TheHeparin-Binding Haemagglutinin (HBHA) is a mycobacterial adhesin involved in the dissemination ofMycobacterium tuberculosis from the site of primary infection and a potential candidate for thedevelopment of a new vaccine against tuberculosis. Methylation of HBHA is a novel post-translationalevent that imparts important immunological properties to the protein. Since recombinant HBHAexpressed in Escherichia coli is not methylated, we investigated the possibility of producing recombinantmethylated HBHA in fast growing mycobacteria for use in immunological and biochemical studies. Thecomplete coding sequence of HBHA was cloned in the plasmid pMV206, under the control of a strongpromoter (hsp60) or its own promoter. The constructs generated were electroporated into Mycobacteriumsmegmatis and the recombinant strains obtained were analyzed for the presence of the HBHA proteinusing the anti-HBHA monoclonal antibodies D2 and E4. Our results indicate that expression of highamounts of intact protein can be toxic for the mycobacteria, that methylated HBHA can be obtained in M.smegmatis only when using a promoter sequence weaker than hsp60 and that the expression of thecomplete structural gene is required in order to obtain methylated HBHA. We constructed a recombinantM. smegmatis strain (pMV3-38) that expresses a histidine-tagged methylated HBHA that can be easilypurified. The use of fast-growing strains of M. smegmatis to obtain significant amounts of purified HBHAprotein within a short timeframe, should be an effective strategy for the evaluation of a new HBHA-basedvaccine candidate for tuberculosis.", "metadata": {}}
+{"_id": "18263406", "title": "", "text": "Detection of alternative lengthening of telomeres by telomere quantitative PCRAlternative lengthening oftelomeres (ALT) is one of the two known telomere length maintenance mechanisms that are essential forthe unlimited proliferation potential of cancer cells. Existing methods for detecting ALT in tumors requiresubstantial amounts of tumor material and are labor intensive, making it difficult to study prevalence andprognostic significance of ALT in large tumor cohorts. Here, we present a novel strategy utilizing telomerequantitative PCR to diagnose ALT. The protocol is more rapid than conventional methods and scrutinizestwo distinct characteristics of ALT cells concurrently: long telomeres and the presence of C-circles(partially double-stranded circles of telomeric C-strand DNA). Requiring only 30 ng of genomic DNA, thisprotocol will facilitate large-scale studies of ALT in tumors and can be readily adopted by clinicallaboratories.", "metadata": {}}
+{"_id": "18264714", "title": "", "text": "Noise and interlocking signaling pathways promote distinct transcription factor dynamics in response todifferent stressesAll cells perceive and respond to environmental stresses through elaboratestress-sensing networks. Yeast cells sense stress through diverse signaling pathways that converge onthe transcription factors Msn2 and Msn4, which respond by initiating rapid, idiosyncratic cycles into andout of the nucleus. To understand the role of Msn2/4 nuclear localization dynamics, we combinedtime-lapse studies of Msn2-GFP localization in living cells with computational modeling of stress-sensingsignaling networks. We find that several signaling pathways, including Ras/protein kinase A,AMP-activated kinase, the high-osmolarity response mitogen-activated protein kinase pathway, andprotein phosphatase 1, regulate activation of Msn2 in distinct ways in response to different stresses.Moreover, we find that bursts of nuclear localization elicit a more robust transcriptional response thandoes sustained nuclear localization. Using stochastic modeling, we reproduce in silico the responses ofMsn2 to different stresses, and demonstrate that bursts of localization arise from noise in the signalingpathways amplified by the small number of Msn2 molecules in the cell. This noise imparts diversebehaviors to genetically identical cells, allowing cell populations to \"hedge their bets\" in responding to anuncertain future, and to balance growth and survival in an unpredictable environment.", "metadata": {}}
+{"_id": "18268012", "title": "", "text": "Long-term financing needs for HIV control in sub-Saharan Africa in 2015-2050: a modellingstudy.OBJECTIVES To estimate the present value of current and future funding needed for HIV treatmentand prevention in 9 sub-Saharan African (SSA) countries that account for 70% of HIV burden in Africaunder different scenarios of intervention scale-up. To analyse the gaps between current expenditures andfunding obligation, and discuss the policy implications of future financing needs. DESIGN We used theGoals module from Spectrum, and applied the most up-to-date cost and coverage data to provide a rangeof estimates for future financing obligations. The four different scale-up scenarios vary by treatmentinitiation threshold and service coverage level. We compared the model projections to current domesticand international financial sources available in selected SSA countries. RESULTS In the 9 SSA countries,the estimated resources required for HIV prevention and treatment in 2015-2050 range from US$98billion to maintain current coverage levels for treatment and prevention with eligibility for treatmentinitiation at CD4 count of <500/mm(3) to US$261 billion if treatment were to be extended to allHIV-positive individuals and prevention scaled up. With the addition of new funding obligations forHIV--which arise implicitly through commitment to achieve higher than current treatment coveragelevels--overall financial obligations (sum of debt levels and the present value of the stock of future HIVfunding obligations) would rise substantially. CONCLUSIONS Investing upfront in scale-up of HIV servicesto achieve high coverage levels will reduce HIV incidence, prevention and future treatment expendituresby realising long-term preventive effects of ART to reduce HIV transmission. Future obligations are toosubstantial for most SSA countries to be met from domestic sources alone. New sources of funding, inaddition to domestic sources, include innovative financing. Debt sustainability for sustained HIV responseis an urgent imperative for affected countries and donors.", "metadata": {}}
+{"_id": "18275697", "title": "", "text": "Cell-mediated immunity and antibody responses elicited by attenuated Salmonella enterica Serovar Typhistrains used as live oral vaccines in humans.The development of improved typhoid vaccines is a highglobal public health priority. However, their development has been hampered by a lack of informationregarding the specific determinants of protective immunity to Salmonella enterica serovar Typhi (S.Typhi) infection in humans. Although antibodies to S. Typhi O, H, and Vi appear to be involved inprotection against S. Typhi infection, it is unknown whether such antibodies mediate protection, act inconjunction with other adaptive responses, or serve as a surrogate for the presence of other, moredominant protective immune responses (e.g., cell-mediated immunity [CMI]). CMI responses elicited byimmunization of subjects with attenuated S. Typhi oral vaccines include lymphoproliferation; productionof type 1 cytokines (e.g., interferon- gamma and tumor necrosis factor- alpha ); and classical majorhistocompatibility complex (MHC) class Ia-restricted and novel, nonclassical MHC class Ib (humanleukocyte antigen [HLA]-E)-restricted CD8(+) cytotoxic T cell responses. In sum, human immunity to S.Typhi elicited by immunization is unexpectedly broad and complex. However, the immunologic correlatesof protection remain largely undefined.", "metadata": {}}
+{"_id": "18276599", "title": "", "text": "Extensive Promoter-Centered Chromatin Interactions Provide a Topological Basis for TranscriptionRegulationHigher-order chromosomal organization for transcription regulation is poorly understood ineukaryotes. Using genome-wide Chromatin Interaction Analysis with Paired-End-Tag sequencing(ChIA-PET), we mapped long-range chromatin interactions associated with RNA polymerase II in humancells and uncovered widespread promoter-centered intragenic, extragenic, and intergenic interactions.These interactions further aggregated into higher-order clusters, wherein proximal and distal genes wereengaged through promoter-promoter interactions. Most genes with promoter-promoter interactions wereactive and transcribed cooperatively, and some interacting promoters could influence each other implyingcombinatorial complexity of transcriptional controls. Comparative analyses of different cell lines showedthat cell-specific chromatin interactions could provide structural frameworks for cell-specific transcription,and suggested significant enrichment of enhancer-promoter interactions for cell-specific functions.Furthermore, genetically-identified disease-associated noncoding elements were found to be spatiallyengaged with corresponding genes through long-range interactions. Overall, our study provides insightsinto transcription regulation by three-dimensional chromatin interactions for both housekeeping andcell-specific genes in human cells.", "metadata": {}}
+{"_id": "18321590", "title": "", "text": "Resazurin microtiter assay plate: simple and inexpensive method for detection of drug resistance inMycobacterium tuberculosis.A method for detecting multidrug-resistant Mycobacterium tuberculosis byusing a reduction of resazurin is described. Eighty clinical isolates were evaluated against isoniazid andrifampin; results at 7 days were compared with those of the proportion method. Specificity and sensitivitywere excellent. The method is simple, inexpensive, and rapid and might be used with otherantituberculosis drugs.", "metadata": {}}
+{"_id": "18333304", "title": "", "text": "The pervasiveness and plasticity of circadian oscillations: the coupled circadian-oscillatorsframework.MOTIVATION Circadian oscillations have been observed in animals, plants, fungi andcyanobacteria and play a fundamental role in coordinating the homeostasis and behavior of biologicalsystems. Genetically encoded molecular clocks found in nearly every cell, based on negativetranscription/translation feedback loops and involving only a dozen genes, play a central role inmaintaining these oscillations. However, high-throughput gene expression experiments reveal that in atypical tissue, a much larger fraction ([Formula: see text]) of all transcripts oscillate with the day-nightcycle and the oscillating species vary with tissue type suggesting that perhaps a much larger fraction ofall transcripts, and perhaps also other molecular species, may bear the potential for circadian oscillations.RESULTS To better quantify the pervasiveness and plasticity of circadian oscillations, we conduct the firstlarge-scale analysis aggregating the results of 18 circadian transcriptomic studies and 10 circadianmetabolomic studies conducted in mice using different tissues and under different conditions. We findthat over half of protein coding genes in the cell can produce transcripts that are circadian in at least oneset of conditions and similarly for measured metabolites. Genetic or environmental perturbations candisrupt existing oscillations by changing their amplitudes and phases, suppressing them or giving rise tonovel circadian oscillations. The oscillating species and their oscillations provide a characteristic signatureof the physiological state of the corresponding cell/tissue. Molecular networks comprise many oscillatorloops that have been sculpted by evolution over two trillion day-night cycles to have intrinsic circadianfrequency. These oscillating loops are coupled by shared nodes in a large network of coupled circadianoscillators where the clock genes form a major hub. Cells can program and re-program their circadianrepertoire through epigenetic and other mechanisms. AVAILABILITY AND IMPLEMENTATIONHigh-resolution and tissue/condition specific circadian data and networks available athttp://circadiomics.igb.uci.edu. CONTACT pfbaldi@ics.uci.edu   SUPPLEMENTARY INFORMATIONSupplementary data are available at Bioinformatics online.", "metadata": {}}
+{"_id": "18340282", "title": "", "text": "Gene–environment interactions in 7610 women with breast cancer: prospective evidence from the MillionWomen StudyBACKGROUND Information is scarce about the combined effects on breast cancer incidenceof low-penetrance genetic susceptibility polymorphisms and environmental factors (reproductive,behavioural, and anthropometric risk factors for breast cancer). To test for evidence of gene-environmentinteractions, we compared genotypic relative risks for breast cancer across the other risk factors in alarge UK prospective study. METHODS We tested gene-environment interactions in 7610 women whodeveloped breast cancer and 10 196 controls without the disease, studying the effects of 12polymorphisms (FGFR2-rs2981582, TNRC9-rs3803662, 2q35-rs13387042, MAP3K1-rs889312,8q24-rs13281615, 2p-rs4666451, 5p12-rs981782, CASP8-rs1045485, LSP1-rs3817198, 5q-rs30099,TGFB1-rs1982073, and ATM-rs1800054) in relation to prospectively collected information about tenestablished environmental risk factors (age at menarche, parity, age at first birth, breastfeeding,menopausal status, age at menopause, use of hormone replacement therapy, body-mass index, height,and alcohol consumption). FINDINGS After allowance for multiple testing none of the 120 comparisonsyielded significant evidence of a gene-environment interaction. By contrast with previous suggestions,there was little evidence that the genotypic relative risks were affected by use of hormone replacementtherapy, either overall or for oestrogen-receptor-positive disease. Only one of the 12 polymorphisms wascorrelated with any of the ten other risk factors: carriers of the high-risk C allele of MAP3K1-rs889312were significantly shorter than non-carriers (mean height 162.4 cm [95% CI 162.1-162.7] vs 163.1 cm[162.9-163.2]; p=0.01 after allowance for multiple testing). INTERPRETATION Risks of breast cancerassociated with low-penetrance susceptibility polymorphisms do not vary significantly with these tenestablished environmental risk factors. FUNDING Cancer Research UK and the UK Medical ResearchCouncil.", "metadata": {}}
+{"_id": "18344910", "title": "", "text": "Thrombocytopenia as an Indicator of Malaria in Adult PopulationObjectives. To evaluate the predictivevalue of thrombocytopenia in malaria. Patients and Methods. It was a prospective observational study onall febrile patients with thrombocytopenia presenting to the Medical Unit of Hayat Abad Medical Complexduring November 2008 to November 2010. Results. Of the total of 228 patients with fever andthrombocytopenia, 121 patients (53%) proved to be suffering from malaria. Of them 82 patients (68%)had falciparum malaria while 39 patients (32%) had vivax infection. Of these 121 patients, plateletcounts ranged between 25,000 and 150,000/dL with a mean value of 101,000/dL (SD ± 47, 500) and amedian of 75,000/dL. Of the 107 patients who were not suffering from malaria, the counts rangedbetween 10,000 and 150,000/dL with a mean value of 58,000/dL (SD ± 54, 000) and median of50,000/dL. Conclusions. The presence of thrombocytopenia may be a predictor of malaria in adultpopulation.", "metadata": {}}
+{"_id": "18346333", "title": "", "text": "AMPA receptor ligand binding domain mobility revealed by functional cross linking.Glutamate receptorsmediate the majority of excitatory synaptic transmission in the CNS. The AMPA-subtype has rapidkinetics, with activation, deactivation and desensitization proceeding on the millisecond timescale orfaster. Crystallographic, biochemical, and functional studies suggest that GluR2 Cys mutants which formintermolecular disulfide cross-links between the lower D2 lobes of the ligand binding cores can be trappedin a conformation that represents the desensitized state. We used multi-channel rapid perfusiontechniques to examine the state dependence of cross-linking in these mutants. Under reducingconditions, both wild-type GluR2 and the G725C and S729C mutants have normal activation anddesensitization kinetics, but the Cys mutants can be efficiently trapped in nonconducting states whenoxidized. In contrast the I664C mutant is only partially inactivated under oxidizing conditions. For S729C,disulfide cross-links form rapidly when receptors are desensitized in the presence of glutamate, butreceptors also become trapped at rest, in the absence of agonist. We assessed such spontaneoustrapping in various conditions, including CNQX, a competitive antagonist; kainate, a weak partial agonist;or when desensitization was blocked by the L483Y mutation that stabilizes the D1 dimer interface. Theseexperiments suggest that trapping in the absence of glutamate is due to two motions: Spontaneousbreaking of the D1 dimer interface and hyperextension of the lower lobes of the ligand binding core.These data show that the glutamate binding domains are surprisingly mobile in the absence of ligand,which could influence receptor activity in the brain.", "metadata": {}}
+{"_id": "18348376", "title": "", "text": "Ncf1 (p47phox) Is Essential for Direct Regulatory T Cell Mediated Suppression of CD4+ Effector TCellsBACKGROUND Multiple mechanisms have been advanced to account for CD4+FOXP3+ regulatory Tcell (Treg)-mediated suppression of CD4+ effector T cells (Teffs) but none appear to completely explainsuppression. Previous data indicates that Tregs may affect the microenvironment redox state. Given theinherent redox sensitivity of T cells, we tested the hypothesis that oxidants may mediate the directsuppression of Teffs by Tregs. METHODOLOGY/PRINCIPAL FINDINGS Tregs and Teffs were isolated fromthe spleens of wild type (WT) C57BL/6 mice or Ncf1(p47phox)-deficient C57BL/6 mice which lack NADPHoxidase function. Teffs were labeled with CFSE and co-cultured with unlabeled Tregs at varying Treg:Teffratios in the presence of anti-CD3/CD28 coated beads for 3 days in suppression assays. Treg-mediatedsuppression was quantified by flow cytometric analysis of CFSE dilution in Teffs. The presence of theantioxidants n-acetylcysteine (NAC) or 2-mercaptoethanol or inhibitors of NADPH oxidase(diphenyleneiodonium and VAS-2870) resulted in reduced WT Treg-mediated suppression. The observedsuppression was in part dependent upon TGFβ as it was partially blocked with neutralizing antibodies. Thesuppression of Teff proliferation induced by exogenous TGFβ treatment could be overcome with NAC.Ncf1-deficient Teff were slightly but significantly less sensitive than WT Teff to suppression by exogenousTGFβ. Ncf1-deficient Tregs suppressed Ncf1-deficient Teff very poorly compared to wild type controls.There was partial but incomplete reconstitution of suppression in assays with WT Tregs and Ncf1-deficientTeff. CONCLUSIONS/SIGNIFICANCE We present evidence that NADPH oxidase derived ROS plays a role inthe direct Treg mediated suppression of CD4+ effector T cells in a process that is blocked bythiol-containing antioxidants, NADPH oxidase inhibitors or a lack of Ncf1 expression in Tregs and Teffs.Oxidants may represent a potential new target for therapeutic modulation of Treg function.", "metadata": {}}
+{"_id": "18358026", "title": "", "text": "Oxidative damage targets complexes containing DNA methyltransferases, SIRT1, and polycomb membersto promoter CpG Islands.Cancer cells simultaneously harbor global losses and gains in DNA methylation.We demonstrate that inducing cellular oxidative stress by hydrogen peroxide treatment recruits DNAmethyltransferase 1 (DNMT1) to damaged chromatin. DNMT1 becomes part of a complex(es) containingDNMT3B and members of the polycomb repressive complex 4. Hydrogen peroxide treatment causesrelocalization of these proteins from non-GC-rich to GC-rich areas. Key components are similarly enrichedat gene promoters in an in vivo colitis model. Although high-expression genes enriched for members ofthe complex have histone mark and nascent transcription changes, CpG island-containing low-expressiongenes gain promoter DNA methylation. Thus, oxidative damage induces formation and relocalization of asilencing complex that may explain cancer-specific aberrant DNA methylation and transcriptionalsilencing.", "metadata": {}}
+{"_id": "18361917", "title": "", "text": "Expression profiles during dedifferentiation in newt lens regeneration revealed by expressed sequencetagsPURPOSE The adult newt can regenerate lens from pigmented epithelial cells (PECs) of the dorsal irisvia dedifferentiation. The purpose of this research is to obtain sequence resources for a newt lensregeneration study and to obtain insights of dedifferentiation at the molecular level. METHODS mRNA waspurified from iris during dedifferentiation and its cDNA library was constructed. From the cDNA library10,449 clones were sequenced and analyzed. RESULTS From 10,449 reads, 780 contigs and 1,666singlets were annotated. The presence of several cancer- and apoptosis-related genes during newtdedifferentiation was revealed. Moreover, several candidate genes, which might participate inreprogramming during dedifferentiation, were also found. CONCLUSIONS The expression of cancer- andapoptosis-related genes could be hallmarks during dedifferentiation. The expression sequence tag (EST)resource is useful for the future study of newt dedifferentiation, and the sequence information is availablein GenBank (accession numbers; FS290155-FS300559).", "metadata": {}}
+{"_id": "18374364", "title": "", "text": "In vivo proliferation and cell cycle kinetics of long-term self-renewing hematopoietic stem cells.A rare setof hematopoietic stem cells (HSC) must undergo a massive expansion to produce mature blood cells. Thephenotypic isolation of HSC from mice offers the opportunity to determine directly their proliferationkinetics. We analyzed the proliferation and cell cycle kinetics of long-term self-renewing HSC (LT-HSC) innormal adult mice. At any one time, approximately 5% of LT-HSC were in S/G2/M phases of the cell cycleand another 20% were in G1 phase. BrdUrd incorporation was used to determine the rate at whichdifferent cohorts of HSC entered the cell cycle over time. About 50% of LT-HSC incorporated BrdUrd by 6days and >90% incorporated BrdUrd by 30 days. By 6 months, 99% of LT-HSC had incorporated BrdUrd.We calculated that approximately 8% of LT-HSC asynchronously entered the cell cycle per day. Nestedreverse transcription-PCR analysis revealed cyclin D2 expression in a high proportion of LT-HSC. Althoughapproximately 75% of LT-HSC are quiescent in G0 at any one time, all HSC are recruited into cycleregularly such that 99% of LT-HSC divide on average every 57 days.", "metadata": {}}
+{"_id": "18375089", "title": "", "text": "The role of the tissue omega-6/omega-3 fatty acid ratio in regulating tumor angiogenesisAngiogenesis isa necessary step in tumor growth and metastasis. It is well established that the metabolites of omega-6and omega-3 fatty acids, which must be obtained through the diet and cannot be synthesized de novo inmammals, have differential effects on cellular processes. Omega-6 fatty acid (n−6 FA)-derivedmetabolites promote angiogenesis by increasing growth factor expression whereas omega-3 fatty acids(n−3 FA) have anti-angiogenic and antitumor properties. However, most studies thus far have failed toaccount for the role of the n−6 FA/n−3 FA ratio in angiogenesis and instead examined the absolute levelsof n−6 and n−3 FA. This review highlights the biochemical interactions between n−6 and n−3 FA andfocuses on how the n−6/n−3 FA ratio in tissues modulates tumor angiogenesis. We suggest that futurework should consider the n−6/n−3 FA ratio to be a key element in experimental design and analysis.Furthermore, we recommend that clinical interventions should aim to both reduce n−6 metabolites andsimultaneously increase n−3 FA intake.", "metadata": {}}
+{"_id": "18379855", "title": "", "text": "The Natural Statistics of Audiovisual SpeechHumans, like other animals, are exposed to a continuousstream of signals, which are dynamic, multimodal, extended, and time varying in nature. This complexinput space must be transduced and sampled by our sensory systems and transmitted to the brain whereit can guide the selection of appropriate actions. To simplify this process, it's been suggested that thebrain exploits statistical regularities in the stimulus space. Tests of this idea have largely been confined tounimodal signals and natural scenes. One important class of multisensory signals for which a quantitativeinput space characterization is unavailable is human speech. We do not understand what signals our brainhas to actively piece together from an audiovisual speech stream to arrive at a percept versus what isalready embedded in the signal structure of the stream itself. In essence, we do not have a clearunderstanding of the natural statistics of audiovisual speech. In the present study, we identified thefollowing major statistical features of audiovisual speech. First, we observed robust correlations and closetemporal correspondence between the area of the mouth opening and the acoustic envelope. Second, wefound the strongest correlation between the area of the mouth opening and vocal tract resonances. Third,we observed that both area of the mouth opening and the voice envelope are temporally modulated inthe 2-7 Hz frequency range. Finally, we show that the timing of mouth movements relative to the onsetof the voice is consistently between 100 and 300 ms. We interpret these data in the context of recentneural theories of speech which suggest that speech communication is a reciprocally coupled,multisensory event, whereby the outputs of the signaler are matched to the neural processes of thereceiver.", "metadata": {}}
+{"_id": "18399038", "title": "", "text": "Establishment of human iPSC-based models for the study and targeting of glioma initiating cellsGliomatumour-initiating cells (GTICs) can originate upon the transformation of neural progenitor cells (NPCs).Studies on GTICs have focused on primary tumours from which GTICs could be isolated and the use ofhuman embryonic material. Recently, the somatic genomic landscape of human gliomas has beenreported. RTK (receptor tyrosine kinase) and p53 signalling were found dysregulated in \u000090% and 86%of all primary tumours analysed, respectively. Here we report on the use of human-induced pluripotentstem cells (hiPSCs) for modelling gliomagenesis. Dysregulation of RTK and p53 signalling inhiPSC-derived NPCs (iNPCs) recapitulates GTIC properties in vitro. In vivo transplantation of transformediNPCs leads to highly aggressive tumours containing undifferentiated stem cells and their differentiatedderivatives. Metabolic modulation compromises GTIC viability. Last, screening of 101 anti-cancercompounds identifies three molecules specifically targeting transformed iNPCs and primary GTICs.Together, our results highlight the potential of hiPSCs for studying human tumourigenesis.", "metadata": {}}
+{"_id": "18414462", "title": "", "text": "Thyroid Hormone Receptor Repression Linked to Type I Pneumocyte Associated Respiratory DistressSyndromeAlthough the lung is a defining feature of air-breathing animals, the pathway controlling theformation of type I pneumocytes, the cells that mediate gas exchange, is poorly understood. In contrast,the glucocorticoid receptor and its cognate ligand have long been known to promote type II pneumocytematuration; prenatal administration of glucocorticoids is commonly used to attenuate the severity ofinfant respiratory distress syndrome (RDS). Here we show that knock-in mutations of the nuclearco-repressor SMRT (silencing mediator of retinoid and thyroid hormone receptors) in C57BL/6 mice(SMRTmRID) produces a previously unidentified respiratory distress syndrome caused by prematurity ofthe type I pneumocyte. Though unresponsive to glucocorticoids, treatment with anti-thyroid hormonedrugs (propylthiouracil or methimazole) completely rescues SMRT-induced RDS, suggesting anunrecognized and essential role for the thyroid hormone receptor (TR) in lung development. We showthat TR and SMRT control type I pneumocyte differentiation through Klf2, which, in turn, seems todirectly activate the type I pneumocyte gene program. Conversely, mice without lung Klf2 lack maturetype I pneumocytes and die shortly after birth, closely recapitulating the SMRTmRID phenotype. Theseresults identify TR as a second nuclear receptor involved in lung development, specifically type Ipneumocyte differentiation, and suggest a possible new type of therapeutic option in the treatment ofRDS that is unresponsive to glucocorticoids.", "metadata": {}}
+{"_id": "18421962", "title": "", "text": "Assessing the ceRNA hypothesis with quantitative measurements of miRNA and target abundance.Recentstudies have reported that competitive endogenous RNAs (ceRNAs) can act as sponges for a microRNA(miRNA) through their binding sites and that changes in ceRNA abundances from individual genes canmodulate the activity of miRNAs. Consideration of this hypothesis would benefit from knowing thequantitative relationship between a miRNA and its endogenous target sites. Here, we altered intracellulartarget site abundance through expression of an miR-122 target in hepatocytes and livers and analyzedthe effects on miR-122 target genes. Target repression was released in a threshold-like manner at hightarget site abundance (≥1.5 × 10(5) added target sites per cell), and this threshold was insensitive to theeffective levels of the miRNA. Furthermore, in response to extreme metabolic liver disease models, globaltarget site abundance of hepatocytes did not change sufficiently to affect miRNA-mediated repression.Thus, modulation of miRNA target abundance is unlikely to cause significant effects on gene expressionand metabolism through a ceRNA effect.", "metadata": {}}
+{"_id": "18429416", "title": "", "text": "Immunological mechanisms for desensitization and tolerance in food allergyFood allergy is a major publichealth concern in westernized countries, estimated to affect 5 % of children and 3–4 % of adults.Allergen-specific immunotherapy for food allergy is currently being actively evaluated, but is stillexperimental. The optimal protocol, in terms of the route of administration of the food, targetmaintenance dose, and duration of maintenance therapy, and the optimal patient for these proceduresare still being worked out. The mechanisms underlying successful food desensitization are also unclear, inpart, because there is no standard immunotherapy protocol. The mechanisms involved, however, mayinclude mast cell and basophil suppression, development of food-specific IgG4 antibodies, reduction inthe food-specific IgE/IgG4 ratio, up-regulation and expansion of natural or inducible regulatory T cells, askewing from a Th2 to a Th1 profile, and the development of anergy and/or deletion in antigen-specificcells. Additional studies are required to elucidate and understand these mechanisms by whichdesensitization and tolerance are achieved, which may reveal valuable biomarkers for evaluating andfollowing food allergic patients on immunotherapy.", "metadata": {}}
+{"_id": "18446525", "title": "", "text": "Prodromal non-motor symptoms of Parkinson’s diseaseThe motor symptoms of Parkinson’s disease (PD),bradykinesia, muscular rigidity, and tremor depend upon degeneration of the dopaminergic neurons inthe substantia nigra pars compacta. Recent neuropathological studies show that the Lewy bodies, theintraneuronal landmark of PD, accumulate in several neuronal cell types in the brain. An ascendinggradient of pathological involvement, from the medulla oblongata to neocortical areas has been reported.Thus the original view of PD as a disease characterized by selective damage of the dopaminergic neuronsin the mesencephalon should be updated into the concept of a severe multisystemic neurodegenerativedisorder. Additionally, the neuropathological alterations outside the substantia nigra are soundlycorrelated with the non-motor symptoms of PD. As a result of these findings, interest is growing in theidentification of prodromal non-motor symptoms of PD. Indeed, data from the literature suggest thatautonomic disturbances, olfactory dysfunctions, depression and sleep disorders (in particular REM-sleepbehavior disorder) may represent prodromal non-motor symptoms of PD. Several tests are available todetect most of these symptoms. Thus, the identification of prodromal non-motor symptoms maycontribute to the precocious diagnosis of PD, and might be useful in the future to test the efficacy ofneuroprotective agents.", "metadata": {}}
+{"_id": "18447487", "title": "", "text": "Erythroid Krüppel-Like Factor Directly Activates the Basic Krüppel-Like Factor Gene in Erythroid Cells\u0000The Sp/Krüppel-like factor (Sp/Klf) family is comprised of around 25 zinc finger transcription factorsthat recognize CACCC boxes and GC-rich elements. We have investigated basic Krüppel-like factor(Bklf/Klf3) and show that in erythroid tissues its expression is highly dependent on another familymember, erythroid Krüppel-like factor (Eklf/Klf1). We observe that Bklf mRNA is significantly reduced inerythroid tissues from Eklf-null murine embryos. We find that Bklf is driven primarily by two promoters, aubiquitously active GC-rich upstream promoter, 1a, and an erythroid downstream promoter, 1b.Transcripts from the two promoters encode identical proteins. Interestingly, both the ubiquitous and theerythroid promoter are dependent on Eklf in erythroid cells. Eklf also activates both promoters intransient assays. Experiments utilizing an inducible form of Eklf demonstrate activation of theendogenous Bklf gene in the presence of an inhibitor of protein synthesis. The kinetics of activation arealso consistent with Bklf being a direct Eklf target. Chromatin immunoprecipitation assays confirm thatEklf associates with both Bklf promoters. Eklf is typically an activator of transcription, whereas Bklf isnoted as a repressor. Our results support the hypothesis that feedback cross-regulation occurs within theSp/Klf family in vivo.", "metadata": {}}
+{"_id": "18450716", "title": "", "text": "Noncanonical Wnt Signaling Promotes Obesity-Induced Adipose Tissue Inflammation and MetabolicDysfunction Independent of Adipose Tissue ExpansionAdipose tissue dysfunction plays a pivotal role inthe development of insulin resistance in obese individuals. Cell culture studies and gain-of-functionmouse models suggest that canonical Wnt proteins modulate adipose tissue expansion. However, nogenetic evidence supports a role for endogenous Wnt proteins in adipose tissue dysfunction, and the roleof noncanonical Wnt signaling remains largely unexplored. Here we provide evidence from human,mouse, and cell culture studies showing that Wnt5a-mediated, noncanonical Wnt signaling contributes toobesity-associated metabolic dysfunction by increasing adipose tissue inflammation. Wnt5a expression issignificantly upregulated in human visceral fat compared with subcutaneous fat in obese individuals. Inobese mice, Wnt5a ablation ameliorates insulin resistance, in parallel with reductions in adipose tissueinflammation. Conversely, Wnt5a overexpression in myeloid cells augments adipose tissue inflammationand leads to greater impairments in glucose homeostasis. Wnt5a ablation or overexpression did not affectfat mass or adipocyte size. Mechanistically, Wnt5a promotes the expression of proinflammatory cytokinesby macrophages in a Jun NH2-terminal kinase-dependent manner, leading to defective insulin signaling inadipocytes. Exogenous interleukin-6 administration restores insulin resistance in obese Wnt5a-deficientmice, suggesting a central role for this cytokine in Wnt5a-mediated metabolic dysfunction. Takentogether, these results demonstrate that noncanonical Wnt signaling contributes to obesity-inducedinsulin resistance independent of adipose tissue expansion.", "metadata": {}}
+{"_id": "18467982", "title": "", "text": "A cluster of ribosome synthesis factors regulate pre-rRNA folding and 5.8S rRNA maturation by the Rat1exonucleaseThe 5'-exonuclease Rat1 degrades pre-rRNA spacer fragments and processes the 5'-ends ofthe 5.8S and 25S rRNAs. UV crosslinking revealed multiple Rat1-binding sites across the pre-rRNA,consistent with its known functions. The major 5.8S 5'-end is generated by Rat1 digestion of the internaltranscribed spacer 1 (ITS1) spacer from cleavage site A(3). Processing from A(3) requires the'A(3)-cluster' proteins, including Cic1, Erb1, Nop7, Nop12 and Nop15, which show interdependentpre-rRNA binding. Surprisingly, A(3)-cluster factors were not crosslinked close to site A(3), but boundsites around the 5.8S 3'- and 25S 5'-regions, which are base paired in mature ribosomes, and in the ITS2spacer that separates these rRNAs. In contrast, Nop4, a protein required for endonucleolytic cleavage inITS1, binds the pre-rRNA near the 5'-end of 5.8S. ITS2 was reported to undergo structural remodelling.In vivo chemical probing indicates that A(3)-cluster binding is required for this reorganization, potentiallyregulating the timing of processing. We predict that Nop4 and the A(3) cluster establish long-rangeinteractions between the 5.8S and 25S rRNAs, which are subsequently maintained by ribosomal proteinbinding.", "metadata": {}}
+{"_id": "18473550", "title": "", "text": "Synergistic activity of the histone deacetylase inhibitor suberoylanilide hydroxamic acid and thebisphosphonate zoledronic acid against prostate cancer cells in vitro.Bisphosphonates are widely usedagents for the treatment of malignant bone disease. They inhibit osteoclast-mediated bone resorptionand can have direct effects on cancer cells. In this study, we investigated whether the anticancer activityof the third-generation bisphosphonate zoledronic acid (ZOL) could be enhanced by combination with thehistone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA). We found that ZOL and SAHAcooperated to induce cell death in the prostate cancer cell lines LNCaP and PC-3. The effect wassynergistic, as evidenced by combination index isobologram analysis. ZOL and SAHA synergized to inducedissipation of the mitochondrial transmembrane potential, to activate caspase-3, and to trigger DNAfragmentation, showing that the combination of ZOL and SAHA resulted in the initiation of apoptosis.Because ZOL acts by inhibiting the mevalonate pathway, thereby preventing protein prenylation, weexplored whether the mevalonate pathway was also the target of the cooperative action of ZOL andSAHA. We found that geranylgeraniol, but not farnesol, significantly reduced ZOL/SAHA-induced celldeath, indicating that the synergistic action of the agents was due to the inhibition ofgeranylgeranylation. Consistently, a direct inhibitor of geranylgeranylation, GGTI-298, synergized withSAHA to induce cell death, whereas an inhibitor of farnesylation, FTI-277, had no effect. In addition,SAHA synergized with mevastatin, an inhibitor of the proximal enzyme in the mevalonate pathway. Thesein vitro findings provide a rationale for an in vivo exploration into the potential of combining SAHA andZOL, or other inhibitors of the mevalonate pathway, as an effective strategy for anticancer therapy.", "metadata": {}}
+{"_id": "18488986", "title": "", "text": "The Immune Response to Melanoma Is Limited by Thymic Selection of Self-AntigensThe expression ofmelanoma-associated antigens (MAA) being limited to normal melanocytes and melanomas, MAAs areideal targets for immunotherapy and melanoma vaccines. As MAAs are derived from self, immuneresponses to these may be limited by thymic tolerance. The extent to which self-tolerance preventsefficient immune responses to MAAs remains unknown. The autoimmune regulator (AIRE) controls theexpression of tissue-specific self-antigens in thymic epithelial cells (TECs). The level of antigensexpressed in the TECs determines the fate of auto-reactive thymocytes. Deficiency in AIRE leads in bothhumans (APECED patients) and mice to enlarged autoreactive immune repertoires. Here we showincreased IgG levels to melanoma cells in APECED patients correlating with autoimmune skin features.Similarly, the enlarged T cell repertoire in AIRE(-/-) mice enables them to mount anti-MAA andanti-melanoma responses as shown by increased anti-melanoma antibodies, and enhanced CD4(+) andMAA-specific CD8(+) T cell responses after melanoma challenge. We show that thymic expression ofgp100 is under the control of AIRE, leading to increased gp100-specific CD8(+) T cell frequencies inAIRE(-/-) mice. TRP-2 (tyrosinase-related protein), on the other hand, is absent from TECs andconsequently TRP-2 specific CD8(+) T cells were found in both AIRE(-/-) and AIRE(+/+) mice. This studyemphasizes the importance of investigating thymic expression of self-antigens prior to their inclusion invaccination and immunotherapy strategies.", "metadata": {}}
+{"_id": "18489989", "title": "", "text": "Murine embryonic stem cell differentiation is promoted by SOCS-3 and inhibited by the zinc fingertranscription factor Klf4.Embryonic stem (ES) cells homozygous for a Shp-2 mutation(Shp-2(Delta46-110)) demonstrate leukemia inhibitory factor (LIF) hypersensitivity and increasedLIF-stimulated phosphorylation of signal transducer and activator of transcription (STAT3). Wehypothesized that LIF-responsive genes in Shp-2(Delta46-110) cells would represent potential candidatesfor molecules vital for ES cell self-renewal. Using microarray analysis, we detected 41 genes whoseexpression was modified by LIF in Shp-2(Delta46-110) ES cells. Induction of 2 significantly up-regulatedgenes, suppressor of cytokine signaling-3 (SOCS-3) and Kruppel-like factor 4 (Klf4), was verified usingNorthern blotting. ES cells overexpressing SOCS-3 had an increased capacity to differentiate tohematopoietic progenitors, rather than to self-renew. In contrast, ES cells overexpressing Klf4 had agreater capacity to self-renew based on secondary embryoid body (EB) formation. Klf4-transduced d6EBs expressed higher levels of Oct-4, consistent with the notion that Klf4 promotes ES cell self-renewal.These findings verify the negative role of SOCS-3 on LIF signaling and provide a novel role for Klf4 in EScell function.", "metadata": {}}
+{"_id": "18494847", "title": "", "text": "MicroScope—an integrated microbial resource for the curation and comparative analysis of genomic andmetabolic dataMicroScope is an integrated platform dedicated to both the methodical updating ofmicrobial genome annotation and to comparative analysis. The resource provides data from completedand ongoing genome projects (automatic and expert annotations), together with data sources frompost-genomic experiments (i.e. transcriptomics, mutant collections) allowing users to perfect andimprove the understanding of gene functions. MicroScope (http://www.genoscope.cns.fr/agc/microscope)combines tools and graphical interfaces to analyse genomes and to perform the manual curation of geneannotations in a comparative context. Since its first publication in January 2006, the system (previouslynamed MaGe for Magnifying Genomes) has been continuously extended both in terms of data content andanalysis tools. The last update of MicroScope was published in 2009 in the Database journal. Today, theresource contains data for >1600 microbial genomes, of which \u0000300 are manually curated andmaintained by biologists (1200 personal accounts today). Expert annotations are continuously gatheredin the MicroScope database (\u000050 000 a year), contributing to the improvement of the quality of microbialgenomes annotations. Improved data browsing and searching tools have been added, original tools usefulin the context of expert annotation have been developed and integrated and the website has beensignificantly redesigned to be more user-friendly. Furthermore, in the context of the European projectMicrome (Framework Program 7 Collaborative Project), MicroScope is becoming a resource providing forthe curation and analysis of both genomic and metabolic data. An increasing number of projects arerelated to the study of environmental bacterial (meta)genomes that are able to metabolize a large varietyof chemical compounds that may be of high industrial interest.", "metadata": {}}
+{"_id": "18537148", "title": "", "text": "Comparison of Maximal Oxygen Consumption Between Black and White Prepubertal and PubertalChildrenThe purpose of this investigation was to determine whether maximal oxygen consumption(VO2max) differed between two selected groups of black and white children and whether a differenceexisted to determine whether it was related to hematologic profiles, body composition, and/or physicalactivity/inactivity level. Forty-five prepubertal and 42 pubertal, clinically normal black and white childrenparticipated. Dual-energy x-ray absorptiometry was used to determine body composition. A computedtomography scan of the abdomen was used to determine visceral adipose tissue and s.c. adipose tissue.Daily physical activity/inactivity was assessed by questionnaire. Black prepubertal and pubertal childrenhad lower VO2max values when compared with white children (28.8 ± 7.8 versus 35.0 ± 6.5 mL · kg−1 ·min−1, p < 0.01; 33.7 ± 6.4 versus 40.4 ± 10.2 mL · kg−1 · min−1, p < 0.05; respectively). Blackprepubertal and pubertal children had lower Hb concentrations ([Hb]) and hematocrits than whitechildren (prepubertal: 12.1 ± 0.5 versus 12.8 ± 0.9 g/dL, p < 0.001; 35.6 ± 1.4 versus 37.4 ± 2.3%, p< 0.01, respectively; pubertal: 13.0 ± 0.9 versus 13.6 ± 0.7 g/dL, p < 0.05; 37.7 ± 2.5 versus 39.5 ±2.1%, p < 0.05, respectively). In conclusion, these findings indicate that black prepubertal and pubertalchildren had lower VO2max when compared with their white peers matched for age, pubertal stage, andbody mass index. This difference in VO2max could be attributed at least in part to comparatively lower[Hb] and more sedentary lifestyle in the black children. Further investigations should study Hb flow rate(a function of [Hb] × maximal cardiac output) in black and white children as it relates to VO2max.", "metadata": {}}
+{"_id": "18546584", "title": "", "text": "Retinoic acid inhibits Th17 polarization and enhances FoxP3 expression through a Stat-3/Stat-5independent signaling pathway.CD4(+) helper T (Th) cells play a crucial role in the delicate balancebetween host defense and autoimmune disease. Two important populations of helper T cells are theproinflammatory, interleukin-17 (IL-17)-producing (Th17) cells and the anti-inflammatory forkhead boxP3-positive (FoxP3(+)) T regulatory (Treg) cells. Here we show that all-trans retinoic acid (ATRA) andother agonists of the retinoic acid receptor alpha (RARalpha) inhibit the formation of Th17 cells andpromote FoxP3 expression. Conversely, inhibition of retinoic acid signaling constrains transforminggrowth factor beta (TGF-beta1) induction of FoxP3. The effect of ATRA is mediated independently of IL-2,signal transducer and activator of transcription 5 (Stat5) and Stat3, representing a novel mechanism forthe induction of FoxP3 in CD4 T cells. As previous studies have shown that vitamin A derivatives areprotective in animal models of autoimmune disease, the current data suggest a previously unrecognizedrole for RARalpha in the regulation of CD4(+) T-cell differentiation and provide a mechanism for theanti-inflammatory effects of retinoic acid.", "metadata": {}}
+{"_id": "18557974", "title": "", "text": "British Journal of Nutrition (2003), 89, 295–301 q The Authors 2003 DOI: 10.1079/BJN2002776 Plasmahomocysteine concentration is decreased by dietary intervention*High plasma total homocysteine (tHcy)concentration is reported to be a risk factor for vascular diseases. We investigated the extent to whichserum folate and plasma tHcy respond to a high intake of natural folate from food. Thirty-seven healthyfemales volunteered t o participate in a crossover dietary intervention. The study included a baselineperiod and two 5-week diet periods (low- and high-folate diets) with a 3-week washout in between. Thelow-folate diet contained one serving of both vegetables and fruit/d, while during the high-folate diet thesubjects ate at least seven servings of vegetables, berries, and citrus fruit/d. Serum and erythrocyte(RBC) folate, serum vitamin B (12), and plasma tHcy concentrations were measured at the base-line andat the end of each diet period. The mean concentrations of serum and RBC folate were 11.0 (SD 3.0)nmol/l and 412 (SD 120) nmol/l at the end of the low-folate diet and 78 (95 % CI 62, 94) % and 14 (95% CI 8, 20) % higher in response to the high-folate diet (P< 0.001). The serum concentration of vitaminB12 remained unchanged during the intervention. The mean plasma tHcy concentration was 8.0 pmol/ atthe end of the low-folate diet and decreased by 13 (95% CI 9, 18) % in response to the high-folate diet(P<0.001). In conclusion, a diet high in fresh berries, citrus fruit, and vegetables effectively increasesserum and RBC folate and decreases plasma homocysteine.", "metadata": {}}
+{"_id": "18568804", "title": "", "text": "Achieving increased resolution and more pixels with Superresolution Optical Fluctuation Imaging(SOFI)Superresolution Optical Fluctuation Imaging (SOFI) as initially demonstrated allows for a resolutionenhancement in imaging by a factor of square-root of two. Here, we demonstrate how to increase theresolution of SOFI images by re-weighting the Optical Transfer Function (OTF). Furthermore, wedemonstrate how cross-cumulants can be exploited to obtain a fair approximation of the underlyingPoint-Spread Function. We show a two-fold increase of resolution (over the diffraction limit) ofnear-infrared quantum dot labeled tubulin-network of 3T3 fibroblasts.", "metadata": {}}
+{"_id": "18574146", "title": "", "text": "Evaluation of reagent strips in detecting asymptomatic bacteriuria in early pregnancy: prospective caseseries.OBJECTIVE To evaluate the performance of reagent test strips in screening pregnant women forasymptomatic bacteriuria at their first visit to an antenatal clinic. DESIGN Prospective case series.SETTING Antenatal clinic of a large inner city maternity hospital. SUBJECTS All women attending for theirfirst antenatal clinic. Patients taking antibiotics for any reason and those with urinary tract symptomswere excluded. INTERVENTION A midstream urine specimen was divided; half was sent for microscopyand formal bacteriological culture and the other half was tested with a commercial reagent strip test forthe presence of blood, protein, nitrite, and leucocyte esterase. MAIN OUTCOME MEASURES Sensitivity,specificity, and positive and negative predictive values of the reagent strips in diagnosing asymptomaticbacteriuria (defined as 10(5) colony forming units/ml urine). RESULTS Sensitivity was low, with amaximum of 33% when all four tests were used in combination. Specificity was high, with typical valuesof 99% or more. Positive predictive value reached a maximum of 69% and negative predictive value wastypically 95% or more. CONCLUSION Urine reagent strips are not sufficiently sensitive to be of use in thescreening for asymptomatic bacteriuria and therefore many patients would be missed. In view of thepotentially serious sequelae of this condition in pregnant women we recommend that formalbacteriological investigation remain the investigation of choice in this group of patients.", "metadata": {}}
+{"_id": "18575183", "title": "", "text": "Wnt5a functions in planar cell polarity regulation in mice.Planar cell polarity (PCP) refers to thepolarization of cells within the plane of a cell sheet. A distinctive epithelial PCP in vertebrates is theuniform orientation of stereociliary bundles of the sensory hair cells in the mammalian cochlea. Inaddition to establishing epithelial PCP, planar polarization is also required for convergent extension (CE);a polarized cellular movement that occurs during neural tube closure and cochlear extension. Studies inDrosophila and vertebrates have revealed a conserved PCP pathway, including Frizzled (Fz) receptors.Here we use the cochlea as a model system to explore the involvement of known ligands of Fz, Wntmorphogens, in PCP regulation. We show that Wnt5a forms a reciprocal expression pattern with a Wntantagonist, the secreted frizzled-related protein 3 (Sfrp3 or Frzb), along the axis of planar polarization inthe cochlear epithelium. We further demonstrate that Wnt5a antagonizes Frzb in regulating cochlearextension and stereociliary bundle orientation in vitro, and that Wnt5a(-/-) animals have a shortened andwidened cochlea. Finally, we show that Wnt5a is required for proper subcellular distribution of a PCPprotein, Ltap/Vangl2, and that Wnt5a interacts genetically with Ltap/Vangl2 for uniform orientation ofstereocilia, cochlear extension, and neural tube closure. Together, these findings demonstrate that Wnt5afunctions in PCP regulation in mice.", "metadata": {}}
+{"_id": "18576103", "title": "", "text": "The RNA Polymerase “Switch Region” Is a Target for InhibitorsThe alpha-pyrone antibiotic myxopyronin(Myx) inhibits bacterial RNA polymerase (RNAP). Here, through a combination of genetic, biochemical,and structural approaches, we show that Myx interacts with the RNAP \"switch region\"--the hinge thatmediates opening and closing of the RNAP active center cleft--to prevent interaction of RNAP withpromoter DNA. We define the contacts between Myx and RNAP and the effects of Myx on RNAPconformation and propose that Myx functions by interfering with opening of the RNAP active-center cleftduring transcription initiation. We further show that the structurally related alpha-pyrone antibioticcorallopyronin (Cor) and the structurally unrelated macrocyclic-lactone antibiotic ripostatin (Rip) functionanalogously to Myx. The RNAP switch region is distant from targets of previously characterized RNAPinhibitors, and, correspondingly, Myx, Cor, and Rip do not exhibit crossresistance with previouslycharacterized RNAP inhibitors. The RNAP switch region is an attractive target for identification of newbroad-spectrum antibacterial therapeutic agents.", "metadata": {}}
+{"_id": "18592108", "title": "", "text": "How reliable are light traps in estimating biting rates of adult Anopheles gambiae s.l. (Diptera: Culicidae)in the presence of treated bed nets?The sampling efficiency of light trap catches relative to human baitcatches in estimating biting rates of the mosquito Anopheles gambiae Giles was investigated in two typesof community in southern Sierra Leone: (i) where most of the inhabitants slept under treated bed nets;and (ii) where most of the inhabitants slept without bed nets. The number of female A. gambiaemosquitoes caught in these communities by light trap was strongly correlated (r > or = 0.72) with thosefrom corresponding human biting catches performed either on the same or adjacent nights. It was foundthat the relative sampling efficiency of light traps varied slightly but significantly with mosquitoabundance in villages with treated bed nets, but not in those without them. Nevertheless, the relationshipbetween relative sampling efficiency and mosquito abundance did not differ significantly between the twotypes of village. Overall, there was insufficient evidence to show that the presence of treated nets alteredthe relative efficiency of light traps and any bias was only slight, and unlikely to be of any practicalimportance. Hence, it was concluded that light traps can be used as a surrogate for human bait catches inestimating biting rates of A. gambiae mosquitoes in the two communities.", "metadata": {}}
+{"_id": "18600579", "title": "", "text": "Development of a novel mouse glioma model using lentiviral vectorsWe report the development of a newmethod to induce glioblastoma multiforme in adult immunocompetent mice by injectingCre-loxP–controlled lentiviral vectors expressing oncogenes. Cell type- or region-specific expression ofactivated forms of the oncoproteins Harvey-Ras and AKT in fewer than 60 glial fibrillary acidicprotein–positive cells in the hippocampus, subventricular zone or cortex of mice heterozygous for thegene encoding the tumor suppressor Tp53 were tested. Mice developed glioblastoma multiforme whentransduced either in the subventricular zone or the hippocampus. However, tumors were rarely detectedwhen the mice were transduced in the cortex. Transplantation of brain tumor cells into naive recipientmouse brain resulted in the formation of glioblastoma multiforme–like tumors, which contained CD133+cells, formed tumorspheres and could differentiate into neurons and astrocytes. We suggest that the useof Cre-loxP–controlled lentiviral vectors is a novel way to generate a mouse glioblastoma multiformemodel in a region- and cell type-specific manner in adult mice.", "metadata": {}}
+{"_id": "18617259", "title": "", "text": "Research LettersWe report a case of preclinical variant Creutzfeldt-Jakob disease (vCJD) in a patient whodied from a non-neurological disorder 5 years after receiving a blood transfusion from a donor whosubsequently developed vCJD. Protease-resistant prion protein (PrP(res)) was detected by western blot,paraffin-embedded tissue blot, and immunohistochemistry in the spleen, but not in the brain.Immunohistochemistry for prion protein was also positive in a cervical lymph node. The patient was aheterozygote at codon 129 of PRNP, suggesting that susceptibility to vCJD infection is not confined to themethionine homozygous PRNP genotype. These findings have major implications for future estimates andsurveillance of vCJD in the UK.", "metadata": {}}
+{"_id": "18639989", "title": "", "text": "Swi1Timeless Prevents Repeat Instability at Fission Yeast TelomeresGenomic instability associated withDNA replication stress is linked to cancer and genetic pathologies in humans. If not properly regulated,replication stress, such as fork stalling and collapse, can be induced at natural replication impedimentspresent throughout the genome. The fork protection complex (FPC) is thought to play a critical role instabilizing stalled replication forks at several known replication barriers including eukaryotic rDNA genesand the fission yeast mating-type locus. However, little is known about the role of the FPC at othernatural impediments including telomeres. Telomeres are considered to be difficult to replicate due to thepresence of repetitive GT-rich sequences and telomere-binding proteins. However, the regulatorymechanism that ensures telomere replication is not fully understood. Here, we report the role of thefission yeast Swi1(Timeless), a subunit of the FPC, in telomere replication. Loss of Swi1 causes telomereshortening in a telomerase-independent manner. Our epistasis analyses suggest that heterochromatinand telomere-binding proteins are not major impediments for telomere replication in the absence of Swi1.Instead, repetitive DNA sequences impair telomere integrity in swi1Δ mutant cells, leading to the loss ofrepeat DNA. In the absence of Swi1, telomere shortening is accompanied with an increased recruitmentof Rad52 recombinase and more frequent amplification of telomere/subtelomeres, reminiscent of tumorcells that utilize the alternative lengthening of telomeres pathway (ALT) to maintain telomeres. Theseresults suggest that Swi1 ensures telomere replication by suppressing recombination and repeatinstability at telomeres. Our studies may also be relevant in understanding the potential role ofSwi1(Timeless) in regulation of telomere stability in cancer cells.", "metadata": {}}
+{"_id": "18654430", "title": "", "text": "Prediction of guide strand of microRNAs from its sequence and secondary structureBACKGROUNDMicroRNAs (miRNAs) are produced by the sequential processing of a long hairpin RNA transcript byDrosha and Dicer, an RNase III enzymes, and form transitory small RNA duplexes. One strand of theduplex, which incorporates into RNA-induced silencing complex (RISC) and silences the gene expressionis called guide strand, or miRNA; while the other strand of duplex is degraded and called the passengerstrand, or miRNA*. Predicting the guide strand of miRNA is important for better understanding the RNAinterference pathways. RESULTS This paper describes support vector machine (SVM) models developedfor predicting the guide strands of miRNAs. All models were trained and tested on a dataset consisting of329 miRNA and 329 miRNA* pairs using five fold cross validation technique. Firstly, models weredeveloped using mono-, di-, and tri-nucleotide composition of miRNA strands and achieved the highestaccuracies of 0.588, 0.638 and 0.596 respectively. Secondly, models were developed using splitnucleotide composition and achieved maximum accuracies of 0.553, 0.641 and 0.602 for mono-, di-, andtri-nucleotide respectively. Thirdly, models were developed using binary pattern and achieved the highestaccuracy of 0.708. Furthermore, when integrating the secondary structure features with binary pattern,an accuracy of 0.719 was seen. Finally, hybrid models were developed by combining various features andachieved maximum accuracy of 0.799 with sensitivity 0.781 and specificity 0.818. Moreover, theperformance of this model was tested on an independent dataset that achieved an accuracy of 0.80. Inaddition, we also compared the performance of our method with various siRNA-designing methods onmiRNA and siRNA datasets. CONCLUSION In this study, first time a method has been developed topredict guide miRNA strands, of miRNA duplex. This study demonstrates that guide and passenger strandof miRNA precursors can be distinguished using their nucleotide sequence and secondary structure. Thismethod will be useful in understanding microRNA processing and can be implemented in RNA silencingtechnology to improve the biological and clinical research. A web server has been developed based onSVM models described in this study (http://crdd.osdd.net:8081/RISCbinder/).", "metadata": {}}
+{"_id": "18662787", "title": "", "text": "NIPBL, encoding a homolog of fungal Scc2-type sister chromatid cohesion proteins and fly Nipped-B, ismutated in Cornelia de Lange syndromeCornelia de Lange syndrome (CdLS) is a multiple malformationdisorder characterized by dysmorphic facial features, mental retardation, growth delay and limb reductiondefects. We indentified and characterized a new gene, NIPBL, that is mutated in individuals with CdLSand determined its structure and the structures of mouse, rat and zebrafish homologs. We named itsprotein product delangin. Vertebrate delangins have substantial homology to orthologs in flies, worms,plants and fungi, including Scc2-type sister chromatid cohesion proteins, and D. melanogaster Nipped-B.We propose that perturbed delangin function may inappropriately activate DLX genes, therebycontributing to the proximodistal limb patterning defects in CdLS. Genome analyses typically identifyindividual delangin or Nipped-B-like orthologs in diploid animal and plant genomes. The evolution of anancestral sister chromatid cohesion protein to acquire an additional role in developmental gene regulationsuggests that there are parallels between CdLS and Roberts syndrome.", "metadata": {}}
+{"_id": "18676539", "title": "", "text": "Impaired FANCD2 monoubiquitination and hypersensitivity to camptothecin uniquely characterize Fanconianemia complementation group M.FANCM is a component of the Fanconi anemia (FA) core complex andone FA patient (EUFA867) with biallelic mutations in FANCM has been described. Strikingly, we found thatEUFA867 also carries biallelic mutations in FANCA. After correcting the FANCA defect in EUFA867lymphoblasts, a \"clean\" FA-M cell line was generated. These cells were hypersensitive to mitomycin C,but unlike cells defective in other core complex members, FANCM(-/-) cells were proficient inmonoubiquitinating FANCD2 and were sensitive to the topoisomerase inhibitor camptothecin, a featureshared only with the FA subtype D1 and N. In addition, FANCM(-/-) cells were sensitive to UV light.FANCM and a C-terminal deletion mutant rescued the cross-linker sensitivity of FANCM(-/-) cells, whereasa FANCM ATPase mutant did not. Because both mutants restored the formation of FANCD2 foci, weconclude that FANCM functions in an FA core complex-dependent and -independent manner.", "metadata": {}}
+{"_id": "18678095", "title": "", "text": "Vesicular Glycolysis Provides On-Board Energy for Fast Axonal TransportFast axonal transport (FAT)requires consistent energy over long distances to fuel the molecular motors that transport vesicles. Wedemonstrate that glycolysis provides ATP for the FAT of vesicles. Although inhibiting ATP production frommitochondria did not affect vesicles motility, pharmacological or genetic inhibition of the glycolyticenzyme GAPDH reduced transport in cultured neurons and in Drosophila larvae. GAPDH localizes onvesicles via a huntingtin-dependent mechanism and is transported on fast-moving vesicles within axons.Purified motile vesicles showed GAPDH enzymatic activity and produced ATP. Finally, we show thatvesicular GAPDH is necessary and sufficient to provide on-board energy for fast vesicular transport.Although detaching GAPDH from vesicles reduced transport, targeting GAPDH to vesicles was sufficient topromote FAT in GAPDH deficient neurons. This specifically localized glycolytic machinery may supplyconstant energy, independent of mitochondria, for the processive movement of vesicles over longdistances in axons.", "metadata": {}}
+{"_id": "18682109", "title": "", "text": "RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancerTyrosinekinase inhibitors are effective treatments for non-small-cell lung cancers (NSCLCs) with epidermal growthfactor receptor (EGFR) mutations. However, relapse typically occurs after an average of 1 year ofcontinuous treatment. A fundamental histological transformation from NSCLC to small-cell lung cancer(SCLC) is observed in a subset of the resistant cancers, but the molecular changes associated with thistransformation remain unknown. Analysis of tumour samples and cell lines derived from resistant EGFRmutant patients revealed that Retinoblastoma (RB) is lost in 100% of these SCLC transformed cases, butrarely in those that remain NSCLC. Further, increased neuroendocrine marker and decreased EGFRexpression as well as greater sensitivity to BCL2 family inhibition are observed in resistant SCLCtransformed cancers compared with resistant NSCLCs. Together, these findings suggest that this subsetof resistant cancers ultimately adopt many of the molecular and phenotypic characteristics of classicalSCLC.", "metadata": {}}
+{"_id": "18691097", "title": "", "text": "Periostin Deficiency Increases Bone Damage and Impairs Injury Response to Fatigue Loading in AdultMiceBone damage removal and callus formation in response to fatigue loading are essential to preventfractures. Periostin (Postn) is a matricellular protein that mediates adaptive response of cortical bone toloading. Whether and how periostin influences damage and the injury response to fatigue remainsunknown. We investigated the skeletal response of Postn(-/-) and Postn(+/+) mice after fatigue stimulusby axial compression of their tibia. In Postn(+/+) mice, cracks number and surface (CsNb, CsS)increased 1h after fatigue, with a decrease in strength compared to non-fatigued tibia. At 15 days, CsNbhad started to decline, while CtTV and CtBV increased in fatigued vs non-fatigued tibia, reflecting awoven bone response that was present in 75% of the fatigued bones. Cortical porosity and remodellingalso prominently increased in the fatigued tibia of Postn(+/+) mice. At 30 days, paralleling a continuousremoval of cortical damage, strength of the fatigued tibia was similar to the non-fatigue tibia. InPostn(-/-) mice, cracks were detectable even in the absence of fatigue, while the amount of collagencrosslinks and tissue hardness was decreased compared to Postn(+/+). Fatigue significantly increasedCsNb and CsS in Postn(-/-), but was not associated with changes in CtTV and CtBV, as only 16% of thefatigued bones formed some woven bone. Cortical porosity and remodelling did not increase either afterfatigue in Postn(-/-), and the level of damage remained high even after 30 days. As a result, strengthremained compromised in Postn(-/-) mice. Contrary to Postn(+/+), which osteocytic lacunae showed achange in the degree of anisotropy (DA) after fatigue, Postn(-/-) showed no DA change. Hence periostinappears to influence bone materials properties, damage accumulation and repair, including localmodeling/remodeling processes in response to fatigue. These observations suggest that the level ofperiostin expression could influence the propensity to fatigue fractures.", "metadata": {}}
+{"_id": "18694784", "title": "", "text": "Preferential occupancy of histone variant H2AZ at inactive promoters influences local histonemodifications and chromatin remodeling.The yeast histone variant H2AZ (Htz1) is implicated intranscription activation, prevention of the ectopic spread of heterochromatin, and genome integrity. Ourgenome-wide localization analysis revealed that Htz1 is widely, but nonrandomly, distributed throughoutthe genome in an SWR1-dependent manner. We found that Htz1 is enriched in intergenic regionscompared with coding regions. Its occupancy is inversely proportional to transcription rates and theenrichment of the RNA polymerase II under different growth conditions. However, Htz1 does not seem todirectly regulate transcription repression genome-wide; instead, the presence of Htz1 under theinactivated condition is essential for optimal activation of a subset of genes. In addition, Htz1 is notgenerally responsible for nucleosome positioning, even at those promoters where Htz1 is highly enriched.Finally, using a biochemical approach, we demonstrate that incorporation of Htz1 into nucleosomesinhibits activities of histone modifiers associated with transcription, Dot1, Set2, and NuA4 and reducesthe nucleosome mobilization driven by chromatin remodeling complexes. These lines of evidencecollectively suggest that Htz1 may serve to mark quiescent promoters for proper activation.", "metadata": {}}
+{"_id": "18695970", "title": "", "text": "Genomic organisation and transcription characterisation of the gene encoding Leishmania (Leishmania)amazonensis arginase and its protein structure prediction.The genomic organisation of the gene encodingLeishmania (Leishmania) amazonensis arginase as well as its flanking regions were characterised. Thesize of the transcribed RNA was determined, allowing us to map the genomic sites signalling for RNAtrans-splicing and putative polyadenylation regions. The general organisation was compared with genesencoding other proteins already described in organisms of the Trypanosomatid family. The completenucleotide sequence of the arginase open reading frame was obtained and the three-dimensionalstructure of the enzyme was inferred by a computational analysis of the deduced amino acid sequence,based on the established crystal structure described for Rattus norvergicus arginase. The human liverarginase sequence was analysed in the same way and the comparison of the presumed structure of boththe Leishmania and human enzymes identified some differences that may be exploited inchemotherapeutic studies.", "metadata": {}}
+{"_id": "18734652", "title": "", "text": "Endometrial carcinoma risk among women diagnosed with endometrial hyperplasia: the 34-yearexperience in a large health planClassifying endometrial hyperplasia (EH) according to the severity ofglandular crowding (simple hyperplasia (SH) vs complex hyperplasia (CH)) and nuclear atypia (simpleatypical hyperplasia (SAH) vs complex atypical hyperplasia (CAH)) should predict subsequent endometrialcarcinoma risk, but data on progression are lacking. Our nested case–control study of EH progressionincluded 138 cases, who were diagnosed with EH and then with carcinoma (1970–2003) at least 1 year(median, 6.5 years) later, and 241 controls, who were individually matched on age, date, and follow-upduration and counter-matched on EH classification. After centralised pathology panel and medical recordreview, we generated rate ratios (RRs) and 95% confidence intervals (CIs), adjusted for treatment andrepeat biopsies. With disordered proliferative endometrium (DPEM) as the referent, AH significantlyincreased carcinoma risk (RR=14, 95% CI, 5–38). Risk was highest 1–5 years after AH (RR=48, 95% CI,8–294), but remained elevated 5 or more years after AH (RR=3.5, 95% CI, 1.0–9.6). Progression risksfor SH (RR=2.0, 95% CI, 0.9–4.5) and CH (RR=2.8, 95% CI, 1.0–7.9) were substantially lower and onlyslightly higher than the progression risk for DPEM. The higher progression risks for AH could fostermanagement guidelines based on markedly different progression risks for atypical vs non-atypical EH.", "metadata": {}}
+{"_id": "18747744", "title": "", "text": "Redefining the Genetic Hierarchies Controlling Skeletal Myogenesis: Pax-3 and Myf-5 Act Upstream ofMyoDWe analyzed Pax-3 (splotch), Myf-5 (targeted with nlacZ), and splotch/Myf-5 homozygous mutantmice to investigate the roles that these genes play in programming skeletal myogenesis. In splotch andMyf-5 homozygous embryos, myogenic progenitor cell perturbations and early muscle defects aredistinct. Remarkably, splotch/Myf-5 double homozygotes have a dramatic phenotype not seen in theindividual mutants: body muscles are absent. MyoD does not rescue this double mutant phenotype sinceactivation of this gene proves to be dependent on either Pax-3 or Myf-5. Therefore, Pax-3 and Myf-5define two distinct myogenic pathways, and MyoD acts genetically downstream of these genes formyogenesis in the body. This genetic hierarchy does not appear to operate for head muscle formation.", "metadata": {}}
+{"_id": "18750453", "title": "", "text": "Assessment of Volume Depletion in Children with MalariaBackground The degree of volume depletion insevere malaria is currently unknown, although knowledge of fluid compartment volumes can guidetherapy. To assist management of severely ill children, and to test the hypothesis that volume changes influid compartments reflect disease severity, we measured body compartment volumes in Gabonesechildren with malaria. Methods and Findings Total body water volume (TBW) and extracellular watervolume (ECW) were estimated in children with severe or moderate malaria and in convalescence bytracer dilution with heavy water and bromide, respectively. Intracellular water volume (ICW) was derivedfrom these parameters. Bioelectrical impedance analysis estimates of TBW and ECW were calibratedagainst dilution methods, and bioelectrical impedance analysis measurements were taken daily untildischarge. Sixteen children had severe and 19 moderate malaria. Severe childhood malaria wasassociated with depletion of TBW (mean [SD] of 37 [33] ml/kg, or 6.7% [6.0%]) relative tomeasurement at discharge. This is defined as mild dehydration in other conditions. ECW measurementswere normal on admission in children with severe malaria and did not rise in the first few days ofadmission. Volumes in different compartments (TBW, ECW, and ICW) were not related tohyperlactataemia or other clinical and laboratory markers of disease severity. Moderate malaria was notassociated with a depletion of TBW.", "metadata": {}}
+{"_id": "18758057", "title": "", "text": "NSOM/QD-Based Direct Visualization of CD3-Induced and CD28-Enhanced Nanospatial Coclustering ofTCR and Coreceptor in Nanodomains in T Cell ActivationDirect molecular imaging of nano-spatialrelationship between T cell receptor (TCR)/CD3 and CD4 or CD8 co-receptor before and after activation ofa primary T cell has not been reported. We have recently innovated application of near-field scanningoptical microscopy (NSOM) and immune-labeling quantum dots (QD) to image Ag-specific TCR responseduring in vivo clonal expansion, and now up-graded the NSOM/QD-based nanotechnology throughdipole-polarization and dual-color imaging. Using this imaging system scanning cell-membrane moleculesat a best-optical lateral resolution, we demonstrated that CD3, CD4 or CD8 molecules were distinctlydistributed as single QD-bound molecules or nano-clusters equivalent to 2-4 QDfluorescence-intensity/size on cell-membrane of un-stimulated primary T cells, and approximately 6-10%of CD3 were co-clustering with CD4 or CD8 as 70-110 nm nano-clusters without forming nano-domains.The ligation of TCR/CD3 on CD4 or CD8 T cells led to CD3 nanoscale co-clustering or interaction with CD4or CD8 co-receptors forming 200-500 nm nano-domains or >500 nm micro-domains. Such nano-spatialco-clustering of CD3 and CD4 or CD3 and CD8 appeared to be an intrinsic event of TCR/CD3 ligation, notpurely limited to MHC engagement, and be driven by Lck phosphorylation. Importantly, CD28co-stimulation remarkably enhanced TCR/CD3 nanoscale co-clustering or interaction with CD4co-receptor within nano- or micro-domains on the membrane. In contrast, CD28 co-stimulation did notenhance CD8 clustering or CD3-CD8 co-clustering in nano-domains although it increased molecularnumber and density of CD3 clustering in the enlarged nano-domains. These nanoscale findings providenew insights into TCR/CD3 interaction with CD4 or CD8 co-receptor in T-cell activation.", "metadata": {}}
+{"_id": "18806488", "title": "", "text": "Hoxa9 transforms primary bone marrow cells through specific collaboration with Meis1a but notPbx1b.Hoxa9, Meis1 and Pbx1 encode homeodomaincontaining proteins implicated in leukemictransformation in both mice and humans. Hoxa9, Meis1 and Pbx1 proteins have been shown to physicallyinteract with each other, as Hoxa9 cooperatively binds consensus DNA sequences with Meis1 and withPbx1, while Meis1 and Pbx1 form heterodimers in both the presence and absence of DNA. In this study,we sought to determine if Hoxa9 could transform hemopoietic cells in collaboration with either Pbx1 orMeis1. Primary bone marrow cells, retrovirally engineered to overexpress Hoxa9 and Meis1asimultaneously, induced growth factor-dependent oligoclonal acute myeloid leukemia in <3 months whentransplanted into syngenic mice. In contrast, overexpression of Hoxa9, Meis1a or Pbx1b alone, or thecombination of Hoxa9 and Pbx1b failed to transform these cells acutely within 6 monthspost-transplantation. Similar results were obtained when FDC-P1 cells, engineered to overexpress thesegenes, were transplanted to syngenic recipients. Thus, these studies demonstrate a selectivecollaboration between a member of the Hox family and one of its DNA-binding partners in transformationof hemopoietic cells.", "metadata": {}}
+{"_id": "18810195", "title": "", "text": "Tyr26 phosphorylation of PGAM1 provides a metabolic advantage to tumours by stabilizing the activeconformationHow oncogenic signalling coordinates glycolysis and anabolic biosynthesis in cancer cellsremains unclear. We recently reported that the glycolytic enzyme phosphoglycerate mutase 1 (PGAM1)regulates anabolic biosynthesis by controlling intracellular levels of its substrate 3-phosphoglycerate andproduct 2-phosphoglycerate. Here we report a novel mechanism in which Y26 phosphorylation enhancesPGAM1 activation through release of inhibitory E19 that blocks the active site, stabilising cofactor2,3-bisphosphoglycerate binding and H11 phosphorylation. We also report the crystal structure ofH11-phosphorylated PGAM1 and find that phospho-H11 activates PGAM1 at least in part by promotingsubstrate 3-phosphoglycerate binding. Moreover, Y26 phosphorylation of PGAM1 is common in humancancer cells and contributes to regulation of 3-phosphoglycerate and 2-phosphoglycerate levels,promoting cancer cell proliferation and tumour growth. As PGAM1 is a negative transcriptional target ofTP53, and is therefore commonly upregulated in human cancers, these findings suggest that Y26phosphorylation represents an additional acute mechanism underlying phosphoglycerate mutase 1upregulation.", "metadata": {}}
+{"_id": "18816720", "title": "", "text": "Spatial and Temporal Clustering of Dengue Virus Transmission in Thai VillagesBACKGROUNDTransmission of dengue viruses (DENV), the leading cause of arboviral disease worldwide, is known tovary through time and space, likely owing to a combination of factors related to the human host, virus,mosquito vector, and environment. An improved understanding of variation in transmission patterns isfundamental to conducting surveillance and implementing disease prevention strategies. To test thehypothesis that DENV transmission is spatially and temporally focal, we compared geographic andtemporal characteristics within Thai villages where DENV are and are not being actively transmitted.METHODS AND FINDINGS Cluster investigations were conducted within 100 m of homes where febrileindex children with (positive clusters) and without (negative clusters) acute dengue lived during twoseasons of peak DENV transmission. Data on human infection and mosquito infection/density wereexamined to precisely (1) define the spatial and temporal dimensions of DENV transmission, (2) correlatethese factors with variation in DENV transmission, and (3) determine the burden of inapparent andsymptomatic infections. Among 556 village children enrolled as neighbors of 12 dengue-positive and 22dengue-negative index cases, all 27 DENV infections (4.9% of enrollees) occurred in positive clusters (p< 0.01; attributable risk [AR] = 10.4 per 100; 95% confidence interval 1-19.8 per 100]. In positiveclusters, 12.4% of enrollees became infected in a 15-d period and DENV infections were aggregatedcentrally near homes of index cases. As only 1 of 217 pairs of serologic specimens tested in positiveclusters revealed a recent DENV infection that occurred prior to cluster initiation, we attribute theobserved DENV transmission subsequent to cluster investigation to recent DENV transmission activity. Ofthe 1,022 female adult Ae. aegypti collected, all eight (0.8%) dengue-infected mosquitoes came fromhouses in positive clusters; none from control clusters or schools. Distinguishing features betweenpositive and negative clusters were greater availability of piped water in negative clusters (p < 0.01) andgreater number of Ae. aegypti pupae per person in positive clusters (p = 0.04). During primarily DENV-4transmission seasons, the ratio of inapparent to symptomatic infections was nearly 1:1 among childenrollees. Study limitations included inability to sample all children and mosquitoes within each clusterand our reliance on serologic rather than virologic evidence of interval infections in enrollees givenrestrictions on the frequency of blood collections in children. CONCLUSIONS Our data reveal theremarkably focal nature of DENV transmission within a hyperendemic rural area of Thailand. These datasuggest that active school-based dengue case detection prompting local spraying could contain recentvirus introductions and reduce the longitudinal risk of virus spread within rural areas. Our results shouldprompt future cluster studies to explore how host immune and behavioral aspects may impact DENVtransmission and prevention strategies. Cluster methodology could serve as a useful research tool forinvestigation of other temporally and spatially clustered infectious diseases.", "metadata": {}}
+{"_id": "18834078", "title": "", "text": "Secondary T cell–T cell synaptic interactions drive the differentiation of protective CD8+ TcellsImmunization results in the differentiation of CD8+ T cells, such that they acquire effector abilitiesand convert into a memory pool. Priming of T cells takes place via an immunological synapse formed withan antigen-presenting cell (APC). By disrupting synaptic stability at different times, we found that thedifferentiation of CD8+ T cells required cell interactions beyond those made with APCs. We identified acritical differentiation period that required interactions between primed T cells. We found that T cell–T cellsynapses had a major role in the generation of protective CD8+ T cell memory. T cell–T cell synapsesallowed T cells to polarize critical secretion of interferon-γ (IFN-γ) toward each other. Collective activationand homotypic clustering drove cytokine sharing and acted as regulatory stimuli for T cell differentiation.", "metadata": {}}
+{"_id": "18841257", "title": "", "text": "The Histone H3 Lysine-27 Demethylase Jmjd3 Links Inflammation to Inhibition of Polycomb-MediatedGene SilencingEpigenetic chromatin marks restrict the ability of differentiated cells to change geneexpression programs in response to environmental cues and to transdifferentiate. Polycomb group (PcG)proteins mediate gene silencing and repress transdifferentiation in a manner dependent on histone H3lysine 27 trimethylation (H3K27me3). However, macrophages migrated into inflamed tissues cantransdifferentiate, but it is unknown whether inflammation alters PcG-dependent silencing. Here we showthat the JmjC-domain protein Jmjd3 is a H3K27me demethylase expressed in macrophages in responseto bacterial products and inflammatory cytokines. Jmjd3 binds PcG target genes and regulates theirH3K27me3 levels and transcriptional activity. The discovery of an inducible enzyme that erases a histonemark controlling differentiation and cell identity provides a link between inflammation andreprogramming of the epigenome, which could be the basis for macrophage plasticity and might explainthe differentiation abnormalities in chronic inflammation.", "metadata": {}}
+{"_id": "18852643", "title": "", "text": "Apolipoprotein E and atherosclerosis: beyond lipid effect.In humans, apolipoprotein E (apoE) is apolymorphic multifunctional protein.1 It is coded by three alleles (e2, e3, e4) of a modulator gene (level,variability, and susceptibility gene) at the apoE locus on chromosome 19, determining six apoE genotypesand plasma phenotypes. Its pleiotropic effects are exerted on plasma lipoprotein metabolism,coagulation, oxidative processes, macrophage, glial cell and neuronal cell homeostasis, adrenal function,central nervous system physiology, inflammation, and cell proliferation.2,3 ApoE polymorphismmodulates susceptibility to many diseases. It is, however, particularly notorious for its role inneurodegenerative disorders4 and atherosclerotic arterial disease.5,6 The e4 allele (phenotypes E4/4 andE4/3) that is associated with higher low density lipoprotein cholesterol (LDL-C) is consideredproatherogenic, whereas the presence of the e2 allele (E3/2, E2/2), being associated with lower LDL-Clevels, is deemed to have the opposite effect (although it may be associated with increased plasmatriglycerides and lipoprotein remnants). This simple equation, however, is an oversimplification becausethese properties are subject to many environmental and genetic influences. ApoE has allele- andgender-dependent effects on reverse cholesterol transport, platelet aggregation, and oxidative processesthat are likely to affect the overall atherogenic potential ascribed to modulation of lipoproteinmetabolism.2,3,6 Notwithstanding the context dependency, a recent meta-analysis fully supports thepresence of the e4 allele as a significant risk factor for coronary artery disease.7 Several mechanismshave been evoked to link apoE with atherosclerosis, but the relationship is not fully unraveled in humans.Nevertheless, some apoE mimetic peptides that promote LDL clearance are currently tested in animals forpotential clinical applications.8,9  See page 436   The situation is relatively simpler in animals. The mousemodel has been prominently useful to test mechanisms …", "metadata": {}}
+{"_id": "18855191", "title": "", "text": "Exploitative and Hierarchical Antagonism in a Cooperative BacteriumSocial organisms that cooperate withsome members of their own species, such as close relatives, may fail to cooperate with other genotypesof the same species. Such noncooperation may take the form of outright antagonism or socialexploitation. Myxococcus xanthus is a highly social prokaryote that cooperatively develops intospore-bearing, multicellular fruiting bodies in response to starvation. Here we have characterized thenature of social interactions among nine developmentally proficient strains of M. xanthus isolated fromspatially distant locations. Strains were competed against one another in all possible pairwisecombinations during starvation-induced development. In most pairings, at least one competitor exhibitedstrong antagonism toward its partner and a majority of mixes showed bidirectional antagonism thatdecreased total spore production, even to the point of driving whole populations to extinction. Differentialresponse to mixing was the primary determinant of competitive superiority rather than the sporulationefficiencies of unmixed populations. In some competitive pairings, the dominant partner sporulated moreefficiently in mixed populations than in clonal isolation. This finding represents a novel form ofexploitation in bacteria carried out by socially competent genotypes and is the first documentation ofsocial exploitation among natural bacterial isolates. Patterns of antagonistic superiority among thesestrains form a highly linear dominance hierarchy. At least some competition pairs construct chimeric,rather than segregated, fruiting bodies. The cooperative prokaryote M. xanthus has diverged into a largenumber of distinct social types that cooperate with clone-mates but exhibit intense antagonism towarddistinct social types of the same species. Most lengthy migration events in nature may thus result instrong antagonism between migratory and resident populations, and this antagonism may have largeeffects on local population sizes and dynamics. Intense mutual antagonism appears to be more prevalentin this prokaryotic social species than has been observed in the eukaryotic social slime moldDictyostelium discoideum, which also exhibits multicellular development. The finding of several cases offacultative social exploitation among these natural isolates suggests that such exploitation may occurfrequently in nature in many prokaryotes with cooperative traits.", "metadata": {}}
+{"_id": "18872233", "title": "", "text": "Mental Health Conditions Among Patients Seeking and Undergoing Bariatric Surgery: AMeta-analysis.IMPORTANCE Bariatric surgery is associated with sustained weight loss and improvedphysical health status for severely obese individuals. Mental health conditions may be common amongpatients seeking bariatric surgery; however, the prevalence of these conditions and whether they areassociated with postoperative outcomes remains unknown. OBJECTIVE To determine the prevalence ofmental health conditions among bariatric surgery candidates and recipients, to evaluate the associationbetween preoperative mental health conditions and health outcomes following bariatric surgery, and toevaluate the association between surgery and the clinical course of mental health conditions. DATASOURCES We searched PubMed, MEDLINE on OVID, and PsycINFO for studies published between January1988 and November 2015. Study quality was assessed using an adapted tool for risk of bias; quality ofevidence was rated based on GRADE (Grading of Recommendations Assessment, Development andEvaluation) criteria. FINDINGS We identified 68 publications meeting inclusion criteria: 59 reporting theprevalence of preoperative mental health conditions (65,363 patients) and 27 reporting associationsbetween preoperative mental health conditions and postoperative outcomes (50,182 patients). Amongpatients seeking and undergoing bariatric surgery, the most common mental health conditions, based onrandom-effects estimates of prevalence, were depression (19% [95% CI, 14%-25%]) and binge eatingdisorder (17% [95% CI, 13%-21%]). There was conflicting evidence regarding the association betweenpreoperative mental health conditions and postoperative weight loss. Neither depression nor binge eatingdisorder was consistently associated with differences in weight outcomes. Bariatric surgery was, however,consistently associated with postoperative decreases in the prevalence of depression (7 studies; 8%-74%decrease) and the severity of depressive symptoms (6 studies; 40%-70% decrease). CONCLUSIONS ANDRELEVANCE Mental health conditions are common among bariatric surgery patients-in particular,depression and binge eating disorder. There is inconsistent evidence regarding the association betweenpreoperative mental health conditions and postoperative weight loss. Moderate-quality evidence supportsan association between bariatric surgery and lower rates of depression postoperatively.", "metadata": {}}
+{"_id": "18882947", "title": "", "text": "The Nuclear Effector of Wnt-Signaling, Tcf1, Functions as a T-Cell–Specific Tumor Suppressor forDevelopment of LymphomasThe HMG-box factor Tcf1 is required during T-cell development in the thymusand mediates the nuclear response to Wnt signals. Tcf1(-/-) mice have previously been characterized andshow developmental blocks at the CD4-CD8- double negative (DN) to CD4+CD8+ double positivetransition. Due to the blocks in T-cell development, Tcf1(-/-) mice normally have a very small thymus.Unexpectedly, a large proportion of Tcf1(-/-) mice spontaneously develop thymic lymphomas with 50% ofmice developing a thymic lymphoma/leukemia at the age of 16 wk. These lymphomas are clonal, highlymetastatic, and paradoxically show high Wnt signaling when crossed with Wnt reporter mice and havehigh expression of Wnt target genes Lef1 and Axin2. In wild-type thymocytes, Tcf1 is higher expressedthan Lef1, with a predominance of Wnt inhibitory isoforms. Loss of Tcf1 as repressor of Lef1 leads to highWnt activity and is the initiating event in lymphoma development, which is exacerbated by activatingNotch1 mutations. Thus, Notch1 and loss of Tcf1 functionally act as collaborating oncogenic events. Tcf1deficiency predisposes to the development of thymic lymphomas by ectopic up-regulation of Lef1 due tolack of Tcf1 repressive isoforms and frequently by cooperating activating mutations in Notch1. Tcf1therefore functions as a T-cell-specific tumor suppressor gene, besides its established role as a Wntresponsive transcription factor. Thus, Tcf1 acts as a molecular switch between proliferative andrepressive signals during T-lymphocyte development in the thymus.", "metadata": {}}
+{"_id": "18895793", "title": "", "text": "Activator Control of Nucleosome Occupancy in Activation and Repression of TranscriptionThe relationshipbetween chromatin structure and gene expression is a subject of intense study. The universaltranscriptional activator Gal4 removes promoter nucleosomes as it triggers transcription, but how it doesso has remained obscure. The reverse process, repression of transcription, has often been correlated withthe presence of nucleosomes. But it is not known whether nucleosomes are required for that effect. Anew quantitative assay describes, for any given location, the fraction of DNA molecules in the populationthat bears a nucleosome at any given instant. This allows us to follow the time courses of nucleosomeremoval and reformation, in wild-type and mutant cells, upon activation (by galactose) and repression(by glucose) of the GAL genes of yeast. We show that upon being freed of its inhibitor Gal80 by the actionof galactose, Gal4 quickly recruits SWI/SNF to the genes, and that nucleosome \"remodeler\" rapidlyremoves promoter nucleosomes. In the absence of SWI/SNF, Gal4's action also results in nucleosomeremoval and the activation of transcription, but both processes are significantly delayed. Addition ofglucose to cells growing in galactose represses transcription. But if galactose remains present, Gal4continues to work, recruiting SWI/SNF and maintaining the promoter nucleosome-free despite it beingrepressed. This requirement for galactose is obviated in a mutant in which Gal4 works constitutively.These results show how an activator's recruiting function can control chromatin structure both duringgene activation and repression. Thus, both under activating and repressing conditions, the activator canrecruit an enzymatic machine that removes promoter nucleosomes. Our results show that whereaspromoter nucleosome removal invariably accompanies activation, reformation of nucleosomes is notrequired for repression. The finding that there are two routes to nucleosome removal and activation oftranscription-one that requires the action of SWI/SNF recruited by the activator, and a slower one thatdoes not-clarifies our understanding of the early events of gene activation, and in particular correctsearlier reports that SWI/SNF plays no role in GAL gene induction. Our finding that chromatin structure isirrelevant for repression as studied here-that is, repression sets in as efficiently whether or not promoternucleosomes are allowed to reform-contradicts the widely held, but little tested, idea that nucleosomesare required for repression. These findings were made possible by our nucleosome occupancy assay. Theassay, we believe, will prove useful in studying other outstanding issues in the field.", "metadata": {}}
+{"_id": "18909530", "title": "", "text": "Contractile forces sustain and polarize hematopoiesis from stem and progenitor cells.Self-renewal anddifferentiation of stem cells depend on asymmetric division and polarized motility processes that in othercell types are modulated by nonmuscle myosin-II (MII) forces and matrix mechanics. Here, massspectrometry-calibrated intracellular flow cytometry of human hematopoiesis reveals MIIB to be a majorisoform that is strongly polarized in hematopoietic stem cells and progenitors (HSC/Ps) and therebydownregulated in differentiated cells via asymmetric division. MIIA is constitutive and activated bydephosphorylation during cytokine-triggered differentiation of cells grown on stiff, endosteum-like matrix,but not soft, marrow-like matrix. In vivo, MIIB is required for generation of blood, while MIIA is requiredfor sustained HSC/P engraftment. Reversible inhibition of both isoforms in culture with blebbistatinenriches for long-term hematopoietic multilineage reconstituting cells by 5-fold or more as assessed invivo. Megakaryocytes also become more polyploid, producing 4-fold more platelets. MII is thus amultifunctional node in polarized division and niche sensing.", "metadata": {}}
+{"_id": "18914652", "title": "", "text": "Critical Role of the Virus-Encoded MicroRNA-155 Ortholog in the Induction of Marek's DiseaseLymphomasNotwithstanding the well-characterised roles of a number of oncogenes in neoplastictransformation, microRNAs (miRNAs) are increasingly implicated in several human cancers. Discovery ofmiRNAs in several oncogenic herpesviruses such as KSHV has further highlighted the potential ofvirus-encoded miRNAs to contribute to their oncogenic capabilities. Nevertheless, despite theidentification of several possible cancer-related genes as their targets, the direct in vivo role ofvirus-encoded miRNAs in neoplastic diseases such as those induced by KSHV is difficult to demonstrate inthe absence of suitable models. However, excellent natural disease models of rapid-onset Marek's disease(MD) lymphomas in chickens allow examination of the oncogenic potential of virus-encoded miRNAs.Using viruses modified by reverse genetics of the infectious BAC clone of the oncogenic RB-1B strain ofMDV, we show that the deletion of the six-miRNA cluster 1 from the viral genome abolished theoncogenicity of the virus. This loss of oncogenicity appeared to be primarily due to the single miRNAwithin the cluster, miR-M4, the ortholog of cellular miR-155, since its deletion or a 2-nucleotide mutationwithin its seed region was sufficient to inhibit the induction of lymphomas. The definitive role of thismiR-155 ortholog in oncogenicity was further confirmed by the rescue of oncogenic phenotype byrevertant viruses that expressed either the miR-M4 or the cellular homolog gga-miR-155. This is the firstdemonstration of the direct in vivo role of a virus-encoded miRNA in inducing tumors in a natural infectionmodel. Furthermore, the use of viruses deleted in miRNAs as effective vaccines against virulent MDVchallenge, enables the prospects of generating genetically defined attenuated vaccines.", "metadata": {}}
+{"_id": "18924534", "title": "", "text": "Functional insights into the role of nuclear-retained long noncoding RNAs in gene expression control inmammalian cellsThe mammalian genome harbors thousands of long noncoding RNA (lncRNA) genes.Recent studies have indicated the involvement of several of these lncRNAs in the regulation of geneexpression. lncRNAs play crucial roles in various biological processes ranging from epigenetic generegulation, transcriptional control, to post-transcriptional regulation. lncRNAs are localized in varioussubcellular compartments, and major proportion of these are retained in the cell nucleus and could bebroadly classified as nuclear-retained lncRNAs (nrRNAs). Based on the identified functions, members ofthe nrRNAs execute diverse roles, including providing architectural support to the hierarchical subnuclearorganization and influencing the recruitment of chromatin modifier factors to specific chromatin sites. Inthis review, we will summarize the recently described roles of mammalian nrRNAs in controlling geneexpression by influencing chromatin organization, transcription, pre-mRNA processing, nuclearorganization, and their involvement in disease.", "metadata": {}}
+{"_id": "18938992", "title": "", "text": "Downregulation of TAP1 in B lymphocytes by cellular and Epstein-Barr virus-encodedinterleukin-10.Virally infected cells degrade intracellular viral proteins proteolytically and present theresulting peptides in association with major histocompatibility complex (MHC) class I molecules to CD8+cytotoxic T lymphocytes (CTLs). These cells are normally prone to CTL-mediated elimination. However,several viruses have evolved strategies to avoid detection by the immune system that interfere with thepathway of antigen presentation. Epstein-Barr virus (EBV) expresses a predominantly late protein, theBCRF1 gene product vIL-10, that is similar in sequence to the human interleukin-10 (hIL-10). We showhere that vIL-10 affects the expression of one of the two transporter proteins (TAPs) associated withantigen presentation. Similarly, hIL-10 showed the same activity. Expression of the LMP2 and TAP1 genesbut not expression of TAP2 or LMP7 is efficiently downregulated, indicating a specific IL-10 effect on thetwo divergently transcribed TAP1 and LMP2 genes. Downregulation of TAP1 by IL-10 hampers thetransport of peptide antigens into the endoplasmatic reticulum, as shown in the TAP-specific peptidetransporter assay, their loading onto empty MHC I molecules, and the subsequent translocation to the cellsurface. As a consequence, IL-10 causes a general reduction of surface MHC I molecules on Blymphocytes that might also affect the recognition of EBV-infected cells by cytotoxic T cells.", "metadata": {}}
+{"_id": "18949516", "title": "", "text": "TGF-β and Insulin Signaling Regulate Reproductive Aging via Oocyte and Germline QualityMaintenanceReproductive cessation is perhaps the earliest aging phenotype that humans experience.Similarly, reproduction of Caenorhabditis elegans ceases in mid-adulthood. Although somatic aging hasbeen studied in both worms and humans, mechanisms regulating reproductive aging are not yetunderstood. Here, we show that TGF-β Sma/Mab and Insulin/IGF-1 signaling regulate C. elegansreproductive aging by modulating multiple aspects of the reproductive process, including embryointegrity, oocyte fertilizability, chromosome segregation fidelity, DNA damage resistance, and oocyte andgermline morphology. TGF-β activity regulates reproductive span and germline/oocyte qualitynoncell-autonomously and is temporally and transcriptionally separable from its regulation of growth.Chromosome segregation, cell cycle, and DNA damage response genes are upregulated in TGF-β mutantoocytes, decline in aged mammalian oocytes, and are critical for oocyte quality maintenance. Our datasuggest that C. elegans and humans share many aspects of reproductive aging, including the correlationbetween reproductive aging and declining oocyte quality and mechanisms determining oocyte quality.", "metadata": {}}
+{"_id": "18953920", "title": "", "text": "The Epithelial-Mesenchymal Transition Generates Cells with Properties of Stem CellsTheepithelial-mesenchymal transition (EMT) is a key developmental program that is often activated duringcancer invasion and metastasis. We here report that the induction of an EMT in immortalized humanmammary epithelial cells (HMLEs) results in the acquisition of mesenchymal traits and in the expressionof stem-cell markers. Furthermore, we show that those cells have an increased ability to formmammospheres, a property associated with mammary epithelial stem cells. Independent of this, stemcell-like cells isolated from HMLE cultures form mammospheres and express markers similar to those ofHMLEs that have undergone an EMT. Moreover, stem-like cells isolated either from mouse or humanmammary glands or mammary carcinomas express EMT markers. Finally, transformed human mammaryepithelial cells that have undergone an EMT form mammospheres, soft agar colonies, and tumors moreefficiently. These findings illustrate a direct link between the EMT and the gain of epithelial stem cellproperties.", "metadata": {}}
+{"_id": "18956141", "title": "", "text": "NEMO Prevents RIP Kinase 1-Mediated Epithelial Cell Death and Chronic Intestinal Inflammation byNF-κB-Dependent and -Independent FunctionsIntestinal epithelial cells (IECs) regulate gut immunehomeostasis, and impaired epithelial responses are implicated in the pathogenesis of inflammatory boweldiseases (IBD). IEC-specific ablation of nuclear factor κB (NF-κB) essential modulator (NEMO) causedPaneth cell apoptosis and impaired antimicrobial factor expression in the ileum, as well as colonocyteapoptosis and microbiota-driven chronic inflammation in the colon. Combined RelA, c-Rel, and RelBdeficiency in IECs caused Paneth cell apoptosis but not colitis, suggesting that NEMO prevents coloninflammation by NF-κB-independent functions. Inhibition of receptor-interacting protein kinase 1 (RIPK1)kinase activity or combined deficiency of Fas-associated via death domain protein (FADD) and RIPK3prevented epithelial cell death, Paneth cell loss, and colitis development in mice with epithelial NEMOdeficiency. Therefore, NEMO prevents intestinal inflammation by inhibiting RIPK1 kinaseactivity-mediated IEC death, suggesting that RIPK1 inhibitors could be effective in the treatment of colitisin patients with NEMO mutations and possibly in IBD.", "metadata": {}}
+{"_id": "18987782", "title": "", "text": "Suppression of Myc oncogenic activity by ribosomal protein haploinsufficiencyThe Myc oncogene regulatesthe expression of several components of the protein synthetic machinery, including ribosomal proteins,initiation factors of translation, RNA polymerase III and ribosomal DNA. Whether and how increasing thecellular protein synthesis capacity affects the multistep process leading to cancer remains to beaddressed. Here we use ribosomal protein heterozygote mice as a genetic tool to restore increasedprotein synthesis in Emu-Myc/+ transgenic mice to normal levels, and show that the oncogenic potentialof Myc in this context is suppressed. Our findings demonstrate that the ability of Myc to increase proteinsynthesis directly augments cell size and is sufficient to accelerate cell cycle progression independently ofknown cell cycle targets transcriptionally regulated by Myc. In addition, when protein synthesis isrestored to normal levels, Myc-overexpressing precancerous cells are more efficiently eliminated byprogrammed cell death. Our findings reveal a new mechanism that links increases in general proteinsynthesis rates downstream of an oncogenic signal to a specific molecular impairment in the modality oftranslation initiation used to regulate the expression of selective messenger RNAs. We show that anaberrant increase in cap-dependent translation downstream of Myc hyperactivation specifically impairsthe translational switch to internal ribosomal entry site (IRES)-dependent translation that is required foraccurate mitotic progression. Failure of this translational switch results in reduced mitotic-specificexpression of the endogenous IRES-dependent form of Cdk11 (also known as Cdc2l and PITSLRE), whichleads to cytokinesis defects and is associated with increased centrosome numbers and genome instabilityin Emu-Myc/+ mice. When accurate translational control is re-established in Emu-Myc/+ mice, genomeinstability is suppressed. Our findings demonstrate how perturbations in translational control provide ahighly specific outcome for gene expression, genome stability and cancer initiation that have importantimplications for understanding the molecular mechanism of cancer formation at the post-genomic level.", "metadata": {}}
+{"_id": "18988265", "title": "", "text": "Susceptibility to exacerbation in chronic obstructive pulmonary disease.BACKGROUND Although we knowthat exacerbations are key events in chronic obstructive pulmonary disease (COPD), our understanding oftheir frequency, determinants, and effects is incomplete. In a large observational cohort, we tested thehypothesis that there is a frequent-exacerbation phenotype of COPD that is independent of diseaseseverity. METHODS We analyzed the frequency and associations of exacerbation in 2138 patients enrolledin the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study.Exacerbations were defined as events that led a care provider to prescribe antibiotics or corticosteroids(or both) or that led to hospitalization (severe exacerbations). Exacerbation frequency was observed overa period of 3 years. RESULTS Exacerbations became more frequent (and more severe) as the severity ofCOPD increased; exacerbation rates in the first year of follow-up were 0.85 per person for patients withstage 2 COPD (with stage defined in accordance with Global Initiative for Chronic Obstructive LungDisease [GOLD] stages), 1.34 for patients with stage 3, and 2.00 for patients with stage 4. Overall, 22%of patients with stage 2 disease, 33% with stage 3, and 47% with stage 4 had frequent exacerbations(two or more in the first year of follow-up). The single best predictor of exacerbations, across all GOLDstages, was a history of exacerbations. The frequent-exacerbation phenotype appeared to be relativelystable over a period of 3 years and could be predicted on the basis of the patient's recall of previoustreated events. In addition to its association with more severe disease and prior exacerbations, thephenotype was independently associated with a history of gastroesophageal reflux or heartburn, poorerquality of life, and elevated white-cell count. CONCLUSIONS Although exacerbations become morefrequent and more severe as COPD progresses, the rate at which they occur appears to reflect anindependent susceptibility phenotype. This has implications for the targeting of exacerbation-preventionstrategies across the spectrum of disease severity. (Funded by GlaxoSmithKline; ClinicalTrials.govnumber, NCT00292552.)", "metadata": {}}
+{"_id": "18997216", "title": "", "text": "Sympathetic baroreflex gain in normotensive pregnant women.Muscle sympathetic nerve activity isincreased during normotensive pregnancy while mean arterial pressure is maintained or reduced,suggesting baroreflex resetting. We hypothesized spontaneous sympathetic baroreflex gain would bereduced in normotensive pregnant women relative to nonpregnant matched controls. Integrated musclesympathetic burst incidence and total sympathetic activity (microneurography), blood pressure(Finometer), and R-R interval (ECG) were assessed at rest in 11 pregnant women (33 ± 1 wk gestation,31 ± 1 yr, prepregnancy BMI: 23.5 ± 0.9 kg/m(2)) and 11 nonpregnant controls (29 ± 1 yr; BMI: 25.2 ±1.7 kg/m(2)). Pregnant women had elevated baseline sympathetic burst incidence (43 ± 2 vs. 33 ± 2bursts/100 heart beats, P = 0.01) and total sympathetic activity (1,811 ± 148 vs. 1,140 ± 55 au, P <0.01) relative to controls. Both mean (88 ± 3 vs. 91 ± 2 mmHg, P = 0.4) and diastolic (DBP) (72 ± 3 vs.73 ± 2 mmHg, P = 0.7) pressures were similar between pregnant and nonpregnant women, respectively,indicating an upward resetting of the baroreflex set point with pregnancy. Baroreflex gain, calculated asthe linear relationship between sympathetic burst incidence and DBP, was reduced in pregnant womenrelative to controls (-3.7 ± 0.5 vs. -5.4 ± 0.5 bursts·100 heart beats(-1)·mmHg(-1), P = 0.03), as wasbaroreflex gain calculated with total sympathetic activity (-294 ± 24 vs. -210 ± 24 au·100 heartbeats(-1)·mmHg(-1); P = 0.03). Cardiovagal baroreflex gain (sequence method) was not differentbetween nonpregnant controls and pregnant women (49 ± 8 vs. 36 ± 8 ms/mmHg; P = 0.2). However,sympathetic (burst incidence) and cardiovagal gains were negatively correlated in pregnant women (R =-0.7; P = 0.02). Together, these data indicate that the influence of the sympathetic nervous system overarterial blood pressure is reduced in normotensive pregnancy, in terms of both long-term andbeat-to-beat regulation of arterial pressure, likely through a baroreceptor-dependent mechanism.", "metadata": {}}
+{"_id": "18998807", "title": "", "text": "Facilitators and Impediments of the Pluripotency Reprogramming Factors' Initial Engagement with theGenomeThe ectopic expression of transcription factors can reprogram cell fate, yet it is unknown how theinitial binding of factors to the genome relates functionally to the binding seen in the minority of cells thatbecome reprogrammed. We report a map of Oct4, Sox2, Klf4, and c-Myc (O, S, K, and M) on the humangenome during the first 48 hr of reprogramming fibroblasts to pluripotency. Three striking aspects of theinitial chromatin binding events include an unexpected role for c-Myc in facilitating OSK chromatinengagement, the primacy of O, S, and K as pioneer factors at enhancers of genes that promotereprogramming, and megabase-scale chromatin domains spanned by H3K9me3, including many genesrequired for pluripotency, that prevent initial OSKM binding and impede the efficiency of reprogramming.We find diverse aspects of initial factor binding that must be overcome in the minority of cells thatbecome reprogrammed.", "metadata": {}}
+{"_id": "19004126", "title": "", "text": "Fibrillar Collagen Inhibits Arterial Smooth Muscle Proliferation through Regulation of Cdk2InhibitorsArterial smooth muscle cells (SMCs) are arrested in the G1 phase of the cell cycle onpolymerized type I collagen fibrils, while monomer collagen supports SMC proliferation. CyclinE-associated kinase and cyclin-dependent kinase 2 (cdk2) phosphorylation are inhibited on polymerizedcollagen, and levels of the cdk2 inhibitors p27Kip1 and p21Cip1/Waf1 are increased compared with SMCson monomer collagen. p27Kip1 associates with the cyclin E-cdk2-p21Cip1/Waf1 complex in SMCs onpolymerized collagen. Monovalent blocking antibodies to alpha2 integrins, integrins that mediateadhesion to both forms of collagen, mimic these effects on monomer collagen. Furthermore, polymerizedcollagen rapidly suppresses p70 S6 kinase, a possible regulator of p27Kip1. Thus, fibrillar collagenspecifically regulates early integrin signaling that may lead to up-regulation of cdk2 inhibitors andinhibition of SMC proliferation.", "metadata": {}}
+{"_id": "19005293", "title": "", "text": "Memory CD4+ T cells induce innate responses independently of pathogenInflammation induced byrecognition of pathogen-associated molecular patterns markedly affects subsequent adaptive responses.We asked whether the adaptive immune system can also affect the character and magnitude of innateinflammatory responses. We found that the response of memory, but not naive, CD4+ T cells enhancesproduction of multiple innate inflammatory cytokines and chemokines (IICs) in the lung and that, duringinfluenza infection, this leads to early control of virus. Memory CD4+ T cell–induced IICs and viral controlrequire cognate antigen recognition and are optimal when memory cells are either T helper type 1 (TH1)or TH17 polarized but are independent of interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α)production and do not require activation of conserved pathogen recognition pathways. This represents apreviously undescribed mechanism by which memory CD4+ T cells induce an early innate response thatenhances immune protection against pathogens.", "metadata": {}}
+{"_id": "19047331", "title": "", "text": "Direct Upregulation of STAT3 by MicroRNA-551b-3p Deregulates Growth and Metastasis of OvarianCancer.3q26.2 amplification in high-grade serous ovarian cancer leads to increased expression of maturemicroRNA miR551b-3p, which is associated with poor clinical outcome. Importantly, miR551b-3pcontributes to resistance to apoptosis and increased survival and proliferation of cancer cells in vitro andin vivo. miR551b-3p upregulates STAT3 protein levels, and STAT3 is required for the effects ofmiR551b-3p on cell proliferation. Rather than decreasing levels of target mRNA as expected, wedemonstrate that miR551b-3p binds a complementary sequence on the STAT3 promoter, recruiting RNApolymerase II and the TWIST1 transcription factor to activate STAT3 transcription, and thus directlyupregulates STAT3 expression. Furthermore, anti-miR551b reduced STAT3 expression in ovarian cancercells in vitro and in vivo and reduced ovarian cancer growth in vivo. Together, our data demonstrate arole for miR551b-3p in transcriptional activation. Thus, miR551b-3p represents a promising candidatebiomarker and therapeutic target in ovarian cancer.", "metadata": {}}
+{"_id": "19052713", "title": "", "text": "Human albumin administration in critically ill patients: systematic review of randomised controlledtrials.OBJECTIVE To quantify effect on mortality of administering human albumin or plasma proteinfraction during management of critically ill patients. DESIGN Systematic review of randomised controlledtrials comparing administration of albumin or plasma protein fraction with no administration or withadministration of crystalloid solution in critically ill patients with hypovolaemia, burns, orhypoalbuminaemia. SUBJECTS 30 randomised controlled trials including 1419 randomised patients. MAINOUTCOME MEASURE Mortality from all causes at end of follow up for each trial. RESULTS For each patientcategory the risk of death in the albumin treated group was higher than in the comparison group. Forhypovolaemia the relative risk of death after albumin administration was 1.46 (95% confidence interval0.97 to 2.22), for burns the relative risk was 2.40 (1.11 to 5.19), and for hypoalbuminaemia it was 1.69(1.07 to 2.67). Pooled relative risk of death with albumin administration was 1.68 (1.26 to 2.23). Pooleddifference in the risk of death with albumin was 6% (95% confidence interval 3% to 9%) with a fixedeffects model. These data suggest that for every 17 critically ill patients treated with albumin there is oneadditional death. CONCLUSIONS There is no evidence that albumin administration reduces mortality incritically ill patients with hypovolaemia, burns, or hypoalbuminaemia and a strong suggestion that it mayincrease mortality. These data suggest that use of human albumin in critically ill patients should beurgently reviewed and that it should not be used outside the context of rigorously conducted, randomisedcontrolled trials.", "metadata": {}}
+{"_id": "19058822", "title": "", "text": "A fine-scale map of recombination rates and hotspots across the human genome.Genetic maps, whichdocument the way in which recombination rates vary over a genome, are an essential tool for manygenetic analyses. We present a high-resolution genetic map of the human genome, based on statisticalanalyses of genetic variation data, and identify more than 25,000 recombination hotspots, together withmotifs and sequence contexts that play a role in hotspot activity. Differences between the behavior ofrecombination rates over large (megabase) and small (kilobase) scales lead us to suggest a two-stagemodel for recombination in which hotspots are stochastic features, within a framework in whichlarge-scale rates are constrained.", "metadata": {}}
+{"_id": "19071857", "title": "", "text": "Mental Health Support Provided Throughout the Bariatric Surgery Clinical Pathway in French SpecializedCare Centers for ObesityPre-operative psychological assessment is recommended by internationalguidelines for bariatric surgery candidates. Thereby, service teams caring for bariatric patients shouldinclude at least one mental health provider (e.g., a psychologist or psychiatrist). The objective of thisstudy was to evaluate the psychology and psychiatry resources and practices in the 37 specialized obesitycenters (CSOs) created by the French Ministry of Health. CSO coordinators were contacted by e-mail tocollect general information on the centers (e.g., number of bariatric operations). Secondly, psychologistsand psychiatrists of each center completed an anonymous questionnaire assessing their professionalpractices and their organization of care pathways. The vast majority of CSO coordinators (81%, n =26/32) answered our survey. These results show significant differences and shortages in terms of thepsychology/psychiatry resources available. Most of the psychologists (n = 26/31) and psychiatrists (n =10/10) stated that they systematically meet new patients only before surgery (56%) or both before andafter the operation (30%); however, some psychologists and psychiatrists (14%) do not systematicallymeet all the patients (before and/or after surgery). Nevertheless, all the professionals provide psychologyassessments, and about 75% of them offer a psychological follow-up, indicating a similarity regarding thepractices of psychologists and psychiatrists. Our results highlight the place of psychological/psychiatricevaluations in French CSOs and emphasize the absence of mental health providers in several of theseservices. Post-operative psychological follow-up is not usually provided. It would be appropriate to createclear recommendations for post-operative psychological or psychiatric long-term follow-up.", "metadata": {}}
+{"_id": "19079491", "title": "", "text": "Calcium: Regulation of cell death: the calcium–apoptosis linkTo live or to die? This crucial questioneloquently reflects the dual role of Ca2+ in living organisms – survival factor or ruthless killer. It has longbeen known that Ca2+ signals govern a host of vital cell functions and so are necessary for cell survival.However, more recently it has become clear that cellular Ca2+ overload, or perturbation of intracellularCa2+ compartmentalization, can cause cytotoxicity and trigger either apoptotic or necrotic cell death.", "metadata": {}}
+{"_id": "19099739", "title": "", "text": "Breaking the code of DNA binding specificity of TAL-type III effectors.The pathogenicity of many bacteriadepends on the injection of effector proteins via type III secretion into eukaryotic cells in order tomanipulate cellular processes. TAL (transcription activator-like) effectors from plant pathogenicXanthomonas are important virulence factors that act as transcriptional activators in the plant cellnucleus, where they directly bind to DNA via a central domain of tandem repeats. Here, we show howtarget DNA specificity of TAL effectors is encoded. Two hypervariable amino acid residues in each repeatrecognize one base pair in the target DNA. Recognition sequences of TAL effectors were predicted andexperimentally confirmed. The modular protein architecture enabled the construction of artificial effectorswith new specificities. Our study describes the functionality of a distinct type of DNA binding domain andallows the design of DNA binding domains for biotechnology.", "metadata": {}}
+{"_id": "19130782", "title": "", "text": "Interferon-Gamma at the Crossroads of Tumor Immune Surveillance or EvasionInterferon-gamma(IFN-γ) is a pleiotropic molecule with associated antiproliferative, pro-apoptotic and antitumormechanisms. This effector cytokine, often considered as a major effector of immunity, has been used inthe treatment of several diseases, despite its adverse effects. Although broad evidence implicating IFN-γin tumor immune surveillance, IFN-γ-based therapies undergoing clinical trials have been of limitedsuccess. In fact, recent reports suggested that it may also play a protumorigenic role, namely, throughIFN-γ signaling insensitivity, downregulation of major histocompatibility complexes, and upregulation ofindoleamine 2,3-dioxygenase and of checkpoint inhibitors, as programmed cell-death ligand 1. However,the IFN-γ-mediated responses are still positively associated with patient's survival in several cancers.Consequently, major research efforts are required to understand the immune contexture in which IFN-γinduces its intricate and highly regulated effects in the tumor microenvironment. This review discussesthe current knowledge on the pro- and antitumorigenic effects of IFN-γ as part of the complex immuneresponse to cancer, highlighting the relevance to identify IFN-γ responsive patients for the improvementof therapies that exploit associated signaling pathways.", "metadata": {}}
+{"_id": "19132741", "title": "", "text": "Role of antioxidants in paraquat toxicity.Paraquat, a quarternary nitrogen herbicide, is a highly toxiccompound for humans and animals and many cases of acute poisoning and death have been reportedover the past few decades. The mechanisms of paraquat toxicity involve: the generation of thesuperoxide anion, which can lead to the formation of more toxic reactive oxygen species, such ashydrogen peroxide and hydroxyl radical; and the oxidation of the cellular NADPH, the major source ofreducing equivalents for the intracellular reduction of paraquat, which results in the disruption ofimportant NADPH-requiring biochemical processes. The major cause of death in paraquat poisoning isrespiratory failure due to an oxidative insult to the alveolar epithelium with subsequent obliteratingfibrosis. Management of paraquat poisoning has remained mostly supportive and has been directedtowards the modification of the toxicokinetics of the poison. Currently, there are no true pharmacologicalantagonists for paraquat and there are no chelating agents capable of binding the poison in the blood orother tissues. Recognizing the fact that paraquat induces its toxic effects via oxidative stress-mediatedmechanisms, innovations in the management of paraquat poisoning are directed towards the use ofantioxidants. In this review, the status of antioxidants in ameliorating or treating the toxic effectsproduced by paraquat is presented.", "metadata": {}}
+{"_id": "19138874", "title": "", "text": "Nucleation of nuclear bodies by RNAThe biogenesis of the many functional compartments contained in themammalian cell nucleus is poorly understood. More specifically, little is known regarding the initialnucleation step required for nuclear body formation. Here we show that RNA can function as a structuralelement and a nucleator of nuclear bodies. We find that several types of coding and noncoding RNAs aresufficient to de novo assemble, and are physiologically enriched in, histone locus bodies (with associatedCajal bodies), nuclear speckles, paraspeckles and nuclear stress bodies. Formation of nuclear bodiesoccurs through recruitment and accumulation of proteins resident in the nuclear bodies by nucleatingRNA. These results demonstrate that transcription is a driving force in nuclear body formation and RNAtranscripts can function as a scaffold in the formation of major nuclear bodies. Together, these datasuggest that RNA-primed biogenesis of nuclear bodies is a general principle of nuclear organization.", "metadata": {}}
+{"_id": "19140422", "title": "", "text": "Evaluation of human papillomavirus testing in primary screening for cervical abnormalities: comparison ofsensitivity, specificity, and frequency of referral.CONTEXT Human papillomavirus (HPV) DNA testing ofwomen having Papanicolaou (Pap) smears showing atypical squamous cells of undetermined significance(ASCUS) has clinical usefulness. Whether HPV DNA testing alone is useful in primary screening remains tobe determined. OBJECTIVE To determine the accuracy of HPV DNA testing for detecting cervicalintraepithelial neoplasia (CIN) grade 3 or cancer (the criterion standard). DESIGN, SETTING, ANDPARTICIPANTS Between December 1997 and October 2000, 4075 women who attended PlannedParenthood clinics in Washington State were screened simultaneously using thin-layer Pap and HPV DNAtesting by a polymerase chain reaction (PCR)-based method and by a liquid-based RNA-DNA hybridizationcapture with signal amplification assay (signal amplification). Women who were positive for high-risk HPVtypes, or had Pap results of ASCUS or higher, were considered to have positive screening test results andwere referred for colposcopy and biopsy. Additionally, a random sample of women with negativescreening test results was referred for colposcopy. Based on individual and combined thin-layer Pap, HPVPCR, and HPV signal amplification test results from the screening and the colposcopy visits, 7 colposcopytriage strategies were defined and evaluated. MAIN OUTCOME MEASURE Sensitivity and specificity fordetecting cervical lesions graded CIN 3 or higher for each of the 7 triage strategies. RESULTS Theestimated prevalence of CIN 3 or higher was 3.2%. The sensitivity (95% confidence interval) of thin-layerPap (with a result of > or = ASCUS) for identifying women with CIN 3 or higher was only 61.3%(48.5%-70.9%) compared with 88.2% (78.9%-93.8%) for HPV testing by PCR and 90.8%(83.1%-95.8%) by signal amplification. Differences in specificities were also observed: 82.4%(81.8%-83.1%) for thin-layer Pap (with a result of > or = ASCUS), 78.8% (77.9%-79.7%) for PCR, and72.6% (69.4%-75.0%) for signal amplification. Compared with referral for colposcopy of all women withASCUS or higher, signal amplification testing of women with ASCUS and referral of those with a positiveresult was about as sensitive (61.3% vs 60.3%, respectively) and significantly more specific (82.4% vs88.9%, respectively). The strategy requiring repeat positive PCR tests on 2 visits had a sensitivity of84.2% (75.3%-91.0%) and a specificity of 86.2% (85.1%-87.3%). All tests were more specific and lesssensitive in older (> or = 30 years) vs younger women. CONCLUSIONS Testing for HPV has highersensitivity but lower specificity than thin-layer Pap screening. In some settings, particularly wherescreening intervals are long or haphazard, screening for HPV DNA may be a reasonable alternative tocytology-based screening of reproductive-age women.", "metadata": {}}
+{"_id": "19149247", "title": "", "text": "Breaking the chains: structure and function of the deubiquitinasesUbiquitylation is a reversible proteinmodification that is implicated in many cellular functions. Recently, much progress has been made in thecharacterization of a superfamily of isopeptidases that remove ubiquitin: the deubiquitinases (DUBs; alsoknown as deubiquitylating or deubiquitinating enzymes). Far from being uniform in structure andfunction, these enzymes display a myriad of distinct mechanistic features. The small number (<100) ofDUBs might at first suggest a low degree of selectivity; however, DUBs are subject to multiple layers ofregulation that modulate both their activity and their specificity. Due to their wide-ranging involvement inkey regulatory processes, these enzymes might provide new therapeutic targets.", "metadata": {}}
+{"_id": "19165076", "title": "", "text": "Replication protein A: a heterotrimeric, single-stranded DNA-binding protein required for eukaryotic DNAmetabolism.Replication protein A [RPA; also known as replication factor A (RFA) and humansingle-stranded DNA-binding protein] is a single-stranded DNA-binding protein that is required formultiple processes in eukaryotic DNA metabolism, including DNA replication, DNA repair, andrecombination. RPA homologues have been identified in all eukaryotic organisms examined and are allabundant heterotrimeric proteins composed of subunits of approximately 70, 30, and 14 kDa. Members ofthis family bind nonspecifically to single-stranded DNA and interact with and/or modify the activities ofmultiple proteins. In cells, RPA is phosphorylated by DNA-dependent protein kinase when RPA is bound tosingle-stranded DNA (during S phase and after DNA damage). Phosphorylation of RPA may play a role incoordinating DNA metabolism in the cell. RPA may also have a role in modulating gene expression.", "metadata": {}}
+{"_id": "19182166", "title": "", "text": "Internal fixation versus nonoperative treatment of displaced 3-part proximal humeral fractures in elderlypatients: a randomized controlled trial.BACKGROUND The aim of the study was to report the 2-yearoutcome after a displaced 3-part fracture of the proximal humerus in elderly patients randomized totreatment with a locking plate or nonoperative treatment. PATIENTS AND METHODS We included 60patients, mean age 74 years (range, 56-92), 81% being women. The main outcome measures were theConstant and Disabilities of the Arm, Shoulder and Hand (DASH) scores and the health-related quality oflife (HRQoL) according to the EQ-5D. RESULTS At the final 2-year follow-up, the results for range ofmotion (ROM), function and HRQoL were all in favor of the locking plate group. The mean flexion in thelocking plate group was 120° compared to 111° in the nonoperative group (P = .36) and the meanabduction was 114° compared to 106° (P = .28). The corresponding values for the Constant score were61 versus 58 (P = .64), for DASH 26 versus 35 (P = .19), and the mean EQ-5D (index) score was 0.70compared to 0.59 (P = .26). In spite of good primary reduction in 86% of the fractures in the lockingplate group, 13% of the patients had a fracture complication requiring a major reoperation and 17% hada minor reoperation. CONCLUSION The results of our study indicate an advantage in functional outcomeand HRQoL in favor of the locking plate compared to nonoperative treatment in elderly patients with adisplaced 3-part fracture of the proximal humerus, but at the cost of additional surgery in 30% of thepatients.", "metadata": {}}
+{"_id": "19185192", "title": "", "text": "Good and bad consequences of altered fatty acid metabolism in heart failure: evidence from mousemodels.The shift in substrate preference away from fatty acid oxidation (FAO) towards increased glucoseutilization in heart failure has long been interpreted as an oxygen-sparing mechanism. Inhibition of FAOhas therefore evolved as an accepted approach to treat heart failure. However, recent data indicate thatincreased reliance on glucose might be detrimental rather than beneficial for the failing heart. This reviewdiscusses new insights into metabolic adaptations in heart failure. A particular focus lies on data obtainedfrom mouse models with modulations of cardiac FA metabolism at different levels of the FA metabolicpathway and how these differently affect cardiac function. Based on studies in which these mouse modelswere exposed to ischaemic and non-ischaemic heart failure, we discuss whether and when modulations inFA metabolism are protective against heart failure.", "metadata": {}}
+{"_id": "19204979", "title": "", "text": "Pericytes of human skeletal muscle are myogenic precursors distinct from satellite cellsCells derived fromblood vessels of human skeletal muscle can regenerate skeletal muscle, similarly to embryonicmesoangioblasts. However, adult cells do not express endothelial markers, but instead express markersof pericytes, such as NG2 proteoglycan and alkaline phosphatase (ALP), and can be prospectively isolatedfrom freshly dissociated ALP+ cells. Unlike canonical myogenic precursors (satellite cells),pericyte-derived cells express myogenic markers only in differentiated myotubes, which they formspontaneously with high efficiency. When transplanted into severe combined immune deficient–X-linked,mouse muscular dystrophy (scid–mdx) mice, pericyte-derived cells colonize host muscle and generatenumerous fibres expressing human dystrophin. Similar cells isolated from Duchenne patients, andengineered to express human mini-dystrophin, also give rise to many dystrophin-positive fibres in vivo.These data show that myogenic precursors, distinct from satellite cells, are associated with microvascularwalls in the human skeletal muscle, may represent a correlate of embryonic 'mesoangioblasts' presentafter birth and may be a promising candidate for future cell-therapy protocols in patients.", "metadata": {}}
+{"_id": "19205326", "title": "", "text": "Ten years' experience with alendronate for osteoporosis in postmenopausal women.BACKGROUNDAntiresorptive agents are widely used to treat osteoporosis. We report the results of a multinationalrandomized, double-blind study, in which postmenopausal women with osteoporosis were treated withalendronate for up to 10 years. METHODS The initial three-year phase of the study compared three dailydoses of alendronate with placebo. Women in the original placebo group received alendronate in years 4and 5 and then were discharged. Women in the original active-treatment groups continued to receivealendronate during the initial extension (years 4 and 5). In two further extensions (years 6 and 7, and 8through 10), women who had received 5 mg or 10 mg of alendronate daily continued on the sametreatment. Women in the discontinuation group received 20 mg of alendronate daily for two years and 5mg daily in years 3, 4, and 5, followed by five years of placebo. Randomized group assignments andblinding were maintained throughout the 10 years. We report results for the 247 women who participatedin all four phases of the study. RESULTS Treatment with 10 mg of alendronate daily for 10 yearsproduced mean increases in bone mineral density of 13.7 percent at the lumbar spine (95 percentconfidence interval, 12.0 to 15.5 percent), 10.3 percent at the trochanter (95 percent confidence interval,8.1 to 12.4 percent), 5.4 percent at the femoral neck (95 percent confidence interval, 3.5 to 7.4 percent),and 6.7 percent at the total proximal femur (95 percent confidence interval, 4.4 to 9.1 percent) ascompared with base-line values; smaller gains occurred in the group given 5 mg daily. Thediscontinuation of alendronate resulted in a gradual loss of effect, as measured by bone density andbiochemical markers of bone remodeling. Safety data, including fractures and stature, did not suggestthat prolonged treatment resulted in any loss of benefit. CONCLUSIONS The therapeutic effects ofalendronate were sustained, and the drug was well tolerated over a 10-year period. The discontinuationof alendronate resulted in the gradual loss of its effects.", "metadata": {}}
+{"_id": "19205437", "title": "", "text": "UCP1-independent signaling involving SERCA2b-mediated calcium cycling regulates beige fatthermogenesis and systemic glucose homeostasisUncoupling protein 1 (UCP1) plays a central role innonshivering thermogenesis in brown fat; however, its role in beige fat remains unclear. Here we report arobust UCP1-independent thermogenic mechanism in beige fat that involves enhanced ATP-dependentCa2+ cycling by sarco/endoplasmic reticulum Ca2+-ATPase 2b (SERCA2b) and ryanodine receptor 2(RyR2). Inhibition of SERCA2b impairs UCP1-independent beige fat thermogenesis in humans and miceas well as in pigs, a species that lacks a functional UCP1 protein. Conversely, enhanced Ca2+ cycling byactivation of α1- and/or β3-adrenergic receptors or the SERCA2b-RyR2 pathway stimulatesUCP1-independent thermogenesis in beige adipocytes. In the absence of UCP1, beige fat dynamicallyexpends glucose through enhanced glycolysis, tricarboxylic acid metabolism and pyruvate dehydrogenaseactivity for ATP-dependent thermogenesis through the SERCA2b pathway; beige fat thereby functions asa 'glucose sink' and improves glucose tolerance independently of body weight loss. Our study uncovers anoncanonical thermogenic mechanism through which beige fat controls whole-body energy homeostasisvia Ca2+ cycling.", "metadata": {}}
+{"_id": "19255949", "title": "", "text": "Poly(A)-specific ribonuclease (PARN) mediates 3′-end maturation of the telomerase RNAcomponentMutations in the PARN gene (encoding poly(A)-specific ribonuclease) cause telomere diseasesincluding familial idiopathic pulmonary fibrosis (IPF) and dyskeratosis congenita, but how PARN deficiencyimpairs telomere maintenance is unclear. Here, using somatic cells and induced pluripotent stem cells(iPSCs) from patients with dyskeratosis congenita with PARN mutations, we show that PARN is requiredfor the 3′-end maturation of the telomerase RNA component (TERC). Patient-derived cells as well asimmortalized cells in which PARN is disrupted show decreased levels of TERC. Deep sequencing of TERCRNA 3′ termini shows that PARN is required for removal of post-transcriptionally acquired oligo(A) tailsthat target nuclear RNAs for degradation. Diminished TERC levels and the increased proportion of oligo(A)forms of TERC are normalized by restoring PARN, which is limiting for TERC maturation in cells. Ourresults demonstrate a new role for PARN in the biogenesis of TERC and provide a mechanism linkingPARN mutations to telomere diseases.", "metadata": {}}
+{"_id": "19278208", "title": "", "text": "Folic acid supplementation and dietary folate intake, and risk of preeclampsiaBackground/Objectives:Folicacid supplementation has been suggested to reduce the risk of preeclampsia. However, results from fewepidemiologic studies have been inconclusive. We investigated the hypothesis that folic acidsupplementation and dietary folate intake before conception and during pregnancy reduce the risk ofpreeclampsia. Subjects/Methods:A birth cohort study was conducted in 2010–2012 at the GansuProvincial Maternity & Child Care Hospital in Lanzhou, China. A total of 10 041 pregnant women withoutchronic hypertension or gestational hypertension were enrolled. Results:Compared with nonusers, folicacid supplement users had a reduced risk of preeclampsia (OR=0.61, 95% CI: 0.43–0.87). A significantdose–response of duration of use was observed among women who used folic acid supplemention duringpregnancy only (P-trend=0.007). The reduced risk associated with folic acid supplement was similar formild or severe preeclampsia and for early- or late-onset preeclampsia, although the statistical significantassociations were only observed for mild (OR=0.50, 95% CI: 0.30–0.81) and late-onset (OR=0.60, 95%CI: 0.42–0.86) preeclampsia. The reduced risk associated with dietary folate intake during pregnancywas only seen for severe preeclampsia (OR=0.52, 95% CI: 0.31–0.87, for the highest quartile of dietaryfolate intake compared with the lowest).Conclusions:Our study results suggest that folic acidsupplementation and higher dietary folate intake during pregnancy reduce the risk of preeclampsia.Future studies are needed to confirm the associations.", "metadata": {}}
+{"_id": "19293654", "title": "", "text": "Model-based Analysis of ChIP-Seq (MACS)We present Model-based Analysis of ChIP-Seq data, MACS,which analyzes data generated by short read sequencers such as Solexa's Genome Analyzer. MACSempirically models the shift size of ChIP-Seq tags, and uses it to improve the spatial resolution ofpredicted binding sites. MACS also uses a dynamic Poisson distribution to effectively capture local biasesin the genome, allowing for more robust predictions. MACS compares favorably to existing ChIP-Seqpeak-finding algorithms, and is freely available.", "metadata": {}}
+{"_id": "19307912", "title": "", "text": "Familial obesity and leanness.Using the Princeton School District Family Study cohort, our specific aimwas to estimate the prevalence of suspected familial ponderosity and leanness, to provide empirical riskestimates for the proportion of probands' first-degree relatives who were similarly affected, and toestimate the contributions of diseases, drugs and caloric intake to relative obesity and leanness. Westudied 379 probands, 125 whites and 52 blacks from a random recall group, 147 whites and 55 blacksfrom a hyperlipidemic recall group. Suspected familial obesity and leanness were arbitrarily identified inthose kindreds with at least two first-degree relatives in the same Quetelet index decile as the proband,top or bottom respectively. Suspected familial obesity was observed in 2.4 percent and 6 percentrespectively of random and hyperlipidemic recall group whites. Suspected familial leanness was identifiedin 2.4 percent and 1.4 percent of random and hyperlipidemic recall whites and in 3.8 percent of randomlyrecalled blacks. Approximately twice as many as expected white first-degree relatives of top Queteletindex decile probands themselves had top decile Quetelet indices; approximately three times as many asexpected first-degree relatives of bottom decile Quetelet index probands themselves had bottom decileQuetelet indices. Nineteen percent and 31 percent of top decile Quetelet index white probands fromrandom and hyperlipidemic recall groups came from families where at least two other first-degreerelatives were similarly obese; 18 percent and 20 percent of white random and hyperlipidemic recallgroup probands with bottom decile Quetelet indices had suspected familial leanness. Nearly all subjectswith familial obesity or leanness had no overt metabolic or pharmacological explanations for their bodyhabitus. Within-family clustering of hypertension was common in kindreds with suspected familial obesityand was absent in kindreds with suspected familial leanness. Marked within-family clustering of bothobesity and leanness is useful diagnostically; therapeutic intervention to reduce obesity, to be mosteffective, should be family-wide in the many kindreds which share familial obesity.", "metadata": {}}
+{"_id": "19308127", "title": "", "text": "In-hospital switching of oral P2Y12 inhibitor treatment in patients with acute coronary syndromeundergoing percutaneous coronary intervention: prevalence, predictors and short-termoutcome.BACKGROUND P2Y12 inhibitor switching has appeared in clinical practice as a consequence ofprasugrel and ticagrelor availability, apart from clopidogrel, for use in patients with acute coronarysyndrome (ACS) undergoing percutaneous coronary intervention (PCI). METHODS In the context of theGReek AntiPlatelet REgistry (GRAPE) we assessed the prevalence, predictive factors and short-termoutcome of in-hospital P2Y12 inhibitor switching in 1794 ACS patients undergoing PCI. RESULTSSwitching occurred in 636 (35.5%) patients of which in the form of clopidogrel to a novel agent, novelagent to clopidogrel and between prasugrel and ticagrelor in 574 (90.4%), 34 (5.3%) and 27 (4.3%)patients, respectively. Presentation to non PCI-capable hospital, bivalirudin use, age ≥75 years (inversepredictor), and regional trends emerged as predictive factors of switching to a novel agent. At combinedin-hospital and one-month follow-up, propensity matched pairs analysis showed no differences in majoradverse cardiovascular (MACE) or bleeding events between switching from clopidogrel to a novel agent vsnovel agent constant administration. More Bleeding Academic Research Consortium type 1, type 2 andany type events and fewer MACE were seen when switching from clopidogrel to a novel agent vs onlyclopidogrel administration (23.7%, 3.8%, 30.6%, 1.2% vs 8.9%, 1.2%, 12.0%, 3.8% with P < .001, P =.03, P < .001 and P = .03 respectively). CONCLUSIONS In a real-life experience with contemporaryantiplatelet treatment in ACS patients undergoing PCI, in-hospital switching represents common clinicalpractice. Clinical factors and regional practice differences seem to affect this strategy's choice, whileswitching to a novel agent may be associated with higher risk of bleeding.", "metadata": {}}
+{"_id": "19313533", "title": "", "text": "Structural basis of allosteric and synergistic activation of AMPK by furan-2-phosphonic derivative C2binding.The metabolic stress-sensing enzyme AMP-activated protein kinase (AMPK) is responsible forregulating metabolism in response to energy supply and demand. Drugs that activate AMPK may beuseful in the treatment of metabolic diseases including type 2 diabetes. We have determined the crystalstructure of AMPK in complex with its activator 5-(5-hydroxyl-isoxazol-3-yl)-furan-2-phosphonic acid(C2), revealing two C2-binding sites in the γ-subunit distinct from nucleotide sites. C2 acts synergisticallywith the drug A769662 to activate AMPK α1-containing complexes independent of upstream kinases. Ourresults show that dual drug therapies could be effective AMPK-targeting strategies to treat metabolicdiseases.", "metadata": {}}
+{"_id": "19315511", "title": "", "text": "Validity of age at menarche self-reported in adulthood.OBJECTIVE To test the validity of age at menarcheself-reported in adulthood and examine whether socioeconomic position, education, experience ofgynaecological events and psychological symptoms influence the accuracy of recall. DESIGN Prospectivebirth cohort study. SETTING England, Scotland and Wales. PARTICIPANTS 1050 women from the MedicalResearch Council National Survey of Health and Development, with two measures of age at menarche,one recorded in adolescence and the other self-reported at age 48 years. RESULTS By calculating thelimits of agreement, kappa statistic and Pearson's correlation coefficients (r), we found that the validity ofage at menarche self-reported in middle age compared with that recorded in adolescence was moderate(kappa = 0.35, r = 0.66, n = 1050). Validity was improved by categorising age at menarche into threegroups: early, normal and late (kappa = 0.43). Agreement was influenced by educational level andhaving had a stillbirth or miscarriage. CONCLUSIONS The level of validity shown in this study throwssome doubt on whether it is justifiable to use age at menarche self-reported in middle age. It is likely tointroduce error and bias, and researchers should be aware of these limitations and use such measureswith caution.", "metadata": {}}
+{"_id": "19327364", "title": "", "text": "Seroepidemiologic survey of captive Old-World primates for antibodies to human and simian retroviruses,and isolation of a lentivirus from sooty mangabeys (Cercocebus atys).Sera from 526 Old-World monkeysand apes, representing 50 species and 20 genera and living in US zoos and vivaria, were screened forantibodies to HTLV-I, HTLV-III/LAV, and simian-AIDS retrovirus, type I (SRV-I). Sera were screenedinitially by ELISA, and ELISA-positive sera, as well as ELISA-negative sera from cage contacts, werefurther tested by Western blotting. A large number of false-positive and a small number of false-negativeELISA sera were identified. Although most true positive reactions were directed to a single retrovirus, anumber of individuals from 4 species were positive for more than one retrovirus. Specific seroreactivity toHTLV-I was found in 39/526 (7%) animals of 15 species. True positive reactions to SRV-I were found in21/516 (4%) animals, including talapoins and 2 species of macaques. Specific serologic reactions toHTLV-III/LAV were detected in 23/526 (4%) monkeys. Many of the HTLV-III/LAV seropositive animalswere from one mixed-species zoo exhibit, containing sooty mangabeys, mandrills, Kolb's guenons, andtalapoins. A type D virus was isolated from the blood of 3/10 SRV-I antibody-positive Tonkeanamacaques, but from none of 11 seropositive talapoins. A lentivirus was isolated from the blood of 4/7HTLV-III/LAV seropositive sooty mangabeys, but not from seropositive talapoins in the same exhibit orfrom 2 seropositive colobus from another zoo. The sooty mangabey lentivirus produced generalizedlymphadenopathy, leukopenia, and decreased levels of T4 lymphocytes in 2 experimentally infectedrhesus macaques.", "metadata": {}}
+{"_id": "19332616", "title": "", "text": "Coronary plaque disruption.Coronary atherosclerosis is by far the most frequent cause of ischemic heartdisease, and plaque disruption with superimposed thrombosis is the main cause of the acute coronarysyndromes of unstable angina, myocardial infarction, and sudden death.1 2 3 4 5 Therefore, forevent-free survival, the vital question is not why atherosclerosis develops but rather why, after years ofindolent growth, it suddenly becomes complicated by life-threatening thrombosis. The composition andvulnerability of plaque rather than its volume or the consequent severity of stenosis produced haveemerged as being the most important determinants for the development of the thrombus-mediated acutecoronary syndromes; lipid-rich and soft plaques are more dangerous than collagen-rich and hard plaquesbecause they are more unstable and rupture-prone and highly thrombogenic after disruption.6 Thisreview will explore potential mechanisms responsible for the sudden conversion of a stableatherosclerotic plaque to an unstable and life-threatening atherothrombotic lesion—an event known asplaque fissuring, rupture, or disruption.7 8   Atherosclerosis is the result of a complex interactionbetween blood elements, disturbed flow, and vessel wall abnormality, involving several pathologicalprocesses: inflammation, with increased endothelial permeability, endothelial activation, and monocyterecruitment9 10 11 12 13 14 ; growth, with smooth muscle cell (SMC) proliferation, migration, andmatrix synthesis15 16 ; degeneration, with lipid accumulation17 18 ; necrosis, possibly related to thecytotoxic effect of oxidized lipid19 ; calcification/ossification, which may represent an active rather than adystrophic process20 21 ; and thrombosis, with platelet recruitment and fibrin formation.1 22 23Thrombotic factors may play a role early during atherogenesis, but a flow-limiting thrombus does notdevelop until mature plaques are present, which is why thrombosis often is classified as a complicationrather than a genuine component of atherosclerosis. ### Mature Plaques: Atherosis and Sclerosis   Asthe name atherosclerosis implies, mature …", "metadata": {}}
+{"_id": "19343151", "title": "", "text": "p16INK4A is a robust in vivo biomarker of cellular aging in human skin.The cell-cycle regulating gene,p16INK4A, encoding an inhibitor of cyclin-dependent kinases 4 and 6, is considered to play an importantrole in cellular aging and in premature senescence. Although there is an age-dependent increase ofp16INK4A expression in human fibroblast senescence in vitro, no data are available regarding the agedependency of p16INK4A in vivo. To determine whether p16INK4A expression in human skin correlateswith donor age, p16INK4A expression was analyzed by immunohistochemistry as well as the expressionof the p16INK4A repressor BMI1. Samples from the age groups 0-20, 21-70, and 71-95 years wereselected from a bank of healthy human skin. We show that the number of p16INK4A positive cells issignificantly higher in elderly individuals compared to the younger age groups. The number of p16INK4Apositive cells was found to be increased in both epidermis and dermis, compartments with strictlydifferent proliferative activities. BMI1 gene expression was significantly down-regulated with increasingdonor age, whereas no striking age differences were observed for Ki67. In immunofluorescenceco-expression studies, Ki67-positive cells were negative for p16INK4A and BMI1-expressing cells alsostained negatively for Ki67. In conclusion, we provide for the first time evidence that p16INK4Aexpression directly correlates with chronological aging of human skin in vivo. p16INK4A therefore is abiomarker for human aging in vivo. The data reported here suggest a model for changes in regulatorygene expression that drive aging in human skin.", "metadata": {}}
+{"_id": "19356271", "title": "", "text": "hPrimpol1/CCDC111 is a human DNA primase-polymerase required for the maintenance of genomeintegrity.Prim-pol is a recently identified DNA primase-polymerase belonging to the archaeao-eukaryoticprimase (AEP) superfamily. Here, we characterize a previously unrecognized prim-pol in human cells,which we designate hPrimpol1 (human primase-polymerase 1). hPrimpol1 possesses primase and DNApolymerase activities in vitro, interacts directly with RPA1 and is recruited to sites of DNA damage andstalled replication forks in an RPA1-dependent manner. Cells depleted of hPrimpol1 display increasedspontaneous DNA damage and defects in the restart of stalled replication forks. Both RPA1 binding andthe primase activity of hPrimpol1 are required for its cellular function during DNA replication. Our resultsindicate that hPrimpol1 is a novel factor involved in the response to DNA replication stress.", "metadata": {}}
+{"_id": "19358586", "title": "", "text": "Functional proteomics identifies miRNAs to target a p27/Myc/phospho-Rb signature in breast and ovariancancerThe myc oncogene is overexpressed in almost half of all breast and ovarian cancers, but attemptsat therapeutic interventions against myc have proven to be challenging. Myc regulates multiple biologicalprocesses, including the cell cycle, and as such is associated with cell proliferation and tumor progression.We identified a protein signature of high myc, low p27 and high phospho-Rb significantly correlated withpoor patient survival in breast and ovarian cancers. Screening of a miRNA library by functionalproteomics in multiple cell lines and integration of data from patient tumors revealed a panel of fivemicroRNAs (miRNAs) (miR-124, miR-365, miR-34b*, miR-18a and miR-506) as potential tumorsuppressors capable of reversing the p27/myc/phospho-Rb protein signature. Mechanistic studiesrevealed an RNA-activation function of miR-124 resulting in direct induction of p27 protein levels bybinding to and inducing transcription on the p27 promoter region leading to a subsequent G1 arrest.Additionally, in vivo studies utilizing a xenograft model demonstrated that nanoparticle-mediated deliveryof miR-124 could reduce tumor growth and sensitize cells to etoposide, suggesting a clinical application ofmiRNAs as therapeutics to target the functional effect of myc on tumor growth.", "metadata": {}}
+{"_id": "19368793", "title": "", "text": "The potential role of miRNAs 21 and 199-a in early diagnosis of hepatocellular carcinoma.BACKGROUNDHepatocellular carcinoma (HCC) is regarded as one of the most common malignancies and among theleading causes of cancer death among the whole world. The most urgent needs are to find sensitivemarkers for early diagnosis for HCC. MicroRNAs (miRNAs) are reported as a group of small non-codingRNAs that can function as endogenous RNA interference to regulate expression of the targeted genes.This study was conducted to detect the serum and tissue expression of miR 21 and miR 199-a to beapplied as early detectors for HCC. METHODS A total of 40 serum and tissue samples (17 samples fromchronic hepatitis and 23 samples from HCC patients) were collected. The levels of the two mature miRNAs(miR-21 and miR-199-a) were detected by real time quantitative reverse-transcriptase PCR (RT-qPCR) insera and tissues of chronic hepatitis and HCC patients. Besides, miR-21 and miR-199-a levels in relationto clinical and pathological factors were explored. RESULTS We found that the expression of serummiR-21 was distinctly increased in HCC compared with chronic hepatitis (P<0.001). miR 199-a wasdistinctly decreased in HCC compared with chronic hepatitis (P<0.001). In addition, median of miR 21was increased in malignant when compared to adjacent non-malignant tissues without significantdifferences (P=0.191) while miR 199-a was significantly decreased in malignant when compared toadjacent nonmalignant tissues (P<0.001). ROC analysis showed that miR-21 and miR-199-a might bepotential biomarkers for HCC. CONCLUSIONS In conclusion, the expression of miR-21 was significantlyup-regulated and miR-199-a was significantly down regulated in serum of patients with HCC. Due to theirreasonable sensitivity and specificity for disease progression, miR-21 and miR-199-a could be used aspotential circulating biomarkers for HCC.", "metadata": {}}
+{"_id": "19384430", "title": "", "text": "Tex10 Coordinates Epigenetic Control of Super-Enhancer Activity in Pluripotency andReprogramming.Super-enhancers (SEs) are large clusters of transcriptional enhancers that areco-occupied by multiple lineage-specific transcription factors driving expression of genes that define cellidentity. In embryonic stem cells (ESCs), SEs are highly enriched for the core pluripotency factors Oct4,Sox2, and Nanog. In this study, we sought to dissect the molecular control mechanism of SE activity inpluripotency and reprogramming. Starting from a protein interaction network surrounding Sox2, weidentified Tex10 as a key pluripotency factor that plays a functionally significant role in ESC self-renewal,early embryo development, and reprogramming. Tex10 is enriched at SEs in a Sox2-dependent mannerand coordinates histone acetylation and DNA demethylation at SEs. Tex10 activity is also important forpluripotency and reprogramming in human cells. Our study therefore highlights Tex10 as a corecomponent of the pluripotency network and sheds light on its role in epigenetic control of SE activity forcell fate determination.", "metadata": {}}
+{"_id": "19408393", "title": "", "text": "Value of whole brain re-irradiation for brain metastases--single centre experience.AIMS There iscontroversy in published studies regarding the role of repeat whole brain radiation (WBRT) for previouslyirradiated brain metastases. The aim of our retrospective study was to document the practice at PrincessMargaret Hospital with respect to the re-irradiation of patients with progressive or recurrent brainmetastatic disease after initial WBRT. MATERIALS AND METHODS A comprehensive computeriseddatabase was used to identify patients treated for brain metastases with more than one course of WBRTbetween 1997 and 2003. Seventy-two patients were treated with WBRT for brain metastases andretreated with WBRT at a later date. The records of these patients were reviewed. RESULTS The medianage was 56.5 years. The most common primary sites were lung (51 patients) and breast (17 patients).The most frequent dose used for the initial radiotherapy was 20 Gy/5 fractions (62 patients). The mostcommon doses of re-irradiation were 25 Gy/10 fractions (22 patients), 20 Gy/10 fractions (12 patients),15 Gy/5 fractions (11 patients) and 20 Gy/8 fractions (10 patients). Thirty-one per cent of patientsexperienced a partial clinical response after re-irradiation, as judged by follow-up clinical notes; 27%remained stable; 32% deteriorated after re-irradiation. Patients who had Eastern Cooperative OncologyGroup performance status 0-1 at the time of retreatment lived longer. In responders, the mean durationof response was 5.1 months. The median survival after re-irradiation was 4.1 months. One patient wasreported as having memory impairment and pituitary insufficiency after 5 months of progression-freesurvival. CONCLUSION Repeat radiotherapy may be a useful treatment in carefully selected patients.With increased survival and better systemic options for patients with metastatic disease, more patientsmay be candidates for consideration of repeat WBRT for recurrent brain metastases, but prospectivestudies are needed to more clearly document their outcomes.", "metadata": {}}
+{"_id": "19419439", "title": "", "text": "Bisphosphonates in oncology: rising stars or fallen heroes.The introduction of bisphosphonates inoncology has dramatically changed the management of patients with metastatic bone disease. In thismanuscript, we thoroughly scrutinize the available body of clinical trials supporting the use ofbisphosphonates in this setting and review new and ongoing research. Additionally, we summarize thedata showing the benefits of bisphosphonate use in the prevention of treatment-induced bone loss andthe intriguing emerging evidence on the antitumor potential of some of these agents when used in theadjuvant setting. Finally, we address the need for a careful consideration of potential benefits ofbisphosphonate therapy and the risk for osteonecrosis of the jaw, a recently recognized late-toxicity oftheir use.", "metadata": {}}
+{"_id": "19427410", "title": "", "text": "IL-33, a recently identified interleukin-1 gene family member, is expressed in humanadipocytes.Inflammation occurs in adipose tissue in obesity. We have examined whether IL-33, a recentlyidentified IL-1 gene family member, and its associated receptors are expressed in human adipocytes.IL-33, IL-1RL1 and IL-1RAP gene expression was observed in human visceral white fat, in preadipocytesand in adipocytes (SGBS cells). Treatment with TNFalpha for 24h induced a 6-fold increase in IL-33mRNA level in preadipocytes and adipocytes. Time-course studies with adipocytes showed that theincrease in IL-33 mRNA with TNFalpha was maximal (>55-fold) at 12h. This response was markedlydifferent to IL-1beta (peak mRNA increase at 2h; 5.4-fold) and 1L-18 (peak mRNA increase at 6h;>1500-fold). Exposure of adipocytes to hypoxia (1% O(2), 24h) did not alter IL-33 mRNA level; inpreadipocytes, however, there was a 3-fold increase. Human adipocytes and preadipocytes expressIL-33, but the various IL-1 family members exhibit major differences in responsiveness to TNFalpha.", "metadata": {}}
+{"_id": "19450341", "title": "", "text": "Imaging techniques for assaying lymphocyte activation in actionImaging techniques have greatlyimproved our understanding of lymphocyte activation. Technical advances in spatial and temporalresolution and new labelling tools have enabled researchers to directly observe the activation process.Consequently, research using imaging approaches to study lymphocyte activation has expanded,providing an unprecedented level of cellular and molecular detail in the field. As a result, certain modelsof lymphocyte activation have been verified, others have been revised and yet others have been replacedwith new concepts. In this article, we review the current imaging techniques that are used to assesslymphocyte activation in different contexts, from whole animals to single molecules, and discuss theadvantages and potential limitations of these methods.", "metadata": {}}
+{"_id": "19460822", "title": "", "text": "Extending healthy life span--from yeast to humans.When the food intake of organisms such as yeast androdents is reduced (dietary restriction), they live longer than organisms fed a normal diet. A similar effectis seen when the activity of nutrient-sensing pathways is reduced by mutations or chemical inhibitors. Inrodents, both dietary restriction and decreased nutrient-sensing pathway activity can lower the incidenceof age-related loss of function and disease, including tumors and neurodegeneration. Dietary restrictionalso increases life span and protects against diabetes, cancer, and cardiovascular disease in rhesusmonkeys, and in humans it causes changes that protect against these age-related pathologies. Tumorsand diabetes are also uncommon in humans with mutations in the growth hormone receptor, and naturalgenetic variants in nutrient-sensing pathways are associated with increased human life span. Dietaryrestriction and reduced activity of nutrient-sensing pathways may thus slow aging by similarmechanisms, which have been conserved during evolution. We discuss these findings and their potentialapplication to prevention of age-related disease and promotion of healthy aging in humans, and thechallenge of possible negative side effects.", "metadata": {}}
+{"_id": "19464037", "title": "", "text": "Hospital and 1-year survival of patients admitted to intensive care units with acute exacerbation ofchronic obstructive pulmonary disease.OBJECTIVE To describe outcomes and identify variables associatedwith hospital and 1-year survival for patients admitted to an intensive care unit (ICU) with an acuteexacerbation of chronic obstructive pulmonary disease (COPD). DESIGN Prospective, multicenter,inception cohort study. SETTING Forty-two ICUs at 40 US hospitals. PATIENTS A total of 362 admissionsfor COPD exacerbation selected from the Acute Physiology and Chronic Health Evaluation (APACHE) IIIdatabase of 17,440 ICU admissions. MEASUREMENTS AND RESULTS Hospital mortality for the 362admissions was 24%. For the 167 patients aged 65 years or older, mortality was 30% at hospitaldischarge, 41% at 90 days, 47% at 180 days, and 59% at 1 year. Median survival for all patients was224 days, and median survival for the patients who died within 1 year was 30.5 days. On multipleregression analysis, variables associated with hospital mortality included age, severity of respiratory andnonrespiratory organ system dysfunction, and hospital length of stay before ICU admission. Developmentof nonrespiratory organ system dysfunction was the major predictor of hospital mortality (60% of totalexplanatory power) and 180-day outcomes (54% of explanatory power). Respiratory physiologicalvariables (respiratory rate, serum pH, PaCO2, PaO2, and alveolar-arterial difference in partial pressure ofoxygen [PAO2-PaO2]) indicative of advanced dysfunction were more strongly associated with 180-daymortality rates (22% of explanatory power) than hospital death rates (4% of explanatory power). Aftercontrolling for severity of illness, mechanical ventilation at ICU admission was not associated with eitherhospital mortality or subsequent survival. CONCLUSIONS Patients with COPD admitted to an ICU for anacute exacerbation have a substantial hospital mortality (24%). For patients aged 65 years or older,mortality doubles in 1 year from 30% to 59%. Hospital and longer-term mortality is closely associatedwith development of nonrespiratory organ system dysfunction; severity of the underlying respiratoryfunction substantially influences mortality following hospital discharge. The need for mechanicalventilation at ICU admission did not influence either short- or long-term outcomes. Physicians should beaware of these relationships when making treatment decisions or evaluating new therapies.", "metadata": {}}
+{"_id": "19482914", "title": "", "text": "Kindlin-3 is essential for integrin activation and platelet aggregationIntegrin-mediated platelet adhesionand aggregation are essential for sealing injured blood vessels and preventing blood loss, and excessiveplatelet aggregation can initiate arterial thrombosis, causing heart attacks and stroke. To ensure thatplatelets aggregate only at injury sites, integrins on circulating platelets exist in a low-affinity state andshift to a high-affinity state (in a process known as integrin activation or priming) after contacting awounded vessel. The shift is mediated through binding of the cytoskeletal protein Talin to the β subunitcytoplasmic tail. Here we show that platelets lacking the adhesion plaque protein Kindlin-3 cannotactivate integrins despite normal Talin expression. As a direct consequence, Kindlin-3 deficiency results insevere bleeding and resistance to arterial thrombosis. Mechanistically, Kindlin-3 can directly bind toregions of β-integrin tails distinct from those of Talin and trigger integrin activation. We have thereforeidentified Kindlin-3 as a novel and essential element for platelet integrin activation in hemostasis andthrombosis.", "metadata": {}}
+{"_id": "19485243", "title": "", "text": "Opening of compacted chromatin by early developmental transcription factors HNF3 (FoxA) andGATA-4.The transcription factors HNF3 (FoxA) and GATA-4 are the earliest known to bind the albumingene enhancer in liver precursor cells in embryos. To understand how they access sites in silentchromatin, we assembled nucleosome arrays containing albumin enhancer sequences and compactedthem with linker histone. HNF3 and GATA-4, but not NF-1, C/EBP, and GAL4-AH, bound their sites incompacted chromatin and opened the local nucleosomal domain in the absence of ATP-dependentenzymes. The ability of HNF3 to open chromatin is mediated by a high affinity DNA binding site and bythe C-terminal domain of the protein, which binds histones H3 and H4. Thus, factors that potentiatetranscription in development are inherently capable of initiating chromatin opening events.", "metadata": {}}
+{"_id": "19485649", "title": "", "text": "N- and E-cadherins in Xenopus are specifically required in the neural and non-neural ectoderm,respectively, for F-actin assembly and morphogenetic movements.Transmembrane cadherins arecalcium-dependent intercellular adhesion molecules. Recently, they have also been shown to be sites ofactin assembly during adhesive contact formation. However, the roles of actin assembly ontransmembrane cadherins during development are not fully understood. We show here, using thedeveloping ectoderm of the Xenopus embryo as a model, that F-actin assembly is a primary function ofboth N-cadherin in the neural ectoderm and E-cadherin in the non-neural (epidermal) ectoderm, and thateach cadherin is essential for the characteristic morphogenetic movements of these two tissues.However, depletion of N-cadherin and E-cadherin did not cause dissociation in these tissues at theneurula stage, probably owing to the expression of C-cadherin in each tissue. Depletion of each of thesecadherins is not rescued by the other, nor by the expression of C-cadherin, which is expressed in bothtissues. One possible reason for this is that each cadherin is expressed in a different domain of the cellmembrane. These data indicate the combinatorial nature of cadherin function, the fact that N- andE-cadherin play primary roles in F-actin assembly in addition to roles in cell adhesion, and that thisfunction is specific to individual cadherins. They also show how cell adhesion and motility can becombined in morphogenetic tissue movements that generate the form and shape of the embryonicorgans.", "metadata": {}}
+{"_id": "19487477", "title": "", "text": "Mutation of the fumarase gene in two siblings with progressive encephalopathy and fumarasedeficiency.We report an inborn error of the tricarboxylic acid cycle, fumarase deficiency, in two siblingsborn to first cousin parents. They presented with progressive encephalopathy, dystonia, leucopenia, andneutropenia. Elevation of lactate in the cerebrospinal fluid and high fumarate excretion in the urine led usto investigate the activities of the respiratory chain and of the Krebs cycle, and to finally identifyfumarase deficiency in these two children. The deficiency was profound and present in all tissuesinvestigated, affecting the cytosolic and the mitochondrial fumarase isoenzymes to the same degree.Analysis of fumarase cDNA demonstrated that both patients were homozygous for a missense mutation, aG-955-->C transversion, predicting a Glu-319-->Gln substitution. This substitution occurred in a highlyconserved region of the fumarase cDNA. Both parents exhibited half the expected fumarase activity intheir lymphocytes and were found to be heterozygous for this substitution. The present study is to ourknowledge the first molecular characterization of tricarboxylic acid deficiency, a rare inherited inbornerror of metabolism in childhood.", "metadata": {}}
+{"_id": "19489351", "title": "", "text": "Adult Neurogenesis Is Sustained by Symmetric Self-Renewal and Differentiation.Somatic stem cells havebeen identified in multiple adult tissues. Whether self-renewal occurs symmetrically or asymmetrically iskey to understanding long-term stem cell maintenance and generation of progeny for cell replacement. Inthe adult mouse brain, neural stem cells (NSCs) (B1 cells) are retained in the walls of the lateralventricles (ventricular-subventricular zone [V-SVZ]). The mechanism of B1 cell retention into adulthoodfor lifelong neurogenesis is unknown. Using multiple clonal labeling techniques, we show that the vastmajority of B1 cells divide symmetrically. Whereas 20%-30% symmetrically self-renew and can remain inthe niche for several months before generating neurons, 70%-80% undergo consuming divisionsgenerating progeny, resulting in the depletion of B1 cells over time. This cellular mechanism decouplesself-renewal from the generation of progeny. Limited rounds of symmetric self-renewal and consumingsymmetric differentiation divisions can explain the levels of neurogenesis observed throughout life.", "metadata": {}}
+{"_id": "19497526", "title": "", "text": "A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopeniaThiopurinetherapy, commonly used in autoimmune conditions, can be complicated by life-threatening leukopenia.This leukopenia is associated with genetic variation in TPMT (encoding thiopurine S-methyltransferase).Despite a lower frequency of TPMT mutations in Asians, the incidence of thiopurine-induced leukopenia ishigher in Asians than in individuals of European descent. Here we performed an Immunochip-based2-stage association study in 978 Korean subjects with Crohn's disease treated with thiopurines. Weidentified a nonsynonymous SNP in NUDT15 (encoding p. Arg139Cys) that was strongly associated withthiopurine-induced early leukopenia (odds ratio (OR) = 35.6; Pcombined = 4.88 × 10−94). In Koreans,this variant demonstrated sensitivity and specificity of 89.4% and 93.2%, respectively, forthiopurine-induced early leukopenia (in comparison to 12.1% and 97.6% for TPMT variants). Althoughrare, this SNP was also strongly associated with thiopurine-induced leukopenia in subjects withinflammatory bowel disease of European descent (OR = 9.50; P = 4.64 × 10−4). Thus, NUDT15 is apharmacogenetic determinant for thiopurine-induced leukopenia in diverse populations.", "metadata": {}}
+{"_id": "19510470", "title": "", "text": "Induction of cell cycle entry eliminates human leukemia stem cells in a mouse model of AMLCancer stemcells have been proposed to be important for initiation, maintenance and recurrence of variousmalignancies, including acute myeloid leukemia (AML). We have previously reported that CD34+CD38−human primary AML stem cells residing in the endosteal region of the bone marrow are relativelychemotherapy resistant. Using a NOD/SCID/IL2rγnull mouse model of human AML, we now show that theAML stem cells in the endosteal region are cell cycle quiescent and that these stem cells can be inducedto enter the cell cycle by treatment with granulocyte colony-stimulating factor (G-CSF). In combinationwith cell cycle-dependent chemotherapy, G-CSF treatment significantly enhances induction of apoptosisand elimination of human primary AML stem cells in vivo. The combination therapy leads to significantlyincreased survival of secondary recipients after transplantation of leukemia cells compared withchemotherapy alone.", "metadata": {}}
+{"_id": "19511011", "title": "", "text": "Reconstitution of the immune system after hematopoietic stem cell transplantation inhumansHematopoietic stem cell transplantation is associated with a severe immune deficiency. As aresult, the patient is at high risk of infections. Innate immunity, including epithelial barriers, monocytes,granulocytes, and NK cells recovers within weeks after transplantation. By contrast, adaptive immunityrecovers much slower. B- and T-cell counts normalize during the first months after transplantation, but inparticular, T-cell immunity may remain impaired for years. During the last decade, much of theunderlying mechanisms have been identified. These insights may provide new therapies to acceleraterecovery.", "metadata": {}}
+{"_id": "19521501", "title": "", "text": "Vision tests in the mouse: Functional phenotyping with electroretinography.Electroretinography (ERG) isan established diagnostic technique in clinical ophthalmology and provides objective information aboutretinal function. This technique is also applied in basic research, where animal models of hereditaryretinopathies have significantly contributed to our understanding of the composition of ERG responses ingeneral and how retinal degenerative pathologies alter retinal function specifically. Indeed,electrophysiologic assessment of transgenic mice, which are genetically engineered to mimic humanmutations that lead to retinal diseases, can be well compared with clinical data. Furthermore, limitationson examinations (e.g. length of measurement, range of light intensity) are much less of a concern whenassessing mice compared to human patients. In order to measure and analyze retinal responses properly,several important aspects have to be considered. This paper focuses on these aspects, and showsexemplary ERG data which were obtained from normal wild-type mice and from transgenic mice withspecific functional properties, namely Rho-/- (rod opsin knockout, cone function only), and Cnga3-/-(cone CNG channel deficient, rod function only) to illustrate rod and cone system contributions to ERGresponses.", "metadata": {}}
+{"_id": "19522248", "title": "", "text": "Cyclin-dependent kinase 2 is essential for meiosis but not for mitotic cell division in miceWe targeted thelocus encoding the cyclin-dependent kinase 2 (CDK2) by homologous recombination in mouse embryonicstem (ES) cells. Embryonic fibroblasts lacking CDK2 proliferate normally and become immortal aftercontinuous passage in culture. Elimination of a conditional Cdk2 allele in immortal cells does not have asignificant effect on proliferation. Cdk2−/− mice are viable and survive for up to two years, indicatingthat CDK2 is also dispensable for proliferation and survival of most cell types. But CDK2 is essential forcompletion of prophase I during meiotic cell division in male and female germ cells, an unforeseen rolefor this cell cycle kinase.", "metadata": {}}
+{"_id": "19529370", "title": "", "text": "Capsaicin-sensitive sensory nerve fibers contribute to the generation and maintenance of skeletal fracturepain.Although skeletal pain can have a marked impact on a patient's functional status and quality of life,relatively little is known about the specific populations of peripheral nerve fibers that drive non-malignantbone pain. In the present report, neonatal male Sprague-Dawley rats were treated with capsaicin orvehicle and femoral fracture was produced when the animals were young adults (15-16 weeks old).Capsaicin treatment, but not vehicle, resulted in a significant (>70%) depletion in the density ofcalcitonin-gene related peptide positive (CGRP(+)) sensory nerve fibers, but not 200 kDa neurofilament Hpositive (NF200(+)) sensory nerve fibers in the periosteum. The periosteum is a thin, cellular and fibroustissue that tightly adheres to the outer surface of all but the articulated surface of bone and appears toplay a pivotal role in driving fracture pain. In animals treated with capsaicin, but not vehicle, there was a50% reduction in the severity, but no change in the time course, of fracture-induced skeletal pain-relatedbehaviors as measured by spontaneous flinching, guarding and weight bearing. These results suggestthat both capsaicin-sensitive (primarily CGRP(+) C-fibers) and capsaicin-insensitive (primarily NF200(+)A-delta fibers) sensory nerve fibers participate in driving skeletal fracture pain. Skeletal pain can be asignificant impediment to functional recovery following trauma-induced fracture, osteoporosis-inducedfracture and orthopedic surgery procedures such as knee and hip replacement. Understanding the specificpopulations of sensory nerve fibers that need to be targeted to inhibit the generation and maintenance ofskeletal pain may allow the development of more specific mechanism-based therapies that can effectivelyattenuate acute and chronic skeletal pain.", "metadata": {}}
+{"_id": "19532163", "title": "", "text": "Surgical therapy for dystonia.Surgical treatments for dystonia have been available since the early 20thcentury, but have improved in their efficacy to adversity ratio through a combination of technologicadvances and better understanding of the role of the basal ganglia in dystonia. The word \"dystonia\"describes a phenotype of involuntary movement that may manifest from a variety of conditions. Dystoniamay affect only certain regions of the body or may be generalized. It appears to be critical to determinewhether the etiology underlying the dystonia is \"primary\" (ie, occurring from a genetic or idiopathicorigin) or \"secondary\" (ie, occurring as a result of structural, metabolic, or neurodegenerative disorders).Secondary dystonias are far more common than primary dystonias. Primary dystonias respond well topallidotomy or deep brain stimulation of the internal segment of the globus pallidum, whereas secondarydystonias appear to respond partially at best. Limited historic and current data suggest that the thalamusmay be a promising target for the treatment of secondary dystonias, but more careful, prospective,randomized studies are needed. Combinations of bilateral targets are possible with the currenttechnology of DBS, but not widely used due to surgical morbidity and expense. This article reviews thesurgical treatment of dystonia from past to present, with a focus on separating the outcomes for primaryversus secondary and generalized versus cervical dystonia.", "metadata": {}}
+{"_id": "19541444", "title": "", "text": "MEG3 imprinted gene contribution in tumorigenesis.Maternally expressed gene 3 (MEG3) is a maternallyexpressed imprinted gene representing a large noncoding RNA in which microRNAs (miRNAs) and smallnucleolar RNAs are also hosted. It is capable of interacting with cyclic AMP, p53, murine double minute 2(MDM2) and growth differentiation factor 15 (GDF15) playing a role in cell proliferation control. MEG3expression is under epigenetic control, and aberrant CpG methylation has been observed in several typesof cancer. Moreover, gene copy number loss has been reported as additional mechanism associated withtumorigenesis. MEG3 deletion seems to upregulate the paternally expressed genes and on the other handdownregulate the expression of downstream maternally expressed genes and tumor suppressor miRNAs,although there are conflicting data on the topic. MEG3 could represent a tumor suppressor gene locatedin chromosome 14q32 and its association with tumorigenesis is growing every day.", "metadata": {}}
+{"_id": "19546104", "title": "", "text": "Uptake of rosuvastatin by isolated rat hepatocytes: comparison with pravastatin.1. The liver is the targetorgan for the lipid-regulating effect of rosuvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme Areductase inhibitor, and liver-selective uptake of this drug is therefore a desirable property. The uptakekinetics of rosuvastatin were investigated and compared with those of pravastatin using isolated rathepatocytes. 2. Uptake for both drugs involved both active transport and passive diffusion processes. TheMichaelis constant (K(m)) of uptake rate for rosuvastatin (9.17 micro M) was approximately half that forpravastatin (16.5 micro M). However, the maximum uptake rate (V(max)) and carrier-mediated uptakeclearance (V(max)/K(m)) of rosuvastatin were significantly (p < 0.01) greater than those of pravastatin,and a larger contribution of carrier-mediated uptake clearance to total uptake clearance was shown forrosuvastatin (contribution ratio 0.903 versus pravastatin 0.654). 3. Sodium and chloride ions did not playa significant role in the uptake of rosuvastatin and pravastatin, but the uptake of both drugs was inhibitedboth by depletion of cellular ATP and by organic anions such as bromosulfophthalein. 4. Rosuvastatincompetitively inhibited the uptake of pravastatin, with an inhibition constant (K(i)) (2.75 micro M)relatively similar to its K(m). 5. The results suggest that an organic anion transport protein is the mainmediator of the hepatic uptake of rosuvastatin and pravastatin, which occurs in an ATP-dependentmanner. Our results indicated that rosuvastatin was taken up by the hepatocytes via the same transportsystems as pravastatin, but with a greater affinity and efficiency than pravastatin.", "metadata": {}}
+{"_id": "19561411", "title": "", "text": "Junctophilin-4, a component of the endoplasmic reticulum-plasma membrane junctions, regulates Ca2+dynamics in T cells.Orai1 and stromal interaction molecule 1 (STIM1) mediate store-operated Ca(2+)entry (SOCE) in immune cells. STIM1, an endoplasmic reticulum (ER) Ca(2+) sensor, detects storedepletion and interacts with plasma membrane (PM)-resident Orai1 channels at the ER-PM junctions.However, the molecular composition of these junctions in T cells remains poorly understood. Here, weshow that junctophilin-4 (JP4), a member of junctional proteins in excitable cells, is expressed in T cellsand localized at the ER-PM junctions to regulate Ca(2+) signaling. Silencing or genetic manipulation ofJP4 decreased ER Ca(2+) content and SOCE in T cells, impaired activation of the nuclear factor ofactivated T cells (NFAT) and extracellular signaling-related kinase (ERK) signaling pathways, anddiminished expression of activation markers and cytokines. Mechanistically, JP4 directly interacted withSTIM1 via its cytoplasmic domain and facilitated its recruitment into the junctions. Accordingly,expression of this cytoplasmic fragment of JP4 inhibited SOCE. Furthermore, JP4 also formed a complexwith junctate, a Ca(2+)-sensing ER-resident protein, previously shown to mediate STIM1 recruitment intothe junctions. We propose that the junctate-JP4 complex located at the junctions cooperatively interactswith STIM1 to maintain ER Ca(2+) homeostasis and mediate SOCE in T cells.", "metadata": {}}
+{"_id": "19565018", "title": "", "text": "The PI3K inhibitor arsenal: choose your weapon!Owing to its widespread activation in inflammation andcancer, a growing appreciation of the therapeutic potential of inhibitors of the phosphoinositide 3-kinase(PI3K) pathway has stimulated intense interest in compounds with suitable pharmacological profiles.These are primarily directed toward PI3K itself. However, as class I PI3Ks are also essential for a range ofnormal physiological processes, broad spectrum PI3K inhibition could be poorly tolerated. In recent years,patents describing a new generation of PI3K inhibitors have started to appear, with a particular focus onthe development of compounds with enhanced isoform selectivity for use as anti-cancer andanti-inflammatory therapies. However, challenges remain for the efforts to pharmacologically target thisenzyme family in a successful manner.", "metadata": {}}
+{"_id": "19571273", "title": "", "text": "Infralimbic BDNF/TrkB enhancement of GluN2B currents facilitates extinction of a cocaine-conditionedplace preference.Brain-derived neurotrophic factor (BDNF) regulates synaptic activity and behavioralflexibility, and reduction of BDNF strongly predicts psychiatric disorders and cognitive dysfunction.Restoration of BDNF-dependent activity could alleviate these impairments, but BDNF has limited clinicalutility due to its pharmacokinetics. Here we demonstrate that activation of a primary BDNF target, thetropomyosin-related kinase B (TrkB) receptor, enhances the amplitude and prolongs the decay kinetics ofN-methyl-d-aspartate receptor (NMDAR) currents in male rat infralimbic prefrontal pyramidal neurons.Moreover, these effects were prevented and reversed by blockade of NMDARs containing the GluN2Bsubunit. Our results show that this signaling cascade bidirectionally regulates extinction of acocaine-induced conditioned place preference (CPP), a task that requires behavioral flexibility. Blockadeof infralimbic TrkB receptors or GluN2B-containing NMDARs disrupted consolidation of extinction of theCPP. In contrast, extinction was strengthened by potentiation of TrkB receptor activity with infralimbicinfusions of BDNF or systemic injections of 7,8 dihydroxyflavone (7,8DHF), the newly synthesized TrkBreceptor agonist. The 7,8DHF-induced enhancement of extinction was prevented by infralimbic infusionsof a GluN2B-specific receptor antagonist, demonstrating that TrkB receptor activation enhances extinctionof cocaine-CPP via GluN2B-containing NMDARs. Together, infralimbic TrkB receptor activationstrengthens GluN2B-containing NMDAR currents to support extinction learning. TrkB receptor agonistswould therefore be useful as pharmacological adjuncts for extinction-based therapies for treatment ofpsychiatric disorders associated with reduced BDNF activity.", "metadata": {}}
+{"_id": "19572798", "title": "", "text": "Compaction of chromatin by diverse Polycomb group proteins requires localized regions of highcharge.Polycomb group (PcG) proteins are required for the epigenetic maintenance of developmentalgenes in a silent state. Proteins in the Polycomb-repressive complex 1 (PRC1) class of the PcG areconserved from flies to humans and inhibit transcription. One hypothesis for PRC1 mechanism is that itcompacts chromatin, based in part on electron microscopy experiments demonstrating that DrosophilaPRC1 compacts nucleosomal arrays. We show that this function is conserved between Drosophila andmouse PRC1 complexes and requires a region with an overrepresentation of basic amino acids. While theactive region is found in the Posterior Sex Combs (PSC) subunit in Drosophila, it is unexpectedly found ina different PRC1 subunit, a Polycomb homolog called M33, in mice. We provide experimental support forthe general importance of a charged region by predicting the compacting capability of PcG proteins fromspecies other than Drosophila and mice and by testing several of these proteins using solution assays andmicroscopy. We infer that the ability of PcG proteins to compact chromatin in vitro can be predicted bythe presence of domains of high positive charge and that PRC1 components from a variety of speciesconserve this highly charged region. This supports the hypothesis that compaction is a key aspect of PcGfunction.", "metadata": {}}
+{"_id": "19583924", "title": "", "text": "Angiopoietin-like proteins stimulate ex vivo expansion of hematopoietic stem cellsSuccessful ex vivoexpansion of hematopoietic stem cells (HSCs) would greatly benefit the treatment of disease and theunderstanding of crucial questions of stem cell biology. Here we show, using microarray studies, that theHSC-supportive mouse fetal liver CD3+ cells specifically express the proteins angiopoietin-like 2(Angptl2) and angiopoietin-like 3 (Angptl3). We observed a 24- or 30-fold net expansion of long-termHSCs by reconstitution analysis when we cultured highly enriched HSCs for 10 days in the presence ofAngptl2 or Angptl3 together with saturating levels of other growth factors. The coiled-coil domain ofAngptl2 was capable of stimulating expansion of HSCs. Furthermore, angiopoietin-like 5, angiopoietin-like7 and microfibril-associated glycoprotein 4 also supported expansion of HSCs in culture.", "metadata": {}}
+{"_id": "19603353", "title": "", "text": "Balancing co-stimulation and inhibition with BTLA and HVEMThe interaction between B- and T-lymphocyteattenuator (BTLA), an inhibitory receptor whose extracellular domain belongs to the immunoglobulinsuperfamily, and herpesvirus-entry mediator (HVEM), a co-stimulatory tumour-necrosis factor receptor,is unique in that it is the only receptor–ligand interaction that directly bridges these two families ofreceptors. This interaction has raised many questions about how receptors from two different familiescould interact and what downstream signalling events might occur as a result of receptor ligation. As wediscuss, recent studies show that engagement of HVEM with its endogenous ligand (LIGHT) from thetumour-necrosis factor family induces a powerful immune response, whereas HVEM interactions withBTLA negatively regulate T-cell responses.", "metadata": {}}
+{"_id": "19644821", "title": "", "text": "Lin28b is sufficient to drive liver cancer and necessary for its maintenance in murine models.Lin28a/b areRNA-binding proteins that influence stem cell maintenance, metabolism, and oncogenesis. Poorlydifferentiated, aggressive cancers often overexpress Lin28, but its role in tumor initiation or maintenancehas not been definitively addressed. We report that LIN28B overexpression is sufficient to initiatehepatoblastoma and hepatocellular carcinoma in murine models. We also detected Lin28b overexpressionin MYC-driven hepatoblastomas, and liver-specific deletion of Lin28a/b reduced tumor burden, extendedlatency, and prolonged survival. Both intravenous siRNA against Lin28b and conditional Lin28b deletionreduced tumor burden and prolonged survival. Igf2bp proteins are upregulated, and Igf2bp3 is requiredin the context of LIN28B overexpression to promote growth. Therefore, multiple murine modelsdemonstrate that Lin28b is both sufficient to initiate liver cancer and necessary for its maintenance.", "metadata": {}}
+{"_id": "19651306", "title": "", "text": "Nanoenzymology of the 20S proteasome: proteasomal actions are controlled by the allosterictransition.The proteasome is a major cytosolic proteolytic assembly, essential for the physiology ofeukaryotic cells. Both the architecture and enzymatic properties of the 20S proteasome are relatively wellunderstood. However, despite longstanding interest, the integration of structural and functionalproperties of the proteasome into a coherent model explaining the mechanism of its enzymatic actionshas been difficult. Recently, we used tapping mode atomic force microscopy (AFM) in liquid todemonstrate that the alpha-rings of the proteasome imaged in a top-view position repeatedly switchedbetween their open and closed conformations, apparently to control access to the central channel. Here,we show with AFM that the molecules in a side-view position acquired two stable conformations. Theoverall shapes of the 20S particles were classified as either barrel-like or cylinder-like. The relativeabundance of the two conformers depended on the nature of their interactions with ligands. Similarly tothe closed molecules in top view, the barrels predominated in control or inhibited molecules. Thecylinders and open molecules prevailed when the proteasome was observed in the presence of peptidesubstrates. Based on these data, we developed the two-state model of allosteric transitions to explain thedynamics of proteasomal structure. This model helps to better understand the observed properties of the20S molecule, and sets foundations for further studies of the structural dynamics of the proteasome.", "metadata": {}}
+{"_id": "19658917", "title": "", "text": "Changes in plasma copeptin, the c-terminal portion of arginine vasopressin during water deprivation andexcess in healthy subjects.CONTEXT The measurement of arginine vasopressin (AVP) is oftencumbersome because it is unstable with a short half-life time. AVP is derived from a larger precursorpeptide along with the more stable peptide copeptin. Copeptin is the C-terminal part of provasopressinand has been shown to be a useful tool to indicate AVP concentration in critically ill patients. OBJECTIVEThe objective of the study was to evaluate the clinical usefulness of copeptin as a new marker indisordered states of blood volume and plasma osmolality. DESIGN AND SETTING This was a prospectiveobservational study in a university hospital. PARTICIPANTS AND MAIN OUTCOME MEASURES Threetechniques with respective control studies were used in 24 healthy adults to produce changes in plasmaosmolality and/or volume: 1) a 28-h water deprivation, 2) a 17-h hypertonic saline infusion combinedwith thirsting, and 3) a hypotonic saline infusion with iv desmopressin administration during free waterintake. RESULTS Water deprivation produced a weight loss of 1.7 kg, an increase in plasma osmolality to294.8 +/- 4.3 mosmol/kg, and an increase of copeptin from 4.6 +/- 1.7 pmol/liter to 9.2 +/- 5.2pmol/liter (P < 0.0001). During hypertonic saline infusion and thirsting with a raise of plasma osmolalityto 296.1 +/- 3.4 mosmol/kg, copeptin increased from 4.9 +/- 3.0 pmol/liter to 19.9 +/- 4.8 pmol/liter (P< 0.0001). Conversely, during hypotonic saline infusion, plasma osmolality decreased to 271.3 +/- 4.1mosmol/kg, and copeptin decreased from 6.2 +/- 2.4 pmol/liter to 2.4 +/- 2.1 pmol/liter (P < 0.01).CONCLUSION Copeptin shows identical changes during disordered water states as previously shown forAVP. It might be a reliable marker of AVP secretion and substitute for the measurement of circulating AVPlevels in clinical routine.", "metadata": {}}
+{"_id": "19661996", "title": "", "text": "Propagation and recovery of intact, infectious Epstein-Barr virus from prokaryotic to human cells.Withcurrent techniques, genetic alterations of herpesviruses are difficult to perform, mostly because of thelarge size of their genomes. To solve this problem, we have designed a system that allows the cloning ofany gamma-herpesvirus in Escherichia coli onto an F factor-derived plasmid. Immortalized B cell lineswere readily established with recombinant Epstein-Barr virus (EBV), demonstrating that the Ffactor-cloned EBV genome has all the characteristics of wild-type EBV. Because any genetic modificationis possible in E. coli, this experimental approach opens the way to the genetic analysis of all EBVfunctions. Moreover, it is now feasible to generate attenuated EBV strains in vitro such that vaccinestrains can be designed. Because we incorporated the genes for hygromycin resistance and greenfluorescent protein onto the E. coli cloned EBV genome, the still open question of the EBV target cellsother than B lymphocytes will be addressed.", "metadata": {}}
+{"_id": "19673227", "title": "", "text": "Chemosensitivity profile assay of circulating cancer cells: prognostic and predictive value in epithelialtumors.The prognostic value associated with the detection of circulating tumor cells (CTCs) in metastaticbreast cancer by the CellSearch technology raise additional issues regarding the biological value of thisinformation. We postulated that a drug-resistance profile of CTCs may predict response to chemotherapyin cancer patients and therefore could be used for patient selection. One hundred 5 patients withdiagnosis of carcinoma were enrolled in a prospective trial. CTCs were isolated from peripheral blood, andpositive samples were evaluated for the expression of a panel of genes involved in anticancer drugsresistance. The drug-resistance profile was correlated with disease-free survival (DFS; patients inadjuvant setting) and time to progression (TTP; metastatic patients) in a 24-months follow-up. Objectiveresponse correlation was a secondary end point. Fifty-one percent of patients were found positive forCTCs while all blood samples from healthy donors were negative. The drug-resistance profile correlateswith DFS and TTP (p < 0.001 in both). Sensitivity of the test: able to predict treatment response in 98%of patients. Specificity of the test: 100%; no sample from healthy subject was positive for the presenceof CTCs. Positive and negative predictive values were found to be 96.5 and 100%, respectively. Weidentified a drug-resistance profile of CTCs, which is predictive of response to chemotherapy, independentof tumor type and stage of disease. This approach may represent a first step toward the individualizationof chemotherapy in cancer patients.", "metadata": {}}
+{"_id": "19675911", "title": "", "text": "Trends in heart failure incidence and survival in a community-based population.CONTEXT The epidemic ofheart failure has yet to be fully investigated, and data on incidence, survival, and sex-specific temporaltrends in community-based populations are limited. OBJECTIVE To test the hypothesis that the incidenceof heart failure has declined and survival after heart failure diagnosis has improved over time but thatsecular trends have diverged by sex. DESIGN, SETTING, AND PARTICIPANTS Population-based cohortstudy using the resources of the Rochester Epidemiology Project conducted in Olmsted County,Minnesota. Patients were 4537 Olmsted County residents (57% women; mean [SD] age, 74 [14] years)with a diagnosis of heart failure between 1979 and 2000. Framingham criteria and clinical criteria wereused to validate the diagnosis   MAIN OUTCOME MEASURES Incidence of heart failure and survival afterheart failure diagnosis. RESULTS The incidence of heart failure was higher among men (378/100 000persons; 95% confidence interval [CI], 361-395 for men; 289/100 000 persons; 95% CI, 277-300 forwomen) and did not change over time among men or women. After a mean follow-up of 4.2 years(range, 0-23.8 years), 3347 deaths occurred, including 1930 among women and 1417 among men.Survival after heart failure diagnosis was worse among men than women (relative risk, 1.33; 95% CI,1.24-1.43) but overall improved over time (5-year age-adjusted survival, 43% in 1979-1984 vs 52% in1996-2000, P<.001). However, men and younger persons experienced larger survival gains, contrastingwith less or no improvement for women and elderly persons. CONCLUSION In this community-basedcohort, the incidence of heart failure has not declined during 2 decades, but survival after onset of heartfailure has increased overall, with less improvement among women and elderly persons.", "metadata": {}}
+{"_id": "19683625", "title": "", "text": "Doxycycline induces apoptosis in PANC-1 pancreatic cancer cells.BACKGROUND Tetracyclines such asdoxycycline are reported to possess cytotoxic activity against mammalian tumor cells, but the mechanismof their effects on cell proliferation remains unclear. MATERIALS AND METHODS The antitumor effect ofdoxycycline was investigated in human pancreatic cancer cell line, PANC-1. We also investigated theeffect of doxycycline on expression of a potent proangiogenic factor, interleukin (IL)-8. RESULTS Inexcess of 20 microg/ml, cytotoxic effects of doxycycline were accompanied by G(1)-S cell cycle arrestand DNA fragmentation in PANC-1 cells. Doxycycline consistently activated transcription of p53, p21 andFas/FasL-cascade-related genes, while reducing the expression of Bcl-xL and Mcl-1. Doxycycline (5microg/ml) below the cytotoxic level suppressed endogenous and paclitaxel-induced IL-8 expression. Inthe mouse xenograft model, doxycycline treatment was shown to suppress tumor growth by 80%.CONCLUSION These data suggest that doxycycline exerts its antitumor effect by activating proapoptoticgenes, inhibiting IL-8 expression, and suppressing antiapoptotic genes.", "metadata": {}}
+{"_id": "19685306", "title": "", "text": "Orientationally invariant indices of axon diameter and density from diffusion MRI.This paper proposes andtests a technique for imaging orientationally invariant indices of axon diameter and density in whitematter using diffusion magnetic resonance imaging. Such indices potentially provide more specificmarkers of white matter microstructure than standard indices from diffusion tensor imaging.Orientational invariance allows for combination with tractography and presents new opportunities formapping brain connectivity and quantifying disease processes. The technique uses a four-compartmenttissue model combined with an optimized multishell high-angular-resolution pulsed-gradient-spin-echoacquisition. We test the method in simulation, on fixed monkey brains using a preclinical scanner and onlive human brains using a clinical 3T scanner. The human data take about one hour to acquire. Thesimulation experiments show that both monkey and human protocols distinguish distributions of axondiameters that occur naturally in white matter. We compare the axon diameter index with the mean axondiameter weighted by axon volume. The index differs from this mean and is protocol dependent, butcorrelation is good for the monkey protocol and weaker, but discernible, for the human protocol wheregreater diffusivity and lower gradient strength limit sensitivity to only the largest axons. Maps of axondiameter and density indices from the monkey and human data in the corpus callosum and corticospinaltract reflect known trends from histology. The results show orientationally invariant sensitivity to naturalaxon diameter distributions for the first time with both specialist and clinical hardware. Thisdemonstration motivates further refinement, validation, and evaluation of the precise nature of theindices and the influence of potential confounds.", "metadata": {}}
+{"_id": "19688024", "title": "", "text": "IFI16 and cGAS cooperate in the activation of STING during DNA sensing in human keratinocytesManyhuman cells can sense the presence of exogenous DNA during infection though the cytosolic DNAreceptor cyclic GMP-AMP synthase (cGAS), which produces the second messenger cyclic GMP-AMP(cGAMP). Other putative DNA receptors have been described, but whether their functions are redundant,tissue-specific or integrated in the cGAS-cGAMP pathway is unclear. Here we show that interferon-γinducible protein 16 (IFI16) cooperates with cGAS during DNA sensing in human keratinocytes, as bothcGAS and IFI16 are required for the full activation of an innate immune response to exogenous DNA andDNA viruses. IFI16 is also required for the cGAMP-induced activation of STING, and interacts with STINGto promote STING phosphorylation and translocation. We propose that the two DNA sensors IFI16 andcGAS cooperate to prevent the spurious activation of the type I interferon response.", "metadata": {}}
+{"_id": "19701340", "title": "", "text": "Oncostatic effects of the indole melatonin and expression of its cytosolic and nuclear receptors in culturedhuman melanoma cell lines.Melatonin has been shown to have oncostatic effects on malignant melanomain vitro and in vivo. We studied the growth suppressive effects of melatonin over a wide range ofconcentrations in four melanoma cell lines (SBCE2, WM-98, WM-164 and SKMEL-188) representative fordifferent growth stages and phenotype. Melanoma cells were incubated with melatonin 10(-12)-10(-3) M,and proliferation and clonogenicity was assessed at 12 h and 14 days, respectively. We also determinedthe expression of cytosolic quinone oxidoreductases NQO1, NQO2 (known as MT3 receptor) and nuclearreceptor RORalpha by RT-PCR. Melatonin at pharmacological concentrations (10(-3)-10(-7) M)suppressed proliferation in all melanoma cell lines. In SKMEL-188 cells cultured in serum-free media,melatonin at low concentrations (10(-12)-10(-10) M) also slightly attenuated the proliferation. Theeffects of pharmacological doses of melatonin were confirmed in the clonogenic assay. Expression ofNQO1 was detected in all cell lines, whereas NQO2 and nuclear receptor RORalpha including its isoformRORalpha4 were present only in SBCE2, WM-164 and WM-98. Thus, melatonin differentially suppressedproliferation in melanoma cell lines of different behaviour. The intensity of the oncostatic response tomelatonin could be related to the cell-line specific pattern of melatonin cellular receptors and cytosolicbinding protein expression.", "metadata": {}}
+{"_id": "19708993", "title": "", "text": "Lysosomal localization of TRPML3 depends on TRPML2 and the mucolipidosis-associated proteinTRPML1.Mucolipidosis type IV is an autosomal recessive lysosomal storage disorder characterized bysevere neurodegeneration, achlorhydria, and visual impairments such as corneal opacity and strabismus.The disease arises due to mutations in a group 2 transient receptor potential (TRP)-related cationchannel, TRPML1. Mammals encode two additional TRPML proteins named TRPML2 and TRPML3.Information regarding the propensity of these proteins to multimerize, their subcellular distribution andmechanisms that regulate their trafficking are limited. Here we demonstrate that TRPMLs interact to formhomo- and heteromultimers. Moreover, the presence of either TRPML1 or TRPML2 specifically influencesthe spatial distribution of TRPML3. TRPML1 and TRPML2 homomultimers are lysosomal proteins, whereasTRPML3 homomultimers are in the endoplasmic reticulum. However, TRPML3 localizes to lysosomes whencoexpressed with either TRPML1 or TRPML2 and is comparably mislocalized when lysosomal targeting ofTRPML1 and TRPML2 is disrupted. Conversely, TRPML3 does not cause retention of TRPML1 or TRPML2 inthe endoplasmic reticulum. These data demonstrate that there is a hierarchy controlling the subcellulardistributions of the TRPMLs such that TRPML1 and TRPML2 dictate the localization of TRPML3 and not viceversa.", "metadata": {}}
+{"_id": "19736671", "title": "", "text": "Evolution of metastasis revealed by mutational landscapes of chemically induced skin cancersHumantumors show a high level of genetic heterogeneity, but the processes that influence the timing and routeof metastatic dissemination of the subclones are unknown. Here we have used whole-exome sequencingof 103 matched benign, malignant and metastatic skin tumors from genetically heterogeneous mice todemonstrate that most metastases disseminate synchronously from the primary tumor, supportingparallel rather than linear evolution as the predominant model of metastasis. Shared mutations betweenprimary carcinomas and their matched metastases have the distinct A-to-T signature of the initiatingcarcinogen dimethylbenzanthracene, but non-shared mutations are primarily G-to-T, a signatureassociated with oxidative stress. The existence of carcinomas that either did or did not metastasize in thesame host animal suggests that there are tumor-intrinsic factors that influence metastatic seeding. Wealso demonstrate the importance of germline polymorphisms in determining allele-specific mutations, andwe identify somatic genetic alterations that are specifically related to initiation of carcinogenesis by Hrasor Kras mutations. Mouse tumors that mimic the genetic heterogeneity of human cancers can aid ourunderstanding of the clonal evolution of metastasis and provide a realistic model for the testing of noveltherapies.", "metadata": {}}
+{"_id": "19752008", "title": "", "text": "A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one(LY294002).Phosphatidylinositol (PtdIns) 3-kinase is an enzyme implicated in growth factor signaltransduction by associating with receptor and nonreceptor tyrosine kinases, including the platelet-derivedgrowth factor receptor. Inhibitors of PtdIns 3-kinase could potentially give a better understanding of thefunction and regulatory mechanisms of the enzyme. Quercetin, a naturally occurring bioflavinoid, waspreviously shown to inhibit PtdIns 3-kinase with an IC50 of 1.3 microgram/ml (3.8 microM); inhibitionappeared to be directed at the ATP-binding site of the kinase. Analogs of quercetin were investigated asPtdIns 3-kinase inhibitors, with the most potent ones exhibiting IC50 values in the range of 1.7-8.4micrograms/ml. In contrast, genistein, a potent tyrosine kinase inhibitor of the isoflavone class, did notinhibit PtdIns 3-kinase significantly (IC50 > 30 micrograms/ml). Since quercetin has also been shown toinhibit other PtdIns and protein kinases, other chromones were evaluated as inhibitors of PtdIns 3-kinasewithout affecting PtdIns 4-kinase or selected protein kinases. One such compound,2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (also known as2-(4-morpholinyl)-8-phenylchromone, LY294002), completely and specifically abolished PtdIns 3-kinaseactivity (IC50 = 0.43 microgram/ml; 1.40 microM) but did not inhibit PtdIns 4-kinase or tested proteinand lipid kinases. Analogs of LY294002 demonstrated a very selective structure-activity relationship, withslight changes in structure causing marked decreases in inhibition. LY294002 was shown to completelyabolish PtdIns 3-kinase activity in fMet-Leu-Phe-stimulated human neutrophils, as well as inhibitproliferation of smooth muscle cells in cultured rabbit aortic segments. Since PtdIns 3-kinase appears tobe centrally involved with growth factor signal transduction, the development of specific inhibitors againstthe kinase may be beneficial in the treatment of proliferative diseases as well as in elucidating thebiological role of the kinase in cellular proliferation and growth factor response.", "metadata": {}}
+{"_id": "19756935", "title": "", "text": "A simple two-step protocol for the purification of human pancreatic beta cellsIsolated pure human betacells would be helpful for a number of research purposes. However, lack of beta cell-specific surfaceantigens has been a major problem. We aimed to develop a simple method for human beta cell isolationbased on the initial elimination of ductal cells by their expression of carbohydrate antigen 19-9 (CA19-9),followed by positive selection of beta cells by their expression of polysialic acid–neural cell adhesionmolecule (PSA-NCAM). Cell type-specific expression of CA19-9, NCAM and PSA-NCAM was studied insections of adult human pancreas and in cultured primary endocrine and exocrine cells. Dispersed humanislet cells were purified in two steps, after 4 days of suspension culture, by binding to magneticmicrobeads coupled to antibodies against CA19-9 and PSA-NCAM. NCAM expression was detected inducts and islets in the human pancreas. In contrast, PSA-NCAM immunoreactivity was detected only inislets. PSA-NCAM staining in dispersed cells revealed that the marker is expressed in all endocrine celltypes, but not in duct cells. Purification of dispersed islet cells using PSA-NCAM microbeads alone did notcompletely eliminate contaminating duct cells. However, elimination of the duct cells by CA19-9microbeads followed by positive sorting of the PSA-NCAM-positive cells in five consecutive isletpreparations resulted in 90 to 98% pure endocrine cells, of which 89 to 97% were beta cells. We describea simple and reproducible method for purification of viable human pancreatic beta cells devoid of exocrineacini and ducts.", "metadata": {}}
+{"_id": "19770974", "title": "", "text": "Prev | Table of Contents Reports Embryonic Stem Cell Lines Derived from HumanHumanblastocyst-derived, pluripotent cell lines are described that have normal karyotypes, express high levelsof telomerase activity, and express cell surface markers that characterize primate embryonic stem cellsbut do not characterize other early lineages. After undifferentiated proliferation in vitro for 4 to 5 months,these cells still maintained the developmental potential to form trophoblast and derivatives of all threeembryonic germ layers, including gut epithelium (endoderm); cartilage, bone, smooth muscle, andstriated muscle (mesoderm); and neural epithelium, embryonic ganglia, and stratified squamousepithelium (ectoderm). These cell lines should be useful in human developmental biology, drug discovery,and transplantation medicine.", "metadata": {}}
+{"_id": "19799455", "title": "", "text": "Ascorbic-acid transporter Slc23a1 is essential for vitamin C transport into the brain and for perinatalsurvivalThe only proven requirement for ascorbic acid (vitamin C) is in preventing scurvy, presumablybecause it is a cofactor for hydroxylases required for post-translational modifications that stabilizecollagen. We have created mice deficient in the mouse ortholog (solute carrier family 23 member 1 orSlc23a1) of a rat ascorbic-acid transporter, Svct2 (ref. 4). Cultured embryonic fibroblasts fromhomozygous Slc23a1−/− mice had less than 5% of normal ascorbic-acid uptake. Ascorbic-acid levelswere undetectable or markedly reduced in the blood and tissues of Slc23a1−/− mice. Prenatalsupplementation of pregnant females did not elevate blood ascorbic acid in Slc23a1−/− fetuses,suggesting Slc23a1 is important in placental ascorbic-acid transport. Slc23a1−/− mice died within a fewminutes of birth with respiratory failure and intraparenchymal brain hemorrhage. Lungs showed nopostnatal expansion but had normal surfactant protein B levels. Brain hemorrhage was unlikely to besimply a form of scurvy since Slc23a1−/− mice showed no hemorrhage in any other tissues and their skinhad normal skin 4-hydroxyproline levels despite low ascorbic-acid content. We conclude that Slc23a1 isrequired for transport of ascorbic acid into many tissues and across the placenta. Deficiency of thetransporter is lethal in newborn mice, thereby revealing a previously unrecognized requirement forascorbic acid in the perinatal period.", "metadata": {}}
+{"_id": "19800147", "title": "", "text": "MVP-mediated exosomal sorting of miR-193a promotes colon cancer progressionExosomes are emergingmediators of intercellular communication; whether the release of exosomes has an effect on the exosomedonor cells in addition to the recipient cells has not been investigated to any extent. Here, we examinedifferent exosomal miRNA expression profiles in primary mouse colon tumour, liver metastasis of coloncancer and naive colon tissues. In more advanced disease, higher levels of tumour suppressor miRNAsare encapsulated in the exosomes. miR-193a interacts with major vault protein (MVP). Knockout of MVPleads to miR-193a accumulation in the exosomal donor cells instead of exosomes, inhibiting tumourprogression. Furthermore, miR-193a causes cell cycle G1 arrest and cell proliferation repression throughtargeting of Caprin1, which upregulates Ccnd2 and c-Myc. Human colon cancer patients with moreadvanced disease show higher levels of circulating exosomal miR-193a. In summary, our datademonstrate that MVP-mediated selective sorting of tumour suppressor miRNA into exosomes promotestumour progression.", "metadata": {}}
+{"_id": "19804204", "title": "", "text": "Casual blood pressure and neurocognitive function in children with chronic kidney disease: a report of thechildren with chronic kidney disease cohort study.BACKGROUND AND OBJECTIVES Children with chronickidney disease (CKD) are at risk for cognitive dysfunction, and over half have hypertension. Data on thepotential contribution of hypertension to CKD-associated neurocognitive deficits in children are limited.Our objective was to determine whether children with CKD and elevated BP (EBP) had decreasedperformance on neurocognitive testing compared with children with CKD and normal BP. DESIGN,SETTING, PARTICIPANTS, & MEASUREMENTS This was a cross-sectional analysis of the relation betweenauscultatory BP and neurocognitive test performance in children 6 to 17 years enrolled in the ChronicKidney Disease in Children (CKiD) project. RESULTS Of 383 subjects, 132 (34%) had EBP (systolic BPand/or diastolic BP ≥90(th) percentile). Subjects with EBP had lower mean (SD) scores on WechslerAbbreviated Scales of Intelligence (WASI) Performance IQ than those with normal BP (normal BP versusEBP, 96.1 (16.7) versus 92.4 (14.9), P = 0.03) and WASI Full Scale IQ (97.0 (16.2) versus 93.4 (16.5), P= 0.04). BP index (subject's BP/95(th) percentile BP) correlated inversely with Performance IQ score(systolic, r = -0.13, P = 0.01; diastolic, r = -0.19, P < 0.001). On multivariate analysis, the associationbetween lower Performance IQ score and increased BP remained significant after controlling fordemographic and disease-related variables (EBP, β = -3.7, 95% confidence interval [CI]: -7.3 to -0.06;systolic BP index, β = -1.16 to 95% CI: -2.1, -0.21; diastolic BP index, β = -1.17, 95% CI: -1.8 to-0.55). CONCLUSIONS Higher BP was independently associated with decreased WASI Performance IQscores in children with mild-to-moderate CKD.", "metadata": {}}
+{"_id": "19822046", "title": "", "text": "Bone marrow failure and developmental delay caused by mutations in poly(A)-specific ribonuclease(PARN).BACKGROUND Deadenylation regulates RNA function and fate. Poly(A)-specific ribonuclease(PARN) is a deadenylase that processes mRNAs and non-coding RNA. Little is known about the biologicalsignificance of germline mutations in PARN. METHODS We identified mutations in PARN in patients withhaematological and neurological manifestations. Genomic, biochemical and knockdown experiments inhuman marrow cells and in zebrafish have been performed to clarify the role of PARN in the humandisease. RESULTS We identified large monoallelic deletions in PARN in four patients with developmentaldelay or mental illness. One patient in particular had a severe neurological phenotype, centralhypomyelination and bone marrow failure. This patient had an additional missense mutation on thenon-deleted allele and severely reduced PARN protein and deadenylation activity. Cells from this patienthad impaired oligoadenylation of specific H/ACA box small nucleolar RNAs. Importantly, PARN-deficientpatient cells manifested short telomeres and an aberrant ribosome profile similar to those described insome variants of dyskeratosis congenita. Knocking down PARN in human marrow cells and zebrafishimpaired haematopoiesis, providing further evidence for a causal link with the human disease.CONCLUSIONS Large monoallelic mutations of PARN can cause developmental/mental illness. BiallelicPARN mutations cause severe bone marrow failure and central hypomyelination.", "metadata": {}}
+{"_id": "19824183", "title": "", "text": "The changing epidemiology of malaria in Ifakara Town, southern Tanzania.Between 1995 and 2000 therewere marked changes in the epidemiology of malaria in Ifakara, southern Tanzania. We documentedthese changes using parasitological and clinical data from a series of community- and hospital-basedstudies involving children up to the age of 5 years. There was a right shift and lowering in the age-specificparasite prevalence in the community-based cohort studies. The incidence of clinical malaria inplacebo-receiving infants in additional study cohorts dropped from 0.8 in 1995 to 0.43 episodes per infantper year in 2000, an incidence rate ratio of 0.53 (95% confidence interval: 0.404, 0.70, P<0.0001). Atthe same time, there was an increase in the total number of malaria admissions and a marked right shiftin the age pattern of these admissions (median age in 1995 1.55 years vs. 2.33 in 2000, P<0.0001).However, the burden of malaria deaths remained in infants. We discuss how these dramatic changes inthe epidemiology of malaria may have arisen from the use of currently available malaria control tools.Caution is required in the interpretation of hospital-based data as it is likely to underestimate the impactof anaemia on mortality in the community, where most paediatric deaths occur. Even in low/moderatemalaria transmission settings, where older children suffer most malaria episodes, targeting effectivemalaria control at infants may produce important reductions in infant mortality caused by malaria.", "metadata": {}}
+{"_id": "19828689", "title": "", "text": "MicroRNA-192 in diabetic kidney glomeruli and its function in TGF-beta-induced collagen expression viainhibition of E-box repressors.Key features of diabetic nephropathy (DN) include the accumulation ofextracellular matrix proteins such as collagen 1-alpha 1 and -2 (Col1a1 and -2). Transforming growthfactor beta1 (TGF-beta), a key regulator of these extracellular matrix genes, is increased in mesangialcells (MC) in DN. By microarray profiling, we noted that TGF-beta increased Col1a2 mRNA in mouse MC(MMC) but also decreased mRNA levels of an E-box repressor, deltaEF1. TGF-beta treatment or shorthairpin RNAs targeting deltaEF1 increased enhancer activity of upstream E-box elements in the Col1a2gene. TGF-beta also decreased the expression of Smad-interacting protein 1 (SIP1), another E-boxrepressor similar to deltaEF1. Interestingly, we noted that SIP1 is a target of microRNA-192 (miR-192), akey miR highly expressed in the kidney. miR-192 levels also were increased by TGF-beta in MMC.TGF-beta treatment or transfection with miR-192 decreased endogenous SIP1 expression as well asreporter activity of a SIP1 3' UTR-containing luciferase construct in MMC. Conversely, a miR-192 inhibitorenhanced the luciferase activity, confirming SIP1 to be a miR-192 target. Furthermore, miR-192synergized with deltaEF1 short hairpin RNAs to increase Col1a2 E-box-luc activity. Importantly, the invivo relevance was noted by the observation that miR-192 levels were enhanced significantly in glomeruliisolated from streptozotocin-injected diabetic mice as well as diabetic db/db mice relative tocorresponding nondiabetic controls, in parallel with increased TGF-beta and Col1a2 levels. These resultsuncover a role for miRs in the kidney and DN in controlling TGF-beta-induced Col1a2 expression bydown-regulating E-box repressors.", "metadata": {}}
+{"_id": "19843244", "title": "", "text": "Activation of PAR(2) receptors sensitizes primary afferents and causes leukocyte rolling and adherence inthe rat knee joint.BACKGROUND AND PURPOSE The PAR(2) receptors are involved in chronic arthritis bymechanisms that are as yet unclear. Here, we examined PAR(2) activation in the rat knee joint.EXPERIMENTAL APPROACH PAR(2) in rat knee joint dorsal root ganglia (DRG) cells at L3-L5, retrogradelylabelled with Fluoro-gold (FG) were demonstrated immunohistochemically. Electrophysiological recordingsfrom knee joint nerve fibres in urethane anaesthetized Wistar rats assessed the effects of stimulatingjoint PAR(2) with its activating peptide, 2-furoyl-LIGRLO-NH(2) (1-100 nmol·100 μL(-1) , via closeintra-arterial injection). Fibre firing rate was recorded during joint rotations before and 15 min afteradministration of PAR(2) activating peptide or control peptide. Leukocyte kinetics in the synovialvasculature upon PAR(2) activation were followed by intravital microscopy for 60 min after perfusion of2-furoyl-LIGRLO-NH(2) or control peptide. Roles for transient receptor potential vanilloid-1 (TRPV1) orneurokinin-1 (NK(1) ) receptors in the PAR(2) responses were assessed using the selective antagonists,SB366791 and RP67580 respectively. KEY RESULTS PAR(2) were expressed in 59 ± 5% of FG-positiveDRG cells; 100 nmol 2-furoyl-LIGRLO-NH(2) increased joint fibre firing rate during normal and noxiousrotation, maximal at 3 min (normal; 110 ± 43%, noxious; 90 ± 31%). 2-Furoyl-LIGRLO-NH(2) alsosignificantly increased leukocyte rolling and adhesion over 60 min. All these effects were blocked bypre-treatment with SB366791 and RP67580 (P < 0.05 compared with 2-furoyl-LIGRLO-NH(2) alone).CONCLUSIONS AND IMPLICATIONS PAR(2) receptors play an acute inflammatory role in the knee jointvia TRPV1- and NK(1) -dependent mechanisms involving both PAR(2) -mediated neuronal sensitizationand leukocyte trafficking.", "metadata": {}}
+{"_id": "19851614", "title": "", "text": "Polyphosphate kinase 1, a central node in the stress response network of Mycobacterium tuberculosis,connects the two-component systems MprAB and SenX3-RegX3 and the extracytoplasmic function sigmafactor, sigma E.Polyphosphate (poly P) metabolism regulates the stress response in mycobacteria. Herewe describe the regulatory architecture of a signal transduction system involving the two-componentsystem (TCS) SenX3-RegX3, the extracytoplasmic function sigma factor sigma E (SigE) and the polyP-synthesizing enzyme polyphosphate kinase 1 (PPK1). The ppk1 promoter of Mycobacteriumtuberculosis is activated under phosphate starvation. This is attenuated upon deletion of an imperfectpalindrome likely representing a binding site for the response regulator RegX3, a component of thetwo-component system SenX3-RegX3 that responds to phosphate starvation. Binding of phosphorylatedRegX3 to this site was confirmed by electrophoretic mobility shift assay. The activity of the ppk1promoter was abrogated upon deletion of a putative SigE binding site. Pull-down of SigE from M.tuberculosis lysates of phosphate-starved cells with a biotinylated DNA harbouring the SigE binding siteconfirmed the likely binding of SigE to the ppk1 promoter. In vitro transcription corroborated theinvolvement of SigE in ppk1 transcription. Finally, the overexpression of RseA (anti-SigE) attenuatedppk1 expression under phosphate starvation, supporting the role of SigE in ppk1 transcription. Theregulatory elements identified in ppk1 transcription in this study, combined with our earlier observationthat PPK1 is itself capable of regulating sigE expression via the MprAB TCS, suggest the presence ofmultiple positive-feedback loops in this signalling circuit. In combination with the sequestering effect ofRseA, we hypothesize that this architecture could be linked to bistability in the system that, in turn, couldbe a key element of persistence in M. tuberculosis.", "metadata": {}}
+{"_id": "19854543", "title": "", "text": "Natural history of asymptomatic unruptured cerebral aneurysms evaluated at CT angiography: growthand rupture incidence and correlation with epidemiologic risk factors.PURPOSE To characterize therelationship between aneurysm size and epidemiologic risk factors with growth and rupture by usingcomputed tomographic (CT) angiography. MATERIALS AND METHODS In this HIPAA-compliant,institutional review board approved study, patients with known asymptomatic unruptured intracerebralaneurysms were followed up longitudinally with CT angiographic examinations. Growth was defined as anincrease in one or more dimensions above the measurement error, and at least 5% volume by using theABC/2 method. Associations of epidemiologic factors with aneurysm growth and rupture were analyzedby using logistic regression analysis. Intra- and interobserver agreement coefficients for dimension,volume, and growth were evaluated by using the Pearson correlation coefficient and difference of meanswith 95% confidence intervals, the agreement statistic, and the McNemar χ(2). RESULTS Patients (n =165) with aneurysms (n = 258) had a mean follow-up time of 2.24 years from time of diagnosis.Forty-six of 258 (18%) aneurysms in 38 patients grew larger. Spontaneous rupture occurred in four of228 (1.8%) intradural aneurysms of average size (6.2 mm). Risk of aneurysm rupture per patient-yearwas 2.4% (95% CI: 0.5%, 7.12%) with growth and 0.2% (95% CI: 0.006%, 1.22%) without growth (P= .034). There was a 12-fold higher risk of rupture for growing aneurysms (P < .002), with high intra-and interobserver correlation coefficients for size, volume, and growth. Tobacco smoking (3.806, onedegree of freedom; P < .015,) and initial size (5.895, two degrees of freedom; P < .051) wereindependent covariates, predicting 78.4% of growing aneurysms. CONCLUSION These results supportimaging follow-up of all patients with aneurysms, including those whose aneurysms are smaller than thecurrent 7-mm treatment threshold. Aneurysm growth, size, and smoking were associated with increasedrupture risk.", "metadata": {}}
+{"_id": "19854744", "title": "", "text": "A search for the presence of the enteroviral capsid protein VP1 in pancreases of patients with Type 1(insulin-dependent) diabetes and pancreases and hearts of infants who died of coxsackieviralmyocarditisUsing an antiserum raised to a recombinant coxsackie virus B3 capsid protein, VP1, animmunocytochemical technique was developed which was capable of detecting the presence of allcoxsackie B viruses in formalin fixed paraffin embedded infected tissue culture cells. This technique wastested on autopsy heart and pancreas from 21 patients who were thought to have died of acutecoxsackievirus B myocarditis. Cardiac myocytes were positive for the VP1 protein in 12 of 20 cases wherethe heart was available for study. Insulitis was present in the pancreas in seven of these cases and in allseven islet endocrine cells containing VP1 were found. VP1 was only rarely found in exocrine pancreas. Inheart and pancreas, cells shown to contain VP1 usually showed signs of necrosis. Autopsy pancreasesfrom 88 patients who had died at clinical presentation of Type 1 (insulin-dependent) diabetes mellitusshowed no evidence of the presence of VP1. The continuing destruction of insulin-secreting B cells seen atthe time of death in the diabetic pancreas is unlikely to be due to a direct cytopathic effect of a coxsackieB virus. However, this study does not exclude the possibility that a persistent infection of B cells by adefective enterovirus may result in their destruction by an autoimmune mechanism.", "metadata": {}}
+{"_id": "19855358", "title": "", "text": "Direct reprogramming of mouse fibroblasts to cardiomyocyte-like cells using Yamanaka factors onengineered poly(ethylene glycol) (PEG) hydrogels.Direct reprogramming strategies enable rapidconversion of somatic cells to cardiomyocytes or cardiomyocyte-like cells without going through thepluripotent state. A recently described protocol couples Yamanaka factor induction with pluripotencyinhibition followed by BMP4 treatment to achieve rapid reprogramming of mouse fibroblasts to beatingcardiomyocyte-like cells. The original study was performed using Matrigel-coated tissue culturepolystyrene (TCPS), a stiff material that also non-specifically adsorbs serum proteins. Proteinadsorption-resistant poly(ethylene glycol) (PEG) materials can be covalently modified to present preciseconcentrations of adhesion proteins or peptides without the unintended effects of non-specificallyadsorbed proteins. Here, we describe an improved protocol that incorporates custom-engineeredmaterials. We first reproduced the Efe et al. protocol on Matrigel-coated TCPS (the original material),reprogramming adult mouse tail-tip mouse fibroblasts (TTF) and mouse embryonic fibroblasts (MEF) tocardiomyocyte-like cells that demonstrated striated sarcomeric α-actinin staining, spontaneous calciumtransients, and visible beating. We then designed poly(ethylene glycol) culture substrates to promoteMEF adhesion via laminin and RGD-binding integrins. PEG hydrogels improved proliferation andreprogramming efficiency (evidenced by beating patch number and area, gene expression, and flowcytometry), yielding almost twice the number of sarcomeric α-actinin positive cardiomyocyte-like cells asthe originally described substrate. These results illustrate that cellular reprogramming may be enhancedusing custom-engineered materials.", "metadata": {}}
+{"_id": "19878070", "title": "", "text": "Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausalosteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) StudyGroup.CONTEXT Risedronate, a potent bisphosphonate, has been shown to be effective in the treatmentof Paget disease of bone and other metabolic bone diseases but, to our knowledge, it has not beenevaluated in the treatment of established postmenopausal osteoporosis. OBJECTIVE To test the efficacyand safety of daily treatment with risedronate to reduce the risk of vertebral and other fractures inpostmenopausal women with established osteoporosis. DESIGN, SETTING, AND PARTICIPANTSRandomized, double-blind, placebo-controlled trial of 2458 ambulatory postmenopausal women youngerthan 85 years with at least 1 vertebral fracture at baseline who were enrolled at 1 of 110 centers in NorthAmerica conducted between December 1993 and January 1998. INTERVENTIONS Subjects wererandomly assigned to receive oral treatment for 3 years with risedronate (2.5 or 5 mg/d) or placebo. Allsubjects received calcium, 1000 mg/d. Vitamin D (cholecalciferol, up to 500 IU/d) was provided ifbaseline levels of 25-hydroxyvitamin D were low. MAIN OUTCOME MEASURES Incidence of new vertebralfractures as detected by quantitative and semiquantitative assessments of radiographs; incidence ofradiographically confirmed nonvertebral fractures and change from baseline in bone mineral density asdetermined by dual x-ray absorptiometry. RESULTS The 2.5 mg/d of risedronate arm was discontinuedafter 1 year; in the placebo and 5 mg/d of risedronate arms, 450 and 489 subjects, respectively,completed all 3 years of the trial. Treatment with 5 mg/d of risedronate, compared with placebo,decreased the cumulative incidence of new vertebral fractures by 41 % (95% confidence interval [CI],18%-58%) over 3 years (11.3 % vs 16.3%; P= .003). A fracture reduction of 65% (95% CI, 38%-81 %)was observed after the first year (2.4% vs 6.4%; P<.001). The cumulative incidence of nonvertebralfractures over 3 years was reduced by 39% (95% CI, 6%-61 %) (5.2 % vs 8.4%; P = .02). Bone mineraldensity increased significantly compared with placebo at the lumbar spine (5.4% vs 1.1 %), femoral neck(1.6% vs -1.2%), femoral trochanter (3.3% vs -0.7%), and midshaft of the radius (0.2% vs -1.4%).Bone formed during risedronate treatment was histologically normal. The overall safety profile ofrisedronate, including gastrointestinal safety, was similar to that of placebo. CONCLUSIONS These datasuggest that risedronate therapy is effective and well tolerated in the treatment of women withestablished postmenopausal osteoporosis.", "metadata": {}}
+{"_id": "19882228", "title": "", "text": "Hypoxia — a key regulatory factor in tumour growthCells undergo a variety of biological responses whenplaced in hypoxic conditions, including activation of signalling pathways that regulate proliferation,angiogenesis and death. Cancer cells have adapted these pathways, allowing tumours to survive andeven grow under hypoxic conditions, and tumour hypoxia is associated with poor prognosis andresistance to radiation therapy. Many elements of the hypoxia-response pathway are therefore goodcandidates for therapeutic targeting.", "metadata": {}}
+{"_id": "19912367", "title": "", "text": "Loss of fibronectin from the aged stem cell niche affects the regenerative capacity of skeletal muscle inmiceAge-related changes in the niche have long been postulated to impair the function of somatic stemcells. Here we demonstrate that the aged stem cell niche in skeletal muscle contains substantiallyreduced levels of fibronectin (FN), leading to detrimental consequences for the function and maintenanceof muscle stem cells (MuSCs). Deletion of the gene encoding FN from young regenerating musclesreplicates the aging phenotype and leads to a loss of MuSC numbers. By using an extracellular matrix(ECM) library screen and pathway profiling, we characterize FN as a preferred adhesion substrate forMuSCs and demonstrate that integrin-mediated signaling through focal adhesion kinase and the p38mitogen-activated protein kinase pathway is strongly de-regulated in MuSCs from aged mice because ofinsufficient attachment to the niche. Reconstitution of FN levels in the aged niche remobilizes stem cellsand restores youth-like muscle regeneration. Taken together, we identify the loss of stem cell adhesion toFN in the niche ECM as a previously unknown aging mechanism.", "metadata": {}}
+{"_id": "19922508", "title": "", "text": "Monitoring starvation-induced reactive oxygen species formation.Reactive oxygen species (ROS) arepotentially harmful to cells because of their ability to oxidize cell constituents such as DNA, proteins, andlipids. However, at low levels, and under tight control, this feature makes them excellent modifiers in avariety of signal transduction pathways, including autophagy. Autophagy was traditionally associated withoxidative stress, acting in the degradation of oxidized proteins and organelles. Recently, a signaling rolewas suggested for ROS in the regulation of autophagy, leading, under different circumstances, either tosurvival or to death. To study the effects of ROS on this pathway, one must determine the localization,intensity, kinetics, and essentiality of the oxidative signal in autophagy. Moreover, once characterized,detection and manipulation of ROS formation could be used to monitor and control autophagic activity. Inthis chapter we discuss methods to examine ROS in the context of autophagy.", "metadata": {}}
+{"_id": "19945096", "title": "", "text": "Why do patients with multimorbidity in England report worse experiences in primary care? Evidence fromthe General Practice Patient SurveyOBJECTIVES To describe and explain the primary care experiences ofpeople with multiple long-term conditions in England. DESIGN AND METHODS Using questionnaire datafrom 906,578 responders to the English 2012 General Practice Patient Survey, we describe the primarycare experiences of patients with long-term conditions, including 583,143 patients who reported one ormore long-term conditions. We employed mixed effect logistic regressions to analyse data on six itemscovering three care domains (access, continuity and communication) and a single item on overall primarycare experience. We controlled for sociodemographic characteristics, and for general practice using arandom effect, and further, controlled for, and explored the importance of, health-related quality of lifemeasured using the EuroQoL (EQ-5D) scale. RESULTS Most patients with long-term conditions report apositive experience of care at their general practice (after adjusting for sociodemographic characteristicsand general practice, range 74.0-93.1% reporting positive experience of care across seven questions)with only modest variation by type of condition. For all three domains of patient experience, an increasingnumber of comorbid conditions is associated with a reducing percentage of patients reporting a positiveexperience of care. For example, compared with respondents with no long-term condition, the OR forreporting a positive experience is 0.83 (95% CI 0.80 to 0.87) for respondents with four or morelong-term conditions. However, this relationship is no longer observed after adjusting for health-relatedquality of life (OR (95% CI) single condition=1.23 (1.21 to 1.26); four or more conditions=1.31 (1.25 to1.37)), with pain making the greatest difference among five quality of life variables included in theanalysis. CONCLUSIONS Patients with multiple long-term conditions more frequently report worseexperiences in primary care. However, patient-centred measures of health-related quality of life,especially pain, are more important than the number of conditions in explaining why patients withmultiple long-term conditions report worse experiences of care.", "metadata": {}}
+{"_id": "19950357", "title": "", "text": "The rice FISH BONE gene encodes a tryptophan aminotransferase, which affects pleiotropic auxin-relatedprocesses.Auxin is a fundamental plant hormone and its localization within organs plays pivotal roles inplant growth and development. Analysis of many Arabidopsis mutants that were defective in auxinbiosynthesis revealed that the indole-3-pyruvic acid (IPA) pathway, catalyzed by the TRYPTOPHANAMINOTRANSFERASE OF ARABIDOPSIS (TAA) and YUCCA (YUC) families, is the major biosyntheticpathway of indole-3-acetic acid (IAA). In contrast, little information is known about the molecularmechanisms of auxin biosynthesis in rice. In this study, we identified a auxin-related rice mutant, fishbone (fib). FIB encodes an orthologue of TAA genes and loss of FIB function resulted in pleiotropicabnormal phenotypes, such as small leaves with large lamina joint angles, abnormal vasculardevelopment, small panicles, abnormal organ identity and defects in root development, together with areduction in internal IAA levels. Moreover, we found that auxin sensitivity and polar transport activitywere altered in the fib mutant. From these results, we suggest that FIB plays a pivotal role in IAAbiosynthesis in rice and that auxin biosynthesis, transport and sensitivity are closely interrelated.", "metadata": {}}
+{"_id": "19951373", "title": "", "text": "Successful mouse cloning of an outbred strain by trichostatin A treatment after somatic nucleartransfer.Although the somatic cloning technique has been used for numerous applications and basicresearch of reprogramming in various species, extremely low success rates have plagued this techniquefor a decade. Further in mice, the \"clonable\" strains have been limited to mainly hybrid F1 strains such asB6D2F1. Recently, we established a new efficient cloning technique using trichostatin A (TSA) which leadsto a 2-5 fold increase in success rates for mouse cloning of B6D2F1 cumulus cells. To further test thevalidity of this TSA cloning technique, we tried to clone the adult ICR mouse, an outbred strain, which hasnever been directly cloned before. Only when TSA was used did we obtain both male and female clonedmice from cumulus and fibroblast cells of adult ICR mice with 4-5% success rates, which is comparable to5-7% of B6D2F1. Thus, the TSA treatment is the first cloning technique to allow us to successfully cloneoutbred mice, demonstrating that this technique not only improves the success rates of cloning fromhybrid strains, but also enables mouse cloning from normally \"unclonable\" strains.", "metadata": {}}
+{"_id": "19957813", "title": "", "text": "A Genome-wide CRISPR Death Screen Identifies Genes Essential for Oxidative Phosphorylation.Oxidativephosphorylation (OXPHOS) is the major pathway for ATP production in humans. Deficiencies in OXPHOScan arise from mutations in either mitochondrial or nuclear genomes and comprise the largest collectionof inborn errors of metabolism. At present we lack a complete catalog of human genes and pathwaysessential for OXPHOS. Here we introduce a genome-wide CRISPR \"death screen\" that actively selectsdying cells to reveal human genes required for OXPHOS, inspired by the classic observation that humancells deficient in OXPHOS survive in glucose but die in galactose. We report 191 high-confidence hitsessential for OXPHOS, including 72 underlying known OXPHOS diseases. Our screen reveals a functionalmodule consisting of NGRN, WBSCR16, RPUSD3, RPUSD4, TRUB2, and FASTKD2 that regulates themitochondrial 16S rRNA and intra-mitochondrial translation. Our work yields a rich catalog of genesrequired for OXPHOS and, more generally, demonstrates the power of death screening for functionalgenomic analysis.", "metadata": {}}
+{"_id": "19958277", "title": "", "text": "RecQ helicases: caretakers of the genomeRecQ helicases are highly conserved from bacteria to man.Germline mutations in three of the five known family members in humans give rise to debilitatingdisorders that are characterized by, amongst other things, a predisposition to the development of cancer.One of these disorders — Bloom's syndrome — is uniquely associated with a predisposition to cancers ofall types. So how do RecQ helicases protect against cancer? They seem to maintain genomic stability byfunctioning at the interface between DNA replication and DNA repair.", "metadata": {}}
+{"_id": "19961177", "title": "", "text": "Mortality from causes amenable and non-amenable to medical care: the experience of easternEurope.OBJECTIVE To investigate comparative national trends in mortality from conditions amenable totimely, appropriate medical care and from those considered not to be amenable to such care. DESIGNAnalysis of trends in direct age standardised mortality from the 1950s to 1987. SETTING Four easternEuropean nations (Hungary, Czechoslovakia, Poland, the German Democratic Republic) and two westernEuropean (the Federal Republic of Germany and England and Wales) and two North American nations(United States and Canada). SUBJECTS The total populations of the relevant countries during the periodexamined. MAIN OUTCOME MEASURES Proportional changes over time in age standardised mortality.Mortality from amenable and non-amenable causes was restricted to the age group 0-64. RESULTS Adivergence in the trends for all cause mortality between eastern Europe and the western nations occurredin about 1970, when the rates in western countries steadily declined but those in eastern Europeremained fairly static. In the age group 0-64 mortality from causes considered amenable to medical carefell less quickly in eastern Europe than in the West, particularly after 1970. In the same age group,mortality from non-amenable causes rose in eastern European countries from the late 1960s comparedwith substantial declines in such mortality in the West. CONCLUSIONS Non-amenable causes of deathseem to be the principal, but not exclusive, reason for lack of improvement in trends in all causemortality in eastern Europe from 1970. The agenda for action in eastern Europe should give priority to ahealthier lifestyle and improvement of the environment though not neglect enhancements in the qualityand efficiency of direct health services.", "metadata": {}}
+{"_id": "19966976", "title": "", "text": "Dynamic regulation of heterochromatin function via phosphorylation of HP1-familyproteins.Heterochromatin is characterized by methylation of histone H3 at lysine 9, which is recognizedby well-conserved HP1-family proteins. Heterochromatin participates in various chromosome functions,which include transcriptional gene silencing and sister-chromatid cohesion. These heterochromaticfunctions are carried out by various effector proteins that associate with HP1-family proteins; however,the regulation of this association with the effectors is not well understood. Recently, we showed thatphosphorylation of the fission-yeast HP1 homolog Swi6 regulates the association of the transcriptionalregulators differentially and changes the transcriptional activity of heterochromatin, without affectingsister-chromatid cohesion. This study, together with another study performed using other systems,indicates that phosphorylation of HP1/Swi6 provides a dynamic pathway for the differential regulation ofheterochromatin in response to inter- and intracellular signals.", "metadata": {}}
+{"_id": "19970015", "title": "", "text": "Modeling neurogenesis impairment in Down syndrome with induced pluripotent stem cells from Trisomy21 amniotic fluid cells.Down syndrome (DS), or Trisomy 21 (T21) syndrome, one of the most commonchromosomal abnormalities, is caused by an extra duplication of chromosome 21. In studies of neurondevelopment, experimental models based on human cells are considered to be the most desired andaccurate for basic research. The generation of diseased induced pluripotetn stem (iPS) cell is a criticalstep in understanding the developmental stages of complex neuronal diseases. Here, we generatedhuman DS iPS cell lines from second trimester amniotic fluid (AF) cells with T21 by co-expressingYamanaka factors through lentiviral delivery and subsequently differentiated them into neuronalprogenitor cells (NPCs) for further analyses. T21 AF-iPS cells were characterized for the expression ofpluripotent markers and for their ability to differentiate into all three germ layers by forming embryoidbodies in vitro and teratomas in vivo. The T21 AF-iPS cells maintained their unique pattern ofchromosomal karyotypes: three pairs of chromosome 21. The level of amyloid precursor protein wassignificantly increased in NPCs derived from T21 AF-iPS cells compared with NPCs from normal AF-iPScells. The expression levels of miR-155 and miR-802 in T21 AF-iPS-NPCs were highly elevated in thepresence of low expression of MeCP2. We observed that T21 iPS-NPCs generated fewer neuronscompared with controls. T21 iPS-NPCs exhibit developmental defects during neurogenesis. Our findingssuggest that T21 AF-iPS cells serve as a good source to further elucidate the impairment neurogenesis ofDS and the onset of Alzheimer's disease.", "metadata": {}}
+{"_id": "19974105", "title": "", "text": "Control over DNA replication in time and space.DNA replication is precisely regulated in time and space,thereby safeguarding genomic integrity. In eukaryotes, replication initiates from multiple sites along thegenome, termed origins of replication, and propagates bidirectionally. Dynamic origin bound complexesdictate where and when replication should initiate. During late mitosis and G1 phase, putative origins arerecognized and become \"licensed\" through the assembly of pre-replicative complexes (pre-RCs) thatinclude the MCM2-7 helicases. Subsequently, at the G1/S phase transition, a fraction of pre-RCs areactivated giving rise to the establishment of replication forks. Origin location is influenced by chromatinand nuclear organization and origin selection exhibits stochastic features. The regulatory mechanismsthat govern these cell cycle events rely on the periodic fluctuation of cyclin dependent kinase (CDK)activity through the cell cycle.", "metadata": {}}
+{"_id": "19979816", "title": "", "text": "MYC/MIZ1-dependent gene repression inversely coordinates the circadian clock with cell cycle andproliferationThe circadian clock and the cell cycle are major cellular systems that organize globalphysiology in temporal fashion. It seems conceivable that the potentially conflicting programs arecoordinated. We show here that overexpression of MYC in U2OS cells attenuates the clock and converselypromotes cell proliferation while downregulation of MYC strengthens the clock and reduces proliferation.Inhibition of the circadian clock is crucially dependent on the formation of repressive complexes of MYCwith MIZ1 and subsequent downregulation of the core clock genes BMAL1 (ARNTL), CLOCK and NPAS2.We show furthermore that BMAL1 expression levels correlate inversely with MYC levels in 102 humanlymphomas. Our data suggest that MYC acts as a master coordinator that inversely modulates the impactof cell cycle and circadian clock on gene expression.", "metadata": {}}
+{"_id": "19994006", "title": "", "text": "Relevance of asystole during head-up tilt testing.The prognosis of patients manifesting prolongedasystole during head-up tilt testing is unclear. In 209 consecutive patients with a history of syncope andpositive head-up tilt tests, 19 had asystole lasting > 5 seconds (mean duration 15 +/- 10) (group 1a).When compared with patients without asystole (group 1b), group 1a patients were younger (32 +/- 12 vs47 +/- 21 years, p < 0.005), but clinical manifestations were not any more dramatic (the number ofepisodes of syncope [7 +/- 5 vs 8 +/- 6 episodes, p = NS] and injury during syncope [2 vs 13 patients, p= NS] were similar). During follow-up (mean 2 +/- 1 year), with the patient taking pharmacologictherapy such as beta blockers, ephedrine, theophylline, or disopyramide, the recurrence rate was 11%and 8% in groups 1a and 1b (p = NS). No patient in the asystole group underwent pacemakerimplantation. Additionally, of 75 normal volunteers (group 2) with no history of syncope undergoing tilttests to define its specificity, 3 had asystole (mean duration 10 seconds). During > 1 year of follow-up,despite no treatment, all 3 are symptom free. Thus, asystole during head-up tilt testing does not predicteither a more malignant outcome or a poor response to pharmacologic therapy. Moreover, an asystolicresponse does not enhance the specificity of the head-up tilt test because it may be present inasymptomatic \"normal\" volunteers.", "metadata": {}}
+{"_id": "20008796", "title": "", "text": "Increasing informed uptake and non-uptake of screening: evidence from a systematic review.OBJECTIVETo report data relating to the informed uptake of screening tests. SEARCH STRATEGY Electronicdatabases, bibliographies and experts were used to identify relevant published and unpublished studiesup until August 2000. INCLUSION CRITERIA RCTs, quasi-RCTs and controlled trials of interventions aimedat increasing the informed uptake of screening. All participants were eligible as defined by the entrycriteria of individual programmes. Studies had to report actual uptake and meet three out of four criteriaused to define informed uptake. DATA EXTRACTION AND SYNTHESIS Relevant studies were identified,data extracted and their validity assessed by two reviewers independently. Outcome data includedscreening uptake, knowledge, informed decision-making and attitudes to screening. A random-effectsmodel was used to calculate individual relative risks and 95% confidence intervals. MAIN RESULTS Sixcontrolled trials (five RCTs and one quasi-RCT), focusing on antenatal and prostate specific antigenscreening, were included. All reported risks/benefits of screening and assessed knowledge. Two alsoassessed decision-making. Two reported risks/benefits to all randomized groups and evaluated differentways of presenting information. Neither found that interventions such as videos, information leaflets withdecision trees, or touch screen computers conveyed any additional benefits over well-prepared leaflets.CONCLUSIONS There is some evidence to suggest that changing the format of informed choiceinterventions in screening does not alter knowledge, satisfaction or decisions about screening. It is notclear whether informed choice in screening affects uptake. More well-designed RCTs are required andfurther research should also be directed towards the development of a valid instrument for measuring allcomponents of informed choice in screening.", "metadata": {}}
+{"_id": "20018321", "title": "", "text": "Mitochondrial RNA Granules Are Centers for Posttranscriptional RNA Processing and RibosomeBiogenesis.Cytoplasmic RNA granules play a central role in mRNA metabolism, but the importance ofmitochondrial RNA granules remains relatively unexplored. We characterized their proteome and foundthat they contain a large toolbox of proteins dedicated to RNA metabolism. Investigation of fouruncharacterized putative RNA-binding proteins-two RNA helicases, DHX30 and DDX28, and two proteinsof the Fas-activated serine-threonine kinase (FASTKD) family, FASTKD2 and FASTKD5-demonstrated thatboth helicases and FASTKD2 are required for mitochondrial ribosome biogenesis. RNA-sequencing(RNA-seq) analysis showed that DDX28 and FASTKD2 bound the 16S rRNA. FASTKD5 is required formaturing precursor mRNAs that are not flanked by tRNAs and that therefore cannot be processed by thecanonical mRNA maturation pathway. Silencing FASTKD5 rendered mature COX I mRNA almostundetectable, which severely reduced the synthesis of COX I, resulting in a complex IV assembly defect.These data demonstrate that mitochondrial RNA granules are centers for posttranscriptional RNAprocessing and the biogenesis of mitochondrial ribosomes.", "metadata": {}}
+{"_id": "20028729", "title": "", "text": "Controlling nuclear receptors: the circular logic of cofactor cyclesNuclear receptors regulate manybiologically important processes in development and homeostasis by their bimodal function as repressorsand activators of gene transcription. A finely tuned modulation of the transcriptional activities of nuclearreceptors is crucial for determining highly specific and diversified programmes of gene expression. Recentstudies have provided insights into the molecular mechanisms that are required to switch betweenrepression and activation functions, the combinatorial roles of the multiple cofactor complexes that arerequired for mediating transcriptional regulation, and the central question of how several differentsignalling pathways can be integrated at the nuclear level to achieve specific profiles of gene expression.", "metadata": {}}
+{"_id": "20033112", "title": "", "text": "Reprogramming fibroblasts into bipotential hepatic stem cells by defined factors.Recent studies havedemonstrated direct reprogramming of fibroblasts into a range of somatic cell types, but to date stem orprogenitor cells have only been reprogrammed for the blood and neuronal lineages. We previouslyreported generation of induced hepatocyte-like (iHep) cells by transduction of Gata4, Hnf1α, and Foxa3 inp19 Arf null mouse embryonic fibroblasts (MEFs). Here, we show that Hnf1β and Foxa3, liverorganogenesis transcription factors, are sufficient to reprogram MEFs into induced hepatic stem cells(iHepSCs). iHepSCs can be stably expanded in vitro and possess the potential of bidirectionaldifferentiation into both hepatocytic and cholangiocytic lineages. In the injured liver offumarylacetoacetate hydrolase (Fah)-deficient mice, repopulating iHepSCs become hepatocyte-like cells.They also engraft as cholangiocytes into bile ducts of mice with DDC-induced bile ductular injury. Lineageconversion into bipotential expandable iHepSCs provides a strategy to enable efficient derivation of bothhepatocytes and cholangiocytes for use in disease modeling and tissue engineering.", "metadata": {}}
+{"_id": "20045514", "title": "", "text": "Spatial genome organization: contrasting views from chromosome conformation capture and fluorescencein situ hybridization.Although important for gene regulation, most studies of genome organization useeither fluorescence in situ hybridization (FISH) or chromosome conformation capture (3C) methods. FISHdirectly visualizes the spatial relationship of sequences but is usually applied to a few loci at a time. Thefrequency at which sequences are ligated together by formaldehyde cross-linking can be measuredgenome-wide by 3C methods, with higher frequencies thought to reflect shorter distances. FISH and 3Cshould therefore give the same views of genome organization, but this has not been tested extensively.We investigated the murine HoxD locus with 3C carbon copy (5C) and FISH in different developmentaland activity states and in the presence or absence of epigenetic regulators. We identified situations inwhich the two data sets are concordant but found other conditions under which chromatin topographiesextrapolated from 5C or FISH data are not compatible. We suggest that products captured by 3C do notalways reflect spatial proximity, with ligation occurring between sequences located hundreds ofnanometers apart, influenced by nuclear environment and chromatin composition. We conclude thatresults obtained at high resolution with either 3C methods or FISH alone must be interpreted with cautionand that views about genome organization should be validated by independent methods.", "metadata": {}}
+{"_id": "20048431", "title": "", "text": "Development and evaluation of a self-administered computerized 24-h dietary recall method foradolescents in EuropeObjective:To describe the development of a European computerized 24-h dietaryrecall method for adolescents, and to investigate the feasibility of self-administration (self report) bycomparison with administration by a dietician (interview).Methods:Two hundred and thirty-sixadolescents (mean age 14.6 years (s.d.=1.7)) of eight European cities completed the 24-h recall (YoungAdolescents Nutrition Assessment on Computer (YANA-C)) twice (once by self-report and once byinterview).Results:A small but significant underestimate in energy (61 (s.e.=31) kcal) and fat (4.2(s.e.=1.7) g) intake was found in the self-reports in comparison with the interviews; no significantdifferences were found for the intake of carbohydrates, proteins, fibre, calcium, iron and ascorbic acid.Spearman's correlations were highly significant for all nutrients and energy ranging between 0.86 and0.91. Agreement in categorizing the respondents as consumers and non-consumers for the 29 foodgroups was high (kappa statistics \u00000.73). Percentage omissions were on average 3.7%; percentageintrusions: 2.0%. Spearman's correlations between both modes were high for all food groups, for thetotal sample (\u00000.76) as well as for the consumers only (\u00000.72). Analysing the consumer only, on anaverage 54% of the consumed amounts were exactly the same; nevertheless, only for one group ‘riceand pasta’ a significant difference in consumption was found. Conclusion:Adaptation, translation andstandardization of YANA-C make it possible to assess the dietary intake of adolescents in a broadinternational context. In general, good agreement between the administration modes was found, thelatter offering significant potential for large-scale surveys where the amount of resources to gather datais limited.", "metadata": {}}
+{"_id": "20052986", "title": "", "text": "JTK_CYCLE: an efficient nonparametric algorithm for detecting rhythmic components in genome-scaledata sets.Circadian rhythms are oscillations of physiology, behavior, and metabolism that have periodlengths near 24 hours. In several model organisms and humans, circadian clock genes have beencharacterized and found to be transcription factors. Because of this, researchers have used microarraysto characterize global regulation of gene expression and algorithmic approaches to detect cycling. Thisarticle presents a new algorithm, JTK_CYCLE, designed to efficiently identify and characterize cyclingvariables in large data sets. Compared with COSOPT and the Fisher's G test, two commonly usedmethods for detecting cycling transcripts, JTK_CYCLE distinguishes between rhythmic and nonrhythmictranscripts more reliably and efficiently. JTK_CYCLE's increased resistance to outliers results inconsiderably greater sensitivity and specificity. Moreover, JTK_CYCLE accurately measures the period,phase, and amplitude of cycling transcripts, facilitating downstream analyses. Finally, JTK_CYCLE isseveral orders of magnitude faster than COSOPT, making it ideal for large-scale data sets. JTK_CYCLEwas used to analyze legacy data sets including NIH3T3 cells, which have comparatively low amplitudeoscillations. JTK_CYCLE's improved power led to the identification of a novel cluster of RNA-interactinggenes whose abundance is under clear circadian regulation. These data suggest that JTK_CYCLE is anideal tool for identifying and characterizing oscillations in genome-scale data sets.", "metadata": {}}
+{"_id": "20054396", "title": "", "text": "Polo-like kinase 1 regulates Nlp, a centrosome protein involved in microtubule nucleation.In animal cells,most microtubules are nucleated at centrosomes. At the onset of mitosis, centrosomes undergo astructural reorganization, termed maturation, which leads to increased microtubule nucleation activity.Centrosome maturation is regulated by several kinases, including Polo-like kinase 1 (Plk1). Here, weidentify a centrosomal Plk1 substrate, termed Nlp (ninein-like protein), whose properties suggest animportant role in microtubule organization. Nlp interacts with two components of the gamma-tubulin ringcomplex and stimulates microtubule nucleation. Plk1 phosphorylates Nlp and disrupts both its centrosomeassociation and its gamma-tubulin interaction. Overexpression of an Nlp mutant lacking Plk1phosphorylation sites severely disturbs mitotic spindle formation. We propose that Nlp plays an importantrole in microtubule organization during interphase, and that the activation of Plk1 at the onset of mitosistriggers the displacement of Nlp from the centrosome, allowing the establishment of a mitotic scaffoldwith enhanced microtubule nucleation activity.", "metadata": {}}
+{"_id": "20083834", "title": "", "text": "Consumption of isoflavone-rich soy protein does not alter homocysteine or markers of inflammation inpostmenopausal womenBackground/Objective:To investigate the effect of soy protein containingisoflavones on homocysteine (Hcy), C-reactive protein (CRP), soluble E-selectin (sE-selectin), solublevascular adhesion molecule-1 (sVCAM-1) and soluble intercellular adhesion molecule-1(sICAM-1).Subject/Methods:In a randomized crossover design, 34 postmenopausal women consumedsoy protein isolate (26±5 g protein containing 44±8 mg isoflavones per day) or milk protein isolate(26±5 g protein per day) for 6 weeks each. Fasting blood samples were collected at the end of each dietperiod and end points analyzed by enzyme-linked immunosorbent assay. Results:Concentrations of Hcy,CRP, sE-selectin, sVCAM-1 and sICAM-1 were not different between soy and milk diet treatments. Resultsdid not differ by equol production status or by baseline lipid concentration. Adjustment for intake of folateand methionine did not alter the Hcy results. Conclusions:These data suggest that decreasing vascularinflammation and Hcy concentration are not likely mechanisms by which soy consumption reducescoronary heart disease risk.", "metadata": {}}
+{"_id": "20101846", "title": "", "text": "Homogeneously dispersed multimetal oxygen-evolving catalystsEarth-abundant first-row (3d) transitionmetal–based catalysts have been developed for the oxygen-evolution reaction (OER); however, theyoperate at overpotentials substantially above thermodynamic requirements. Density functional theorysuggested that non-3d high-valency metals such as tungsten can modulate 3d metal oxides, providingnear-optimal adsorption energies for OER intermediates. We developed a room-temperature synthesis toproduce gelled oxyhydroxides materials with an atomically homogeneous metal distribution. These gelledFeCoW oxyhydroxides exhibit the lowest overpotential (191 millivolts) reported at 10 milliamperes persquare centimeter in alkaline electrolyte. The catalyst shows no evidence of degradation after more than500 hours of operation. X-ray absorption and computational studies reveal a synergistic interplaybetween tungsten, iron, and cobalt in producing a favorable local coordination environment and electronicstructure that enhance the energetics for OER.", "metadata": {}}
+{"_id": "20109325", "title": "", "text": "Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease:GOLD executive summary.Chronic obstructive pulmonary disease (COPD) is a global health problem, andsince 2001, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) has published its strategydocument for the diagnosis and management of COPD. This executive summary presents the maincontents of the second 5-year revision of the GOLD document that has implemented some of the vastknowledge about COPD accumulated over the last years. Today, GOLD recommends that spirometry isrequired for the clinical diagnosis of COPD to avoid misdiagnosis and to ensure proper evaluation ofseverity of airflow limitation. The document highlights that the assessment of the patient with COPDshould always include assessment of (1) symptoms, (2) severity of airflow limitation, (3) history ofexacerbations, and (4) comorbidities. The first three points can be used to evaluate level of symptomsand risk of future exacerbations, and this is done in a way that splits patients with COPD into fourcategories-A, B, C, and D. Nonpharmacologic and pharmacologic management of COPD match thisassessment in an evidence-based attempt to relieve symptoms and reduce risk of exacerbations.Identification and treatment of comorbidities must have high priority, and a separate section in thedocument addresses management of comorbidities as well as COPD in the presence of comorbidities. Therevised document also contains a new section on exacerbations of COPD. The GOLD initiative willcontinue to bring COPD to the attention of all relevant shareholders and will hopefully inspire futurenational and local guidelines on the management of COPD.", "metadata": {}}
+{"_id": "20127522", "title": "", "text": "Circulating tumor cells: a useful predictor of treatment efficacy in metastatic breast cancer.PURPOSE Fiveor more circulating tumor cells (CTCs) per 7.5 mL of blood predicts for poorer progression-free survival(PFS) in patients with metastatic breast cancer (MBC). We conducted a prospective study to demonstratethat CTC results correlate strongly with radiographic disease progression at the time of and in advance ofimaging. PATIENTS AND METHODS Serial CTC levels were obtained in patients starting a new treatmentregimen for progressive, radiographically measurable MBC. Peripheral blood was collected for CTCenumeration at baseline and at 3- to 4-week intervals. Clinical outcomes were based on radiographicstudies performed in 9- to 12-week intervals. RESULTS Sixty-eight patients were evaluable for theCTC-imaging correlations, and 74 patients were evaluable for the PFS analysis. Median follow-up was13.3 months. A statistically significant correlation was demonstrated between CTC levels and radiographicdisease progression in patients receiving chemotherapy or endocrine therapy. This correlation applied toCTC results obtained at the time of imaging (odds ratio [OR], 6.3), 3 to 5 weeks before imaging (OR,3.1), and 7 to 9 weeks before imaging (OR, 4.9). Results from analyses stratified by type of therapyremained statistically significant. Shorter PFS was observed for patients with five or more CTCs at 3 to 5weeks and at 7 to 9 weeks after the start of treatment. CONCLUSION We provide, to our knowledge, thefirst evidence of a strong correlation between CTC results and radiographic disease progression inpatients receiving chemotherapy or endocrine therapy for MBC. These findings support the role of CTCenumeration as an adjunct to standard methods of monitoring disease status in MBC.", "metadata": {}}
+{"_id": "20128547", "title": "", "text": "Recovery of supraspinal control of stepping via indirect propriospinal relay connections after spinal cordinjurySpinal cord injuries (SCIs) in humans and experimental animals are often associated with varyingdegrees of spontaneous functional recovery during the first months after injury. Such recovery is widelyattributed to axons spared from injury that descend from the brain and bypass incomplete lesions, but itsmechanisms are uncertain. To investigate the neural basis of spontaneous recovery, we used kinematic,physiological and anatomical analyses to evaluate mice with various combinations of spatially andtemporally separated lateral hemisections with or without the excitotoxic ablation of intrinsic spinal cordneurons. We show that propriospinal relay connections that bypass one or more injury sites are able tomediate spontaneous functional recovery and supraspinal control of stepping, even when there has beenessentially total and irreversible interruption of long descending supraspinal pathways in mice. Ourfindings show that pronounced functional recovery can occur after severe SCI without the maintenance orregeneration of direct projections from the brain past the lesion and can be mediated by thereorganization of descending and propriospinal connections. Targeting interventions toward augmentingthe remodeling of relay connections may provide new therapeutic strategies to bypass lesions and restorefunction after SCI and in other conditions such as stroke and multiple sclerosis.", "metadata": {}}
+{"_id": "20130904", "title": "", "text": "\"Grazing\": a high-risk behavior.BACKGROUND Gastric bypass patients with a range of disturbed eatingpatterns before surgery may be at risk of returning to old patterns postoperatively. Recent research hasshown that binge eating is common among the obese before surgery as well as in the postoperativemaintenance phase and appears to be linked to poorer outcome. Although \"grazing\" behavior has notbeen specifically studied, it is also a high-risk pattern. This paper is a descriptive investigationsummarizing postoperative eating patterns in a group of patients. METHODS Patients completedself-report questionnaires before surgery and were seen for a preoperative mental health evaluation withparticular focus on assessing eating patterns. Patients with high-risk eating patterns, both binge eatingand \"grazing\", were identified, invited to attend a post-surgery therapy group, and were given additionalfollow-up questionnaires regarding postoperative eating patterns. RESULTS Consistent with recentstudies, many high-risk patients reported recurrent loss of control over eating and, in some cases,subsequent weight gain. Although no longer able to eat large amounts, \"grazing\" became a morecommon pattern, appearing >or=6 months following surgery. CONCLUSION Different forms of overeatingneed to be assessed in this population, focusing on the subjective loss of control rather than on thequantity consumed. Although many patients do not meet strict criteria for binge eating disorder beforesurgery, these \"grazers\" are also high-risk. Former binge eaters often turn into \"grazers\" followingsurgery. Interventions are needed for at-risk patients.", "metadata": {}}
+{"_id": "20132778", "title": "", "text": "Molecular strategies in biological evolution of antimicrobial peptides.Gene-encoded antimicrobial peptidesthat protect the skin of hylid and ranin frogs against noxious microorganisms are processed from aunique family of precursor polypeptides with a unique pattern of conserved and variable regions oppositeto that of conventional secreted peptides. Precursors belonging to this family, designated thepreprodermaseptin, have a common N-terminal preproregion that is remarkably well conserved bothwithin and between species, but a hypervariable C-terminal domain corresponding to antimicrobialpeptides with very different lengths, sequences, charges and antimicrobial spectra. Each frog species hasits own distinct panoply of 10-20 antimicrobial peptides so that the 5000 species of ranids and hylids mayproduce approximately 100,000 different peptide antibiotics. The strategy that these frogs have evolvedto generate this enormous array of peptides includes repeated duplications of a 150 million years oldancestral gene, focal hypermutation of the antimicrobial peptide domain maybe involving a mutagenicDNA polymerase similar to Escherichia coli Pol V, and subsequent actions of positive (diversifying)selection. The hyperdivergence of skin antimicrobial peptides can be viewed as the successful evolution ofa multi-drug defense system that provides frogs with maximum protection against rapidly changingmicrobial biota and minimizes the chance of microorganisms developing resistance to individual peptides.The impressive variations in the expression of frog skin antimicrobial peptides may be exploited fordiscovering new molecules and structural motifs targeting specific microorganisms for which thetherapeutic armamentarium is scarce.", "metadata": {}}
+{"_id": "20148808", "title": "", "text": "Microbiome-driven allergic lung inflammation is ameliorated by short-chain fatty acidsThe mammaliangastrointestinal tract harbors a microbial community with metabolic activity critical for host health,including metabolites that can modulate effector functions of immune cells. Mice treated with vancomycinhave an altered microbiome and metabolite profile, exhibit exacerbated T helper type 2 cell (Th2)responses, and are more susceptible to allergic lung inflammation. Here we show that dietarysupplementation with short-chain fatty acids (SCFAs) ameliorates this enhanced asthma susceptibility bymodulating the activity of T cells and dendritic cells (DCs). Dysbiotic mice treated with SCFAs have fewerinterleukin-4 (IL4)-producing CD4+ T cells and decreased levels of circulating immunoglobulin E (IgE). Inaddition, DCs exposed to SCFAs activate T cells less robustly, are less motile in response to CCL19 invitro, and exhibit a dampened ability to transport inhaled allergens to lung draining nodes. Our data thusdemonstrate that gut dysbiosis can exacerbate allergic lung inflammation through both T cell- andDC-dependent mechanisms that are inhibited by SCFAs.", "metadata": {}}
+{"_id": "20155713", "title": "", "text": "Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral selfExpression ofperipheral antigens in the thymus has been implicated in T cell tolerance and autoimmunity. Here weidentified medullary thymic epithelial cells as being a unique cell type that expresses a diverse range oftissue-specific antigens. We found that this promiscuous gene expression was a cell-autonomous propertyof medullary epithelial cells and was maintained during the entire period of thymic T cell output. It mayfacilitate tolerance induction to self-antigens that would otherwise be temporally or spatially secludedfrom the immune system. However, the array of promiscuously expressed self-antigens appeared randomrather than selected and was not confined to secluded self-antigens.", "metadata": {}}
+{"_id": "20179918", "title": "", "text": "Signal transducer and activator of transcription 3 is a transcriptional factor regulating the geneexpression of SALL4.Both signal transducer and activator of transcription 3 (STAT3) and SALL4 areimportant in maintaining the pluripotent and self-renewal state of embryonic stem cells. We hypothesizedthat STAT3, a latent transcriptional factor, may regulate the gene expression of SALL4. In support of thishypothesis, DNA sequence analysis of the SALL4 gene promoter revealed four putative STAT3-bindingsites. Using a SALL4-luciferase reporter gene assay, we found that modulation of the STAT3 activitysignificantly up-regulated the luciferase activity. By chromatin immunoprecipitation, the segment of theSALL4 promoter showing the highest affinity to STAT3 was localized to -366 to -163, in which there wasonly one putative STAT3 binding site starting at -199. Site-directed mutagenesis of all four putativeSTAT3-binding sites in the SALL4 promoter significantly reduced its responsiveness to STAT3, althoughthe most dramatic effect was seen at the binding site starting at -199. We further tested the functionalrelationship between STAT3 and SALL4 using MDA-MB-231, a breast cell line carrying constitutive SALL4expression and STAT3 activity. Down-regulation of the STAT3 activity using a dominant-negativeconstruct resulted in a significant decrease in the expression of SALL4. To conclude, our data suggest thatSTAT3 and SALL4 probably cooperate in both physiological and pathological states.", "metadata": {}}
+{"_id": "20183360", "title": "", "text": "GATA3 transcription factor abrogates Smad4 transcription factor-mediated fascin overexpression,invadopodium formation, and breast cancer cell invasion.Transforming growth factor β (TGFβ) is a potentand context-dependent regulator of tumor progression. TGFβ promotes the lung metastasis of basal-like(but not the luminal-like) breast cancer. Here, we demonstrated that fascin, a pro-metastasis actinbundling protein, was a direct target of the canonical TGFβ-Smad4 signaling pathway in basal-like breastcancer cells. TGFβ and Smad4 induced fascin overexpression by directly binding to a Smad bindingelement on the fascin promoter. We identified GATA3, a transcription factor crucial for mammary glandmorphogenesis and luminal differentiation, as a negative regulator of TGFβ- and Smad4-induced fascinoverexpression. When ectopically expressed in basal-like breast cancer cells, GATA-3 abrogated TGFβ-and Smad4-mediated overexpression of fascin and other TGFβ response genes, invadopodium formation,cell migration, and invasion, suggesting suppression of the canonical TGFβ-Smad signaling axis.Mechanistically, GATA3 abrogated the canonical TGFβ-Smad signaling by abolishing interactions betweenSmad4 and its DNA binding elements, potentially through physical interactions between the N-terminal ofGATA3 and Smad3/4 proteins. Our findings provide mechanistic insight into how TGFβ-mediated cellmotility and invasiveness are differentially regulated in breast cancer.", "metadata": {}}
+{"_id": "20186513", "title": "", "text": "The American Rheumatism Association 1987 revised criteria for the classification of rheumatoidarthritis.The revised criteria for the classification of rheumatoid arthritis (RA) were formulated from acomputerized analysis of 262 contemporary, consecutively studied patients with RA and 262 controlsubjects with rheumatic diseases other than RA (non-RA). The new criteria are as follows: 1) morningstiffness in and around joints lasting at least 1 hour before maximal improvement; 2) soft tissue swelling(arthritis) of 3 or more joint areas observed by a physician; 3) swelling (arthritis) of the proximalinterphalangeal, metacarpophalangeal, or wrist joints; 4) symmetric swelling (arthritis); 5) rheumatoidnodules; 6) the presence of rheumatoid factor; and 7) radiographic erosions and/or periarticularosteopenia in hand and/or wrist joints. Criteria 1 through 4 must have been present for at least 6 weeks.Rheumatoid arthritis is defined by the presence of 4 or more criteria, and no further qualifications(classic, definite, or probable) or list of exclusions are required. In addition, a \"classification tree\" schemais presented which performs equally as well as the traditional (4 of 7) format. The new criteriademonstrated 91-94% sensitivity and 89% specificity for RA when compared with non-RA rheumaticdisease control subjects.", "metadata": {}}
+{"_id": "20186814", "title": "", "text": "A new look at the origin, function, and \"stem-cell\" status of muscle satellite cells.Muscle satellite cellshave long been considered a distinct myogenic lineage responsible for postnatal growth, repair, andmaintenance of skeletal muscle. Recent studies in mice, however, have revealed the potential for highlypurified hematopoietic stem cells from bone marrow to participate in muscle regeneration. Perhaps moresignificantly, a population of putative stem cells isolated directly from skeletal muscle efficientlyreconstitutes the hematopoietic compartment and participates in muscle regeneration followingintravenous injection in mice. The plasticity of muscle stem cells has raised important questions regardingthe relationship between the muscle-derived stem cells and the skeletal muscle satellite cells.Furthermore, the ability of hematopoietic cells to undergo myogenesis has prompted new investigationsinto the embryonic origin of satellite cells. Recent developmental studies suggest that a population ofsatellite cells is derived from progenitors in the embryonic vasculature. Taken together, these studiesprovide the first evidence that pluripotential stem cells are present within adult skeletal muscle.Tissue-specific stem cells, including satellite cells, may share a common embryonic origin and possess thecapacity to activate diverse genetic programs in response to environmental stimuli. Manipulation of suchtissue-specific stem cells may eventually revolutionize therapies for degenerative diseases, includingmuscular dystrophy.", "metadata": {}}
+{"_id": "20187433", "title": "", "text": "Involving family members in cancer care: focus group considerations of patients and oncologicalproviders.Family members are an integral part of a patient's cancer care from the moment the diagnosisis delivered to the conclusion of treatment. Family members bring with them a range of emotionalreactions, interpersonal dynamics and expectations for the care the patient receives. This study is part ofa multi-institutional project to continue to improve the process of cancer care. In this study, 19 focusgroups (11 patient and 8 provider) were conducted concerning issues related to doctor-patientcommunication in eight cancer centers in the United States. The content of the conversations wasanalyzed and thematic categories emerged that highlight the various strengths and difficulties associatedwith family involvement. The focus groups' comments support the need for explicit conversationsbetween professional caregivers, patients and their loved ones, in order to negotiate the expectations andneeds of each team member. Implications for clinical practice and strategies for working with familymembers are offered.", "metadata": {}}
+{"_id": "20188586", "title": "", "text": "Improving Adherence to Antiretroviral Therapy With Triggered Real-time Text Message Reminders: TheChina Adherence Through Technology Study.BACKGROUND Real-time adherence monitoring is nowpossible through medication storage devices equipped with cellular technology. We assessed the effect oftriggered cell phone reminders and counseling using objective adherence data on antiretroviral therapy(ART) adherence among Chinese HIV-infected patients. METHODS We provided ART patients in Nanning,China, with a medication device (Wisepill) to monitor their ART adherence electronically. After 3 months,we randomized subjects within optimal (≥95%) and suboptimal (<95%) adherence strata to interventionvs. control arms. In months 4-9, intervention subjects received individualized reminders triggered by latedose taking (no device opening by 30 minutes past dose time) and counseling using device-generateddata. Controls received no reminders or data-informed counseling. We compared postinterventionproportions achieving optimal adherence, mean adherence, and clinical outcomes. RESULTS Of 120subjects enrolled, 116 (96.7%) completed the trial. Preintervention optimal adherence was similar inintervention vs. control arms (63.5% vs. 58.9%, respectively; P = 0.60). In the last intervention month,87.3% vs. 51.8% achieved optimal adherence [risk ratio (RR): 1.7, 95% confidence interval (CI): 1.3 to2.2] and mean adherence was 96.2% vs. 89.1% (P = 0.003). Among preintervention suboptimaladherers, 78.3% vs. 33.3% (RR: 2.4, CI: 1.2 to 4.5) achieved optimal adherence and mean adherencewas 93.3% vs. 84.7% (P = 0.039). Proportions were 92.5% and 62.9% among optimal adherers,respectively (RR: 1.5, CI: 1.1 to 1.9) and mean adherence was 97.8% vs. 91.7% (P = 0.028).Postintervention clinical outcomes were not significant. CONCLUSIONS Real-time reminders significantlyimproved ART adherence in this population. This approach seems promising for managing HIV and otherchronic diseases and warrants further investigation and adaptation in other settings.", "metadata": {}}
+{"_id": "20220731", "title": "", "text": "Origin and T cell receptor diversity of Foxp3+CD4+CD25+ T cells.Foxp3(+)CD4(+)CD25(+) regulatory Tcells can differentiate from Foxp3(-)CD4(+) medullary thymocytes and Foxp3(-)CD4(+) naive T cells.However, the impact of these two processes on size and composition of the peripheral repertoire ofregulatory T cells is unclear. Here we followed the fate of individual Foxp3(+)CD4(+)CD25(+) thymocytesand T cells in vivo in T cell receptor (TCR) transgenic mice that express a restricted but polyclonalrepertoire of TCRs. By utilizing high-throughput single-cell analysis, we showed that Foxp3(+)CD4(+)peripheral T cells were derived from thymic precursors that expressed a different TCRs thanFoxp3(-)CD4(+) medullary thymocytes and Foxp3(-)CD4(+) T cells. Furthermore, the diversity of TCRson Foxp3(+)CD4(+) regulatory T cells exceeded the diversity of TCRs on Foxp3(-)CD4(+) naive T cells,even in mice that lack expression of tissue-specific antigens. Our results imply that higher TCR diversityon Foxp3(+) regulatory T cells helps these cells to match the specificities of autoreactive and naive Tcells.", "metadata": {}}
+{"_id": "20221907", "title": "", "text": "Reproducibility of the diagnosis of atypical endometrial hyperplasia: a Gynecologic Oncology Groupstudy.BACKGROUND Most gynecologists determine therapy based on current International Society ofGynecologic Pathologists (ISGP)/World Health Organization classification of endometrial hyperplasia, thereproducibility of which has been questioned. The Gynecologic Oncology Group (GOG) initiated a protocolto assess the efficacy of hormonal therapy of atypical endometrial hyperplasia (AEH). Primary goals ofthe first phase (Part A) were to prospectively determine reproducibility of referring institution'spathologist's diagnosis of AEH by a panel of 3 gynecologic pathologists and to determine reproducibility ofdiagnoses by panel members. METHODS Three hundred six women were entered on this protocol with areferring institution's pathologist diagnosis of AEH based on biopsy or curettage. Available slides wereassessed independently and interpreted by each of a panel of 3 gynecologic pathologists who usedInternational Society of Gynecologic Pathologists (ISGP)/World Health Organization criteria. The majoritydiagnosis was based on diagnostic concordance by at least 2 of the 3 panelists. RESULTS The referringinstitution's pathologist's diagnosis of AEH was supported by the majority of the panel in only 38% ofcases. Overall kappa value for the panel diagnosis of AEH was 0.28. The majority diagnosis wasadenocarcinoma in 29%, cycling endometrium in 7%, and nonatypical hyperplasia in 18% of cases.Unanimous agreement for any diagnosis was reached among all 3 of the panel in 40% of cases. For thepanel, paired kappa values for any diagnosis ranged 0.34-0.43, with an overall kappa value of 0.40.CONCLUSION Reproducibility of referring institution's pathologists' diagnosis of AEH by a panel ofgynecologic pathologists is poor. Both underestimation and overestimation of the severity of the lesionare very common. The level of reproducibility among subspecialist panel members for diagnosis of AEH inthese specimens also is poor. Better criteria and better sampling are needed to improve reproducibility ofthis diagnosis, particularly if it is to be used for clinical decisions.", "metadata": {}}
+{"_id": "20231138", "title": "", "text": "Replication Fork Slowing and Reversal upon DNA Damage Require PCNA Polyubiquitination and ZRANB3DNA Translocase ActivityDNA damage tolerance during eukaryotic replication is orchestrated by PCNAubiquitination. While monoubiquitination activates mutagenic translesion synthesis, polyubiquitinationactivates an error-free pathway, elusive in mammals, enabling damage bypass by template switching.Fork reversal is driven in vitro by multiple enzymes, including the DNA translocase ZRANB3, shown tobind polyubiquitinated PCNA. However, whether this interaction promotes fork remodeling and templateswitching in vivo was unknown. Here we show that damage-induced fork reversal in mammalian cellsrequires PCNA ubiquitination, UBC13, and K63-linked polyubiquitin chains, previously involved inerror-free damage tolerance. Fork reversal in vivo also requires ZRANB3 translocase activity and itsinteraction with polyubiquitinated PCNA, pinpointing ZRANB3 as a key effector of error-free DNA damagetolerance. Mutations affecting fork reversal also induced unrestrained fork progression and chromosomalbreakage, suggesting fork remodeling as a global fork slowing and protection mechanism. Targetingthese fork protection systems represents a promising strategy to potentiate cancer chemotherapy.", "metadata": {}}
+{"_id": "20240998", "title": "", "text": "Bed sharing when parents do not smoke: is there a risk of SIDS? An individual level analysis of five majorcase–control studiesOBJECTIVE To resolve uncertainty as to the risk of Sudden Infant Death Syndrome(SIDS) associated with sleeping in bed with your baby if neither parent smokes and the baby is breastfed.DESIGN Bed sharing was defined as sleeping with a baby in the parents' bed; room sharing as babysleeping in the parents' room. Frequency of bed sharing during last sleep was compared between babieswho died of SIDS and living control infants. Five large SIDS case-control datasets were combined. Missingdata were imputed. Random effects logistic regression controlled for confounding factors. SETTING Homesleeping arrangements of infants in 19 studies across the UK, Europe and Australasia. PARTICIPANTS1472 SIDS cases, and 4679 controls. Each study effectively included all cases, by standard criteria.Controls were randomly selected normal infants of similar age, time and place. RESULTS In the combineddataset, 22.2% of cases and 9.6% of controls were bed sharing, adjusted OR (AOR) for all ages 2.7; 95%CI (1.4 to 5.3). Bed sharing risk decreased with increasing infant age. When neither parent smoked, andthe baby was less than 3 months, breastfed and had no other risk factors, the AOR for bed sharing versusroom sharing was 5.1 (2.3 to 11.4) and estimated absolute risk for these room sharing infants was verylow (0.08 (0.05 to 0.14)/1000 live-births). This increased to 0.23 (0.11 to 0.43)/1000 when bed sharing.Smoking and alcohol use greatly increased bed sharing risk. CONCLUSIONS Bed sharing for sleep whenthe parents do not smoke or take alcohol or drugs increases the risk of SIDS. Risks associated with bedsharing are greatly increased when combined with parental smoking, maternal alcohol consumptionand/or drug use. A substantial reduction of SIDS rates could be achieved if parents avoided bed sharing.", "metadata": {}}
+{"_id": "20261352", "title": "", "text": "Decoupling activation and exhaustion of B cells in spontaneous controllers of HIV infection.OBJECTIVE Todefine the impact of chronic viremia and associated immune activation on B-cell exhaustion in HIVinfection. DESIGN Progressive HIV infection is marked by B-cell anergy and exhaustion coupled withdramatic hypergammaglobulinemia. Although both upregulation of CD95 and loss of CD21 have beenused as markers of infection-associated B-cell dysfunction, little is known regarding the specific profiles ofdysfunctional B cells and whether persistent viral replication and its associated immune activation play acentral role in driving B-cell dysfunction. METHODS Multiparameter flow cytometry was used to define theprofile of dysfunctional B cells. The changes in the expression of CD21 and CD95 were tracked on B-cellsubpopulations in patients with differential control of viral replication. RESULTS : Although the emergenceof exhausted, CD21 tissue-like memory B cells followed similar patterns in both progressors andcontrollers, the frequency of CD21 activated memory B cells was lower in spontaneous controllers.CONCLUSION Our results suggest that the loss of CD21 and the upregulation of CD95 occur as separateevents during the development of B-cell dysfunction. The loss of CD21 is a marker of B-cell exhaustioninduced in the absence of appreciable viral replication, whereas the upregulation of CD95 is tightly linkedto persistent viral replication and its associated immune activation. Thus, these dysfunctional profilespotentially represent two functionally distinct states within the B-cell compartment.", "metadata": {}}
+{"_id": "20279166", "title": "", "text": "Label-free DNA imaging in vivo with stimulated Raman scattering microscopy.Label-free DNA imaging ishighly desirable in biology and medicine to perform live imaging without affecting cell function and toobtain instant histological tissue examination during surgical procedures. Here we show a label-free DNAimaging method with stimulated Raman scattering (SRS) microscopy for visualization of the cell nuclei inlive animals and intact fresh human tissues with subcellular resolution. Relying on the distinct Ramanspectral features of the carbon-hydrogen bonds in DNA, the distribution of DNA is retrieved from thestrong background of proteins and lipids by linear decomposition of SRS images at three optimallyselected Raman shifts. Based on changes on DNA condensation in the nucleus, we were able to capturechromosome dynamics during cell division both in vitro and in vivo. We tracked mouse skin cellproliferation, induced by drug treatment, through in vivo counting of the mitotic rate. Furthermore, wedemonstrated a label-free histology method for human skin cancer diagnosis that provides comparableresults to other conventional tissue staining methods such as H&E. Our approach exhibits highersensitivity than SRS imaging of DNA in the fingerprint spectral region. Compared with spontaneousRaman imaging of DNA, our approach is three orders of magnitude faster, allowing both chromatindynamic studies and label-free optical histology in real time.", "metadata": {}}
+{"_id": "20280410", "title": "", "text": "A common variant in BRCA2 is associated with both breast cancer risk and prenatal viabilityInheritedmutations in the gene BRCA2 predispose carriers to early onset breast cancer, but such mutationsaccount for fewer than 2% of all cases in East Anglia. It is likely that low penetrance alleles explain thegreater part of inherited susceptibility to breast cancer; polymorphic variants in strongly predisposinggenes, such as BRCA2, are candidates for this role. BRCA2 is thought to be involved in DNA double strandbreak-repair. Few mice in which Brca2 is truncated survive to birth; of those that do, most are male,smaller than their normal littermates and have high cancer incidence. Here we show that a commonhuman polymorphism (N372H) in exon 10 of BRCA2 confers an increased risk of breast cancer: the HHhomozygotes have a 1.31-fold (95% CI, 1.07–1.61) greater risk than the NN group. Moreover, in normalfemale controls of all ages there is a significant deficiency of homozygotes compared with that expectedfrom Hardy-Weinberg equilibrium, whereas in males there is an excess of homozygotes: the HH grouphas an estimated fitness of 0.82 in females and 1.38 in males. Therefore, this variant of BRCA2 appearsalso to affect fetal survival in a sex-dependent manner.", "metadata": {}}
+{"_id": "20287253", "title": "", "text": "Pathophysiology of obstructive nephropathy in the newborn.Congenital obstructive nephropathy is aconsequence abnormal urinary tract development resulting in renal growth failure and injury manifestedby progressive tubular atrophy and interstitial fibrosis. We have studied the renal cellular andphysiological response to unilateral ureteral obstruction (UUO) in the neonatal rodent (guinea pig, rat,and mouse). Whereas in the adult, UUO stimulates renal cellular proliferation, UUO in the neonatereduces nephrogenesis, glomerular maturation, and tubular cellular proliferation. This is accompanied bya proportionately greater compensatory growth of the intact opposite kidney in the neonate. Impairedrenal growth and tubular atrophy are likely owing at least in part to stimulation of renal tubular apoptosis.This, in turn, may result from a combination of factors, including loss of epithelial cell polarity, areduction in the oncoprotein bcl-2 and epidermal growth factor (EGF), and increased expression of thefibrogenic cytokine, transforming growth factor-beta1 (TGF-beta1). Infusion of EGF stimulates cellularproliferation, suppresses apoptosis, and reduces tubular atrophy and interstitial fibrosis. TGF-beta1 isregulated by the renin-angiotensin system, which is markedly activated by UUO in the neonate. Thefunctional consequences of obstructive nephropathy in early development are hyperfiltration byremaining nephrons, followed by progressive decrease in glomerular filtration rate that may only developin later life. Improved management of congenital urinary tract obstruction will depend on a betterunderstanding of the cellular mechanisms, which may lead to specific treatment using gene therapy ormodulators of renal growth and development.", "metadata": {}}
+{"_id": "20288322", "title": "", "text": "Lipid homeostasis, lipotoxicity and the metabolic syndrome.In the 20th century industrialized nationshave become afflicted with an unprecedented pandemic of increased adiposity. In the United States, theepicenter of the epidemic, over 2/3 of the population, is overweight and 1 of every 6 Americans carriesthe diagnosis of metabolic syndrome. Although genes determine susceptibility to environmental factors,the epidemic is clearly due to increased consumption of calorie-dense, highly lipogenic foods, coupledwith a marked decrease in physical exertion resulting from modern technologies. If this lifestylecontinues, morbid consequences are virtually inevitable. They include type II diabetes and a cluster ofdisorders known as \"the metabolic syndrome\" usually appearing in middle age. The morbid consequencesof the chronic caloric surplus are buffered before middle age by the partitioning of these calories as fat inthe adipocyte compartment which is specifically designed to store triglycerides. Leptin has been proposedas the major hormonal regulator of the partitioning of surplus calories. However, multiple factors candetermine the storage capacity of the fat tissue and when it is exceeded ectopic lipid deposition begins.The organs affected in metabolic syndrome include skeletal muscle, liver, heart and pancreas, which arenow known to contain abnormal levels of triglycerides. While neutral fat is probably harmless, it is anindex of ectopic lipid overload. Fatty acid derivatives can interfere with the function of the cell andultimately lead to its demise through lipoapoptosis, the consequences of which are gradual organ failure.", "metadata": {}}
+{"_id": "20302714", "title": "", "text": "A twin-study of genetic contributions to morningness-eveningness and depression.Circadian rhythms areassociated with the preference for sleep-wake timing, also known as morningness-eveningness (ME).Both circadian rhythms and ME are influenced by genetic factors. Studies show an association betweeneveningness and depression. This study investigates the heritability of ME and whether ME anddepression share common genetic influences. Study participants (n = 1237) were from the Vietnam EraTwin Study of Aging, a longitudinal study of aging with a baseline in midlife. Participants received theMorningness-Eveningness Questionnaire (MEQ) and the Center for Epidemiologic Studies Depression(CES-D) Scale as part of an extensive neurocognitive and psychosocial assessment. MEQ correlationsbetween members of twin pairs were 0.41 (95% CI 0.31-0.49) for monozygotic (MZ) twins and 0.28 fordizygotic (DZ) twins (95% CI 0.19-0.41). CES-D correlations were 0.38 (95% CI 0.28-0.46) for MZ twinsand 0.24 (95% CI 0.14-0.36) for DZ twins. Greater eveningness (i.e. lower MEQ scores) was significantlyrelated to more depression symptoms (phenotypic correlation = -0.15 (95% CI -0.21 to -0.09). In thebest fitting model, the heritability estimates are 0.42 for the MEQ and 0.37 for the CES-D. A significantgenetic correlation of -0.21 indicated that ME and depression share a significant amount of theirunderlying genetic variance. The genetic covariance between ME and depression accounted for 59.1% ofthe phenotypic correlation. Of the CES-D sub-scales, Depressed Mood and Interpersonal Difficulties weresignificantly heritable, while only Well-Being had a significant genetic correlation with ME. ME anddepression are both heritable (ME 0.42, depression 0.37) and share common genetic factors, suggestingan overlap in etiology and the relevance of circadian rhythms to depression. Further study of thisrelationship may help elucidate etiological factors in depression and targets for treatment.", "metadata": {}}
+{"_id": "20310709", "title": "", "text": "The Transcription Factor T-bet Regulates Intestinal Inflammation Mediated by Interleukin-7 Receptor+Innate Lymphoid CellsMice lacking the transcription factor T-bet in the innate immune system developmicrobiota-dependent colitis. Here, we show that interleukin-17A (IL-17A)-producing IL-7Rα(+) innatelymphoid cells (ILCs) were potent promoters of disease in Tbx21(-/-)Rag2(-/-) ulcerative colitis (TRUC)mice. TNF-α produced by CD103(-)CD11b(+) dendritic cells synergized with IL-23 to drive IL-17Aproduction by ILCs, demonstrating a previously unrecognized layer of cellular crosstalk between dendriticcells and ILCs. We have identified Helicobacter typhlonius as a key disease trigger driving excess TNF-αproduction and promoting colitis in TRUC mice. Crucially, T-bet also suppressed the expression of IL-7R,a key molecule involved in controlling intestinal ILC homeostasis. The importance of IL-7R signaling inTRUC disease was highlighted by the dramatic reduction in intestinal ILCs and attenuated colitis followingIL-7R blockade. Taken together, these data demonstrate the mechanism by which T-bet regulates thecomplex interplay between mucosal dendritic cells, ILCs, and the intestinal microbiota.", "metadata": {}}
+{"_id": "20311968", "title": "", "text": "Chimeric Antigen Receptor-Redirected Regulatory T Cells Suppress Experimental Allergic AirwayInflammation, a Model of AsthmaCellular therapy with chimeric antigen receptor (CAR)-redirectedcytotoxic T cells has shown impressive efficacy in the treatment of hematologic malignancies. Weexplored a regulatory T cell (Treg)-based therapy in the treatment of allergic airway inflammation, amodel for asthma, which is characterized by an airway hyper-reactivity (AHR) and a chronic, T helper-2(Th2) cell-dominated immune response to allergen. To restore the immune balance in the lung, weredirected Tregs by a CAR toward lung epithelia in mice upon experimentally induced allergic asthma,closely mimicking the clinical situation. Adoptively transferred CAR Tregs accumulated in the lung and intracheobronchial lymph nodes, reduced AHR and diminished eosinophilic airway inflammation, indicatedby lower cell numbers in the bronchoalveolar lavage fluid and decreased cell infiltrates in the lung. CARTreg cells furthermore prevented excessive pulmonary mucus production as well as increase inallergen-specific IgE and Th2 cytokine levels in exposed animals. CAR Tregs were more efficient incontrolling asthma than non-modified Tregs, indicating the pivotal role of specific Treg cell activation inthe affected organ. Data demonstrate that lung targeting CAR Treg cells ameliorate key features ofexperimental airway inflammation, paving the way for cell therapy of severe allergic asthma.", "metadata": {}}
+{"_id": "20313748", "title": "", "text": "α-Catenin as a tension transducer that induces adherens junction developmentAdherens junctions (AJs),which are organized by adhesion proteins and the underlying actin cytoskeleton, probably sense pullingforces from adjacent cells and modulate opposing forces to maintain tissue integrity, but the regulatorymechanism remains unknown at the molecular level. Although the possibility that α-catenin acts as adirect linker between the membrane and the actin cytoskeleton for AJ formation and function has beenminimized, here we show that α-catenin recruits vinculin, another main actin-binding protein of AJs,through force-dependent changes in α-catenin conformation. We identified regions in the α-cateninmolecule that are required for its force-dependent binding of vinculin by introducing mutant α-catenininto cells and using in vitro binding assays. Fluorescence recovery after photobleaching analysis forα-catenin mobility and the existence of an antibody recognizing α-catenin in a force-dependent mannerfurther supported the notion that α-catenin is a tension transducer that translates mechanical stimuli intoa chemical response, resulting in AJ development.", "metadata": {}}
+{"_id": "20321154", "title": "", "text": "A population-based cohort study to elucidate temporal relationship between schizophrenia and metabolicsyndrome (KCIS no. PSY3).BACKGROUND The bidirectional relationships between metabolic syndrome(MetS) and schizophrenia (SCZ) play a crucial role in clinical treatment of both diseases but suchbidirectional causal effects have not been comprehensively elucidated. AIMS To investigate the influenceof MetS on incident SCZ and the opposite direction as well as their predictors for each direction with apopulation-based cohort sample. METHOD We enrolled 76,545 subjects who had participated in acommunity-based health screening program during 1999-2004. After excluding those with the existingMetS or SCZ at baseline, the two normal prospective cohorts corresponding to each independent variableof MetS or SCZ, respectively, were followed over time to ascertain incident outcome of SCZ and MetS.The crude and adjusted hazard ratios for the effect of the predictor on each incident outcome wereestimated after controlling for the possible confounding factors. RESULTS The overall incidence rate (per10(5)person-years) of SCZ was 61.15. The incidence rate in patients with MetS was lower than thosewithout (44.24 versus 64.20), indicating the presence of MetS failed to find an increased risk ofdeveloping incident SCZ. However, participants with abnormal waist circumference (WC) were two times(95% CI: 1.37 to 2.93) more likely to yield incident SCZ compared to those with normal WC. In theopposite direction, the incidence of MetS was statistically higher in patients with SCZ than those withoutSCZ (11.25% vs 7.94%, respectively), suggesting SCZ conferred a higher risk for yielding incident MetS(adjusted hazard ratio=1.89, 95% CI: 1.36, 2.63). CONCLUSIONS After examining the bidirectionalcausal relationships between SCZ and MetS with the theoretically sound and large population-basedprospective cohort study, central obesity, one of the individual components of MetS, was corroborated asan independent predictor for incident SCZ. Patients diagnosed with SCZ were at greater risk of havingincident cases of MetS. Such significant temporal bidirectional relationships between SCZ and centralobesity suggest a reciprocal interaction exits between SCZ and central obesity.", "metadata": {}}
+{"_id": "20326526", "title": "", "text": "DEVELOPMENT AND VALIDATION OF A MEASURE OF EMOTIONAL INTELLIGENCEThis series of studiesdescribes the development of a measure of emotional intelligence based on the model of emotionalintelligence developed by Salovey and Mayer [Salovey, P. & Mayer, J. D. (1990). Emotional intelligence.Imagination, Cognition and Personality, 9, 185–211.]. A pool of 62 items represented the differentdimensions of the model. A factor analysis of the responses of 346 participants suggested the creation ofa 33-item scale. Additional studies showed the 33-item measure to have good internal consistency andtestretest reliability. Validation studies showed that scores on the 33-item measure  1. (a) correlated witheight of nine theoretically related constructs, including alexithymia, attention to feelings, clarity offeelings, mood repair, optimism and impulse control;    2.  (b) predicted first-year college grades;    3.(c) were significantly higher for therapists than for therapy clients or for prisoners;    4.  (d) weresignificantly higher for females than males, consistent with prior findings in studies of emotionalskills;    5. (e) were not related to cognitive ability and    6. (f) were associated with the openness toexperience trait of the big five personality dimensions.", "metadata": {}}
+{"_id": "20330519", "title": "", "text": "Cholesterol glucosylation promotes immune evasion by Helicobacter pyloriHelicobacter pylori infectioncauses gastric pathology such as ulcer and carcinoma. Because H. pylori is auxotrophic for cholesterol,we have explored the assimilation of cholesterol by H. pylori in infection. Here we show that H. pylorifollows a cholesterol gradient and extracts the lipid from plasma membranes of epithelial cells forsubsequent glucosylation. Excessive cholesterol promotes phagocytosis of H. pylori by antigen-presentingcells, such as macrophages and dendritic cells, and enhances antigen-specific T cell responses. Acholesterol-rich diet during bacterial challenge leads to T cell–dependent reduction of the H. pylori burdenin the stomach. Intrinsic α-glucosylation of cholesterol abrogates phagocytosis of H. pylori andsubsequent T cell activation. We identify the gene hp0421 as encoding the enzymecholesterol-α-glucosyltransferase responsible for cholesterol glucosylation. Generation of knockoutmutants lacking hp0421 corroborates the importance of cholesteryl glucosides for escaping phagocytosis,T cell activation and bacterial clearance in vivo. Thus, we propose a mechanism regulating thehost–pathogen interaction whereby glucosylation of a lipid tips the scales towards immune evasion orresponse.", "metadata": {}}
+{"_id": "20333864", "title": "", "text": "Regulation of in situ to invasive breast carcinoma transition.The transition of ductal carcinoma in situ(DCIS) to invasive carcinoma is a poorly understood key event in breast tumor progression. Here, weanalyzed the role of myoepithelial cells and fibroblasts in the progression of in situ carcinomas using amodel of human DCIS and primary breast tumors. Progression to invasion was promoted by fibroblastsand inhibited by normal myoepithelial cells. Molecular profiles of isolated luminal epithelial andmyoepithelial cells identified an intricate interaction network involving TGFbeta, Hedgehog, cell adhesion,and p63 required for myoepithelial cell differentiation, the elimination of which resulted in loss ofmyoepithelial cells and progression to invasion.", "metadata": {}}
+{"_id": "20334484", "title": "", "text": "Health and access to care: perspectives of homeless youth in Baltimore City, U.S.A.Homeless youth sufferfrom high rates of health problems, yet little is known about their perceptions of or context for their ownhealth issues. In this study, a combination of qualitative techniques from participatory rural appraisal andrapid assessment procedures was used to investigate the perceptions of health needs of shelter-basedyouth in Baltimore, MD in the U.S.A. The most common youth-identified health problems included STDs,HIV/AIDS, pregnancy, depression, drug use and injuries. These correlate well with more objective healthstatus data for the same youth. The youth spoke of environmental safety threats of violence andvictimization by adults, as well as racism and sexism in their lives. Youth reported that trusted adultfigures such as grandmothers are important sources of health advice. Many homeless youth from lessthan ideal family situations remain in contact with and continue to seek advice from parents and otherfamily members. Health interventions with urban street youth need to acknowledge the primacy of thesocial context for these youth, as well as the reality of violence as a daily health threat.", "metadata": {}}
+{"_id": "20344442", "title": "", "text": "Differential requirement for CARMA1 in agonist-selected T-cell development.Caspase recruitmentdomain-containing membrane-associated guanylate kinase protein-1 (CARMA1) is a critical component ofthe NF-kappaB signaling cascade mediated by TCR engagement. In addition to activation of naïve T cells,TCR signaling is important for the development of agonist-selected T-cell subsets such as Treg, NKT cells,and CD8-alpha alpha T cells. However, little is known about the role of CARMA1 in the development ofthese lineages. Here we show that CARMA1-deficient mice (CARMA1(-/-)) have altered populations ofspecific subsets of agonist-selected T cells. Specifically, CARMA1(-/-) mice have impaired natural andadaptive Treg development, whereas NKT cell numbers are normal compared with wild-type mice.Interestingly, CD8-alpha alpha T cells, which may also be able to develop through an extrathymicselection pathway, are enriched in the gut of CARMA1(-/-) mice, whereas memory-phenotype CD4(+) Tcells (CD62L(low)/CD44(high)) are present at reduced numbers in the periphery. These results indicatethat CARMA1 is essential for Treg development, but is not necessary for the development of otheragonist-selected T-cell subsets. Overall, these data reveal an important but differential role forCARMA1-mediated TCR signaling in T-cell development.", "metadata": {}}
+{"_id": "20357868", "title": "", "text": "Simian immunodeficiency viruses of diverse origin can use CXCR4 as a coreceptor for entry into humancells.Primary simian immunodeficiency virus (SIV) isolated from sooty mangabey (SIVsm [n = 6]),stumptail (SIVstm [n = 1]), mandrill (SIVmnd [n = 1]), and African green (SIVagm [n = 1]) primateswere examined for their ability to infect human cells and for their coreceptor requirements. All isolatesinfected human peripheral blood mononuclear cells (PBMCs) from a CCR5(+/+) donor, and seven of eightisolates tested also infected CCR5(-/-) PBMCs. Analysis of coreceptor utilization using GHOST and U87cell lines revealed that all of the isolates tested used CCR5 and the orphan receptors STRL33 and GPR15.Coreceptors such as CCR2b, CCR3, CCR8, and CX3CR1 were also utilized by some primary SIV isolates.More importantly, we found that CXCR4 was used as a coreceptor by the SIVstm, the SIVagm, and fourof the SIVsm isolates in GHOST and U87 cells. These data suggest that primary SIV isolates from diverseprimate species can utilize CXCR4 for viral entry, similar to what has been described for humanimmunodeficiency viruses.", "metadata": {}}
+{"_id": "20363389", "title": "", "text": "Cloning of rat uncoupling protein-3 and uncoupling protein-2 cDNAs: their gene expression in rats fedhigh-fat diet.In order to elucidate energy balance in the skeletal muscle, we cloned cDNA of a homologueof uncoupling protein (UCP) from rat skeletal muscle. We also cloned rat UCP-2 cDNA from rat brownadipose tissue (BAT). The UCP cloned from rat skeletal muscle showed 57% and 72% identity with ratUCP-1 and UCP-2. The mRNA was expressed abundantly in the skeletal muscle, moderately in the BAT,and slightly in the white adipose tissue (WAT) with a major band at 2.5 kb and a minor band at 2.8 kb,while the UCP-2 gene expression was widely detected in the whole body with substantial levels in theWAT and with slight levels in the skeletal muscle and BAT. The rat UCP cloned in the present studyshowed 86% identity with the recently cloned human UCP-3, which was also expressed abundantly in theskeletal muscle with a signal of 2.4 kb. Therefore, the rat UCP was considered to be rat UCP-3. In rats fedhigh-fat diet the UCP-3 gene expression was augmented 2-fold in the skeletal muscle while UCP-2 mRNAlevels were increased significantly (1.6-fold) in the epididymal WAT. Augmented expression of UCPs mayprovide defense against high-fat induced obesity and impairment of glucose metabolism.", "metadata": {}}
+{"_id": "20368353", "title": "", "text": "A two-step mechanism for epigenetic specification of centromere identity and functionThe basicdeterminant of chromosome inheritance, the centromere, is specified in many eukaryotes by anepigenetic mark. Using gene targeting in human cells and fission yeast, chromatin containing thecentromere-specific histone H3 variant CENP-A is demonstrated to be the epigenetic mark that actsthrough a two-step mechanism to identify, maintain and propagate centromere function indefinitely.Initially, centromere position is replicated and maintained by chromatin assembled with thecentromere-targeting domain (CATD) of CENP-A substituted into H3. Subsequently, nucleation ofkinetochore assembly onto CATD-containing chromatin is shown to require either the amino- orcarboxy-terminal tail of CENP-A for recruitment of inner kinetochore proteins, including stabilizingCENP-B binding to human centromeres or direct recruitment of CENP-C, respectively.", "metadata": {}}
+{"_id": "20372201", "title": "", "text": "Cancer stem cell theory in gastrointestinal malignancies: recent progress and upcoming challengesAgrowing body of evidence supports the notion that malignant tumors are heterogeneous and containdiverse subpopulations of cells with unique characteristics including the ability to initiate a tumor andmetastasize. This phenomenon might be explained by the so-called cancer stem cell (CSC) theory. Recenttechnological developments have allowed a deeper understanding and characterization of CSCs. Eventhough the application of this theory to hematopoietic malignancies and solid tumors holds promise fornew ways to treat cancer, it also brings some skepticism. Efficacious therapeutic approaches targetingthe CSC population should be explored to overcome therapeutic failure and improve patient outcomes.This review will focus on the intrinsic and extrinsic regulation of CSCs, as well as the development oftherapeutic approaches against CSCs, predominantly focusing on gastrointestinal malignancies.", "metadata": {}}
+{"_id": "20374609", "title": "", "text": "In vitro splicing pathways of pre-mRNAs containing multiple intervening sequences?We analyzed the invitro splicing pathways of three multi-intervening-sequence (IVS) pre-mRNAs: human beta-globin, whichcontains two IVSs (K. M. Lang, V. L. van Santen, and R. A. Spritz, EMBO J. 4:1991-1996, 1985); ratalpha-lactalbumin, which contains three IVSs; and murine interleukin-3, which contains four IVSs. Wefound that there are highly preferred pathways of IVS removal from these multi-IVS pre-mRNAs in vitro.The three IVSs of rat alpha-lactalbumin pre-mRNA were excised sequentially from 5' to 3'; in mostmolecules, IVS1 was removed first, followed by IVS2 and finally by IVS3. The splicing pathway ofinterleukin-3 pre-mRNA in vitro was more complex. The four IVSs were excised in a highly preferredtemporal order, but the order was not strictly sequential or directional. In most molecules, IVS1 and IVS4were removed first, either simultaneously or in rapid succession. Subsequently, IVS2 was excised,followed by IVS3. The observed splicing pathways apparently resulted from differences in lag times andmaximum excision rates of the different IVSs. We detected no exon skipping during splicing of thesetranscripts in vitro. These observations have implication for proposed models of splice site selection.", "metadata": {}}
+{"_id": "20375264", "title": "", "text": "Automated genome sequence analysis and annotation.MOTIVATION Large-scale genome projectsgenerate a rapidly increasing number of sequences, most of them biochemically uncharacterized.Research in bioinformatics contributes to the development of methods for the computationalcharacterization of these sequences. However, the installation and application of these methods requireexperience and are time consuming. RESULTS We present here an automatic system for preliminaryfunctional annotation of protein sequences that has been applied to the analysis of sets of sequencesfrom complete genomes, both to refine overall performance and to make new discoveries comparable tothose made by human experts. The GeneQuiz system includes a Web-based browser that allowsexamination of the evidence leading to an automatic annotation and offers additional information, viewsof the results, and links to biological databases that complement the automatic analysis. Systemstructure and operating principles concerning the use of multiple sequence databases, underlyingsequence analysis tools, lexical analyses of database annotations and decision criteria for functionalassignments are detailed. The system makes automatic quality assessments of results based on priorexperience with the underlying sequence analysis tools; overall error rates in functional assignment areestimated at 2.5-5% for cases annotated with highest reliability ('clear' cases). Sources ofover-interpretation of results are discussed with proposals for improvement. A conservative definition forreporting 'new findings' that takes account of database maturity is presented along with examples ofpossible kinds of discoveries (new function, family and superfamily) made by the system. Systemperformance in relation to sequence database coverage, database dynamics and database searchmethods is analysed, demonstrating the inherent advantages of an integrated automatic approach usingmultiple databases and search methods applied in an objective and repeatable manner. AVAILABILITYThe GeneQuiz system is publicly available for analysis of protein sequences through a Web server athttp://www.sander.ebi.ac. uk/gqsrv/submit", "metadata": {}}
+{"_id": "20381484", "title": "", "text": "GAPDH Mediates Nitrosylation of Nuclear ProteinsS-nitrosylation of proteins by nitric oxide is a majormode of signalling in cells. S-nitrosylation can mediate the regulation of a range of proteins, includingprominent nuclear proteins, such as HDAC2 (ref. 2) and PARP1 (ref. 3). The high reactivity of the nitricoxide group with protein thiols, but the selective nature of nitrosylation within the cell, implies theexistence of targeting mechanisms. Specificity of nitric oxide signalling is often achieved by the binding ofnitric oxide synthase (NOS) to target proteins, either directly or through scaffolding proteins such asPSD-95 (ref. 5) and CAPON. As the three principal isoforms of NOS--neuronal NOS (nNOS), endothelialNOS (eNOS) and inducible NOS (iNOS)--are primarily non-nuclear, the mechanisms by which nuclearproteins are selectively nitrosylated have been elusive. Glyceraldehyde-3-phosphate dehydrogenase(GAPDH) is physiologically nitrosylated at its Cys 150 residue. Nitrosylated GAPDH (SNO-GAPDH) binds toSiah1, which possesses a nuclear localization signal, and is transported to the nucleus. Here, we showthat SNO-GAPDH physiologically transnitrosylates nuclear proteins, including the deacetylating enzymesirtuin-1 (SIRT1), histone deacetylase-2 (HDAC2) and DNA-activated protein kinase (DNA-PK). Ourfindings reveal a novel mechanism for targeted nitrosylation of nuclear proteins and suggest thatprotein-protein transfer of nitric oxide groups may be a general mechanism in cellular signal transduction.", "metadata": {}}
+{"_id": "20388894", "title": "", "text": "The transcription factor c-Maf controls the production of interleukin-4 but not other Th2 cytokines.IL-4promotes the differentiation of naive CD4+ T cells into IL-4-producing T helper 2 (Th2) cells. Previouswork provided suggestive but not conclusive evidence that the transcription factor c-Maf directed thetissue-specific expression of IL-4. It was not known whether c-Maf controlled the transcription of otherTh2 cytokine genes. To elucidate the role of c-Maf in vivo, we examined cytokine production in micelacking c-Maf (c-maf(-/-)). CD4+ T cells and NK T cells from c-maf(-/-) mice were markedly deficient inIL-4 production. However, the mice produced normal levels of IL-13 and IgE, and, when differentiated inthe presence of exogenous IL-4, c-maf(-/-) T cells produced approximately normal levels of other Th2cytokines. We conclude that c-Maf has a critical and selective function in IL-4 gene transcription in vivo.", "metadata": {}}
+{"_id": "20399078", "title": "", "text": "Genome-wide association of IL28B with response to pegylated interferon-α and ribavirin therapy forchronic hepatitis CThe recommended treatment for patients with chronic hepatitis C, pegylatedinterferon-α (PEG-IFN-α) plus ribavirin (RBV), does not provide sustained virologic response (SVR) in allpatients. We report a genome-wide association study (GWAS) to null virological response (NVR) in thetreatment of patients with hepatitis C virus (HCV) genotype 1 within a Japanese population. We foundtwo SNPs near the gene IL28B on chromosome 19 to be strongly associated with NVR (rs12980275, P =1.93 × 10−13, and rs8099917, 3.11 × 10−15). We replicated these associations in an independentcohort (combined P values, 2.84 × 10−27 (OR = 17.7; 95% CI = 10.0–31.3) and 2.68 × 10−32 (OR =27.1; 95% CI = 14.6–50.3), respectively). Compared to NVR, these SNPs were also associated with SVR(rs12980275, P = 3.99 × 10−24, and rs8099917, P = 1.11 × 10−27). In further fine mapping of theregion, seven SNPs (rs8105790, rs11881222, rs8103142, rs28416813, rs4803219, rs8099917 andrs7248668) located in the IL28B region showed the most significant associations (P = 5.52 ×10−28–2.68 × 10−32; OR = 22.3–27.1). Real-time quantitative PCR assays in peripheral bloodmononuclear cells showed lower IL28B expression levels in individuals carrying the minor alleles (P =0.015).", "metadata": {}}
+{"_id": "20402596", "title": "", "text": "The WUSCHEL-related homeobox gene WOX11 is required to activate shoot-borne crown rootdevelopment in rice.In rice (Oryza sativa), the shoot-borne crown roots are the major root type and areinitiated at lower stem nodes as part of normal plant development. However, the regulatory mechanismof crown root development is poorly understood. In this work, we show that a WUSCHEL-relatedHomeobox (WOX) gene, WOX11, is involved in the activation of crown root emergence and growth.WOX11 was found to be expressed in emerging crown roots and later in cell division regions of the rootmeristem. The expression could be induced by exogenous auxin or cytokinin. Loss-of-function mutationor downregulation of the gene reduced the number and the growth rate of crown roots, whereasoverexpression of the gene induced precocious crown root growth and dramatically increased the rootbiomass by producing crown roots at the upper stem nodes and the base of florets. The expressions ofauxin- and cytokinin-responsive genes were affected in WOX11 overexpression and RNA interferencetransgenic plants. Further analysis showed that WOX11 directly repressed RR2, a type-Acytokinin-responsive regulator gene that was found to be expressed in crown root primordia. The resultssuggest that WOX11 may be an integrator of auxin and cytokinin signaling that feeds into RR2 to regulatecell proliferation during crown root development.", "metadata": {}}
+{"_id": "20418809", "title": "", "text": "Inducible depletion of satellite cells in adult, sedentary mice impairs muscle regenerative capacity withoutaffecting sarcopeniaA key determinant of geriatric frailty is sarcopenia, the age-associated loss of skeletalmuscle mass and strength. Although the etiology of sarcopenia is unknown, the correlation during agingbetween the loss of activity of satellite cells, which are endogenous muscle stem cells, and impairedmuscle regenerative capacity has led to the hypothesis that the loss of satellite cell activity is also a causeof sarcopenia. We tested this hypothesis in male sedentary mice by experimentally depleting satellitecells in young adult animals to a degree sufficient to impair regeneration throughout the rest of theirlives. A detailed analysis of multiple muscles harvested at various time points during aging in differentcohorts of these mice showed that the muscles were of normal size, despite low regenerative capacity,but did have increased fibrosis. These results suggest that lifelong reduction of satellite cells neitheraccelerated nor exacerbated sarcopenia and that satellite cells did not contribute to the maintenance ofmuscle size or fiber type composition during aging, but that their loss may contribute to age-relatedmuscle fibrosis.", "metadata": {}}
+{"_id": "20419913", "title": "", "text": "Reproductive clonality in protozoan pathogens--truth or artefact?The debate around the frequency andimportance of genetic exchange in parasitic protozoa is now several decades old. Recently, freshassertions have been made that predominant clonal evolution explains the population structures ofseveral key protozoan pathogens. Here, we present an alternative perspective. On the assumption thatmuch apparent clonality may be an artefact of inadequate sampling and study design, we review currentresearch to define why sex might be so difficult to detect in protozoan parasite populations. In doing so,we contrast laboratory models of genetic exchange in parasitic protozoa with natural patterns of geneticdiversity and consider the fitness advantage of sex at different evolutionary scales. We discussapproaches to improve the accuracy of efforts to characterize genetic exchange in the field. We alsoexamine the implications of the first population genomic studies for the debate around sex and clonalityin parasitic protozoa and discuss caveats for the future.", "metadata": {}}
+{"_id": "20420780", "title": "", "text": "The ACF1 complex is required for DNA double-strand break repair in human cells.DNA double-strandbreaks (DSBs) are repaired via nonhomologous end-joining (NHEJ) or homologous recombination (HR),but cellular repair processes remain elusive. We show here that the ATP-dependentchromatin-remodeling factors, ACF1 and SNF2H, accumulate rapidly at DSBs and are required for DSBrepair in human cells. If the expression of ACF1 or SNF2H is suppressed, cells become extremelysensitive to X-rays and chemical treatments producing DSBs, and DSBs remain unrepaired. ACF1interacts directly with KU70 and is required for the accumulation of KU proteins at DSBs. The KU70/80complex becomes physically more associated with the chromatin-remodeling factors of the CHRACcomplex, which includes ACF1, SNF2H, CHRAC15, and CHRAC17, after treatments producing DSBs.Furthermore, the frequency of NHEJ as well as HR induced by DSBs in chromosomal DNA is significantlydecreased in cells depleted of either of these factors. Thus, ACF1 and its complexes play important rolesin DSBs repair.", "metadata": {}}
+{"_id": "20422174", "title": "", "text": "Findings to date from the ASCUS-LSIL Triage Study (ALTS).Controversy exists in the United Statesregarding the proper evaluation and management of low-grade squamous intraepithelial lesion (LSIL) andequivocal (atypical squamous cells of undetermined significance [ASCUS, now ASC-US]) cervical cytologicinterpretations. To address this issue, the National Cancer Institute initiated the ASCUS-LSIL TriageStudy (ALTS). ALTS is a multicenter, randomized clinical trial designed to evaluate 3 alternative methodsof management, namely, immediate colposcopy, cytologic follow-up, and triage by human papillomavirus(HPV) DNA testing. This article summarizes the major findings of ALTS that have been published to date.Patients with ASCUS (n = 3488) or LSIL (n = 1572) were randomly assigned to research arms betweenNovember 1996 and December 1998, and were monitored for 2 years. The disease outcome washistologic cervical intraepithelial neoplasia (CIN) 3/cancer. The prevalence of oncogenic HPV was too highto permit effective triage of LSIL using HPV DNA testing by Hybrid Capture 2. However, for the womenreferred with a cytologic interpretation of ASCUS, HPV triage proved useful, with sensitivity equivalent toimmediate colposcopy and a halving of colposcopic referrals. Among older women with ASCUS, HPVtesting remained sensitive for detecting CIN 3 and cancer, but the referral percentage was dramaticallylower compared to younger women. ALTS yielded insight into the performance of cytology andhistopathology; experienced pathologists differed significantly in their interpretations of cervicalabnormalities, especially histologic CIN 1 and cytologic ASCUS. Nonetheless, it was possible to distinguisha relatively uncommon type of ASCUS, equivocal for high-grade squamous intraepithelial lesion, that hasa high positive predictive value for identifying women with underlying high-grade CIN. Many additionalanalyses are underway.", "metadata": {}}
+{"_id": "20428155", "title": "", "text": "Marine organisms as a source of new anticancer agents.Various active anticancer agents are derived fromplants and terrestrial microorganisms. The isolation of C-nucleosides from the Caribbean sponge,Cryptotheca crypta, four decades ago, provided the basis for the synthesis of cytarabine, the firstmarine-derived anticancer agent to be developed for clinical use. Cytarabine is currently used in theroutine treatment of patients with leukaemia and lymphoma. Gemcitabine, one of its fluorinatedderivatives, has also been approved for use in patients with pancreatic, breast, bladder, andnon-small-cell lung cancer. Over the past decade, several new experimental anticancer agents derivedfrom marine sources have entered preclinical and clinical trials. This field has expanded significantly as aresult of improvements in the technology of deep-sea collection, extraction, and large-scale productionthrough aquaculture and synthesis. In this paper, examples of marine-derived experimental agents thatare currently undergoing preclinical and early clinical evaluation are briefly discussed. A summary of theavailable information on the results of phase I and II trials of agents such as aplidine, ecteinascidin-734(ET-734), dolastatin 10 and bryostatin 1 is also presented.", "metadata": {}}
+{"_id": "20454006", "title": "", "text": "A randomized, placebo-controlled trial of diindolylmethane for breast cancer biomarker modulation inpatients taking tamoxifenDiindolylmethane (DIM), a bioactive metabolite of indole-3-carbinol found incruciferous vegetables, has proposed cancer chemoprevention activity in the breast. There is limitedevidence of clinically relevant activity of DIM or long-term safety data of its regular use. A randomized,double-blind, placebo-controlled trial was conducted to determine the activity and safety of combined useof BioResponse DIM® (BR-DIM) with tamoxifen. Women prescribed tamoxifen (n = 130) were randomlyassigned oral BR-DIM at 150 mg twice daily or placebo, for 12 months. The primary study endpoint waschange in urinary 2/16α-hydroxyestrone (2/16α-OHE1) ratio. Changes in 4-hydroxyestrone (4-OHE1),serum estrogens, sex hormone-binding globulin (SHBG), breast density, and tamoxifen metabolites wereassessed. Ninety-eight women (51 placebo, 47 DIM) completed intervention; compliance with treatmentwas >91%. BR-DIM increased the 2/16α-OHE1 ratio (+3.2 [0.8, 8.4]) compared to placebo (−0.7 [−1.7,0.8], P < 0.001). Serum SHBG increased with BR-DIM compared to placebo (+25 ± 22 and +1.1 ± 19nmol/L, respectively). No change in breast density measured by mammography or by MRI was observed.Plasma tamoxifen metabolites (endoxifen, 4-OH tamoxifen, and N-desmethyl-tamoxifen) were reduced inwomen receiving BR-DIM versus placebo (P < 0.001). Minimal adverse events were reported and did notdiffer by treatment arm. In patients taking tamoxifen for breast cancer, daily BR-DIM promoted favorablechanges in estrogen metabolism and circulating levels of SHBG. Further research is warranted todetermine whether BR-DIM associated decreases in tamoxifen metabolites, including effects on endoxifenlevels, attenuates the clinical benefit of tamoxifen. Trial Registration: ClinicalTrials.gov NCT01391689.", "metadata": {}}
+{"_id": "20456030", "title": "", "text": "Intracellular coenzymes as natural biomarkers for metabolic activities and mitochondrialanomalies.Mitochondria play a pivotal role in energy metabolism, programmed cell death and oxidativestress. Mutated mitochondrial DNA in diseased cells compromises the structure of key enzyme complexesand, therefore, mitochondrial function, which leads to a myriad of health-related conditions such ascancer, neurodegenerative diseases, diabetes and aging. Early detection of mitochondrial and metabolicanomalies is an essential step towards effective diagnoses and therapeutic intervention. Reducednicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD) play important roles in awide range of cellular oxidation-reduction reactions. Importantly, NADH and FAD are naturallyfluorescent, which allows noninvasive imaging of metabolic activities of living cells and tissues.Furthermore, NADH and FAD autofluorescence, which can be excited using distinct wavelengths forcomplementary imaging methods and is sensitive to protein binding and local environment. This articlehighlights recent developments concerning intracellular NADH and FAD as potential biomarkers formetabolic and mitochondrial activities.", "metadata": {}}
+{"_id": "20457190", "title": "", "text": "Biochemical differences in the alphabeta T cell receptor.CD3 surface complex between CD8+ and CD4+human mature T lymphocytes.We have reported the existence of biochemical and conformationaldifferences in the alphabeta T cell receptor (TCR) complex between CD4(+) and CD8(+)CD3gamma-deficient (gamma(-)) mature T cells. In the present study, we have furthered ourunderstanding and extended the observations to primary T lymphocytes from normal (gamma(+))individuals. Surface TCR.CD3 components from CD4(+) gamma(-) T cells, other than CD3gamma, weredetectable and similar in size to CD4(+) gamma(+) controls. Their native TCR.CD3 complex was alsosimilar to CD4(+) gamma(+) controls, except for an alphabeta(deltaepsilon)(2)zeta(2) instead of analphabetagammaepsilondeltaepsilonzeta(2) stoichiometry. In contrast, the surface TCRalpha, TCRbeta,and CD3delta chains of CD8(+) gamma(-) T cells did not possess their usual sizes. Using confocalimmunofluorescence, TCRalpha was hardly detectable in CD8(+) gamma(-) T cells. Blue native gels(BN-PAGE) demonstrated the existence of a heterogeneous population of TCR.CD3 in these cells. Usingprimary peripheral blood T lymphocytes from normal (gamma(+)) donors, we performed a broad epitopicscan. In contrast to all other TCR.CD3-specific monoclonal antibodies, RW2-8C8 stained CD8(+) betterthan it did CD4(+) T cells, and the difference was dependent on glycosylation of the TCR.CD3 complexbut independent of T cell activation or differentiation. RW2-8C8 staining of CD8(+) T cells was shown tobe more dependent on lipid raft integrity than that of CD4(+) T cells. Finally, immunoprecipitation studieson purified primary CD4(+) and CD8(+) T cells revealed the existence of TCR glycosylation differencesbetween the two. Collectively, these results are consistent with the existence of conformational ortopological lineage-specific differences in the TCR.CD3 from CD4(+) and CD8(+) wild type T cells. Thedifferences may be relevant for cis interactions during antigen recognition and signal transduction.", "metadata": {}}
+{"_id": "20459964", "title": "", "text": "Circulating mitochondrial DNA in serum of patients with granulomatosis with polyangiitis.Neutrophil is akey cell in pathophysiology of granulomatosis with polyangiitis. Recently, neutrophil extracellular trapswere described in this disease. Mitochondrial DNA is also released during traps formation. We measuredcirculating cell-free mitochondrial and genomic DNA in serum of patients with granulomatosis withpolyangiitis. Subjects with the disease (14 active and 11 in remission stage) and 10 healthy controls wereenrolled. Quantitative real-time polymerase chain reaction (PCR) was used to measure 79 base pairs (bp)and 230 bp mtDNA fragments. Alu repeats were quantified to evaluate abundance of nuclear DNA inserum at the presence of plasmid control. Both fragments of mtDNA (79 bp and 230 bp) and genomicDNA were elevated significantly in granulomatosis with polyangiitis compared to controls. Only theshorter 79 bp mtDNA correlated with active stage of granulomatosis with polyangiitis and clinicalsymptoms. A mechanism of extracellular release of mitochondrial DNA accompanies the active stage ofthe disease. Circulating mtDNA is extremely high in untreated patients. This suggests that biomarkerproperties of mtDNA are useful for monitoring of treatment.", "metadata": {}}
+{"_id": "20460020", "title": "", "text": "Estrogen receptor-alpha promotes alternative macrophage activation during cutaneous repair.Efficientlocal monocyte/macrophage recruitment is critical for tissue repair. Recruited macrophages are polarizedtoward classical (proinflammatory) or alternative (prohealing) activation in response to cytokines, withtight temporal regulation crucial for efficient wound repair. Estrogen acts as a potent anti-inflammatoryregulator of cutaneous healing. However, an understanding of estrogen/estrogen receptor (ER)contribution to macrophage polarization and subsequent local effects on wound healing is lacking. Herewe identify, to our knowledge previously unreported, a role whereby estrogen receptor α (ERα) signalingpreferentially polarizes macrophages from a range of sources to an alternative phenotype. Cell-specificER ablation studies confirm an in vivo role for inflammatory cell ERα, but not ERβ, in poor healingassociated with an altered cytokine profile and fewer alternatively activated macrophages. Furthermore,we reveal intrinsic changes in ERα-deficient macrophages, which are unable to respond to alternativeactivation signals in vitro. Collectively, our data reveal that inflammatory cell-expressed ERα promotesalternative macrophage polarization, which is beneficial for timely healing. Given the diverse physiologicalroles of ERs, these findings will likely be of relevance to many pathologies involving excessiveinflammation.", "metadata": {}}
+{"_id": "20471181", "title": "", "text": "Disturbance in cerebral spinal fluid sphingolipid content is associated with memory impairment in subjectsinfected with the human immunodeficiency virusDespite widespread use of antiretroviral therapies tocontrol replication of the human immunodeficiency virus (HIV), dysfunctions of cognition that arecollectively termed HIV-associated neurocognitive disorders (HAND) still occur in approximately 50% ofthose infected by the virus. Currently there is not a biomarker that can identify HIV-infected people whoare at risk for the development of HAND. Previous studies have identified particular sphingolipid speciesthat are dysregulated in HAND, but the neurocognitive correlates of these biochemical findings are notcurrently understood. To address this question, we compared cerebrospinal fluid (CSF) levels ofsphingomyelin, ceramide, and sterol species with performance on standard neurological tests designed toassess the function of multiple cognitive and motor domains in HIV-infected subjects. We found thatsphingomyelin:ceramide ratios for acyl chain lengths of C16\u00000, C18\u00000, C22\u00000, and C24\u00000 wereassociated with worse performance on several indices of memory. The most striking finding was for theacyl chain of C18\u00000 that consistently associatedwith performance onmultiple tests of memory. Thesefindings suggest that the sphingomyelin:ceramide ratio for C18\u00000 may be a reasonable surrogatemarker for memory dysfunction in HIV-infected subjects.", "metadata": {}}
+{"_id": "20473074", "title": "", "text": "An observational study fluid balance and patient outcomes in the Randomized Evaluation of Normal vs.Augmented Level of Replacement Therapy trial.OBJECTIVE To examine associations between mean dailyfluid balance during intensive care unit study enrollment and clinical outcomes in patients enrolled in theRandomized Evaluation of Normal vs. Augmented Level (RENAL) replacement therapy study. DESIGNStatistical analysis of data from multicenter, randomized, controlled trials. SETTING Thirty-five intensivecare units in Australia and New Zealand. PATIENTS Cohort of 1453 patients enrolled in the RENAL study.INTERVENTIONS We analyzed the association between daily fluid balance on clinical outcomes usingmultivariable logistic regression, Cox proportional hazards, time-dependent analysis, and repeatedmeasure analysis models. MEASUREMENTS AND MAIN RESULTS During intensive care unit stay, meandaily fluid balance among survivors was -234 mL/day compared with +560 mL/day among nonsurvivors(p < .0001). Mean cumulative fluid balance over the same period was -1941 vs. +1755 mL (p = .0003).A negative mean daily fluid balance during study treatment was independently associated with adecreased risk of death at 90 days (odds ratio 0.318; 95% confidence interval 0.24-0.43; p < .000.1)and with increased survival time (p < .0001). In addition, a negative mean daily fluid balance wasassociated with significantly increased renal replacement-free days (p = .0017), intensive care unit-freedays (p < .0001), and hospital-free days (p = .01). These findings were unaltered after the application ofdifferent statistical models. CONCLUSIONS In the RENAL study, a negative mean daily fluid balance wasconsistently associated with improved clinical outcomes. Fluid balance may be a target for specificmanipulation in future interventional trials of critically ill patients receiving renal replacement therapy.", "metadata": {}}
+{"_id": "20491205", "title": "", "text": "Prison health care: a review of the literature.The prison population is increasing and the health problemsof prisoners are considerable. Prison is designed with punishment, correction and rehabilitation to thecommunity in mind and these goals may conflict with the aims of health care. A literature review showedthat the main issues in prison health care are mental health, substance abuse and communicablediseases. Women prisoners and older prisoners have needs which are distinct from other prisoners.Health promotion and the health of the community outside prisons are desirable aims of prison healthcare. The delivery of effective health care to prisoners is dependent upon partnership between health andprison services and telemedicine is one possible mode of delivery.", "metadata": {}}
+{"_id": "20492020", "title": "", "text": "A Brief History of Long-Term PotentiationSince the discovery of long-term potentiation (LTP) in 1973,thousands of papers have been published on this intriguing phenomenon, which provides a compellingcellular model for learning and memory. Although LTP has suffered considerable growing pains over theyears, LTP has finally come of age. Here the rich history of LTP is reviewed. These are exciting times andthe pace of discovery is remarkable.", "metadata": {}}
+{"_id": "20501163", "title": "", "text": "Tumor-Induced IL-6 Reprograms Host Metabolism to Suppress Anti-tumor ImmunityIn patients withcancer, the wasting syndrome, cachexia, is associated with caloric deficiency. Here, we describetumor-induced alterations of the host metabolic response to caloric deficiency that cause intratumoralimmune suppression. In pre-cachectic mice with transplanted colorectal cancer or autochthonouspancreatic ductal adenocarcinoma (PDA), we find that IL-6 reduces the hepatic ketogenic potentialthrough suppression of PPARalpha, the transcriptional master regulator of ketogenesis. When these miceare challenged with caloric deficiency, the resulting relative hypoketonemia triggers a marked rise inglucocorticoid levels. Multiple intratumoral immune pathways are suppressed by this hormonal stressresponse. Moreover, administering corticosterone to elevate plasma corticosterone to a level that is lowerthan that occurring in cachectic mice abolishes the response of mouse PDA to an immunotherapy that hasadvanced to clinical trials. Therefore, tumor-induced IL-6 impairs the ketogenic response to reducedcaloric intake, resulting in a systemic metabolic stress response that blocks anti-cancer immunotherapy.", "metadata": {}}
+{"_id": "20524091", "title": "", "text": "Chaperoning stem cells: a role for heat shock proteins in the modulation of stem cell self-renewal anddifferentiation?Self-renewal and differentiation of stem cells are tightly regulated processes subject tointrinsic and extrinsic signals. Molecular chaperones and co-chaperones, especially heat shock proteins(Hsp), are ubiquitous molecules involved in the modulation of protein conformational and complexationstates. The function of Hsp, which are typically associated with stress response and tolerance, is wellcharacterized in differentiated cells, while their role in stem cells remains unclear. It appears thatembryonic stem cells exhibit increased stress tolerance and concomitant high levels of chaperoneexpression. This review critically evaluates stem cell research from a molecular chaperone perspective.Furthermore, we propose a model of chaperone-modulated self-renewal in mouse embryonic stem cells.", "metadata": {}}
+{"_id": "20526907", "title": "", "text": "How much alcohol and how often? Population based case-control study of alcohol consumption and risk ofa major coronary event.OBJECTIVE To quantify the effects of quantity and frequency of alcoholconsumption on risk of acute myocardial infarction and coronary death. DESIGN Case-control study.SETTING Lower Hunter region of New South Wales, Australia, 1983-94. SUBJECTS Men and women aged35-69 years. MAIN OUTCOME MEASURE Acute myocardial infarction or coronary death. RESULTS Alcoholconsumption patterns were compared between 11,511 cases of acute myocardial infarction or coronarydeath and 6077 controls randomly selected from the same study population. After adjusting for theeffects of age, smoking, and medical history, men and women who consumed one or two drinks ofalcohol on five or six days a week had a reduction in risk of a major coronary event compared with menand women who were non-drinkers (odds ratios: men 0.31 (95% confidence interval 0.22 to 0.45);women 0.33 (0.18 to 0.59)). A similar reduction in risk was found after excluding non-drinkers who wereformerly moderate to heavy drinkers. An acute protective effect of alcohol consumption was also foundfor regular drinkers who consumed one or two drinks in the 24 hours preceding the onset of symptoms(odds ratios: men 0.74 (0.51 to 1.09); women 0.43 (0.20 to 0.95)). CONCLUSIONS Frequency andquantity of alcohol consumption are important in assessing the risk of a major coronary event. Risk islowest among men who report one to four drinks daily on five or six days a week and among women whoreport one or two drinks daily on five or six days a week.", "metadata": {}}
+{"_id": "20532591", "title": "", "text": "Tracking adipogenesis during white adipose tissue development, expansion and regenerationWhiteadipose tissue displays high plasticity. We developed a system for the inducible, permanent labeling ofmature adipocytes that we called the AdipoChaser mouse. We monitored adipogenesis duringdevelopment, high-fat diet (HFD) feeding and cold exposure. During cold-induced 'browning' ofsubcutaneous fat, most 'beige' adipocytes stem from de novo–differentiated adipocytes. During HFDfeeding, epididymal fat initiates adipogenesis after 4 weeks, whereas subcutaneous fat undergoeshypertrophy for a period of up to 12 weeks. Gonadal fat develops postnatally, whereas subcutaneous fatdevelops between embryonic days 14 and 18. Our results highlight the extensive differences inadipogenic potential in various fat depots.", "metadata": {}}
+{"_id": "20544428", "title": "", "text": "Blockade of adrenoreceptors inhibits the splenic response to stroke.Recent studies have highlighted theinvolvement of the peripheral immune system in delayed cellular degeneration after stroke. In thepermanent middle cerebral artery occlusion (MCAO) model of stroke, the spleen decreases in size. Thisreduction occurs through the release of splenic immune cells. Systemic treatment with human umbilicalcord blood cells (HUCBC) 24 h post-stroke blocks the reduction in spleen size while significantly reducinginfarct volume. Splenectomy 2 weeks prior to MCAO also reduces infarct volume, further demonstratingthe detrimental role of this organ in stroke-induced neurodegeneration. Activation of the sympatheticnervous system after MCAO results in elevated catecholamine levels both at the level of the spleen,through direct splenic innervation, and throughout the systemic circulation upon release from the adrenalmedulla. These catecholamines bind to splenic alpha and beta adrenoreceptors. This study examineswhether catecholamines regulate the splenic response to stroke. Male Sprague-Dawley rats eitherunderwent splenic denervation 2 weeks prior to MCAO or received injections of carvedilol, a panadrenergic receptor blocker, prazosin, an alpha1 receptor blocker, or propranolol, a beta receptor blocker.Denervation was confirmed by reduced splenic expression of tyrosine hydroxylase. Denervation prior toMCAO did not alter infarct volume or spleen size. Propranolol treatment also had no effects on theseoutcomes. Treatment with either prazosin or carvedilol prevented the reduction in spleen size, yet onlycarvedilol significantly reduced infarct volume (p < 0.05). These results demonstrate that circulatingblood borne catecholamines regulate the splenic response to stroke through the activation of both alphaand beta adrenergic receptors.", "metadata": {}}
+{"_id": "20554003", "title": "", "text": "Effects of Thiazolidinediones on Stroke Recovery: A Case-Matched Controlled StudyAnti-inflammatorytherapy decreases infarct size and enhances stroke recovery. Thiazolidinedione peroxisomeproliferator-activated receptor (PPAR)gamma agonists have potent anti-inflammatory andinsulin-sensitizing anti-diabetic actions. Thirty stroke patients with type 2 diabetes admitted for acuteinpatient stroke rehabilitation receiving pioglitazone or rosiglitazone were matched for age, sex, initialFIMTM score and interval post-stroke with 30 stroke patients with type 2 diabetes not receivingthiazolidinediones. Relevant outcome variables were compared for both groups. The thiazolidinedionetreated group showed significantly greater mean improvement in FIMTM score compared to control group(25.6 ± 10.2 SD vs. 19.8 ± 10.5, respectively, P = 0.015). There was no significant difference in lengthof rehabilitation hospital stay (24.2 ± 7.6 vs. 25.1 ± 7.4 days, P = 0.657) or final discharge destination(home/institution, 19/11 versus 17/13, P = 0.792). Use of thiazolidinediones was associated withenhanced functional recovery in stroke patients with type 2 diabetes.", "metadata": {}}
+{"_id": "20568364", "title": "", "text": "Crosstalk between tumor and endothelial cells promotes tumor angiogenesis by MAPK activation of Notchsignaling.While significant progress has been made in understanding the induction of tumor vasculatureby secreted angiogenic factors, little is known regarding contact-dependent signals that promote tumorangiogenesis. Here, we report that the Notch ligand Jagged1 induced by growth factors viamitogen-activating protein kinase (MAPK) in head and neck squamous cell carcinoma (HNSCC) cellstriggered Notch activation in neighboring endothelial cells (ECs) and promoted capillary-like sproutformation. Jagged1-expressing HNSCC cells significantly enhanced neovascularization and tumor growthin vivo. Moreover, the level of Jagged1 was significantly correlated with tumor blood vessel content andassociated with HNSCC development. Our results elucidate a novel mechanism by which the directinterplay between tumor cells and ECs promotes angiogenesis through MAPK and Notch signalingpathways.", "metadata": {}}
+{"_id": "20585600", "title": "", "text": "A Sequential splicing mechanism promotes selection of an optimal exon by repositioning a downstream 5'splice site in preprotachykinin pre-mRNA.To explore the structural basis of alternative splicing, we haveanalyzed the splicing of pre-mRNAs containing an optional exon, E4, from the preprotachykinin gene. Thisgene encodes substance P and related tachykinin peptides by alternative splicing of a commonpre-mRNA. We have shown that alternative splicing of preprotachykinin pre-mRNA occurs by preferentialskipping of optional E4. The competing mechanism that incorporates E4 into the final spliced RNA isconstrained by an initial block to splicing of the immediate upstream intervening sequence (IVS), IVS3.This block is relieved by sequential splicing, in which the immediate downstream IVS4 is removed first.The structural change resulting from the first splicing event is directly responsible for activation of IVS3splicing. This structural rearrangement replaces IVS4 sequences with E5 and its adjacent IVS5sequences. To determine how this structural change promoted IVS3 splicing, we asked what structuralchange(s) would restore activity of IVS3 splicing-defective mutants. The most significant effect wasobserved by a 2-nucleotide substitution that converted the 5' splice site of E4 to an exact consensusmatch, GUAAGU. Exon 5 sequences alone were found not to promote splicing when present in one ormultiple copies. However, when a 15-nucleotide segment of IVS5 containing GUAAGU was inserted into asplicing-defective mutant just downstream of the hybrid exon segment E4E5, splicing activity wasrecovered. Curiously, the 72-nucleotide L2 exon of adenovirus, without its associated 5' splice site,activates splicing when juxtaposed to E4. Models for the activation of splicing by an RNA structuralchange are discussed.", "metadata": {}}
+{"_id": "20602517", "title": "", "text": "Melatonin and the circadian regulation of sleep initiation, consolidation, structure, and the sleep EEG.Theendogenous circadian rhythm of melatonin, driven by the suprachiasmatic nucleus, exhibits a closeassociation with the endogenous circadian component of the sleep propensity rhythm and theendogenous circadian component of the variation in electroencephalogram (EEG) oscillations such assleep spindles and slow waves. This association is maintained even when the sleep-wake cycle isdesynchronized from the endogenous circadian rhythm of melatonin. Administration of melatonin duringthe day increases daytime sleep propensity as indexed by both the latency to sleep onset and sleepconsolidation. The EEG during daytime sleep after melatonin administration exhibits characteristicsreminiscent of the nocturnal sleep EEG, that is, increased sleep spindle activity and reduced slow-wavesleep and slow-wave activity, as detected by quantitative EEG analysis. Administration of higher doses ofmelatonin (5 mg or more) prior to nocturnal sleep results in an increase in rapid eye movement (REM)sleep. These data demonstrate that melatonin exerts effects on the main characteristics of human sleep,that is, latency to sleep onset, sleep consolidation, slow waves, sleep spindles, and REM sleep. There is aneed for further studies using physiological doses and delivery systems that generate physiologicalplasma melatonin profiles to firmly establish the role of the endogenous circadian rhythm of melatonin inthe circadian regulation of sleep.", "metadata": {}}
+{"_id": "20606520", "title": "", "text": "Long-term survival, quality of life, and quality-adjusted life-years among critically ill elderlypatients.OBJECTIVES To assess mortality, quality of life (QOL), and quality-adjusted life-years (QALYs)for critically ill elderly patients. DESIGN Cross-sectional survey. SETTING A ten-bed medical-surgicalintensive care unit (ICU) in a tertiary care university hospital. PATIENTS The study group included 882elderly patients (> or =65 yrs of age) and 1,827 controls (<65 yrs of age) treated during the period of1995 to 2000. INTERVENTION None. MEASUREMENTS AND MAIN RESULTS Mortality was assessed duringthe ICU and hospital stays, and 12, 24, and 36 months after ICU discharge. The cumulative 3-yr mortalityrate among the elderly (57%) was higher (p < .05) than that among the controls (40%). The majority(66%) of the elderly nonsurvivors died within 1 month after intensive care discharge. All elderly patientswith day-1 Sequential Organ Failure (SOFA) scores >15 died during the ICU stay. QOL was assessed withEQ-5D and RAND-36 measures from 10 months to 7 yrs after discharge. The majority (88%) of theelderly survivors assessed their present health state as good or satisfactory; 66% found it to be similar orbetter than 12 months earlier, and 48% similar or better than their preadmission state. QOL measures byRAND-36 revealed that aging decreased their competencies most in physical functioning, physical rolelimitations, and vitality, but the elderly had better values in mental health than the controls. However,QALYs of the elderly respondents were 21% to 35% lower than the mean QALY minus 2 sd units of theage- and gender-adjusted general population. CONCLUSIONS High age alone is not a valid reason torefuse intensive care, but the benefits perceived by intensive care seem to decrease with aging, ifreflected as QALYs. However, 97% of the elderly survivors lived at home and 88% of them consideredtheir QOL satisfactory or good after hospital discharge. Therefore, more reliable information on theoutcome for the elderly is clearly needed.", "metadata": {}}
+{"_id": "20608982", "title": "", "text": "Recent developments and complexities in neutrophil transmigration.PURPOSE OF REVIEW As themigration of neutrophils from blood to inflamed tissues is an essential component of innate immunity anda key contributing factor to the pathogenesis of inflammatory disorders, this aspect of leukocyte biologycontinues to be a highly dynamic field of research. This review summarizes recent findings in this area,focusing on the mechanisms that mediate neutrophil transmigration, an area where significant progresshas been made. RECENT FINDINGS The topics to be covered will include responses that are prerequisiteto neutrophil migration through venular walls, such as leukocyte luminal crawling and cellular andmolecular changes in leukocytes and endothelial cells (e.g. formation of protrusions) that collectivelysupport leukocyte transendothelial cell migration. Advances in both paracellular and transcellularneutrophil migration through endothelial cells will be discussed, addressing the associated roles andregulation of expression of endothelial cell luminal and junctional adhesion molecules. Beyond theendothelium, migration through the vascular pericyte coverage and basement membrane will bereviewed. SUMMARY The unquestionable role of neutrophils in the development and progression ofinflammatory conditions suggests that a better understanding of the tissue-specific and stimulus-specificmechanisms that mediate this response may identify novel pathways that could be exploited for thedevelopment of more specific anti-inflammatory interventions.", "metadata": {}}
+{"_id": "20610390", "title": "", "text": "Exploring the epidemiological characteristics of cancers of unknown primary site in an Australianpopulation: implications for research and clinical care.OBJECTIVES To investigate incidence, mortality andcase survival trends for cancer of unknown primary site (CUP) and consider clinical implications. METHODSouth Australian Cancer Registry data were used to calculate age-standardised incidence and mortalityrates from 1977 to 2004. Disease-specific survivals, socio-demographic, histological and secularpredictors of CUP, compared with cancers of known primary site, and of CUP histological types, usingmultivariable logistic regression were investigated. RESULTS Incidence and mortality rates increasedapproximately 60% between 1977--80 and 1981--84. Rates peaked in 1993--96. Male to femaleincidence and mortality rate ratios approximated 1.3:1. Incidence and mortality rates increased with age.The odds of unspecified histological type, compared with the more common adenocarcinomas, werehigher for males than females, non-metropolitan residents, low socio-economic areas, and for 1977--88than subsequent diagnostic periods. CUP represented a higher proportion of cancers in Indigenouspatients. Case survival was 7% at 10 years from diagnosis. Factors predictive of lower case survivalincluded older age, male sex, Indigenous status, lower socio-economic status, and unspecified histologytype. CONCLUSION Results point to poor CUP outcomes, but with a modest improvement in survival. Thestudy identifies socio-demographic groups at elevated risk of CUP and of worse treatment outcomeswhere increased research and clinical attention are required.", "metadata": {}}
+{"_id": "20610557", "title": "", "text": "Alkylating agent melphalan augments the efficacy of adoptive immunotherapy using tumor-specific CD4+T cells.In recent years, the immune-potentiating effects of some widely used chemotherapeutic agentshave been increasingly appreciated. This provides a rationale for combining conventional chemotherapywith immunotherapy strategies to achieve durable therapeutic benefits. Previous studies have implicatedthe immunomodulatory effects of melphalan, an alkylating agent commonly used to treat multiplemyeloma, but the underlying mechanisms remain obscure. In the present study, we investigated theimpact of melphalan on endogenous immune cells as well as adoptively transferred tumor-specificCD4(+) T cells in tumor-bearing mice. We showed that melphalan treatment resulted in a rapid burst ofinflammatory cytokines and chemokines during the cellular recovery phase after melphalan-inducedmyelodepletion and leukodepletion. After melphalan treatment, tumor cells exhibited characteristics ofimmunogenic cell death, including membrane translocation of the endoplasmic reticulum-residentcalreticulin and extracellular release of high-mobility group box 1. Additionally, there was enhancedtumor Ag uptake by dendritic cells in the tumor-draining lymph node. Consistent with theseimmunomodulatory effects, melphalan treatment of tumor-bearing mice led to the activation of theendogenous CD8(+) T cells and, more importantly, effectively drove the clonal expansion and effectordifferentiation of adoptively transferred tumor-specific CD4(+) T cells. Notably, the combination ofmelphalan and CD4(+) T cell adoptive cell therapy was more efficacious than either treatment alone inprolonging the survival of mice with advanced B cell lymphomas or colorectal tumors. These findingsprovide mechanistic insights into melphalan's immunostimulatory effects and demonstrate thetherapeutic potential of combining melphalan with adoptive cell therapy utilizing antitumor CD4(+) Tcells.", "metadata": {}}
+{"_id": "20611846", "title": "", "text": "Influence of cigarette smoking on inhaled corticosteroid treatment in mild asthma.BACKGROUNDAlthough inhaled corticosteroids have an established role in the treatment of asthma, studies havetended to concentrate on non-smokers and little is known about the possible effect of cigarette smokingon the efficacy of treatment with inhaled steroids in asthma. A study was undertaken to investigate theeffect of active cigarette smoking on responses to treatment with inhaled corticosteroids in patients withmild asthma. METHODS The effect of treatment with inhaled fluticasone propionate (1000 microg daily)or placebo for 3 weeks was studied in a double blind, prospective, randomised, placebo controlled studyof 38 steroid naïve adult asthmatic patients (21 non-smokers). Efficacy was assessed using morning andevening peak expiratory flow (PEF) readings, spirometric parameters, bronchial hyperreactivity, andsputum eosinophil counts. Comparison was made between responses to treatment in non-smoking andsmoking asthmatic patients. RESULTS There was a significantly greater increase in mean morning PEF innon-smokers than in smokers following inhaled fluticasone (27 l/min v -5 l/min). Non-smokers had astatistically significant increase in mean morning PEF (27 l/min), mean forced expiratory volume in 1second (0.17 l), and geometric mean PC20 (2.6 doubling doses), and a significant decrease in theproportion of sputum eosinophils (-1.75%) after fluticasone compared with placebo. No significantchanges were observed in the smoking asthmatic patients for any of these parameters. CONCLUSIONSActive cigarette smoking impairs the efficacy of short term inhaled corticosteroid treatment in mildasthma. This finding has important implications for the management of patients with mild asthma whosmoke.", "metadata": {}}
+{"_id": "20620012", "title": "", "text": "Hitting the target: emerging technologies in the search for kinase substrates.Through phosphorylation,protein kinases can alter the activity, localization, protein association, and stability of their targets.Despite the importance to our understanding of all aspects of cell biology, progress toward identifyingbona fide substrates of specific protein kinases has been slow. Traditionally used techniques to identifytrue kinase substrates, such as genetics, yeast two-hybrid screens, and biochemical purification, areoften laborious and unreliable. However, several new approaches have recently been developed and usedsuccessfully to identify genuine in vivo substrates of certain protein kinases. These methods includescreening for phosphorylation of proteins from phage expression libraries, peptide library screens todetermine optimal motifs favored by specific kinases, the use of phospho-motif antibodies, and anapproach that uses structurally altered kinases and allele-specific adenosine triphosphate analogs andkinase inhibitors. We describe these approaches and discuss their utility and inherent caveats.", "metadata": {}}
+{"_id": "20630805", "title": "", "text": "Histone phosphorylation: a chromatin modification involved in diverse nuclear events.Histoneposttranslational modifications are key components of diverse processes that modulate chromatinstructure. These marks function as signals during various chromatin-based events, and act as platformsfor recruitment, assembly or retention of chromatin-associated factors. The best-known function ofhistone phosphorylation takes place during cellular response to DNA damage, when phosphorylatedhistone H2A(X) demarcates large chromatin domains around the site of DNA breakage. However, multiplestudies have also shown that histone phosphorylation plays crucial roles in chromatin remodeling linkedto other nuclear processes. In this review, we summarize the current knowledge of histonephosphorylation and describe the many kinases and phosphatases that regulate it. We discuss the keyroles played by this histone mark in DNA repair, transcription and chromatin compaction during celldivision and apoptosis. Additionally, we describe the intricate crosstalk that occurs betweenphosphorylation and other histone modifications and allows for sophisticated control over the chromatinremodeling processes.", "metadata": {}}
+{"_id": "20645335", "title": "", "text": "Neurodevelopmental Outcome After a Single Course of Antenatal Steroids in Children Born Preterm: ASystematic Review and Meta-analysis.OBJECTIVE To systematically review and integrate data on theneurodevelopmental outcome of children after administration of a single course of antenatalcorticosteroids for threatened preterm labor. DATA SOURCES MEDLINE, Scopus, CENTRAL, andwww.clinicaltrials.gov (inception to August 2014) using combinations of the terms \"prenatal,\" \"antenatal,\"\"cortico*,\" \"*steroid*,\" \"betamethasone,\" \"dexamethasone,\" \"neurodevelopment*,\" \"*development*,\"and \"follow-up. \" We perused the references of the retrieved articles. METHODS OF STUDY SELECTIONWe included randomized and nonrandomized trials reporting on the neurodevelopmental outcomes ofchildren whose mothers were administered a single course of betamethasone or dexamethasoneantenatally for threatened preterm birth as opposed to placebo or no treatment. TABULATION,INTEGRATION, AND RESULTS Summary risk ratio (RR) was calculated for dichotomous data;standardized mean difference was calculated for trials that measured the same outcome but useddifferent methods. Heterogeneity was assessed using the I statistic. Sensitivity and subgroup analyseswere planned according to study design, specific steroid, and mean gestational age at birth. A singlecourse of antenatal corticosteroids was associated with reduced risk for cerebral palsy (seven studies;treated: 390 of 5,199, untreated: 146 of 1,379; RR 0.678, 95% confidence interval [CI] 0.564-0.815),psychomotor development index less than 70 (two studies; treated: 783 of 3,049, untreated: 258 of 969;RR 0.829, 95% CI 0.737-0.933), and severe disability (five studies; treated: 1,567 of 4,840, untreated:475 of 1,211; RR 0.787, 95% CI 0.729-0.850). Steroid treatment increased the rates of intact survival(six studies; treated: 1,082 of 2,013, untreated: 273 of 561; RR 1.186, 95% CI 1.056-1.332).Betamethasone was found to significantly decrease the risk for severe disability and increase the rate ofintact survival. Dexamethasone increased the rate of intact survival; however, data for dexametasoneand the other planned subgroup analyses were limited (fewer than 1,000 children at most). The majorlimitations involved inclusion of nonrandomized studies and scarcity of data on finer neurodevelopmentaloutcomes. CONCLUSION A single course of antenatal corticosteroids in women at high risk for pretermbirth appears to improve most neurodevelopmental outcomes in offspring born before 34 weeks ofgestation.", "metadata": {}}
+{"_id": "20645538", "title": "", "text": "Prognostic impact of minimal pleural effusion in non-small-cell lung cancer.PURPOSE Minimal (< 10 mmthick) pleural effusion (PE) may represent an early phase of malignant PE, but its clinical relevance hasrarely been studied. Therefore, we examined the proportion of minimal PE in patients with non-small-celllung cancer (NSCLC) and its impact on survival. We also considered possible accumulation mechanisms inour data set. PATIENTS AND METHODS On the basis of PE status from chest computed tomography scansat diagnosis, 2,061 patients were classified into three groups: no PE, minimal PE, and malignant PE.Twenty-one variables associated with four factors-patient, stage migration, tumor, and treatment-wereinvestigated for correlation with survival. RESULTS Minimal PE presented in 272 patients (13.2%). Of2,061 patients, the proportion of each stage was the following: 5.2% stage I, 10.9% stage II, 13.2%stage IIIA, 23.8% stage IIIB, and 13.9% stage IV. Minimal PE correlated significantly with shortersurvival time than did no PE (median survival time, 7.7 v 17.7 months; log-rank P < .001), even after fulladjustment with all variables (adjusted hazard ratio, 1.40; 95% CI, 1.21 to 1.62). Prognostic impact ofminimal PE was higher in early versus advanced stages (Pinteraction = .001). In 237 patients (87.8%)with minimal PE, pleural invasion or attachment as a direct mechanism was observed, and it was anindependent factor predicting worse survival (P = .03). CONCLUSION Minimal PE is a commonlyencountered clinical concern in staging NSCLCs. Its presence is an important prognostic factor of worsesurvival, especially in early-stage disease.", "metadata": {}}
+{"_id": "20646904", "title": "", "text": "Fusion proteins for versatile antigen targeting to cell surface receptors reveal differential capacity toprime immune responses.Targeting of proteins to APCs is an attractive strategy for eliciting adaptiveimmune responses. However, the relationship between the choice of the targeted receptor and the qualityand quantity of responses remains poorly understood. We describe a strategy for expression of Agsincluding hydrophobic proteins as soluble fusion proteins that are optimized for proteasome-dependentMHC class I-restricted cross-presentation and form stable complexes with a wide variety of targeting Abs.Upon s.c. immunization, these complexes were initially taken up by CD169+ lymph node subcapsularsinus macrophages. In the OVA model system, receptor-targeted antigenic complexes primed specific Tand B cell responses in vitro and in vivo at least 100-fold more efficiently than Ag alone. Comparison of10 targeting receptors allowed us to establish a ranking with respect to priming of CD8+ T cell responsesand demonstrated striking differences with respect to the relative efficacy of CD8+ and CD4+ T cellsubset and B cell priming. The described fusion proteins should help in developing optimized strategiesfor targeted delivery of protein Ags in the context of tolerization or vaccination.", "metadata": {}}
+{"_id": "20649327", "title": "", "text": "A sequential model for peptide binding and transport by the transporters associated with antigenprocessing.The TAP proteins translocate antigenic peptides into the endoplasmic reticulum. Investigationof the specificity of this process has been complicated by TAP-independent factors that influence theamount of peptide that accumulates in the ER in transport assays. We have developed an overexpressionsystem in which binding of peptides to the TAP substrate-binding site and peptide transport by TAP canbe quantified separately. Efficiency of peptide accumulation in the ER parallels affinity for the TAPsubstrate-binding site, but can be modified by interaction with the glycosylation system within the ERand, probably, peptide efflux. Random peptide mixtures of 9-16 aa display significantly higher affinity forthe binding site than mixtures of shorter or longer peptides. Peptide binds to TAP heteromers in theabsence of ATP and is released by the binding of ATP, suggesting a model for TAP function.", "metadata": {}}
+{"_id": "20649735", "title": "", "text": "Outcome of repeated radiosurgery for recurrent metastatic brain tumors.OBJECTIVE We investigated theoutcome of repeated gamma knife radiosurgery (GKS) for local or remote recurrence after initialradiosurgery. MATERIAL AND METHODS We retrospectively reviewed 204 patients who were treated withGKS. Among them 43 patients (21%) underwent GKS more than once. The second GKS was given forrecurrence at the previously treated sites in 16 patients, new lesions at remote sites in 13, and both localrecurrence and new lesions in 14. RESULTS The median survival from the first GKS was 36 (7-190) weeksin all patients and 68 (16-156) weeks in 43 patients with repeated GKS. The median time from the firstGKS to the second was 37 weeks. The median survival from the second radiosurgical intervention was 32(7-132) weeks. Local control rate at 6 months after salvage GKS was 90.7%. RPA class was thecommonly dominant prognostic factor in both initial and salvage GKS. CONCLUSION Recurrence iscommon for patients with metastatic brain tumors after initial radiosurgery. Local control and survivaltime after salvage treatment are comparable with those after initial radiosurgery. GKS as a salvagetreatment may provide additional survival benefit in selected patients.", "metadata": {}}
+{"_id": "20659283", "title": "", "text": "Human CYP3A4 and murine Cyp3A11 are regulated by equol and genistein via the pregnane X receptor ina species-specific manner.Pregnane X receptor (PXR) is an important component of the body's adaptivedefense system responsible for the elimination of various toxic xenobiotics. PXR activation by endogenousand exogenous chemicals, including steroids, antibiotics, bile acids, and herbal compounds, results ininduction of drug metabolism. We investigated the ability of the isoflavones genistein, daidzein, and thedaidzein metabolite equol to activate human and mouse PXR in vitro using cell-based transienttransfection studies and primary hepatocytes and in vivo in a mouse model. In transient transfectionassays, the isoflavones genistein and daidzein activate full-length, wild-type mouse PXR, but not amutant form, with genistein being the most potent. In contrast, equol was a more potent activator ofhuman PXR than genistein or daidzein. In a mammalian 2-hybrid assay, isoflavones induced recruitmentof the coactivator steroid receptor coactivator 1 to PXR. When tested against the native humanCytochrome P450 3A4 (CYP3A4) promoter, equol was the more potent activator and treatment of humanhepatocytes with equol increased CYP3A4 mRNA and immunoreactive protein expression. Treatment ofwild-type, but not PXR(-/-), mouse hepatocytes showed that genistein and daidzein induced theexpression of Cytochrome P450 3A11 (Cyp3A11) mRNA, whereas equol had no effect. Cyp3A11 mRNAwas also induced in vivo in mice fed a soy protein-containing diet. The results presented hereindemonstrate that there is a species-specific difference in the activation of PXR by isoflavones and equol.", "metadata": {}}
+{"_id": "20672596", "title": "", "text": "Metabolism of glucose, glutamine, long-chain fatty acids and ketone bodies by murinemacrophages.Maximum activities of some key enzymes of metabolism were studied in elicited(inflammatory) macrophages of the mouse and lymph-node lymphocytes of the rat. The activity ofhexokinase in the macrophage is very high, as high as that in any other major tissue of the body, andhigher than that of phosphorylase or 6-phosphofructokinase, suggesting that glucose is a more importantfuel than glycogen and that the pentose phosphate pathway is also important in these cells. The lattersuggestion is supported by the high activities of both glucose-6-phosphate dehydrogenase and6-phosphogluconate dehydrogenase. However, the rate of glucose utilization by 'resting' macrophagesincubated in vitro is less than the 10% of the activity of 6-phosphofructokinase: this suggests that therate of glycolysis is increased dramatically during phagocytosis or increased secretory activity. Themacrophages possess higher activities of citrate synthase and oxoglutarate dehydrogenase than dolymphocytes, suggesting that the tricarboxylic acid cycle may be important in energy generation in thesecells. The activity of 3-oxoacid CoA-transferase is higher in the macrophage, but that of3-hydroxybutyrate dehydrogenase is very much lower than those in the lymphocytes. The activity ofcarnitine palmitoyltransferase is higher in macrophages, suggesting that fatty acids as well asacetoacetate could provide acetyl-CoA as substrate for the tricarboxylic acid cycle. No detectable rate ofacetoacetate or 3-hydroxybutyrate utilization was observed during incubation of resting macrophages,but that of oleate was 1.0 nmol/h per mg of protein or about 2.2% of the activity of palmitoyltransferase.The activity of glutaminase is about 4-fold higher in macrophages than in lymphocytes, which suggeststhat the rate of glutamine utilization could be very high. The rate of utilization of glutamine by restingincubated macrophages was similar to that reported for rat lymphocytes, but was considerably lower thanthe activity of glutaminase.", "metadata": {}}
+{"_id": "20675284", "title": "", "text": "TGF-beta inhibition of endothelial cell proliferation: alteration of EGF binding and EGF-inducedgrowth-regulatory (competence) gene expression.Transforming growth factor-beta (TGF-beta) inhibitsthe growth of endothelial cells derived from various sources, including human umbilical vein, bovineaorta, and rat heart. Long-term exposure of rat heart endothelial cells to TGF-beta also induces dramaticchanges in morphology that are characteristic of senescent cells. These changes are accompanied by adecrease in the number of high-affinity receptors for epidermal growth factor (EGF), with almost nochange in total receptor number. Additionally, the EGF-induced expression of specific competence genes(c-myc, JE, KC) is decreased, whereas the induction of c-fos gene expression by EGF is unaltered byTGF-beta treatment. These data suggest that growth inhibitors such as TGF-beta may act by altering thecell's response to growth-stimulatory factors.", "metadata": {}}
+{"_id": "20690388", "title": "", "text": "Human NK cells in acute myeloid leukaemia patients: analysis of NK cell-activating receptors and theirligandsNatural killer (NK) cell activation is strictly regulated to ensure that healthy cells are preserved,but tumour-transformed or virus-infected cells are recognized and eliminated. To carry out this selectivekilling, NK cells have an ample repertoire of receptors on their surface. Signalling by inhibitory andactivating receptors by interaction with their ligands will determine whether the NK cell becomesactivated and kills the target cell. Here, we show reduced expression of NKp46, NKp30, DNAM-1, CD244and CD94/NKG2C activating receptors on NK cells from acute myeloid leukaemia patients. This reductionmay be induced by chronic exposure to their ligands on leukaemic blasts. The analysis of ligands for NKcell-activating receptors showed that leukaemic blasts from the majority of patients express ligands forNK cell-activating receptors. DNAM-1 ligands are frequently expressed on blasts, whereas the expressionof the NKG2D ligand MICA/B is found in half of the patients and CD48, a ligand for CD244, in onlyone-fourth of the patients. The decreased expression of NK cell-activating receptors and/or theheterogeneous expression of ligands for major receptors on leukaemic blasts can lead to an inadequatetumour immunosurveillance by NK cells. A better knowledge of the activating receptor repertoire on NKcells and their putative ligands on blasts together with the possibility to modulate their expression willopen new possibilities for the use of NK cells in immunotherapy against leukaemia.", "metadata": {}}
+{"_id": "20696397", "title": "", "text": "Production of interleukin-6 in contracting human skeletal muscles can account for the exercise-inducedincrease in plasma interleukin-6.1. Plasma interleukin (IL)-6 concentration is increased with exercise andit has been demonstrated that contracting muscles can produce IL-The question addressed in the presentstudy was whether the IL-6 production by contracting skeletal muscle is of such a magnitude that it canaccount for the IL-6 accumulating in the blood. 2. This was studied in six healthy males, who performedone-legged dynamic knee extensor exercise for 5 h at 25 W, which represented 40% of peak poweroutput (Wmax). Arterial-femoral venous (a-fv) differences over the exercising and the resting leg wereobtained before and every hour during the exercise. Leg blood flow was measured in parallel by theultrasound Doppler technique. IL-6 was measured by enzyme-linked immunosorbent assay (ELISA). 3.Arterial plasma concentrations for IL-6 increased 19-fold compared to rest. The a-fv difference for IL-6over the exercising leg followed the same pattern as did the net IL-6 release. Over the resting leg, therewas no significant a-fv difference or net IL-6 release. The work was produced by 2.5 kg of active muscle,which means that during the last 2 h of exercise, the median IL-6 production was 6.8 ng min-1 (kg activemuscle)-1 (range, 3.96-9.69 ng min-1 kg-1). 4. The net IL-6 release from the muscle over the last 2 h ofexercise was 17-fold higher than the elevation in arterial IL-6 concentration and at 5 h of exercise the netrelease during 1 min was half of the IL-6 content in the plasma. This indicates a very high turnover ofIL-6 during muscular exercise. We suggest that IL-6 produced by skeletal contracting muscle contributesto the maintenance of glucose homeostasis during prolonged exercise.", "metadata": {}}
+{"_id": "20697217", "title": "", "text": "Symptoms of hypoglycemia in children with IDDM.OBJECTIVE To examine the symptoms of hypoglycemiain children with insulin-dependent diabetes, from the perspective both of the child and of the child'sparents, and to compare the symptom reporting of the diabetic children with that of adult diabeticpatients. RESEARCH DESIGN AND METHODS Interviews were conducted with 100 parents and 43 of theirchildren. The frequency and intensity of symptoms of hypoglycemia were documented using a structuredinterview and classified into groups using Principal Components Analysis (PCA). RESULTS Diabeticchildren and their parents showed close agreement concerning the relative frequency and the intensity ofsymptoms reported. PCA of the symptom reports showed that diabetic children and their parentsidentified the same distinct subgroups of hypoglycemia-related symptoms: behavioral disturbance andautonomic-neuroglycopenic subgroups. CONCLUSIONS Hypoglycemic symptoms in children with diabetesclearly differ from those experienced by insulin-treated adults and, in particular, include behavioralchanges as primary features of a low blood glucose. These observations have important implications forparental education on hypoglycemia.", "metadata": {}}
+{"_id": "20707861", "title": "", "text": "Comparative Protein Structure Modeling Using MODELLER.Comparative protein structure modelingpredicts the three-dimensional structure of a given protein sequence (target) based primarily on itsalignment to one or more proteins of known structure (templates). The prediction process consists of foldassignment, target-template alignment, model building, and model evaluation. This unit describes how tocalculate comparative models using the program MODELLER and how to use the ModBase database ofsuch models, and discusses all four steps of comparative modeling, frequently observed errors, and someapplications. Modeling lactate dehydrogenase from Trichomonas vaginalis (TvLDH) is described as anexample. The download and installation of the MODELLER software is also described. © 2016 by JohnWiley & Sons, Inc.", "metadata": {}}
+{"_id": "20722510", "title": "", "text": "IL-6 as a keystone cytokine in health and diseaseInterleukin 6 (IL-6) has a broad effect on cells of theimmune system and those not of the immune system and often displays hormone-like characteristics thataffect homeostatic processes. IL-6 has context-dependent pro- and anti-inflammatory properties and isnow regarded as a prominent target for clinical intervention. However, the signaling cassette that controlsthe activity of IL-6 is complicated, and distinct intervention strategies can inhibit this pathway. Clinicalexperience with antagonists of IL-6 has raised new questions about how and when to block this cytokineto improve disease outcome and patient wellbeing. Here we discuss the effect of IL-6 on innate andadaptive immunity and the possible advantages of various antagonists of IL-6 and consider how theimmunobiology of IL-6 may inform clinical decisions.", "metadata": {}}
+{"_id": "20725212", "title": "", "text": "Chaperoning 5S RNA assembly.In eukaryotes, three of the four ribosomal RNAs (rRNAs)—the 5.8S, 18S,and 25S/28S rRNAs—are processed from a single pre-rRNA transcript and assembled into ribosomes. Thefourth rRNA, the 5S rRNA, is transcribed by RNA polymerase III and is assembled into the 5Sribonucleoprotein particle (RNP), containing ribosomal proteins Rpl5/uL18 and Rpl11/uL5, prior to itsincorporation into preribosomes. In mammals, the 5S RNP is also a central regulator of the homeostasisof the tumor suppressor p53. The nucleolar localization of the 5S RNP and its assembly into preribosomesare performed by a specialized complex composed of Rpf2 and Rrs1 in yeast or Bxdc1 and hRrs1 inhumans. Here we report the structural and functional characterization of the Rpf2-Rrs1 complex alone, incomplex with the 5S RNA, and within pre-60S ribosomes. We show that the Rpf2-Rrs1 complex containsa specialized 5S RNA E-loop-binding module, contacts the Rpl5 protein, and also contacts the ribosomeassembly factor Rsa4 and the 25S RNA. We propose that the Rpf2-Rrs1 complex establishes a network ofinteractions that guide the incorporation of the 5S RNP in preribosomes in the initial conformation prior toits rotation to form the central protuberance found in the mature large ribosomal subunit.", "metadata": {}}
+{"_id": "20732789", "title": "", "text": "Chronic obstructive pulmonary disease and neutrophil infiltration: role of cigarette smoke andcyclooxygenase products.Cigarette smoke is the main cause of chronic obstructive pulmonary disease(COPD), where it can contribute to the observed airway inflammation. PGE(2) is produced within humanairways, and both pro- and anti-inflammatory activities have been reported. We quantitated PGE(2)concentrations in induced sputum supernatants from different groups of subjects and correlated theobtained values to neutrophil infiltration as well as to the expression of cyclooxygenase-2 (COX-2).Cigarette smoke extract (CSE) was used to evaluate the effect of smoking on COX-2 and PGE(2) receptorexpression as well as on PGE(2) release in neutrophils and alveolar macrophages (AM) obtained fromnormal donors. The effects of PGE(2) and of PGE receptor agonists and antagonists were evaluated onthe adhesion of neutrophil to a human bronchial epithelial cell line (16HBE). PGE(2) levels, COX-2expression, and neutrophil infiltration were significantly higher in normal smokers and COPD smokers (P< 0.0001) compared with controls and COPD former smokers. Induced sputum supernatant causedneutrophil adhesion to 16HBE that was significantly reduced, in COPD smokers only, by PGE(2)immunoprecipitation. In vitro experiments confirmed that CSE increased PGE(2) release and COX-2 andPGE(2) receptor expression in neutrophils and AM; PGE(2) enhanced the adhesion of neutrophils to16HBE, and a specific E-prostanoid 4 (EP(4)) receptor antagonist blunted its effect. These results suggestthat CSE promote the induction of COX-2 and contributes to the proinflammatory effects of PGE(2) in theairways of COPD subjects.", "metadata": {}}
+{"_id": "20738970", "title": "", "text": "Non-receptor tyrosine kinase Etk is involved in the apoptosis of small cell lung cancer cells.Epithelial andendothelial tyrosine kinase (Etk), also known as Bmx (bone marrow X kinase) plays an important role inapoptosis of epithelial cells. The goal of this study was to investigate whether Etk is involved in apoptosisof small cell lung cancer (SCLC) cells and correlated with the expression levels of apoptosis-associatedproteins such as Bcl-2, Bcl-X(L) and p53. One hundred and seventy-one cases of lung cancer specimensincluding seventy-one SCLCs and one hundred NSCLCs were immunostained for Etk, Bcl-2, Bcl-X(L) andp53. Parental SCLC H446 cell line, and its subline (H446-Etk) that overexpresses Etk, were used to studythe role of Etk in apoptosis induced by doxorubicin. It was found that high expression of Etk occurs in74.6% of SCLC cases, but only in 40% of NSCLC cases, and there is marked difference in the expressionlevels of Bcl-2, Bcl-X(L) and p53 between Etk-positive and Etk-negative SCLC cases. Furthermore, thelevels of Bcl-2 and Bcl-X(L) significantly increased in H446-Etk cells than that in H446 cells afterdoxorubicin treatment, and were positively associated with Etk expression. However, p53 did notcorrespond with Etk expression although its expression decreased greatly with apoptosis both inH446-Etk and H446 cells. After doxorubicin treatment, the cell viability was significantly higher inH446-Etk cells than in parental H446 cells. Downregulation of Etk by Etk siRNA sensitized H446 cells todoxorubicin. Our results indicate that upregulation of tyrosine kinase Etk may be a new mechanisminvolved in protection of SCLC cells from apoptosis. Bcl-2 and Bcl-X(L) but not p53 may contribute todoxorubicin-induced apoptosis through Etk pathway.", "metadata": {}}
+{"_id": "20743803", "title": "", "text": "No Pasaran! Role of the axon initial segment in the regulation of protein transport and the maintenance ofaxonal identity.The transmission of information in the brain depends on the highly polarized architectureof neurons. A number of cellular transport processes support this organization, including active targetingof proteins and passive corralling between compartments. The axon initial segment (AIS), whichseparates the somatodendritic and axonal compartments, has a key role in neuronal physiology, as boththe initiation site of action potentials and the gatekeeper of the axonal arborization. Over the years, theAIS main components and their interactions have been progressively unraveled, as well as their role inthe AIS assembly and maintenance. Two mechanisms have been shown to contribute to the regulation ofprotein transport at the AIS: a surface diffusion barrier and an intracellular traffic filter. However, amolecular understanding of these processes is still lacking. In the view of recent results on the AIScytoskeleton structure, we will discuss how a better knowledge of the AIS architecture can helpunderstanding its role in the regulation of protein transport and the maintenance of axonal identity.", "metadata": {}}
+{"_id": "20746604", "title": "", "text": "The effectiveness of right heart catheterization in the initial care of critically ill patients. SUPPORTInvestigators.OBJECTIVE To examine the association between the use of right heart catheterization(RHC) during the first 24 hours of care in the intensive care unit (ICU) and subsequent survival, length ofstay, intensity of care, and cost of care. DESIGN Prospective cohort study. SETTING Five US teachinghospitals between 1989 and 1994. SUBJECTS A total of 5735 critically ill adult patients receiving care inan ICU for 1 of 9 prespecified disease categories. MAIN OUTCOME MEASURES Survival time, cost of care,intensity of care, and length of stay in the ICU and hospital, determined from the clinical record and fromthe National Death Index. A propensity score for RHC was constructed using multivariable logisticregression. Case-matching and multivariable regression modeling techniques were used to estimate theassociation of RHC with specific outcomes after adjusting for treatment selection using the propensityscore. Sensitivity analysis was used to estimate the potential effect of an unidentified or missingcovariate on the results. RESULTS By case-matching analysis, patients with RHC had an increased 30-daymortality (odds ratio, 1.24; 95% confidence interval, 1.03-1.49). The mean cost (25th, 50th, 75thpercentiles) per hospital stay was $49 300 ($17 000, $30 500, $56 600) with RHC and $35 700 ($11300, $20 600, $39 200) without RHC. Mean length of stay in the ICU was 14.8 (5, 9, 17) days with RHCand 13.0 (4, 7, 14) days without RHC. These findings were all confirmed by multivariable modelingtechniques. Subgroup analysis did not reveal any patient group or site for which RHC was associated withimproved outcomes. Patients with higher baseline probability of surviving 2 months had the highestrelative risk of death following RHC. Sensitivity analysis suggested that a missing covariate would have toincrease the risk of death 6-fold and the risk of RHC 6-fold for a true beneficial effect of RHC to bemisrepresented as harmful. CONCLUSION In this observational study of critically ill patients, afteradjustment for treatment selection bias, RHC was associated with increased mortality and increasedutilization of resources. The cause of this apparent lack of benefit is unclear. The results of this analysisshould be confirmed in other observational studies. These findings justify reconsideration of a randomizedcontrolled trial of RHC and may guide patient selection for such a study.", "metadata": {}}
+{"_id": "20754359", "title": "", "text": "Natural history of adult T-cell leukemia/lymphoma and approaches to therapyAfter cell-to-celltransmission, HTLV-I increases its viral genome by de novo infection and proliferation of infected cells.Proliferation of infected cells is clonal and persistent in vivo. During the carrier state, infected cells areselected in vivo by the host's immune system, the genetic and epigenetic environment of proviralintegration sites, and other factors. In leukemic cells, tax gene expression is frequently impaired bygenetic and epigenetic mechanisms. Such loss of Tax expression enables ATL cells to escape the hostimmune system. On the other hand, ATL cells acquire the ability to proliferate without Tax by intracellulargenetic and epigenetic changes. Despite advances in support and the development of novel treatmentagents, the prognosis for ATLL remains poor. A number of therapies, however, do appear to improveprognosis compared to CHOP (VEPA). These include interferon-α plus zidovudine (probably after 1–2cycles of CHOP), intensive chemotherapy as in LSG-15 with G-CSF support and Allo-SCT (which includesthe potential for cure). Emerging novel approaches include HDAC inhibitors, monoclonal antibodies, andproteasome inhibitors. Comparison between different therapeutic approaches is complicated by the rangeof natural history of ATLL, different recruitments of naïve-to-therapy, refractory or relapsed patients, andvariations in the reporting of outcome that frequently excludes difficult-to-evaluate patients. Moreover,results from relatively small proof-of-principle studies have not been extended with randomized,controlled trials. As a result, currently, there is no clear evidence to support the value of any particulartreatment approach over others. To avoid further unnecessary patient suffering and to identify optimaltherapy as rapidly as possible, large randomized, controlled trials encompassing multicenter,international collaborations will be necessary.", "metadata": {}}
+{"_id": "20758340", "title": "", "text": "Hierarchical organization of the plasma membrane: investigations by single-molecule tracking vs.fluorescence correlation spectroscopy.Single-molecule tracking and fluorescence correlation spectroscopy(FCS) applied to the plasma membrane in living cells have allowed a number of unprecedentedobservations, thus fostering a new basic understanding of molecular diffusion, interaction, and signaltransduction in the plasma membrane. It is becoming clear that the plasma membrane is aheterogeneous entity, containing diverse structures on nano-meso-scales (2-200 nm) with a variety oflifetimes, where certain membrane molecules stay together for limited durations. Molecular interactionsoccur in the time-dependent inhomogeneous two-dimensional liquid of the plasma membrane, whichmight be a key for plasma membrane functions.", "metadata": {}}
+{"_id": "20761364", "title": "", "text": "Stability of the antimalarial drug dihydroartemisinin under physiologically relevant conditions:implications for clinical treatment and pharmacokinetic and in vitro assays.Artemisinins are peroxidicantimalarial drugs known to be very potent but highly chemically unstable; they degrade in the presenceof ferrous iron, Fe(II)-heme, or biological reductants. Less documented is how this translates intochemical stability and antimalarial activity across a range of conditions applying to in vitro testing andclinical situations. Dihydroartemisinin (DHA) is studied here because it is an antimalarial drug on its ownand the main metabolite of other artemisinins. The behaviors of DHA in phosphate-buffered saline,plasma, or erythrocyte lysate at different temperatures and pH ranges were examined. The antimalarialactivity of the residual drug was evaluated using the chemosensitivity assay on Plasmodium falciparum,and the extent of decomposition of DHA was established through use of high-performance liquidchromatography with electrochemical detection analysis. The role of the Fe(II)-heme was investigated byblocking its reactivity using carbon monoxide (CO). A significant reduction in the antimalarial activity ofDHA was seen after incubation in plasma and to a lesser extent in erythrocyte lysate. Activity wasreduced by half after 3 h and almost completely abolished after 24 h. Serum-enriched media also affectedDHA activity. Effects were temperature and pH dependent and paralleled the increased rate ofdecomposition of DHA from pH 7 upwards and in plasma. These results suggest that particular careshould be taken in conducting and interpreting in vitro studies, prone as their results are to experimentaland drug storage conditions. Disorders such as fever, hemolysis, or acidosis associated with malariaseverity may contribute to artemisinin instability and reduce their clinical efficacy.", "metadata": {}}
+{"_id": "20764484", "title": "", "text": "Modulation of anxiety through blockade of anandamide hydrolysisThe psychoactive constituent ofcannabis, Δ9-tetrahydrocannabinol, produces in humans subjective responses mediated by CB1cannabinoid receptors, indicating that endogenous cannabinoids may contribute to the control ofemotion. But the variable effects of Δ9-tetrahydrocannabinol obscure the interpretation of these resultsand limit the therapeutic potential of direct cannabinoid agonists. An alternative approach may be todevelop drugs that amplify the effects of endogenous cannabinoids by preventing their inactivation. Herewe describe a class of potent, selective and systemically active inhibitors of fatty acid amide hydrolase,the enzyme responsible for the degradation of the endogenous cannabinoid anandamide. Like clinicallyused anti-anxiety drugs, in rats the inhibitors exhibit benzodiazepine-like properties in the elevatedzero-maze test and suppress isolation-induced vocalizations. These effects are accompanied byaugmented brain levels of anandamide and are prevented by CB1 receptor blockade. Our results indicatethat anandamide participates in the modulation of emotional states and point to fatty acid amidehydrolase inhibition as an innovative approach to anti-anxiety therapy.", "metadata": {}}
+{"_id": "20767776", "title": "", "text": "Familial clustering of reflux symptomsObjective:A number of case reports describe multiple familymembers with gastroesophageal reflux disease and Barrett's esophagus. The wider importance of familialfactors in gastroesophageal reflux disease has not been established. Therefore, we have studied theprevalence of reflux symptoms and medication use among relatives of patients with documentedgastroesophageal reflux disease. Methods:A postal questionnaire study of the first degree relatives of sixgroups of matched patients. The groups comprised patients with 1) no dyspeptic symptoms; 2) refluxsymptoms and a normal pH study; 3) reflux symptoms, an abnormal pH study, and a lower esophagealsphincter (LOS) pressure more than 10 mm Hg; 4) reflux symptoms, an abnormal pH study, and a LOSpressure less than 10 mm Hg; 5) Barrett's esophagus; and 6) peptic stricture. Results:Four hundredeighteen subjects replied (78% response). Infrequent reflux symptoms were equally common in allgroups of relatives. Frequent reflux symptoms, however, were more common among relatives of patientswith an abnormal pH study and normal (26%, p= 0.007) or low LOS pressure (27%, p= 0.01) orBarrett's esophagus (30%, p= 0.003), compared with relatives of nondyspeptic patients (9%). Frequentreflux symptoms were no more common among relatives of patients with a normal pH study (16%) orpeptic stricture (18%). Reflux medication use showed a similar pattern. Conclusions:Familial clustering ofreflux symptoms is seen in relatives of patients with reflux symptoms and increased esophageal acidexposure and in relatives of patients with Barrett's esophagus.", "metadata": {}}
+{"_id": "20781656", "title": "", "text": "Histone chaperones: 30 years from isolation to elucidation of the mechanisms of nucleosome assemblyand disassemblySome three decades have passed since the discovery of nucleosomes in 1974 and thefirst isolation of a histone chaperone in 1978. While various types of histone chaperones have beenisolated and functionally analyzed, the elementary processes of nucleosome assembly and disassemblyhave been less well characterized. Recently, the tertiary structure of a hetero-trimeric complex composedof the histone chaperone CIA/ASF1 and the histone H3-H4 dimer was determined, and this complex wasproposed to be an intermediate in nucleosome assembly and disassembly reactions. In addition, CIAalone was biochemically shown to dissociate the histone (H3-H4)2 tetramer into two histone H3-H4dimers. This activity suggested that CIA regulates the semi-conservative replication of nucleosomes.Here, we provide an overview of prominent histone chaperones with the goal of elucidating themechanisms that preserve and modify epigenetic information. We also discuss the reactions involved innucleosome assembly and disassembly.", "metadata": {}}
+{"_id": "20821402", "title": "", "text": "Specificity of the dRP/AP lyase of Ku promotes nonhomologous end joining (NHEJ) fidelity at damagedends.Nonhomologous end joining (NHEJ) is essential for efficient repair of chromosome breaks. However,the NHEJ ligation step is often obstructed by break-associated nucleotide damage, including base loss(abasic site or 5'-dRP/AP sites). Ku, a 5'-dRP/AP lyase, can excise such damage at ends in preparation forthe ligation step. We show here that this activity is greatest if the abasic site is within a short 5'overhang, when this activity is necessary and sufficient to prepare such termini for ligation. In contrast,Ku is less active near 3' strand termini, where excision would leave a ligation-blocking α,β-unsaturatedaldehyde. The Ku AP lyase activity is also strongly suppressed by as little as two paired bases 5' of theabasic site. Importantly, in vitro end joining experiments show that abasic sites significantly embedded indouble-stranded DNA do not block the NHEJ ligation step. Suppression of the excision activity of Ku inthis context therefore is not essential for ligation and further helps NHEJ retain terminal sequence injunctions. We show that the DNA between the 5' terminus and the abasic site can also be retained injunctions formed by cellular NHEJ, indicating that these sites are at least partly resistant to other abasicsite-cleaving activities as well. High levels of the 5'-dRP/AP lyase activity of Ku are thus restricted tosubstrates where excision of an abasic site is required for ligation, a degree of specificity that promotesmore accurate joining.", "metadata": {}}
+{"_id": "20829129", "title": "", "text": "Gut-expressed gustducin and taste receptors regulate secretion of glucagon-like peptide-1.Glucagon-likepeptide-1 (GLP-1), released from gut endocrine L cells in response to glucose, regulates appetite, insulinsecretion, and gut motility. How glucose given orally, but not systemically, induces GLP-1 secretion isunknown. We show that human duodenal L cells express sweet taste receptors, the taste G proteingustducin, and several other taste transduction elements. Mouse intestinal L cells also expressalpha-gustducin. Ingestion of glucose by alpha-gustducin null mice revealed deficiencies in secretion ofGLP-1 and the regulation of plasma insulin and glucose. Isolated small bowel and intestinal villi fromalpha-gustducin null mice showed markedly defective GLP-1 secretion in response to glucose. The humanL cell line NCI-H716 expresses alpha-gustducin, taste receptors, and several other taste signalingelements. GLP-1 release from NCI-H716 cells was promoted by sugars and the noncaloric sweetenersucralose, and blocked by the sweet receptor antagonist lactisole or siRNA for alpha-gustducin. Weconclude that L cells of the gut \"taste\" glucose through the same mechanisms used by taste cells of thetongue. Modulating GLP-1 secretion in gut \"taste cells\" may provide an important treatment for obesity,diabetes and abnormal gut motility.", "metadata": {}}
+{"_id": "20839751", "title": "", "text": "Apoptosis in breast cancer: relationship with other pathological parameters.Apoptosis is a frequentphenomenon in breast cancer and it can be detected by light microscopy in conventional histopathologicalsections or by special staining techniques. The number of apoptotic cells as a percentage of cells present,or the number of apoptotic cells per square millimetre of neoplastic tissue, is usually described as theapoptotic index (AI). In breast cancer, the AI is not related to tumour size, axillary lymph nodemetastasis or distant metastasis at diagnosis. It is greater in invasive ductal carcinomas than in otherhistological types. High AI is also related to high histological grade, high nuclear grade, comedo-typenecrosis, lack of tubule formation, and dense infiltration of the tumour by lymphocytes. Sex steroidreceptor-negative tumours have greater AIs than the sex steroid receptor-positive ones. Aneuploid breastcancers with high S-phase fractions (SPFs) also have high AI values compared with diploid tumours withlow SPFs. p53-Positive breast cancers have high AIs, whereas tumours that are Bcl-2 positive have lowAIs. The AI shows a strong positive correlation to all direct or indirect indicators of cell proliferation, suchas mitotic index and Ki67 immunolabelling. Univariate survival analyses show that a high AI is linked withunfavourable disease outcome in axillary lymph node-negative and -positive breast cancer, butmultivariate analyses indicate that AI is not an independent prognostic factor. In conclusion, a high AI isrelated to malignant cellular features and indicators of invasiveness and cell proliferation in breast cancer.", "metadata": {}}
+{"_id": "20851402", "title": "", "text": "Dietary flavonoids: bioavailability, metabolic effects, and safety.Flavonoids comprise the most commongroup of plant polyphenols and provide much of the flavor and color to fruits and vegetables. More than5000 different flavonoids have been described. The six major subclasses of flavonoids include theflavones (e.g., apigenin, luteolin), flavonols (e.g., quercetin, myricetin), flavanones (e.g., naringenin,hesperidin), catechins or flavanols (e.g., epicatechin, gallocatechin), anthocyanidins (e.g., cyanidin,pelargonidin), and isoflavones (e.g., genistein, daidzein). Most of the flavonoids present in plants areattached to sugars (glycosides), although occasionally they are found as aglycones. Interest in thepossible health benefits of flavonoids has increased owing to their potent antioxidant and free-radicalscavenging activities observed in vitro. There is growing evidence from human feeding studies that theabsorption and bioavailability of specific flavonoids is much higher than originally believed. However,epidemiologic studies exploring the role of flavonoids in human health have been inconclusive. Somestudies support a protective effect of flavonoid consumption in cardiovascular disease and cancer, otherstudies demonstrate no effect, and a few studies suggest potential harm. Because there are manybiological activities attributed to the flavonoids, some of which could be beneficial or detrimentaldepending on specific circumstances, further studies in both the laboratory and with populations arewarranted.", "metadata": {}}
+{"_id": "20864487", "title": "", "text": "Virus-specific cytotoxic T-lymphocyte responses select for amino-acid variation in simianimmunodeficiency virus Env and NefCytotoxic T-lymphocyte (CTL) responses to human immunodeficiencyvirus arise early after infection, but ultimately fail to prevent progression to AIDS. Humanimmunodeficiency virus may evade the CTL response by accumulating amino-acid replacements withinCTL epitopes. We studied 10 CTL epitopes during the course of simian immunodeficiency virus diseaseprogression in three related macaques. All 10 of these CTL epitopes accumulated amino-acidreplacements and showed evidence of positive selection by the time the macaques died. Many of theamino-acid replacements in these epitopes reduced or eliminated major histocompatibility complex classI binding and/or CTL recognition. These findings strongly support the CTL 'escape' hypothesis.", "metadata": {}}
+{"_id": "20868160", "title": "", "text": "TRICHOME BIREFRINGENCE and its homolog AT5G01360 encode plant-specific DUF231 proteins requiredfor cellulose biosynthesis in Arabidopsis.The Arabidopsis (Arabidopsis thaliana) trichome birefringence(tbr) mutant has severely reduced crystalline cellulose in trichomes, but the molecular nature of TBR wasunknown. We determined TBR to belong to the plant-specific DUF231 domain gene family comprising 46members of unknown function in Arabidopsis. The genes harbor another plant-specific domain, called theTBL domain, which contains a conserved GDSL motif known from some esterases/lipases. TBR andTBR-like3 (TBL3) are transcriptionally coordinated with primary and secondary CELLULOSE SYNTHASE(CESA) genes, respectively. The tbr and tbl3 mutants hold lower levels of crystalline cellulose and havealtered pectin composition in trichomes and stems, respectively, tissues generally thought to containmainly secondary wall crystalline cellulose. In contrast, primary wall cellulose levels remain unchanged inboth mutants as measured in etiolated tbr and tbl3 hypocotyls, while the amount of esterified pectins isreduced and pectin methylesterase activity is increased in this tissue. Furthermore, etiolated tbrhypocotyls have reduced length with swollen epidermal cells, a phenotype characteristic for primary cesamutants or the wild type treated with cellulose synthesis inhibitors. Taken together, we show that twoTBL genes contribute to the synthesis and deposition of secondary wall cellulose, presumably byinfluencing the esterification state of pectic polymers.", "metadata": {}}
+{"_id": "20886584", "title": "", "text": "Genetic predictors of taxane-induced neurotoxicity in a SWOG phase III intergroup adjuvant breastcancer treatment trial (S0221)Taxanes have resulted in improved survival for breast cancer patients, butoften cause neurological toxicities. Identification of biomarkers related to toxicities could be important fordictating treatment regimen. We evaluated single nucleotide polymorphisms (SNPs) in the FanconiAnemia (FA)/BRCA pathway in relation to grade 3/4 neurotoxicities in patients (n = 888) fromSWOG0221, a phase III adjuvant trial for breast cancer of 4 dose/schedules of cyclophosphamide (C),doxorubicin (A), and paclitaxel (T). In a separate cohort, we measured the correlation of significantFANCD2 SNPs with corresponding gene expression. For FANCD2, permutation testing revealed that 4 (outof 20) SNPs were significantly associated with an almost two-fold increased risk of toxicity. Two FANCD2haplotypes were also associated with neurological toxicity, with odds ratios (OR) in the overall populationof 1.8 (95% confidence interval (CI) 1.3, 2.5) and 1.7 (95% CI, 1.2, 2.4). Although numbers were small,an African-American-specific haplotype was associated with an almost 3-fold increase in risk of neurologictoxicity (OR = 2.84, 95% CI = 1.2, 6.9). Expression analyses revealed that significant FANCD2 SNPswere associated with FANCD2 expression levels (P = 0.03). There were no associations between SNPs inBRCA1 and neurotoxicities. In this trial of CA+T for breast cancer, SNPs in FANCD2, but not in BRCA1,were associated with a 70–80% increase in the odds of grade 3/4 neurological toxicities and increasedexpression of the gene. If replicated, women with these genotypes should be closely monitored fortoxicities and could be targeted for preventive measures or alternative therapeutic approaches.", "metadata": {}}
+{"_id": "20887554", "title": "", "text": "Preoperative C-reactive protein predicts mid-term outcome after cardiac surgery.BACKGROUNDC-reactive protein (CRP) is a known risk factor for cardiovascular events in the healthy population and inpatients with coronary artery disease. High CRP levels before cardiac surgery are associated with worseshort-term outcome, but its role after discharge home remains unknown. The study objective was toevaluate the effect of CRP on short-term and mid-term outcome after cardiac surgery. METHODS FromAugust 2000 to May 2004, values for preoperative CRP were available for 597 unselected patientsundergoing cardiac operations. CRP was used to divide this cohort in two groups: a low inflammatorystatus (LHS) group of 354 patients with CRP of less than 0.5 mg/dL, and a high inflammatory status(HIS) group of 243 patients with a CRP of 0.5 mg/dL or more. Follow-up lasted a maximum of 3 years(median, 1.8 +/- 1.5 years) and was 92.6% complete. RESULTS In-hospital mortality was 8.2% in theHIS group and 3.4% in the LIS group (odds ratio [OR], 2.61; p = 0.02). Incidence of postoperativeinfections was 16.5% in the HIS group and 5.1% in the LIS group (OR, 3.25; p = 0.0001). Sternal woundinfections were also more frequent in the HIS group (10.7% versus 2.8%; OR, 3.43; p = 0.002). Duringfollow-up, the HIS group had worse survival (88.5% +/- 2.9% versus 91.9% +/- 2.5%; OR, 1.93; p =0.05) and a higher need of hospitalization for cardiac-related causes (73.6% +/- 6% versus 86.5% +/-3.2%; OR, 1.82; p = 0.05). CONCLUSIONS Patients undergoing cardiac surgery with a CRP level of 0.5mg/dL or more are exposed to a higher risk of in-hospital mortality and postoperative infections. Despitesurgical correction of cardiac disease, a high preoperative CRP value is an independent risk factor formid-term survival and hospitalization for cardiac causes.", "metadata": {}}
+{"_id": "20888849", "title": "", "text": "Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreaticcancer.Pancreatic ductal adenocarcinoma (PDA) is among the most lethal human cancers in part becauseit is insensitive to many chemotherapeutic drugs. Studying a mouse model of PDA that is refractory to theclinically used drug gemcitabine, we found that the tumors in this model were poorly perfused and poorlyvascularized, properties that are shared with human PDA. We tested whether the delivery and efficacy ofgemcitabine in the mice could be improved by coadministration of IPI-926, a drug that depletestumor-associated stromal tissue by inhibition of the Hedgehog cellular signaling pathway. Thecombination therapy produced a transient increase in intratumoral vascular density and intratumoralconcentration of gemcitabine, leading to transient stabilization of disease. Thus, inefficient drug deliverymay be an important contributor to chemoresistance in pancreatic cancer.", "metadata": {}}
+{"_id": "20904154", "title": "", "text": "Mutant SOD1 inhibits ER-Golgi transport in amyotrophic lateral sclerosis.Cu/Zn-superoxide dismutase ismisfolded in familial and sporadic amyotrophic lateral sclerosis, but it is not clear how this triggersendoplasmic reticulum (ER) stress or other pathogenic processes. Here, we demonstrate that mutantSOD1 (mSOD1) is predominantly found in the cytoplasm in neuronal cells. Furthermore, we show thatmSOD1 inhibits secretory protein transport from the ER to Golgi apparatus. ER-Golgi transport is linkedto ER stress, Golgi fragmentation and axonal transport and we also show that inhibition of ER-Golgitrafficking preceded ER stress, Golgi fragmentation, protein aggregation and apoptosis in cells expressingmSOD1. Restoration of ER-Golgi transport by over-expression of coatomer coat protein II subunit Sar1protected against inclusion formation and apoptosis, thus linking dysfunction in ER-Golgi transport tocellular pathology. These findings thus link several cellular events in amyotrophic lateral sclerosis into asingle mechanism occurring early in mSOD1 expressing cells.", "metadata": {}}
+{"_id": "20931483", "title": "", "text": "High spatial resolution mapping of malaria transmission risk in the Gambia, west Africa, using LANDSATTM satellite imagery.Understanding local variability in malaria transmission risk is critically importantwhen designing intervention or vaccine trials. Using a combination of field data, satellite image analysis,and GIS modeling, we developed a high-resolution map of malaria entomological inoculation rates (EIR)in The Gambia, West Africa. The analyses are based on the variation in exposure to malaria parasitesexperienced in 48 villages in 1996 and 21 villages in 1997. The entomological inoculation rate (EIR)varied from 0 to 166 infective bites per person per rainy season. Detailed field surveys identified themajor Anopheles gambiae s.l. breeding habitats. These habitats were mapped by classification of aLANDSAT TM satellite image with an overall accuracy of 85%. Village EIRs decreased as a power functionbased on the breeding areas size and proximity. We use this relationship and the breeding habitats tomap the variation in EIR over the entire 2500-km(2) study area.", "metadata": {}}
+{"_id": "20935673", "title": "", "text": "Functional analysis of repressor binding sites in the iab-2 regulatory region of the abdominal-A homeoticgene.Spatial boundaries of homeotic gene expression are initiated and maintained by two sets oftranscriptional repressors: the gap gene products and the Polycomb group proteins. Previously, theHunchback (HB) protein has been implicated in setting the anterior expression limit of the UBX homeoticprotein in parasegment 6. Here we investigate DNA elements and trans-acting repressors that controlspatial expression of the Abdominal-A (ABD-A) homeotic protein. Analysis of a 1.7-kb enhancer element[iab-2(1.7)] from the iab-2 regulatory region shows that in contrast to Ubx enhancer elements, both HBand Krüppel (KR) are required to set the ABD-A anterior boundary in parasegment 7. DNase I footprintingand site-directed mutagenesis show that HB and KR are direct regulators of this iab-2 enhancer. Thesingle KR site can be moved to a new location 100 bp away and still maintain repressive activity, whereasrelocation by 300 bp abolishes activity. These results suggest that KR repression occurs through a localquenching mechanism. We also show that the gap repressor Giant (GT) initially establishes a posteriorexpression limit at PS9, which shifts posteriorly after the blastoderm stage. Finally, we show that thisiab-2 enhancer contains multiple binding sites for the Polycomb group protein Pleiohomeotic (PHO).These iab-2 PHO sites are required in vivo for chromosome pairing-dependent repression of a mini-whitereporter. However, the PHO sites are not sufficient to maintain repression of a homeotic reporter geneanterior to PS7. Full maintenance at late embryonic stages requires additional sequences adjacent to theiab-2(1.7) enhancer.", "metadata": {}}
+{"_id": "20937018", "title": "", "text": "Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele inlate-onset familial Alzheimer disease.Apolipoprotein E is immunochemically localized to the senileplaques, vascular amyloid, and neurofibrillary tangles of Alzheimer disease. In vitro, apolipoprotein E incerebrospinal fluid binds to synthetic beta A4 peptide (the primary constituent of the senile plaque) withhigh avidity. Amino acids 12-28 of the beta A4 peptide are required. The gene for apolipoprotein E islocated on chromosome 19q13.2, within the region previously associated with linkage of late-onsetfamilial Alzheimer disease. Analysis of apolipoprotein E alleles in Alzheimer disease and controlsdemonstrated that there was a highly significant association of apolipoprotein E type 4 allele(APOE-epsilon 4) and late-onset familial Alzheimer disease. The allele frequency of the APOE-epsilon 4 in30 random affected patients, each from a different Alzheimer disease family, was 0.50 +/- 0.06; theallele frequency of APOE-epsilon 4 in 91 age-matched unrelated controls was 0.16 +/- 0.03 (Z = 2.44, P= 0.014). A functional role of the apolipoprotein E-E4 isoform in the pathogenesis of late-onset familialAlzheimer disease is suggested.", "metadata": {}}
+{"_id": "20942644", "title": "", "text": "Unmarked gene deletion and host–vector system for the hyperthermophilic crenarchaeon SulfolobusislandicusSulfolobus islandicus is being used as a model for studying archaeal biology, geo-biology andevolution. However, no genetic system is available for this organism. To produce an S. islandicus mutantsuitable for genetic analyses, we screened for colonies with a spontaneous pyrEF mutation. One mutantwas obtained containing only 233 bp of the original pyrE sequence in the mutant allele and it was used asa host to delete the β-glycosidase (lacS) gene. Two unmarked gene deletion methods were employed,namely plasmid integration and segregation, and marker replacement and looping out, and unmarkedlacS mutants were obtained by each method. A new alternative recombination mechanism, i.e., markercircularization and integration, was shown to operate in the latter method, which did not yield thedesigned deletion mutation. Subsequently, Sulfolobus–E. coli plasmid shuttle vectors were constructed,which genetically complemented ΔpyrEFΔlacS mutation after transformation. Thus, a complete set ofgenetic tools was established for S. islandicus with pyrEF and lacS as genetic markers.", "metadata": {}}
+{"_id": "20943272", "title": "", "text": "ADAM13 disintegrin and cysteine-rich domains bind to the second heparin-binding domain offibronectin.ADAM13 is a member of the disintegrin and metalloprotease protein family that is expressedon cranial neural crest cells surface and is essential for their migration. ADAM13 is an active protease thatcan cleave fibronectin in vitro and remodel a fibronectin substrate in vivo. Using a recombinant secretedprotein containing both disintegrin and cysteine-rich domains of ADAM13, we show that this \"adhesive\"region of the protein binds directly to fibronectin. Fibronectin fusion proteins corresponding to the variousfunctional domains were used to define the second heparin-binding domain as the ADAM13 binding site.Mutation of the syndecan-binding site (PPRR --> PPTM) within this domain abolishes binding of therecombinant disintegrin and cysteine-rich domains of ADAM13. We further show that the adhesivedisintegrin and cysteine-rich domain of ADAM13 can promote cell adhesion via beta(1) integrins. Thisadhesion requires integrin activation and can be prevented by antibodies to the cysteine-rich domain ofADAM13 and beta(1) integrin. Finally, wild type, but not the E/A mutant of ADAM13 metalloproteasedomain, can be shed from the cell surface, releasing the metalloprotease domain associated with thedisintegrin and cysteine-rich domains. This suggests that ADAM13 shedding may involve its ownmetalloprotease activity and that the released protease may interact with both integrins and extracellularmatrix proteins.", "metadata": {}}
+{"_id": "20945963", "title": "", "text": "Clinical epidemiology of heart failure.The aim of this paper is to review the clinical epidemiology of heartfailure. The last paper comprehensively addressing the epidemiology of heart failure in Heart appeared in2000. Despite an increase in manuscripts describing epidemiological aspects of heart failure since the1990s, additional information is still needed, as indicated by various editorials.", "metadata": {}}
+{"_id": "20960682", "title": "", "text": "Toll-like receptor 7 agonist GS-9620 induces prolonged inhibition of HBV via a type Iinterferon-dependent mechanism.BACKGROUND & AIMS GS-9620, an oral agonist of toll-like receptor 7(TLR7), is in clinical development for the treatment of chronic hepatitis B (CHB). GS-9620 was previouslyshown to induce prolonged suppression of serum viral DNA and antigens in the woodchuck andchimpanzee models of CHB. Herein, we investigated the molecular mechanisms that contribute to theantiviral response to GS-9620 using in vitro models of hepatitis B virus (HBV) infection. METHODSCryopreserved primary human hepatocytes (PHH) and differentiated HepaRG (dHepaRG) cells wereinfected with HBV and treated with GS-9620, conditioned media from human peripheral bloodmononuclear cells treated with GS-9620 (GS-9620 conditioned media [GS-9620-CM]), or other innateimmune stimuli. The antiviral and transcriptional response to these agents was determined. RESULTSGS-9620 had no antiviral activity in HBV-infected PHH, consistent with low level TLR7 mRNA expressionin human hepatocytes. In contrast, GS-9620-CM induced prolonged reduction of HBV DNA, RNA, andantigen levels in PHH and dHepaRG cells via a type I interferon (IFN)-dependent mechanism.GS-9620-CM did not reduce covalently closed circular DNA (cccDNA) levels in either cell type.Transcriptional profiling demonstrated that GS-9620-CM strongly induced various HBV restriction factors- although not APOBEC3A or the Smc5/6 complex - and indicated that established HBV infection does notmodulate innate immune sensing or signaling in cryopreserved PHH. GS-9620-CM also inducedexpression of immunoproteasome subunits and enhanced presentation of an immunodominant viralpeptide in HBV-infected PHH. CONCLUSIONS Type I IFN induced by GS-9620 durably suppressed HBV inhuman hepatocytes without reducing cccDNA levels. Moreover, HBV antigen presentation was enhanced,suggesting additional components of the TLR7-induced immune response played a role in the antiviralresponse to GS-9620 in animal models of CHB. LAY SUMMARY GS-9620 is a drug currently being testedin clinical trials for the treatment of chronic hepatitis B virus (HBV) infection. GS-9620 has previouslybeen shown to suppress HBV in various animal models, but the underlying antiviral mechanisms were notcompletely understood. In this study, we determined that GS-9620 does not directly activate antiviralpathways in human liver cells, but can induce prolonged suppression of HBV via induction of an antiviralcytokine called interferon. However, interferon did not destroy the HBV genome, suggesting that otherparts of the immune response (e.g. activation of immune cells that kill infected cells) also play animportant role in the antiviral response to GS-9620.", "metadata": {}}
+{"_id": "20977638", "title": "", "text": "Depletion of glutathione induces 4-hydroxynonenal protein adducts and hydroxyurea teratogenicity in theorganogenesis stage mouse embryo.Glutathione (GSH) homeostasis is important during organogenesis.To elucidate the impact of GSH depletion in organogenesis stage embryos on oxidative stress and drugteratogenicity, l-buthionine-S,R-sulfoximine (BSO) was given to timed pregnant CD-1 mice 4 h beforeexposure to a model teratogen, hydroxyurea (HU) [400 mg/kg (HU-400) or 600 mg/kg (HU-600)].Treatment with BSO or HU alone or with BSO plus HU-400 did not alter the ratios of glutathionedisulfide/GSH in the embryo; in contrast, the combination of BSO plus HU-600 did increase this ratio atboth 0.5 and 3 h post-HU, indicating the induction of oxidative stress in the embryos. Immunoreactivityto a product of lipid peroxidation, 4-hydroxynonenal (4-HNE) protein adducts, was detected insaline-treated embryos; the intensity and nuclear localization of 4-HNE protein adduct immunoreactivityin specific regions in the embryo was significantly increased by exposure to BSO alone or BSO and eitherdose of HU. BSO pretreatment increased the spectrum and incidence of external and skeletalmalformations (curly tail, hind limb malformations, hydrocephaly, exencephaly, open eye, spina bifida,and gastroschisis) induced by HU-400 and HU-600; BSO exposure did not alter the effects of HU on fetalmortality or fetal weights or HU induction of c-Fos heterodimer-dependent activator protein 1 DNAbinding activity. The formation of 4-HNE protein adducts in teratogen-exposed embryos was localized toregions of the embryo that were highly susceptible to insult, namely the somites and caudal neural tube,correlating the presence of 4-HNE adducts with the disruption of pattern formation during organogenesis.", "metadata": {}}
+{"_id": "20996244", "title": "", "text": "Nonproductive human immunodeficiency virus type 1 infection in nucleoside-treated G0lymphocytes.Productive infection by human immunodeficiency virus type 1 (HIV-1) requires theactivation of target cells. Infection of quiescent peripheral CD4 lymphocytes by HIV-1 results inincomplete, labile, reverse transcripts. We have previously identified G1b as the cell cycle stage requiredfor the optimal completion of the reverse transcription process in T lymphocytes. However, themechanism(s) involved in the blockage of reverse transcription remains undefined. In this study weinvestigated whether nucleotide levels influence viral reverse transcription in G0 cells. For this purposethe role of the enzyme ribonucleotide reductase was bypassed, by adding exogenousdeoxyribonucleosides to highly purified T cells in the G0 or the G1a phase of the cell cycle. Our datashowed a significant increase in the efficiency of the reverse transcription process following the additionof the deoxyribonucleosides. To define the stability and functionality of these full reverse transcripts, weused an HIV-1 reporter virus that expresses the murine heat-stable antigen on the surfaces of infectedcells. Following activation of infected quiescent cells treated with exogenous nucleosides, no increasedrescue of productive infection was seen. Thus, in addition to failure to complete reverse transcription,there was an additional nonreversible blockage of productive infection in quiescent T cells. Theseexperiments have important relevance in the gene therapy arena, in terms of improving the ability oflentivirus vectors to enter metabolically inactive cells, such as hematopoietic stem cells.", "metadata": {}}
+{"_id": "20999249", "title": "", "text": "Imported malaria in children: a national surveillance in the Netherlands and a review of Europeanstudies.BACKGROUND Falciparum malaria or malaria tropica is one of the leading causes of childhoodmortality worldwide. Malaria-related deaths occur mainly in sub-Saharan Africa, where an estimated 365million clinical cases of Plasmodium falciparum malaria occur each year. In Europe, imported malariacases occur due to returning travellers or immigration mostly from African countries. Children are more atrisk than adults. The objective of this study was to identify high risk groups for imported childhoodmalaria in Europe in order to guide development of strategies for prevention, early recognition andmanagement. METHODS In the period May 2003-January 2005 we reviewed all cases of paediatricmalaria in the Netherlands notified by the Dutch Paediatric Surveillance System (Nederland SignaleringsCentrum Kindergeneeskunde, NSCK) and the literature on imported malaria in children in Europepublished between 1996 and 2006. RESULTS Malaria occurred mainly in children of long-term (n = 15,47%) and new (n = 8, 25%) immigrants and was mostly acquired in sub-Saharan Africa. The dominantspecies was P. falciparum. Only one quarter of children had used adequate malaria chemoprophylaxis.Complicated disease occurred in 10 (31%) of cases. We also reviewed the literature and found 6082reported cases of imported malaria among children in Europe; among these, four died and only one wasreported to develop neurological sequelae. CONCLUSION Imported malaria in children remains animportant problem and is unlikely to decrease unless the reasons for inadequate prophylaxis areaddressed.", "metadata": {}}
+{"_id": "21003930", "title": "", "text": "Respiratory and cardiovascular responses to walking down a traffic-polluted road compared with walkingin a traffic-free area in participants aged 60 years and older with chronic lung or heart disease andage-matched healthy controls: a randomised, crossover studyBACKGROUND Long-term exposure topollution can lead to an increase in the rate of decline of lung function, especially in older individuals andin those with chronic obstructive pulmonary disease (COPD), whereas shorter-term exposure at higherpollution levels has been implicated in causing excess deaths from ischaemic heart disease andexacerbations of COPD. We aimed to assess the effects on respiratory and cardiovascular responses ofwalking down a busy street with high levels of pollution compared with walking in a traffic-free area withlower pollution levels in older adults. METHODS In this randomised, crossover study, we recruited menand women aged 60 years and older with angiographically proven stable ischaemic heart disease or stage2 Global initiative for Obstructive Lung Disease (GOLD) COPD who had been clinically stable for 6 months,and age-matched healthy volunteers. Individuals with ischaemic heart disease or COPD were recruitedfrom existing databases or outpatient respiratory and cardiology clinics at the Royal Brompton & HarefieldNHS Foundation Trust and age-matched healthy volunteers using advertising and existing databases. Allparticipants had abstained from smoking for at least 12 months and medications were taken asrecommended by participants' doctors during the study. Participants were randomly assigned by drawingnumbered disks at random from a bag to do a 2 h walk either along a commercial street in London(Oxford Street) or in an urban park (Hyde Park). Baseline measurements of participants were takenbefore the walk in the hospital laboratory. During each walk session, black carbon, particulate matter(PM) concentrations, ultrafine particles, and nitrogen dioxide (NO2) concentrations were measured.FINDINGS Between October, 2012, and June, 2014, we screened 135 participants, of whom 40 healthyvolunteers, 40 individuals with COPD, and 39 with ischaemic heart disease were recruited. Concentrationsof black carbon, NO2, PM10, PM2.5, and ultrafine particles were higher on Oxford Street than in HydePark. Participants with COPD reported more cough (odds ratio [OR] 1·95, 95% CI 0·96-3·95; p<0·1),sputum (3·15, 1·39-7·13; p<0·05), shortness of breath (1·86, 0·97-3·57; p<0·1), and wheeze (4·00,1·52-10·50; p<0·05) after walking down Oxford Street compared with Hyde Park. In all participants,irrespective of their disease status, walking in Hyde Park led to an increase in lung function (forcedexpiratory volume in the first second [FEV1] and forced vital capacity [FVC]) and a decrease in pulsewave velocity (PWV) and augmentation index up to 26 h after the walk. By contrast, these beneficialresponses were attenuated after walking on Oxford Street. In participants with COPD, a reduction in FEV1and FVC, and an increase in R5-20 were associated with an increase in during-walk exposure to NO2,ultrafine particles and PM2.5, and an increase in PWV and augmentation index with NO2 and ultrafineparticles. In healthy volunteers, PWV and augmentation index were associated both with black carbonand ultrafine particles. INTERPRETATION Short-term exposure to traffic pollution prevents the beneficialcardiopulmonary effects of walking in people with COPD, ischaemic heart disease, and those free fromchronic cardiopulmonary diseases. Medication use might reduce the adverse effects of air pollution inindividuals with ischaemic heart disease. Policies should aim to control ambient levels of air pollutionalong busy streets in view of these negative health effects. FUNDING British Heart Foundation.", "metadata": {}}
+{"_id": "21009874", "title": "", "text": "Overall and cancer related mortality among patients with ocular inflammation treated withimmunosuppressive drugs: retrospective cohort study.CONTEXT Whether immunosuppressive treatmentadversely affects survival is unclear. OBJECTIVE To assess whether immunosuppressive drugs increasemortality. DESIGN Retrospective cohort study evaluating overall and cancer mortality in relation toimmunosuppressive drug exposure among patients with ocular inflammatory diseases. Demographic,clinical, and treatment data derived from medical records, and mortality results from United StatesNational Death Index linkage. The cohort's mortality risk was compared with US vital statistics usingstandardised mortality ratios. Overall and cancer mortality in relation to use or non-use ofimmunosuppressive drugs within the cohort was studied with survival analysis. SETTING Five tertiaryocular inflammation clinics. Patients 7957 US residents with non-infectious ocular inflammation, 2340 ofwhom received immunosuppressive drugs during follow up. Exposures Use of antimetabolites, T cellinhibitors, alkylating agents, and tumour necrosis factor inhibitors. MAIN OUTCOME MEASURES Overallmortality, cancer mortality. RESULTS Over 66 802 person years (17 316 after exposure toimmunosuppressive drugs), 936 patients died (1.4/100 person years), 230 (24.6%) from cancer. Forpatients unexposed to immunosuppressive treatment, risks of death overall (standardised mortality ratio1.02, 95% confidence interval [CI] 0.94 to 1.11) and from cancer (1.10, 0.93 to 1.29) were similar tothose of the US population. Patients who used azathioprine, methotrexate, mycophenolate mofetil,ciclosporin, systemic corticosteroids, or dapsone had overall and cancer mortality similar to that ofpatients who never took immunosuppressive drugs. In patients who used cyclophosphamide, overallmortality was not increased and cancer mortality was non-significantly increased. Tumour necrosis factorinhibitors were associated with increased overall (adjusted hazard ratio [HR] 1.99, 95% CI 1.00 to 3.98)and cancer mortality (adjusted HR 3.83, 1.13 to 13.01). CONCLUSIONS Most commonly usedimmunosuppressive drugs do not seem to increase overall or cancer mortality. Our results suggestingthat tumour necrosis factor inhibitors might increase mortality are less robust than the other findings;additional evidence is needed.", "metadata": {}}
+{"_id": "21012916", "title": "", "text": "Ephrin B1–mediated repulsion and signaling control germinal center T cell territoriality andfunctionFollicular T helper (TFH) cells orchestrate the germinal center (GC) reaction locally. Localmechanisms regulating their dynamics and helper functions are not well defined. Here we found thatGC-expressed ephrin B1 (EFNB1) repulsively inhibited T cell to B cell adhesion and GC TFH retention bysignaling through TFH-expressed EPHB6 receptor. At the same time, EFNB1 promoted interleukin-21production from GC TFH cells by signaling predominantly through EPHB4. Consequently, EFNB1-null GCswere associated with defective production of plasma cells despite harboring excessive TFH cells. In acompetitive GC reaction, EFNB1-deficient B cells more efficiently interacted with TFH cells and producedmore bone-marrow plasma cells, likely as a result of gaining more contact-dependent help. Our resultsreveal a contact-dependent repulsive guidance system that controls GC TFH dynamics and effectorfunctions locally.", "metadata": {}}
+{"_id": "21033230", "title": "", "text": "Molecular profiling and predictive value of circulating tumor cells in patients with metastatic breastcancer: an option for monitoring response to breast cancer related therapiesPurpose We analyzedcirculating tumor cells (CTC) in blood of metastatic breast cancer patients (n = 42) and determined theability of this method to predict therapy response. Methods CTC from blood were analyzed before andduring therapy for EpCAM, MUC1 and HER2 transcripts with the AdnaTest BreastCancer. The estrogen(ER) and progesterone (PR) receptor expression was assessed by RT-PCR. Results The overall detectionrate for CTC was 52% (thereof 86% EpCAM; 86% MUC1; 32% HER2; 35% ER; 12% PR). CTC were ER,PR and HER2 negative in 45% (ER), 78% (PR) and 60% (HER-2) of patients with steroid receptor-positivetumors. 29% of patients with HER2-negative tumors had HER2-positive CTC. The test predicted therapyresponse in 78% of all cases. Persistence of CTC significantly correlated with shorter overall survival (P =0.005). Conclusions Molecular profiling of CTC may offer superior prognostic information with regard torisk assessment for recurrence and predictive judgement of therapeutical regimens.", "metadata": {}}
+{"_id": "21046889", "title": "", "text": "Alternate-day wheel access: effects on feeding, body weight, and running.For rats access to a runningwheel results in a pronounced but temporary suppression of feeding. The reasons for the feedingsuppression and its temporary nature are unclear. The effects of alternate-day wheel access wereexplored by comparing feeding and running in 25 male Sprague-Dawley rats given either no wheelaccess, continuous wheel access, or alternate-day wheel access. With alternate-day wheel access foodintake was suppressed on wheel days and elevated on non-wheel days for the full 32 days of theexperiment. Body weight decreased on wheel days and showed a large increase on non-wheel days.Acquisition of running over days was similar in both wheel groups and plateaued at the same level, butrunning was elevated, compared to continuous-access rats, for the first few hours when alternate-dayrats were returned to the wheel. These results suggest that wheel-induced feeding suppression is not dueto the novelty of the wheel and that this suppression can be extended by providing periods with no wheelaccess. The temporary nature of feeding suppression in chronic access conditions may be due tosecondary longer term motivational changes.", "metadata": {}}
+{"_id": "21048969", "title": "", "text": "Evaluation of the association between the first observation and the longitudinal change in C-reactiveprotein, and all-cause mortality.OBJECTIVE To evaluate the association between vascular inflammation asmeasured by subacute C-reactive protein (CRP; 1-10 mg/l) and all-cause mortality and the associationbetween change in CRP status (normal <or=3 mg/l and elevated >3 mg/l) and all-cause mortality.METHODS Probabilistic record linkage was used to match hospital episode data, laboratory reports andmortality statistics in a large urban population. Survival was evaluated using Cox proportional hazardsregression models. RESULTS 22 962 patients had their first CRP measurement in the subacute range(1-10 mg/l). Analysis grouped by each additional unit increase in CRP across the subacute range wasassociated with a 7.3% (95% CI 5.4% to 9.2%) increase in the hazard ratio (HR) of death over 4 years,after controlling for confounding factors (p<0.001). Repeated CRP observations around 1 year apart wererecorded in 5811 subjects. After controlling for confounding factors, in patients whose CRP changed fromnormal (<or=3 mg/l) to elevated (>3 mg/l), the HR increased 6.7-fold (p<0.001) relative to cases whoseCRP remained normal. By comparison, among those subjects whose CRP was reduced from elevated tonormal, the hazard ratio halved to 3.5 (p = 0.018). In an underpowered analysis of time tocardiovascular events, an identical pattern of risk emerged. CONCLUSIONS CRP level predicted all-causemortality, and additional inclusion of prior change in CRP level and current CRP level more so. Increasingvascular inflammation, as measured by CRP, increases the likelihood of death.", "metadata": {}}
+{"_id": "21050357", "title": "", "text": "Research Priorities in Sudden Unexpected Infant Death: An International Consensus.Despite the successof safe sleep campaigns and the progress in understanding risk factors, the rate of reduction in the casesof sudden infant death syndrome has now slowed and it remains a leading cause of postneonatalmortality in many developed countries. Strategic action is needed to tackle this problem and it is nowvital to identify how the sudden infant death research community may best target its efforts. The GlobalAction and Prioritization of Sudden Infant Death Project was an international consensus process thataimed to define and direct future research by investigating the priorities of expert and lay members ofthe sudden unexpected infant death (SUID) community across countries. The aim was to identify whichareas of research should be prioritized to reduce the number of SUID deaths globally. Scientificresearchers, clinicians, counselors, educators, and SUID parents from 25 countries took part across 2online surveys to identify potential research priorities. Workshops subsequently took place in the UnitedKingdom, United States, and Australia to reach consensus and 10 priority areas for research wereestablished. Three main themes among the priorities emerged: (1) a better understanding ofmechanisms underlying SUID, (2) ensuring best practice in data collection, management and sharing,and (3) a better understanding of target populations and more effective communication of risk. SUID is aglobal problem and this project provides the international SUID community with a list of shared researchpriorities to more effectively work toward explaining and reducing the number of sudden infant deaths.", "metadata": {}}
+{"_id": "21053753", "title": "", "text": "Modification of the Constant-Murley shoulder score-introduction of the individual relative Constant scoreIndividual shoulder assessment.The Constant-Murley shoulder assessment score has proven to be avaluable diagnostic instrument. Thus, in the literature it has been mentioned that the clinical accuracy ofthis score varies especially when comparing patients in larger, inhomogeneous patient groups. The\"relative Constant score\" (CS(rel)) tries to minimize these problems by using reference parameters out ofhealthy age and gender related control groups. The authors of this study tried to show that it is evenmore accurate to use the functional performance of the uninjured collateral shoulder of the sameindividual as reference, introducing the \"individual relative Constant score\" (CS(indiv)). The CS(indiv) andthe CS(rel) were compared for 125 consecutive patients with shoulder disorders, and a group of 125healthy volunteers as a control group. In a non-parametric comparison of the reciever operatingcharacteristics the CS(indiv) shows the higher ability to discriminate between patients and healthyvolunteers (p=0.004). This indicates that the individual relative Constant score gives a more accurateview about the functional result for shoulder disorders. It is expected to be more reliable for larger andincoherent patient populations, because specific interindividual differences, regarding the patient's age,gender and constitution are eliminated as well as other individual physiological parameters.", "metadata": {}}
+{"_id": "21060008", "title": "", "text": "Celiac disease screening by immunochromatographic visual assays: results of a multicenterstudy.OBJECTIVE To assay the efficiency for celiac disease (CD) screening of 2 immunochromatographicvisual stick assays based on human recombinant tissue transglutaminase (tTG). One was the antitissuetransglutaminase antibodies (AtTGA) stick for IgA/G antibodies to tTG detection, the other was theAtTGA/antigliadin antibodies (AGA) stick for IgA antibodies for tTG and/or gliadins. PATIENTS ANDMETHODS In a prospective multicenter study, 4 pediatric gastroenterology units from Spain and 2 fromLatin America enrolled 72 control children with a normal small bowel mucosa and 113 untreated patientswith CD with Marsh type 3 lesions. RESULTS Evaluation of results by the gastroenterologists and by 2independent observers at the coordination center showed a remarkably low interobserver variability. Forthe AtTGA stick, sensitivity was 96.5% and specificity was 98.6%. The AtTGA/AGA stick displayed asensitivity of 94.5% and a specificity of 98.6% for AtTGA and a sensitivity of 63.1% and a specificity of95.2% for AGA. The highest efficiency and positive likelihood ratio was obtained for the AtTGA stick,higher than for IgA AtTGA by enzyme-linked immunosorbent assay. One additional advantage was thatprevious investigation of total serum IgA levels could be eluded. The IgA AtTGA/AGA stick, with anefficiency of 95.1%, compared with 89.2% when the combined results of the 2 enzyme-linkedimmunosorbent assays were considered, turned out to be an excellent diagnostic tool for infants with noIgA deficiency. CONCLUSION These 2 assays are extremely efficient for CD screening, by combining ahigh diagnostic accuracy with the simplicity and rapidity of visual methods.", "metadata": {}}
+{"_id": "21063817", "title": "", "text": "Down-regulation of keratin 4 and keratin 13 expression in oral squamous cell carcinoma and epithelialdysplasia: a clue for histopathogenesis.AIMS This study aimed to identify relevant keratin subtypes thatmay associate with the pathogenesis of oral epithelial neoplasms. METHODS AND RESULTS Expression ofall the keratin subtypes was examined by cDNA microarray analysis of 43 oral squamous cell carcinoma(OSCC) cases. Immunohistochemical expression of the major keratins was examined in 100 OSCC andoral epithelial dysplasia (OED) cases. Many changes in keratin expression were observed and,significantly, consistent down-regulation of keratin 4 (K4) and K13 expression was observed. Aberrantexpression of K4 and K13 was associated with morphological changes in the affected oral epithelium.Experiments with cell cultures transfected with various keratin subtypes suggested that alterations inkeratin subtype expression can cause changes in cell shape and movement. CONCLUSIONS Aberrantexpression of K4 and K13, which are the dominant pair of differentiation-related keratins in oralkeratinocytes, indicates dysregulation of epithelial differentiation in OSCC and OED. These keratins,especially K4, may be useful for pathological diagnosis. We propose that the aberrant expression of K4and K13 and concomitant up-regulation of the other keratins may be one of the causative factors formorphological alterations in the affected epithelium.", "metadata": {}}
+{"_id": "21093407", "title": "", "text": "Identification of short-lived long non-coding RNAs as surrogate indicators for chemical stressresponse.Abiotic and biotic stressors in human cells are often a result of sudden and/or frequent changesin environmental factors. The molecular response to stress involves elaborate modulation of geneexpression and is of homeostatic, ecological, and evolutionary importance. Although attention hasprimarily focused on signaling pathways and protein networks, long non-coding RNAs (ncRNAs) areincreasingly involved in the molecular mechanisms associated with responses to cellular stresses. Weidentified six novel short-lived long ncRNAs (MIR22HG, GABPB-AS1, LINC00152, IDI2-AS1, SNHG15, andFLJ33630) that responded to chemical stressors (cisplatin, cycloheximide, and mercury (II) oxide) inHeLa Tet-off cells. Our results indicate that short-lived long ncRNAs respond to general and specificchemical stressors. The expression levels of the short-lived long ncRNAs were elevated because ofprolonged decay rates in response to chemical stressors and interruption of RNA degradation pathways.We propose that these long ncRNAs have the potential to be surrogate indicators of cellular stressresponses.", "metadata": {}}
+{"_id": "21108759", "title": "", "text": "Isolation of a gene encoding a functional zinc finger protein homologous to erythroid Krüppel-like factor:identification of a new multigene family.We have identified and characterized the gene for a novel zincfinger transcription factor which we have termed lung Krüppel-like factor (LKLF). LKLF was isolatedthrough the use of the zinc finger domain of erythroid Krüppel-like factor (ELKF) as a hybridization probeand is closely related to this erythroid cell-specific gene. LKLF is expressed in a limited number of tissues,with the predominant expression seen in the lungs and spleen. The gene is developmentally controlled,with expression noted in the 7-day embryo followed by a down-regulation at 11 days and subsequentreactivation. A high degree of similarity is noted in the zinc finger regions of LKLF and EKLF. Beyond thisdomain, the sequences diverge significantly, although the putative transactivation domains for both LKLFand EKLF are proline-rich regions. In the DNA-binding domain, the three zinc finger motifs are so closelyconserved that the predicted DNA contact sites are identical, suggesting that both proteins may bind tothe same core sequence. This was further suggested by transactivation assays in which mouse fibroblastswere transiently transfected with a human beta-globin reporter gene in the absence and presence of anLKLF cDNA construct. Expression of the LKLF gene activates this human beta-globin promoter containingthe CACCC sequence previously shown to be a binding site for EKLF. Mutation of this potential bindingsite results in a significant reduction in the reporter gene expression. LKLF and EKLF can thus be groupedas members of a unique family of transcription factors which have discrete patterns of expression indifferent tissues and which appear to recognize the same DNA-binding site.", "metadata": {}}
+{"_id": "21114100", "title": "", "text": "A small molecule restores function to TRPML1 mutant isoforms responsible for mucolipidosis typeIV.Mucolipidosis type IV (MLIV) is an autosomal recessive lysosomal storage disorder often characterizedby severe neurodevelopmental abnormalities and neuro-retinal degeneration. Mutations in the TRPML1gene are causative for MLIV. We used lead optimization strategies to identify--and MLIV patientfibroblasts to test--small-molecule activators for their potential to restore TRPML1 mutant channelfunction. Using the whole-lysosome planar patch-clamp technique, we found that activation of MLIVmutant isoforms by the endogenous ligand PI(3,5)P2 is strongly reduced, while activity can be increasedusing synthetic ligands. We also found that the F465L mutation renders TRPML1 pH insensitive, whileF408Δ impacts synthetic ligand binding. Trafficking defects and accumulation of zinc in lysosomes of MLIVmutant fibroblasts can be rescued by the small molecule treatment. Collectively, our data demonstratethat small molecules can be used to restore channel function and rescue disease associated abnormalitiesin patient cells expressing specific MLIV point mutations.", "metadata": {}}
+{"_id": "21141798", "title": "", "text": "Characterization of a murine monoclonal antibody to Cryptococcus neoformans polysaccharide that is acandidate for human therapeutic studies.The murine monoclonal antibody (MAb) 18B7 [immunoglobulinG1(kappa)] is in preclinical development for treatment of Cryptococcus neoformans infections. Inanticipation of its use in humans, we defined the serological and biological properties of MAb 18B7 indetail. Structural comparison to the related protective MAb 2H1 revealed conservation of the antigenbinding site despite several amino acid differences. MAb 18B7 was shown by immunofluorescence andagglutination studies to bind to all four serotypes of C. neoformans, opsonize C. neoformans serotypes Aand D, enhance human and mouse effector cell antifungal activity, and activate the complement pathwayleading to deposition of complement component 3 (C3) on the cryptococcal capsule. Administration ofMAb 18B7 to mice led to rapid clearance of serum cryptococcal antigen and deposition in the liver andspleen. Immunohistochemical studies revealed that MAb 18B7 bound to capsular glucuronoxylomannan ininfected mouse tissues. No reactivity of MAb 18B7 with normal human, rat, or mouse tissues wasdetected. The results show that both the variable and constant regions of MAb 18B7 are biologicallyfunctional and support the use of this MAb in human therapeutic trials.", "metadata": {}}
+{"_id": "21150010", "title": "", "text": "Treatment with cyclooxygenase-2 inhibitors enables repeated administration of vaccinia virus for controlof ovarian cancer.Metastatic ovarian cancer is the leading cause of death among women with gynecologicmalignancies in the United States. The lack of effective treatment for patients with advanced ovariancancer warrants development of innovative therapies. Cancer therapy using oncolytic viruses representsa promising new approach for controlling tumors. Vaccinia virus has been shown to preferentially infecttumor cells but not normal tissue. However, oncolytic therapy using recombinant viruses faces thelimitation of viral clearance due to generation of neutralizing antibodies. In the current study, we foundthat cyclooxygenase-2 (Cox-2) inhibitors circumvented this limitation, enabling repeated administrationof vaccinia virus without losing infectivity. We quantified the antivaccinia antibody response usingenzyme-linked immunosorbent assay (ELISA) and neutralization assays to show that treatment of Cox-2inhibitors inhibited the generation of neutralizing antibodies. Furthermore, we showed that combinationtreatment of Cox-2 inhibitors with vaccinia virus was more effective that either treatment alone intreating MOSEC/luc tumor-bearing mice. Thus, the combination of Cox-2 inhibitors and vaccinia virusrepresents a potential innovative approach to controlling ovarian tumors.", "metadata": {}}
+{"_id": "21164071", "title": "", "text": "Ser-752-->Pro mutation in the cytoplasmic domain of integrin beta 3 subunit and defective activation ofplatelet integrin alpha IIb beta 3 (glycoprotein IIb-IIIa) in a variant of Glanzmannthrombasthenia.Integrins are membrane receptors which mediate cell-cell or cell-matrix adhesion.Integrin alpha IIb beta 3 (glycoprotein IIb-IIIa) acts as a fibrinogen receptor of platelets and mediatesplatelet aggregation. Platelet activation is required for alpha IIb beta 3 to shift from noncompetent tocompetent for binding soluble fibrinogen. The steps involved in this transition are poorly understood. Wehave studied a variant of Glanzmann thrombasthenia, a congenital bleeding disorder characterized byabsence of platelet aggregation and fibrinogen binding. The patient's platelets did not bind fibrinogenafter platelet activation by ADP or thrombin, though his platelets contained alpha IIb beta 3. However,isolated alpha IIb beta 3 was able to bind to an Arg-Gly-Asp-Ser affinity column, and binding of solublefibrinogen to the patient's platelets could be triggered by modulators of alpha IIb beta 3 conformationsuch as the Arg-Gly-Asp-Ser peptide and alpha-chymotrypsin. These data suggested that a functionalArg-Gly-Asp binding site was present within alpha IIb beta 3 and that the patient's defect was notsecondary to a blockade of alpha IIb beta 3 in a noncompetent conformational state. This was evocativeof a defect in the coupling between platelet activation and alpha IIb beta 3 up-regulation. We thereforesequenced the cytoplasmic domain of beta 3, following polymerase chain reaction (PCR) on platelet RNA,and found a T-->C mutation at nucleotide 2259, corresponding to a Ser-752-->Pro substitution. Thismutation is likely to be responsible for the uncoupling of alpha IIb beta 3 from cellular activation because(i) it is not a polymorphism, (ii) it is the only mutation in the entire alpha IIb beta 3 sequence, and (iii)genetic analysis of the family showed that absence of the Pro-752 beta 3 allele was associated with thenormal phenotype. Our data thus identify the C-terminal portion of the cytoplasmic domain of beta 3 asan intrinsic element in the coupling between alpha IIb beta 3 and platelet activation.", "metadata": {}}
+{"_id": "21170174", "title": "", "text": "Crossover and noncrossover pathways in mouse meiosis.During meiosis, recombination betweenhomologous chromosomes generates crossover (CR) and noncrossover (NCR) products. CRs establishconnections between homologs, whereas intermediates leading to NCRs have been proposed toparticipate in homologous pairing. How these events are differentiated and regulated remains to bedetermined. We have developed a strategy to detect, quantify, and map NCRs in parallel to CRs, at thePsmb9 meiotic recombination hot spot, in male and female mouse germ lines. Our results report directmolecular evidence for distinct CR and NCR pathways of DNA double-strand break (DSB) repair in mousemeiosis based on three observations: both CRs and NCRs require Spo11, NCR products have shorterconversion tracts than CRs, and only CRs require the MutL homolog Mlh1. We show that both productsare formed from middle to late pachytene of meiotic prophase and provide evidence for anMlh1-independent CR pathway, where mismatch repair does not require Mlh1.", "metadata": {}}
+{"_id": "21179714", "title": "", "text": "IAP regulation of metastasis.Inhibitor-of-Apoptosis (IAP) proteins contribute to tumor progression, butthe requirements of this pathway are not understood. Here, we show that intermolecular cooperationbetween XIAP and survivin stimulates tumor cell invasion and promotes metastasis. This pathway isindependent of IAP inhibition of cell death. Instead, a survivin-XIAP complex activates NF-kappaB, whichin turn leads to increased fibronectin gene expression, signaling by beta1 integrins, and activation of cellmotility kinases FAK and Src. Therefore, IAPs are direct metastasis genes, and their antagonists couldprovide antimetastatic therapies in patients with cancer.", "metadata": {}}
+{"_id": "21181273", "title": "", "text": "15-Hydroxyprostaglandin dehydrogenase is down-regulated in colorectal cancer.Prostaglandin E2 (PGE2)can stimulate tumor progression by modulating several proneoplastic pathways, including proliferation,angiogenesis, cell migration, invasion, and apoptosis. Although steady-state tissue levels of PGE2 stemfrom relative rates of biosynthesis and breakdown, most reports examining PGE2 have focused solely onthe cyclooxygenase-dependent formation of this bioactive lipid. Enzymatic degradation of PGE2 involvesthe NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH). The present study examineda range of normal tissues in the human and mouse and found high levels of 15-PGDH in the largeintestine. By contrast, the expression of 15-PGDH is decreased in several colorectal carcinoma cell linesand in other human malignancies such as breast and lung carcinomas. Consistent with these findings, weobserve diminished 15-Pgdh expression in ApcMin+/- mouse adenomas. Enzymatic activity of 15-PGDHcorrelates with expression levels and the genetic disruption of 15-Pgdh completely blocks production ofthe urinary PGE2 metabolite. Finally, 15-PGDH expression and activity are significantly down-regulated inhuman colorectal carcinomas relative to matched normal tissue. In summary, these results suggest anovel tumor suppressive role for 15-PGDH due to loss of expression during colorectal tumor progression.", "metadata": {}}
+{"_id": "21185923", "title": "", "text": "Stimulation of CD25+CD4+ regulatory T cells through GITR breaks immunologicalself-toleranceCD25+CD4+ regulatory T cells in normal animals are engaged in the maintenance ofimmunological self-tolerance. We show here that glucocorticoid-induced tumor necrosis factor receptorfamily–related gene (GITR, also known as TNFRSF18)—a member of the tumor necrosis factor–nervegrowth factor (TNF-NGF) receptor gene superfamily—is predominantly expressed on CD25+CD4+ T cellsand on CD25+CD4+CD8− thymocytes in normal naïve mice. We found that stimulation of GITRabrogated CD25+CD4+ T cell–mediated suppression. In addition, removal of GITR-expressing T cells oradministration of a monoclonal antibody to GITR produced organ-specific autoimmune disease inotherwise normal mice. Thus, GITR plays a key role in dominant immunological self-tolerance maintainedby CD25+CD4+ regulatory T cells and could be a suitable molecular target for preventing or treatingautoimmune disease.", "metadata": {}}
+{"_id": "21186109", "title": "", "text": "The missing cases of tuberculosis in Malawi: the contribution from cross-border registrations.Low casedetection rates of new smear-positive pulmonary tuberculosis (PTB) patients globally are a cause forconcern. The aim of this study was to determine for patients registered for TB in Malawi the number andpercentage who lived in a neighbouring country and the registration, recording and reporting practices forthese 'foreign' patients. All 44 non-private hospitals, which register and treat all TB patients in the publichealth sector in Malawi, were visited. Ten (23%) hospitals in 2001 and 14 (32%) in 2002 maintained aseparate register for cross-border TB cases. Patients recorded in these registers were not formallyreported to the Malawi National TB Programme (NTP), the neighbouring country's NTP, nor to WHO. Theytherefore constitute missing cases. In Malawi, the number of cross-border new smear-positive PTB caseswas 77 in 2001 and 91 in 2002, constituting about 3% of missing smear-positive cases in those hospitalsthat maintain cross-border registers and about 1% of missing cases nationally.", "metadata": {}}
+{"_id": "21199527", "title": "", "text": "Parathyroid hormone induces E4bp4 messenger ribonucleic acid expression primarily through cyclicadenosine 3',5'-monophosphate signaling in osteoblasts.PTH binding to its receptor activates proteinkinase A (PKA), protein kinase C (PKC), and calcium signaling to induce transcription of primary responsegenes in osteoblasts. Adenovirus E4 promoter-binding protein/nuclear factor regulated by IL-3(E4BP4/NFIL3), a transcriptional repressor, is a PTH-induced primary response gene in primary mouseosteoblasts (MOBs). Here we investigate the signaling pathway(s) that lead to PTH induction of E4bp4mRNA expression. Ten and 100 nm PTH induced maximum E4bp4 expression in MOBs. Forskolin (FSK),an adenylate cyclase inducer, 8-bromo-cAMP, a cAMP analog, and phorbol myristate acetate, a PKCactivator, increased E4bp4 mRNA levels, whereas ionomycin, a calcium ionophore, had no effect.Pretreatment of cells with 30 microm H89, a PKA inhibitor, strongly inhibited PTH- and FSK-inducedE4bp4 expression. In contrast, overnight pretreatment with 1 microm phorbol myristate acetate todown-regulate PKC signaling did not alter PTH and FSK effects. Moreover, PTH (3-34) that does notactivate cAMP signaling did not increase E4bp4 expression. Prostaglandin E(2), which signals throughcAMP, increased E4bp4 mRNA at all doses, whereas prostaglandin F(2alpha) that primarily activates PKCand calcium signaling, induced E4bp4 only at high doses and fluprostenol that only activates PKC andcalcium signaling, had no effect. Finally, 80 microg/kg PTH (1-34) ip injection induced E4bp4 mRNAexpression at 1 h in mice. In contrast, 80 microg/kg PTH (3-34) had no effect. Our data suggest thatPTH-induced E4bp4 mRNA expression is mediated primarily through cAMP-PKA signaling in vitro and invivo. In conjunction with our previous report, we hypothesize that E4bp4 attenuates transcription ofosteoblastic genes possessing E4bp4 promoter binding sites.", "metadata": {}}
+{"_id": "21203899", "title": "", "text": "Managing finances of shipping living donor kidneys for donor exchanges.Kidney donor exchanges enablerecipients with immunologically incompatible donors to receive compatible living donor grafts; however,the financial management of these exchanges, especially when an organ is shipped, is complex and thushas the potential to impede the broader implementation of donor exchange programs. Representativesfrom transplant centers that utilize the National Kidney Registry database to facilitate donor exchangetransplants developed a financial model applicable to paired donor exchanges and donor chaintransplants. The first tenet of the model is to eliminate financial liability to the donor. Thereafter, itaccounts for the donor evaluation, donor nephrectomy hospital costs, donor nephrectomy physician fees,organ transport, donor complications and recipient inpatient services. Billing between hospitals is basedon Medicare cost report defined costs rather than charges. We believe that this model complies withcurrent federal regulations and effectively captures costs of the donor and recipient services. It could beconsidered as a financial paradigm for the United Network for Organ Sharing managed donor exchangeprogram.", "metadata": {}}
+{"_id": "21216726", "title": "", "text": "Human herpesvirus 8 infection and Kaposi's sarcoma among human immunodeficiency virus-infected and-uninfected women.Little is known about the epidemiology of human herpesvirus 8 (HHV-8) infectionsamong women. A cross-sectional study was conducted of HHV-8 infection among humanimmunodeficiency virus (HIV)-infected and high-risk HIV-uninfected women. Serological tests withnoninduced (latent) and induced (lytic) HHV-8 antigens were used to detect infection among 2483participants of a multisite cohort. Reactivity to latent antigen was present in 4.1% and to inducedantigens in 12.0% of women. Seven of 8 women who reported Kaposi's sarcoma had HHV-8 antibodies.Among HIV-positive women, HHV-8 infection was associated with use of crack, cocaine, or heroin (76%vs. 65%; P<.001), past syphilis (29% vs. 20%; P<.001), an injection drug-using male sex partner (61%vs. 53%; P=.014), black race (P=.010), and enrollment site (P=.015). In multivariate analysis, HIVinfection, older age, past syphilis, black race, and enrollment site were independently associated withHHV-8 infection. In this cohort of North American women, HHV-8 infection was associated with HIVinfection, drug use, and risky sexual behavior.", "metadata": {}}
+{"_id": "21219071", "title": "", "text": "Cloning of three novel neuronal Cdk5 activator binding proteins.Neuronal Cdc2-like kinase (Nclk) isinvolved in the regulation of neuronal differentiation and neuro-cytoskeleton dynamics. The active kinaseconsists of a catalytic subunit, Cdk5, and a 25 kDa activator protein (p25nck5a) derived from a 35 kDaneuronal-specific protein (p35nck5a). As an extension of our previous study (Qi, Z., Tang, D., Zhu, X.,Fujita, D.J., Wang, J.H., 1998. Association of neurofilament proteins with neuronal Cdk5 activator. J. Biol.Chem. 270, 2329-2335), which showed that neurofilament is one of the p35nck5a-associated proteins,we now report the isolation of three other novel p35nck5a-associated proteins using the yeast two-hybridscreen. The full-length forms of these three novel proteins, designated C42, C48 and C53, have amolecular mass of 66, 24, and 57 kDa, respectively. Northern analysis indicates that these novel proteinsare widely expressed in human tissues, including the heart, brain, skeletal muscle, placenta, lung, liver,kidney and pancreas. The bacterially expressed glutathione S-transferase (GST)-fusion forms of thesethree proteins were able to co-precipitate p35nck5a complexed with Cdk5 from insect cell lysate. Amongthese three proteins, only C48 and C53 can be phosphorylated by Nclk, suggesting that they may be thesubstrates of Nclk. Sequence homology searches have suggested that the C48 protein is marginallyrelated to restin protein, whereas the C42 protein has homologues of unknown function in Caenorhabditiselegans and Arabidopsis thaliana.", "metadata": {}}
+{"_id": "21221346", "title": "", "text": "The Artemis:DNA-PKcs endonuclease cleaves DNA loops, flaps, and gaps.In eukaryotic cells,nonhomologous DNA end joining (NHEJ) is a major pathway for repair of double-strand DNA breaks(DSBs). Artemis and the 469kDa DNA-dependent protein kinase (DNA-PKcs) together form a keynuclease for NHEJ in vertebrate organisms. The structure-specific endonucleolytic activity of Artemis isactivated by binding to and phosphorylation by DNA-PKcs. We tested various DNA structures in order tounderstand the range of structural features that are recognized by the Artemis:DNA-PKcs complex. Wefind that all tested substrates that contain single-to-double-strand transitions can be cleaved by theArtemis:DNA-PKcs complex near the transition region. The cleaved substrates include heterologous loops,stem-loops, flaps, and gapped substrates. Such versatile activity on single-/double-strand transitionregions is important in understanding how reconstituted NHEJ systems that lack DNA polymerases canjoin incompatible DNA ends and yet preserve 3' overhangs. Additionally, the flexibility of theArtemis:DNA-PKcs nuclease may be important in removing secondary structures that hinder processingof DNA ends during NHEJ.", "metadata": {}}
+{"_id": "21230110", "title": "", "text": "A promoter derived from taro bacilliform badnavirus drives strong expression in transgenic banana andtobacco plantsTaro bacilliform virus (TaBV) is a pararetrovirus of the genus Badnavirus which infects themonocotyledonous plant, taro (Colocasia esculenta). A region of the TaBV genome spanning nucleotides6,281 to 12 (T1200), including the 3′ end of open reading frame 3 (ORF 3) and the intergenic region tothe end of the tRNAmet-binding site, was tested for promoter activity along with four different 5′ deletionfragments (T600, T500, T250 and T100). In transient assays, only the T1200, T600, T500 fragmentswere shown to have promoter activity in taro leaf, banana suspension cells and tobacco callus. Whenthese three promoters were evaluated in stably transformed, in vitro-grown transgenic banana andtobacco plants, all were found to drive near-constitutive expression of either the green fluorescent proteinor β-glucuronidase (GUS) reporter gene in the stem (or pseudostem), leaves and roots, with strongestexpression observed in the vascular tissue. In transgenic banana leaves, the T600 promoter directedfour-fold greater GUS activity than that of the T1200, T500 and the maize polyubiquitin-1 promoters. Intransgenic tobacco leaves, the levels of GUS expression directed by the three promoters was betweenfour- and ten-fold lower than that of the double Cauliflower mosaic virus 35S promoter. These resultsindicate that the TaBV-derived promoters may be useful for the high-level constitutive expression oftransgenes in either monocotyledonous or dicotyledonous species.", "metadata": {}}
+{"_id": "21232018", "title": "", "text": "Age of ovary determines remaining life expectancy in old ovariectomized mice.We investigated thecapacity of young ovaries, transplanted into old ovariectomized CBA mice, to improve remaining lifeexpectancy of the hosts. Donor females were sexually mature 2-month-olds; recipients wereprepubertally ovariectomized at 3 weeks and received transplants at 5, 8 or 11 months of age. Relative toovariectomized control females, life expectancy at 11 months was increased by 60% in 11-monthrecipient females and by 40% relative to intact control females. Only 20% of the 11-month transplantfemales died in the 300-day period following ovarian transplantation, whereas nearly 65% of theovariectomized control females died during this same period. The 11-month-old recipient femalesresumed oestrus and continued to cycle up to several months beyond the age of control femalereproductive senescence. Across the three recipient age groups, transplantation of young ovariesincreased life expectancy in proportion to the relative youth of the ovary. Our results relate to recentfindings on the gonadal input upon aging in Caenorhabditis elegans and may suggest how themammalian gonad, including that of humans, could regulate aging and determine longevity.", "metadata": {}}
+{"_id": "21239672", "title": "", "text": "Use of macrolides in mother and child and risk of infantile hypertrophic pyloric stenosis: nationwidecohort studyOBJECTIVE To assess the association between use of macrolide antibiotics in mothers andinfants from pregnancy onset until 120 days after birth and infantile hypertrophic pyloric stenosis (IHPS).DESIGN Nationwide register based cohort study. SETTING Denmark, 1996-2011. PARTICIPANTS 999,378liveborn singletons and linked individual level information on macrolide prescriptions (maternal useduring pregnancy, n=30,091; maternal use after birth, n=21,557; use in infants, n=6591), surgery forIHPS, and potential confounders. MAIN OUTCOME MEASURES Surgery for IHPS by three categories ofmacrolide use: in mothers during pregnancy, in mothers after birth, and in infants after birth. RESULTS880 infants developed IHPS (0.9 cases per 1000 births). Compared with infants with no use ofmacrolides, the adjusted rate ratio for IHPS in infants with use of macrolides during days 0 to 13 afterbirth was 29.8 (95% confidence interval 16.4 to 54.1) and during days 14 to 120 was 3.24 (1.20 to8.74); the corresponding absolute risk differences were 24.4 (95% confidence interval 13.0 to 44.1) and0.65 (0.06 to 2.21) cases per 1000 infants exposed to macrolides, respectively. The rate ratio formaternal use of macrolides for days 0 to 13 after birth was 3.49 (1.92 to 6.34) and for days 14 to 120was 0.70 (0.26 to 1.90); the corresponding absolute risk differences were 2.15 (0.82 to 4.64) and -0.11(-0.26 to 0.31). The rate ratios for maternal use of macrolides during pregnancy were 1.02 (0.65 to 1.59)for weeks 0 to 27 and 1.77 (0.95 to 3.31) for weeks 28 to birth; the corresponding absolute riskdifferences were 0.01 (-0.31 to 0.50) and 0.67 (-0.06 to 2.02). CONCLUSIONS Treatment of younginfants with macrolide antibiotics was strongly associated with IHPS and should therefore only beadministered if potential treatment benefits outweigh the risk. Maternal use of macrolides during the firsttwo weeks after birth was also associated with an increased risk of IHPS. A possible association was alsofound with use during late pregnancy.", "metadata": {}}
+{"_id": "21246752", "title": "", "text": "The psychiatric manifestations of mitochondrial disorders: a case and review of the literature.OBJECTIVEMitochondrial disorders are caused by gene mutations in mitochondrial or nuclear DNA and affectenergy-dependent organs such as the brain. Patients with psychiatric illness, particularly those withmedical comorbidities, may have primary mitochondrial disorders. To date, this issue has received littleattention in the literature, and mitochondrial disorders are likely underdiagnosed in psychiatric patients.DATA SOURCES This article describes a patient who presented with borderline personality disorder andtreatment-resistant depression and was ultimately diagnosed with mitochondrial encephalomyopathy withlactic acidosis and stroke-like episodes (MELAS) 3271. We also searched the literature for all case reportsof patients with mitochondrial disorders who initially present with prominent psychiatric symptoms byusing MEDLINE (from 1948-February 2011), Embase (from 1980-February 2011), PsycINFO (from1806-February 2011), and the search terms mitochondrial disorder, mitochondria, psychiatry, mentaldisorders, major depression, anxiety, schizophrenia, and psychosis. STUDY SELECTION Fifty cases ofmitochondrial disorders with prominent psychiatric symptomatology were identified. DATA EXTRACTIONInformation about the psychiatric presentation of the cases was extracted. This information wascombined with our case, the most common psychiatric manifestations of mitochondrial disorders wereidentified, and the important diagnostic and treatment implications for patients with psychiatric illnesswere reviewed. RESULTS The most common psychiatric presentations in the cases of mitochondrialdisorders included mood disorder, cognitive deterioration, psychosis, and anxiety. The most commondiagnosis (52% of cases) was a MELAS mutation. Other genetic mitochondrial diagnoses includedpolymerase gamma mutations, Kearns-Sayre syndrome, mitochondrial DNA deletions, point mutations,twinkle mutations, and novel mutations. CONCLUSIONS Patients with mitochondrial disorders can presentwith primary psychiatric symptomatology, including mood disorder, cognitive impairment, psychosis, andanxiety. Psychiatrists need to be aware of the clinical features that are indicative of a mitochondrialdisorder, investigate patients with suggestive presentations, and be knowledgeable about the treatmentimplications of the diagnosis.", "metadata": {}}
+{"_id": "21250322", "title": "", "text": "Polo kinase and Asp are needed to promote the mitotic organizing activity of centrosomesInterfering withthe activity of polo-like kinases can lead to the formation of monopolar spindles. Polo-like kinases alsoregulate mitotic entry, activation of the anaphase-promoting complex and the necessary preconditions forcytokinesis. Similarities between the phenotypes of the Drosophila mutants asp and polo point towards acommon role in spindle pole function. The abnormal spindles of asp mutants are bipolar but havedisorganized broad poles at which γ-tubulin has an abnormal distribution. Moreover, the synergism or ofpolo1 aspE3 double mutants indicates a possible involvement of these genes in a common process. Asp isa microtubule-associated protein of relative molecular mass 220,000 (Mr 220K) found at the face of thecentrosome that contacts spindle microtubules. In partially purified centrosomes, it is required withγ-tubulin to organize microtubule asters. Here, we show that Asp is the previously identified Mr 220Ksubstrate of Polo kinase. Polo phosphorylates Asp in vitro, converting it into an MPM2 epitope. Polo andAsp proteins immunoprecipitate together and exist as part of a 25–38S complex. Extracts of polo-derivedembryos are unable to restore the ability of salt-stripped centrosomes to nucleate microtubule asters.This can be rescued by addition of phosphorylated Asp or active Polo kinase.", "metadata": {}}
+{"_id": "21257564", "title": "", "text": "How long will long-term potentiation last?The paramount feature of long-term potentiation (LTP) as amemory mechanism is its characteristic persistence over time. Although the basic phenomenology of LTPpersistence was established 30 years ago, new insights have emerged recently about the extent of LTPpersistence and its regulation by activity and experience. Thus, it is now evident that LTP, at least in thedentate gyrus, can either be decremental, lasting from hours to weeks, or stable, lasting months orlonger. Although mechanisms engaged during the induction of LTP regulate its subsequent persistence,the maintenance of LTP is also governed by activity patterns post-induction, whether inducedexperimentally or generated by experience. These new findings establish dentate gyrus LTP as a usefulmodel system for studying the mechanisms governing the induction, maintenance and interference withlong-term memory, including very long-term memory lasting months or longer. The challenge is to studyLTP persistence in other brain areas, and to relate, if possible, the properties and regulation of LTPmaintenance to these same properties of the information that is actually stored in those regions.", "metadata": {}}
+{"_id": "21258863", "title": "", "text": "An IL-13 inhibitor blocks the development of hepatic fibrosis during a T-helper type 2-dominatedinflammatory response.In schistosomiasis, chronic parasite egg-induced granuloma formation can lead totissue destruction and fibrosis, which causes much of the morbidity and mortality associated with thisdisease. Here we show the importance of IL-13 in the pathogenesis of schistosomiasis, and demonstrate,perhaps for the first time, the therapeutic efficacy of an IL-13 inhibitor, sIL-13Ralpha2-Fc, in the controlof hepatic fibrosis. T-helper type 2 (Th2) cytokines dominate the immune response in mice infected withSchistosoma mansoni, yet the specific contributions of IL-13 and IL-4 to the development of fibrosis werenot previously investigated. Our studies demonstrate that both cytokines play redundant roles ingranuloma formation, which explains the ability of IL-4-deficient mice to form granulomas around eggs.More importantly, however, these studies demonstrate that IL-13 is the dominant Th2-type cytokineregulating fibrosis. IL-13 stimulated collagen production in fibroblasts, and procollagen I and procollagenIII mRNA expression was decreased in sIL-13Ralpha2-Fc-treated mice. Moreover, the reduction in fibrosisobserved in IL-4-deficient mice was much less pronounced than that in sIL-13Ralpha2-Fc-treatedanimals. Fibrosis is a major pathological manifestation of a number of allergic, autoimmune, andinfectious diseases. Thus, our findings provide evidence that IL-13 inhibitors may be of generaltherapeutic benefit in preventing damaging tissue fibrosis resulting from Th2-dominated inflammatoryresponses.", "metadata": {}}
+{"_id": "21260231", "title": "", "text": "Validity and reliability of observational methods for studying medication administration errors.The validityand reliability of observational methods for studying medication administration errors (MAEs) werestudied. Between January and June 1998, two pharmacists observed consecutive drug administrationrounds by nurses on two wards in a U.K. hospital and recorded all MAEs identified. The observersintervened in cases of potentially harmful errors. MAE records were audited to determine the percentageof omitted doses for which a corresponding reason was documented for the observation periods and fornonobservation periods. Error rates for each drug administration round were analyzed according towhether they were for the nurse's first, second, third (and so on) observed round. Error rates werecalculated before and after the first intervention with nurses for whom an intervention was made.Observer reliability was calculated by comparing the rates of errors identified by the two observers. Therewas no difference between the observation and nonobservation periods in the percentage of omitteddoses for which a reason was documented, and there was no change in the error rate with repeatedobservations. There was no difference in error rates before and after the first intervention for each nurse.There was also no difference in error detection between the two observers and no change with increasingduration of observation. Observation of nurses during drug administration at a U.K. hospital did notsignificantly affect the MAE rate; nor did tactful interventions by the observers. Observer reliability washigh. Concerns about the validity and reliability of observational methods for identifying MAEs may beunfounded.", "metadata": {}}
+{"_id": "21271817", "title": "", "text": "Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissuecontribution.Ectopic expression of the four transcription factors Oct4, Sox2, c-Myc, and Klf4 is sufficientto confer a pluripotent state upon the fibroblast genome, generating induced pluripotent stem (iPS) cells.It remains unknown if nuclear reprogramming induced by these four factors globally resets epigeneticdifferences between differentiated and pluripotent cells. Here, using novel selection approaches, we havegenerated iPS cells from fibroblasts to characterize their epigenetic state. Female iPS cells showedreactivation of a somatically silenced X chromosome and underwent random X inactivation upondifferentiation. Genome-wide analysis of two key histone modifications indicated that iPS cells are highlysimilar to ES cells. Consistent with these observations, iPS cells gave rise to viable high-degree chimeraswith contribution to the germline. These data show that transcription factor-induced reprogramming leadsto the global reversion of the somatic epigenome into an ES-like state. Our results provide a paradigm forstudying the epigenetic modifications that accompany nuclear reprogramming and suggest that abnormalepigenetic reprogramming does not pose a problem for the potential therapeutic applications of iPS cells.", "metadata": {}}
+{"_id": "21272977", "title": "", "text": "Exocrine ontogenies: on the development of pancreatic acinar, ductal and centroacinar cells.This reviewsummarizes our current understanding of exocrine pancreas development, including the formation ofacinar, ductal and centroacinar cells. We discuss the transcription factors associated with various stagesof exocrine differentiation, from multipotent progenitor cells to fully differentiated acinar and ductal cells.Within the branching epithelial tree of the embryonic pancreas, this involves the progressive restriction ofmultipotent pancreatic progenitor cells to either a central \"trunk\" domain giving rise to the islet andductal lineages, or a peripheral \"tip\" domain giving rise to acinar cells. This review also discusses thesoluble morphogens and other signaling pathways that influence these events. Finally, we examinecentroacinar cells as an enigmatic pancreatic cell type whose lineage remains uncertain, and whosepossible progenitor capacities continue to be explored.", "metadata": {}}
+{"_id": "21274496", "title": "", "text": "The history of SIVS and AIDS: epidemiology, phylogeny and biology of isolates from naturally SIVinfected non-human primates (NHP) in Africa.Simian immunodeficiency virus (SIV) naturally infectsnon-human primates in Africa. To date, 40 SIVs have been described both in natural hosts and inheterologous species. These viruses are highly diverse and the majority cluster in 6 relatively equidistantphylogenetic lineages. At least 8 SIVs are currently considered as recombinant viruses, based on differentclustering patterns in different genomic regions. Only three types of genomes are known, based on thenumber of accessory genes: vpr-containing genomes, vpr-vpx containing genomes andvpr-vpu-containing genomes. vpx resulted by a duplication of the vpr gene following non-homologousrecombination and is characteristic of SIVs infecting the Papionini tribe of monkeys and HIV-2 in humans.vpu is characteristic of SIVcpz and HIV-1 and may have originated from a recombination involving SIVsfrom cercopitecini monkeys. SIV seems to be non-pathogenic in the vast majority of natural hosts in spiteof a high levels of viral replication. This is probably a consequence of virus-host adaptation, in which theincubation period of the disease generally exceeds the life span of the African primate host. SIVs alsohave a high propensity for cross-species transmission. In the new host, the outcome may vary frominapparent infection to highly pathogenic, the former being reported for African monkeys, whereas thelatter being observed in macaques and humans. The high diversity of SIVs was generated by a highmutation rate due to a low fidelity of the reverse-transcriptase and active viral and host cell turnover,host-dependent evolution and recombination. Cross-species transmission is not rare, howeverpreferential host switching may drive the majority of cross-species transmissions. Numerous SIVs testedso far are able to grow in vitro on human PBMC, therefore it has been postulated that SIV represents athreat for infection of humans in Central Africa and that AIDS is a zoonosis. However, although the simianorigin of the two HIV types is broadly acknowledged, there are no data that AIDS is acquired like azoonosis. SIV may undergo adaptation in the new human host in order to emerge in the generalpopulation. The study of SIV in their natural hosts should provide important clues to the real threat tohuman populations and also elucidate the mechanisms associated with a long-term persistent viralinfection without clinical consequences for the host.", "metadata": {}}
+{"_id": "21274919", "title": "", "text": "The association between common physical impairments and dementia in low and middle incomecountries, and, among people with dementia, their association with cognitive function and disability. A10/66 Dementia Research Group population-based study.OBJECTIVE Chronic physical comorbidity iscommon in dementia. However, there is an absence of evidence to support good practice guidelines forattention to these problems. We aimed to study the extent of this comorbidity and its impact on cognitivefunction and disability in population-based studies in low and middle income countries, where chronicdiseases and impairments are likely to be both common and undertreated. METHODS A multicentrecross-sectional survey of all over 65 year old residents (n = 15 022) in 11 catchment areas in China,India, Cuba, Dominican Republic, Venezuela, Mexico and Peru. We estimated the prevalence of pain,incontinence, hearing and visual impairments, mobility impairment and undernutrition according to thepresence of dementia and its severity, and, among those with dementia, the independent contribution ofthese impairments to cognitive function and disability, adjusting for age, gender, education and dementiaseverity. RESULTS Incontinence, hearing impairment, mobility impairment and undernutrition wereconsistently linearly associated with the presence of dementia and its severity across regions. Amongpeople with dementia, incontinence, hearing impairment and mobility impairment were independentlyassociated with disability in all regions while the contributions of pain, visual impairment andundernutrition were inconsistent. Only hearing impairment made a notable independent contribution tocognitive impairment. CONCLUSIONS There is an urgent need for clinical trials of the feasibility, efficacyand cost-effectiveness of regular physical health checks and remediation of identified pathologies, giventhe considerable comorbidity identified in our population based studies, and the strong evidence forindependent impact upon functioning.", "metadata": {}}
+{"_id": "21287352", "title": "", "text": "Serum biomarkers as predictors of lung function decline in chronic obstructive pulmonarydisease.BACKGROUND Recent studies show that COPD patients exhibit low-grade systemic inflammation,and that plasma fibrinogen and high neutrophil counts are related to faster declines in lung function. Weexamined correlations between serum biomarkers and the decline of lung function in COPD patients.METHOD Baseline levels of 9 serum biomarkers (TIMP-1, alpha1-antitrypsin, MMP-9, TNF-alpha,TGF-beta, IL-6, IL-8, neutrophil elastase and CRP), fibrinogen and white blood cell counts (WCC) weremeasured in 96 COPD patients. Lung function was measured at the time of blood sampling and every 3-6months during the observation period (median 25.0 months). RESULTS Twenty patients were rapiddecliners of lung function and 53 patients were non-decliners. Neutrophil counts, serum CRP and MMP-9were significantly higher in the rapid decliners (p<0.05). The annual change of % predicted FEV(1) wasinversely correlated with MMP-9 (r=-0.288; p<0.01) and CRP (r=-0.354; p<0.005) (partial correlationcoefficients adjusted for age, sex, cardiovascular disease, smoking history, and baseline % predictedFEV(1)). The remaining biomarkers were not correlated with the annual change of % predicted FEV(1).CONCLUSION Serum CRP and MMP-9 levels were related to FEV(1) decline. These markers are goodcandidates as predictors for rapid decline of FEV(1) in COPD patients. Additional long-term and larger sizestudies of COPD patients could help determine the exact roles for these biomarkers.", "metadata": {}}
+{"_id": "21295300", "title": "", "text": "Phosphorylation of ATM by Cdk5 mediates DNA damage signaling and regulates neuronal deathThephosphatidylinositol-3-kinase-like kinase ATM (ataxia-telangiectasia mutated) has a central role incoordinating DNA damage responses, including cell-cycle checkpoint control, DNA repair and apoptosis.Mutations of ATM cause a spectrum of defects ranging from neurodegeneration to cancer predisposition.However, the mechanism by which DNA damage activates ATM is poorly understood. Here we show thatCdk5 (cyclin-dependent kinase 5), activated by DNA damage, directly phosphorylates ATM at Ser 794 inpost-mitotic neurons. Phosphorylation at Ser 794 precedes, and is required for, ATM autophosphorylationat Ser 1981, and activates ATM kinase activity. The Cdk5-ATM signal regulates phosphorylation andfunction of the ATM targets p53 and H2AX. Interruption of the Cdk5-ATM pathway attenuatesDNA-damage-induced neuronal cell cycle re-entry and expression of the p53 targets PUMA and Bax,protecting neurons from death. Thus, activation of Cdk5 by DNA damage serves as a critical signal toinitiate the ATM response and regulate ATM-dependent cellular processes.", "metadata": {}}
+{"_id": "21297708", "title": "", "text": "Nerve-induced release of nitric oxide in the rabbit gastrointestinal tract as measured by in vivomicrodialysis.1. Nitric oxide (NO) has been suggested as a gastrointestinal neurotransmitter, mediatingthe gastric receptive relaxation and the relaxation in the peristaltic reflex. The aim of the present studywas to measure nerve-induced NO formation in vivo in the gastrointestinal tract. 2. Formation of thenitric oxide oxidation products nitrite and nitrate during vagal nerve stimulation were measured in theanaesthetized rabbit. Microdialysis probes were inserted into the wall of the stomach and proximal colon,and nitrite and nitrate in dialysate measured by capillary electrophoresis. 3. During bilateral vagal nervestimulation there was an increase in nitrite and nitrate formation at the level of the stomach and in nitriteformation at the level of the colon. This increase was inhibited by intravenous administration of the NOsynthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME 30 mg kg-1). Furthermore, L-NAMEsignificantly increased nerve-induced gastric and colonic contractions, as well as spontaneous coloniccontractions. 4. In summary, we present a new methodological procedure for quantification of smallchanges in nitric oxide formation in vivo. This study provides evidence that nitric oxide is released in thestomach and colonic wall during vagal nerve activity, at concentrations able to cause inhibition of smoothmuscle contractions in vivo.", "metadata": {}}
+{"_id": "21301090", "title": "", "text": "Screening for concomitant diseases in peripheral vascular patients. Results of a systematicapproach.BACKGROUND Patients considered for arterial surgery, have been shown to have a highincidence of coexistent cardiac, vascular and other diseases, affecting operative risk and survival. Wedeveloped a systematic workup strategy for detecting these coexistent diseases in our vascular surgicalpatients, mainly based on non-invasive diagnostic techniques. METHODS We evaluated 200 consecutivepatients, admitted to the department of vascular surgery in an academic teaching hospital, in order toestablish the total incidence of relevant concomitant disorders, the extent to which this screening yieldedpreviously unknown diagnostic information, and the impact on short-term (one year) survival. RESULTSCoronary artery disease was present in 46% of the patients; 22% had active ischaemia, newly diagnosedin 5.5%. Impaired cardiac function was found in 37%: severely impaired in 12%, newly diagnosed in27%. Carotid artery disease was present in 32%: critical stenoses were found in 9%; new diagnoses in29.9%. Aortic aneurysms were present in 7%, newly diagnosed in 5%. Severe renal artery stenosis waspresent in 5%, newly diagnosed in 3.5%. Sixteen % of the patients had chronic obstructive pulmonarydisease, newly diagnosed in 3.5%, and 4.5% had unexpected disorders, which were all new diagnoses.Overall, new diagnoses were reached in 64.5% of the population, affecting therapeutic strategyimmediately in 21% of the patients. The presence of coronary artery disease and of cardiac failure wereclearly related to one year survival. CONCLUSIONS We conclude that a systematic screening strategy,mainly based on noninvasive techniques, can detect the presence of concomitant diseases in the vascularsurgical patient. Most important seem the newly diagnosed diseases altering surgical management in oneout of every five patients; they also have important implications for patient prognosis.", "metadata": {}}
+{"_id": "21302115", "title": "", "text": "Archetypal trajectories of social, psychological, and spiritual wellbeing and distress in family care givers ofpatients with lung cancer: secondary analysis of serial qualitative interviewsOBJECTIVE To assess iffamily care givers of patients with lung cancer experience the patterns of social, psychological, andspiritual wellbeing and distress typical of the patient, from diagnosis to death. DESIGN Secondaryanalysis of serial qualitative interviews carried out every three months for up to a year or tobereavement. SETTING South east Scotland. PARTICIPANTS 19 patients with lung cancer and their 19family carers, totalling 88 interviews (42 with patients and 46 with carers). RESULTS Carers followedclear patterns of social, psychological, and spiritual wellbeing and distress that mirrored the experiencesof those for whom they were caring, with some carers also experiencing deterioration in physical healththat impacted on their ability to care. Psychological and spiritual distress were particularly dynamic andcommonly experienced. In addition to the \"Why us?\" response, witnessing suffering triggered personalreflections in carers on the meaning and purpose of life. Certain key time points in the illness tended tobe particularly problematic for both carers and patients: at diagnosis, at home after initial treatment, atrecurrence, and during the terminal stage. CONCLUSIONS Family carers witness and share much of theillness experience of the dying patient. The multidimensional experience of distress suffered by patientswith lung cancer was reflected in the suffering of their carers in the social, psychological, and spiritualdomains, with psychological and spiritual distress being most pronounced. Carers may need to besupported throughout the period of illness not just in the terminal phase and during bereavement, ascurrently tends to be the case.", "metadata": {}}
+{"_id": "21307488", "title": "", "text": "HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylationHER-2/neu amplificationor overexpression can make cancer cells resistant to apoptosis and promotes their growth. p53 is crucialin regulating cell growth and apoptosis, and is often mutated or deleted in many types of tumour.Moreover, many tumours with a wild-type gene for p53 do not have normal p53 function, suggesting thatsome oncogenic signals suppress the function of p53. In this study, we show that HER-2/neu-mediatedresistance to DNA-damaging agents requires the activation of Akt, which enhances MDM2-mediatedubiquitination and degradation of p53. Akt physically associates with MDM2 and phosphorylates it atSer166 and Ser186. Phosphorylation of MDM2 enhances its nuclear localization and its interaction withp300, and inhibits its interaction with p19ARF, thus increasing p53 degradation. Our study indicates thatblocking the Akt pathway mediated by HER-2/neu would increase the cytotoxic effect of DNA-damagingdrugs in tumour cells with wild-type p53.", "metadata": {}}
+{"_id": "21320417", "title": "", "text": "T cell memory.T cell memory induced by prior infection or vaccination provides enhanced protectionagainst subsequent microbial infections. The processes involved in generating and maintaining T cellmemory are becoming better understood due to recent technological advances in identifying memory Tcells and monitoring their behavior and function in vivo. Memory T cells develop in response to aprogressive set of cues-starting with signals from antigen-loaded, activated antigen-presenting cells(APCs) and inflammatory mediators induced by the innate immune response, to the poorly definedsubsequent signals triggered as the immune response wanes toward homeostasis. The persistence of theresting memory T cells that eventually develop is regulated by cytokines. This chapter discusses recentfindings on how memory T cells develop to confer long-term protective immunity.", "metadata": {}}
+{"_id": "21323587", "title": "", "text": "The impact of organisational change on outcome in an intensive care unit in the UnitedKingdomObjectives: To study the change in outcome for patients admitted to an intensive care unitfollowing the establishment of a team of resident medical staff and a change from an \"open\" to a \"closed\"organisational format. Design: Database review of prospectively collected data. Setting: Intensive careunit of a postgraduate teaching hospital. Subjects: 1134 admissions to the intensive care unit over a3-year period, of whom 476 (42%) followed elective surgery. Main outcome measure: Hospital mortalitycorrected for illness severity by using the APACHE II scoring system. Results: Crude hospital mortality fellfrom 28% before the changes to 20% afterwards (P=0.01). With correction for case-mix factors, theprobability of death after the changes was reduced by almost half (OR 0.51; CI 0.32, 0.82, P=0.005).Conclusion: A \"closed\" format of organisation of the delivery of care may result in improved outcomes forpatients admitted to intensive care units.", "metadata": {}}
+{"_id": "21323758", "title": "", "text": "Monitoring effectiveness and safety of Tafamidis in transthyretin amyloidosis in Italy: a longitudinalmulticenter study in a non-endemic areaTafamidis is a transthyretin (TTR) stabilizer able to prevent TTRtetramer dissociation. There have been a few encouraging studies on Tafamidis efficacy in early-onsetinherited transthyretin amyloidosis (ATTR) due to Val30Met mutation. However, less is known about itsefficacy in later disease stages and in non-Val30Met mutations. We performed a multi-centerobservational study on symptomatic ATTR patients prescribed to receive Tafamidis. We followed uppatients according to a standardized protocol including general medical, cardiological and neurologicalassessments at baseline and every 6 months up to 3 years. Sixty-one (42 males) patients were recruited.Only 28 % of enrolled subjects had the common Val30Met mutation, mean age of onset was remarkablylate (59 years) and 18 % was in advanced disease stage at study entry. Tafamidis proved safe andwell-tolerated. One-third of patients did not show significant progression along 36 months, independentlyfrom mutation type and disease stage. Neurological function worsened particularly in the first 6 monthsbut progression slowed significantly thereafter. Autonomic function remained stable in 33 %, worsened in56 % and improved in 10 %. Fifteen percent of patients showed cardiac disease progression and 30 %new onset of cardiomyopathy. Overall, Tafamidis was not able to prevent functional progression of thedisease in 23 (43 %) subjects, including 16 patients who worsened in their walking ability and 12 patientswho reached a higher NYHA score during the follow-up period. A higher mBMI at baseline was associatedwith better preservation of neurological function. In conclusion, neuropathy and cardiomyopathyprogressed in a significant proportion of patients despite treatment. However, worsening of neurologicalfunction slowed after the first 6 months and also subjects with more advanced neuropathy, as well aspatients with non-Val30Met mutation, benefited from treatment. Body weight preservation is animportant favorable prognostic factor.", "metadata": {}}
+{"_id": "21330280", "title": "", "text": "The Spliceosome: Design Principles of a Dynamic RNP MachineRibonucleoproteins (RNPs) mediate keycellular functions such as gene expression and its regulation. Whereas most RNP enzymes are stable incomposition and harbor preformed active sites, the spliceosome, which removes noncoding introns fromprecursor messenger RNAs (pre-mRNAs), follows fundamentally different strategies. In order to provideboth accuracy to the recognition of reactive splice sites in the pre-mRNA and flexibility to the choice ofsplice sites during alternative splicing, the spliceosome exhibits exceptional compositional and structuraldynamics that are exploited during substrate-dependent complex assembly, catalytic activation, andactive site remodeling.", "metadata": {}}
+{"_id": "21363424", "title": "", "text": "Blimp-1 attenuates Th1 differentiation by repression of ifng, tbx21, and bcl6 gene expression.Tcell-specific deletion of Blimp-1 causes abnormal T cell homeostasis and function, leading to spontaneous,fatal colitis in mice. Herein we explore the role of Blimp-1 in Th1/Th2 differentiation. Blimp-1 mRNA andprotein are more highly expressed in Th2 cells compared with Th1 cells, and Blimp-1 attenuatesIFN-gamma production in CD4 cells activated under nonpolarizing conditions. Although Blimp-1-deficientT cells differentiate normally to Th2 cytokines in vitro, Blimp-1 is required in vivo for normal Th2 humoralresponses to NP-KLH (4-hydroxy-3-nitrophenylacetyl/keyhole lymphocyte hemocyanin) immunization.Lack of Blimp-1 in CD4 T cells causes increased IFN-gamma, T-bet, and Bcl-6 mRNA. By chromatinimmunoprecipitation we show that Blimp-1 binds directly to a distal regulatory region in the ifng gene andat multiple sites in tbx21 and bcl6 genes. Our data provide evidence that Blimp-1 functions in Th2 cells toreinforce Th2 differentiation by repressing critical Th1 genes.", "metadata": {}}
+{"_id": "21366394", "title": "", "text": "CX3CR1 is required for airway inflammation by promoting T helper cell survival and maintenance ininflamed lungAllergic asthma is a T helper type 2 (T(H)2)-dominated disease of the lung. In people withasthma, a fraction of CD4(+) T cells express the CX3CL1 receptor, CX3CR1, and CX3CL1 expression isincreased in airway smooth muscle, lung endothelium and epithelium upon allergen challenge. Here wefound that untreated CX3CR1-deficient mice or wild-type (WT) mice treated with CX3CR1-blockingreagents show reduced lung disease upon allergen sensitization and challenge. Transfer of WT CD4(+) Tcells into CX3CR1-deficient mice restored the cardinal features of asthma, and CX3CR1-blocking reagentsprevented airway inflammation in CX3CR1-deficient recipients injected with WT T(H)2 cells. We foundthat CX3CR1 signaling promoted T(H)2 survival in the inflamed lungs, and injection of B cellleukemia/lymphoma-2 protein (BCl-2)-transduced CX3CR1-deficient T(H)2 cells into CX3CR1-deficientmice restored asthma. CX3CR1-induced survival was also observed for T(H)1 cells upon airwayinflammation but not under homeostatic conditions or upon peripheral inflammation. Therefore, CX3CR1and CX3CL1 may represent attractive therapeutic targets in asthma.", "metadata": {}}
+{"_id": "21369472", "title": "", "text": "TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal functionProgressivekidney failure is a genetically and clinically heterogeneous group of disorders. Podocyte foot processesand the interposed glomerular slit diaphragm are essential components of the permeability barrier in thekidney. Mutations in genes encoding structural proteins of the podocyte lead to the development ofproteinuria, resulting in progressive kidney failure and focal segmental glomerulosclerosis. Here, we showthat the canonical transient receptor potential 6 (TRPC6) ion channel is expressed in podocytes and is acomponent of the glomerular slit diaphragm. We identified five families with autosomal dominant focalsegmental glomerulosclerosis in which disease segregated with mutations in the gene TRPC6 onchromosome 11q. Two of the TRPC6 mutants had increased current amplitudes. These data show thatTRPC6 channel activity at the slit diaphragm is essential for proper regulation of podocyte structure andfunction.", "metadata": {}}
+{"_id": "21372171", "title": "", "text": "Usefulness of high mobility group box 1 protein as a plasma biomarker in patient with peripheral arterydisease.Atherosclerosis is often associated with chronic vascular inflammation. High-mobility group box 1protein (HMGB1) plays various roles, not only as a transcriptional regulatory factor in the nucleus, butalso as an inflammatory mediator. A previous study suggested that fibrinogen is an important factorassociated with atherosclerosis progression. The present study was performed to examine the levels ofplasma HMGB1 protein in atherosclerosis patients. We studied 24 patients with peripheral artery disease(PAD) with atherosclerosis, and 10 healthy controls. We found that the concentrations of HMGB1 wereincreased in the plasma of the patients with atherosclerosis, and there were significant correlationsbetween the plasma HMGB1 and fibrinogen levels. Plasma HMGB1 may play a key role in thepathogenesis of clinical and experimental atherosclerosis.", "metadata": {}}
+{"_id": "21373240", "title": "", "text": "Functional specialization of Piwi proteins in Paramecium tetraurelia from post-transcriptional genesilencing to genome remodellingProteins of the Argonaute family are small RNA carriers that guideregulatory complexes to their targets. The family comprises two major subclades. Members of the Agosubclade, which are present in most eukaryotic phyla, bind different classes of small RNAs and regulategene expression at both transcriptional and post-transcriptional levels. Piwi subclade members appear tohave been lost in plants and fungi and were mostly studied in metazoa, where they bind piRNAs and haveessential roles in sexual reproduction. Their presence in ciliates, unicellular organisms harbouring bothgermline micronuclei and somatic macronuclei, offers an interesting perspective on the evolution of theirfunctions. Here, we report phylogenetic and functional analyses of the 15 Piwi genes from Parameciumtetraurelia. We show that four constitutively expressed proteins are involved in siRNA pathways thatmediate gene silencing throughout the life cycle. Two other proteins, specifically expressed duringmeiosis, are required for accumulation of scnRNAs during sexual reproduction and for programmedgenome rearrangements during development of the somatic macronucleus. Our results indicate thatParamecium Piwi proteins have evolved to perform both vegetative and sexual functions throughmechanisms ranging from post-transcriptional mRNA cleavage to epigenetic regulation of genomerearrangements.", "metadata": {}}
+{"_id": "21373821", "title": "", "text": "A parasomnia overlap disorder involving sleepwalking, sleep terrors, and REM sleep behavior disorder in33 polysomnographically confirmed cases.A series of 33 patients with combined (injurious) sleepwalking,sleep terrors, and rapid eye movement (REM) sleep behavior disorder (viz. \"parasomnia overlapdisorder\") was gathered over an 8-year period. Patients underwent clinical and polysomnographicevaluations. Mean age was 34 +/- 14 (SD) years; mean age of parasomnia onset was 15 +/- 16 years(range 1-66); 70% (n = 23) were males. An idiopathic subgroup (n = 22) had a significantly earlier meanage of parasomnia onset (9 +/- 7 years) than a symptomatic subgroup (n = 11) (27 +/- 23 years, p =0.002), whose parasomnia began with either of the following: neurologic disorders, n = 6 [congenitalMobius syndrome, narcolepsy, multiple sclerosis, brain tumor (and treatment), brain trauma,indeterminate disorder (exaggerated startle response/atypical cataplexy)]; nocturnal paroxysmal atrialfibrillation, n = 1; posttraumatic stress disorder/major depression, n = 1; chronic ethanol/amphetamineabuse and withdrawal, n = 1; or mixed disorders (schizophrenia, brain trauma, substance abuse), n = 2.The rate of DSM-III-R (Diagnostic and Statistical Manual, 3rd edition, revised) Axis 1 psychiatric disorderswas not elevated; group scores on various psychometric tests were not elevated. Forty-five percent (n =15) had previously received psychologic or psychiatric therapy for their parasomnia, without benefit.Treatment outcome was available for n = 20 patients; 90% (n = 18) had substantial parasomnia controlwith bedtime clonazepam (n = 13), alprazolam and/or carbamazepine (n = 4), or self-hypnosis (n = 1).Thus, \"parasomnia overlap disorder\" is a treatable condition that emerges in various clinical settings andcan be understood within the context of current knowledge on parasomnias and motor control/dyscontrolduring sleep.", "metadata": {}}
+{"_id": "21377587", "title": "", "text": "How can health care organizations be reliably compared?: Lessons from a national survey of patientexperience.BACKGROUND Patient experience is increasingly used to assess organizational performance,for example in public reporting or pay-for-performance schemes. Conventional approaches using 95%confidence intervals are commonly used to determine required survey samples or to report performancebut these may result in unreliable organizational comparisons. METHODS We analyzed data from 2.2million patients who responded to the English 2009 General Practice Patient Survey, which included 45patient experience questions nested within 6 different care domains (access, continuity of care,communication, anticipatory care planning, out-of-hours care, and overall care satisfaction). For eachquestion, unadjusted and case-mix adjusted (for age, sex, and ethnicity) organization-level reliability,and intraclass correlation coefficients were calculated. RESULTS Mean responses per organization rangedfrom 23 to 256 for questions evaluating primary care practices, and from 1454 to 2758 for questionsevaluating out-of-hours care organizations. Adjusted and unadjusted reliability values were similar.Twenty-six questions had excellent reliability (≥0.90). Seven nurse communication questions had verygood reliability (≥0.85), but 3 anticipatory care planning questions had lower reliability (<0.70).Reliability was typically <0.70 for questions with <100 mean responses per practice, usually indicatingquestions which only a subset of patients were eligible to answer. Nine questions had both excellentreliability and high intraclass correlation coefficients (≥0.10) indicating both reliable measurement andsubstantial performance variability. CONCLUSIONS High reliability is a necessary property of indicatorsused to compare health care organizations. Using the English General Practice Patient Survey as a casestudy, we show how reliability and intraclass correlation coefficients can be used to select measures tosupport robust organizational comparisons, and to design surveys that will both provide high-qualitymeasurement and optimize survey costs.", "metadata": {}}
+{"_id": "21380232", "title": "", "text": "Conservation of methylation reprogramming in mammalian development: aberrant reprogramming incloned embryos.Mouse embryos undergo genome-wide methylation reprogramming by demethylation inearly preimplantation development, followed by remethylation thereafter. Here we show thatgenome-wide reprogramming is conserved in several mammalian species and ask whether it also occursin embryos cloned with the use of highly methylated somatic donor nuclei. Normal bovine, rat, and pigzygotes showed a demethylated paternal genome, suggesting active demethylation. In bovine embryosmethylation was further reduced during cleavage up to the eight-cell stage, and this reduction inmethylation was followed by de novo methylation by the 16-cell stage. In cloned one-cell embryos therewas a reduction in methylation consistent with active demethylation, but no further demethylationoccurred subsequently. Instead, de novo methylation and nuclear reorganization of methylation patternsresembling those of differentiated cells occurred precociously in many cloned embryos. Cloned, but notnormal, morulae had highly methylated nuclei in all blastomeres that resembled those of the fibroblastdonor cells. Our study shows that epigenetic reprogramming occurs aberrantly in most cloned embryos;incomplete reprogramming may contribute to the low efficiency of cloning.", "metadata": {}}
+{"_id": "21380348", "title": "", "text": "Intracellular transport of fat-soluble vitamins A and E.Vitamins are compounds that are essential for thenormal growth, reproduction and functioning of the human body. Of the 13 known vitamins, vitamins A,D, E and K are lipophilic compounds and are therefore called fat-soluble vitamins. Because of theirlipophilicity, fat-soluble vitamins are solubilized and transported by intracellular carrier proteins to exerttheir actions and to be metabolized properly. Vitamin A and its derivatives, collectively called retinoids,are solubilized by intracellular retinoid-binding proteins such as cellular retinol-binding protein (CRBP),cellular retinoic acid-binding protein (CRABP) and cellular retinal-binding protein (CRALBP). Theseproteins act as chaperones that regulate the metabolism, signaling and transport of retinoids.CRALBP-mediated intracellular retinoid transport is essential for vision in human. α-Tocopherol, the mainform of vitamin E found in the body, is transported by α-tocopherol transfer protein (α-TTP) in hepaticcells. Defects of α-TTP cause vitamin E deficiency and neurological disorders in humans. Recently, it hasbeen shown that the interaction of α-TTP with phosphoinositides plays a critical role in the intracellulartransport of α-tocopherol and is associated with familial vitamin E deficiency. In this review, wesummarize the mechanisms and biological significance of the intracellular transport of vitamins A and E.", "metadata": {}}
+{"_id": "21382907", "title": "", "text": "Reduced Cytokine Release in Ex Vivo Response to Cilengitide and Cetuximab Is a Marker for ImprovedSurvival of Head and Neck Cancer PatientsTargeting of αVβ3 and αVβ5 integrins by cilengitide mayreduce growth of solid tumors including head and neck squamous cell carcinoma (HNSCC). Preclinicalinvestigations suggest increased activity of cilengitide in combination with other treatment modalities.The only published trial in HNSCC (ADVANTAGE) investigated cisplatin, 5-fluorouracil, and cetuximab(PFE) without or with once (PFE+CIL1W) or twice weekly cilengitide (PFE+CIL2W) in recurrent/metastaticHNSCC. ADVANTAGE showed good tolerability of the cilengitide arms and even lower adverse events(AEs) compared to PFE but not the benefit in overall survival expected based on preclinical data. As wefound in the FLAVINO assay, a short-time ex vivo assay for prediction of chemosensitivity, only asubgroup of HNSCC had an increased suppressive effect of cilengitide containing combination therapieson colony formation of epithelial cells (CFec) and release of pro-angiogenetic and pro-inflammatorycytokines, whereas other HNSCC failed to respond. Response to αVβ3 and αVβ5 integrin targeting bycilengitide classifies HNSCC regarding outcome. We present FLAVINO data arguing for furtherdevelopment of cilengitide plus cetuximab in treatment of a subgroup of HNSCC potentially identified bythe FLAVINO assay using a set of biomarkers for response evaluation.", "metadata": {}}
+{"_id": "21383026", "title": "", "text": "Genes required for mycobacterial growth defined by high density mutagenesis.Despite over a century ofresearch, tuberculosis remains a leading cause of infectious death worldwide. Faced with increasing ratesof drug resistance, the identification of genes that are required for the growth of this organism shouldprovide new targets for the design of antimycobacterial agents. Here, we describe the use of transposonsite hybridization (TraSH) to comprehensively identify the genes required by the causative agent,Mycobacterium tuberculosis, for optimal growth. These genes include those that can be assigned toessential pathways as well as many of unknown function. The genes important for the growth of M.tuberculosis are largely conserved in the degenerate genome of the leprosy bacillus, Mycobacteriumleprae, indicating that non-essential functions have been selectively lost since this bacterium divergedfrom other mycobacteria. In contrast, a surprisingly high proportion of these genes lack identifiableorthologues in other bacteria, suggesting that the minimal gene set required for survival varies greatlybetween organisms with different evolutionary histories.", "metadata": {}}
+{"_id": "21387297", "title": "", "text": "Production of de novo cardiomyocytes: human pluripotent stem cell differentiation and directreprogramming.Cardiovascular disease is a leading cause of death worldwide. The limited capability ofheart tissue to regenerate has prompted methodological developments for creating de novocardiomyocytes, both in vitro and in vivo. Beyond uses in cell replacement therapy, patient-specificcardiomyocytes may find applications in drug testing, drug discovery, and disease modeling. Recently,approaches for generating cardiomyocytes have expanded to encompass three major sources of startingcells: human pluripotent stem cells (hPSCs), adult heart-derived cardiac progenitor cells (CPCs), andreprogrammed fibroblasts. We discuss state-of-the-art methods for generating de novo cardiomyocytesfrom hPSCs and reprogrammed fibroblasts, highlighting potential applications and future challenges.", "metadata": {}}
+{"_id": "21392223", "title": "", "text": "Within the hemopoietic system, LAR phosphatase is a T cell lineage-specific adhesion receptor-likeprotein whose phosphatase activity appears dispensable for T cell development, repertoire selection andfunction.Expression of the receptor-type tyrosine phosphatase LAR was studied in cells of the murinehemopoietic system. The gene is expressed in all cells of the T cell lineage but not in cells of any otherhemopoietic lineage and the level of expression in T cells is developmentally regulated. TheCD4(-)8(-)44(+) early thymic immigrants and mature (CD4(+)8(-)/CD4(-)8(+)) thymocytes and T cellsexpress low levels, whereas immature (CD4(-)8(-)44(-) and CD4(+)8(+)) thymocytes express high levelsof LAR. Among bone marrow cells only uncommitted c-kit(+)B220(+)CD19(-) precursors, but not B celllineage committed c-kit(+)B220(+)CD19(+) precursors, express low levels of LAR. In contrast to thec-kit(+)B220(+)CD19(+) pre-BI cells from normal mice, counterparts of pre-BI cells from PAX-5-deficientmice express LAR, indicating that PAX-5-mediated commitment to the B cell lineage results insuppression of LAR. During differentiation of PAX-5-deficient pre-BI cell line into non-T cell lineages,expression of LAR is switched off, but it is up-regulated during differentiation into thymocytes. Thus,within the hemopoietic system, LAR appears to be a T cell lineage-specific receptor-type phosphatase.However, surprisingly, truncation of its phosphatase domains has no obvious effect on T celldevelopment, repertoire selection or function.", "metadata": {}}
+{"_id": "21392703", "title": "", "text": "Competition and the evolution of reproductive restraint in malaria parasites.All organisms must trade offresource allocation between different life processes that determine their survival and reproduction.Malaria parasites replicate asexually in the host but must produce sexual stages to transmit betweenhosts. Because different specialized stages are required for these functions, the division of resourcesbetween these life-history components is a key problem for natural selection to solve. Despite themedical and economic importance of these parasites, their reproductive strategies remain poorlyunderstood and often seem counterintuitive. Here, we tested recent theory predicting that in-hostcompetition shapes how parasites trade off investment in in-host replication relative to between-hosttransmission. We demonstrate, across several genotypes, that Plasmodium chabaudi parasites detect thepresence of competing genotypes and facultatively respond by reducing their investment in sexual stagesin the manner predicted to maximize their competitive ability. Furthermore, we show that genotypesadjust their allocation to sexual stages in line with the availability of exploitable red blood cell resources.Our findings are predicted by evolutionary theory developed to explain life-history trade-offs in moretraditionally studied multicellular taxa and suggest that the answer to the long-standing question of whyso few transmission stages are produced is that in most natural infections heavy investment inreproduction may compromise in-host survival.", "metadata": {}}
+{"_id": "21395936", "title": "", "text": "[Neutrophils and macrophages related to the pathogenesis and disease development of chronicobstructive pulmonary disease by the inflammatory reaction].Chronic obstructive pulmonary disease(COPD) is a chronic airway disorder characterized by obstructive airflow limitation which is not completelyreversible with treatment. Inflammatory changes in the peripheral airways, especially those with thediameter less than 2mm (so-called small airway disease) have been speculated to be initial steps ofCOPD. And so it must be quite clear that neutrophils and macrophages play an essential role in thepathogenesis of these lesions. Studies with bronchoalveolar lavage demonstrated an increase inneutrophil numbers and the neutrophil chemoattractant interleukin-8. Recent studies demonstrated thatneutrophils and macrophages are increased and contain a variety of proteases, which are involved in cellinfiltration and activation. Studies with gene-engineered animals and anti-cytokine treatment willfacilitate better understanding the role of neutrophils and macrophages, and eventual novel therapy.", "metadata": {}}
+{"_id": "21414718", "title": "", "text": "Piezo1 Is as a Novel Trefoil Factor Family 1 Binding Protein that Promotes Gastric Cancer Cell Mobility InVitroTrefoil factor family 1 (TFF1) is a member of the TFF-domain peptide family involved in epithelialrestitution and cell motility. Recently, we screened Piezo1 as a candidate TFF1-binding protein. We aimedto confirm Piezo1 as a novel TFF1 binding protein and to assess the role of this interaction in mediatinggastric cancer cell mobility. This interaction was confirmed by co-immunoprecipitation and co-localisationof TFF1 and Piezo1 in GES-1 cells. We used stable RNA interference to knockdown Piezo1 proteinexpression and restored the expression of TFF1 in the gastric cancer cell lines SGC-7901 and BGC-823.Cell motility was evaluated using invasion assay and migration assay in vitro. The expression levels of theintegrin subunits β1, β5, α1 as well as the expression of β-catenin and E-cadherin were detected byWestern blot. We demonstrate that TFF1, but not TFF2 or TFF3, bind to and co-localize with Piezo1 in thecytoplasm in vitro. TFF1 interacts with the C-terminal portion of the Piezo1 protein. Wound healing andtrans-well assays demonstrated that the restored expression of TFF1 promoted cell mobility in gastriccancer cells, and this effect was attenuated by the knockdown of Piezo1. Western blots demonstrated thedecreased expression of integrin β1 in Piezo1-knockdown cells. Our data demonstrate that Piezo1 is anovel TFF1 binding protein that is important for TFF1-mediated cell migration and suggest that thisinteraction may be a therapeutic target in the invasion and metastasis of gastric cancer.", "metadata": {}}
+{"_id": "21425864", "title": "", "text": "A conditionally lethal yeast mutant blocked at the first step in glycosyl phosphatidylinositol anchorsynthesis.Glycosyl phosphatidylinositols (GPIs) anchor many proteins to the surface of eukaryotic cellsand may also serve as sorting signals on proteins and participate in signal transduction. We have isolateda Saccharomyces cerevisiae GPI anchoring mutant, gpi1, using a colony screen for cells blocked in[3H]inositol incorporation into protein. The gpi1 mutant is defective in vitro in the synthesis ofN-acetylglucosaminyl phosphatidylinositol, the first intermediate in GPI synthesis, and is alsotemperature-sensitive for growth. Completion of the first step in GPI assembly is therefore required forgrowth of the unicellular eukaryote S. cerevisiae. GPI synthesis could therefore be exploited as a targetfor antifungal or antiparasitic agents.", "metadata": {}}
+{"_id": "21439293", "title": "", "text": "Beyond pattern recognition: five immune checkpoints for scaling the microbial threatPattern recognitionby the innate immune system enables the detection of microorganisms, but how the level of microbialthreat is evaluated — a process that is crucial for eliciting measured antimicrobial responses with minimalinflammatory tissue damage — is less well understood. New evidence has shown that features ofmicrobial viability can be detected by the immune system and thereby induce robust responses that arenot warranted for dead microorganisms. Here, we propose five immune checkpoints that, as definedhere, collectively determine the gravity of microbial encounters.", "metadata": {}}
+{"_id": "21439640", "title": "", "text": "Macrophages induce COX-2 expression in breast cancer cells: role of IL-1βautoamplification.Tumor-associated macrophages and high levels of cyclooxygenase-2 (COX-2) areassociated with poor prognosis in breast cancer patients, but their potential interdependence has notbeen evaluated. The objective of this study was to determine whether macrophages regulate COX-2expression in breast cancer cells. For this purpose, THP-1 cells were cocultured with HCC1954 breastcancer cells. Coculture led to increased COX-2 expression in the HCC1954 cells and elevatedprostaglandin E(2) levels in conditioned media. Similar results were observed when THP-1 cells wereincubated with HCC1937 breast cancer cells or when human monocyte-derived macrophages werecocultured with HCC1954 cells. Coculture triggered production of reactive oxygen species (ROS) inHCC1954 cells. COX-2 induction was blocked in cells preincubated with an reduced nicotinamide adeninedinucleotide phosphate (NADPH) oxidase inhibitor or by silencing p67PHOX, a subunit of NADPH oxidase.ROS production triggered activation of Src and mitogen-activated protein kinases (MAPKs). Blocking Srcor MAPK activities or antagonizing the activator protein-1 (AP-1) transcription factor attenuated COX-2induction in HCC1954 cells. Coculture caused rapid induction of interleukin-1β (IL-1β) in both breastcancer cells and macrophages. Increased IL-1β expression was blocked by an interleukin-1 receptorantagonist (IL-1Ra), suggesting autocrine and paracrine effects. Importantly, macrophage-inducedCOX-2 expression was blocked in HCC1954 cells preincubated with IL-1Ra or anti-IL-1β IgG. Together,these results indicate that macrophage-mediated induction of COX-2 in breast cancer cells is aconsequence of IL-1β-mediated stimulation of ROS\u0000Src\u0000MAPK\u0000AP-1 signaling. IL-1β-dependentinduction of COX-2 in breast cancer cells provides a mechanism whereby macrophages contribute totumor progression and potential therapeutic targets in breast cancer.", "metadata": {}}
+{"_id": "21456232", "title": "", "text": "A graphene-based platform for induced pluripotent stem cells culture and differentiation.Inducedpluripotent stem cells (iPSCs) hold great promise as a cell source for regenerative medicine yet itsculture, maintenance of pluripotency and induction of differentiation remain challenging. Conversely,graphene (G) and graphene oxide (GO) have captured tremendous interests in the fields of materialsscience, physics, chemistry and nanotechnology. Here we report on that G and GO can support themouse iPSCs culture and allow for spontaneous differentiation. Intriguingly, G and GO surfaces led todistinct cell proliferation and differentiation characteristics. In comparison with the glass surface, iPSCscultured on the G surface exhibited similar degrees of cell adhesion and proliferation while iPSCs on theGO surface adhered and proliferated at a faster rate. Moreover, G favorably maintained the iPSCs in theundifferentiated state while GO expedited the differentiation. The iPSCs cultured on both G and GOsurfaces spontaneously differentiated into ectodermal and mesodermal lineages without significantdisparity, but G suppressed the iPSCs differentiation towards the endodermal lineage whereas GOaugmented the endodermal differentiation. These data collectively demonstrated that the differentsurface properties of G and GO governed the iPSCs behavior and implicate the potentials ofgraphene-based materials as a platform for iPSCs culture and diverse applications.", "metadata": {}}
+{"_id": "21459247", "title": "", "text": "Aerobic capacity in black adolescent girls.Our purpose was to determine the aerobic capacities (VO2max)of a group of black female adolescents (age = 11.4-15.8 years) randomly chosen from a single urbanschool. Of 91 girls selected, 64 performed an incremental treadmill running test to volitional exhaustionand achieved VO2max as determined from expired gas measures. Other measures included height (m),weight (kg), and calf and triceps skinfolds (for % fat estimates). Girls were also asked whether they hadachieved menarche. VO2max averaged 37.3 +/- 6.2 ml.kg-1 x min-1 and was significantly correlated(r[62]) with height (-.32, p < .01), body mass index (-.63, p < .001), and % fat (-.65, p < .001) but notwith age (-.16, p > .10). Postmenarchal girls were significantly taller and older than premenarchal girls.Contrary to previous studies, the girls' VO2max values were not related to biological age. Our subjects'aerobic capacity values averaged 14% less than those of nonblack U.S. female adolescents previouslyreported in the literature. This difference in VO2max was primarily a function of body weight. Studyimplications support the possibility that overweight in adult black women may originate prior to or duringearly adolescence. Future longitudinal studies should be designed to investigate the effects of aerobicfitness on cardiovascular risk factor reduction in black adolescent girls.", "metadata": {}}
+{"_id": "21465696", "title": "", "text": "Acetylation controls Notch3 stability and function in T-cell leukemiaPost-translational modifications ofNotch3 and their functional role with respect to Notch3 overexpression in T-cell leukemia are still poorlyunderstood. We identify here a specific novel property of Notch3 that is acetylated and deacetylated atlysines 1692 and 1731 by p300 and HDAC1, respectively, a balance impaired by HDAC inhibitors (HDACi)that favor hyperacetylation. By using HDACi and a non-acetylatable Notch3 mutant carryingK/R1692−1731 mutations in the intracellular domain, we show that Notch3 acetylation primesubiquitination and proteasomal-mediated degradation of the protein. As a consequence, Notch3 proteinexpression and its transcriptional activity are decreased both in vitro and in vivo in Notch3 transgenic (tg)mice, thus impairing downstream signaling upon target genes. Consistently, Notch3-induced T-cellproliferation is inhibited by HDACi, whereas it is enhanced by the non-acetylatableNotch3-K/R1692−1731 mutant. Finally, HDACi-induced Notch3 hyperacetylation prevents in vivo growthof T-cell leukemia/lymphoma in Notch3 tg mice. Together, our findings suggest a novel level of Notchsignaling control in which Notch3 acetylation/deacetylation process represents a key regulatory switch,thus representing a suitable druggable target for Notch3-sustained T-cell acute lymphoblastic leukemiatherapy.", "metadata": {}}
+{"_id": "21472388", "title": "", "text": "Hypoglycemia: incidence and clinical predictors in a large population-based sample of children andadolescents with IDDM.OBJECTIVE To determine the frequency of moderate and severe hypoglycemiaand to identify clinical predictors associated with its occurrence in a large population-based sample ofchildren and adolescents with IDDM. RESEARCH DESIGN AND METHODS A total of 657 patients (age:12.1 +/- 4.4 years, mean +/- SD) were included in the study, yielding 1,449 patient-years of data. Aprospective assessment of severe hypoglycemia (an event resulting in a seizure or coma) and moderatehypoglycemia (an event requiring assistance of another, excluding severe episodes) was made over a3-year period. Patients and caregivers detailed episodes of significant hypoglycemia (moderate andsevere events) and these were recorded at each 3-month clinic visit along with HbA1c. Data wereanalyzed using generalized estimating equation models fitted with the exchange correlation structure.RESULTS The overall incidence of severe events was 4.8/100 patient-years and of moderate events was13.1/100 patient-years. Over 3 years, severe events occurred in 8.5% of children and moderate eventsoccurred in 26.9%. Significant hypoglycemia was rare in the first 12 months after diagnosis. Rates ofhypoglycemia were increased in children < 6 years of age versus > 6 years of age (40.9 vs. 16.6/100patient-years, age < or = 6 years vs. age > 6 years, P < 0.001). Rates of hypoglycemia doubled whenHbA1c fell below 8%, and children with HbA1c < 7% had a threefold increase in both moderate andsevere hypoglycemia (e.g., severe episodes 14.9 vs. 4.1/100 patient-years, HbA1c < or = 7% vs. HbA1c> 7%, P < 0.001). Most severe events were seizures, and 75% of them occurred at night. The majorityof events were related to missed meals or increased activity. However, in 38% no predisposing factor wasevident. CONCLUSIONS Newly diagnosed children appear to be protected from severe hypoglycemia.Rates increase with lower glycated hemoglobin, especially when mean HbA1c is < 8.0%. Youngerchildren, who may be more susceptible to the adverse effects of neuroglycopenia, are at a particular riskof significant hypoglycemia.", "metadata": {}}
+{"_id": "21479231", "title": "", "text": "Efficacy of a 6-month versus 9-month intermittent treatment regimen in HIV-infected patients withtuberculosis: a randomized clinical trial.RATIONALE The outcome of fully intermittent thrice-weeklyantituberculosis treatment of various durations in HIV-associated tuberculosis is unclear. OBJECTIVES Tocompare the efficacy of an intermittent 6-month regimen (Reg6M: 2EHRZ(3)/4HR(3) [ethambutol, 1,200mg; isoniazid, 600 mg; rifampicin, 450 or 600 mg depending on body weight <60 or > or =60 kg; andpyrazinamide, 1,500 mg for 2 mo; followed by 4 mo of isoniazid and rifampicin at the same doses])versus a 9-month regimen (Reg9M: 2EHRZ(3)/7HR(3)) in HIV/tuberculosis (TB). METHODS HIV-infectedpatients with newly diagnosed pulmonary or extrapulmonary TB were randomly assigned to Reg6M (n =167) or Reg9M (n = 160) and monitored by determination of clinical, immunological, and bacteriologicalparameters for 36 months. Primary outcomes included favorable responses at the end of treatment andrecurrences during follow-up, whereas the secondary outcome was death. Intent-to-treat andon-treatment analyses were performed. All patients were antiretroviral treatment-naive duringtreatment. MEASUREMENTS AND MAIN RESULTS Of the patients, 70% had culture-positive pulmonaryTB; the median viral load was 155,000 copies/ml and the CD4(+) cell count was 160 cells/mm(3).Favorable response to antituberculosis treatment was similar by intent to treat (Reg6M, 83% and Reg9M,76%; P = not significant). Bacteriological recurrences occurred significantly more often in Reg6M than inReg9M (15 vs. 7%; P < 0.05) although overall recurrences were not significantly different (Reg6M, 19%vs. Reg9M, 13%). By 36 months, 36% of patients undergoing Reg6M and 35% undergoing Reg9M haddied, with no significant difference between regimens. All 19 patients who failed treatment developedacquired rifamycin resistance (ARR), the main risk factor being baseline isoniazid resistance.CONCLUSIONS Among antiretroviral treatment-naive HIV-infected patients with TB, a 9-month regimenresulted in a similar outcome at the end of treatment but a significantly lower bacteriological recurrencerate compared with a 6-month thrice-weekly regimen. ARR was high with these intermittent regimensand neither mortality nor ARR was altered by lengthening TB treatment. Clinical Trials RegistryInformation: ID# NCT00376012 registered at www.clinicaltrials.gov.", "metadata": {}}
+{"_id": "21479575", "title": "", "text": "High prevalence of evolutionarily conserved and species-specific genomic aberrations in mousepluripotent stem cells.Mouse pluripotent stem cells (PSCs) are the best studied pluripotent system andare regarded as the \"gold standard\" to which human PSCs are compared. However, while the genomicintegrity of human PSCs has recently drawn much attention, mouse PSCs have not been systematicallyevaluated in this regard. The genomic stability of PSCs is a matter of profound significance, as it affectstheir pluripotency, differentiation, and tumorigenicity. We thus performed a thorough analysis of thegenomic integrity of 325 samples of mouse PSCs, including 127 induced pluripotent stem cell (iPSC)samples. We found that genomic aberrations occur frequently in mouse embryonic stem cells of variousmouse strains, add in mouse iPSCs of various cell origins and derivation techniques. Four hotspots ofchromosomal aberrations were detected: full trisomy 11 (with a minimally recurrent gain in 11qE2), fulltrisomy 8, and deletions in chromosomes 10qB and 14qC-14qE. The most recurrent aberration in mousePSCs, gain 11qE2, turned out to be fully syntenic to the common aberration 17q25 in human PSCs, whileother recurrent aberrations were found to be species specific. Analysis of chromosomal aberrations in 74samples of rhesus macaque PSCs revealed a gain in chromosome 16q, syntenic to the hotspot in human17q. Importantly, these common aberrations jeopardize the interpretation of published comparisons ofPSCs, which were unintentionally conducted between normal and aberrant cells. Therefore, this workemphasizes the need to carefully monitor genomic integrity of PSCs from all species, for their proper usein biomedical research.", "metadata": {}}
+{"_id": "21487212", "title": "", "text": "Inhibition of cell proliferation and induction of apoptosis by ExFABP gene targeting.Ex-FABP, anextracellular fatty acid binding lipocalin, is physiologically expressed by differentiating chickenchondrocytes and myoblasts. Its expression is enhanced after cell treatment with inflammatory stimuliand repressed by anti-inflammatory agents, behaving as an acute phase protein. Chicken liver fragmentsin culture show enhanced protein expression after bacterial endotoxin treatment. To investigate thebiological role of Ex-FABP, we stably transfected proliferating chondrocytes with an expression vectorcarrying antisense oriented Ex-FABP cDNA. We observed a dramatic loss of cell viability and a stronginhibition of cell proliferation and differentiation. When chondrocytes were transfected with the antisenseoriented Ex-FABP cDNA we observed that Ex-FABP down-modulation increased apoptotic cell number.Myoblasts transfected with the same expression vector showed extensive cell death and impairedmyotube formation. We suggest that Ex-FABP acts as a constitutive survival protein and that itsexpression and activation are fundamental to protect chondrocytes from cell death.", "metadata": {}}
+{"_id": "21489324", "title": "", "text": "Profile of the Navrongo Health and Demographic Surveillance System.Located in the Kassena-Nankanadistricts of northern Ghana, the Navrongo health and demographic surveillance system (NHDSS) wasestablished in 1992 by the Navrongo health research centre (NHRC). The NHRC is one of three researchcentres of the Ghana health service. The activities and potential of the NHDSS for collaborative researchare described. The NHDSS monitors health and demographic dynamics of the two Kassena-Nankanadistricts of northern Ghana and facilitates evaluation of the morbidity and mortality impact of health andsocial interventions. The total population currently under surveillance is 152 000 residing in 32 000households. Events monitored routinely include pregnancies, births, morbidity, deaths, migration,marriages and vaccination coverage. Data updates are done every 4 months by trained fieldworkers. TheNHRC also undertakes biomedical and socio-economic studies. Additional features of the NHDSS includethe community key informant system where trained volunteers routinely report key events, such as birthsand deaths as they occur in their locality and the verbal autopsy (VA) system for determining theprobable causes of deaths that occur at the community level. Data from the NHDSS are shared withfunders and collaborators and partners in the INDEPTH Network. The Director of the NHDSS is the contactperson for potential collaboration with the NHDSS and the use of its data.", "metadata": {}}
+{"_id": "21495419", "title": "", "text": "The impact of COPD on lung health worldwide: epidemiology and incidence.Information on the prevalenceof COPD was obtained from vital statistics, health interview surveys, hospital charge records, nationalpublications, and the World Health Organization (WHO). These data indicate that COPD is a commondisease with implications for global health. In the United States, morbidity caused by COPD is 4%,making COPD the fourth leading cause of death, exceeded only by heart attacks, cancer, and stroke.Internationally, there is substantial variation in death rates possibly reflecting smoking behavior, typeand processing of tobacco, pollution, climate, respiratory management, and genetic factors. The GlobalObstructive Lung Disease Initiative, initiated by the National Heart, Lung, and Blood Institute and theWHO, aims to raise awareness of the increasing burden of COPD, decrease morbidity and mortality,promote further study of the condition, and implement programs to prevent COPD.", "metadata": {}}
+{"_id": "21498497", "title": "", "text": "TLR activation triggers the rapid differentiation of monocytes into macrophages and dendritic cellsLeprosyenables investigation of mechanisms by which the innate immune system contributes to host defenseagainst infection, because in one form, the disease progresses, and in the other, the infection is limited.We report that Toll-like receptor (TLR) activation of human monocytes induces rapid differentiation intotwo distinct subsets: DC-SIGN+ CD16+ macrophages and CD1b+ DC-SIGN− dendritic cells. DC-SIGN+phagocytic macrophages were expanded by TLR-mediated upregulation of interleukin (IL)-15 and IL-15receptor. CD1b+ dendritic cells were expanded by TLR-mediated upregulation ofgranulocyte-macrophage colony-stimulating factor (GM-CSF) and its receptor, promoted T cell activationand secreted proinflammatory cytokines. Whereas DC-SIGN+ macrophages were detected in lesions andafter TLR activation in all leprosy patients, CD1b+ dendritic cells were not detected in lesions or after TLRactivation of peripheral monocytes in individuals with the progressive lepromatous form, except duringreversal reactions in which bacilli were cleared by T helper type 1 (TH1) responses. In tuberculoidlepromatous lesions, DC-SIGN+ cells were positive for macrophage markers, but negative for dendriticcell markers. Thus, TLR-induced differentiation of monocytes into either macrophages or dendritic cellsseems to crucially influence effective host defenses in human infectious disease.", "metadata": {}}
+{"_id": "21502234", "title": "", "text": "Mismatch repair status and clinical outcome in endometrial cancer: a systematic review andmeta-analysis.BACKGROUND The association between the deficiency in mismatch repair (MMR) genesand prognosis in women with endometrial cancer is unclear. Here we report a systematic review andmeta-analysis exploring this association. METHODS We searched literature databases (MEDLINE,EMBASE, and Cochrane) from 1980 until December 2011 to identify studies evaluating the associationbetween MMR status and clinical outcome in endometrial cancer. The main outcome measures wereoverall survival (OS) and disease-free survival (DFS). RESULTS Twenty-three studies met the inclusioncriteria. The median sample size of studies was 112, 74% were retrospective case-series and 70%performed microsatellite instability (MSI) analysis to evaluate the status of MMR. Only 22% of studiesused the panel of five microsatellite markers recommended by the National Cancer Institute. Sevenstudies used immunohistochemistry to define MMR deficiency, but only two of them determined theexpression of all four MMR proteins. Overall, significant associations between MMR and outcome wereobserved in 32% of studies. There was marked inter-study heterogeneity for estimates of OS and DFS.Pooled analysis did not show any significant association between deficiency in MMR and worse OS (6studies, hazard ratio [HR] 2.0, p=0.11) or DFS (4 studies, HR ratio 1.31, p=0.66). CONCLUSION There isno definitive evidence of a significant association between MMR status and detrimental survival inendometrial cancer.", "metadata": {}}
+{"_id": "21521236", "title": "", "text": "p53 induces formation of NEAT1 lncRNA-containing paraspeckles that modulate replication stressresponse and chemosensitivityIn a search for mediators of the p53 tumor suppressor pathway, whichinduces pleiotropic and often antagonistic cellular responses, we identified the long noncoding RNA(lncRNA) NEAT1. NEAT1 is an essential architectural component of paraspeckle nuclear bodies, whosepathophysiological relevance remains unclear. Activation of p53, pharmacologically or byoncogene-induced replication stress, stimulated the formation of paraspeckles in mouse and human cells.Silencing Neat1 expression in mice, which prevents paraspeckle formation, sensitized preneoplastic cellsto DNA-damage-induced cell death and impaired skin tumorigenesis. We provide mechanistic evidencethat NEAT1 promotes ATR signaling in response to replication stress and is thereby engaged in a negativefeedback loop that attenuates oncogene-dependent activation of p53. NEAT1 targeting in establishedhuman cancer cell lines induced synthetic lethality with genotoxic chemotherapeutics, including PARPinhibitors, and nongenotoxic activation of p53. This study establishes a key genetic link between NEAT1paraspeckles, p53 biology and tumorigenesis and identifies NEAT1 as a promising target to enhancesensitivity of cancer cells to both chemotherapy and p53 reactivation therapy.", "metadata": {}}
+{"_id": "21535641", "title": "", "text": "Regulation of innate immunity by NADPH oxidase.NADPH oxidase is a critical regulator of bothantimicrobial host defense and inflammation. Activated in nature by microbes and microbial-derivedproducts, the phagocyte NADPH oxidase is rapidly assembled, and generates reactive oxidantintermediates (ROIs) in response to infectious threat. Chronic granulomatous disease (CGD) is aninherited disorder of the NADPH oxidase characterized by recurrent and severe bacterial and fungalinfections, and pathology related to excessive inflammation. Studies in CGD patients and CGD mousemodels indicate that NADPH oxidase plays a key role in modulating inflammation and injury that isdistinct from its antimicrobial function. The mechanisms by which NADPH oxidase mediates killing ofpathogens and regulation of inflammation have broad relevance to our understanding of normalphysiological immune responses and pathological states, such as acute lung injury and bacterial or fungalinfections.", "metadata": {}}
+{"_id": "21547032", "title": "", "text": "Protection from olanzapine-induced metabolic toxicity in mice by acetaminophen andtetrahydroindenoindoleObjective:In mice and in humans, treatment with the second-generationantipsychotic drug olanzapine (OLZ) produces excessive weight gain, adiposity and secondary metaboliccomplications, including loss of glucose and insulin homeostasis. In mice consuming a high-fat (HF) diet,a similar phenotype develops, which is inhibited by the analgesic acetaminophen (APAP) and by theantioxidant tetrahydroindenoindole (THII). Therefore, we examined the ability of APAP and THII toprevent metabolic changes in mice receiving OLZ.Design and Measurement:C57BL/6J mice receivedeither a normal diet or a HF diet, and were administered daily dosages of OLZ (3 mg kg−1 body weight),alone or with APAP (30 mg kg−1 body weight) or THII (4.5 mg kg−1 body weight), for 10 weeks.Parameters of body composition and metabolism, including glucose and insulin homeostasis and oxidativestress, were examined. Results:OLZ treatment doubled the HF diet-induced increases in body weight andpercent body fat. These increases were partially prevented by both APAP and THII, although foodconsumption was constant in all groups. The THII protection was associated with an increase in wholebody and mitochondrial respiration. OLZ also exacerbated, and both APAP and THII prevented, HFdiet-induced loss of glucose tolerance and insulin resistance. As increased body fat promotes insulinresistance by a pathway involving oxidative stress, we evaluated production of reactive oxygen and lipidperoxidation in white adipose tissue (WAT). HF diet caused an increase in lipid peroxidation,NADPH-dependent O2 uptake and H2O2 production, which were further exacerbated by OLZ. APAP, THIIand the NADPH oxidase inhibitor, diphenyleneiodonium chloride, each abolished oxidative stress inWAT.Conclusions:We conclude that both APAP and THII intervene in the development of obesity andmetabolic complications associated with OLZ treatment.", "metadata": {}}
+{"_id": "21550246", "title": "", "text": "Detection of prions in bloodPrion diseases are caused by an unconventional infectious agent termed prion,composed mainly of the misfolded prion protein (PrPSc). The development of highly sensitive assays forbiochemical detection of PrPSc in blood is a top priority for minimizing the spread of the disease. Here weshow that the protein misfolding cyclic amplification (PMCA) technology can be automated and optimizedfor high-efficiency amplification of PrPSc. We show that 140 PMCA cycles leads to a 6,600-fold increase insensitivity over standard detection methods. Two successive rounds of PMCA cycles resulted in a 10million–fold increase in sensitivity and a capability to detect as little as 8,000 equivalent molecules ofPrPSc. Notably, serial PMCA enables detection of PrPSc in blood samples of scrapie-afflicted hamsterswith 89% sensitivity and 100% specificity. These findings represent the first time that PrPSc has beendetected biochemically in blood, offering promise for developing a noninvasive method for early diagnosisof prion diseases.", "metadata": {}}
+{"_id": "21551568", "title": "", "text": "Genetic alterations and their relationship in the phosphatidylinositol 3-kinase/Akt pathway in thyroidcancer.PURPOSE To investigate the overall occurrence and relationship of genetic alterations in thephosphatidylinositol 3-kinase (PI3K)/Akt pathway in thyroid tumors and explore the scope of thispathway as a therapeutic target for thyroid cancer. EXPERIMENTAL DESIGN We examined collectively themajor genetic alterations and their relationship in this pathway, including PIK3CA copy number gain andmutation, Ras mutation, and PTEN mutation, in a large series of primary thyroid tumors. RESULTSOccurrence of any of these genetic alterations was found in 25 of 81 (31%) benign thyroid adenoma(BTA), 47 of 86 (55%) follicular thyroid cancer (FTC), 21 of 86 (24%) papillary thyroid cancer (PTC), and29 of 50 (58%) anaplastic thyroid cancer (ATC), with FTC and ATC most frequently harboring thesegenetic alterations. PIK3CA copy gain was associated with increased PIK3CA protein expression. A mutualexclusivity among these genetic alterations was seen in BTA, FTC, and PTC, suggesting an independentrole of each of them through the PI3K/Akt pathway in the tumorigenesis of the differentiated thyroidtumors. However, coexistence of these genetic alterations was increasingly seen with progression fromdifferentiated tumor to undifferentiated ATC. Their coexistence with BRAF mutation was also frequent inPTC and ATC. CONCLUSIONS The data provide strong genetic implication that aberrant activation ofPI3K/Akt pathway plays an extensive role in thyroid tumorigenesis, particularly in FTC and ATC, andpromotes progression of BTA to FTC and to ATC as the genetic alterations of this pathway accumulate.Progression of PTC to ATC may be facilitated by coexistence of PI3K/Akt pathway-related geneticalterations and BRAF mutation. The PI3K/Akt pathway may thus be a major therapeutic target in thyroidcancers.", "metadata": {}}
+{"_id": "21553394", "title": "", "text": "Vitamin D and obesity: current perspectives and future directions.In recent years, new functional roles ofvitamin D beyond its traditional role in calcium homoeostasis and bone metabolism have emerged linkingthe fat-soluble vitamin to various non-communicable diseases. Vitamin D deficiency (25-hydroxyvitaminD (25(OH)D) < 25-30 nmol/l) and sub-optimal status (25(OH)D < 50-100 nmol/l) are increasinglyassociated with unfavourable metabolic phenotypes, including insulin resistance, type 2 diabetes andCVD; conditions also commonly linked with overweight and obesity. Early studies reported poor vitamin Dstatus in the morbidly obese. More recently, it has been observed that a graded relationship betweenvitamin D status and BMI, or specifically adiposity, exists in the general population. A number ofhypotheses have been proposed to explain the potential mechanisms whereby alterations in the vitaminD endocrine system occur in the obese state. Plausible explanations include sequestration in adiposetissue, volumetric dilution or negative feedback mechanisms from increased circulating1,25-dihydroxyvitamin D3. Others hypothesise that heavier individuals may partake in less outdooractivity, may also cover-up and wear more clothing than leaner individuals, thus decreasing sun exposureand limiting endogenous production of cholecalciferol in the skin. Moreover, in some but not all studies,BMI and adiposity have been negatively associated with the change in vitamin D status following vitaminD supplementation. It therefore remains unclear if body size and/or adiposity should be taken intoaccount when determining the dietary requirements for vitamin D. This review will evaluate the currentevidence linking vitamin D status and supplementation to overweight and obesity, and discuss theimplications for setting dietary requirements.", "metadata": {}}
+{"_id": "21557055", "title": "", "text": "Transcriptional regulation by p53 through intrinsic DNA/chromatin binding and site-directed cofactorrecruitment.The tumor suppressor protein, p53, plays a critical role in mediating cellular response tostress signals by regulating genes involved in cell cycle arrest and apoptosis. p53 is believed to beinactive for DNA binding unless its C terminus is modified or structurally altered. We show thatunmodified p53 actively binds to two sites at -1.4 and -2.3 kb within the chromatin-assembled p21promoter and requires the C terminus and the histone acetyltransferase, p300, for transcription.Acetylation of the C terminus by p300 is not necessary for binding or promoter activation. Instead, p300acetylates p53-bound nucleosomes in the p21 promoter with spreading to the TATA box. Thus, p53 is anactive DNA and chromatin binding protein that may selectively regulate its target genes by recruitment ofspecific cofactors to structurally distinct binding sites.", "metadata": {}}
+{"_id": "21557614", "title": "", "text": "Pleiotropic effects of statins.Statins are potent inhibitors of cholesterol biosynthesis. In clinical trials,statins are beneficial in the primary and secondary prevention of coronary heart disease. However, theoverall benefits observed with statins appear to be greater than what might be expected from changes inlipid levels alone, suggesting effects beyond cholesterol lowering. Indeed, recent studies indicate thatsome of the cholesterol-independent or \"pleiotropic\" effects of statins involve improving endothelialfunction, enhancing the stability of atherosclerotic plaques, decreasing oxidative stress and inflammation,and inhibiting the thrombogenic response. Furthermore, statins have beneficial extrahepatic effects onthe immune system, CNS, and bone. Many of these pleiotropic effects are mediated by inhibition ofisoprenoids, which serve as lipid attachments for intracellular signaling molecules. In particular, inhibitionof small GTP-binding proteins, Rho, Ras, and Rac, whose proper membrane localization and function aredependent on isoprenylation, may play an important role in mediating the pleiotropic effects of statins.", "metadata": {}}
+{"_id": "21561474", "title": "", "text": "Increasing the efficiency of precise genome editing with CRISPR-Cas9 by inhibition of nonhomologous endjoiningMethods to introduce targeted double-strand breaks (DSBs) into DNA enable precise genomeediting by increasing the rate at which externally supplied DNA fragments are incorporated into thegenome through homologous recombination. The efficiency of these methods is limited bynonhomologous end joining (NHEJ), an alternative DNA repair pathway that competes withhomology-directed repair (HDR). To promote HDR at the expense of NHEJ, we targeted DNA ligase IV, akey enzyme in the NHEJ pathway, using the inhibitor Scr7. Scr7 treatment increased the efficiency ofHDR-mediated genome editing, using Cas9 in mammalian cell lines and in mice for all four genesexamined, up to 19-fold. This approach should be applicable to other customizable endonucleases, suchas zinc finger nucleases and transcription activator–like effector nucleases, and to nonmammalian cellswith sufficiently conserved mechanisms of NHEJ and HDR.", "metadata": {}}
+{"_id": "21562657", "title": "", "text": "Molecular mechanism of BST2/tetherin downregulation by K5/MIR2 of Kaposi's sarcoma-associatedherpesvirus.K3/MIR1 and K5/MIR2 of Kaposi's sarcoma-associated herpesvirus (KSHV) are viral membersof the membrane-associated RING-CH (MARCH) ubiquitin ligase family and contribute to viral immuneevasion by directing the conjugation of ubiquitin to immunostimulatory transmembrane proteins. In aquantitative proteomic screen for novel host cell proteins downregulated by viral immunomodulators, wepreviously observed that K5, as well as the human immunodeficiency virus type 1 (HIV-1)immunomodulator VPU, reduced steady-state levels of bone marrow stromal cell antigen 2 (BST2; alsocalled CD317 or tetherin), suggesting that BST2 might be a novel substrate of K5 and VPU. Recent workrevealed that in the absence of VPU, HIV-1 virions are tethered to the plasma membrane inBST2-expressing HeLa cells. By targeting BST2, K5 might thus similarly overcome an innate antiviral hostdefense mechanism. Here we establish that despite its type II transmembrane topology andcarboxy-terminal glycosylphosphatidylinositol (GPI) anchor, BST2 represents a bona fide target of K5 thatis downregulated during primary infection by and reactivation of KSHV. Upon exit of the protein from theendoplasmic reticulum, lysines in the short amino-terminal domain of BST2 are ubiquitinated by K5,resulting in rapid degradation of BST2. Ubiquitination of BST2 is required for degradation, since BST2lacking cytosolic lysines was K5 resistant and ubiquitin depletion by proteasome inhibitors restored BST2surface expression. Thus, BST2 represents the first type II transmembrane protein targeted by K5 andthe first example of a protein that is both ubiquitinated and GPI linked. We further demonstrate thatKSHV release is decreased in the absence of K5 in a BST2-dependent manner, suggesting that K5contributes to the evasion of intracellular antiviral defense programs.", "metadata": {}}
+{"_id": "21564598", "title": "", "text": "Regulation of beta catenin signaling and parathyroid hormone anabolic effects in bone by thematricellular protein periostin.Periostin (Postn) is a matricellular protein preferentially expressed byosteocytes and periosteal osteoblasts in response to mechanical stimulation and parathyroid hormone(PTH). Whether and how periostin expression influences bone anabolism, however, remains unknown. Weinvestigated the skeletal response of adult Postn(-/-) and Postn(+/+) mice to intermittent PTH.Compared with Postn(+/+), Postn(-/-) mice had a lower bone mass, cortical bone volume, and strengthresponse to PTH. PTH-stimulated bone-forming indices were all significantly lower in Postn(-/-) mice,particularly at the periosteum. Furthermore, in vivo stimulation of Wnt-β-catenin signaling by PTH, asevaluated in TOPGAL reporter mice, was inhibited in the absence of periostin (TOPGAL;Postn(-/-) mice).PTH stimulated periostin and inhibited MEF2C and sclerostin (Sost) expression in bone and osteoblasts invitro. Recombinant periostin also suppressed Sost expression, which was mediated through the integrinαVβ3 receptor, whereas periostin-blocking antibody prevented inhibition of MEF2C and Sost by PTH. Inturn, administration of a Sost-blocking antiboby partially restored the PTH-mediated increase in bonemass in Postn(-/-) mice. In addition, primary osteoblasts from Postn(-/-) mice showed a lowerproliferation, mineralization, and migration, both spontaneously and in response to PTH. Osteoblasticgene expression levels confirmed a defect of Postn(-/-) osteoblast differentiation with and without PTH,as well as an increased osteoblast apoptosis in the absence of periostin. These data elucidate the complexrole of periostin on bone anabolism, through the regulation of Sost, Wnt-β-catenin signaling, andosteoblast differentiation.", "metadata": {}}
+{"_id": "21571708", "title": "", "text": "Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascularmortality.CONTEXT Circulating concentration of lipoprotein(a) (Lp[a]), a large glycoprotein attached to alow-density lipoprotein-like particle, may be associated with risk of coronary heart disease (CHD) andstroke. OBJECTIVE To assess the relationship of Lp(a) concentration with risk of major vascular andnonvascular outcomes. STUDY SELECTION Long-term prospective studies that recorded Lp(a)concentration and subsequent major vascular morbidity and/or cause-specific mortality publishedbetween January 1970 and March 2009 were identified through electronic searches of MEDLINE and otherdatabases, manual searches of reference lists, and discussion with collaborators. DATA EXTRACTIONIndividual records were provided for each of 126,634 participants in 36 prospective studies. During 1.3million person-years of follow-up, 22,076 first-ever fatal or nonfatal vascular disease outcomes ornonvascular deaths were recorded, including 9336 CHD outcomes, 1903 ischemic strokes, 338hemorrhagic strokes, 751 unclassified strokes, 1091 other vascular deaths, 8114 nonvascular deaths,and 242 deaths of unknown cause. Within-study regression analyses were adjusted for within-personvariation and combined using meta-analysis. Analyses excluded participants with known preexisting CHDor stroke at baseline. DATA SYNTHESIS Lipoprotein(a) concentration was weakly correlated with severalconventional vascular risk factors and it was highly consistent within individuals over several years.Associations of Lp(a) with CHD risk were broadly continuous in shape. In the 24 cohort studies, the ratesof CHD in the top and bottom thirds of baseline Lp(a) distributions, respectively, were 5.6 (95%confidence interval [CI], 5.4-5.9) per 1000 person-years and 4.4 (95% CI, 4.2-4.6) per 1000person-years. The risk ratio for CHD, adjusted for age and sex only, was 1.16 (95% CI, 1.11-1.22) per3.5-fold higher usual Lp(a) concentration (ie, per 1 SD), and it was 1.13 (95% CI, 1.09-1.18) followingfurther adjustment for lipids and other conventional risk factors. The corresponding adjusted risk ratioswere 1.10 (95% CI, 1.02-1.18) for ischemic stroke, 1.01 (95% CI, 0.98-1.05) for the aggregate ofnonvascular mortality, 1.00 (95% CI, 0.97-1.04) for cancer deaths, and 1.00 (95% CI, 0.95-1.06) fornonvascular deaths other than cancer. CONCLUSION Under a wide range of circumstances, there arecontinuous, independent, and modest associations of Lp(a) concentration with risk of CHD and strokethat appear exclusive to vascular outcomes.", "metadata": {}}
+{"_id": "21578627", "title": "", "text": "The biphasic behavior of incoherent feed-forward loops in biomolecular regulatory networks.Anincoherent feed-forward loop (FFL) is one of the most-frequently observed motifs in biomolecularregulatory networks. It has been thought that the incoherent FFL is designed simply to induce a transientresponse shaped by a 'fast activation and delayed inhibition'. We find that the dynamics of variousincoherent FFLs can be further classified into two types: time-dependent biphasic responses anddose-dependent biphasic responses. Why do the structurally identical incoherent FFLs play such differentdynamical roles? Through computational studies, we show that the dynamics of the two types ofincoherent FFLs are mutually exclusive. Following from further computational results and experimentalobservations, we hypothesize that incoherent FFLs have been optimally designed to achieve distinctbiological function arising from different cellular contexts. Additional Supporting Information may befound in the online version of the article.", "metadata": {}}
+{"_id": "21590125", "title": "", "text": "Antipsychotic prescribing patterns in Germany: a retrospective analysis using a large outpatientprescription database.Data of prescribing practices for antipsychotics are of great interest with respect toquality of care. Consequently, we analysed all prescriptions under the statutory health insuranceredeemed at pharmacies in Southern Germany between July 1999 and December 2001. The databasecovers prescriptions for approximately 25 million people. Up to 6% of the population were prescribed anantipsychotic at least once during the study period. Most prescriptions were for conventionalantipsychotics and written by non-specialists. Patients receiving second generation antipsychotics weremore likely to receive continuous antipsychotic therapy. For a large proportion of patients, antipsychoticpolypharmacy, as well as comedication for somatic illnesses, were observed. In particular, drugs for thetreatment of cardiovascular and metabolic disorders were frequently co-prescribed. Physicians shouldconsider patients' cardiovascular and metabolic risk profile when making treatment choices. The datasuggest that the majority of antipsychotics are used for the treatment of disorders other thanschizophrenia. It is important to raise awareness among non-specialists about the indications, efficacyand side-effects of the antipsychotics because these physicians account for the majority of antipsychoticprescriptions.", "metadata": {}}
+{"_id": "21598000", "title": "", "text": "Structural basis for the activation of microtubule assembly by the EB1 and p150Glued complex.Plus-endtracking proteins, such as EB1 and the dynein/dynactin complex, regulate microtubule dynamics. Theseproteins are thought to stabilize microtubules by forming a plus-end complex at microtubule growingends with ill-defined mechanisms. Here we report the crystal structure of two plus-end complexcomponents, the carboxy-terminal dimerization domain of EB1 and the microtubule binding (CAP-Gly)domain of the dynactin subunit p150Glued. Each molecule of the EB1 dimer contains two helices forminga conserved four-helix bundle, while also providing p150Glued binding sites in its flexible tail region.Combining crystallography, NMR, and mutational analyses, our studies reveal the critical interactingelements of both EB1 and p150Glued, whose mutation alters microtubule polymerization activity.Moreover, removal of the key flexible tail from EB1 activates microtubule assembly by EB1 alone,suggesting that the flexible tail negatively regulates EB1 activity. We, therefore, propose that EB1possesses an auto-inhibited conformation, which is relieved by p150Glued as an allosteric activator.", "metadata": {}}
+{"_id": "21601459", "title": "", "text": "Epigenetic regulation of NANOG by miR-302 cluster-MBD2 completes induced pluripotent stem cellreprogramming.While most somatic cells undergoing induced pluripotent stem (iPS) cell reprogrammingwith Yamanaka factors accumulate at stable partially reprogrammed stages, the molecular mechanismsrequired to achieve full reprogramming are unknown. MicroRNAs (miRNAs) fine-tune mRNA translationand are implicated in reprogramming, but miRNA functional targets critical for complete iPS cellreprogramming remain elusive. We identified methyl-DNA binding domain protein 2 (MBD2) as anepigenetic suppressor, blocking full reprogramming of somatic to iPS cells through direct binding toNANOG promoter elements preventing transcriptional activation. When we overexpressed miR-302cluster we observed a significant increase in conversion of partial to fully reprogrammed iPS cells bysuppressing MBD2 expression, thereby increasing NANOG expression. Thus, expression of exogenousmiR-302 cluster (without miR-367) is efficient in attaining a fully reprogrammed iPS state in partiallyreprogrammed cells by relieving MBD2-mediated inhibition of NANOG expression. Our studies provide adirect molecular mechanism involved in generating complete human iPS cell reprogramming to studydisease pathogenesis, drug screening, and for potential cell-based therapies.", "metadata": {}}
+{"_id": "21602220", "title": "", "text": "Complex physiology and compound stress responses during fermentation of alkali-pretreated corn stoverhydrolysate by an Escherichia coli ethanologen.The physiology of ethanologenic Escherichia coli grownanaerobically in alkali-pretreated plant hydrolysates is complex and not well studied. To gain insight intohow E. coli responds to such hydrolysates, we studied an E. coli K-12 ethanologen fermenting ahydrolysate prepared from corn stover pretreated by ammonia fiber expansion. Despite the high sugarcontent (\u00006% glucose, 3% xylose) and relatively low toxicity of this hydrolysate, E. coli ceased growthlong before glucose was depleted. Nevertheless, the cells remained metabolically active and continuedconversion of glucose to ethanol until all glucose was consumed. Gene expression profiling revealedcomplex and changing patterns of metabolic physiology and cellular stress responses during anexponential growth phase, a transition phase, and the glycolytically active stationary phase. During theexponential and transition phases, high cell maintenance and stress response costs were mitigated, inpart, by free amino acids available in the hydrolysate. However, after the majority of amino acids weredepleted, the cells entered stationary phase, and ATP derived from glucose fermentation was consumedentirely by the demands of cell maintenance in the hydrolysate. Comparative gene expression profilingand metabolic modeling of the ethanologen suggested that the high energetic cost of mitigating osmotic,lignotoxin, and ethanol stress collectively limits growth, sugar utilization rates, and ethanol yields inalkali-pretreated lignocellulosic hydrolysates.", "metadata": {}}
+{"_id": "21616324", "title": "", "text": "Systemic arterial hypertension in children following renal transplantation: prevalence and riskfactors.BACKGROUND Control of blood pressure (BP) following renal transplantation may improveallograft and patient survival. Our aims were (i) to describe the distribution of BP and the prevalence ofsystolic and/or diastolic hypertension in children over the first 5 years following renal transplantation and(ii) to evaluate clinical risk factors and centre-specific factors associated with hypertension in thispopulation. METHODS We conducted a retrospective case note review of all current paediatric kidneytransplant patients in the UK, with data collected at 6 months, 1, 2 and 5 years following transplantationin subjects with hypertension (systolic and/or diastolic BP > 95th > ) and non-hypertensive subjects BP ≤95th > . RESULTS In total, 27.3% (117/428), 27.6% (118/428), 26.0% (95/365) and 25.6% (50/195) ofthe patients were hypertensive (systolic and/or diastolic BP > 95th > ) at 6 months, 1, 2 and 5 yearsfollowing transplantation, respectively. A total of 58.4% of the patients at 6 months, 52.8% at 1 year,48.2% at 2 years and 48.2% at 5 years were receiving anti-hypertensive therapy, of whom 31.6-36.6%remained hypertensive. When subjects were identified as being hypertensive, on anti-hypertensivemedication or had untreated hypertension (systolic and/or diastolic BP > 95th > ), 66.4, 61.0, 56.4 and55.9% of patients were hypertensive at 6 months, 1, 2 and 5 years, respectively. In a multivariatemodel, odds ratios for systolic hypertension were 4.16 (deceased versus living donor), 2.65 (lowestversus highest quartile of height z-score) and 2.07 (if on anti-hypertensive; yes versus no). There wassignificant variation in prevalent rates of hypertension between centres (P < 0.0001) that remainedsignificant (P = 0.003) after adjustment for all the factors in the multivariate model. CONCLUSIONSControl of BP after kidney transplantation remains sub-optimal in paediatric centres in the UK. Just over25% of patients remain hypertensive 5 years following transplantation. Significant differences betweencentres remain unexplained and may reflect differences in assessment and management of hypertension.", "metadata": {}}
+{"_id": "21622715", "title": "", "text": "Coupling cAMP signaling to transcription in the liver: pivotal role of CREB and CREM.Transcriptionalfactors binding to cAMP-responsive elements (CREs) in the promoters of various genes belong to thebasic domain-leucine zipper superfamily and are composed of three genes in mammals, CREB, CREM, andATF-1. A large number of CREB, CREM, and ATF-1 proteins are generated by posttranscriptional events,mostly alternative splicing, and regulate gene expression by acting as activators or repressors. Activationis classically brought about by signaling-dependent phosphorylation of a key acceptor site (Ser133 inCREB) by a number of possible kinases, including PKA, CamKIV, and Rsk-2. Phosphorylation is theprerequisite for the interaction of CBP (CREB-binding protein), a co-activator that has also histoneacetyltransferase activity. Repression may involve dynamic dephosphorylation of the activators and thusdecreased association with CBP. Another pathway of transcriptional repression on CRE sites implicatesthe inducible repressor ICER (inducible cAMP early repressor), a product of the CREM gene. Being aninducible repressor, ICER is involved in autoregulatory feedback loops of transcription that govern thedown-regulation of early response genes, such as the proto-oncogene c-fos. The liver represents aremarkable physiological setting where cAMP-responsive signaling plays a major role. Indeed, a finelytuned program of gene expression is triggered by partial hepatectomy, so that through specificcheckpoints a coordinated regeneration of the tissue is obtained. Temporal kinetics of transcriptionalactivation after hepatectomy reveals a pattern of early induction for several genes, some of themcontrolled by the CREB/CREM transcription factors. An important role of CREM in liver physiology wassuggested by the robust induction of ICER after partial hepatectomy. The delay in tissue regeneration inCREM-deficient mice confirmed the important function of this factor in regulating hepatocyte proliferation.As gene induction is accompanied by critical changes in chromatin organization, the deciphering of thespecific modification codes that histones display during liver regeneration and physiology will provideexciting new insights into the dynamics of chromatin architecture.", "metadata": {}}
+{"_id": "21623140", "title": "", "text": "Comparison of dietary assessment methods in a Southern French population: use of weighed records,estimated-diet records and a food-frequency questionnaireObjective: The main objective of the study wasto develop appropriate dietary assessment instruments for the French Mediterranean region and tovalidate the measurements they provide. Subjects and Methods: Three different assessment methodswere submitted to a sample of 150 male and female volunteers. 98 completed the protocol, whichconsisted of a 4 d weighed dietary record (PETRA) and a 7 d estimated-diet record (S7) based on a checklist and a set of photographs, both these records being completed once in each season of the year, and asemi-quantitative (standard portion) food-frequency questionnaire (FFQ) including questions elicitingsocio-demographic and anthropometric data, which was completed once only. The days when PETRA wasused to evaluate food consumption coincided with the first 4 d of S7 (S4).Results: Validation was basedon nutrients and foods. Energy-adjusted Pearson correlation coefficients between S4 and PETRA rangedfrom 0.32 for vitamin E to 0.81 for vitamin C (mean: 0.65 for 21 nutrients). There was practically nomisclassification in opposite extreme quartiles. Spearman correlation coefficients ranged from 0.63 forfish and sea-food to 0.90 for wine (mean: 0.76 for 16 food groups). There was practically nomisclassification in opposite extreme quartiles. De-attenuated energy-adjusted Pearson correlationcoefficients between FFQ and S7 ranged from 0.22 for proteins and monounsaturated fatty acids to 0.80for iron (mean: 0.45). 10% or less of subjects were misclassified in opposite extreme quartiles (exceptfor vitamin C, 12%). Spearman correlation coefficients ranged from 0.25 for green-yellow-red rawvegetables to 0.76 for wine (mean: 0.42). 8% or less of subjects were misclassified in opposite extremequartiles (except for citrus fruit, 11%).Conclusions: Portion estimation using the set of photographs wasvalidated by the correlation between S4 and PETRA for both nutrients and foods. The FFQ provides areasonably reliable measure of macronutrient intake and a good measure of micronutrient intake whencompared with the data in the literature. It performs less well for food intake. Better results can beachieved for FFQ: (i) by using the set of photographs instead of standard portions and (ii) by addingfurther questions on foods which are insufficiently covered. Sponsorship: This work has been financiallysupported by INSERM contract 91-1006 and the Ardèche and Hérault Committees of the ‘Ligue contre lecancer’.", "metadata": {}}
+{"_id": "21626639", "title": "", "text": "Substrate fate in activated macrophages: a comparison between innate, classic, and alternativeactivation.Macrophages play a relevant role in innate and adaptive immunity depending on the balance ofthe stimuli received. From an analytical and functional point of view, macrophage stimulation can besegregated into three main modes, as follows: innate, classic, and alternative pathways. Thesedifferential activations result in the expression of specific sets of genes involved in the release of pro- oranti-inflammatory stimuli. In the present work, we have analyzed whether specific metabolic patternsdepend on the signaling pathway activated. A [1,2-(13)C(2)]glucose tracer-based metabolomicsapproach has been used to characterize the metabolic flux distributions in macrophages stimulatedthrough the classic, innate, and alternative pathways. Using this methodology combined with massisotopomer distribution analysis of the new formed metabolites, the data show that activatedmacrophages are essentially glycolytic cells, and a clear cutoff between the classic/innate activation andthe alternative pathway exists. Interestingly, macrophage activation through LPS/IFN-gamma or TLR-2,-3, -4, and -9 results in similar flux distribution patterns regardless of the pathway activated. However,stimulation through the alternative pathway has minor metabolic effects. The molecular basis of thedifferences between these two types of behavior involves a switch in the expression of6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK2) from the liver type-PFK2 to the moreactive ubiquitous PFK2 isoenzyme, which responds to Hif-1alpha activation and increasesfructose-2,6-bisphosphate concentration and the glycolytic flux. However, using macrophages targetedfor Hif-1alpha, the switch of PFK2 isoenzymes still occurs in LPS/IFN-gamma-activated macrophages,suggesting that this pathway regulates ubiquitous PFK2 expression through Hif-1alpha-independentmechanisms.", "metadata": {}}
+{"_id": "21636085", "title": "", "text": "The effect of folic acid supplementation on plasma homocysteine in an elderly population.BACKGROUNDIncreased plasma homocysteine is associated with coronary artery disease, peripheral vascular diseaseand venous thrombosis. Folic acid is the most effective therapy for reducing homocysteine levels. Thelowest effective supplement of folic acid is not known, particularly for the elderly who have the highestprevalence of these conditions. AIM To explore the effects of daily supplements of 0, 50, 100, 200, 400and 600 microg folic acid on plasma homocysteine in an elderly population. DESIGN Randomizeddouble-blind placebo-controlled trial. METHODS Participants (n=368) aged 65-75 years were randomlyallocated to receive one of the treatments for 6 weeks. Plasma homocysteine was recorded after 3 weeksand 6 weeks of supplementation. RESULTS Only the 400 microg and 600 microg groups had significantlylower homocysteine levels compared to placebo (p=0.038 and p<0.001, respectively). Using multiplelinear regression and each individual's total folic acid intake (diet plus supplement), a total daily folic acidintake of 926 microg per day would be required to ensure that 95% of the elderly population would bewithout cardiovascular risk from folate deficiency. DISCUSSION A daily folic acid intake of 926 microg isunlikely to be achieved by diet alone. Individual supplementation or fortification of food with folic acid willbe required to reach this target.", "metadata": {}}
+{"_id": "21641088", "title": "", "text": "Central obesity and hyperinsulinaemia in women are associated with polymorphism in the 5' flankingregion of the human insulin gene.Obesity is a multifactorial disease with a marked genetic component.The situation is further complicated by the heterogeneity of obesity demonstrated by the topographicaldistribution of body fat, e.g. upper body (central) and lower body (gluteal) obesity. Furthermore, thedistribution of fat shows a stronger heritable tendency compared with total body fat. Central obesity ischaracterized by hyperinsulinaemia and insulin resistance, a feature in common with non-insulindependent diabetes mellitus, hypertension and atherosclerosis. In order to study the molecular geneticsof central obesity we have examined 56 severely obese (mean body mass index 40), unrelated BritishCaucasoid young non-diabetic women for associations of restriction fragment length polymorphism ofcandidate genes with anthropometric measurements and indices of insulin secretion and resistance. Thecandidate genes examined were insulin receptor, insulin sensitive glucose transporter and insulin. Anassociation of the class 3 allele of the hypervariable region in the 5' flanking region of the insulin genewas found with upper segment obesity (P = 0.005). Furthermore, the class 3 allele was also associatedwith fasting hyperinsulinaemia (P = 0.01), stimulated insulin secretion (P = 0.01) and insulin resistanceas calculated from the homeostatic model of assessment (HOMA; P = 0.008). No such associations werefound with the other candidate genes studied. This data suggests that polymorphisms in the 5' flankingregion of the insulin gene may affect expression of the gene and thereby modulate insulin production inseverely obese female subjects.", "metadata": {}}
+{"_id": "21644993", "title": "", "text": "Population density profiles of nasopharyngeal carriage of 5 bacterial species in pre-school childrenmeasured using quantitative PCR offer potential insights into the dynamics of transmission.Bacterialvaccines can reduce carriage rates. Colonization is usually a binary endpoint. Real time quantitative PCR(qPCR) can quantify bacterial DNA in mucosal samples over a wide range. Using culture and single-genespecies-specific qPCRs for Streptococcus pneumoniae (lytA), Streptococcus pyogenes (ntpC), Moraxellacatarrhalis (ompJ), Haemophilus influenzae (hdp) and Staphylococcus aureus (nuc) and standard curvesagainst log-phase reference strain broth cultures we described frequency and peak density distributionsof carriage in nasopharyngeal swabs from 161 healthy 2-4 y old children collected into STGG broth. Ingeneral, detection by qPCR and culture was consistent. Discordance mostly occurred at lower detectionthresholds of both methods, although PCR assays for S. pyogenes and S. aureus were less sensitive.Density varied across 5-7 orders of magnitude for the 5 species with the abundant species skewed towardhigh values (modes: S. pneumoniae log3-4, M. catarrhalis & H. influenzae log4-5 CFU/ml broth). Wideranges of bacterial DNA concentrations in healthy children carrying these bacteria could mean thatdifferent individuals at different times vary greatly in infectiousness. Understanding the host, microbialand environmental determinants of colonization density will permit more accurate prediction of vaccineeffectiveness.", "metadata": {}}
+{"_id": "21645205", "title": "", "text": "Circadian mechanisms in murine and human bone marrow mesenchymal stem cells followingdexamethasone exposure.A core group of regulatory factors control circadian rhythms in mammaliancells. While the suprachiasmatic nucleus in the brain serves as the central core circadian oscillator,circadian clocks also exist within peripheral tissues and cells. A growing body of evidence hasdemonstrated that >20% of expressed mRNAs in bone and adipose tissues oscillate in a circadianmanner. The current manuscript reports evidence of the core circadian transcriptional apparatus withinprimary cultures of murine and human bone marrow-derived mesenchymal stem cells (BMSCs). Exposureof confluent, quiescent BMSCs to dexamethasone synchronized the oscillating expression of the mRNAsencoding the albumin D binding protein (dbp), brain-muscle arnt-like 1 (bmal1), period 3 (per3), rev-erbalpha (Rev A), and rev-erb beta (Rev B). The genes displayed a mean oscillatory period of 22.2 to 24.3 h.The acrophase or peak expression of mRNAs encoding \"positive\" (bmal1) and \"negative\" (per3)components of the circadian regulatory apparatus were out of phase with each other by approximately8-12 h, consistent with in vivo observations. In vivo, phosphyrylation by glycogen synthase kinase 3beta(GSK3beta) is known to regulate the turnover of per3 and components of the core circadian regulatoryapparatus. In vitro addition of lithium chloride, a GSK3beta inhibitor, significantly shifted the acrophaseof all genes by 4.2-4.7 h oscillation in BMSCs; however, only the male murine BMSCs displayed asignificant increase in the length of the period of oscillation. We conclude that human and murine BMSCsrepresent a valid in vitro model for the analysis of circadian mechanisms in bone metabolism and stemcell biology.", "metadata": {}}
+{"_id": "21651116", "title": "", "text": "Herpesvirus-encoded GPCRs: neglected players in inflammatory and proliferative diseases?Herpesvirusesencode membrane-associated G protein-coupled receptors (GPCRs) in their viral genomes that arestructurally similar to chemokine receptors. These GPCRs hijack GPCR-mediated cellular signallingnetworks of the host for survival, replication and pathogenesis. In particular the herpesvirus-encodedchemokine receptors ORF74, BILF1 and US28, which are present at inflammatory sites and tumour cells,provide important virus-specific targets for directed therapies. Given the high druggability of GPCRs ingeneral, these viral GPCRs can be considered promising antiviral drug targets.", "metadata": {}}
+{"_id": "21676556", "title": "", "text": "Midbody accumulation through evasion of autophagy contributes to cellular reprogramming andtumorigenicityThe midbody is a singular organelle formed between daughter cells during cytokinesis andrequired for their final separation. Midbodies persist in cells long after division as midbody derivatives(MBds), but their fate is unclear. Here we show that MBds are inherited asymmetrically by the daughtercell with the older centrosome. They selectively accumulate in stem cells, induced pluripotent stem cellsand potential cancer ‘stem cells’ in vivo and in vitro. MBd loss accompanies stem-cell differentiation, andinvolves autophagic degradation mediated by binding of the autophagic receptor NBR1 to the midbodyprotein CEP55. Differentiating cells and normal dividing cells do not accumulate MBds and possess highautophagic activity. Stem cells and cancer cells accumulate MBds by evading autophagosomeencapsulation and exhibit low autophagic activity. MBd enrichment enhances reprogramming to inducedpluripotent stem cells and increases the in vitro tumorigenicity of cancer cells. These results indicateunexpected roles for MBds in stem cells and cancer ‘stem cells’.", "metadata": {}}
+{"_id": "21692235", "title": "", "text": "Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized byabnormalities in PDGFRA, IDH1, EGFR, and NF1.The Cancer Genome Atlas Network recently catalogedrecurrent genomic abnormalities in glioblastoma multiforme (GBM). We describe a robust geneexpression-based molecular classification of GBM into Proneural, Neural, Classical, and Mesenchymalsubtypes and integrate multidimensional genomic data to establish patterns of somatic mutations andDNA copy number. Aberrations and gene expression of EGFR, NF1, and PDGFRA/IDH1 each define theClassical, Mesenchymal, and Proneural subtypes, respectively. Gene signatures of normal brain cell typesshow a strong relationship between subtypes and different neural lineages. Additionally, response toaggressive therapy differs by subtype, with the greatest benefit in the Classical subtype and no benefit inthe Proneural subtype. We provide a framework that unifies transcriptomic and genomic dimensions forGBM molecular stratification with important implications for future studies.", "metadata": {}}
+{"_id": "21700295", "title": "", "text": "Chronic Hepatitis B Infection: A ReviewImportance More than 240 million individuals worldwide areinfected with chronic hepatitis B virus (HBV). Among individuals with chronic HBV infection who areuntreated, 15% to 40% progress to cirrhosis, which may lead to liver failure and liver cancer.Observations Pegylated interferon and nucleos(t)ide analogues (lamivudine, adefovir, entecavir, tenofovirdisoproxil, and tenofovir alafenamide) suppress HBV DNA replication and improve liver inflammation andfibrosis. Long-term viral suppression is associated with regression of liver fibrosis and reduced risk ofhepatocellular carcinoma in cohort studies. The cure (defined as hepatitis B surface antigen loss withundetectable HBV DNA) rates after treatment remain low (3%-7% with pegylated interferon and1%-12% with nucleos[t]ide analogue therapy). Pegylated interferon therapy can be completed in 48weeks and is not associated with the development of resistance; however, its use is limited by poortolerability and adverse effects such as bone marrow suppression and exacerbation of existingneuropsychiatric symptoms such as depression. Newer agents (entecavir, tenofovir disoproxil, andtenofovir alafenamide) may be associated with a significantly reduced risk of drug resistance comparedwith older agents (lamivudine and adefovir) and should be considered as the first-line treatment.Conclusions and Relevance Antiviral treatment with either pegylated interferon or a nucleos(t)ideanalogue (lamivudine, adefovir, entecavir, tenofovir disoproxil, or tenofovir alafenamide) should beoffered to patients with chronic HBV infection and liver inflammation in an effort to reduce progression ofliver disease. Nucleos(t)ide analogues should be considered as first-line therapy. Because cure rates arelow, most patients will require therapy indefinitely.", "metadata": {}}
+{"_id": "21719289", "title": "", "text": "CD64 expression distinguishes monocyte-derived and conventional dendritic cells and reveals theirdistinct role during intramuscular immunization.Although most vaccines are administered i.m., little isknown about the dendritic cells (DCs) that are present within skeletal muscles. In this article, we showthat expression of CD64, the high-affinity IgG receptor FcγRI, distinguishes conventional DCs frommonocyte-derived DCs (Mo-DCs). By using such a discriminatory marker, we defined the distinct DCsubsets that reside in skeletal muscles and identified their migratory counterparts in draining lymphnodes (LNs). We further used this capability to analyze the functional specialization that exists amongmuscle DCs. After i.m. administration of Ag adsorbed to alum, we showed that alum-injected musclescontained large numbers of conventional DCs that belong to the CD8α(+)- and CD11b(+)-type DCs. Bothconventional DC types were capable of capturing Ag and of migrating to draining LNs, where theyefficiently activated naive T cells. In alum-injected muscles, Mo-DCs were as numerous as conventionalDCs, but only a small fraction migrated to draining LNs. Therefore, alum by itself poorly induces Mo-DCsto migrate to draining LNs. We showed that addition of small amounts of LPS to alum enhanced Mo-DCmigration. Considering that migratory Mo-DCs had, on a per cell basis, a higher capacity to induceIFN-γ-producing T cells than conventional DCs, the addition of LPS to alum enhanced the overallimmunogenicity of Ags presented by muscle-derived DCs. Therefore, a full understanding of the role ofadjuvants during i.m. vaccination needs to take into account the heterogeneous migratory and functionalbehavior of muscle DCs and Mo-DCs revealed in this study.", "metadata": {}}
+{"_id": "21746539", "title": "", "text": "T-cell-antigen recognition and the immunological synapseMuch excitement of the past five years in thearea of T-cell-antigen recognition has centred around the immunological synapse — a complex cellularstructure that forms at the interface of a T cell and a cell that expresses the appropriate peptide–MHCcomplexes. Thanks to new imaging technologies, we are now beginning to understand the role ofcell-surface molecules and some of their attendant signalling modules in the context of cell-to-cellcommunication. Progress has been so rapid that T-cell-antigen recognition might be the first system inwhich the molecular basis of cell–cell recognition is understood.", "metadata": {}}
+{"_id": "21754541", "title": "", "text": "Key interactions by conserved polar amino acids located at the transmembrane helical boundaries inClass B GPCRs modulate activation, effector specificity and biased signalling in the glucagon-likepeptide-1 receptor.Class B GPCRs can activate multiple signalling effectors with the potential to exhibitbiased agonism in response to ligand stimulation. Previously, we highlighted key TM domain polar aminoacids that were crucial for the function of the GLP-1 receptor, a key therapeutic target for diabetes andobesity. Using a combination of mutagenesis, pharmacological characterisation, mathematical andcomputational molecular modelling, this study identifies additional highly conserved polar residueslocated towards the TM helical boundaries of Class B GPCRs that are important for GLP-1 receptorstability and/or controlling signalling specificity and biased agonism. This includes (i) three positivelycharged residues (R3.30227, K4.64288, R5.40310) located at the extracellular boundaries of TMs 3, 4and 5 that are predicted in molecular models to stabilise extracellular loop 2, a crucial domain for ligandaffinity and receptor activation; (ii) a predicted hydrogen bond network between residues located in TMs2 (R2.46176), 6 (R6.37348) and 7 (N7.61406 and E7.63408) at the cytoplasmic face of the receptor thatis important for stabilising the inactive receptor and directing signalling specificity, (iii) residues at thebottom of TM 5 (R5.56326) and TM6 (K6.35346 and K6.40351) that are crucial for receptor activationand downstream signalling; (iv) residues predicted to be involved in stabilisation of TM4 (N2.52182 andY3.52250) that also influence cell signalling. Collectively, this work expands our understanding ofpeptide-mediated signalling by the GLP-1 receptor.", "metadata": {}}
+{"_id": "21767325", "title": "", "text": "Influence of lifestyle modification on arterial stiffness and wave reflections.Arterial stiffness and wavereflections exert a number of adverse effects on cardiovascular function and disease risk and areassociated with a greater rate of mortality in patients with end-stage renal failure and essentialhypertension. Accordingly, the prevention and treatment of arterial stiffness are of paramountimportance. Because arterial stiffening is being recognized as a critical precursor of cardiovasculardisease (CVD), it is essential to understand the role of lifestyle modifications on preventing and reversingarterial stiffening. Available evidence indicates that lifestyle modifications, in particular aerobic exerciseand sodium restriction, appear to be clinically efficacious therapeutic interventions for preventing andtreating arterial stiffening. Thus, sufficient evidence is available to recommend lifestyle modifications aspart of a first-line therapeutic approach for arterial stiffening. However, more information is needed for afull understanding and optimal use of lifestyle modifications in the management of arterial stiffening.", "metadata": {}}
+{"_id": "21789744", "title": "", "text": "Effect of exercise-induced ischemia on QT interval dispersion.An increased spatial dispersion ofventricular repolarization duration (QT dispersion) is associated with an increased vulnerability toarrhythmias. This study was designed to examine the effect of exercise on QT dispersion in ischemicheart disease (IHD). QT dispersion, corrected QT dispersion, and percentage change in uncorrected andcorrected QT dispersion between rest and peak exercise were examined in 14 members of a controlgroup, 17 patients with IHD, and 14 patients with IHD who were receiving beta-blockers (IHD-B). Allsubjects had undergone a standard Bruce protocol exercise test, and QT intervals were measured at restand peak exercise with a digitizing tablet interfaced to a personal computer. QT dispersion at rest wasmarkedly increased in the IHD group compared with that in the control and IHD-B groups, respectively(corrected QT dispersion in milliseconds), 74 +/- 7, 40 +/- 4, 49 +/- 5, p < 0.03). The corrected QTdispersion at peak exercise was greater in the IHD group compared with that in the control group (57 +/-5 vs 26 +/- 3 msec, p < 0.03). The percentage change in QT dispersion with exercise was significantlyhigher in the IHD group (52% +/- 5%) compared with that in both the control group (28% +/- 4%, p <0.002) and the IHD-B group (30% +/- 3%, p < 0.01). A larger mean QT dispersion at peak exercise andan increased percentage change in QT dispersion with exercise may help explain the increasedsusceptibility of the IHD group for arrhythmias. The cardioprotective action of beta-blockers may beexplained by their blunting effect on exercise-related changes in QT dispersion.", "metadata": {}}
+{"_id": "21790313", "title": "", "text": "Effects of powered mobility on self-initiated behaviors of very young children with locomotordisability.This study reports the effects of powered mobility on the self-initiated behavior of six childrenwith various disabilities who, between 23 and 38 months of age, learnt to use motorized wheelchairs inless than three weeks. Using a multiple baseline design, two-hour observation periods werevideo-recorded at 10-day intervals before and after they achieved independent mobility. Frequency ofself-initiated interaction with objects, spatial exploration and communication with care-giver wereanalyzed. Three children increased all three types of behavior; one increased in two types but decreasedin interaction with objects; and two increased in spatial exploration only.", "metadata": {}}
+{"_id": "21793890", "title": "", "text": "BCR/ABL modifies the kinetics and fidelity of DNA double-strand breaks repair in hematopoietic cells.Theoncogenic BCR/ABL tyrosine kinase facilitates the repair of DNA double-strand breaks (DSBs). We findthat after gamma-irradiation BCR/ABL-positive leukemia cells accumulate more DSBs in comparison tonormal cells. These lesions are efficiently repaired in a time-dependent fashion by BCR/ABL-stimulatednon-homologous end-joining (NHEJ) followed by homologous recombination repair (HRR) mechanisms.However, mutations and large deletions were detected in HRR and NHEJ products, respectively, inBCR/ABL-positive leukemia cells. We propose that unfaithful repair of DSBs may contribute to genomicinstability in the Philadelphia chromosome-positive leukemias.", "metadata": {}}
+{"_id": "21804115", "title": "", "text": "Bone morphogenetic protein signaling in nephron progenitor cellsBone morphogenetic protein (BMP)signaling plays an essential role in many aspects of kidney development, and is a major determinant ofoutcome in kidney injury. BMP treatment is also an essential component of protocols for differentiation ofnephron progenitors from pluripotent stem cells. This review discusses the role of BMP signaling tonephron progenitor cells in each of these contexts.", "metadata": {}}
+{"_id": "21853444", "title": "", "text": "Computational analysis of 3'-ends of ESTs shows four classes of alternative polyadenylation in human,mouse, and rat.Alternative initiation, splicing, and polyadenylation are key mechanisms used by manyorganisms to generate diversity among mature mRNA transcripts originating from the same transcriptionunit. While previous computational analyses of alternative polyadenylation have focused onpolyadenylation activities within or downstream of the normal 3'-terminal exons, we present the resultsof the first genome-wide analysis of patterns of alternative polyadenylation in the human, mouse, and ratgenomes occurring over the entire transcribed regions of mRNAs using 3'-ESTs with poly(A) tails alignedto genomic sequences. Four distinct classes of patterns of alternative polyadenylation result from thisanalysis: tandem poly(A) sites, composite exons, hidden exons, and truncated exons. We estimate thatat least 49% (human), 31% (mouse), and 28% (rat) of polyadenylated transcription units havealternative polyadenylation. A portion of these alternative polyadenylation events result in new proteinisoforms.", "metadata": {}}
+{"_id": "21855837", "title": "", "text": "Epigenetic instability in ES cells and cloned mice.Cloning by nuclear transfer (NT) is an inefficient processin which most clones die before birth and survivors often display growth abnormalities. In an effort tocorrelate gene expression with survival and fetal overgrowth, we have examined imprinted geneexpression in both mice cloned by nuclear transfer and in the embryonic stem (ES) cell donor populationsfrom which they were derived. The epigenetic state of the ES cell genome was found to be extremelyunstable. Similarly, variation in imprinted gene expression was observed in most cloned mice, even inthose derived from ES cells of the same subclone. Many of the animals survived to adulthood despitewidespread gene dysregulation, indicating that mammalian development may be rather tolerant toepigenetic aberrations of the genome. These data imply that even apparently normal cloned animals mayhave subtle abnormalities in gene expression.", "metadata": {}}
+{"_id": "21859699", "title": "", "text": "Successful three-way kidney paired donation with cross-country live donor allograft transport.Providingtransplantation opportunities for patients with incompatible live donors through kidney paired donation(KPD) is seen as one of the important strategies for easing the crisis in organ availability. It has beenestimated that an additional 1000-2000 transplants per year could be accomplished if a national KPDprogram were implemented in the United States. While most of these transplants could be arrangedwithin the participants' local or regional area, patients with hard-to-match blood types or broad HLAsensitization would benefit from matching across larger geographic areas. In this case, either patients ororgans would need to travel in order to obtain maximum benefit from a national program. In this study,we describe how a triple KPD enabled a highly sensitized patient (PRA 96%) to receive a well-matchedkidney from a live donor on the opposite coast. The kidney was removed in San Francisco andtransported to Baltimore where it was reperfused 8 h later. The patient had prompt function and 1 yearlater has a serum creatinine of 1.1 mg/dl. This case provides a blueprint for solving some of thecomplexities that are inherent in the implementation of a national KPD program in a large country like theUnited States.", "metadata": {}}
+{"_id": "21866916", "title": "", "text": "Role of PACAP and VIP in astroglial functions.Astrocytes represent at least 50% of the volume of thehuman brain. Besides their roles in various supportive functions, astrocytes are involved in the regulationof stem cell proliferation, synaptic plasticity and neuroprotection. Astrocytes also influence neuronalphysiology by responding to neurotransmitters and neuropeptides and by releasing regulatory factorstermed gliotransmitters. In particular, astrocytes express the PACAP-specific receptor PAC1-R and thePACAP/VIP mutual receptors VPAC1-R and VPAC2-R during development and/or in the adult. There is nowclear evidence that PACAP and VIP modulate a number of astrocyte activities such as proliferation,plasticity, glycogen production, and biosynthesis of neurotrophic factors and gliotransmitters.", "metadata": {}}
+{"_id": "21868715", "title": "", "text": "A subset of 26S proteasomes is activated at critically low ATP concentrations and contributes tomyocardial injury during cold ischemia.Molecular mechanisms leading to myocardial injury during warmor cold ischemia are insufficiently understood. Although proteasomes are thought to contribute tomyocardial ischemia-reperfusion injury, their roles during the ischemic period remain elusive. Becausedonor hearts are commonly exposed to prolonged global cold ischemia prior to cardiac transplantation,we evaluated the role and regulation of the proteasome during cold ischemic storage of rat hearts incontext of the myocardial ATP content. When measured at the actual tissue ATP concentration, cardiacproteasome peptidase activity increased by 225% as ATP declined during cold ischemic storage of heartsin University of Wisconsin (UW) solution for up to 48h. Addition of the specific proteasome inhibitorepoxomicin to the UW solution inhibited proteasome activity in the cardiac extracts, significantly reducededema formation and preserved the ultrastructural integrity of the cardiomyocyte. Utilizing purified20S/26S proteasome enzyme preparations, we demonstrate that this activation can be attributed to asubset of 26S proteasomes which are stable at ATP concentrations far below physiological levels, that ATPnegatively regulates its activity and that maximal activation occurs at ATP concentrations in the lowmumol/L range. These data suggest that proteasome activation is a pathophysiologically relevantmechanism of cold ischemic myocardial injury. A subset of 26S proteasomes appears to be acell-destructive protease that is activated as ATP levels decline. Proteasome inhibition during coldischemia preserves the ultrastructural integrity of the cardiomyocyte.", "metadata": {}}
+{"_id": "21870716", "title": "", "text": "Coping and satisfaction with growth hormone treatment among short-stature children.The ability ofchildren to cope with a chronic medical problem requiring prolonged treatment has an effect on thequality of life of these children and of their parents and serves as an index of the quality of treatment.This study deals with coping ability and satisfaction with treatment of children whose stature was two ormore SD below the average for age and gender. The study population included 96 patients, 53 of whomwere male, who were on growth hormone (GH) treatment for at least 1 year. 65 patients were withoutany underlying disease, 15 had classical GH deficiency and 16 had Turner syndrome or renal disease. Allpatients were treated with daily injections at home from 12 to 66 months. Using a self-administeredquestionnaire, the ability to cope and the degree of satisfaction and compliance with treatment wereassessed. No significant differences were found with respect to gender, the presence of an underlyingdisease, age at which treatment commenced or duration of treatment. Despite the fact that the outcomeof GH treatment on final height has yet to be established, satisfaction and compliance were high.", "metadata": {}}
+{"_id": "21874312", "title": "", "text": "Risk for breast cancer development determined by mammographic parenchymal pattern.A classificationof risk for developing breast cancer has been devised based solely on the appearance of the breastparenchyma by mammography. Four groups of patients were isolated. The study encompassed afive-year period and was done by reviewing the mammograms of all women over the age of 30 who hadbeen examined at Hutzel Hospital, Detroit. The average time of followup would be approximately 2 1/2years. Four groups had an incidence of developing breast cancer of 0.1, 0.4, 1.7, and 2.2. Theseparenchymal patterns are described and criteria for their identification are given.", "metadata": {}}
+{"_id": "21874414", "title": "", "text": "Accurate coarse-grained modeling of red blood cells.We develop a systematic coarse-graining procedurefor modeling red blood cells (RBCs) using arguments based on mean-field theory. The three-dimensionalRBC membrane model takes into account the bending energy, in-plane shear energy, and constraints offixed surface area and fixed enclosed volume. The coarse-graining procedure is general, it can be usedfor arbitrary level of coarse-graining and does not employ any fitting parameters. The sensitivity of thecoarse-grained model is investigated and its behavior is validated against available experimental dataand in dissipative particle dynamics (DPD) simulations of RBCs in capillary and shear flows.", "metadata": {}}
+{"_id": "21878751", "title": "", "text": "Mice deficient in CD4 T cells have only transiently diminished levels of IFN-gamma, yet succumb totuberculosis.CD4 T cells are important in the protective immune response against tuberculosis. Twomouse models deficient in CD4 T cells were used to examine the mechanism by which these cellsparticipate in protection against Mycobacterium tuberculosis challenge. Transgenic mice deficient in eitherMHC class II or CD4 molecules demonstrated increased susceptibility to M. tuberculosis, compared withwild-type mice. MHC class II-/- mice were more susceptible than CD4-/- mice, as measured by survivalfollowing M. tuberculosis challenge, but the relative resistance of CD4-/- mice did not appear to be due toincreased numbers of CD4-8- (double-negative) T cells. Analysis of in vivo IFN-gamma production in thelungs of infected mice revealed that both mutant mouse strains were only transiently impaired in theirability to produce IFN-gamma following infection. At 2 wk postinfection, IFN-gamma production, assessedby RT-PCR and intracellular cytokine staining, in the mutant mice was reduced by >50% compared withthat in wild-type mice. However, by 4 wk postinfection, both mutant and wild-type mice had similar levelsof IFN-gamma mRNA and protein production. In CD4 T cell-deficient mice, IFN-gamma production wasdue to CD8 T cells. Thus, the importance of IFN-gamma production by CD4 T cells appears to be early ininfection, lending support to the hypothesis that early events in M. tuberculosis infection are crucialdeterminants of the course of infection.", "metadata": {}}
+{"_id": "21884059", "title": "", "text": "Treatment and management of graft-versus-host disease: improving response andsurvival.Graft-versus-host disease (GVHD) is a significant cause of morbidity and mortality followingallogenic haematopoietic stem-cell transplantation and thus the focus of much ongoing research. Despiteconsiderable advances in our understanding of the pathophysiology, diagnosis and predisposing factorsfor both acute and chronic forms of the disease, a standardised therapeutic strategy is still lacking. Thereis good evidence for initial treatment of both acute and chronic forms of the disease with corticosteroidtherapy. However, the most effective approach to steroid-refractory disease remains controversial, withcurrent practice based mainly on smaller studies and varying considerably between local institutions.Timely diagnosis, multidisciplinary working and good supportive care, including infection prophylaxis, areclearly important in optimizing response and survival in such patients. It is hoped that in the futuresystematic research strategies and the identification of novel therapeutic targets may improve outcomefurther. The following review aims to outline some of the existing options for the treatment andmanagement of acute and chronic GVHD.", "metadata": {}}
+{"_id": "21884449", "title": "", "text": "The value of self-report assessment of adherence, rhinitis and smoking in relation to asthma control.AIMSTo explore the utility of self-report measures of inhaled corticosteroid (ICS) adherence, degree of rhinitisand smoking status and their association with asthma control. METHODS Patients prescribed ICS forasthma at 85 UK practices were sent validated questionnaire measures of control (Asthma ControlQuestionnaire; ACQ) and adherence (Medication Adherence Report Scale), a two-item measure ofsmoking status, and a single-item measure of rhinitis. RESULTS Complete anonymised questionnaireswere available for 3916 participants. Poor asthma control (ACQ >1.5) was associated with reportedrhinitis (OR = 4.62; 95% CI: 3.71-5.77), smoking (OR = 4.33; 95% CI: 3.58-5.23) and low adherence toICS (OR = 1.35; 95% CI: 1.18-1.55). The degree of rhinitis was important, with those reporting severerhinitis exhibiting the worst asthma control, followed by those reporting mild rhinitis and then thosereporting no rhinitis symptoms (F(2, 3913)=128.7, p<.001). There was a relationship between thenumber of cigarettes smoked each day and asthma control (F(5,655)=6.08, p<.001). CONCLUSIONSPoor asthma control is associated with self-reported rhinitis, smoking and low medication adherence.These potentially modifiable predictors of poor asthma control can be identified through a brief self-reportquestionnaire, used routinely as part of an asthma review.", "metadata": {}}
+{"_id": "21891856", "title": "", "text": "Development of a syngeneic mouse model for events related to ovarian cancer.Mouse ovarian surfaceepithelial cells (MOSEC) were obtained from virgin, mature mice by mild trypsinization and wererepeatedly passaged in vitro. Early passage cells (<20 passages) exhibited a cobblestone morphologyand contact inhibition of growth. After approximately 20 passages in vitro, cobblestone morphology andcontact inhibition of growth was lost. Tumor forming potential was determined by s.c. and i.p. injection ofearly and late passage cells into athymic and syngeneic C57BL6 mice. Subcutaneous tumors formed inapproximately 4 months and were present only at the injection site. Intraperitoneal injection of latepassage MOSEC into athymic and syngeneic mice resulted in growth of tumor implants throughout theabdominal cavity, and production of hemorrhagic ascitic fluid. Early passage MOSEC did not form tumorsin vivo. Histopathologic analysis of tumors revealed a highly malignant neoplasm containing bothcarcinomatous and sarcomatous components. Late passage MOSEC expressed cytokeratin and did notproduce ovarian steroids in response to gonadotropin stimulation in vitro. Ten clonal lines wereestablished from late passage MOSEC. Each clone formed multiple peritoneal tumors and ascitic fluidafter i.p. injection into C57BL6 mice. Three cell lines examined cytogenetically were polyploid withnear-tetraploid modal chromosome numbers. Common clonal chromosome gains and losses included +5,+15, +19 and -X, -3, -4. One cell line had a clonal translocation between chromosomes 15 and 18 andanother had a small marker chromosome; common structural abnormalities were not observed. Thesedata describe the development of a mouse model for the study of events related to ovarian cancer inhumans. The ability of the MOSEC to form extensive tumors within the peritoneal cavity, similar to thoseseen in women with Stage III and IV cancer, and the ability of the MOSEC to produce tumors in mice withintact immune systems, makes this model unique for investigations of molecular and immune interactionsin ovarian cancer development.", "metadata": {}}
+{"_id": "21902400", "title": "", "text": "Hypoxia in cancer: significance and impact on clinical outcomeHypoxia, a characteristic feature of locallyadvanced solid tumors, has emerged as a pivotal factor of the tumor (patho-)physiome since it canpromote tumor progression and resistance to therapy. Hypoxia represents a “Janus face” in tumor biologybecause (a) it is associated with restrained proliferation, differentiation, necrosis or apoptosis, and (b) itcan also lead to the development of an aggressive phenotype. Independent of standard prognosticfactors, such as tumor stage and nodal status, hypoxia has been suggested as an adverse prognosticfactor for patient outcome. Studies of tumor hypoxia involving the direct assessment of the oxygenationstatus have suggested worse disease-free survival for patients with hypoxic cervical cancers or soft tissuesarcomas. In head & neck cancers the studies suggest that hypoxia is prognostic for survival and localcontrol. Technical limitations of the direct O2 sensing technique have prompted the use of surrogatemarkers for tumor hypoxia, such as hypoxia-related endogenous proteins (e.g., HIF-1α, GLUT-1, CA IX)or exogenous bioreductive drugs. In many—albeit not in all—studies endogenous markers showedprognostic significance for patient outcome. The prognostic relevance of exogenous markers, however,appears to be limited. Noninvasive assessment of hypoxia using imaging techniques can be achieved withPET or SPECT detection of radiolabeled tracers or with MRI techniques (e.g., BOLD). Clinical experiencewith these methods regarding patient prognosis is so far only limited. In the clinical studies performed upuntil now, the lack of standardized treatment protocols, inconsistencies of the endpoints characterizingthe oxygenation status and methodological differences (e.g., different immunohistochemical stainingprocedures) may compromise the power of the prognostic parameter used.", "metadata": {}}
+{"_id": "21902910", "title": "", "text": "Knowledge and Practice of Standard Precautions and Awareness Regarding Post-Exposure Prophylaxis forHIV among Interns of a Medical College in West Bengal, India.OBJECTIVES To assess the knowledge ofinterns on standard precautions and post-exposure prophylaxis for HIV, and identify the gap betweenknowledge and practice relating to standard precautions, as well as determining the perceived barriersagainst adherence to standard precautions. METHODS The study was conducted on 130 interns of2010-11 batch from a government-run medical college in Kolkata, India. All participants completed aself-administered questionnaire with items relating to basic components of standard precautions andpost-exposure prophylaxis for HIV. The questionnaire also included open ended questions relating toreasons for non-adherence to the practice of standard precautions along with additional space for specificcomments, if any. RESULTS Poor adherence in the use of personal protective equipment, hand washing,safe handling and disposal of needles and sharp objects were found to be among the practices for whichthe interns expressed correct knowledge. While the main reasons for non-adherence were found to beclumsiness in handling needles, wearing gloves, feeling uncomfortable when wearing aprons,impracticality of regular hand-washing and non-availability of equipment. Although the majority of therespondents (84.6%) expressed awareness of washing sites of injured with soap and water,approximately 32.3% did not know that antiseptics could cause more damage. Also, only 63.8%expressed awareness of reporting any incidence of occupational exposure, while knowledge onpost-exposure prophylaxis regimens was generally found to be poor. CONCLUSION The considerable gapbetween knowledge and practice of standard precautions and inadequate knowledge of post-exposureprophylaxis emphasizes the need for continuous onsite training of interns with supportive supervision andmonitoring of their activities.", "metadata": {}}
+{"_id": "21909315", "title": "", "text": "Viruses and microRNAsThe discovery of RNA interference and cellular microRNAs (miRNAs) has not onlyaffected how biological research is conducted but also revealed an entirely new level ofpost-transcriptional gene regulation. Here, I discuss the potential functions of the virally encoded miRNAsrecently identified in several pathogenic human viruses and propose that cellular miRNAs may have had asubstantial effect on viral evolution and may continue to influence the in vivo tissue tropism of viruses.Our increasing knowledge of the role and importance of virally encoded miRNAs will probably offer newinsights into how viruses that establish latent infections, such as herpesviruses, avoid elimination by thehost innate or adaptive immune system. Research into viral miRNA function might also suggest newapproaches for treating some virally induced diseases.", "metadata": {}}
+{"_id": "21914176", "title": "", "text": "Economic impact of primary open-angle glaucoma in Australia.BACKGROUND Glaucoma is the World'sleading cause of irreversible blindness, and poses serious public health and economic concerns.DESIGN   Review. SAMPLES Published randomized trials and population-based studies since 1985.METHODS We report the economic impact of primary open-angle glaucoma and model the effect ofchanges in detection rates and management strategies. MAIN OUTCOME MEASURES Thecost-effectiveness of different interventions to prevent vision loss from primary open-angle glaucoma wasmeasured in terms of financial cost (Australian dollars) and disability-adjusted life years. RESULTS Theprevalence of glaucoma in Australia is expected to increase from 208 000 in 2005 to 379 000 in 2025because of the aging population. Health system costs over the same time period are estimated toincrease from $AU355 million to $AU784 million. Total costs (health system costs, indirect costs and costsof loss of well-being) will increase from $AU1.9 billion to $AU4.3 billion in Australia. CONCLUSIONPrimary open-angle glaucoma poses a significant economic burden, which will increase substantially by2025. This dynamic model provides a valuable tool for ongoing policy formulation and determining theeconomic impact of interventions to better prevent visual impairment and blindness from glaucoma.", "metadata": {}}
+{"_id": "21922424", "title": "", "text": "The LIM domain-containing homeo box gene Xlim-1 is expressed specifically in the organizer region ofXenopus gastrula embryos.A novel cysteine-rich motif, named LIM, has been identified in the homeo boxgenes lin-11, Isl-1, and mec-3; the mec-3 and lin-11 genes determine cell lineages in Caenorhabditiselegans. We isolated LIM class homeo box genes from Xenopus laevis that are closely related to lin-11and mec-3 in the LIM and homeo domains. This paper deals with one of these genes, Xlim-1. Xlim-1mRNA is found at low abundance in the unfertilized egg, has a major expression phase at the gastrulastage, decreases, and rises again during the tadpole stage. In adult tissues the brain shows the highestabundance, by far, of Xlim-1 mRNA. The maternal and late expression phases of the Xlim-1 gene suggestthat it has multiple functions at different stages of the Xenopus life cycle. In the gastrula embryo, Xlim-1mRNA is localized in the dorsal lip and the dorsal mesoderm, that is, in the region of Spemann'sorganizer. Explant experiments showed that Xlim-1 mRNA is induced by the mesoderm-inducer activin Aand by retinoic acid, which is not a mesoderm inducer but affects patterning during Xenopusembryogenesis; application of activin A and retinoic acid together results in synergistic induction. Thestructure, inducibility, and localized expression in the organizer of the Xlim-1 gene suggest that it has arole in establishing body pattern during gastrulation.", "metadata": {}}
+{"_id": "21931005", "title": "", "text": "Signal transduction proteins that associate with the platelet-derived growth factor (PDGF) receptormediate the PDGF-induced release of glucose-6-phosphate dehydrogenase from permeabilizedcells.Permeabilized rat kidney cells rapidly released glucose 6-phosphate dehydrogenase (G6PD)following stimulation with peptide growth factors (Stanton, R.C., Seifter, J.L., Boxer, D.C., Zimmerman,E., and Cantley, L. C. (1991) J. Biol. Chem. 266, 12442-12448). To evaluate the signal transductionpathways mediating release of G6PD, two cell lines transfected with wild type or mutant platelet-derivedgrowth factor (PDGF) receptors (PDGFR) were studied using two permeabilization protocols. G6PD releasewas evaluated by enzyme activity and Western blot analysis. PDGF caused a significant increase in G6PDrelease in 1 min in cells transfected with wild type PDGFR. PDGF did not stimulate G6PD release in cellstransfected with tyrosine kinase-deficient PDGFR. PDGF did not stimulate G6PD release in cellstransfected with partially autophosphorylation-deficient PDGFR in which four known signaling proteins donot associate with the PDGFR. The PDGF-stimulated release of G6PD was partially restored in PDGFRmutants in which either phosphatidylinositol-3-kinase or phospholipase C gamma 1 could associate withthe PDGFR. Lastly, there was no basal or PDGF-stimulated phosphorylation of G6PD. We conclude thatrelease of G6PD: 1) requires intrinsic PDGFR tyrosine kinase activity; 2) requires PDGFRautophosphorylation; 3) is mediated by signaling proteins that associate with the PDGFR; 4) is notmediated by direct phosphorylation of G6PD.", "metadata": {}}
+{"_id": "21932050", "title": "", "text": "Microarrays for the study of viral gene expression during human cytomegalovirus latent infection.Humancytomegalovirus (HCMV) is one of the largest known DNA viruses. It is ubiquitous, and followingresolution of primary productive infection, it persists in the human host by establishing a lifelong latentinfection in myeloid lineage cells such as monocytes and their progenitors. Most adults with HCMVinfection are healthy but it can cause neurologic deficits in infants, and remains an important cause ofmorbidity and mortality in the immunosuppressed patient. Microarray-based studies of HCMV haveprovided useful information about genes that are transcriptionally active during both productive andlatent phases of infection. This chapter describes how to study genes in HCMV using microarrays and twocell types (productively infected human foreskin fibroblasts, and latently infected primary human myeloidprogenitor cells).", "metadata": {}}
+{"_id": "21932297", "title": "", "text": "Physiological implications of hydrogen sulfide: a whiff exploration that blossomed.The importantlife-supporting role of hydrogen sulfide (H(2)S) has evolved from bacteria to plants, invertebrates,vertebrates, and finally to mammals. Over the centuries, however, H(2)S had only been known for itstoxicity and environmental hazard. Physiological importance of H(2)S has been appreciated for about adecade. It started by the discovery of endogenous H(2)S production in mammalian cells and gainedmomentum by typifying this gasotransmitter with a variety of physiological functions. TheH(2)S-catalyzing enzymes are differentially expressed in cardiovascular, neuronal, immune, renal,respiratory, gastrointestinal, reproductive, liver, and endocrine systems and affect the functions of thesesystems through the production of H(2)S. The physiological functions of H(2)S are mediated by differentmolecular targets, such as different ion channels and signaling proteins. Alternations of H(2)S metabolismlead to an array of pathological disturbances in the form of hypertension, atherosclerosis, heart failure,diabetes, cirrhosis, inflammation, sepsis, neurodegenerative disease, erectile dysfunction, and asthma, toname a few. Many new technologies have been developed to detect endogenous H(2)S production, andnovel H(2)S-delivery compounds have been invented to aid therapeutic intervention of diseases relatedto abnormal H(2)S metabolism. While acknowledging the challenges ahead, research on H(2)S physiologyand medicine is entering an exponential exploration era.", "metadata": {}}
+{"_id": "21943141", "title": "", "text": "TatC is a specificity determinant for protein secretion via the twin-arginine translocation pathway.Therecent discovery of a ubiquitous translocation pathway, specifically required for proteins with atwin-arginine motif in their signal peptide, has focused interest on its membrane-bound components, oneof which is known as TatC. Unlike most organisms of which the genome has been sequenced completely,the Gram-positive eubacterium Bacillus subtilis contains two tatC-like genes denoted tatCd and tatCy.The corresponding TatCd and TatCy proteins have the potential to be involved in the translocation of 27proteins with putative twin-arginine signal peptides of which approximately 6-14 are likely to be secretedinto the growth medium. Using a proteomic approach, we show that PhoD of B. subtilis, aphosphodiesterase belonging to a novel protein family of which all known members are synthesized withtypical twin-arginine signal peptides, is secreted via the twin-arginine translocation pathway. Strikingly,TatCd is of major importance for the secretion of PhoD, whereas TatCy is not required for this process.Thus, TatC appears to be a specificity determinant for protein secretion via the Tat pathway. Based onour observations, we hypothesize that the TatC-determined pathway specificity is based on specificinteractions between TatC-like proteins and other pathway components, such as TatA, of which threeparalogues are present in B. subtilis.", "metadata": {}}
+{"_id": "21948782", "title": "", "text": "Function and regulation of SUMO proteasesCovalent attachment of small ubiquitin-like modifier (SUMO)to proteins is highly dynamic, and both SUMO–protein conjugation and cleavage can be regulated. Proteindesumoylation is carried out by SUMO proteases, which control cellular mechanisms ranging fromtranscription and cell division to ribosome biogenesis. Recent advances include the discovery of two novelclasses of SUMO proteases, insights regarding SUMO protease specificity, and revelations of previouslyunappreciated SUMO protease functions in several key cellular pathways. These developments, togetherwith new connections between SUMO proteases and the recently discovered SUMO-targeted ubiquitinligases (STUbLs), make this an exciting period to study these enzymes.", "metadata": {}}
+{"_id": "21956124", "title": "", "text": "Review article: prebiotics in the gastrointestinal tract.BACKGROUND Prebiotics are short-chaincarbohydrates that alter the composition, or metabolism, of the gut microbiota in a beneficial manner. Itis therefore expected that prebiotics will improve health in a way similar to probiotics, whilst at the sametime being cheaper, and carrying less risk and being easier to incorporate into the diet than probiotics.AIM To review published evidence for prebiotic effects on gut function and human health. METHODS Wesearched the Science Citation Index with the terms prebiotic, microbiota, gut bacteria, large intestine,mucosa, bowel habit, constipation, diarrhoea, inflammatory bowel disease, Crohn's disease, ulcerativecolitis, pouchitis, calcium and cancer, focussing principally on studies in humans and reports in theEnglish language. Search of the Cochrane Library did not identify any clinical study or meta-analysis onthis topic. RESULTS Three prebiotics, oligofructose, galacto-oligosaccharides and lactulose, clearly alterthe balance of the large bowel microbiota by increasing bifidobacteria and Lactobacillus numbers. Thesecarbohydrates are fermented and give rise to short-chain fatty acid and intestinal gas; however, effectson bowel habit are relatively small. Randomized-controlled trials of their effect in a clinical context arefew, although animal studies show anti-inflammatory effects in inflammatory bowel disease, whilecalcium absorption is increased. CONCLUSIONS It is still early days for prebiotics, but they offer thepotential to modify the gut microbial balance in such a way as to bring direct health benefits cheaply andsafely.", "metadata": {}}
+{"_id": "21957231", "title": "", "text": "Pain catastrophizing and general health status in a large Dutch community sample.The aim of the presentstudy was to examine the association between pain catastrophizing and general health status in a Dutchadult community sample, including various subgroups of people with musculoskeletal pain in theanalyses. For exploratory reasons this study partly replicated previous studies of the factor structure,reliability, and validity of the Pain Catastrophizing Scale (PCS). Results demonstrated that across differentpain subgroups, catastrophizing uniquely contributed variance to the prediction of the various aspects ofgeneral health status beyond the variance explained by pain intensity, age, gender, and chronicity.Across subgroups strongest associations were found between catastrophizing and mental health, generalhealth perception, social functioning, and vitality. Furthermore, the association between catastrophizingand the various aspects of general health status was not moderated by the chronicity of the pain. Resultsof the confirmatory factor analysis statistically confirmed a three-factor model of the PCS, which wasinvariant across different subgroups of people with musculoskeletal pain. Inter-factor correlations werehigh, and the incremental explanatory power of the three-factor model over that of a one-factor modelwas only marginal. This implies that a one-factor model might be justifiable as well, at least in thegeneral community. Across various pain subgroups the reliability of the PCS total and subscales wasadequate. Additional evidence for the concurrent validity of the PCS was found as well.", "metadata": {}}
+{"_id": "21958900", "title": "", "text": "Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs:results of a collaborative meta-analysis.OBJECTIVE To compare the relative risks of seriousgastrointestinal complications reported with individual non-steroidal anti-inflammatory drugs. DESIGNSystematic review of controlled epidemiological studies that found a relation between use of the drugsand admission to hospital for haemorrhage or perforation. SETTING Hospital and community basedcase-control and cohort studies. MAIN OUTCOME MEASURES (a) Estimated relative risks ofgastrointestinal complications with use of individual drugs, exposure to ibuprofen being used asreference; (b) a ranking that best summarised the sequence of relative risks observed in the studies.RESULTS 12 studies met the inclusion criteria. 11 provided comparative data on ibuprofen and otherdrugs. Ibuprofen ranked lowest or equal lowest for risk in 10 of the 11 studies. Pooled relative riskscalculated with exposure to ibuprofen used as reference were all significantly greater than 1.0 (interval ofpoint estimates 1.6 to 9.2). Overall, ibuprofen was associated with the lowest relative risk, followed bydiclofenac. Azapropazone, tolmetin, ketoprofen, and piroxicam ranked highest for risk and indomethacin,naproxen, sulindac, and aspirin occupied intermediate positions. Higher doses of ibuprofen wereassociated with relative risks similar to those with naproxen and indomethacin. CONCLUSIONS The lowrisk of serious gastrointestinal complications with ibuprofen seems to be attributable mainly to the lowdoses of the drug used in clinical practice. In higher doses ibuprofen is associated with a similar risk toother non-steroidal anti-inflammatory drugs. Use of low risk drugs in low dosage as first line treatmentwould substantially reduce the morbidity and mortality due to serious gastrointestinal toxicity from thesedrugs.", "metadata": {}}
+{"_id": "21993510", "title": "", "text": "Accuracy of weighed dietary records in studies of diet and health.OBJECTIVE To provide an independentevaluation of seven day weighed dietary records, which are currently accepted as the most accuratetechnique for assessing habitual dietary intake in studies investigating the links between diet and health.DESIGN Subjects who had previously participated in the Northern Ireland diet and health study werereselected by stratified random sampling to represent the range of energy intakes in the study asassessed by the seven day weighed dietary record. SETTING Northern Ireland. SUBJECTS 31 Free livingadults (16 men and 15 women). MAIN OUTCOME MEASURES Energy intake as measured by the sevenday weighed dietary record and total energy expenditure estimated concurrently by the doubly labelledwater technique. RESULTS Average recorded energy intakes were significantly lower than measuredexpenditure in the group overall (9.66 MJ/day v 12.15 MJ/day, 95% confidence interval 1.45 to 3.53MJ/day). Among those in the upper third of energy intakes the mean (SE) ratio of intake to expenditurewas close to 1.0, indicating accurate records (men 1.01 (0.11), women 0.96 (0.08]. In the middle andlower thirds the ratios for men were only 0.74 (0.05) and 0.70 (0.07) respectively and for women 0.89(0.07) and 0.61 (0.07). CONCLUSIONS These results show a serious bias in reporting habitual energyintake. If substantiated they may have wide implications for the interpretation of many nutritionalstudies.", "metadata": {}}
+{"_id": "22003328", "title": "", "text": "A novel family of sequence-specific endoribonucleases associated with the clustered regularly interspacedshort palindromic repeats.Clustered regularly interspaced short palindromic repeats (CRISPRs) togetherwith the associated CAS proteins protect microbial cells from invasion by foreign genetic elements usingpresently unknown molecular mechanisms. All CRISPR systems contain proteins of the CAS2 family,suggesting that these uncharacterized proteins play a central role in this process. Here we show that theCAS2 proteins represent a novel family of endoribonucleases. Six purified CAS2 proteins from diverseorganisms cleaved single-stranded RNAs preferentially within U-rich regions. A representative CAS2enzyme, SSO1404 from Sulfolobus solfataricus, cleaved the phosphodiester linkage on the 3'-side andgenerated 5'-phosphate- and 3'-hydroxyl-terminated oligonucleotides. The crystal structure of SSO1404was solved at 1.6A resolution revealing the first ribonuclease with a ferredoxin-like fold. Mutagenesis ofSSO1404 identified six residues (Tyr-9, Asp-10, Arg-17, Arg-19, Arg-31, and Phe-37) that are importantfor enzymatic activity and suggested that Asp-10 might be the principal catalytic residue. Thus, CAS2proteins are sequence-specific endoribonucleases, and we propose that their role in the CRISPR-mediatedanti-phage defense might involve degradation of phage or cellular mRNAs.", "metadata": {}}
+{"_id": "22007333", "title": "", "text": "Menstrual and reproductive factors in relation to mammographic density: the Study of Women’s HealthAcross the Nation (SWAN)Menstrual and reproductive factors may increase breast cancer risk through apathway that includes increased mammographic density. We assessed whether known or suspectedmenstrual and reproductive breast cancer risk factors were cross-sectionally associated withmammographic density, by measuring area of radiographic density and total breast area onmammograms from 801 participants in the Study of Women’s Health Across the Nation (SWAN), amulti-ethnic cohort of pre- and early perimenopausal women. From multivariable linear regression, thefollowing menstrual or reproductive factors were independently associated with percent mammographicdensity (area of dense breast/breast area): older age at menarche (β = 10.3, P < 0.01, for >13 vs. <12years), premenstrual cravings and bloating (β = −3.36, P = 0.02), younger age at first full-term birth (β= −8.12, P < 0.01 for ≤23 years versus no births), greater number of births (β = −6.80, P < 0.01 for ≥3births versus no births), and premenopausal status (β = 3.78, P < 0.01 versus early perimenopausal).Only number of births remained associated with percent density after adjustment for age, race/ethnicity,study site, body mass index (BMI), and smoking. In addition, stratified analyses revealed that theassociation with number of births was confined to women within the lowest BMI tertile (β = −12.2, P <0.01 for ≥3 births versus no births). Our data support a mechanism for parity and breast cancer thatinvolves mammographic density among pre- and early perimenopausal women that may be modified bybody size.", "metadata": {}}
+{"_id": "22023404", "title": "", "text": "Genetic and environmental determinants of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels inHispanic and African Americans.CONTEXT Vitamin D deficiency is associated with many adverse healthoutcomes, yet little is known about the genetic epidemiology of vitamin D or its metabolites. OBJECTIVEOur objective was to examine the relationship among three vitamin D-related genes and levels of25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] in Hispanics (HAs) andAfrican Americans (AAs). DESIGN AND SETTING The cross-sectional Insulin Resistance AtherosclerosisFamily Study recruited and examined subjects in: Los Angeles, California (AAs; 513 individuals from 42families); San Luis Valley (SLV), Colorado (HAs; 513 individuals from 30 families); and San Antonio (SA),Texas (HAs; 504 individuals from 58 families). MAIN OUTCOME MEASURES Plasma levels of 25(OH)D and1,25(OH)2D were measured. RESULTS Levels of 25(OH)D were highest in SLV-HAs [18.3 +/- 7.7 ng/ml(45.7 +/- 19.2 nmol/liter)], lower in SA-HAs [14.6 +/- 6.4 ng/ml (36.4 +/- 16.0 nmol/liter)], and lowestin AAs [11.0 +/- 5.4 ng/ml (27.5 +/- 13.5 nmol/liter)]. Levels of 1,25(OH)2D were similar in AAs [43.5+/- 13.9 pg/ml (113.1 +/- 36.1 pmol/liter)] and SLV-HAs [43.2 +/- 13.3 pg/ml (112.3 +/- 34.6pmol/liter)], but higher in SA-HAs [48.6 +/- 17.0 pg/ml (126.4 +/- 44.2 pmol/liter)]. After adjusting forgender and age within the site, two single nucleotide polymorphisms (SNPs) in the vitamin D bindingprotein gene (DBP), rs4588 and rs7041, were associated with 25(OH)D, and one SNP in the DBP, rs4588,was associated with 1,25(OH)2D at all three study centers. CONCLUSIONS SNPs in the DBP areassociated with levels of 25(OH)D and 1,25(OH)2D in HA and AA participants in the Insulin ResistanceAtherosclerosis Family Study.", "metadata": {}}
+{"_id": "22025252", "title": "", "text": "Changes in the levels of inositol phosphates after agonist-dependent hydrolysis of membranephosphoinositides.The formation of inositol phosphates in response to agonists was studied in brainslices, parotid gland fragments and in the insect salivary gland. The tissues were first incubated with[3H]inositol, which was incorporated into the phosphoinositides. All the tissues were found to containglycerophosphoinositol, inositol 1-phosphate, inositol 1,4-bisphosphate and inositol 1,4,5-trisphosphate,which were identified by using anion-exchange and high-resolution anion-exchange chromatography,high-voltage paper ionophoresis and paper chromatography. There was no evidence for the existence ofinositol 1:2-cyclic phosphate. A simple anion-exchange chromatographic method was developed forseparating these inositol phosphates for quantitative analysis. Stimulation caused no change in the levelsof glycerophosphoinositol in any of the tissues. The most prominent change concerned inositol1,4-bisphosphate, which increased enormously in the insect salivary gland and parotid gland afterstimulation with 5-hydroxytryptamine and carbachol respectively. Carbachol also induced a large increasein the level of inositol 1,4,5-trisphosphate in the parotid. Stimulation of brain slices with carbacholinduced modest increase in the bis- and tris-phosphate. In all the tissues studied, there was a significantagonist-dependent increase in the level of inositol 1-phosphate. The latter may be derived from inositol1,4-bisphosphate, because homogenates of the insect salivary gland contain a bisphosphatase in additionto a trisphosphatase. These results suggest that the earliest event in the stimulus-response pathway isthe hydrolysis of polyphosphoinositides by a phosphodiesterase to yield inositol 1,4,5-trisphosphate andinositol 1,4-bisphosphate, which are subsequently hydrolysed to inositol 1-phosphate and inositol. Theabsence of inositol 1:2-cyclic phosphate could indicate that, at very short times after stimulation,phosphatidylinositol is not catabolized by its specific phosphodiesterase, or that any cyclic derivativeliberated is rapidly hydrolysed by inositol 1:2-cyclic phosphate 2-phosphohydrolase.", "metadata": {}}
+{"_id": "22029384", "title": "", "text": "RNA editing in brain controls a determinant of ion flow in glutamate-gated channels.L-glutamate, theprincipal excitatory transmitter in the brain, gates ion channels mediating fast neurotransmission.Subunit components of two related classes of glutamate receptor channels have been characterized bycDNA cloning and shown to carry either an arginine or a glutamine residue in a defined position of theirputative channel-forming segment. The arginine residue in this segment profoundly alters, anddominates, the properties of ion flow, as demonstrated for one channel class. We now show that thegenomic DNA sequences encoding the particular channel segment of all subunits harbor a glutaminecodon (CAG), even though an arginine codon (CGG) is found in mRNAs of three subunits. Multiple genesand alternative exons were excluded as sources for the arginine codon; hence, we propose thattranscripts for three subunits are altered by RNA editing. This process apparently edits subunit transcriptsof the two glutamate receptor classes with different efficiency and selectivity.", "metadata": {}}
+{"_id": "22036571", "title": "", "text": "Post-translational modifications of the beta-1 subunit of AMP-activated protein kinase affect enzymeactivity and cellular localization.The AMP-activated protein kinase (AMPK) is a ubiquitous mammalianprotein kinase important in the adaptation of cells to metabolic stress. The enzyme is a heterotrimer,consisting of a catalytic alpha subunit and regulatory beta and gamma subunits, each of which is amember of a larger isoform family. The enzyme is allosterically regulated by AMP and by phosphorylationof the alpha subunit. The beta subunit is post-translationally modified by myristoylation and multi-sitephosphorylation. In the present study, we have examined the impact of post-translational modification ofthe beta-1 subunit on enzyme activity, heterotrimer assembly and subcellular localization, usingsite-directed mutagenesis and expression of subunits in mammalian cells. Removal of the myristoylationsite (G2A mutant) results in a 4-fold activation of the enzyme and relocalization of the beta subunit froma particulate extranuclear distribution to a more homogenous cell distribution. Mutation of the serine-108phosphorylation site to alanine is associated with enzyme inhibition, but no change in cell localization. Incontrast, the phosphorylation site mutations, SS24, 25AA and S182A, while having no effects on enzymeactivity, are associated with nuclear redistribution of the subunit. Taken together, these results indicatethat both myristoylation and phosphorylation of the beta subunit of AMPK modulate enzyme activity andsubunit cellular localization, increasing the complexity of AMPK regulation.", "metadata": {}}
+{"_id": "22038539", "title": "", "text": "Caloric restriction delays age-related methylation driftIn mammals, caloric restriction consistently resultsin extended lifespan. Epigenetic information encoded by DNA methylation is tightly regulated, but showsa striking drift associated with age that includes both gains and losses of DNA methylation at varioussites. Here, we report that epigenetic drift is conserved across species and the rate of drift correlates withlifespan when comparing mice, rhesus monkeys, and humans. Twenty-two to 30-year-old rhesusmonkeys exposed to 30% caloric restriction since 7-14 years of age showed attenuation of age-relatedmethylation drift compared to ad libitum-fed controls such that their blood methylation age appeared 7years younger than their chronologic age. Even more pronounced effects were seen in 2.7-3.2-year-oldmice exposed to 40% caloric restriction starting at 0.3 years of age. The effects of caloric restriction onDNA methylation were detectable across different tissues and correlated with gene expression. Wepropose that epigenetic drift is a determinant of lifespan in mammals. Caloric restriction has been shownto increase lifespan in mammals. Here, the authors provide evidence that age-related methylation driftcorrelates with lifespan and that caloric restriction in mice and rhesus monkeys results in attenuation ofage-related methylation drift.", "metadata": {}}
+{"_id": "22042345", "title": "", "text": "Structural analysis of multiprotein complexes by cross-linking, mass spectrometry, and databasesearching.Most protein complexes are inaccessible to high resolution structural analysis. We report theresults of a combined approach of cross-linking, mass spectrometry, and bioinformatics to two humancomplexes containing large coiled-coil segments, the NDEL1 homodimer and the NDC80 heterotetramer.An important limitation of the cross-linking approach, so far, was the identification of cross-linkedpeptides from fragmentation spectra. Our novel approach overcomes the data analysis bottleneck ofcross-linking and mass spectrometry. We constructed a purpose-built database to match spectra withcross-linked peptides, define a score that expresses the quality of our identification, and estimate falsepositive rates. We show that our analysis sheds light on critical structural parameters such as thedirectionality of the homodimeric coiled coil of NDEL1, the register of the heterodimeric coiled coils of theNDC80 complex, and the organization of a tetramerization region in the NDC80 complex. Our approach isespecially useful to address complexes that are difficult in addressing by standard structural methods.", "metadata": {}}
+{"_id": "22049489", "title": "", "text": "The long non-coding RNA H19-derived miR-675 modulates human gastric cancer cell proliferation bytargeting tumor suppressor RUNX1.The lncRNA H19 has been recently shown to be upregulated and playimportant roles in gastric cancer tumorigenesis. However, the precise molecular mechanism of H19 andits mature product miR-675 in the carcinogenesis of gastric cancer remains unclear. In this study, wefound that miR-675 was positively expressed with H19 and was a pivotal mediator in H19-induced gastriccancer cell growth promotion. Subsequently, the tumor suppressor Runt Domain Transcription Factor1(RUNX1) was confirmed to be a direct target of miR-675 using a luciferase reporter assay and Westernblotting analyses. A series of rescue assays indicated that RUNX1 mediated H19/miR-67-induced gastriccancer cell phenotypic changes. Moreover, the inverse relationship between the expression of RUNX1 andH19/miR-675 was also revealed in gastric cancer tissues and gastric cancer cell lines. Taken together, ourstudy demonstrated that the novel pathway H19/miR-675/RUNX1 regulates gastric cancer developmentand may serve as a potential target for gastric cancer therapy.", "metadata": {}}
+{"_id": "22057077", "title": "", "text": "Methylphenidate-induced erections in a prepubertal child.Methylphenidate is a medication used routinelyin the management of attention deficit hyperactivity disorder. We report a case of a prepubertal child whodeveloped unwanted erections after commencing a response-adjusted dosing regimen of sustainedrelease methylphenidate. Despite priapism being a rare adverse reaction associated withmethylphenidate, physicians and parents need to be aware as it can have significant long-termcomplications.", "metadata": {}}
+{"_id": "22059387", "title": "", "text": "Mechanism of NO-mediated oxidative and nitrative DNA damage in hamsters infected with Opisthorchisviverrini: a model of inflammation-mediated carcinogenesis.Inflammation mediated by infection is animportant factor causing carcinogenesis. Opisthorchis viverrini (OV) infection is a risk factor ofcholangiocarcinoma (CHCA), probably through chronic inflammation. Formation of 8-nitroguanine and8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), and expression of inducible nitric oxide synthase(iNOS) and heme oxygenase-1 (HO-1) were assessed in the liver of hamsters infected with OV. We newlyproduced specific anti-8-nitroguanine antibody without cross-reaction. Double immunofluorescencestaining revealed that 8-oxodG and 8-nitroguanine were formed mainly in the same inflammatory cellsand epithelium of bile ducts from day 7 and showed the strongest immunoreactivity on days 21 and 30,respectively. It is noteworthy that 8-oxodG and 8-nitroguanine still remained in epithelium of bile ductson day 180, although amount of alanine aminotransferase activity returned to normal level. A time courseof 8-nitroguanine was associated with iNOS expression. Furthermore, this study demonstrated that HO-1expression and subsequent iron accumulation may be involved in enhancement of oxidative DNA damagein epithelium of small bile ducts. In conclusion, nitrative and oxidative DNA damage via iNOS expressionin hamsters infected with OV may participate in CHCA carcinogenesis.", "metadata": {}}
+{"_id": "22067786", "title": "", "text": "Monte Carlo tests for associations between disease and alleles at highly polymorphic loci.In an associationanalysis comparing cases and controls with respect to allele frequencies at a highly polymorphic locus, apotential problem is that the conventional chi-squared test may not be valid for a large, sparsecontingency table. However, reliance on statistics with known asymptotic distribution is now unnecessary,as Monte Carlo simulations can be performed to estimate the significance level of any test statistic. Wehave implemented a Monte Carlo method for four 'chi-squared' test statistics, three of which involvedcombination of alleles, and evaluated their performance on a real data set. Combining rare alleles toavoid small expected cell counts, and considering each allele in turn against the rest, reduced the powerto detect a genuine association when the number of alleles was very large. We should either not combinealleles at all, or combine them in such a way that preserves the evidence for an association.", "metadata": {}}
+{"_id": "22080671", "title": "", "text": "KLF4-dependent phenotypic modulation of smooth muscle cells has a key role in atherosclerotic plaquepathogenesisPrevious studies investigating the role of smooth muscle cells (SMCs) and macrophages inthe pathogenesis of atherosclerosis have provided controversial results owing to the use of unreliablemethods for clearly identifying each of these cell types. Here, using Myh11-CreERT2 ROSA floxed STOPeYFP Apoe−/− mice to perform SMC lineage tracing, we find that traditional methods for detecting SMCsbased on immunostaining for SMC markers fail to detect >80% of SMC-derived cells within advancedatherosclerotic lesions. These unidentified SMC-derived cells exhibit phenotypes of other cell lineages,including macrophages and mesenchymal stem cells (MSCs). SMC-specific conditional knockout ofKrüppel-like factor 4 (Klf4) resulted in reduced numbers of SMC-derived MSC- and macrophage-like cells,a marked reduction in lesion size, and increases in multiple indices of plaque stability, including anincrease in fibrous cap thickness as compared to wild-type controls. On the basis of in vivo KLF4chromatin immunoprecipitation–sequencing (ChIP-seq) analyses and studies of cholesterol-treatedcultured SMCs, we identified >800 KLF4 target genes, including many that regulate pro-inflammatoryresponses of SMCs. Our findings indicate that the contribution of SMCs to atherosclerotic plaques hasbeen greatly underestimated, and that KLF4-dependent transitions in SMC phenotype are critical in lesionpathogenesis.", "metadata": {}}
+{"_id": "22107641", "title": "", "text": "Late-life depression and microstructural abnormalities in dorsolateral prefrontal cortex whitematter.OBJECTIVE The purpose of this study was to determine whether microstructural abnormalities inthe white matter of the dorsolateral prefrontal cortex are associated with late-life depression. METHODSeventeen elderly depressed subjects were compared with 16 elderly subjects who were not depressed.Diffusion tensor imaging was used to measure the fractional anisotropy of the white matter in thedorsolateral prefrontal cortex's superior and middle frontal gyri bilaterally and in the left occipital lobe asa control region. The authors compared results between groups while controlling for age, sex, andcomorbid medical disorders. RESULTS Even after controlling for age, sex, hypertension, and heartdisease, the authors found significantly lower fractional anisotropy values in the right superior frontalgyrus white matter of depressed patients than comparison subjects. CONCLUSIONS Microstructuralchanges in the white matter of the right superior frontal gyrus are associated with late-life depression.Further work is needed to determine how these changes contribute to depression outcomes.", "metadata": {}}
+{"_id": "22116439", "title": "", "text": "Pioglitazone prevents tau oligomerization.Tau aggregation and amyloid β protein (Aβ) deposition are themain causes of Alzheimer's disease (AD). Peroxisome proliferator-activated receptor γ (PPARγ) activationmodulates Aβ production. To test whether the PPARγ agonist pioglitazone (PIO) is also effective inpreventing tau aggregation in AD, we used a cellular model in which wild-type tau protein (4R0N) isoverexpressed (M1C cells) (Hamano et al., 2012) as well as primary neuronal cultures. PIO reduced bothphosphorylated and total tau levels, and inactivated glycogen synthase kinase 3β, a major tau kinase,associated with activation of Akt. In addition, PIO decreased cleaved caspase3 and C-terminal truncatedtau species by caspase, which is expected to decrease tau aggregation. A fractionation study showed thatPIO reduced high molecular-weight (120 kDa), oligomeric tau species in Tris Insoluble, sarkosyl-solublefractions. Tau decrease was reversed by adding GW9662, a PPARγ antagonist. Together, our currentresults support the idea that PPARγ agonists may be useful therapeutic agents for AD.", "metadata": {}}
+{"_id": "22123421", "title": "", "text": "Prognostic impact of the mean platelet volume/platelet count ratio in terms of survival in advancednon-small cell lung cancer.BACKGROUND Mean platelet volume (MPV) is a platelet volume index.Classically, MPV was recognized as a hallmark of platelet activation. Recent studies have revealed thatthe MPV and MPV/platelet count (PC) ratio can predict long-term mortality in patients with ischemiccardio-vascular disease. In addition, these indices were correlated with the pathophysiologicalcharacteristics of patients with various disorders, including malignant tumors. PATIENTS AND METHODSWe retrospectively analyzed various hematological indices of patients with advanced non-small cell lungcancer (NSCLC). The aim of this study was to evaluate the contribution of platelet volume indices tosurvival in these patients. RESULTS A total of 268 patients were enrolled in the study. The median age ofthe patients was 68 years (range: 31-87 years). We compared various hematological indices between theNSCLC group and an age- and sex-matched comparator group. MPV was significantly decreased in theNSCLC group compared to the comparator group. In contrast, the PC was significantly increased in theNSCLC group. Consequently, the MPV/PC ratio was also decreased in the NSCLC group (0.397 vs. 0.501).In receiver operating characteristics (ROC) curve analysis, the MPV/PC ratio was associated with asensitivity of 62.3% and a specificity of 74.6% at a cutoff value of 0.408730 (area under the curve[AUC], 0.72492)]. Univariate analysis revealed that overall survival (OS) was significantly shorter in thegroup with a low MPV/PC ratio than in the other group (median survival time [MST]: 10.3 months vs.14.5 months, log-rank, P=0.0245). Multivariate analysis confirmed that a low MPV/PC ratio was anindependent unfavorable predictive factor for OS (hazard ratio [HR]: 1.668, 95% confidence interval[CI]: 1.235-2.271, P=0.0008). CONCLUSION These data clearly demonstrate that the MPV/PC ratio wasclosely associated with survival in patients with advanced NSCLC.", "metadata": {}}
+{"_id": "22130056", "title": "", "text": "Traceability of biologicals: present challenges in pharmacovigilance.INTRODUCTION Traceability isimportant in the postmarketing surveillance of biologicals, since changes in the manufacturing processmay give rise to product- or batch-specific risks. With the expected expansion of the biosimilar market,there have been concerns about the ability to trace individual products within pharmacovigilancedatabases. AREAS COVERED The authors discuss the present challenges in the traceability of biologicalsin relation to pharmacovigilance, by exploring the processes involved in ensuring traceability. Theyexplore both the existing systems that are in place for the recording of exposure information in clinicalpractice, as well as the critical steps involved in the transfer of exposure data to variouspharmacovigilance databases. EXPERT OPINION The existing systems ensure the traceability ofbiologicals down to the manufacturer within pharmacy records, but do not support the routine recordingof batch information. Expected changes in supply chain standards provide opportunities to systematicallyrecord detailed exposure information. Spontaneous reporting systems are the most vulnerable link inensuring traceability, due to the manual nature of data transfer. Efforts to improve the traceabilityshould, in the short term, be focused toward encouraging health professionals and patients tosystematically record and report detailed exposure information. Long-term solutions lie in expanding theaccessibility to, and increasing the electronic exchange of exposure data.", "metadata": {}}
+{"_id": "22134353", "title": "", "text": "Regulation of self-ligands for activating natural killer cell receptors.Natural killer (NK) cells are able tolyse infected and tumor cells while sparing healthy cells. Recognition of diseased cells by NK cells isgoverned by several activating and inhibitory receptors. We review numerous pathways that have beenimplicated in the regulation of self-ligands for activating receptors, including NKG2D, DNAM-1, LFA-1,NKp30, NKp44, NKp46, NKp65, and NKp80 found on NK cells and some T cells. Understanding how theregulation of self-encoded ligand expression is regulated may provide novel avenues for futuretherapeutic approaches to infections and cancer.", "metadata": {}}
+{"_id": "22150633", "title": "", "text": "A core Klf circuitry regulates self-renewal of embryonic stem cellsEmbryonic stem (ES) cells are unique intheir ability to self-renew indefinitely and maintain pluripotency. These properties require transcriptionfactors that specify the gene expression programme of ES cells. It has been possible to reverse the highlydifferentiated state of somatic cells back to a pluripotent state with a combination of four transcriptionfactors: Klf4 is one of the reprogramming factors required, in conjunction with Oct4, Sox2 and c-Myc.Maintenance of self-renewal and pluripotency of ES cells requires Oct4, Sox2 and c-Myc, but Klf4 isdispensable. Here, we show that Krüppel-like factors are required for the self-renewal of ES cells.Simultaneous depletion of Klf2, Klf4 and Klf5 lead to ES cell differentiation. Chromatinimmunoprecipitation coupled to microarray assay reveals that these Klf proteins share many commontargets of Nanog, suggesting a close functional relationship between these factors. Expression analysisafter triple RNA interference (RNAi) of the Klfs shows that they regulate key pluripotency genes, such asNanog. Taken together, our study provides new insight into how the core Klf circuitry integrates into theNanog transcriptional network to specify gene expression that is unique to ES cells.", "metadata": {}}
+{"_id": "22153455", "title": "", "text": "A myeloid hypoxia-inducible factor 1α-Krüppel-like factor 2 pathway regulates gram-positiveendotoxin-mediated sepsis.Although gram-positive infections account for the majority of cases of sepsis,the molecular mechanisms underlying their effects remains poorly understood. We investigated how cellwall components of gram-positive bacteria contribute to the development of sepsis. Experimentalobservations derived from cultured primary macrophages and the cell line indicate that gram-positivebacterial endotoxins induce hypoxia-inducible factor 1α (HIF-1α) mRNA and protein expression.Inoculation of live or heat-inactivated gram-positive bacteria with macrophages induced HIF-1transcriptional activity in macrophages. Concordant with these results, myeloid deficiency of HIF-1αattenuated gram-positive bacterial endotoxin-induced cellular motility and proinflammatory geneexpression in macrophages. Conversely, gram-positive bacteria and their endotoxins reduced expressionof the myeloid anti-inflammatory transcription factor Krüppel-like transcription factor 2 (KLF2). Sustainedexpression of KLF2 reduced and deficiency of KLF2 enhanced gram-positive endotoxins induced HIF-1αmRNA and protein expression in macrophages. More importantly, KLF2 attenuated gram-positiveendotoxins induced cellular motility and proinflammatory gene expression in myeloid cells. Consistentwith these results, mice deficient in myeloid HIF-1α were protected from gram-positiveendotoxin-induced sepsis mortality and clinical symptomatology. By contrast, myeloid KLF2-deficientmice were susceptible to gram-positive sepsis induced mortality and clinical symptoms. Collectively,these observations identify HIF-1α and KLF2 as critical regulators of gram-positive endotoxin-mediatedsepsis.", "metadata": {}}
+{"_id": "22159299", "title": "", "text": "Autophagy controls Salmonella infection in response to damage to the Salmonella-containingvacuole.Salmonella enterica serovar Typhimurium (S. Typhimurium) is a facultative intracellularpathogen that causes disease in a variety of hosts. S. Typhimurium actively invade host cells andtypically reside within a membrane-bound compartment called the Salmonella-containing vacuole (SCV).The bacteria modify the fate of the SCV using two independent type III secretion systems (TTSS). TTSSare known to damage eukaryotic cell membranes and S. Typhimurium has been suggested to damage theSCV using its Salmonella pathogenicity island (SPI)-1 encoded TTSS. Here we show that this damagegives rise to an intracellular bacterial population targeted by the autophagy system during in vitroinfection. Approximately 20% of intracellular S. Typhimurium colocalized with the autophagy markerGFP-LC3 at 1 h postinfection. Autophagy of S. Typhimurium was dependent upon the SPI-1 TTSS andbacterial protein synthesis. Bacteria targeted by the autophagy system were often associated withubiquitinated proteins, indicating their exposure to the cytosol. Surprisingly, these bacteria alsocolocalized with SCV markers. Autophagy-deficient (atg5-/-) cells were more permissive for intracellulargrowth by S. Typhimurium than normal cells, allowing increased bacterial growth in the cytosol. Wepropose a model in which the host autophagy system targets bacteria in SCVs damaged by the SPI-1TTSS. This serves to retain intracellular S. Typhimurium within vacuoles early after infection to protectthe cytosol from bacterial colonization. Our findings support a role for autophagy in innate immunity anddemonstrate that Salmonella infection is a powerful model to study the autophagy process.", "metadata": {}}
+{"_id": "22174015", "title": "", "text": "PI3K-Akt-mTORC1-S6K1/2 axis controls Th17 differentiation by regulating Gfi1 expression and nucleartranslocation of RORγ.The PI3K-Akt-mTORC1 axis contributes to the activation, survival, and proliferationof CD4(+) T cells upon stimulation through TCR and CD28. Here, we demonstrate that the suppression ofthis axis by deletion of p85α or PI3K/mTORC1 inhibitors as well as T cell-specific deletion of raptor, anessential component of mTORC1, impairs Th17 differentiation in vitro and in vivo in a S6K1/2-dependentfashion. Inhibition of PI3K-Akt-mTORC1-S6K1 axis impairs the downregulation of Gfi1, a negativeregulator of Th17 differentiation. Furthermore, we demonstrate that S6K2, a nuclear counterpart ofS6K1, is induced by the PI3K-Akt-mTORC1 axis, binds RORγ, and carries RORγ to the nucleus. Theseresults point toward a pivotal role of PI3K-Akt-mTORC1-S6K1/2 axis in Th17 differentiation.", "metadata": {}}
+{"_id": "22178316", "title": "", "text": "Disrupted-in-schizophrenia 1 and neuregulin 1 are required for the specification of oligodendrocytes andneurones in the zebrafish brain.Schizophrenia may arise from subtle abnormalities in brain developmentdue to alterations in the functions of candidate susceptibility genes such as Disrupted-in-schizophrenia 1(DISC1) and Neuregulin 1 (NRG1). To provide novel insights into the functions of DISC1 in braindevelopment, we mapped the expression of zebrafish disc1 and set out to characterize its role in earlyembryonic development using morpholino antisense methods. These studies revealed a criticalrequirement for disc1 in oligodendrocyte development by promoting specification of olig2-positive cells inthe hindbrain and other brain regions. Since NRG1 has well-documented roles in myelination, we alsoanalyzed the roles of nrg1 and ErbB signalling in zebrafish brain development and we observed strikinglysimilar defects to those seen in disc1 morphant embryos. In addition to their effects on oligodendrocytedevelopment, knock-down of disc1 or nrg1 caused near total loss of olig2-positive cerebellar neurones,but caused no apparent loss of spinal motor neurones. These findings suggest that disc1 and nrg1function in common or related pathways controlling development of oligodendrocytes and neurones fromolig2-expressing precursor cells. Like DISC1 and NRG1, OLIG2 and ERBB4 are promising candidatesusceptibility genes for schizophrenia. Hence our findings in the zebrafish embryo suggest that hithertounappreciated neurodevelopmental connections may exist between key human schizophreniasusceptibility genes. These connections could be investigated in Disc1 and Nrg1 mouse models and ingenetically defined groups of patients in order to determine whether they are relevant to thepathobiology of schizophrenia. GenBank accession number for Danio rerio disc1: EU273350.", "metadata": {}}
+{"_id": "22180793", "title": "", "text": "Monoclonal antibody targeting of N-cadherin inhibits prostate cancer growth, metastasis and castrationresistanceThe transition from androgen-dependent to castration-resistant prostate cancer (CRPC) is alethal event of uncertain molecular etiology. Comparing gene expression in isogenic androgen-dependentand CRPC xenografts, we found a reproducible increase in N-cadherin expression, which was alsoelevated in primary and metastatic tumors of individuals with CRPC. Ectopic expression of N-cadherin innonmetastatic, androgen-dependent prostate cancer models caused castration resistance, invasion andmetastasis. Monoclonal antibodies against the ectodomain of N-cadherin reduced proliferation, adhesionand invasion of prostate cancer cells in vitro. In vivo, these antibodies slowed the growth of multipleestablished CRPC xenografts, blocked local invasion and metastasis and, at higher doses, led to completeregression. N-cadherin–specific antibodies markedly delayed the time to emergence of castrationresistance, markedly affected tumor histology and angiogenesis, and reduced both AKT serine-threoninekinase activity and serum interleukin-8 (IL-8) secretion. These data indicate that N-cadherin is a majorcause of both prostate cancer metastasis and castration resistance. Therapeutic targeting of this factorwith monoclonal antibodies may have considerable clinical benefit.", "metadata": {}}
+{"_id": "22185730", "title": "", "text": "PP2A regulates tau phosphorylation directly and also indirectly via activating GSK-3beta.Abnormalhyperphosphorylation of tau appears to be crucial in neurofibrillary degeneration in Alzheimer's disease(AD). Previous studies suggest that a down-regulation of protein phosphatase 2A (PP2A), the major tauphosphatase in human brain, contributes to tau hyperphosphorylation in AD. However, the effects ofPP2A down-regulation on site-specific tau hyperphosphorylation is not well understood. In the presentstudy, we showed that PP2A dephosphorylated tau at several phosphorylation sites with differentefficiencies. Among the sites studied, Thr205, Thr212, Ser214, and Ser262 were the most favorable sites,and Ser199 and Ser404 were the least favorable sites for PP2A in vitro. Inhibition of PP2A with okadaicacid in metabolically active rat brain slices caused inhibition of glycogen synthase kinase-3beta(GSK-3beta) via an increase in its phosphorylation at Ser9. GSK-3beta phosphorylated tau at many sites,with Ser199, Thr205, and Ser396 being the most favorable sites in cells. The overall alterations in tauphosphorylation induced by PP2A inhibition were the result of the combined effects of both reduced taudephosphorylation due to PP2A inhibition directly and reduced phosphorylation by GSK-3beta due to itsinhibition. Because the impacts of tau phosphorylation on its biological activity and on neurofibrillarydegeneration are site-specific, this study provides a new insight into the role of PP2A down-regulation inneurofibrillary degeneration in AD.", "metadata": {}}
+{"_id": "22186938", "title": "", "text": "Human artificial chromosomes containing chromosome 17 alphoid DNA maintain an active centromere inmurine cells but are not stable.Human artificial chromosomes (HACs) are autonomous molecules that canfunction and segregate as normal chromosomes in human cells. De novo HACs have successfully beenused as gene expression vectors to complement genetic deficiencies in human cultured cells. HACs nowoffer the possibility of studying the regulation and expression of large genes in a variety of cell types fromdifferent tissues and correcting gene deficiencies caused by human inherited diseases. Complementarygene expression studies in mice, especially in mouse models of human genetic diseases, are alsoimportant in determining if large human transgenes can be expressed appropriately from artificialchromosomes. Toward this aim we are establishing artificial chromosomes in murine cells as novel geneexpression vectors. Initially we transferred HAC vectors into murine cells, but were unable to generate denovo HACs at a reasonable frequency. We then transferred HACs previously established in humanHT1080 cells to three different murine cell types by microcell fusion, followed by positive selection. Weobserved that the HACs in murine cells bound centromere protein C (CENP-C), a marker of activecentromeres, and were detected under selection but rapidly lost when selection was removed. Theseresults suggest that the HACs maintain at least a partially functional centromere complex in murine cells,but other factors are required for stability and segregation. Artificial chromosomes containing mousecentromeric sequences may be required for better stability and maintenance in murine cells.", "metadata": {}}
+{"_id": "22190276", "title": "", "text": "How nascent phagosomes mature to become phagolysosomes.Phagocytosis mediates the clearance ofapoptotic bodies and also the elimination of microbial pathogens. The nascent phagocytic vacuole formedupon particle engulfment lacks microbicidal and degradative activity. These capabilities are acquired asthe phagosome undergoes maturation; a progressive remodeling of its membrane and contents thatculminates in the formation of phagolysosomes. Maturation entails orderly sequential fusion of thephagosomal vacuole with specialized endocytic and secretory compartments. Concomitantly, thephagosomal membrane undergoes both inward and outward vesiculation and tubulation followed byfission, thereby recycling components and maintaining its overall size. Here, we summarize what isknown about the molecular machinery that governs this complex metamorphosis of phagosomematuration.", "metadata": {}}
+{"_id": "22191759", "title": "", "text": "Purification and structural characterization of bovine cathelicidins, precursors of antimicrobialpeptides.Cathelicidins are a novel family of antimicrobial peptide precursors from mammalian myeloidcells. They are characterized by a conserved N-terminal region while the C-terminal antimicrobial domaincan vary considerably in both primary sequence and length. Four cathelicidins, proBac5, proBac7,prododecapeptide and proBMAP-28, have been concurrently purified from bovine neutrophils, usingsimple and rapid methodologies. The correlation of ES-MS data from the purified proteins with theircDNA-deduced sequences has revealed several common features of their primary sequence, such as thepresence of N-terminal 5-oxoproline (pyroglutamate) residues and two disulfide bridges in a 1-2, 3-4arrangement. The N-terminal domains of the cathelicidins present one or two Asp-Pro bonds, which areparticularly acid-labile in proBac5 and proBac7, but stable in prododecapeptide. This suggests that thespatial organization around these bonds may vary in different cathelicidins, and favour hydrolysis in somecases. An unexpected feature of the prododecapeptide is that it exists as dimers formed by three possiblecombinations of its two isoforms. The isolation of a truncated, monomeric form of this protein, lacking thecysteine-containing antimicrobial dodecapeptide, indicates that dimerization occurs via disulfide bridgeformation at the level of the C-terminal domain and that the dodecapeptide is likely released as a dimerfrom its precursor. Sequence-based secondary structure predictions and CD results indicate forcathelicidins a 30-50% content of extended conformation and <20% content of alpha-helicalconformation, with the alpha-helical segment placed near the N-terminus. Finally, similarity searchingand topology-based structure prediction underline a significant sequential and structural similaritybetween the conserved N-terminal domain of cathelicidins and cystatin-like domains, placing this familywithin the cystatin superfamily. When assayed against cathepsin L, unlike the potent cystatin inhibitors,three of the four cathelicidins show only a poor inhibitory activity (Ki = 0.6-3 microM).", "metadata": {}}
+{"_id": "22194407", "title": "", "text": "Tuberculosis mortality in England and Wales during 1982-1992: its association with poverty, ethnicity andAIDS.This paper seeks to establish the strength of association between contemporary tuberculosis (TB) inEngland and Wales and several potential aetiological factors. It presents an ecological analysis ofstandardised annual TB mortality rates for the 403 local authority districts between 1982 and 1992,disaggregated by age and sex. Social, demographic and ethnicity measures from the 1981 and 1991censuses and standardised annual AIDS-related mortality rates for young men are used to calculatePoisson regression models. A strong association was found between all TB mortality groups andovercrowding at the household level. For women, no other measures improved the explanatory power ofthe models. In multiple regressions, both poverty and AIDS-related mortality explained additionalvariation in the model for younger men. The link between ethnicity and tuberculosis notifications was notreflected in this analysis of mortality. For all groups no evidence of a positive relationship with ethnicitywas found, once overcrowding had been accounted for. The significance of household as opposed todistrict level crowding suggests that prolonged contact is required for disease transmission. Regressionanalysis indicates that it is the overcrowding and poverty among ethnic populations that is significant fortheir tuberculosis mortality. The fact that the relationship between AIDS and TB is confined to the groupmost typical of AIDS patients provides evidence that AIDS has little influence on the level of tuberculosismortality in the wider population. Explanations for the observed relationship include preferentialcertification, migration for treatment and shortcomings in health care provision.", "metadata": {}}
+{"_id": "22198971", "title": "", "text": "Noncognate interaction with MHC class II molecules is essential for maintenance of T cell metabolism toestablish optimal memory CD4 T cell function.CD4 memory T cells surviving in the absence of MHC classII contact lose their characteristic memory function. To investigate the mechanisms underlying theimpaired function of memory T cells in the absence of MHC class II molecules, we analyzed geneexpression profiles of resting memory T cells isolated from MHC class II-competent or -deficient hosts.The analysis focused on five transcripts related to T cell activation, metabolism, and survival that areunderexpressed in resting memory T cells from MHC class II-deficient hosts compared with MHC classII-competent hosts. CD4 memory cells isolated from MHC class II-deficient hosts display alterations intheir degree of differentiation as well as metabolic activity, and these changes are already manifest in theeffector phase despite the presence of Ag-expressing dendritic cells. Our data suggest that the absence ofinteractions with noncognate MHC class II molecules compromises the progressive accumulation ofsignals that ensure optimal survival and fitness to sustain the metabolic activity of activated T cells andshape the functional capacity of the future memory compartment. Signals via AKT coordinate survival andmetabolic pathways and may be one of the crucial events linking interaction with MHC class II moleculesto the successful generation of a long-lived functional memory CD4 T cell population.", "metadata": {}}
+{"_id": "22210434", "title": "", "text": "The kinase TAK1 integrates antigen and cytokine receptor signaling for T cell development, survival andfunctionThe kinase TAK1 is critical for innate and B cell immunity. The function of TAK1 in T cells isunclear, however. We show here that T cell–specific deletion of the gene encoding TAK1 resulted inreduced development of thymocytes, especially of regulatory T cells expressing the transcription factorFoxp3. In mature thymocytes, TAK1 was required for interleukin 7–mediated survival and T cellreceptor–dependent activation of transcription factor NF-κB and the kinase Jnk. In effector T cells, TAK1was dispensable for T cell receptor–dependent NF-κB activation and cytokine production, but wasimportant for proliferation and activation of the kinase p38 in response to interleukins 2, 7 and 15. Thus,TAK1 is essential for the integration of T cell receptor and cytokine signals to regulate the development,survival and function of T cells.", "metadata": {}}
+{"_id": "22227889", "title": "", "text": "Caregiver burden in HIV-positive and HIV-negative partners of men with AIDS.This study examinesfactors associated with caregiver burden in 82 HIV-positive (HIV+) and 162 HIV-negative (HIV-) partnersof men with AIDS. We expected HIV+ caregivers to report more burden than HIV- caregivers because ofthe toll of their disease on their resources. HIV+ caregivers did report more burden and, compared withthe HIV- caregivers, they were more religious or spiritual, had less income, and coped by using morepositive reappraisal and cognitive escape-avoidance and by seeking social support. Comparisons of HIV+caregivers with 61 HIV+ partners of healthy men indicated that most differences between HIV+ and HIV-caregivers were associated with HIV seropositivity rather than caregiving. However, of the variablesassociated with HIV seropositivity, only religiosity or spirituality contributed independently to burden inHIV+ caregivers, suggesting a relatively weak link between HIV seropositivity and caregiver burden. Themodel explained 62% of the variance in burden in HIV+ caregivers and 36% of the variance in HIV-caregivers.", "metadata": {}}
+{"_id": "22236223", "title": "", "text": "Renal Disease and PregnancyPregnancy in women with different renal diseases has importantconsequences for the developing fetus and maternal health. Kidneys and the urinary tract have to adaptto the pregnancy status and therefore suffer significant anatomical, hemodynamic and endocrinechanges. Failure to adapt can aggravate the preexisting maternal disease and can also create suboptimalenvironment for fetal development and increase the risk of obstetric complications. Knowledge andcorrect interpretation of the renal functional tests is necessary for the modern obstetrician, avoiding anincorrect diagnosis for renal disease where only specific renal changes during pregnancy are present, butmeanwhile a correct evaluation of the renal function and changes can detect a pathology that canaggravate both the mother’s and the baby’s condition. Improvement and better understanding of therenal pathophysiology in pregnancy made possible that pregnant woman look forward for a goodoutcome, including here also the women with renal transplant. Nowadays is underlined the concept ofmultidisciplinary teamwork, a very important concept of modern medicine. The obstetrician shouldconsider nephrologists as key players in the team and in our opinion should refer to them the pregnantwomen for a routine check-up of the renal status in the 2nd or beginning of 3rd trimester by ultrasound,beside the usual blood and urine analysis. The nephrologists and urologists should be involved in themanagement of severe medical conditions, such as preeclampsia, acute and chronic renal failure andnever the less in the complex management of dialysis or renal transplant patients. In pregnancy it can beencountered several renal diseases, some of them preexisting the pregnancy and other developed orbeing direct influenced by pregnancy. This chapter will discuss briefly the basic evaluation of renal statusin order to present and better understand the acute and chronic renal disorders in pregnancy. Thechapter will focus on the most common preexisting diseases in pregnancy such as: chronicglomerulonephritis, secondary glomerular nephropathies, interstitial nephropathies (chronicpyelonephritis, renal tuberculosis), diabetes nephropathy, unique surgical kidney, chronic renal failure.From the renal diseases directly influenced by pregnancy it will be discussed: asymptomatic bacteriuria,symptomatic urinary infection, urolithiasis and acute renal failure in pregnancy. It will be presented alsothe management of dialysis in pregnancy and pregnant women with renal transplant.", "metadata": {}}
+{"_id": "22241778", "title": "", "text": "Integrin beta1-mediated matrix assembly and signaling are critical for the normal development andfunction of the kidney glomerulus.The human kidneys filter 180 l of blood every day via about 2.5 millionglomeruli. The three layers of the glomerular filtration apparatus consist of fenestrated endothelium,specialized extracellular matrix known as the glomerular basement membrane (GBM) and the podocytefoot processes with their modified adherens junctions known as the slit diaphragm (SD). In this study weexplored the contribution of podocyte beta1 integrin signaling for normal glomerular function. Mice withpodocyte specific deletion of integrin beta1 (podocin-Cre beta1-fl/fl mice) are born normal but cannotcomplete postnatal renal development. They exhibit detectable proteinuria on day 1 and die within aweek. The kidneys of podocin-Cre beta1-fl/fl mice exhibit normal glomerular endothelium but showsevere GBM defects with multilaminations and splitting including podocyte foot process effacement. Theintegrin linked kinase (ILK) is a downstream mediator of integrin beta1 activity in epithelial cells. Tofurther explore whether integrin beta1-mediated signaling facilitates proper glomerular filtration, wegenerated mice deficient of ILK in the podocytes (podocin-Cre ILK-fl/fl mice). These mice developnormally but exhibit postnatal proteinuria at birth and die within 15 weeks of age due to renal failure.Collectively, our studies demonstrate that podocyte beta1 integrin and ILK signaling is critical forpostnatal development and function of the glomerular filtration apparatus.", "metadata": {}}
+{"_id": "22264117", "title": "", "text": "The Aging Epigenome.During aging, the mechanisms that normally maintain health and stress resistancestrikingly decline, resulting in decrepitude, frailty, and ultimately death. Exactly when and how thisdecline occurs is unknown. Changes in transcriptional networks and chromatin state lie at the heart ofage-dependent decline. These epigenomic changes are not only observed during aging but alsoprofoundly affect cellular function and stress resistance, thereby contributing to the progression of aging.We propose that the dysregulation of transcriptional and chromatin networks is a crucial component ofaging. Understanding age-dependent epigenomic changes will yield key insights into how aging beginsand progresses and should lead to the development of new therapeutics that delay or even reverse agingand age-related diseases.", "metadata": {}}
+{"_id": "22267225", "title": "", "text": "Cancer chemoprevention: Much has been done, but there is still much to do. State of the art and possiblenew approaches.Over the past three decades great efforts have been made in search of cancerchemoprevention strategies. The increase in knowledge of the long process from normal to cancer cellhas enabled interventions in terms of lifestyle modifications, natural compounds or drugs to block orreverse the process. Great successes have been achieved, especially for breast and colorectal cancer.However, these strategies have yet to find clinical application on a large scale. In this article we identifythe achievements, the pitfalls and the next steps to be taken to improve the efficacy and applicability ofchemoprevention strategies. Among the crucial key points to be implemented are educational activitiesfor physicians to appropriately disseminate the aim and indeed the culture of chemoprevention. It isessential to improve the risk-benefit balance, seeking the minimal active doses, intermittent schedules, abetter characterization of the risk categories via a more personalized intervention based on individualcharacteristics, and ensure the containment of costs of public and private health prevention programs.", "metadata": {}}
+{"_id": "22281684", "title": "", "text": "Secreted Frizzled-related Protein 5 Diminishes Cardiac Inflammation and Protects the Heart fromIschemia/Reperfusion Injury.Wnt signaling has diverse actions in cardiovascular development and diseaseprocesses. Secreted frizzled-related protein 5 (Sfrp5) has been shown to function as an extracellularinhibitor of non-canonical Wnt signaling that is expressed at relatively high levels in white adipose tissue.The aim of this study was to investigate the role of Sfrp5 in the heart under ischemic stress. Sfrp5 KOand WT mice were subjected to ischemia/reperfusion (I/R). Although Sfrp5-KO mice exhibited nodetectable phenotype when compared with WT control at baseline, they displayed larger infarct sizes,enhanced cardiac myocyte apoptosis, and diminished cardiac function following I/R. The ischemic lesionsof Sfrp5-KO mice had greater infiltration of Wnt5a-positive macrophages and greater inflammatorycytokine and chemokine gene expression when compared with WT mice. In bone marrow-derivedmacrophages, Wnt5a promoted JNK activation and increased inflammatory gene expression, whereastreatment with Sfrp5 blocked these effects. These results indicate that Sfrp5 functions to antagonizeinflammatory responses after I/R in the heart, possibly through a mechanism involving non-canonicalWnt5a/JNK signaling.", "metadata": {}}
+{"_id": "22309946", "title": "", "text": "Asymptomatic spinal cord lesions predict disease progression in radiologically isolatedsyndrome.BACKGROUND Technological advancements in neuroimaging and the increased use of thesediagnostic modalities are responsible for the discovery of incidentally identified anomalies within the CNS.In addition to the identification of unanticipated brain MRI abnormalities suggestive of demyelinatingdisease in patients undergoing neuroimaging for a medical reason other than evaluation for multiplesclerosis (MS), asymptomatic spinal cord lesions are periodically identified. OBJECTIVE To determine ifasymptomatic spinal cord lesions are associated with clinical progression in subjects with radiologicallyisolated syndrome (RIS). METHODS A retrospective review of RIS cases at the University of California,San Francisco Multiple Sclerosis Center was performed. The presence of asymptomatic cervical spinalcord MRI lesions was analyzed as a potential predictor for clinical progression. RESULTS Twenty-five of 71subjects with RIS possessed findings within the cervical spine that were highly suggestive ofdemyelinating disease. Of these subjects, 21 (84%) progressed clinically to clinically isolated syndrome(n = 19) or primary progressive multiple sclerosis (n = 2) over a median time of 1.6 years from the dateof RIS identification (interquartile range 0.8-3.8). The sensitivity, specificity, and positive predictive valueof an asymptomatic spinal cord lesion for subsequent development of either a first demyelinating attackor primary progressive MS were 87.5%, 91.5%, and 84%, respectively. The odds ratio of clinicalprogression was 75.3 (95% confidence interval 16.1-350.0, p < 0.0001). This association remainedsignificant after adjusting for potential confounders. CONCLUSION These findings suggest that thepresence of asymptomatic spinal cord lesions place subjects with RIS at substantial risk for clinicalconversion to either an acute or progressive event, a risk that is independent of brain lesions on MRI.", "metadata": {}}
+{"_id": "22312627", "title": "", "text": "YqhC regulates transcription of the adjacent Escherichia coli genes yqhD and dkgA that are involved infurfural tolerancePrevious results have demonstrated that the silencing of adjacent genes encodingNADPH-dependent furfural oxidoreductases (yqhD dkgA) is responsible for increased furfural tolerance inan E. coli strain EMFR9 [Miller et al., Appl Environ Microbiol 75:4315–4323, 2009]. This gene silencing isnow reported to result from the spontaneous insertion of an IS10 into the coding region of yqhC, anupstream gene. YqhC shares homology with transcriptional regulators belonging to the AraC/XylS familyand was shown to act as a positive regulator of the adjacent operon encoding YqhD and DkgA. Regulationwas demonstrated by constructing a chromosomal deletion of yqhC, a firefly luciferase reporter plasmidfor yqhC, and by a direct comparison of furfural resistance and NADPH-dependent furfural reductaseactivity. Closely related bacteria contain yqhC, yqhD, and dkgA orthologs in the same arrangement as inE. coli LY180. Orthologs of yqhC are also present in more distantly related Gram-negative bacteria.Disruption of yqhC offers a useful approach to increase furfural tolerance in bacteria.", "metadata": {}}
+{"_id": "22317868", "title": "", "text": "A direct role for Met endocytosis in tumorigenesisCompartmentalization of signals generated by receptortyrosine kinase (RTK) endocytosis has emerged as a major determinant of various cell functions. Here,using tumour-associated Met-activating mutations, we demonstrate a direct link between endocytosis andtumorigenicity. Met mutants exhibit increased endocytosis/recycling activity and decreased levels ofdegradation, leading to accumulation on endosomes, activation of the GTPase Rac1, loss of actin stressfibres and increased levels of cell migration. Blocking endocytosis inhibited mutants’anchorage-independent growth, in vivo tumorigenesis and metastasis while maintaining their activation.One mutant resistant to inhibition by a Met-specific tyrosine kinase inhibitor was sensitive to endocytosisinhibition. Thus, oncogenicity of Met mutants results not only from activation but also from their alteredendocytic trafficking, indicating that endosomal signalling may be a crucial mechanism regulatingRTK-dependent tumorigenesis.", "metadata": {}}
+{"_id": "22328290", "title": "", "text": "Immediate effects of droperidolThe subjective and behavioural responses of 20 healthy volunteers takingdroperidol 5 mg as part of a cognitive challenge programme were catalogued. Some form of akathisiawas universally experienced. Half of the subjects were dysphoric, but there appeared to be a number ofdifferent inputs to their dysphoria and a range of other effects were noted, including sedation,dissociative experiences, alterations in sensation and subtle changes in physiognomy. The duration ofthese effects varied from a few hours to over a week. In the acute phase, insight as to the origin of whatwas happening was mixed. The results have implications for the interpretation of cognitive challengetests, the nature of akathisia, clinical therapeutics and drug development. © 1998 John Wiley & Sons,Ltd.", "metadata": {}}
+{"_id": "22334300", "title": "", "text": "Toxicity of Nerium oleander in the monkey (Cebus apella).The toxic effects of Nerium oleander wereevaluated in capuchin monkeys (Cebus apella) by examination of clinical signs, hematologic and serumchemical values, and gross and microscopic lesions. Dried and ground oleander leaves were given atintervals of 48 h in doses of 30, 7.5, and 3 mg/kg body weight. The cumulative lethal dose ranged from30 to 60 mg/kg body weight in monkeys that were given doses of 30 and 7.5 mg/kg body weight.Monkeys that received doses of 3 mg/kg body weight (total cumulative dose: 60 mg/kg) survived. Clinicalsigns were vomiting, salivation, polyuria, bradycardia, vaginal hemorrhage, abortion, anorexia,constipation, loss of body weight, narcosis, restlessness, weakness, and shallow and rapid respirations.Changes in blood values were leukocytosis; neutrophilia; increased potassium, glutamic-oxalacetictransaminase, glutamic-pyruvic transaminase, blood urea nitrogen and α-globulins; reticulo-cytopenia;and decreased calcium, glucose, total serum protein, albumin, γ-globulin leve...", "metadata": {}}
+{"_id": "22358449", "title": "", "text": "Plzf regulates limb and axial skeletal patterningThe promyelocytic leukaemia zinc finger (Plzf) protein(encoded by the gene Zfp145) belongs to the POZ/zinc-finger family of transcription factors. Here wegenerate Zfp145−/− mice and show that Plzf is essential for patterning of the limb and axial skeleton.Plzf inactivation results in patterning defects affecting all skeletal structures of the limb, includinghomeotic transformations of anterior skeletal elements into posterior structures. We demonstrate thatPlzf acts as a growth-inhibitory and pro-apoptotic factor in the limb bud. The expression of members ofthe abdominal b (Abdb) Hox gene complex, as well as genes encoding bone morphogenetic proteins(Bmps), is altered in the developing limb of Zfp145−/− mice. Plzf regulates the expression of these genesin the absence of aberrant polarizing activity and independently of known patterning genes. Zfp145−/−mice also exhibit anterior-directed homeotic transformation throughout the axial skeleton with associatedalterations in Hox gene expression. Plzf is therefore a mediator of anterior-to-posterior (AP) patterning inboth the axial and appendicular skeleton and acts as a regulator of Hox gene expression.", "metadata": {}}
+{"_id": "22362025", "title": "", "text": "Requirement for the ERI/DICER complex in endogenous RNA interference and sperm development inCaenorhabditis elegans.Small regulatory RNAs are key regulators of gene expression. One class of smallregulatory RNAs, termed the endogenous small interfering RNAs (endo siRNAs), is thought to negativelyregulate cellular transcripts via an RNA interference (RNAi)-like mechanism termed endogenous RNAi(endo RNAi). A complex of proteins composed of ERI-1/3/5, RRF-3, and DICER (the ERI/DICER complex)mediates endo RNAi processes in Caenorhabditis elegans. We conducted a genetic screen to identifyadditional components of the endo RNAi machinery. Our screen recovered alleles of eri-9, which encodesa novel DICER-interacting protein, and a missense mutation within the helicase domain of DICER[DCR-1(G492R)]. ERI-9(-) and DCR-1(G492) animals exhibit defects in endo siRNA expression and aconcomitant failure to regulate mRNAs that exhibit sequence homology to these endo siRNAs, indicatingthat ERI-9 and the DCR-1 helicase domain function in the C. elegans endo RNAi pathway. We define asubset of Eri mutant animals (including eri-1, rrf-3, eri-3, and dcr-1, but not eri-9 or ergo-1) that exhibittemperature-sensitive, sperm-specific sterility and defects in X chromosome segregation. Among thesemutants we find multiple aberrations in sperm development beginning with cytokinesis and extendingthrough terminal differentiation. These results identify novel components of the endo RNAi machinery,demonstrate differential requirements for the Eri factors in the sperm-producing germline, and begin todelineate the functional requirement for the ERI/DICER complex in sperm development.", "metadata": {}}
+{"_id": "22371455", "title": "", "text": "Drug-induced thrombocytopenia: pathogenesis, evaluation, and management.Although drugs are acommon cause of acute immune-mediated thrombocytopenia in adults, the drug etiology is often initiallyunrecognized. Most cases of drug-induced thrombocytopenia (DITP) are caused by drug-dependentantibodies that are specific for the drug structure and bind tightly to platelets by their Fab regions butonly in the presence of the drug. A comprehensive database of 1301 published reports describing 317drugs, available at www.ouhsc.edu/platelets, provides information on the level of evidence for a causalrelation to thrombocytopenia. Typically, DITP occurs 1 to 2 weeks after beginning a new drug or suddenlyafter a single dose when a drug has previously been taken intermittently. However, severethrombocytopenia can occur immediately after the first administration of antithrombotic agents that blockfibrinogen binding to platelet GP IIb-IIIa, such as abciximab, tirofiban, and eptifibatide. Recovery fromDITP usually begins within 1 to 2 days of stopping the drug and is typically complete within a week.Drug-dependent antibodies can persist for many years; therefore, it is important that the drug etiologybe confirmed and the drug be avoided thereafter.", "metadata": {}}
+{"_id": "22401061", "title": "", "text": "Costs and financial feasibility of malaria eliminationThe marginal costs and benefits of converting malariaprogrammes from a control to an elimination goal are central to strategic decisions, but empiricalevidence is scarce. We present a conceptual framework to assess the economics of elimination andanalyse a central component of that framework-potential short-term to medium-term financial savings.After a review that showed a dearth of existing evidence, the net present value of elimination in five siteswas calculated and compared with effective control. The probability that elimination would be cost-savingover 50 years ranged from 0% to 42%, with only one site achieving cost-savings in the base case. Thesefindings show that financial savings should not be a primary rationale for elimination, but that eliminationmight still be a worthy investment if total benefits are sufficient to outweigh marginal costs. Robustresearch into these elimination benefits is urgently needed.", "metadata": {}}
+{"_id": "22401720", "title": "", "text": "Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblastgrowth factor, tumor growth factor beta-1, platelet-derived endothelial cell growth factor, placentagrowth factor, and pleiotrophin in human primary breast cancer and its relation toangiogenesAngiogenesis is a significant prognostic factor in breast cancer, but the factors that controlangiogenesis in vivo are not well defined. Multiple angiogenic polypeptides are known, and we havedetermined the expression of seven of these in primary human breast cancers; the relationship ofexpression to estrogen receptor and vascular density was also examined. Vascular endothelial growthfactor (VEGF) and its four isoforms (121, 165, 189, and 206 amino acids), transforming growth factor(TGF)-beta1, pleiotrophin, acidic and basic fibroblast growth factor (FGF), placental growth factor, andthymidine phosphorylase (platelet-derived endothelial cell growth factor) were quantitated by RNaseprotection analysis. beta-FGF was also measured by ELISA. The estrogen receptor (ER), epidermalgrowth factor receptor, and vascular density were analyzed in 64 primary breast cancers. All tumorsexpressed at least six different vascular growth factors. VEGF was most abundant, and the transcript forthe 121-amino acid form predominated. Other angiogenic factors expressed at high levels were thymidinephosphorylase and TGF-beta1. Expression of most of the angiogenic factors did not correlate with that ofER or vascular density. However, thymidine phosphorylase did, with a correlation coefficient of 0.3 (P =0.03). There were significant associations of pleiotrophin with acidic FGF expression (P = 0.001) andTGF-beta with platelet-derived endothelial cell growth factor expression (P = 0.001). Thus, angiogenesismay involve a coordinate regulation of some vascular growth factors. High VEGF expression correlatedwith poor prognosis in univariate analysis (P = 0.03), as did ER and epidermal growth factor receptorexpression. Basic FGF was also assessed by ELISA and was more highly expressed in tumors than normalbreast tissues (median, 346 microg/ml cytosol; range, 54-1323 versus median, 149; range, 32-509; P =0.01). Implications for therapy are that broad spectrum agents that block features common to thesefactors may be useful (e.g., antagonism of heparin-binding activity agents), because so many angiogenicfactors are expressed. Inhibiting endothelial migration or agents directly toxic to endothelium would be ofvalue in a combined approach to therapy.", "metadata": {}}
+{"_id": "22405338", "title": "", "text": "Cnn1 inhibits the interactions between the KMN complexes of the yeast kinetochoreKinetochores attachthe replicated chromosomes to the mitotic spindle and orchestrate their transmission to the daughtercells. Kinetochore–spindle binding and chromosome segregation are mediated by the multi-copyKNL1Spc105, MIS12Mtw1 and NDC80Ndc80 complexes that form the so-called KMN network.KMN–spindle attachment is regulated by the Aurora BIpl1 and MPS1Mps1 kinases. It is unclear whetherother mechanisms exist that support KMN activity during the cell cycle. Using budding yeast, we showthat kinetochore protein Cnn1 localizes to the base of the Ndc80 complex and promotes a functionallycompetent configuration of the KMN network. Cnn1 regulates KMN activity in a spatiotemporal manner byinhibiting the interaction between its complexes. Cnn1 activity peaks in anaphase and is driven by theCdc28, Mps1 and Ipl1 kinases.", "metadata": {}}
+{"_id": "22406695", "title": "", "text": "Origin and functions of tissue macrophages.Macrophages are distributed in tissues throughout the bodyand contribute to both homeostasis and disease. Recently, it has become evident that most adult tissuemacrophages originate during embryonic development and not from circulating monocytes. Each tissuehas its own composition of embryonically derived and adult-derived macrophages, but it is unclearwhether macrophages of distinct origins are functionally interchangeable or have unique roles at steadystate. This new understanding also prompts reconsideration of the function of circulating monocytes.Classical Ly6c(hi) monocytes patrol the extravascular space in resting organs, and Ly6c(lo) nonclassicalmonocytes patrol the vasculature. Inflammation triggers monocytes to differentiate into macrophages,but whether resident and newly recruited macrophages possess similar functions during inflammation isunclear. Here, we define the tools used for identifying the complex origin of tissue macrophages anddiscuss the relative contributions of tissue niche versus ontological origin to the regulation of macrophagefunctions during steady state and inflammation.", "metadata": {}}
+{"_id": "22414304", "title": "", "text": "Treatment outcome of an unselected cohort of tuberculosis patients in relation to humanimmunodeficiency virus serostatus in Zomba Hospital, Malawi.There is little information about treatmentoutcome in patients with smear-negative pulmonary tuberculosis (PTB) or extrapulmonary tuberculosis(EPTB) treated under routine programme conditions in subsaharan Africa. A prospective study wascarried out to determine treatment outcome in an unselected cohort of TB patients admitted to ZombaGeneral Hospital, Malawi. Eight hundred and twenty-seven adult TB patients (451 men and 376 women)were registered between 1 July and 31 December 1995. Standardized treatment outcomes of treatmentcompletion, death, default, and transfer to another district were assessed in relation to type of TB, humanimmunodeficiency virus (HIV) serostatus, age and gender. Two hundred and fifty-four patients (31%)died by the end of treatment, half of the deaths occurring in the first month. Death rates were 19%among 386 patients with smear-positive PTB, 46% among 211 patients with smear-negative PTB, and37% among 230 patients with EPTB; 77% of the patients were HIV seropositive. Among new patients,HIV-positive patients had higher death rates than HIV-negative patients (hazard ratio [HR] 2.5; 95%confidence interval [95% CI] 1.6-3.8). Smear-negative patients had the highest death rates (HR 3.9;95% CI 2.7-5.5 compared to smear-positive patients), followed by EPTB patients (HR 2.6, 95% CI1.8-3.7 compared to smear-positive patients). Death rates increased with age but were similar in menand women. Adult patients in Malawi with smear-negative PTB and EPTB have low treatment completionand high death rates, related to high levels of HIV infection. National TB control programmes in areas ofhigh HIV prevalence should no longer ignore treatment outcomes in patients with smear-negative PTB orEPTB.", "metadata": {}}
+{"_id": "22420524", "title": "", "text": "Statin use and risk of gallstone disease followed by cholecystectomy.CONTEXT Gallstone disease is aleading cause of morbidity in western countries and carries a high economic burden. Statins decreasehepatic cholesterol biosynthesis and may therefore lower the risk of cholesterol gallstones by reducingthe cholesterol concentration in the bile. Data on this association in humans are scarce. OBJECTIVE Tostudy the association between the use of statins, fibrates, or other lipid-lowering agents and the risk ofincident gallstone disease followed by cholecystectomy. DESIGN, SETTING, AND PARTICIPANTSCase-control analysis using the UK-based General Practice Research Database. Incident patients between1994 and 2008 and 4 controls per each patient were identified and matched on age, sex, generalpractice, calendar time, and years of history in the database. The study population was 76% women andthe mean (SD) age was 53.4 (15.0) years at the index date. Conditional logistic regression was used toestimate the odds ratio (OR) of developing gallstones followed by cholecystectomy in relation to exposureto lipid-lowering agents, stratified by exposure timing and duration. The ORs and 95% confidenceintervals (CIs) were adjusted for smoking, body mass index, ischemic heart disease, stroke, and estrogenuse. MAIN OUTCOME MEASURE The adjusted OR (AOR) for developing gallstone disease followed bycholecystectomy in relation to exposure to lipid-lowering agents. RESULTS A total of 27,035 patients withcholecystectomy and 106,531 matched controls were identified, including 2396 patients and 8868controls who had statin use. Compared with nonuse, current statin use (last prescription recorded within90 days before the first-time diagnosis of the disease) was 1.0% for patients and 0.8% for controls (AOR,1.10; 95% CI, 0.95-1.27) for 1 to 4 prescriptions; 2.6% vs 2.4% (AOR, 0.85; 95% CI, 0.77-0.93) for 5to 19 prescriptions, and 3.2% vs 3.7% (AOR, 0.64; 95% CI, 0.59-0.70) for 20 or more prescriptions. TheAORs for current use of statins defined as 20 or more prescriptions were similar (around 0.6) across age,sex, and body mass index categories, and across the statin class. CONCLUSION Long-term use of statinswas associated with a decreased risk of gallstones followed by cholecystectomy.", "metadata": {}}
+{"_id": "22428640", "title": "", "text": "Chromatin remodeling in embryonic stem cells: regulating the balance between pluripotency anddifferentiation.Embryonic stem cells have an unlimited potential for self-renewal yet are pluripotent,capable of differentiating into three different germ layers and ultimately into multiple cell lineages. Keypluripotency specific factors maintain an undifferentiated ES cell phenotype while lineage specific factorswork in opposition to promote cell specialization. In addition to these important transcriptional regulators,epigenetic modifiers play a defining role in regulating the balance between pluripotency anddifferentiation by promoting changes in chromatin structure.", "metadata": {}}
+{"_id": "22431418", "title": "", "text": "The National Advisory Group on Immunization (NAGI) of the Republic of South Africa.The NationalImmunization Technical Advisory Group (NITAG) in South Africa, known as the National Advisory Groupon Immunization (NAGI), was established in 1993 to advise the National Department of Health (DoH) onissues related to vaccination. Meetings are held as needed but at least twice a year. The scope includesvaccines and immunization and other relevant infectious disease issues. NAGI also makesrecommendations on vaccine schedules and formulations. Agendas are set by DoH and the Chairman ofNAGI. NAGI brings together experts from a range of different fields relevant to vaccines and vaccinationsand has been an important resource for guiding the Expanded Program of Immunization (EPI) in SouthAfrica.", "metadata": {}}
+{"_id": "22442133", "title": "", "text": "Effect of n-3 long chain polyunsaturated fatty acid supplementation in pregnancy on infants’ allergies infirst year of life: randomised controlled trialOBJECTIVE To determine whether dietary n-3 long chainpolyunsaturated fatty acid (LCPUFA) supplementation of pregnant women with a fetus at high risk ofallergic disease reduces immunoglobulin E associated eczema or food allergy at 1 year of age. DESIGNFollow-up of infants at high hereditary risk of allergic disease in the Docosahexaenoic Acid to OptimiseMother Infant Outcome (DOMInO) randomised controlled trial. SETTING Adelaide, South Australia.PARTICIPANTS 706 infants at high hereditary risk of developing allergic disease whose mothers wereparticipating in the DOMInO trial. INTERVENTIONS The intervention group (n=368) was randomlyallocated to receive fish oil capsules (providing 900 mg of n-3 LCPUFA daily) from 21 weeks' gestationuntil birth; the control group (n=338) received matched vegetable oil capsules without n-3 LCPUFA. MAINOUTCOME MEASURE Immunoglobulin E associated allergic disease (eczema or food allergy withsensitisation) at 1 year of age. RESULTS No differences were seen in the overall percentage of infantswith immunoglobulin E associated allergic disease between the n-3 LCPUFA and control groups (32/368(9%) v 43/338 (13%); unadjusted relative risk 0.68, 95% confidence interval 0.43 to 1.05, P=0.08;adjusted relative risk 0.70, 0.45 to 1.09, P=0.12), although the percentage of infants diagnosed ashaving atopic eczema (that is, eczema with associated sensitisation) was lower in the n-3 LCPUFA group(26/368 (7%) v 39/338 (12%); unadjusted relative risk 0.61, 0.38 to 0.98, P=0.04; adjusted relativerisk 0.64, 0.40 to 1.02, P=0.06). Fewer infants were sensitised to egg in the n-3 LCPUFA group (34/368(9%) v 52/338 (15%); unadjusted relative risk 0.61, 0.40 to 0.91, P=0.02; adjusted relative risk 0.62,0.41 to 0.93, P=0.02), but no difference between groups in immunoglobulin E associated food allergy wasseen. CONCLUSION n-3 LCPUFA supplementation in pregnancy did not reduce the overall incidence ofimmunoglobulin E associated allergies in the first year of life, although atopic eczema and eggsensitisation were lower. Longer term follow-up is needed to determine if supplementation has an effecton respiratory allergic diseases and aeroallergen sensitisation in childhood. TRIAL REGISTRATIONAustralian New Zealand Clinical Trials Registry ACTRN12610000735055 (DOMInO trial:ACTRN12605000569606).", "metadata": {}}
+{"_id": "22444939", "title": "", "text": "ModLoop: automated modeling of loops in protein structures.SUMMARY ModLoop is a web server forautomated modeling of loops in protein structures. The input is the atomic coordinates of the proteinstructure in the Protein Data Bank format, and the specification of the starting and ending residues of oneor more segments to be modeled, containing no more than 20 residues in total. The output is thecoordinates of the non-hydrogen atoms in the modeled segments. A user provides the input to the servervia a simple web interface, and receives the output by e-mail. The server relies on the loop modelingroutine in MODELLER that predicts the loop conformations by satisfaction of spatial restraints, withoutrelying on a database of known protein structures. For a rapid response, ModLoop runs on a cluster ofLinux PC computers. AVAILABILITY The server is freely accessible to academic users athttp://salilab.org/modloop", "metadata": {}}
+{"_id": "22446093", "title": "", "text": "What is the best way to help caregivers in cancer and palliative care? A systematic literature review ofinterventions and their effectiveness.Informal carers in cancer and palliative care are known to have highneeds and psychological morbidity, yet a literature review identified few targeted interventions. Thissystematic review of interventions for carers of patients using home cancer and palliative care servicessearched Medline, CancerLit, Psycinfo and Cinahl databases. The terms used were carer(s), caregiver(s),palliative and cancer. Papers that reported interventions for adults actively providing informal care fornoninstitutionalized cancer and palliative care patients were reviewed. Twenty-two interventions wereidentified, comprising home nursing care (four), respite services (three), social networks and activityenhancement (two), problem solving and education (three) and group work (10). Of these, nine weredelivered solely to carers (i.e., were targeted services). Only six of the carers' interventions had beenevaluated, two of these had used a randomized control trial (RCT; grades IB), three employed a singlegroup methodology (two prospective grades IIIC and one retrospective grade IIIC) and one wasevaluated using facilitator feedback. There was a lack of outcome evaluation designs, small sample sizesand a reliance on intervention descriptions and formative evaluations. Methodological challenges maymean alternatives to 'pure' RCTs should be considered. The current evidence contributes more tounderstanding feasibility and acceptability than to effectiveness. Practitioners and evaluators mustprioritize the further development of intervention studies.", "metadata": {}}
+{"_id": "22467585", "title": "", "text": "Brief Internet-Based Intervention Reduces Posttraumatic Stress and Prolonged Grief in Parents after theLoss of a Child during Pregnancy: A Randomized Controlled TrialBackground: The loss of a child duringpregnancy causes significant psychological distress for many women and their partners, and may lead tolong-lasting psychiatric disorders. Internet-based interventions using exposure techniques and cognitiverestructuring have proved effective for posttraumatic stress disorder (PTSD) and prolonged grief. Thisstudy compared the effects of an Internet-based intervention for parents after prenatal loss with awaiting list condition (WLC). Methods: The Impact of Event Scale - Revised assessed symptoms of PTSD;the Inventory of Complicated Grief and the Brief Symptom Inventory assessed depression, anxiety, andgeneral mental health. The 228 participants (92% female) were randomly allocated to a treatment group(TG; n = 115) or a WLC group (n = 113). The TG received a 5-week cognitive behavioral interventionincluding (1) self-confrontation, (2) cognitive restructuring, and (3) social sharing. Results: The TGshowed significantly reduced symptoms of posttraumatic stress, prolonged grief, depression, and anxietyrelative to the WLC control group. Intention-to-treat analysis revealed treatment effects of between d =0.84 and d = 1.02 for posttraumatic stress and prolonged grief from pre- to posttreatment time points.Further significant improvement in all symptoms of PTSD and prolonged grief was found from theposttreatment evaluation to the 12-month follow-up. The attrition rate of 14% was relatively low.Conclusions: The Internet-based intervention proved to be a feasible and cost-effective treatment,reducing symptoms of posttraumatic stress, grief, depression, anxiety, and general mental health afterpregnancy loss. Low-threshold e-health interventions should be further evaluated and implementedroutinely to improve psychological support after pregnancy loss.", "metadata": {}}
+{"_id": "22478394", "title": "", "text": "Up-regulation of PPAR-gamma mRNA expression in the liver of obese patients: an additional reinforcinglipogenic mechanism to SREBP-1c induction.INTRODUCTION Triglyceride accumulation in the liver is anearly feature in the development of nonalcoholic fatty liver disease (NAFLD) associated with humanobesity, which is a multifactorial syndrome and whose underlying mechanisms are beginning to beunderstood. OBJECTIVES Liver peroxisome proliferator-activated receptor-γ (PPAR-γ) mRNA expressionwas measured as a signaling mechanism related to steatosis in obese patients with NAFLD. METHODSLiver PPAR-γ and sterol receptor element-binding protein 1c (SREBP-1c) mRNA (real-time RT-PCR),serum total adiponectin (RIA), and high molecular weight (HMW)-adiponectin (ELISA) levels, and insulinresistance (IR) evolution (homeostasis model assessment-IR) were determined in 22 obese NAFLDpatients (16 with steatosis and six with steatohepatitis) who underwent subtotal gastrectomy withgastrojejunal anastomosis in Roux-en-Y and 16 nonobese subjects who underwent laparoscopiccholecystectomy (controls). RESULTS Liver PPAR-γ mRNA levels were 112 and 188% higher (P < 0.05)than control values in obese patients with steatosis and steatohepatitis, respectively, who also exhibited70 and 62% increases in those of SREBP-1c, concomitantly with IR and lower levels of serum totaladiponectin and HMW-adiponectin (P < 0.05). Liver PPAR-γ expression showed positive associations withSREBP-1c mRNA levels (r = 0.86; P < 0.0001), serum insulin levels (r = 0.39; P < 0.01), andhomeostasis model assessment-IR (r = 0.60; P < 0.0001), and negative correlations with totaladiponectin (r = -0.37; P < 0.01) and HMW-adiponectin (r = -0.51; P < 0.001) levels in serum.CONCLUSIONS PPAR-γ is up-regulated in the liver of obese patients with NAFLD, representing anadditional reinforcing lipogenic mechanism to SREBP-1c induction in the development of hepaticsteatosis.", "metadata": {}}
+{"_id": "22482024", "title": "", "text": "Ribosomal protein S17 gene (RPS17) is mutated in Diamond-Blackfan anemia.Diamond-Blackfan anemia(DBA) is a congenital erythroid aplasia characterized as a normochromic macrocytic anemia with aselective deficiency in red blood cell precursors in otherwise normocellular bone marrow. In 40% of DBApatients, various physical anomalies are also present. Currently two genes are associated with the DBAphenotype--the ribosomal protein (RP) S19 mutated in 25% of DBA patients and RPS24 mutated inapproximately 1.4% of DBA patients. Here we report the identification of a mutation in yet anotherribosomal protein, RPS17. The mutation affects the translation initiation start codon, changing T to G(c.2T>G), thus eliminating the natural start of RPS17 protein biosynthesis. RNA analysis revealed thatthe mutated allele was expressed, and the next downstream start codon located at position +158 shouldgive rise to a short peptide of only four amino acids (Met-Ser-Arg-Ile). The mutation arose de novo, sinceall healthy family members carry the wild-type alleles. The identification of a mutation in the third RP ofthe small ribosomal subunit in DBA patients further supports the theory that impaired translation may bethe main cause of DBA pathogenesis.", "metadata": {}}
+{"_id": "22482820", "title": "", "text": "An overview of the effective combination therapies for the treatment of breast cancer.Breast cancer (BC)is generally classified based on the receptors overexpressed on the cell nucleus, which include hormonereceptors such as progesterone (PR) and estrogen (ER), and HER2. Triple-negative breast cancer (TNBC)is a type of cancer that lacks any of these three types of receptor proteins (ER/PR/HER2). Tumor cellsexhibit drug resistant phenotypes that decrease the efficacy of chemotherapeutic treatments. Generally,drug resistance has a genetic basis that is caused by an abnormal gene expression, nevertheless, thereare several types of drug resistance: efflux pumps reducing the cellular concentration of the drug,alterations in membrane lipids that reduce cellular uptake, increased or altered drug targets, metabolicalteration of the drug, inhibition of apoptosis, repair of the damaged DNA, and alteration of the cell cyclecheckpoints. The use of \"combination therapy\" is recognized as an efficient solution to treat humandiseases, in particular, breast cancer. In this review, we give examples of different nanocarriers used toco-deliver multiple therapeutics (chemotherapeutic agent and nucleic acid) to drug-resistant tumor cells,and lastly, we give our recommendations for the future directions for the co-delivery treatments.", "metadata": {}}
+{"_id": "22483580", "title": "", "text": "Disturbed sleep in bipolar disorder is related to an elevation of IL-6 in peripheral monocytes.Bipolardisorder is a severe psychiatric disorder that is associated with persistent changes in the quality, durationand architecture of sleep. Currently there is no unifying hypothesis explaining the alterations in sleepobservable in patients with bipolar disorder and management is often difficult though vital. Sleep ismodified by various cytokines including IL-6. Elevated levels of IL-6 are associated with a poorer qualityof sleep and changes in the architecture of sleep similar to those observed in bipolar disorder.Therapeutic administration of Interferon causes elevations of intrathecal IL-6 concentrations and appearsto provoke a deteriorating quality of sleep. The blockade of IL-6 with tocilizumab in rheumatoid arthritis isassociated with improvements in the quality of sleep. Bipolar disorder is associated with elevated levels ofIL-6 and in particular elevated levels of mRNA coding for IL-6 in peripheral monocytes. We propose thatthe changes observed in the sleep of patients with bipolar disorder are related to the elevation of IL-6 andthat this correlates with an elevated expression of mRNA coding for IL-6 expression in peripheralmonocytes.", "metadata": {}}
+{"_id": "22488511", "title": "", "text": "Targeted blockade of TGF-β and IL-6/JAK2/STAT3 pathways inhibits lung cancer growth promoted bybone marrow-derived myofibroblastsTo investigate the role of TGF-β and IL-6 in myofibroblasts (MFs) -lung cancer cell interactions, lung cancer cells (Lewis and CTM-167 cell lines) were stimulated by IL-6,MF-conditioned medium (MF-CM) or MFs, with or without TGF-β signaling inhibitor - SB431542 and/orJAK2/STAT3 inhibitor - JSI-124. MFs were stimulated by TGF-β, cancer cell-CM or cancer cells, with orwithout SB431542 and JSI-124. Cell proliferation, the levels of cytokines, expression of mRNA andprotein were determined. Mice bearing xenograft tumors were intraperitoneally treated with SB431542 orJSI-124 and monitored for up to 45 days. In co-culture systems, MFs secreted high levels of IL-6, whilecancer cells produced high levels of TGF-β. Recombinant IL-6 and MF-CM activated STAT3 andupregulated TGF-β in cancer cells. In contrast, cancer cell-CM or TGF-β stimulated MFs to produce IL-6.Blockade of JAK2/STAT3 and TGF-β signaling by specific inhibitors significantly inhibited cell proliferationin vitro and tumor growth in vivo of lung cancer cells. Our study demontrated that the TGF-β andIL-6/JAK2/STAT3 signaling pathways form a positive feedback signaling loop that mediated theinteractions between MFs and lung cancer cells. Targeted inhibiton of this signaling loop could be a newapproach for lung cancer prevention and therapy.", "metadata": {}}
+{"_id": "22490293", "title": "", "text": "Production of cloned mice and ES cells from adult somatic cells by nuclear transfer: how to improvecloning efficiency?Although it has now been 10 years since the first cloned mammals were generatedfrom somatic cells using nuclear transfer (NT), most cloned embryos usually undergo developmentalarrest prior to or soon after implantation, and the success rate for producing live offspring by cloningremains below 5%. The low success rate is believed to be associated with epigenetic errors, includingabnormal DNA hypermethylation, but the mechanism of \"reprogramming\" is unclear. We have been ableto develop a stable NT method in the mouse in which donor nuclei are directly injected into the oocyteusing a piezo-actuated micromanipulator. Especially in the mouse, only a few laboratories can makeclones from adult somatic cells, and cloned mice are never successfully produced from most mousestrains. However, this technique promises to be an important tool for future research in basic biology. Forexample, NT can be used to generate embryonic stem (NT-ES) cell lines from a patient's own somaticcells. We have shown that NT-ES cells are equivalent to ES cells derived from fertilized embryos and thatthey can be generated relatively easily from a variety of mouse genotypes and cell types of both sexes,even though it may be more difficult to generate clones directly. In general, NT-ES cell techniques areexpected to be applied to regenerative medicine; however, this technique can also be applied to thepreservation of genetic resources of mouse strain instead of embryos, oocytes and spermatozoa. Thisreview describes how to improve cloning efficiency and NT-ES cell establishment and further applications.", "metadata": {}}
+{"_id": "22495397", "title": "", "text": "Recruitment of Tat to heterochromatin protein HP1 via interaction with CTIP2 inhibits humanimmunodeficiency virus type 1 replication in microglial cells.The Tat protein of human immunodeficiencyvirus type 1 (HIV-1) plays a key role as inducer of viral gene expression. We report that Tat function canbe potently inhibited in human microglial cells by the recently described nuclear receptor cofactor chickenovalbumin upstream promoter transcription factor-interacting protein 2 (CTIP2). Overexpression of CTIP2leads to repression of HIV-1 replication, as a result of inhibition of Tat-mediated transactivation. Incontrast, the related CTIP1 was unable to affect Tat function and viral replication. Using confocalmicroscopy to visualize Tat subcellular distribution in the presence of the CTIPs, we found thatoverexpression of CTIP2, and not of CTIP1, leads to disruption of Tat nuclear localization and recruitmentof Tat within CTIP2-induced nuclear ball-like structures. In addition, our studies demonstrate that CTIP2colocalizes and associates with the heterochromatin-associated protein HP1alpha. The CTIP2 proteinharbors two Tat and HP1 interaction interfaces, the 145-434 and the 717-813 domains. CTIP2 andHP1alpha associate with Tat to form a three-protein complex in which the 145-434 CTIP2 domaininteracts with the N-terminal region of Tat, while the 717-813 domain binds to HP1. The importance ofthis Tat binding interface and of Tat subnuclear relocation was confirmed by analysis of CTIP2 deletionmutants. Our findings suggest that inhibition of HIV-1 expression by CTIP2 correlates with recruitment ofTat within CTIP2-induced structures and relocalization within inactive regions of the chromatin viaformation of the Tat-CTIP2-HP1alpha complex. These data highlight a new mechanism of Tat inactivationthrough subnuclear relocalization that may ultimately lead to inhibition of viral pathogenesis.", "metadata": {}}
+{"_id": "22500262", "title": "", "text": "Cryptochrome Mediates Circadian Regulation of cAMP Signaling and Hepatic GluconeogenesisDuringfasting, mammals maintain normal glucose homeostasis by stimulating hepatic gluconeogenesis.Elevations in circulating glucagon and epinephrine, two hormones that activate hepatic gluconeogenesis,trigger the cAMP-mediated phosphorylation of cAMP response element-binding protein (Creb) anddephosphorylation of the Creb-regulated transcription coactivator-2 (Crtc2)--two key transcriptionalregulators of this process. Although the underlying mechanism is unclear, hepatic gluconeogenesis is alsoregulated by the circadian clock, which coordinates glucose metabolism with changes in the externalenvironment. Circadian control of gene expression is achieved by two transcriptional activators, Clock andBmal1, which stimulate cryptochrome (Cry1 and Cry2) and Period (Per1, Per2 and Per3) repressors thatfeed back on Clock-Bmal1 activity. Here we show that Creb activity during fasting is modulated by Cry1and Cry2, which are rhythmically expressed in the liver. Cry1 expression was elevated during thenight-day transition, when it reduced fasting gluconeogenic gene expression by blockingglucagon-mediated increases in intracellular cAMP concentrations and in the protein kinase A-mediatedphosphorylation of Creb. In biochemical reconstitution studies, we found that Cry1 inhibited accumulationof cAMP in response to G protein-coupled receptor (GPCR) activation but not to forskolin, a directactivator of adenyl cyclase. Cry proteins seemed to modulate GPCR activity directly through interactionwith G(s)α. As hepatic overexpression of Cry1 lowered blood glucose concentrations and improved insulinsensitivity in insulin-resistant db/db mice, our results suggest that compounds that enhancecryptochrome activity may provide therapeutic benefit to individuals with type 2 diabetes.", "metadata": {}}
+{"_id": "22505190", "title": "", "text": "Toll-like receptor 4 gene Asp299Gly polymorphism in myocardial infarction: a meta-analysis of 15,148subjects.It remains controversial regarding the association between toll-like receptor 4 (TLR4) geneAsp299Gly (+896 A/G) polymorphism and myocardial infarction (MI) risk. Thus, a large-scalemeta-analysis evaluating the potential association between this gene variant and MI risk is required.PubMed, Embase, Web of Science, CBMdisc, CNKI, and Google Scholar were searched until February 6,2013. All the statistical tests were performed using Stata 11.0. Nine articles involving 10 studies wereincluded in the final meta-analysis, covering a total of 8299 MI cases and 6849 controls. Overall, nosignificant association was found between the TLR4 gene Asp299Gly polymorphism and MI risk (G allelevs. A allele: OR=0.95, 95% CI=0.74-1.22, p=0.71; G/G vs. A/A: OR=1.03, 95% CI=0.54-1.98, p=0.93;G/G vs. A/G+A/A: OR=1.05, 95% CI=0.55-2.03, p=0.87; G/G+A/G vs. A/A: OR=0.92, 95%CI=0.75-1.13, p=0.42). In the subgroup analysis based on source of controls, there was also lack ofevidence for significant association between the TLR4 gene Asp299Gly polymorphism and MI risk. Insummary, the present meta-analysis indicated that the TLR4 gene Asp299Gly polymorphism was notassociated with MI risk.", "metadata": {}}
+{"_id": "22505710", "title": "", "text": "Matrix metalloproteinase and proinflammatory cytokine production by chondrocytes of humanosteoarthritic cartilage: associations with degenerative changes.OBJECTIVE To examine byimmunohistochemistry the relative distributions of 6 matrix metalloproteinases (MMPs 1, 2, 3, 8, 9, and13) and the 2 proinflammatory cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor alpha(TNFalpha) in osteoarthritic (OA) cartilage compared with normal, age-matched articular cartilage.METHODS Articular cartilage samples were obtained from the tibial plateau of OA knees removed atarthroplasty and from normal, nonarthritic, knees obtained at autopsy. Specimens were promptly fixed inCarnoy's fixative, processed, embedded in paraffin, sectioned, and examined by immunohistochemistryfor MMP and cytokine production. In addition, human articular chondrocytes (HAC) were treated in vitrowith either IL-1beta, TNFalpha, or phorbol myristate acetate (PMA) to assess their potential to produceeach of the MMPs, as determined by Western blotting and gelatin zymography. RESULTSImmunodetection of the collagenases (MMPs 1, 8, and 13) and stromelysin 1 (MMP-3) was demonstratedin a proportion of chondrocytes in the superficial zone of almost all of the OA specimens that haddegenerative matrix changes. The gelatinases (MMPs 2 and 9) were also demonstrated byimmunohistochemistry but were not so prominent. IL-1beta- and TNFalpha-positive chondrocytes werealso observed in a proportion of cells in the superficial zones of OA specimens. Much less immunostainingfor MMPs and cytokines was observed in the deep zone of all OA specimens, where the cartilage matrixand chondrocyte morphology appeared normal. In contrast, full-thickness normal cartilage specimensshowed virtually no immunostaining for these MMPs or cytokines. Confirmation that chondrocytes canproduce these 6 MMPs was obtained from HAC cultures treated with either IL-1beta, TNFalpha, or PMA;conditioned medium from activated HAC contained all the MMPs demonstrated by immunohistochemistry.Dual immunolocalization studies of OA cartilage specimens demonstrated the coexpression of IL-1 withMMP-8 by individual chondrocytes in situ. CONCLUSION These results indicate that the superficial zone ofOA cartilage specimens, which is characterized by fibrillations, chondrocyte clusters, and degenerativematrix changes, contains a variable proportion of cells that immunostain for IL-1beta, TNFalpha, and 6different MMPs. These observations support the concept that cytokine-MMP associations reflect a modifiedchondrocyte phenotype and an intrinsic process of cartilage degradation in OA.", "metadata": {}}
+{"_id": "22509015", "title": "", "text": "β-catenin-independent WNT signaling in basal-like breast cancer and brain metastasis.A role of WNTsignaling for primary breast cancers of the basal-like subtype and as a predictor of brain metastasis hasbeen described. However, a responsible WNT ligand has not been identified. To further clarify thisquestion, we comparatively investigated 22 human breast cancer brain metastases as well as the highlyinvasive human breast cancer cell line MDA-MB-231 and the weakly motile MCF-7 as models for thebasal-like and the luminal A subtype. WNT5A and B were found overexpressed in MDA-MB-231 cells ascompared with MCF-7. This corresponded to reduction of MDA-MB-231 invasiveness by WNT inhibitors,whereas MCF-7 invasion was enhanced by recombinant WNT5B and abolished by WNT andJun-N-terminal kinase antagonists. Expression and subcellular distribution of β-catenin remaineduninfluenced. Consistently, β-catenin was not localized in the nuclei of brain metastases while there wasstrong nuclear c-Jun staining. Similar to MDA-MB-231, metastases showed expression of WNT5A/B andthe alternative WNT receptors ROR1 and 2. These findings were validated using external gene expressiondatasets (Gene Expression Omnibus) of different breast cancer subtypes and brain metastases.Hierarchical cluster analysis yielded a close relation between basal-like cancers and brain metastases.Gene set enrichment analyses confirmed WNT pathway enrichment not only in basal-like primaries butalso in cerebral metastases of all subtypes. In conclusion, WNT signaling seems highly relevant forbasal-like and other subtypes of breast cancers metastasizing into the brain. β-catenin-independent WNTsignaling, presumably via ROR1-2, plays a major role in this context.", "metadata": {}}
+{"_id": "22517564", "title": "", "text": "Retinal attenuates inflammatory arthritis by reciprocal regulation of IL-17-producing T cells and Foxp3(+)regulatory T cells and the inhibition of osteoclastogenesis.Retinoids (e.g., vitamin A and its derivatives)can regulate immune responses. The aim of this study was to determine whether all-trans retinaldehyde(retinal), a vitamin A derivative, can inhibit inflammatory responses and joint destruction in DBA/1J micewith collagen-induced arthritis (CIA). The arthritis score and incidence of arthritis were lower in micetreated with retinal compared to those treated with cottonseed oil. Histopathologic evidence of jointdamage was lower in mice treated with retinal, corresponding with a reduction in the infiltration ofimmune cells in mice treated with retinal type II collagen (CII)-stimulated spleen cells. In addition, theexpression of proinflammatory cytokines, oxidative stress proteins, and osteoclast markers weresignificantly reduced in mice treated with retinal. In vitro, retinal induced increased Foxp3 expression andinhibited Th17 development. The proportion of Foxp3(+) Treg cells was increased in the spleens of micetreated with retinal, whereas the proportion of Th17 cells was reduced. In both mice and a human culturesystem, tartrate-resistant acid phosphatase (TRAP) positive mononuclear cells and multinucleated cellswere significantly reduced after treatment with retinal. The expression of osteoclast differentiationmarkers was dramatically decreased upon addition of retinal. This is the first study to demonstrate thetherapeutic effect of retinal on an autoimmune arthritis model in mice through reciprocal regulation ofTh17 and regulatory T cells and protection of differentiation and activation of osteoclasts. Taken together,our findings indicate that retinal has profound immunoregulatory functions and potential value for thetreatment of autoimmune inflammatory disorders.", "metadata": {}}
+{"_id": "22521091", "title": "", "text": "NRAGE promotes the malignant phenotype of hepatocellular carcinoma.Hepatocellular carcinoma (HCC) isa fatal disease, primarily due to the limited effective therapies available for patients with advanced orrecurrent stages of the disease. Therefore, in order to improve patient prognosis, it is important toidentify an informative biomarker for HCC progression, as well as a molecular target for therapy.Neurotrophin receptor-interacting melanoma antigen-encoding protein (NRAGE), a member of the type IImelanoma-associated antigen family, mediates apoptosis and cell death through interactions with a widerange of proteins, and is implicated as a tumor suppressor or oncoprotein depending on cell type.However, the role of NRAGE in HCC is currently unknown, therefore, the present study aimed to identifythe underlying function of NRAGE in HCC tumorigenesis. Resected tumor and non-cancerous liver tissuesfrom 151 patients with HCC, alongside HCC cell lines, were analyzed by polymerase chain reaction andimmunohistochemical techniques to determine NRAGE expression levels, as well as the expression levelsof potential genes encoding interacting proteins. It was demonstrated that the expression levels ofNRAGE mRNA correlated significantly with those of apoptosis-antagonizing transcription factor (AATF),and were not affected by cirrhosis in non-cancerous liver tissues when compared to elevated levels inHCC tissues. The expression patterns of NRAGE protein and mRNA were consistent among 30representative specimen pairs. Furthermore, increased NRAGE expression in patients with HCC correlatedsignificantly with a shorter disease-specific survival time, and was identified as an independent prognosticfactor via multivariate analysis (hazard ratio, 2.23; 95% confidence interval, 1.06-3.83; P=0.020).Therefore, the results of the present study indicated that increased NRAGE expression affects HCCprogression via its interaction with AATF, and may represent a novel biomarker and molecular target forthe treatment of HCC.", "metadata": {}}
+{"_id": "22522432", "title": "", "text": "Regulation of ISW2 by concerted action of histone H4 tail and extranucleosomal DNA.The stable contactof ISW2 with nucleosomal DNA approximately 20 bp from the dyad was shown by DNA footprinting andphotoaffinity labeling using recombinant histone octamers to require the histone H4 N-terminal tail.Efficient ISW2 remodeling also required the H4 N-terminal tail, although the lack of the H4 tail can bemostly compensated for by increasing the incubation time or concentration of ISW2. Similarly, the lengthof extranucleosomal DNA affected the stable contact of ISW2 with this same internal nucleosomal site,with the optimal length being 70 to 85 bp. These data indicate the histone H4 tail, in concert with afavorable length of extranucleosomal DNA, recruits and properly orients ISW2 onto the nucleosome forefficient nucleosome remodeling. One consequence of this property of ISW2 is likely its previouslyobserved nucleosome spacing activity.", "metadata": {}}
+{"_id": "22530842", "title": "", "text": "Embryonic Stem Cells for Severe Heart Failure: Why and How?The experience accumulated in cardiac celltherapy suggests that regeneration of extensively necrotic myocardial areas is unlikely to be achieved bythe sole paracrine effects of the grafted cells but rather requires the conversion of these cells intocardiomyocytes featuring the capacity to substitute for those which have been irreversibly lost. In thissetting, the use of human pluripotent embryonic stem cells has a strong rationale. The experimentalresults obtained in animal models of myocardial infarction are encouraging. However, the switch toclinical applications still requires to address some critical issues, among which the optimization of thecardiac specification of the embryonic stem cells, the purification of the resulting progenitor cells so as tograft a purified population devoid from any contamination by residual pluripotent cells which carry therisk of tumorigenesis, and the control of the expected allogeneic rejection by clinically acceptablemethods. If the solution to these problems is a prerequisite, the therapeutic success of this approach willalso depend on the capacity to efficiently transfer the cells to the target tissue, to keep them alive onceengrafted, and to allow them to spatially organize in such a way that they can contribute to thecontractile function of the heart.", "metadata": {}}
+{"_id": "22534357", "title": "", "text": "A comparison of letrozole to gonadotropins for ovulation induction, in subjects who failed to conceive withclomiphene citrate.OBJECTIVE To compare pregnancy rates (PR) for letrozole and gonadotropins inindividuals who failed to conceive with clomiphene citrate (CC). DESIGN Retrospective cohort study.SETTING University reproductive center. PATIENT(S) Individuals treated with letrozole or gonadotropinswho failed to conceive with CC. INTERVENTION(S) Controlled ovarian hyperstimulation (COH),transvaginal ultrasound, ovulation induction, IUI. MAIN OUTCOME MEASURE(S) Pregnancy rates percycle. RESULT(S) Among patients who failed to conceive with at least three cycles of CC, gonadotropinshad a higher PR per cycle than letrozole. Among individuals who failed to conceive with less than threecycles of CC and whose medications were changed because of thin uterine lining or intolerable sideeffects, average PR per cycle for letrozole and gonadotropin treatments were equivalent. All patientsconceived within three stimulation cycles with either gonadotropins or letrozole. CONCLUSION(S) Inpatients who failed to conceive with CC, gonadotropins have higher PR for ovulation induction thanletrozole. However, PR were high enough with letrozole to justify its use in this population of patients.Letrozole and gonadotropins should not be used for more than three cycles without a conception.", "metadata": {}}
+{"_id": "22543403", "title": "", "text": "Epigenetic mechanisms in neurological diseaseThe exploration of brain epigenomes, which consist ofvarious types of DNA methylation and covalent histone modifications, is providing new andunprecedented insights into the mechanisms of neural development, neurological disease and aging.Traditionally, chromatin defects in the brain were considered static lesions of early development thatoccurred in the context of rare genetic syndromes, but it is now clear that mutations and maladaptationsof the epigenetic machinery cover a much wider continuum that includes adult-onset neurodegenerativedisease. Here, we describe how recent advances in neuroepigenetics have contributed to an improvedmechanistic understanding of developmental and degenerative brain disorders, and we discuss how theycould influence the development of future therapies for these conditions.", "metadata": {}}
+{"_id": "22544171", "title": "", "text": "Reversal of the cellular phenotype in the premature aging disease Hutchinson-Gilford progeriasyndromeHutchinson-Gilford progeria syndrome (HGPS) is a childhood premature aging disease causedby a spontaneous point mutation in lamin A (encoded by LMNA), one of the major architectural elementsof the mammalian cell nucleus. The HGPS mutation activates an aberrant cryptic splice site in LMNApre-mRNA, leading to synthesis of a truncated lamin A protein and concomitant reduction in wild-typelamin A. Fibroblasts from individuals with HGPS have severe morphological abnormalities in nuclearenvelope structure. Here we show that the cellular disease phenotype is reversible in cells fromindividuals with HGPS. Introduction of wild-type lamin A protein does not rescue the cellular diseasesymptoms. The mutant LMNA mRNA and lamin A protein can be efficiently eliminated by correction of theaberrant splicing event using a modified oligonucleotide targeted to the activated cryptic splice site. Uponsplicing correction, HGPS fibroblasts assume normal nuclear morphology, the aberrant nucleardistribution and cellular levels of lamina-associated proteins are rescued, defects inheterochromatin-specific histone modifications are corrected and proper expression of severalmisregulated genes is reestablished. Our results establish proof of principle for the correction of thepremature aging phenotype in individuals with HGPS.", "metadata": {}}
+{"_id": "22545779", "title": "", "text": "Agouti-related peptide–expressing neurons are mandatory for feedingMultiple hormones controllingenergy homeostasis regulate the expression of neuropeptide Y (NPY) and agouti-related peptide (AgRP)in the arcuate nucleus of the hypothalamus. Nevertheless, inactivation of the genes encoding NPY and/orAgRP has no impact on food intake in mice. Here we demonstrate that induced selective ablation ofAgRP-expressing neurons in adult mice results in acute reduction of feeding, demonstrating directevidence for a critical role of these neurons in the regulation of energy homeostasis.", "metadata": {}}
+{"_id": "22547508", "title": "", "text": "Predictors of survival after acute paraquat poisoning.Acute paraquat poisoning is often fatal. Many studieshave investigated successful treatment modalities, but no standard treatment yet exists. The purpose ofthis study was to determine the predictors of survival after acute paraquat poisoning in 602 patients. Theparaquat exposure was assessed based on the amount of ingested paraquat and a semiquantitativemeasure of the urine level of paraquat. Initial clinical parameters including vital signs, hemoglobin,white-blood-cell count, pH, PaCO2, PaO2, blood urea nitrogen, creatinine, aspartate aminotransferase,alanine aminotransferase, total bilirubin, amylase, and glucose were obtained at the time of arrival at theemergency room. Outcomes after acute paraquat poisoning were categorized as survivors andnonsurvivors. Multiple logistic regression analysis was applied to assess the predictors of survival afteracute paraquat poisoning. Some patients (55.5%) survived after oral ingestion of paraquat, whereas allthose exposed to paraquat percutaneous or inhalational route survived. The amount of paraquat (24.5%concentrate of 1,1'-dimethyl-4,4'-bipyridium dichloride) ingested was 45.6 +/- 74.1 mL (mean +/- SD).In addition to degree of paraquat exposure, survival after acute paraquat poisoning was associated withage, respiratory rate, pH, PaCO2, hemoglobin, white-blood-cell count, blood urea nitrogen, amylase, andthe number of failed organs in multiple logistic regression analysis. In conclusion, young age,percutaneous or inhalational route, exposure to less paraquat, and lesser degrees of leukocytosis,acidosis, and renal, hepatic, and pancreatic failures on admission are good prognostic factors of survivalafter acute paraquat poisoning.", "metadata": {}}
+{"_id": "22549449", "title": "", "text": "Decreased neurogenesis after cholinergic forebrain lesion in the adult rat.Adult neurogenesis has beenshown to be regulated by a multitude of extracellular cues, including hormones, growth factors, andneurotransmitters. The cholinergic system of the basal forebrain is one of the key transmitter systems forlearning and memory. Because adult neurogenesis has been implicated in cognitive performance, thepresent work aims at defining the role of cholinergic input for adult neurogenesis by using animmunotoxic lesion approach. The immunotoxin 192IgG-saporin was infused into the lateral ventricle ofadult rats to selectively lesion cholinergic neurons of the cholinergic basal forebrain (CBF), which projectto the two main regions of adult neurogenesis: the dentate gyrus and the olfactory bulb. Five weeks afterlesioning, neurogenesis, defined by the number of cells colocalized for bromodeoxyuridine (BrdU) and theneuronal nuclei marker NeuN, declined significantly in the granule cell layers of the dentate gyrus andolfactory bulb. Furthermore, immunotoxic lesions to the CBF led to increased numbers of apoptotic cellsspecifically in the subgranular zone, the progenitor region of the dentate gyrus, and within theperiglomerular layer of the olfactory bulb. We propose that the cholinergic system plays asurvival-promoting role for neuronal progenitors and immature neurons within regions of adultneurogenesis, similar to effects observed previously during brain development. As a working hypothesis,neuronal loss within the CBF system leads not only to cognitive deficits but may also alter on a cellularlevel the functionality of the dentate gyrus, which in turn may aggravate cognitive deficits.", "metadata": {}}
+{"_id": "22551259", "title": "", "text": "DNA Methylation in Major Depressive Disorder.Epigenetic mechanisms regulate gene expression,influencing protein levels and ultimately shaping phenotypes during life. However, both stochasticepigenetic variations and environmental reprogramming of the epigenome might influenceneurodevelopment and ageing, and this may contribute to the origins of mental ill-health. Studying therole of epigenetic mechanisms is challenging, as genotype-, tissue- and cell type-dependent epigeneticchanges have to be taken into account, while the nature of mental disorders also poses significantchallenges for linking them with biological profiles. In this chapter, we summarise the current evidencesuggesting the role of DNA methylation as a key epigenetic mechanism in major depressive disorder.", "metadata": {}}
+{"_id": "22561064", "title": "", "text": "Consensus structural features of purified bacterial TatABC complexes.The twin-arginine translocation(Tat) system transports folded proteins across bacterial plasma membranes and the chloroplast thylakoidmembrane. Here, we investigate the composition and structural organization of three different purifiedTat complexes from Escherichia coli, Salmonella typhimurium and Agrobacterium tumefaciens. First, wedemonstrate the functional activity of these Tat systems in vivo, since expression of the tatABC operonsfrom S.typhimurium or A.tumefaciens in an E.coli tat null mutant strain resulted in efficientTat-dependent export of an E.coli cofactor-containing substrate, TMAO reductase. The three isolated,affinity-tagged Tat complexes comprised TatA, TatB and TatC in each case, demonstrating a stronginteraction between these three subunits. Single-particle electron microscopy studies of all threecomplexes revealed approximately oval-shaped, asymmetric particles with maximal dimensions up to 13nm. A common feature is a number of stain-excluding densities surrounding more or less central pools ofstain, suggesting protein-lined pores or cavities. The characteristics of size variation among the particlessuggest a modular form of assembly and/or the recruitment of varying numbers of TatBC/TatA units.Despite low levels of sequence homology, the combined data indicate structural and functionalconservation in the Tat systems of these three bacterial species.", "metadata": {}}
+{"_id": "22613657", "title": "", "text": "Advances in graft-versus-host disease biology and therapyAllogeneic haematopoietic stem celltransplantation is used to treat a variety of disorders, but its efficacy is limited by the occurrence ofgraft-versus-host disease (GVHD). The past decade has brought impressive advances in ourunderstanding of the role of stimulatory and suppressive elements of the adaptive and innate immunesystems from both the donor and the host in GVHD pathogenesis. New insights from basic immunology,preclinical models and clinical studies have led to novel approaches for prevention and treatment. ThisReview highlights the recent advances in understanding the pathophysiology of GVHD and its treatment,with a focus on manipulations of the immune system that are amenable to clinical application.", "metadata": {}}
+{"_id": "22621251", "title": "", "text": "Ly6Chi monocytes direct alternatively activated profibrotic macrophage regulation of lungfibrosis.RATIONALE Idiopathic pulmonary fibrosis (IPF) is a devastating disease. Antiinflammatorytherapies, including corticosteroids, are of no benefit. The role of monocytes and macrophages istherefore controversial. OBJECTIVES To define the role of monocytes and macrophages during lungfibrogenesis and resolution, and explore the phenotype of the cells involved. METHODS We used multiplein vivo depletional strategies, backed up by adoptive transfer techniques. Further studies were performedon samples from patients with IPF. MEASUREMENTS AND MAIN RESULTS Depletion of lung macrophagesduring fibrogenesis reduced pulmonary fibrosis as measured by lung collagen (P = 0.0079); fibrosis score(P = 0.0051); and quantitative polymerase chain reaction for surrogate markers of fibrosis Col1 (P =0.0083) and a-smooth muscle actin (P = 0.0349). There was an associated reduction in markers of theprofibrotic alternative macrophage activation phenotype, Ym1 (P = 0.0179), and Arginase 1. Thealternative macrophage marker CD163 was expressed on lung macrophages from patients with IPF.Depletion of Ly6Chi circulating monocytes reduced pulmonary fibrosis (P = 0.0052) and the number ofYm1- positive alternatively activated lung macrophages (P = 0.0310). Their adoptive transfer duringfibrogenesis exacerbated fibrosis (P = 0.0304); however, adoptively transferred CD45.1 Ly6Chi cells werenot found in the lungs of recipient CD45.2 mice. CONCLUSIONS We demonstrate the importance ofcirculating monocytes and lung macrophages during pulmonary fibrosis, and emphasize the importanceof the alternatively activated macrophage phenotype. We show that Ly6Chi monocytes facilitate theprogression of pulmonary fibrosis, but are not obviously engrafted into lungs thereafter. Finally, weprovide empirical data to suggest that macrophages may have a resolution-promoting role during thereversible phase of bleomycin-induced pulmonary fibrosis.", "metadata": {}}
+{"_id": "22623275", "title": "", "text": "A single RNA-dependent RNA polymerase assembles with mutually exclusive nucleotidyl transferasesubunits to direct different pathways of small RNA biogenesis.Members of the conserved family ofeukaryotic RNA-dependent RNA polymerases (Rdrs) synthesize double-stranded RNA (dsRNA)intermediates in diverse pathways of small RNA (sRNA) biogenesis and RNA-mediated silencing.Rdr-dependent pathways of sRNA production are poorly characterized relative to Rdr-independentpathways, and the Rdr enzymes themselves are poorly characterized relative to their viralRNA-dependent RNA polymerase counterparts. We previously described a physical and functionalcoupling of the Tetrahymena thermophila Rdr, Rdr1, and a Dicer enzyme, Dcr2, in the production ofapproximately 24-nucleotide (nt) sRNA in vitro. Here we characterize the endogenous complexes thatharbor Rdr1, termed RDRCs. Distinct RDRCs assemble to contain Rdr1 and subsets of the total of fourtightly Rdr1-associated proteins. Of particular interest are two RDRC subunits, Rdn1 and Rdn2, whichpossess noncanonical ribonucleotidyl transferase motifs. We show that the two Rdn proteins areuridine-specific polymerases of separate RDRCs. Two additional RDRC subunits, Rdf1 and Rdf2, arepresent only in RDRCs containing Rdn1. Rdr1 catalytic activity is retained in RDRCs purified from cellextracts lacking any of the nonessential RDRC subunits (Rdn2, Rdf1, Rdf2) or if the RDRC harbors acatalytically inactive Rdn. However, specific disruption of each RDRC imposes distinct loss-of-functionconsequences at the cellular level and has a differential impact on the accumulation of specific 23-24-ntsRNA sequences in vivo. The biochemical and biological phenotypes of RDRC subunit disruption reveal apreviously unanticipated complexity of Rdr-dependent sRNA biogenesis in vivo.", "metadata": {}}
+{"_id": "22632303", "title": "", "text": "Identification of T6SS-dependent effector and immunity proteins by Tn-seq in Vibrio cholerae.Type VIprotein secretion system (T6SS) is important for bacterial competition through contact-dependent killingof competitors. T6SS delivers effectors to neighboring cells and corresponding antagonistic proteinsconfer immunity against effectors that are delivered by sister cells. Although T6SS has been found inmore than 100 gram-negative bacteria including many important human pathogens, few T6SS-dependenteffector and immunity proteins have been experimentally determined. Here we report a high-throughputapproach using transposon mutagenesis and deep sequencing (Tn-seq) to identify T6SS immunityproteins in Vibrio cholerae. Saturating transposon mutagenesis was performed in wild type and a T6SSnull mutant. Genes encoding immunity proteins were predicted to be essential in the wild type butdispensable in the T6SS mutant. By comparing the relative abundance of each transposon mutant in themutant library using deep sequencing, we identified three immunity proteins that render protectionagainst killing by T6SS predatory cells. We also identified their three cognate T6SS-secreted effectors andshow these are important for not only antibacterial and antieukaryotic activities but also assembly ofT6SS apparatus. The lipase and muramidase T6SS effectors identified in this study underscore thediversity of T6SS-secreted substrates and the distinctly different mechanisms that target these forsecretion by the dynamic T6SS organelle.", "metadata": {}}
+{"_id": "22635278", "title": "", "text": "Immunotherapy of metastatic kidney cancer.From April 1986 to September 2000, 122 MRCC patientswere treated by monthly intralymphatic injections (containing a mean of 573 IL-2 U and 26 x 10(6) LAKcells) and i.m. administration of IFN and TF; 71 patients also received a 3-day cycle of monthly IL-2inhalations with a mean of 998 daily U. MRCC cases not treated by immunotherapy (n = 89) representour historical controls. Adverse clinical side effects related to treatment were negligible. CR (n = 11) andPR (n = 13) were noticed in 24/122 patients. Of 24 responding patients, 17 resumed progression,whereas 7 remain in remission 11-69 months later. The overall median survival of treated patients (28months) was 3.5-fold higher than the median survival of historical controls (7.5 months), and aKaplan-Meier curve showed 25% survival 11 years after the beginning of immunotherapy. Apparently,the addition of IL-2 by inhalation improved survival. The present immunotherapy protocol appears to beefficacious, safe, devoid of adverse side effects, far less costly than others and able to offer a goodquality of life to MRCC patients; if confirmed in a multicenter trial, it could set the basis for developinglow-dose immunomodulatory treatments.", "metadata": {}}
+{"_id": "22647695", "title": "", "text": "Autoimmune T cell responses in the central nervous systemAutoreactive T cell responses have a crucialrole in central nervous system (CNS) diseases such as multiple sclerosis. Recent data indicate that CNSautoimmunity can be mediated by two distinct lineages of CD4+ T cells that are defined by the productionof either interferon-γ or interleukin-17. The activity of these CD4+ T cell subsets within the CNSinfluences the pathology and clinical course of disease. New animal models show that myelin-specificCD8+ T cells can also mediate CNS autoimmunity. This Review focuses on recent progress in delineatingthe pathogenic mechanisms, regulation and interplay between these different T cell subsets in CNSautoimmunity.", "metadata": {}}
+{"_id": "22674621", "title": "", "text": "Effects of FXR in foam-cell formation and atherosclerosis development.Farnesoid X receptor (FXR), abile-acid-activated member of the nuclear receptor superfamily, is essential in regulating bile-acid,cholesterol, and triglyceride homeostasis. Disruption of the FXR gene in mice results in aproatherosclerotic lipid profile with increased serum cholesterols and triglycerides. However, the role ofFXR in foam-cell formation and atherosclerosis development remains unclear. The current study showedthat the peritoneal macrophages isolated from FXR-null mice took up less oxidized LDL-cholesterol(oxLDL-C), which was accompanied by a marked reduction in CD36 expression in these cells. This resultappears to be FXR-independent, as FXR was not detected in the peritoneal macrophages. To assess towhat extent FXR modulates atherosclerosis development, FXR/ApoE double-null mice were generated.Female mice were used for atherosclerosis analysis. Compared to ApoE-null mice, the FXR/ApoEdouble-null mice were found to have less atherosclerotic lesion area in the aorta, despite a furtherincrease in the serum cholesterols and triglycerides. Our results indicate that disruption of the FXR genecould attenuate atherosclerosis development, most likely resulting from reduced oxLDL-C uptake bymacrophages. Our study cautions the use of serum lipid levels as a surrogate marker to determine theefficiency of FXR modulators in treating hyperlipidemia.", "metadata": {}}
+{"_id": "22682497", "title": "", "text": "Purkinje cell compartments in the reeler mutant mouse as revealed by Zebrin II and 90-acetylatedglycolipid antigen expressionThe cerebellum is organized into a series of parasagittally aligned bands thatmay be revealed histologically in the adult mouse by largely complementary immunostaining of Purkinjecell sets with the monoclonal antibodies Zebrin II (ZII; antigen:aldolase C) and P-path (PP;antigen:90-acetyl glycolipids). We compared the normal staining pattern using these markers and anantibody to calbindin with that found in the reeler mutants (rl/rl), in which most Purkinje cell migration ishalted beneath the cerebellar white matter. The results revealed that Purkinje cells in reeler mutants,despite their ectopic location in large subcortical masses, show a clear tendency to distribute intoalternating zones that either stain for Zebrin II or for P-path, with variable transition zones of mixedlabeling. However, the estimated number of zones was fewer than in the normal adult cortex: roughly7–9 zones are revealed per side in the mutant compared with 14 major divisions in wild type mice. Theseresults raise the possibility that neurons destined to express these markers are segregated during theirmigration and that the final phase of migration into the cortex might involve further splitting orinterdigitation between cell sets expressing the two antigens.", "metadata": {}}
+{"_id": "22688699", "title": "", "text": "Awake craniotomy with brain mapping as the routine surgical approach to treating patients withsupratentorial intraaxial tumors: a prospective trial of 200 cases.OBJECT Awake craniotomy wasperformed as the standard surgical approach to supratentorial intraaxial tumors, regardless of theinvolvement of eloquent cortex, in a prospective trial of 200 patients surgically treated by the samesurgeon at a single institution. METHODS Patient presentations, comorbid conditions, tumor locations,and the histological characteristics of lesions were recorded. Brain mapping was possible in 195 (97.5%)of 200 patients. The total number of patients sustaining complications was 33 for an overall complicationrate of 16.5%. There were two deaths in this series, for a mortality rate of 1%. New postoperativeneurological deficits were seen in 13% of the patients, but these were permanent in only 4.5% of them.Complication rates were higher in patients who had gliomas or preoperative neurological deficits and inthose who had undergone prior radiation therapy or surgery. No patient who entered the operating roomneurologically intact sustained a permanent neurological deficit postoperatively. Of the most recent 50patients treated, three (6%) required a stay in the intensive care unit, and the median total hospital staywas 1 day. CONCLUSIONS Use of awake craniotomy can result in a considerable reduction in resourceutilization without compromising patient care by minimizing intensive care time and total hospital stay.Awake craniotomy is a practical and effective standard surgical approach to supratentorial tumors with alow complication rate, and provides an excellent alternative to craniotomy performed with the patient inthe state of general anesthesia because it allows the opportunity for brain mapping and avoids generalanesthesia.", "metadata": {}}
+{"_id": "22696649", "title": "", "text": "Reactive Oxygen Species Localization Programs Inflammation to Clear Microbes of Different SizeHow thenumber of immune cells recruited to sites of infection is determined and adjusted to differences in thecellular stoichiometry between host and pathogen is unknown. Here, we have uncovered a role forreactive oxygen species (ROS) as sensors of microbe size. By sensing the differential localization of ROSgenerated in response to microbes of different size, neutrophils tuned their interleukin (IL)-1β expressionvia the selective oxidation of NF-κB, in order to implement distinct inflammatory programs. Smallmicrobes triggered ROS intracellularly, suppressing IL-1β expression to limit neutrophil recruitment aseach phagocyte eliminated numerous pathogens. In contrast, large microbes triggered ROSextracellularly, amplifying IL-1β expression to recruit numerous neutrophils forming cooperative clusters.Defects in ROS-mediated microbe size sensing resulted in large neutrophil infiltrates and clusters inresponse to small microbes that contribute to inflammatory disease. These findings highlight the impactof ROS localization on signal transduction.", "metadata": {}}
+{"_id": "22703082", "title": "", "text": "Helicobacter pylori infection triggers aberrant expression of activation-induced cytidine deaminase ingastric epitheliumInfection with Helicobacter pylori (H. pylori) is a risk factor for the development ofgastric cancer. Here we show that infection of gastric epithelial cells with 'cag' pathogenicity island(cagPAI)-positive H. pylori induced aberrant expression of activation-induced cytidine deaminase (AID), amember of the cytidine-deaminase family that acts as a DNA- and RNA-editing enzyme, via the IκBkinase–dependent nuclear factor-κB activation pathway. H. pylori–mediated upregulation of AID resultedin the accumulation of nucleotide alterations in the TP53 tumor suppressor gene in gastric cells in vitro.Our findings provide evidence that aberrant AID expression caused by H. pylori infection might be amechanism of mutation accumulation in the gastric mucosa during H. pylori–associated gastriccarcinogenesis.", "metadata": {}}
+{"_id": "22705234", "title": "", "text": "The role of the immune response during SIVagm infection of the African green monkey natural host.TheAfrican green monkey (AGM) is one of many African species endemically infected with simianimmunodeficiency virus (SIV). Like the other natural hosts, AGMs do not succumb to AIDS andunderstanding the basis for this resistance to disease progression would be of enormous theoretical andpractical importance. Early efforts by our group that concentrated on identifying immune mechanismspresumed to keep the virus under control failed to find any obvious candidates. The presumption of viruscontrol was invalidated by the finding that SIVagm replicates in AGMs with the same vigor as HIV-1 doesin humans. Focus therefore shifted to identifying possible immunopathologic features present in diseasesusceptible hosts but absent in the AGM natural host. The apparent immunologic tolerance of AGMs to theSIVagm core protein led to the development of a hypothesis implicating anti-Gag antibodies in theformation of immune complexes, virus trapping in the lymph nodes and immune dysfunction. The ideaproved difficult to test in vivo and present work focuses on the possibility that Gag tolerance at the T-celllevel plays an important role in preventing the catastrophic demise of the immune system characteristicof immunodeficiency virus infection of the heterologous primate host.", "metadata": {}}
+{"_id": "22707413", "title": "", "text": "The S-LANSS score for identifying pain of predominantly neuropathic origin: validation for use in clinicaland postal research.This article describes the development and validation of the S-LANSS score, aself-report version of the Leeds Assessment of Neuropathic Symptoms and Signs pain scale. TheS-LANSS aims to identify pain of predominantly neuropathic origin, as distinct from nociceptive pain,without the need for clinical examination. Two hundred patients with chronic pain were asked to completethe S-LANSS unaided. A researcher then administered the S-LANSS scale and the Neuropathic Pain Scale(NPS) in interview format. An independent clinician determined the pain type (neuropathic versusnociceptive) and rated his or her certainty about diagnosis. The S-LANSS scale was also incorporated intoa chronic pain questionnaire that was sent to 160 community patients and 150 newly referred patientswaiting for pain clinic assessment. The S-LANSS scale correctly identified 75% of pain types whenself-completed and 80% when used in interview format. Sensitivity for self-completed S-LANSS scoresranged from 74% to 78%, depending on the cutoff score. There were significant associations betweenNPS items and total score with S-LANSS score. In the postal survey, completed questionnaires werereturned by 57% of patients (n = 174). Internal consistency and convergent validity of the surveyS-LANSS scores were confirmed. The findings support the S-LANSS scale as a valid and reliableself-report instrument for identifying neuropathic pain and it is also acceptable for use in postal surveyresearch. Establishing valid measures of symptoms and signs in neuropathic pain will allow standardizedcomparisons with other investigational measures. This might lead to new insights into the relationshipbetween pathophysiologic mechanisms and clinical manifestations of pain.", "metadata": {}}
+{"_id": "22711954", "title": "", "text": "Bias in meta-analysis detected by a simple, graphical test.OBJECTIVE Funnel plots (plots of effectestimates against sample size) may be useful to detect bias in meta-analyses that were later contradictedby large trials. We examined whether a simple test of asymmetry of funnel plots predicts discordance ofresults when meta-analyses are compared to large trials, and we assessed the prevalence of bias inpublished meta-analyses. DESIGN Medline search to identify pairs consisting of a meta-analysis and asingle large trial (concordance of results was assumed if effects were in the same direction and themeta-analytic estimate was within 30% of the trial); analysis of funnel plots from 37 meta-analysesidentified from a hand search of four leading general medicine journals 1993-6 and 38 meta-analysesfrom the second 1996 issue of the Cochrane Database of Systematic Reviews. MAIN OUTCOME MEASUREDegree of funnel plot asymmetry as measured by the intercept from regression of standard normaldeviates against precision. RESULTS In the eight pairs of meta-analysis and large trial that wereidentified (five from cardiovascular medicine, one from diabetic medicine, one from geriatric medicine,one from perinatal medicine) there were four concordant and four discordant pairs. In all casesdiscordance was due to meta-analyses showing larger effects. Funnel plot asymmetry was present inthree out of four discordant pairs but in none of concordant pairs. In 14 (38%) journal meta-analyses and5 (13%) Cochrane reviews, funnel plot asymmetry indicated that there was bias. CONCLUSIONS A simpleanalysis of funnel plots provides a useful test for the likely presence of bias in meta-analyses, but as thecapacity to detect bias will be limited when meta-analyses are based on a limited number of small trialsthe results from such analyses should be treated with considerable caution.", "metadata": {}}
+{"_id": "22712546", "title": "", "text": "Exploring Metabolic Configurations of Single Cells within Complex Tissue Microenvironments.Over thepast years, plenty of evidence has emerged illustrating how metabolism supports many aspects of cellularfunction and how metabolic reprogramming can drive cell differentiation and fate. Here, we present amethod to assess the metabolic configuration of single cells within their native tissue microenvironmentvia the visualization and quantification of multiple enzymatic activities measured at saturating substrateconditions combined with subsequent cell type identification. After careful validation of the approach andto demonstrate its potential, we assessed the intracellular metabolic configuration of different humanimmune cell populations in healthy and tumor colon tissue. Additionally, we analyzed the intercellularmetabolic relationship between cancer cells and cancer-associated fibroblasts in a breast cancer tissuearray. This study demonstrates that the determination of metabolic configurations in single cells could bea powerful complementary tool for every researcher interested to study metabolic networks in situ.", "metadata": {}}
+{"_id": "22730024", "title": "", "text": "Twenty-four hour and early morning blood pressure control of olmesartan vs. ramipril in elderlyhypertensive patients: pooled individual data analysis of two randomized, double-blind, parallel-groupstudies.OBJECTIVE To assess the antihypertensive efficacy of olmesartan medoxomil and ramipril on 24-hambulatory blood pressure (ABP) in elderly hypertensive patients by pooled data analysis of two studieswith identical designs (one Italian, one European). METHODS After a 2-week placebo wash-out 1453elderly hypertensive patients (65-89 years; sitting office DBP 90-109 mmHg and/or sitting office SBP140-179 mmHg) were randomized to a 12-week double-blind treatment with olmesartan medoxomil 10mg or ramipril 2.5 mg once-daily, up-titrated (20 and 40 mg olmesartan medoxomil; 5 and 10 mgramipril) after 2 and 6 weeks in patients without normalized office BP. 24-h ABP was recorded atrandomization and after 12 weeks. RESULTS In 715 patients with valid baseline and end-of-treatmentrecordings baseline-adjusted 24-h SBP and DBP reductions were greater with olmesartan medoxomil (n =356) than with ramipril (n = 359) [between-treatment differences and 95% confidence interval (CI),SBP: 2.2 (3.8, 0.6), P = 0.006; DBP: 1.3 (2.2, 0.3), P = 0.009]. Olmesartan medoxomil showed larger BPreductions in the last 6 h from the dosing interval and higher smoothness indices than ramipril.Olmesartan medoxomil reduced the SBP morning rise [-2.8 (-4.9, -0.8) mmHg], whereas ramipril did not[+1.5 (-0.6, +3.6) mmHg; P = 0.004 between-treatments]. Five hundred and eighty-two patients withsustained hypertension (office and 24-h ambulatory hypertension) showed the largest antihypertensiveeffect, with between-treatment differences still in favor of olmesartan medoxomil [SBP: 2.1 (3.9, 0.4), P= 0.019; DBP: 1.2 (2.3, 0.1), P = 0.032]. CONCLUSIONS Olmesartan medoxomil provides a moreeffective and sustained 24-h BP control than ramipril in elderly hypertensive patients, particularly in thehours farthest from last intake.", "metadata": {}}
+{"_id": "22767022", "title": "", "text": "Abi1 is essential for the formation and activation of a WAVE2 signalling complexWAVE2 belongs to afamily of proteins that mediates actin reorganization by relaying signals from Rac to the Arp2/3 complex,resulting in lamellipodia protrusion. WAVE2 displays Arp2/3-dependent actin nucleation activity in vitro,and does not bind directly to Rac. Instead, it forms macromolecular complexes that have been reportedto exert both positive and negative modes of regulation. How these complexes are assembled, localizedand activated in vivo remains to be established. Here we use tandem mass spectrometry to identify anAbi1-based complex containing WAVE2, Nap1 (Nck-associated protein) and PIR121. Abi1 interactsdirectly with the WHD domain of WAVE2, increases WAVE2 actin polymerization activity and mediates theassembly of a WAVE2–Abi1–Nap1–PIR121 complex. The WAVE2–Abi1–Nap1–PIR121 complex is as activeas the WAVE2–Abi1 sub-complex in stimulating Arp2/3, and after Rac activation it is re-localized to theleading edge of ruffles in vivo. Consistently, inhibition of Abi1 by RNA interference (RNAi) abrogatesRac-dependent lamellipodia protrusion. Thus, Abi1 orchestrates the proper assembly of the WAVE2complex and mediates its activation at the leading edge in vivo.", "metadata": {}}
+{"_id": "22791348", "title": "", "text": "The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady stateand the inflamed setting.Dendritic cells (DCs) form a remarkable cellular network that shapes adaptiveimmune responses according to peripheral cues. After four decades of research, we now know that DCsarise from a hematopoietic lineage distinct from other leukocytes, establishing the DC system as a uniquehematopoietic branch. Recent work has also established that tissue DCs consist of developmentally andfunctionally distinct subsets that differentially regulate T lymphocyte function. This review discussesmajor advances in our understanding of the regulation of DC lineage commitment, differentiation,diversification, and function in situ.", "metadata": {}}
+{"_id": "22800314", "title": "", "text": "IL-15 Receptor Deletion Results in Circadian Changes of Locomotor and Metabolic ActivityInterleukin-15(IL-15) is a cytokine produced in the normal brain that acts on its specific receptor IL-15Rα andco-receptors IL-2Rβ and IL-2Rγ in neuronal cells. The functions of the cerebral IL-15 system, however,are not yet clear. To test the hypothesis that IL-15Rα regulates metabolic activity and body temperature,we quantified the specific metabolic phenotype of IL-15Rα knockout mice. These normal-appearing micewere leaner with lower fat composition. During the entire circadian cycle, the knockout mice had asignificantly higher acrophase in locomotor activity and heat dissipation. During the light phase, therewas significantly greater food intake, oxygen consumption, and carbon dioxide production. The differencein the dark and light phases suggests that IL-15Rα participates in circadian rhythm regulation. The higheroxygen consumption in the light phase indicates adaptive thermogenesis in the knockout mice. The bodytemperature of the receptor knockout mice was significantly higher than the control in the light phase,and this was mainly caused by a large difference occurring between 0600 and 0900 h. In addition to themetabolic chamber studies and circadian rhythm analyses, qPCR of hypothalamic homogenates indicatedhigher mRNA expression of orexin and transient receptor potential vanilloid 4 cation channels. Consistentwith a direct role of IL-15Rα in the hypothalamus, IL-15 treatment of the wild-type mice induced c-Fosexpression in the preoptic area. We conclude that activation of hypothalamic neurons by IL-15 in micecontributes to thermoregulation and modifies the metabolic phenotype.", "metadata": {}}
+{"_id": "22815457", "title": "", "text": "Vaginal progesterone, cerclage or cervical pessary for preventing preterm birth in asymptomatic singletonpregnant women with a history of preterm birth and a sonographic short cervix.OBJECTIVE To comparethe outcome of pregnancy in cohorts of women with singleton pregnancy and history of preterm birth andsonographic short cervix managed with different treatment protocols, namely cerclage, vaginalprogesterone or cervical pessary. METHODS This was a comparison of three management protocols forwomen with singleton pregnancy and a high risk of preterm birth because of a prior spontaneous pretermbirth before 34 weeks and a shortened cervical length detected by transvaginal ultrasound. The studyincluded 142 women who were initially treated with cerclage (USA), 59 with vaginal progesterone (UK)and 42 with cervical pessary (Spain). Perinatal outcomes were compared between the three cohorts.RESULTS There were no statistically significant differences in perinatal losses, neonatal morbidity andpreterm births among the three groups, apart from a higher rate of preterm birth before 34 weeks'gestation after treatment with vaginal progesterone in comparison with treatment with cervical pessary(32% vs 12%; relative risk (RR) = 2.70; 95% CI, 1.10-6.67). When only the subgroups of women withcervical length < 25 mm, irrespective of gestational age, were compared, the difference between thesetwo cohorts was not statistically significant (RR = 2.21; 95% CI, 0.83-5.89). CONCLUSION Cerclage,vaginal progesterone and pessary appear to have similar effectiveness as management strategies inwomen with singleton pregnancy, previous spontaneous preterm birth and short cervix. Directrandomized comparisons of these strategies, or combinations thereof, are needed to determine optimalmanagement.", "metadata": {}}
+{"_id": "22820637", "title": "", "text": "The oxytocinase subfamily of M1 aminopeptidases.The placental leucine aminopeptidase (P-LAP),adipocyte-derived leucine aminopeptidase (A-LAP) and leukocyte-derived aminopeptidase (L-RAP) belongto one distinct group of the M1 family of amimopeptidases, which we term the \"Oxytocinase subfamily\".They share HEXXH(X)18E Zn-binding and GAMEN motifs essential for the enzymatic activities.Intracellular localization is the characteristic feature of the subfamily members. While P-LAP istranslocated from intracellular vesicles to plasma membrane in a stimulus-dependent manner, bothA-LAP and L-RAP are retained in the endoplasmic reticulum. They contain sequences necessary for thespecific localization in the cell. It is getting evident that the subfamily members play important roles inthe maintenance of homeostasis including maintenance of normal pregnancy, memory retention, bloodpressure regulation and antigen presentation. In this review, current situation of this newly identifiedsubfamily is summarized.", "metadata": {}}
+{"_id": "22843616", "title": "", "text": "Myc represses primitive endoderm differentiation in pluripotent stem cells.The generation of inducedpluripotent stem cells (iPSCs) provides a novel method to facilitate investigations into the mechanismsthat control stem cell pluripotency and self-renewal. Myc has previously been shown to be critical formurine embryonic stem cell (mESC) maintenance, while also enhancing directed reprogramming offibroblasts by effecting widespread changes in gene expression. Despite several studies identifying in vivotarget genes, the precise mechanism by which Myc regulates pluripotency remains unknown. Here wereport that codeletion of c- and N-MYC in iPSCs and ESCs results in their spontaneous differentiation toprimitive endoderm. We show that Myc sustains pluripotency through repression of the primitiveendoderm master regulator GATA6, while also contributing to cell cycle control by regulation of themir-17-92 miRNA cluster. Our findings demonstrate the indispensable requirement for c- or N-myc inpluripotency beyond proliferative and metabolic control.", "metadata": {}}
+{"_id": "22843838", "title": "", "text": "[Vitamin D and latitude as environmental factors in multiple sclerosis].Multiple sclerosis (MS) shows amultifold increase in prevalence with an increase in latitudes, both north and south of the equator. One ofthe potential factors related to the difference of the prevalence is vitamin D, because the strength ofambient ultraviolet light, which is essential for vitamin D production, decreases with increasing latitude. Itis known that vitamin D has immunomodulatory functions and suppresses an animal model of MS. It isalso considered that vitamin D-related genes are critical susceptible genes for MS. An approach fromenvironmental and genetic aspects is needed to investigate the association between vitamin D and MS.", "metadata": {}}
+{"_id": "22852120", "title": "", "text": "Type 2 cytokines: mechanisms and therapeutic strategiesType 2 immune responses are defined by thecytokines interleukin-4 (IL-4), IL-5, IL-9 and IL-13, which can either be host protective or havepathogenic activity. Type 2 immunity promotes antihelminth immunity, suppresses type 1-drivenautoimmune disease, neutralizes toxins, maintains metabolic homeostasis, and regulates wound repairand tissue regeneration pathways following infection or injury. Nevertheless, when type 2 responses aredysregulated, they can become important drivers of disease. Type 2 immunity induces a complexinflammatory response characterized by eosinophils, mast cells, basophils, type 2 innate lymphoid cells,IL-4-and/or IL-13-conditioned macrophages and T helper 2 (TH2) cells, which are crucial to thepathogenesis of many allergic and fibrotic disorders. As chronic type 2 immune responses promotedisease, the mechanisms that regulate their maintenance are thought to function as crucial diseasemodifiers. This Review discusses the many endogenous negative regulatory mechanisms that antagonizetype 2 immunity and highlights how therapies that target some of these pathways are being developed totreat type 2-mediated disease.", "metadata": {}}
+{"_id": "22867765", "title": "", "text": "Implanted microvessels progress through distinct neovascularization phenotypes.We have previouslydemonstrated that implanted microvessels form a new microcirculation with minimal host-derived vesselinvestment. Our objective was to define the vascular phenotypes present during neovascularization inthese implants and identify post-angiogenesis events. Morphological, functional and transcriptionalassessments identified three distinct vascular phenotypes in the implants: sprouting angiogenesis,neovascular remodeling, and network maturation. A sprouting angiogenic phenotype appeared first,characterized by high proliferation and low mural cell coverage. This was followed by a neovascularremodeling phenotype characterized by a perfused, poorly organized neovascular network, reducedproliferation, and re-associated mural cells. The last phenotype included a vascular network organizedinto a stereotypical tree structure containing vessels with normal perivascular cell associations. Inaddition, proliferation was low and was restricted to the walls of larger microvessels. The transition fromangiogenesis to neovascular remodeling coincided with the appearance of blood flow in the implantneovasculature. Analysis of vascular-specific and global gene expression indicates that the intermediate,neovascular remodeling phenotype is transcriptionally distinct from the other two phenotypes. Therefore,this vascular phenotype likely is not simply a transitional phenotype but a distinct vascular phenotypeinvolving unique cellular and vascular processes. Furthermore, this neovascular remodeling phase may bea normal aspect of the general neovascularization process. Given that this phenotype is arguablydysfunctional, many of the microvasculatures present within compromised or diseased tissues may notrepresent a failure to progress appropriately through a normally occurring neovascularization phenotype.", "metadata": {}}
+{"_id": "22871664", "title": "", "text": "Characterization of a highly variable eutherian microRNA gene.Mouse microRNAs (miRNAs)miR-290-miR295 are encoded by a cluster of partially homologous pre-miRNA hairpins and are likely tobe functionally important in embryonic stem (ES) cells and preimplantation embryos. We presentevidence that a spliced, capped, and polyadenylated primary transcript spans this entire Early EmbryonicmicroRNA Cluster (EEmiRC). Partial Drosha processing yields additional large nuclear RNA intermediates.A conserved promoter element containing a TATA-box directs EEmiRC transcription. Sequence analysisshows that the EEmiRC transcription unit is remarkably variable and can only be identifiedbioinformatically in placental (eutherian) mammals. Consistent with eutherian-specific function, EEmiRCis expressed in trophoblastic stem (TS) cells. When analyzing evolutionary and functional relationships,the organization of the entire miRNA loci should be considered in addition to the mature miRNAsequences. Application of this concept suggests that EEmiRC is a recently acquired rapidly evolving geneimportant for eutherian development.", "metadata": {}}
+{"_id": "22874817", "title": "", "text": "The function of follicular helper T cells is regulated by the strength of T cell antigen receptor bindingHowfollicular helper T cells (TFH cells) differentiate to regulate B cell immunity is critical for effective proteinvaccination. Here we define three transcription factor T-bet–expressing antigen-specific effector helper Tcell subsets with distinguishable function, migratory properties and developmental programming in vivo.Expression of the transcriptional repressor Blimp-1 distinguished T zone 'lymphoid' effector helper T cells(CD62LhiCCR7hi) from CXCR5lo 'emigrant' effector helper T cells and CXCR5hi 'resident' TFH cellsexpressing the transcriptional repressor Bcl-6 (CD62LloCCR7lo). We then show by adoptive transfer andintact polyclonal responses that helper T cells with the highest specific binding of peptide–majorhistocompatibility complex class II and the most restricted T cell antigen receptor junctional diversity'preferentially' developed into the antigen-specific effector TFH compartment. Our studies demonstrate acentral function for differences in the binding strength of the T cell antigen receptor in theantigen-specific mechanisms that 'program' specialized effector TFH function in vivo.", "metadata": {}}
+{"_id": "22889972", "title": "", "text": "Disruption of tumor necrosis factor-alpha gene diminishes the development of atherosclerosis inApoE-deficient mice.Inflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha) havebeen implicated in atherogenesis. However, the precise role of TNF-alpha in atherogenesis is still unclear.To examine the effect of TNF-alpha on atherogenesis, we generated compound-deficient mice inapolipoprotein E (apoE) and TNF-alpha (apoE-/-/TNF-alpha-/-) and compared them with apoE-/- mice.Although serum total cholesterol levels were markedly elevated in both apoE-/-/TNF-alpha-/- and apoE-/-mice compared to wild-type mice, no differences were observed between apoE-/-/TNF-alpha-/- andapoE-/- mice. The atherosclerotic plaque area in the aortic luminal surface of apoE-/-/TNF-alpha-/- mice(n=8, 3.1+/-0.4%) was significantly smaller than that of apoE-/- mice (n=7, 4.7+/-0.4%, p<0.001)despite the lack of difference in serum cholesterol levels. The atherosclerotic lesion size in the aortic sinusof apoE-/-/TNF-alpha-/- mice (n=10, 5.1+/-0.3 x 10(5)microm(2)) was also significantly smaller thanthat of apoE-/- mice (n=11, 7.0+/-0.3 x 10(5)microm(2), p<0.0001). RT-PCR analysis indicated that theexpression levels of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1(VCAM-1) and monocyte chemoattractant protein-1 (MCP-1) were significantly higher in apoE-/- thanapoE-/-/TNF-alpha-/- mice. Macrophages from apoE(-/-) mice showed higher uptake level of oxidized LDLand increased expression level of scavenger receptor class A (SRA) compared to those fromapoE-/-/TNF-alpha-/- mice. These results indicate that TNF-alpha plays an atherogenic role byupregulating the expressions of ICAM-1, VCAM-1 and MCP-1 in the vascular wall, and by inducing SRAexpression and oxidized LDL uptake in macrophages.", "metadata": {}}
+{"_id": "22890091", "title": "", "text": "Differential expression of bcl-2 and susceptibility to anti-Fas-mediated cell death in peripheral bloodlymphocytes, monocytes, and neutrophils.The recently identified Fas antigen (Ag) is a cell surfacemolecule that can mediate apoptosis. The cytoplasmic product of proto-oncogene bcl-2 has been shownto prolong the cellular survival by inhibiting apoptosis. To elucidate the physiologic significance ofexpression of both molecules, we examined the expression of Fas Ag and bcl-2 on blood leukocytepopulations and evaluated their sensitivity to the cytolytic action of anti-Fas antibody. Although Fas Agwas expressed on a fraction of lymphocytes, both neutrophils and monocytes expressed Fas Agconstitutively. In contrast, there was marked difference among these leukocytes regarding bcl-2expression. Lymphocytes expressed bcl-2 intensely, but monocytes showed weaker bcl-2 expression, andneutrophils were essentially absent for bcl-2 expression. Seemingly reflecting this lack ofbcl-2-expression, neutrophils more easily underwent apoptotic cell death in vitro as compared withmonocytes and lymphocytes. We showed that anti-Fas antibody affectively accelerated apoptotic celldeath in neutrophils. However, the apoptosis-inducing effect of anti-Fas antibody was minimal onmonocytes, and lymphocytes were resistant to this antibody. These results suggest thatanti-Fas-mediated cell death may, in part, be determined by bcl-2 expression status in Fas+ lymphoidand hematopoietic cells.", "metadata": {}}
+{"_id": "22896384", "title": "", "text": "Foxp2 and Foxp1 cooperatively regulate lung and esophagus development.The airways of the lungdevelop through a reiterative process of branching morphogenesis that gives rise to the intricate andextensive surface area required for postnatal respiration. The forkhead transcription factors Foxp2 andFoxp1 are expressed in multiple foregut-derived tissues including the lung and intestine. In this report,we show that loss of Foxp2 in mouse leads to defective postnatal lung alveolarization, contributing topostnatal lethality. Using in vitro and in vivo assays, we show that T1alpha, a lung alveolar epithelial type1 cell-restricted gene crucial for lung development and function, is a direct target of Foxp2 and Foxp1.Remarkably, loss of a single Foxp1 allele in addition to complete loss of Foxp2 results in increasedseverity of morphological defects in mutant lungs and leads to perinatal loss of all Foxp2(-/-);Foxp1(+/-)mice. Expression of N-myc and Hop, crucial regulators of lung development, is compromised inFoxp2(-/-);Foxp1(+/-) mutants. In addition to the defects in lung development, esophageal muscledevelopment is disrupted in Foxp2(-/-);Foxp1(+/-) embryos, a tissue where Foxp2 and Foxp1 areco-expressed. These data identify Foxp2 and Foxp1 as crucial regulators of lung and esophagealdevelopment, underscoring the necessity of these transcription factors in the development of anteriorforegut-derived tissues and demonstrating functional cooperativity between members of the Foxp1/2/4family in tissues where they are co-expressed.", "metadata": {}}
+{"_id": "22896970", "title": "", "text": "Crystal structure of the eukaryotic 60S ribosomal subunit in complex with initiation factor 6.Proteinsynthesis in all organisms is catalyzed by ribosomes. In comparison to their prokaryotic counterparts,eukaryotic ribosomes are considerably larger and are subject to more complex regulation. The largeribosomal subunit (60S) catalyzes peptide bond formation and contains the nascent polypeptide exittunnel. We present the structure of the 60S ribosomal subunit from Tetrahymena thermophila in complexwith eukaryotic initiation factor 6 (eIF6), cocrystallized with the antibiotic cycloheximide (aeukaryotic-specific inhibitor of protein synthesis), at a resolution of 3.5 angstroms. The structureillustrates the complex functional architecture of the eukaryotic 60S subunit, which comprises an intricatenetwork of interactions between eukaryotic-specific ribosomal protein features and RNA expansionsegments. It reveals the roles of eukaryotic ribosomal protein elements in the stabilization of the activesite and the extent of eukaryotic-specific differences in other functional regions of the subunit.Furthermore, it elucidates the molecular basis of the interaction with eIF6 and provides a structuralframework for further studies of ribosome-associated diseases and the role of the 60S subunit in theinitiation of protein synthesis.", "metadata": {}}
+{"_id": "22901758", "title": "", "text": "Hedgehog signaling regulates brain tumor-initiating cell proliferation and portends shorter survival forpatients with PTEN-coexpressing glioblastomas.The identification of brain tumor stem-like cells (BTSCs)has implicated a role of biological self-renewal mechanisms in clinical brain tumor initiation andpropagation. The molecular mechanisms underlying the tumor-forming capacity of BTSCs, however,remain unknown. Here, we have generated molecular signatures of glioblastoma multiforme (GBM) usinggene expression profiles of BTSCs and have identified both Sonic Hedgehog (SHH) signaling-dependentand -independent BTSCs and their respective glioblastoma surgical specimens. BTSC proliferation couldbe abrogated in a pathway-dependent fashion in vitro and in an intracranial tumor model in athymicmice. Both SHH-dependent and -independent brain tumor growth required phosphoinositide3-kinase-mammalian target of rapamycin signaling. In human GBMs, the levels of SHH and PTCH1expression were significantly higher in PTEN-expressing tumors than in PTEN-deficient tumors. Inaddition, we show that hyperactive SHH-GLI signaling in PTEN-coexpressing human GBM is associatedwith reduced survival time. Thus, distinct proliferation signaling dependence may underpin glioblastomapropagation by BTSCs. Modeling these BTSC proliferation mechanisms may provide a rationale forindividualized glioblastoma treatment.", "metadata": {}}
+{"_id": "22908536", "title": "", "text": "Stress and host immunity amplify Mycobacterium tuberculosis phenotypic heterogeneity and inducenongrowing metabolically active forms.Nonreplicating and metabolically quiescent bacteria are implicatedin latent tuberculosis infections and relapses following \"sterilizing\" chemotherapy. However, evidencelinking bacterial dormancy and persistence in vivo is largely inconclusive. Here we measure the single-celldynamics of Mycobacterium tuberculosis replication and ribosomal activity using quantitative time-lapsemicroscopy and a reporter of ribosomal RNA gene expression. Single-cell dynamics exhibit heterogeneityunder standard growth conditions, which is amplified by stressful conditions such as nutrient limitation,stationary phase, intracellular replication, and growth in mouse lungs. Additionally, the lungs ofchronically infected mice harbor a subpopulation of nongrowing but metabolically active bacteria, whichare absent in mice lacking interferon-γ, a cytokine essential for antituberculosis immunity. These crypticbacterial forms are prominent in mice treated with the antituberculosis drug isoniazid, suggesting a rolein postchemotherapeutic relapses. Thus, amplification of bacterial phenotypic heterogeneity in responseto host immunity and drug pressure may contribute to tuberculosis persistence.", "metadata": {}}
+{"_id": "22914228", "title": "", "text": "Proteomic analysis reveals Warburg effect and anomalous metabolism of glutamine in pancreatic cancercells.In this present work, we characterized the proteomes of pancreatic ductal adenocarcinoma (PDAC)cell line PANC-1 and normal pancreatic duct cells by mass spectrometry using LTQ-Orbitrap and identifiedmore than 1700 proteins from each sample. On the basis of the spectra count label-free quantificationapproach, we identified a large number of differentially expressed metabolic enzymes and proteinsinvolved in cytoskeleton, cell adhesion, transport, transcription, translation, and cell proliferation as well.The data demonstrated that metabolic pathways were altered in PANC-1, consistent with the Warburgeffect. In addition, the comparative MS analysis unveiled anomalous metabolism of glutamine, suggestingthat glutamine was largely consumed as a nitrogen donor in nucleotide and amino acid biosynthesis inPANC-1. Our analysis provides a potentially comprehensive picture of metabolism in PANC-1, which mayserve as the basis of new diagnostics and treatment of PDAC.", "metadata": {}}
+{"_id": "22922353", "title": "", "text": "Prevalence of attempting weight loss and strategies for controlling weight.CONTEXT Overweight andobesity are increasing in the United States. Changes in diet and physical activity are important for weightcontrol. OBJECTIVES To examine the prevalence of attempting to lose or to maintain weight and todescribe weight control strategies among US adults. DESIGN The Behavioral Risk Factor SurveillanceSystem, a random-digit telephone survey conducted in 1996 by state health departments. Setting The 49states (and the District of Columbia) that participated in the survey. PARTICIPANTS Adults aged 18 yearsand older (N = 107 804). MAIN OUTCOME MEASURES Reported current weights and goal weights,prevalence of weight loss or maintenance attempts, and strategies used to control weight (eating fewercalories, eating less fat, or using physical activity) by population subgroup. RESULTS The prevalence ofattempting to lose and maintain weight was 28.8% and 35.1 % among men and 43.6% and 34.4%among women, respectively. Among those attempting to lose weight, a common strategy was toconsume less fat but not fewer calories (34.9% of men and 40.0% of women); only 21.5% of men and19.4% of women reported using the recommended combination of eating fewer calories and engaging inat least 150 minutes of leisure-time physical activity per week. Among men trying to lose weight, themedian weight was 90.4 kg with a goal weight of 81.4 kg. Among women, the median weight was 70.3kg with a goal weight of 59.0 kg. CONCLUSIONS Weight loss and weight maintenance are commonconcerns for US men and women. Most persons trying to lose weight are not using the recommendedcombination of reducing calorie intake and engaging in leisure-time physical activity 150 minutes or moreper week.", "metadata": {}}
+{"_id": "22937651", "title": "", "text": "Antibodies specific for Epstein-Barr virus nuclear antigen-1 cross-react with human heterogeneousnuclear ribonucleoprotein L.Epstein-Barr virus (EBV) is associated with multiple sclerosis (MS), andantibodies to the EBV nuclear antigen-1 (EBNA-1) are consistently increased in MS patients. Thehypothesis of this study is that anti-EBNA-1 antibodies cross-react with a self antigen in MS patients. Weaffinity purified anti-EBNA-1 antibodies from human plasma, used the anti-EBNA-1 to immunoprecipitateantigens from human brain, and identified bound antigens with mass spectrometry. Anti-EBNA-1consistently bound heterogeneous nuclear ribonucleoprotein L (HNRNPL). We expressed both the longand short isoforms of this protein, and verified with Western blots and ELISA that the long isoformcross-reacts with EBNA-1. Immunohistochemistry demonstrated that anti-EBNA-1 bound to an antigen inthe nucleus of cultured rat central nervous system cells. ELISA demonstrated the presence of antibodiesto HNRNPL in the plasma of both healthy controls and MS patients, but anti-HNRNPL was not increased inMS patients. We conclude that HNRNPL is an autoantigen which cross-reacts with EBNA-1. The relevanceof this autoantigen to MS and other autoimmune diseases remains to be investigated.", "metadata": {}}
+{"_id": "22937815", "title": "", "text": "Roles of chromatin remodellers in DNA double strand break repair.Now that we have a goodunderstanding of the DNA double strand break (DSB) repair mechanisms and DSB-induced damagesignalling, attention is focusing on the changes to the chromatin environment needed for efficient DSBrepair. Mutations in chromatin remodelling complexes have been identified in cancers, making itimportant to evaluate how they impact upon genomic stability. Our current understanding of the DSBrepair pathways suggests that each one has distinct requirements for chromatin remodelling. Moreover,restricting the extent of chromatin modifications could be a significant factor regulating the decision ofpathway usage. In this review, we evaluate the distinct DSB repair pathways for their potential need forchromatin remodelling and review the roles of ATP-driven chromatin remodellers in the pathways.", "metadata": {}}
+{"_id": "22938539", "title": "", "text": "Epstein-Barr virus and virus human protein interaction maps.A comprehensive mapping of interactionsamong Epstein-Barr virus (EBV) proteins and interactions of EBV proteins with human proteins shouldprovide specific hypotheses and a broad perspective on EBV strategies for replication and persistence.Interactions of EBV proteins with each other and with human proteins were assessed by using a stringenthigh-throughput yeast two-hybrid system. Overall, 43 interactions between EBV proteins and 173interactions between EBV and human proteins were identified. EBV-EBV and EBV-human proteininteraction, or \"interactome\" maps provided a framework for hypotheses of protein function. Forexample, LF2, an EBV protein of unknown function interacted with the EBV immediate early Rtransactivator (Rta) and was found to inhibit Rta transactivation. From a broader perspective, EBV genescan be divided into two evolutionary classes, \"core\" genes, which are conserved across all herpesvirusesand subfamily specific, or \"noncore\" genes. Our EBV-EBV interactome map is enriched for interactionsamong proteins in the same evolutionary class. Furthermore, human proteins targeted by EBV proteinswere enriched for highly connected or \"hub\" proteins and for proteins with relatively short paths to allother proteins in the human interactome network. Targeting of hubs might be an efficient mechanism forEBV reorganization of cellular processes.", "metadata": {}}
+{"_id": "22942787", "title": "", "text": "Relation between Medicare screening reimbursement and stage at diagnosis for older patients with coloncancer.CONTEXT Medicare's reimbursement policy was changed in 1998 to provide coverage forscreening colonoscopies for patients with increased colon cancer risk, and expanded further in 2001 tocover screening colonoscopies for all individuals. OBJECTIVE To determine whether the Medicarereimbursement policy changes were associated with an increase in either colonoscopy use or early stagecolon cancer diagnosis. DESIGN, SETTING, AND PARTICIPANTS Patients in the Surveillance,Epidemiology, and End Results Medicare linked database who were 67 years of age and older and had aprimary diagnosis of colon cancer during 1992-2002, as well as a group of Medicare beneficiaries whoresided in Surveillance, Epidemiology, and End Results areas but who were not diagnosed with cancer.MAIN OUTCOME MEASURES Trends in colonoscopy and sigmoidoscopy use among Medicare beneficiarieswithout cancer were assessed using multivariate Poisson regression. Among the patients with cancer,stage was classified as early (stage I) vs all other (stages II-IV). Time was categorized as period 1 (noscreening coverage, 1992-1997), period 2 (limited coverage, January 1998-June 2001), and period 3(universal coverage, July 2001-December 2002). A multivariate logistic regression (outcome = earlystage) was used to assess temporal trends in stage at diagnosis; an interaction term between tumor siteand time was included. RESULTS Colonoscopy use increased from an average rate of 285/100,000 perquarter in period 1 to 889 and 1919/100,000 per quarter in periods 2 (P<.001) and 3 (P vs 2<.001),respectively. During the study period, 44,924 eligible patients were diagnosed with colorectal cancer. Theproportion of patients diagnosed at an early stage increased from 22.5% in period 1 to 25.5% in period 2and 26.3% in period 3 (P<.001 for each pairwise comparison). The changes in Medicare coverage werestrongly associated with early stage at diagnosis for patients with proximal colon lesions (adjustedrelative risk period 2 vs 1, 1.19; 95% confidence interval, 1.13-1.26; adjusted relative risk period 3 vs 2,1.10; 95% confidence interval, 1.02-1.17) but weakly associated, if at all, for patients with distal colonlesions (adjusted relative risk period 2 vs 1, 1.07; 95% confidence interval, 1.01-1.13; adjusted relativerisk period 3 vs 2, 0.97; 95% confidence interval, 0.90-1.05). CONCLUSIONS Expansion of Medicarereimbursement to cover colon cancer screening was associated with an increased use of colonoscopy forMedicare beneficiaries, and for those who were diagnosed with colon cancer, an increased probability ofbeing diagnosed at an early stage. The selective effect of the coverage change on proximal colon lesionssuggests that increased use of whole-colon screening modalities such as colonoscopy may have played apivotal role.", "metadata": {}}
+{"_id": "22948960", "title": "", "text": "Direct visualization of the endomitotic cell cycle in living megakaryocytes: differential patterns in low andhigh ploidy cells.Endomitosis in megakaryocytes (MKs) involves repeated DNA replication in the absenceof cytokinesis and is a crucial part of MK development. However, chromosomal dynamics have neverbeen observed in living MKs. We developed a new transgenic mouse model in which the expression ofhuman histone H2B fused in-frame to green fluorescent protein is targeted to MKs. Ex vivo time-lapsemicroscopy analysis indicated that chromosomal condensation occurs at early mitosis in all MKs. In highploidy MKs (>or=8N), late anaphase was marked by a ring-type alignment of chromosomes with multipleterritories formed between them. By contrast, in low ploidy MKs mitotic chromosomes segregated to formtwo groups separated by a clear space before re-joining to one cluster. This is the first study to documentchromosomal segregation patterns during endomitosis ex vivo and to indicate their potential differentialregulation in low and high ploidy cells.", "metadata": {}}
+{"_id": "22963769", "title": "", "text": "Aberrant expression and altered cellular localization of desmosomal and hemidesmosomal proteins areassociated with aggressive clinicopathological features of oral squamous cell carcinomaDisruption of celladhesion plays a central role in dedifferentiation, invasion, and metastasis of various cancers. Thedesmosome and hemidesmosome are anchoring junctions that control cell-cell and cell-matrix adhesion,respectively. To clarify their contributions in mediating the biological properties of oral cancer, weimmunohistochemically examined the expression of desmoglein 1 (DSG1), DSG2, DSG3, desmocollin 2(DSC2), integrin beta 4 (ITGB4), laminin gamma chain 2 (LAMC2), and collagen type 17 alpha 1(COL17A1) in 51 cases of oral squamous cell carcinoma. On normal oral epithelial cells, DSG1, DSG3,DSC2, and COL17A1 were expressed on the plasma membrane, while ITGB4 and mature LAMC2 werepresent at the basement membrane. In cancer, the expression of DSG1, DSG3, DSC2, and COL17A1decreased and internalized to the cytoplasm. Cytoplasmic expression of DSG2, ITGB4, and LAMC2 wasinduced in the cancer cells facing to the stroma. We scored immunohistochemical expression andcorrelated this to clinicopathological parameters including histologic differentiation, pattern of invasion,and presence of lymph node metastasis. Decrease of DSG3 and DSC2 expression correlated with a moreaggressive cancer phenotype: less differentiated and more invasive histologic features and a higherincidence of nodal metastasis. Lower COL17A1 and higher LAMC2 expression were also associated with amore aggressive phenotype. The present study demonstrates that aberrant expression and alteredcellular localization of desmosomal and hemidesmosomal proteins are associated with aggressiveclinicopathological features of oral cancer. This reinforces the notion that disturbance of thekeratin-associated anchoring junctions confers aggressive features to cancer cells.", "metadata": {}}
+{"_id": "22968257", "title": "", "text": "Histone/protein deacetylase inhibitors increase suppressive functions of human FOXP3+Tregs.Histone/protein deacetylases (HDACs) decrease histone and protein acetylation, typically leading tosuppression of gene transcription and modulation of various protein functions. We found significantdifferences in expression of HDAC before and after stimulation of human T regulatory (Treg) and Teffector cells, suggesting the potential for future selective targeting of Tregs with HDAC inhibitors(HDACi). Use of various HDACi small molecules enhanced, by up to 4.5-fold (average 2-fold), thesuppressive functions of both freshly isolated and expanded human Tregs, consistent with our previousmurine data. HDACi use increased Treg expression of CTLA-4, a key negative regulator of immuneresponse, and we found a direct and significant correlation between CTLA-4 expression and Tregsuppression. Hence, HDACi compounds are promising pharmacologic tools to increase Treg suppressivefunctions, and this action may potentially be of use in patients with autoimmunity or post-transplantation.", "metadata": {}}
+{"_id": "22972632", "title": "", "text": "Enhanced pathological angiogenesis in mice lacking β3 integrin or β3 and β5 integrinsInhibition of αvβ3 orαvβ5 integrin function has been reported to suppress neovascularization and tumor growth, suggestingthat these integrins are critical modulators of angiogenesis. Here we report that mice lacking β3 integrinsor both β3 and β5 integrins not only support tumorigenesis, but have enhanced tumor growth as well.Moreover, the tumors in these integrin-deficient mice display enhanced angiogenesis, strongly suggestingthat neither β3 nor β5 integrins are essential for neovascularization. We also observed that angiogenicresponses to hypoxia and vascular endothelial growth factor (VEGF) are augmented significantly in theabsence of β3 integrins. We found no evidence that the expression or functions of other integrins werealtered as a consequence of the β3 deficiency, but we did observe elevated levels of VEGF receptor-2(also called Flk-1) in β3-null endothelial cells. These data indicate that αvβ3 and αvβ5 integrins are notessential for vascular development or pathological angiogenesis and highlight the need for furtherevaluation of the mechanisms of action of αv-integrin antagonists in anti-angiogenic therapeutics.", "metadata": {}}
+{"_id": "22973574", "title": "", "text": "A lineage of myeloid cells independent of Myb and hematopoietic stem cells.Macrophages and dendriticcells (DCs) are key components of cellular immunity and are thought to originate and renew fromhematopoietic stem cells (HSCs). However, some macrophages develop in the embryo before theappearance of definitive HSCs. We thus reinvestigated macrophage development. We found that thetranscription factor Myb was required for development of HSCs and all CD11b(high) monocytes andmacrophages, but was dispensable for yolk sac (YS) macrophages and for the development of YS-derivedF4/80(bright) macrophages in several tissues, such as liver Kupffer cells, epidermal Langerhans cells, andmicroglia--cell populations that all can persist in adult mice independently of HSCs. These results define alineage of tissue macrophages that derive from the YS and are genetically distinct from HSC progeny.", "metadata": {}}
+{"_id": "22975806", "title": "", "text": "Heterogenic Loss of the Wild-Type BRCA Allele in Human Breast TumorigenesisFor individuals geneticallypredisposed to breast and ovarian cancer through inheritance of a mutant BRCA allele, somatic loss ofheterozygosity affecting the wild-type allele is considered obligatory for cancer initiation and/orprogression. However, several lines of evidence suggest that phenotypic effects may result from BRCAhaploinsufficiency. Archival fixed and embedded tissue specimens from women with germ line deleteriousmutations in BRCA1 or BRCA2 were identified. After pathologic review, focal areas of normal breastepithelium, atypical ductal hyperplasia, ductal carcinoma-in-situ, and invasive ductal carcinoma wereidentified from 14 BRCA1-linked and 9 BRCA2-linked breast cancers. Ten BRCA-linked prophylacticmastectomy specimens and 12 BRCA-linked invasive ovarian carcinomas were also studied. Lasercatapult microdissection was used to isolate cells from the various pathologic lesions and correspondingnormal tissues. After DNA isolation, real-time polymerase chain reaction assays were used to quantitatethe proportion of wild-type to mutant BRCA alleles in each tissue sample. Quantitative allelotyping ofmicrodissected cells revealed a high level of heterogeneity in loss of heterozygosity within and betweenpreinvasive lesions and invasive cancers from BRCA1 and BRCA2 heterozygotes with breast cancer. Incontrast, all BRCA-associated ovarian cancers displayed complete loss of the wild-type BRCA allele. Thesedata suggest that loss of the wild-type BRCA allele is not required for BRCA-linked breast tumorigenesis,which would have important implications for the genetic mechanism of BRCA tumor suppression and forthe clinical management of this patient population.", "metadata": {}}
+{"_id": "22980205", "title": "", "text": "Targeted therapies in urothelial carcinoma.PURPOSE OF REVIEW Greater understanding of the biologyand genetics of urothelial carcinoma is helping to identify and define the role of molecules and pathwaysappropriate for novel-targeted therapies. Here, we review the targeted therapies that have been reportedor are in ongoing urothelial carcinoma clinical trials, and highlight molecular targets characterized inpreclinical and clinical studies. RECENT FINDINGS Trials in nonmuscle-invasive bladder cancer areevaluating the role of immunotherapy and agents targeting vascular endothelial growth factor (VEGF) orfibroblast growth factor receptor-3. In muscle-invasive bladder cancer, neoadjuvant studies have focusedon combining VEGF agents with chemotherapy; adjuvant studies are testing vaccines and agentstargeting the human epidermal growth factor receptor 2, p53, and Hsp27. In the first-line treatment ofmetastatic urothelial carcinoma, tubulin, cytotoxic T-lymphocyte antigen 4, Hsp27, and p53 are noveltargets in clinical trials. The majority of targeted agents studied in urothelial carcinoma are in thesecond-line setting; new targets include CD105, polo-like kinase-1, phosphatidylinositide 3-kinases(PI3K), transforming growth factor β receptor/activin receptor-like kinase β, estrogen receptor, and thehepatocyte growth factor receptor (HGFR or MET). SUMMARY Development of targeted therapies forurothelial carcinoma is still in early stages, consequently there have been no major therapeutic advancesto date. However, greater understanding of urothelial carcinoma and solid tumor biology has resulted in aproliferation of clinical trials that could lead to significant advances in treatment strategies.", "metadata": {}}
+{"_id": "22995164", "title": "", "text": "H2S and HS− donor NaHS releases nitric oxide from nitrosothiols, metal nitrosyl complex, brainhomogenate and murine L1210 leukaemia cellsNitrosoglutathione [(GSNO), 500 nmol/l] relaxed thenorepinephrine precontracted rat aortic rings. The relaxation effect was pronouncedly enhanced by H2S-and HS−-donor NaHS (30 μmol/l) at 7.5 pH but not at 6.3 pH. To study molecular mechanism of thiseffect, we investigated whether NaHS can release NO from NO donors. Using an electron paramagneticresonance spectroscopy method of spin trap and by measuring the NO oxidation product, which is nitrite,by the Griess reaction, we report that NaHS released NO from nitrosothiols, namely from GSNO,S-nitroso-N-acetyl-dl-penicillamine (SNAP), from metal nitrosyl complex nitroprusside (SNP) and from ratbrain homogenate and murine L1210 leukaemia cells. From the observation that the releasing effect wasmore pronounced at 8.0 pH than 6.0 pH, we suppose that HS−, rather than H2S, is responsible for theNO-releasing effect. Since in mammals, H2S and HS− are produced endogenously, we assume that theireffect to release NO from nitrosothiols and from metal nitrosyl complexes are responsible for some oftheir biological activities and that this mechanism may be involved in S-nitrosothiol-signalling reactions.", "metadata": {}}
+{"_id": "22995579", "title": "", "text": "Amitriptyline is effective in chronic but not in episodic tension-type headache: pathogeneticimplications.The tricyclic antidepressant, amitriptyline, is an effective drug for the treatment of chronictension-type headache and for other chronic pain syndromes, but it is also effective in the prophylaxis ofan episodic type of headache such as migraine. However, its efficacy in episodic tension-type headachehas not yet been clarified. We compared the efficacy of amitriptyline (25 mg/day) in 82 nondepressedpatients with either chronic or episodic tension-type headache in an open-label study. Amitriptylinesignificantly reduced (P < 0.05) frequency and duration of headache as well as analgesic consumption inchronic, but not in episodic, tension-type headache. Further placebo-controlled trials, possibly with higherdoses of amitriptyline, might confirm if the different pattern of response to amitriptyline can be explainedin terms of different involvement of central nociception and of peripheral myofascial factors in the chronicand in the episodic forms of tension-type headache.", "metadata": {}}
+{"_id": "22997657", "title": "", "text": "Kruppel-like factor 2 is required for trafficking but not quiescence in postactivated T cells.Thetranscription factor Kruppel-like factor 2 (KLF2) was proposed to regulate genes involved in cell cycleentry and T cell trafficking; however, the physiological role of its expression in postactivated T cells is notwell defined. Previous studies suggested that the cytokines IL-2 and IL-15 differentially regulate KLF2re-expression in postactivation T cells and that these cytokines also influence effector versus memory Tcell differentiation. Using conditional and inducible KLF2-knockout model systems, we tested the specificrole of KLF2 expression in activated CD8(+) T cells cultured with these cytokines. KLF2 was required foreffective transcription of sphingosine-1-phosphate receptor-1 (S1P(1)) and CD62L in postactivation Tcells. However, although different cytokines dramatically altered the expression of cell-cycle-relatedgenes, endogenous KLF2 had a minimal impact. Correspondingly, KLF2-deficient T cells showeddysregulated trafficking but not altered proliferative characteristics following in vivo responses to Ag.Thus, our data help to define KLF2-dependent and -independent aspects of activated CD8(+) T celldifferentiation and argue against a physiological role in cell cycle regulation.", "metadata": {}}
+{"_id": "23013317", "title": "", "text": "Hypoalbuminemia in acute illness: is there a rationale for intervention? A meta-analysis of cohort studiesand controlled trials.OBJECTIVE To determine whether hypoalbuminemia is an independent risk factor forpoor outcome in the acutely ill, and to assess the potential of exogenous albumin administration forimproving outcomes in hypoalbuminemic patients. SUMMARY BACKGROUND DATA Hypoalbuminemia isassociated with poor outcomes in acutely ill patients, but whether this association is causal has remainedunclear. Trials investigating albumin therapy to correct hypoalbuminemia have proven inconclusive.METHODS A meta-analysis was conducted of 90 cohort studies with 291,433 total patients evaluatinghypoalbuminemia as an outcome predictor by multivariate analysis and, separately, of nine prospectivecontrolled trials with 535 total patients on correcting hypoalbuminemia. RESULTS Hypoalbuminemia wasa potent, dose-dependent independent predictor of poor outcome. Each 10-g/L decline in serum albuminconcentration significantly raised the odds of mortality by 137%, morbidity by 89%, prolonged intensivecare unit and hospital stay respectively by 28% and 71%, and increased resource utilization by 66%. Theassociation between hypoalbuminemia and poor outcome appeared to be independent of both nutritionalstatus and inflammation. Analysis of dose-dependency in controlled trials of albumin therapy suggestedthat complication rates may be reduced when the serum albumin level attained during albuminadministration exceeds 30 g/L.   CONCLUSIONS Hypoalbuminemia is strongly associated with poorclinical outcomes. Further well-designed trials are needed to characterize the effects of albumin therapyin hypoalbuminemic patients. In the interim, there is no compelling basis to withhold albumin therapy if itis judged clinically appropriate.", "metadata": {}}
+{"_id": "23017040", "title": "", "text": "Methionine restriction decreases visceral fat mass and preserves insulin action in aging male Fischer 344rats independent of energy restriction.Reduced dietary methionine intake (0.17% methionine, MR) andcalorie restriction (CR) prolong lifespan in male Fischer 344 rats. Although the mechanisms are unclear,both regimens feature lower body weight and reductions in adiposity. Reduced fat deposition in CR islinked to preservation of insulin responsiveness in older animals. These studies examine the relationshipbetween insulin responsiveness and visceral fat in MR and test whether, despite lower food intakeobserved in MR animals, decreased visceral fat accretion and preservation of insulin sensitivity is notsecondary to CR. Accordingly, rats pair fed (pf) control diet (0.86% methinone, CF) to match the foodintake of MR for 80 weeks exhibit insulin, glucose, and leptin levels similar to control-fed animals andcomparable amounts of visceral fat. Conversely, MR rats show significantly reduced visceral fat comparedto CF and PF with concomitant decreases in basal insulin, glucose, and leptin, and increased adiponectinand triiodothyronine. Daily energy expenditure in MR animals significantly exceeds that of both PF andCF. In a separate cohort, insulin responses of older MR animals as measured by oral glucose challengeare similar to young animals. Longitudinal assessments of MR and CF through 112 weeks of age revealthat MR prevents age-associated increases in serum lipids. By 16 weeks, MR animals show a 40%reduction in insulin-like growth factor-1 (IGF-1) that is sustained throughout life; CF IGF-1 levels declinemuch later, beginning at 112 weeks. Collectively, the results indicate that MR reduces visceral fat andpreserves insulin activity in aging rats independent of energy restriction.", "metadata": {}}
+{"_id": "23032247", "title": "", "text": "Generation of T cell receptor–retrogenic mice: improved retroviral-mediated stem cell gene transferTheuse of retrogenic mice offers a rapid and flexible approach to T cell receptor (TCR)-transgenic mice. Bytransducing bone marrow progenitor cells with a retrovirus that encodes a given TCR-α/β subunit,TCR-retrogenic mice can be generated in as few as 4–6 weeks, whereas conventional TCR transgenicscan take 6 months or longer. In this updated protocol, we have increased the efficiency of the bonemarrow transduction and bone marrow reconstitution compared with our previously published protocol.The main departure from the previous protocol is the implementation of spin transduction with the viralsupernatant instead of coculture with the viral producer cell line. The changes in this protocol improvebone marrow viability, increase consistency of the bone marrow transduction and bone marrowengraftment, and they reduce the ratio of bone marrow donor mice to bone marrow recipients.", "metadata": {}}
+{"_id": "23036207", "title": "", "text": "Transient delivery of modified mRNA encoding TERT rapidly extends telomeres in human cells.Telomereextension has been proposed as a means to improve cell culture and tissue engineering and to treatdisease. However, telomere extension by nonviral, nonintegrating methods remains inefficient. Here wereport that delivery of modified mRNA encoding TERT to human fibroblasts and myoblasts increasestelomerase activity transiently (24-48 h) and rapidly extends telomeres, after which telomeres resumeshortening. Three successive transfections over a 4 d period extended telomeres up to 0.9 kb in a celltype-specific manner in fibroblasts and myoblasts and conferred an additional 28 ± 1.5 and 3.4 ± 0.4population doublings (PDs), respectively. Proliferative capacity increased in a dose-dependent manner.The second and third transfections had less effect on proliferative capacity than the first, revealing arefractory period. However, the refractory period was transient as a later fourth transfection increasedfibroblast proliferative capacity by an additional 15.2 ± 1.1 PDs, similar to the first transfection. Overall,these treatments led to an increase in absolute cell number of more than 10(12)-fold. Notably, unlikeimmortalized cells, all treated cell populations eventually stopped increasing in number and expressedsenescence markers to the same extent as untreated cells. This rapid method of extending telomeres andincreasing cell proliferative capacity without risk of insertional mutagenesis should have broad utility indisease modeling, drug screening, and regenerative medicine.", "metadata": {}}
+{"_id": "23052989", "title": "", "text": "The death receptor CD95 activates adult neural stem cells for working memory formation and brainrepair.Adult neurogenesis persists in the subventricular zone and the dentate gyrus and can be inducedupon central nervous system injury. However, the final contribution of newborn neurons to neuronalnetworks is limited. Here we show that in neural stem cells, stimulation of the \"death receptor\" CD95does not trigger apoptosis but unexpectedly leads to increased stem cell survival and neuronalspecification. These effects are mediated via activation of the Src/PI3K/AKT/mTOR signaling pathway,ultimately leading to a global increase in protein translation. Induction of neurogenesis by CD95 wasfurther confirmed in the ischemic CA1 region, in the naive dentate gyrus, and after forced expression ofCD95L in the adult subventricular zone. Lack of hippocampal CD95 resulted in a reduction inneurogenesis and working memory deficits. Following global ischemia, CD95-mediated brain repairrescued behavioral impairment. Thus, we identify the CD95/CD95L system as an instructive signal forongoing and injury-induced neurogenesis.", "metadata": {}}
+{"_id": "23073816", "title": "", "text": "Umbilical Cord Blood Therapy Potentiated with Erythropoietin for Children with Cerebral Palsy: ADouble-blind, Randomized, Placebo-Controlled TrialAllogeneic umbilical cord blood (UCB) has therapeuticpotential for cerebral palsy (CP). Concomitant administration of recombinant human erythropoietin(rhEPO) may boost the efficacy of UCB, as it has neurotrophic effects. The objectives of this study were toassess the safety and efficacy of allogeneic UCB potentiated with rhEPO in children with CP. Children withCP were randomly assigned to one of three parallel groups: the pUCB group, which received allogeneicUCB potentiated with rhEPO; the EPO group, which received rhEPO and placebo UCB; and the Controlgroup, which received placebo UCB and placebo rhEPO. All participants received rehabilitation therapy.The main outcomes were changes in scores on the following measures during the 6 months treatmentperiod: the gross motor performance measure (GMPM), gross motor function measure, and Bayley scalesof infant development-II (BSID-II) Mental and Motor scales (18). F-fluorodeoxyglucose positron emissiontomography (18F-FDG-PET/CT) and diffusion tensor images (DTI) were acquired at baseline and followedup to detect changes in the brain. In total, 96 subjects completed the study. Compared with the EPO (n =33) and Control (n = 32) groups, the pUCB (n = 31) group had significantly higher scores on the GMPMand BSID-II Mental and Motor scales at 6 months. DTI revealed significant correlations between theGMPM increment and changes in fractional anisotropy in the pUCB group. 18F-FDG-PET/CT showeddifferential activation and deactivation patterns between the three groups. The incidence of seriousadverse events did not differ between groups. In conclusion, UCB treatment ameliorated motor andcognitive dysfunction in children with CP undergoing active rehabilitation, accompanied by structural andmetabolic changes in the brain.", "metadata": {}}
+{"_id": "23076291", "title": "", "text": "Pituitary adenylate cyclase-activating polypeptide (PACAP(1-38)) enhances N-methyl-D-aspartatereceptor function and brain-derived neurotrophic factor expression via RACK1.We recently identified anovel mechanism for modulation of the phosphorylation state and function of the N-methyl-d-aspartate(NMDA) receptor via the scaffolding protein RACK1. We found that RACK1 binds both the NR2B subunit ofthe NMDA receptor and the nonreceptor protein-tyrosine kinase, Fyn. RACK1 inhibits Fyn phosphorylationof NR2B and decreases NMDA receptor-mediated currents in CA1 hippocampal slices (Yaka, R., Thornton,C., Vagts, A. J., Phamluong, K., Bonci, A., and Ron, D. (2002) Proc. Natl. Acad. Sci. U. S. A. 99,5710-5715). Here, we identified the signaling cascade by which RACK1 is released from the NMDAreceptor complex and identified the consequences of the dissociation. We found that activation of thecAMP/protein kinase A pathway in hippocampal slices induced the release of RACK1 from NR2B and Fyn.This resulted in the induction of NR2B phosphorylation and the enhancement of NMDA receptor-mediatedactivity via Fyn. We identified the neuropeptide, pituitary adenylate cyclase activating polypeptide(PACAP(1-38)), as a ligand that induced phosphorylation of NR2B and enhanced NMDA receptorpotentials. Finally, we found that activation of the cAMP/protein kinase A pathway induced the movementof RACK1 to the nuclear compartment in dissociated hippocampal neurons. Nuclear RACK1 in turn wasfound to regulate the expression of brain-derived neurotrophic factor induced by PACAP(1-38). Takentogether our results suggest that activation of adenylate cyclase by PACAP(1-38) results in the release ofRACK1 from the NMDA receptor and Fyn. This in turn leads to NMDA receptor phosphorylation, enhancedactivity mediated by Fyn, and to the induction of brain-derived neurotrophic factor expression by RACK1.", "metadata": {}}
+{"_id": "23078022", "title": "", "text": "MUC1 oncoprotein activates the IκB kinase β complex and constitutive NF-κB signallingNuclear factor-κB(NF-κB) is constitutively activated in diverse human malignancies by mechanisms that are notunderstood. The MUC1 oncoprotein is aberrantly overexpressed by most human carcinomas and, similarlyto NF-κB, blocks apoptosis and induces transformation. This study demonstrates that overexpression ofMUC1 in human carcinoma cells is associated with constitutive activation of NF-κB p65. We show thatMUC1 interacts with the high-molecular-weight IκB kinase (IKK) complex in vivo and that the MUC1cytoplasmic domain binds directly to IKKβ and IKKγ. Interaction of MUC1 with both IKKβ and IKKγ isnecessary for IKKβ activation, resulting in phosphorylation and degradation of IκBα. Studies innon-malignant epithelial cells show that MUC1 is recruited to the TNF-R1 complex and interacts withIKKβ–IKKγ in response to TNFα stimulation. TNFα-induced recruitment of MUC1 is dependent on TRADDand TRAF2, but not the death-domain kinase RIP1. In addition, MUC1-mediated activation of IKKβ isdependent on TAK1 and TAB2. These findings indicate that MUC1 is important for physiological activationof IKKβ and that overexpression of MUC1, as found in human cancers, confers sustained induction of theIKKβ–NF-κB p65 pathway.", "metadata": {}}
+{"_id": "23100220", "title": "", "text": "Lipoxins: novel series of biologically active compounds formed from arachidonic acid in humanleukocytes.Trihydroxytetraenes, a novel series of oxygenated derivatives formed from arachidonic acid inhuman leukocytes, were recently isolated [Serhan, C. N., Hamberg, M. & Samuelsson, B. (1984)Biochem. Biophys. Res. Commun. 118, 943-949]. The structure of the major compound wasestablished--i.e., 5,6,15L-trihydroxy-7,9,11,13-icosatetraenoic acid. The present study reports thestructure of a second member of the trihydroxytetraene series of compounds--i.e.,5D,14,15L-trihydroxy-6,8,10,12-icosatetraenoic acid. When added to human neutrophils,5,6,15L-trihydroxy-7,9,11,13-icosatetraenoic acid stimulated superoxide anion generation anddegranulation at submicromolar concentrations without provoking a substantial aggregation response.With respect to superoxide anion generation, 5,6,15L-trihydroxy-7,9,11,13-icosatetraenoic acid proved tobe as potent as leukotriene B4. In contrast, the compound was approximately 2 orders of magnitude lesspotent than either leukotriene B4 or fMet-Leu-Phe at provoking degranulation. The results indicate thatinteraction(s) between the 5- and 15-lipoxygenase pathways of human leukocytes leads to formation of anew series of oxygenated derivatives of arachidonic acid that may be involved in regulating specificcellular responses. The trivial names lipoxin A (5,6,15L-trihydroxy-7,9,11,13-icosatetraenoic acid) andlipoxin B (5D,14,15L-trihydroxy-6,8,10,12-icosatetraenoic acid) are proposed for the new compounds.", "metadata": {}}
+{"_id": "23100962", "title": "", "text": "Nitric oxide synthase generates superoxide and nitric oxide in arginine-depleted cells leading toperoxynitrite-mediated cellular injury.Besides synthesizing nitric oxide (NO), purified neuronal NOsynthase (nNOS) can produce superoxide (.O2-) at lower L-Arg concentrations. By using electronparamagnetic resonance spin-trapping techniques, we monitored NO and .O2- formation innNOS-transfected human kidney 293 cells. In control transfected cells, the Ca2+ ionophore A23187triggered NO generation but no .O2- was seen. With cells in L-Arg-free medium, we observed .O2-formation that increased as the cytosolic L-Arg levels decreased, while NO generation declined. .O2-formation was virtually abolished by the specific NOS blocker, N-nitro-L-arginine methyl ester (L-NAME).Nitrotyrosine, a specific nitration product of peroxynitrite, accumulated in L-Arg-depleted cells but not incontrol cells. Activation by A23187 was cytotoxic to L-Arg-depleted, but not to control cells, with markedlactate dehydrogenase release. The cytotoxicity was largely prevented by either superoxide dismutase orL-NAME. Thus, with reduced L-Arg availability NOS elicits cytotoxicity by generating .O2- and NO thatinteract to form the potent oxidant peroxynitrite. Regulating arginine levels may provide a therapeuticapproach to disorders involving .O2-/NO-mediated cellular injury.", "metadata": {}}
+{"_id": "23117378", "title": "", "text": "Sudden infant death syndrome and unclassified sudden infant deaths: a definitional and diagnosticapproach.The definition of sudden infant death syndrome (SIDS) originally appeared in 1969 and wasmodified 2 decades later. During the following 15 years, an enormous amount of additional informationhas emerged, justifying additional refinement of the definition of SIDS to incorporate epidemiologicfeatures, risk factors, pathologic features, and ancillary test findings. An expert panel of pediatric andforensic pathologists and pediatricians considered these issues and developed a new general definition ofSIDS for administrative and vital statistics purposes. The new definition was then stratified to facilitateresearch into sudden infant death. Another category, defined as unclassified sudden infant deaths, wasintroduced for cases that do not meet the criteria for a diagnosis of SIDS and for which alternativediagnoses of natural or unnatural conditions were equivocal. It is anticipated that these new definitionswill be modified in the future to accommodate new understanding of SIDS and sudden infant death.", "metadata": {}}
+{"_id": "23117928", "title": "", "text": "Inter-viral conflicts that exploit host CRISPR immune systems of Sulfolobus.Infection of Sulfolobusislandicus REY15A with mixtures of different Sulfolobus viruses, including STSV2, did not induce spaceracquisition by the host CRISPR immune system. However, coinfection with the tailed fusiform virusesSMV1 and STSV2 generated hyperactive spacer acquisition in both CRISPR loci, exclusively from STSV2,with the resultant loss of STSV2 but not SMV1. SMV1 was shown to activate adaptation while itself beingresistant to CRISPR-mediated adaptation and DNA interference. Exceptionally, a single clone S-1 isolatedfrom an SMV1 + STSV2-infected culture, that carried STSV2-specific spacers and had lost STSV2 but notSMV1, acquired spacers from SMV1. This effect was also reproducible on reinfecting wild-type host cellswith a variant SMV1 isolated from the S-1 culture. The SMV1 variant lacked a virion protein ORF114 thatwas shown to bind DNA. This study also provided evidence for: (i) limits on the maximum sizes of CRISPRloci; (ii) spacer uptake strongly retarding growth of infected cultures; (iii) protospacer selection beingessentially random and non-directional, and (iv) the reversible uptake of spacers from STSV2 and SMV1.A hypothesis is presented to explain the interactive conflicts between SMV1 and the host CRISPR immunesystem.", "metadata": {}}
+{"_id": "23122306", "title": "", "text": "Lung Carcinogenesis by Diesel Exhaust Particles and the Carcinogenic Mechanism Via Active Oxygens.Inan experiment to clarify the involvement of oxygen radicals in lung carcinogenesis induced by dieselexhaust particles (DEP), we found that there is a strong relation between lung tumor response andformation of 8-hydroxydeoxyguanosine (8-OHdG) in lung DNA of mice administered DEP by repeatedintratracheal instillation. Repeated intratracheal instillation of DEP also induced the activity of cytochromeP-450 reductase in the lungs as a representative enzyme of superoxide generation, and two types ofnitric oxide (NO) synthase, cNOS and iNOS, in the lungs. On the other hand, activities ofCuZn-superoxide dismutase (SOD) and Mn-SOD antioxidant enzymes were depressed by the instillationof DEP. These results suggest that generation of superoxide, hydroxyI radical, and nitric oxide areincreased in epithelial cells in airways, and that the increased superoxide and nitric oxide react very easilyto produce peroxynitrite (ONOO(-)). The peroxynitrite also produce hydroxyI radical. The hydroxyl radicalmay play an important role in carcinogenesis by DEP.", "metadata": {}}
+{"_id": "23124332", "title": "", "text": "Prion-induced amyloid heart disease with high blood infectivity in transgenic mice.We investigatedextraneural manifestations in scrapie-infected transgenic mice expressing prion protein lacking theglycophosphatydylinositol membrane anchor. In the brain, blood, and heart, both abnormalprotease-resistant prion protein (PrPres) and prion infectivity were readily detected by immunoblot andby inoculation into nontransgenic recipients. The titer of infectious scrapie in blood plasma exceeded10(7) 50% infectious doses per milliliter. The hearts of these transgenic mice contained PrPres-positiveamyloid deposits that led to myocardial stiffness and cardiac disease.", "metadata": {}}
+{"_id": "23126677", "title": "", "text": "Circulating plasma microRNAs as a screening method for detection of colorectal adenomas.BACKGROUNDMicroRNAs (miRNAs) are small non-coding RNA molecules. Reduced or increased levels of specific miRNAsare observed in colon and other cancers, supporting their role in carcinogenesis. Detection of colorectalpolyps is the cornerstone of the Bowel Cancer Screening Programme in the UK. However, uptake ofscreening nationally remains under 60%. We aimed to see whether circulating plasma miRNAs can beused to screen for patients with colorectal polyps, adenomas, or both. METHODS Blood samples weretaken from patients from the Bowel Cancer Screening Programme (asymptomatic but faecal occult bloodtesting [FOBt] positive). Plasma RNA was extracted, target miRNAs (19a, 98, 146b, 186, 191, 222*,331-5p, 452, 625, 664, 1247) were identified on pooled case miRNA assay cards, and miRNA fraction wasquantified by quantitative RT-PCR assay. Results were compared with endoscopy reports and withhistology of any polyps identified and removed. Analysis was done with Excel (2011) and SPSS (version20) software. FINDINGS 210 patients were included (117 with polyps, 12 with cancer, 81 healthy controls[FOBt positive]). The miRNA panel showed significant differences in expression (on t testing) for patientscompared with controls for those with polyps, cancer, or both (miR-19a, p=0·0184; miR-98, p=0·0206;miR-146b, p=0·0029; miR-186, p=0·0006; miR-62,5 p=0·0008), polyps (miR-19a, p=0·0233; miR-98,p=0·0224; miR-146b, p=0·003; miR-186, p=0·0004; miR-625, p=0·001), adenomas (miR-19a,p=0·0339; miR-98, p=0·0266; miR-146b, p=0·0045; miR-186, p=0·0008; miR-625, p=0·0049), multipleadenomas (both sides of colon; miR-146b, p=0·0194; miR-186, p=0·0226; miR-625, p=0·0013), andright-sided adenomas (miR-98, p=0·031; miR-146b, p=0·0076; miR-186, p=0·0041; miR-331-5p,p=0·0142; miR-625, p=0·0049). Receiver operating characteristic analysis showed sensitivity of 60% ormore, and specificity of 86% or more for men with polyps, men with adenomas, all patients withhaemorrhoids or diverticulosis and polyps, and all patients with haemorrhoids or diverticulosis andadenomas. INTERPRETATION The target miRNAs that we identified showed significant differences inexpression levels for patients with polyps and patients with adenomas from controls. Use of this panelhas potential as a screening test. FUNDING Bowel Disease Research Foundation.", "metadata": {}}
+{"_id": "23136735", "title": "", "text": "Short term persistence of human papillomavirus and risk of cervical precancer and cancer: populationbased cohort studyOBJECTIVE To evaluate the cumulative incidence of cervical intraepithelial neoplasia IIor worse (grade II+) or cervical intraepithelial neoplasia grade III+ after short term persistence ofprevalently detected carcinogenic human papillomavirus (HPV). DESIGN Population based cohort study.SETTING Guanacaste, Costa Rica. PARTICIPANTS 2282 sexually active women actively followed afterenrolment. MAIN OUTCOME MEASURES Primary end points: three year and five year cumulativeincidence of histologically confirmed cervical intraepithelial neoplasia grade II+ (n=70). Cervicalspecimens collected at each visit tested for more than 40 HPV genotypes. HPV 16, 18, 26, 31, 33, 35, 39,45, 51, 52, 56, 58, 59, 66, 68, 73, and 82 were considered the primary carcinogenic genotypes. RESULTSWomen who tested positive for a carcinogenic HPV at enrolment and after about one year (9-21 months)(positive/positive) had a three year cumulative incidence of cervical intraepithelial neoplasia grade II+ of17.0% (95% confidence interval 12.1% to 22.0%). Those who tested negative/positive (3.4%, 0.1% to6.8%), positive/negative (1.2%, -0.2% to 2.5%), and negative/negative (0.5%, 0.1% to 0.9%) were ata significantly lower risk. There was little difference in the cumulative incidence of cervical intraepithelialneoplasia grade II+ between testing positive twice for any carcinogenic HPV genotype (same genotype ordifferent genotypes) v testing positive twice for the same carcinogenic genotype (17.0% v 21.3%,respectively). Short term persistence of HPV 16 strongly predicted cervical intraepithelial neoplasia gradeII+, with a three year cumulative incidence of 40.8% (26.4% to 55.1%). Similar patterns were observedfor the five year cumulative incidence of grade II+ and for three year and five year cumulative incidenceof grade III+. CONCLUSIONS Short term persistence of a prevalently detected carcinogenic HPVinfection, especially HPV 16, strongly predicts a subsequent diagnosis of cervical intraepithelial neoplasiaII+ over the next few years.", "metadata": {}}
+{"_id": "23141360", "title": "", "text": "Nature and anisotropy of cortical forces orienting Drosophila tissue morphogenesisThe morphogenesis ofdeveloping embryos and organs relies on the ability of cells to remodel their contacts with neighbouringcells. Using quantitative modelling and laser nano-dissection, we probed the mechanics of amorphogenetic process, the elongation of Drosophila melanogaster embryos, which results from polarizedcell neighbour exchanges. We show that anisotropy of cortical tension at apical cell junctions is sufficientto drive tissue elongation. We estimated its value through comparisons between in silico and in vivo datausing various tissue descriptors. Nano-dissection of the actomyosin network indicates that tension isanisotropically distributed and depends on myosin II accumulation. Junction relaxation afternano-dissection also suggests that cortical elastic forces are dominant in this process. Interestingly,fluctuations in vertex position (points where three or more cells meet) facilitate neighbour exchanges. Wedelineate the contribution of subcellular tensile activity polarizing junction remodelling, and thepermissive role of vertex fluctuations during tissue elongation.", "metadata": {}}
+{"_id": "23148978", "title": "", "text": "The influence of some metabolic inhibitors on phagocytic activity of mouse macrophages in vitro.Theaction of different metabolic inhibitors on phagocytosis by macrophages from mouse peritoneal exudatecultured in vitro was studied. The following metabolic inhibitors were tested: sodium iodoacetate, sodiumfluoride, sodium fluoroacetate, sodium malonate, 2-4-dinitrophenol, sodium azide, ouabain andcycloheximide, all at the concentration of 10(-3) M. Iodoacetate caused a strong inhibitory effect onphagocytosis; this observation confirms that glycolysis is the main source of energy for the phagocyticprocess. On the contrary, fluoride, although it is an effective inhibitor of glycolysis, did not exert anyeffect. This difference may be explained by the fact that sodium fluoride blocks anaerobic glycolysis onlyin vitro at an unphysiological temperature (0 degrees C). Fluoroacetate and malonate, two compoundswhich interfere with the Krebs cycle, did not inhibit phagocytosis, but it is known that the Krebs cycleactivity is poorly developed in the macrophagic cells. Sodium azide and 2-4-dinitrophenol, two inhibitorsof oxidative phosphorylation, showed an effect on phagocytosis only after 3 h of contact with the cellcultures. Ouabain blocks Na+ and K+ transport across the plasma membrane and, probably, it inhibitedphagocytosis by interfering with the movements of the cell membrane. Finally, the mode of action ofcycloheximide on phagocytosis is uncertain. This compound inhibits the protein synthesis and, perhaps, itcan act by preventing the renewal of the cell membrane.", "metadata": {}}
+{"_id": "23160444", "title": "", "text": "Two-tiered coupling between flowing actin and immobilized N-cadherin/catenin complexes in neuronalgrowth cones.Neuronal growth cones move forward by dynamically connecting actin-based motility tosubstrate adhesion, but the mechanisms at the individual molecular level remain unclear. We culturedprimary neurons on N-cadherin-coated micropatterned substrates, and imaged adhesion and cytoskeletalproteins at the ventral surface of growth cones using single particle tracking combined to photoactivatedlocalization microscopy (sptPALM). We demonstrate transient interactions in the second time scalebetween flowing actin filaments and immobilized N-cadherin/catenin complexes, translating into a localreduction of the actin retrograde flow. Normal actin flow on micropatterns was rescued by expression of adominant negative N-cadherin construct competing for the coupling between actin and endogenousN-cadherin. Fluorescence recovery after photobleaching (FRAP) experiments confirmed the differentialkinetics of actin and N-cadherin, and further revealed a 20% actin population confined at N-cadherinmicropatterns, contributing to local actin accumulation. Computer simulations with relevant kineticparameters modeled N-cadherin and actin turnover well, validating this mechanism. Such a combinationof short- and long-lived interactions between the motile actin network and spatially restricted adhesivecomplexes represents a two-tiered clutch mechanism likely to sustain dynamic environment sensing andprovide the force necessary for growth cone migration.", "metadata": {}}
+{"_id": "23180075", "title": "", "text": "Cloning of factors related to HIV-inducible LBP proteins that regulate steroidogenic factor-1-independenthuman placental transcription of the cholesterol side-chain cleavage enzyme, P450scc.The cholesterolside-chain cleavage enzyme, cytochrome P450scc, initiates the biosynthesis of all steroid hormones.Adrenal and gonadal strategies for P450scc gene transcription are essentially identical and depend on theorphan nuclear receptor steroidogenic factor-1, but the placental strategy for transcription of P450sccemploys cis-acting elements different from those used in the adrenal strategy and is independent ofsteroidogenic factor-1. Because placental expression of P450scc is required for human pregnancy, wesought factors that bind to the -155/-131 region of the human P450scc promoter, which participates in itsplacental but not adrenal or gonadal transcription. A yeast one-hybrid screen of 2.4 x 10(6) cDNA clonesfrom human placental JEG-3 cells yielded two unique clones; one is the previously described transcriptionfactor LBP-1b, which is induced by HIV, type I infection of lymphocytes, and the other is a new factor,termed LBP-9, that shares 83% amino acid sequence identity with LBP-1b. When expressed intransfected yeast, both factors bound specifically to the -155/-131 DNA; antisera to LBP proteinssupershifted the LBP-9.DNA complex and inhibited formation of the LBP-1b. DNA complex. Reversetranscriptase-polymerase chain reaction detected LBP-1b in human placental JEG-3, adrenal NCI-H295A,liver HepG2, cervical HeLa, and monkey kidney COS-1 cells, but LBP-9 was detected only in JEG-3 cells.When the -155/-131 fragment was linked to a minimal promoter, co-expression of LBP-1b increasedtranscription 21-fold in a dose-dependent fashion, but addition of LBP-9 suppressed the stimulatory effectof LBP-1b. The roles of LBP transcription factors in normal human physiology have been unclear. Theirmodulation of placental but not adrenal P450scc transcription underscores the distinctiveness of placentalstrategies for steroidogenic enzyme gene transcription.", "metadata": {}}
+{"_id": "23190392", "title": "", "text": "Functional reprogramming of polyploidization in megakaryocytes.Polyploidization is a natural process thatfrequently accompanies differentiation; its deregulation is linked to genomic instability and cancer.Despite its relevance, why cells select different polyploidization mechanisms is unknown. Here we reporta systematic genetic analysis of endomitosis, a process in which megakaryocytes become polyploid byentering mitosis but aborting anaphase. Whereas ablation of the APC/C cofactor Cdc20 results in mitoticarrest and severe thrombocytopenia, lack of the kinases Aurora-B, Cdk1, or Cdk2 does not affectmegakaryocyte polyploidization or platelet levels. Ablation of Cdk1 forces a switch to endocycles withoutmitosis, whereas polyploidization in the absence of Cdk1 and Cdk2 occurs in the presence of aberrantre-replication events. Importantly, ablation of these kinases rescues the defects in Cdc20 nullmegakaryocytes. These findings suggest that endomitosis can be functionally replaced by alternativepolyploidization mechanisms in vivo and provide the cellular basis for therapeutic approaches aimed todiscriminate mitotic and polyploid cells.", "metadata": {}}
+{"_id": "23195302", "title": "", "text": "Histone methyltransferase activity associated with a human multiprotein complex containing theEnhancer of Zeste protein.Enhancer of Zeste [E(z)] is a Polycomb-group transcriptional repressor and oneof the founding members of the family of SET domain-containing proteins. Several SET-domain proteinspossess intrinsic histone methyltransferase (HMT) activity. However, recombinant E(z) protein was foundto be inactive in a HMT assay. Here we report the isolation of a multiprotein E(z) complex that containsextra sex combs, suppressor of zeste-12 [Su(z)12], and the histone binding proteins RbAp46/RbAp48.This complex, which we termed Polycomb repressive complex (PRC) 2, possesses HMT activity withspecificity for Lys 9 (K9) and Lys 27 (K27) of histone H3. The HMT activity of PRC2 is dependent on anintact SET domain in the E(z) protein. We hypothesize that transcriptional repression by the E(z) proteininvolves methylation-dependent recruitment of PRC1. The presence of Su(z)12, a strong suppressor ofposition effect variegation, in PRC2 suggests that PRC2 may play a widespread role inheterochromatin-mediated silencing.", "metadata": {}}
+{"_id": "23195674", "title": "", "text": "Simvastatin reduces platelet-endocardium adhesion in atrial fibrillation.OBJECTIVES To evaluate therelationship between CD40/CD40L system and increased thrombogenesis in AF, and to test the effects ofsimvastatin treatment. METHODS In vitro study using human tissue, University Hospital (tertiary referralcenter). Experiments on right atrial segments obtained before the onset of cardiopulmonary bypass weredone in either presence or absence of 5 microM simvastatin. Two groups of patients in either chronicatrial fibrillation or sinus rhythm at the time of cardiac surgery. The endocardial expression of CD40, therelease of CD40L, and adhesion of platelets to endocardium. Additionally, the thickness of plateletaggregates and the platelet distribution on the endocardium were also evaluated. RESULTS Atrialfibrillation was associated with a significant increase of endocardial CD40 expression (293.1+/-55.1pg/ml vs. 230.9+/-53.3 pg/ml, p<0.01), and platelet-endocardial adhesion compared with sinus rhythmatria (10.8+/-2.2 vs. 5.2+/-1.3 platelet CD41 AU p<0.01). At immunofluorescence about 62% offibrillating endocardium was covered by platelets, compared with 12% of not sinus rhythm atria. Additionof simvastatin significantly reduced CD40 expression as well as platelet adhesion to fibrillating atria; itsefficacy was not reversed by the addition of mevalonic acid. CONCLUSIONS Chronic atrial fibrillationacutely upregulates CD40 expression as well as platelet adhesion to the endocardium. Simvastatin iseffective in modulating this expression, thus it may potentially contribute to reduce the risk of intra-atrialthrombus formation.", "metadata": {}}
+{"_id": "23203102", "title": "", "text": "Transmission of sporadic Creutzfeldt-Jakob disease by blood transfusion: risk factor or possiblebiases.BACKGROUND The occurrence of transfusion transmissions of variant Creutzfeldt-Jakob disease(CJD) cases has reawakened attention to the possible similar risk posed by other forms of CJD. STUDYDESIGN AND METHODS CJD with a definite or probable diagnosis (sporadic CJD, n = 741; genetic CJD, n= 175) and no-CJD patients with definite alternative diagnosis (n = 482) with available blood transfusionhistory were included in the study. The risk of exposure to blood transfusion occurring more than 10years before disease onset and for some possible confounding factors was evaluated by calculating crudeodds ratios (ORs). Variables with significant ORs in univariate analyses were included in multivariatelogistic regression analyses. RESULTS In the univariate model, blood transfusion occurring more than 10years before clinical onset is 4.1-fold more frequent in sporadic CJD than in other neurologic disorders.This significance is lost when the 10-year lag time was not considered. Multivariate analyses show thatthe risk of developing sporadic CJD after transfusion increases (OR, 5.05) after adjusting for possibleconfounding factors. Analysis conducted on patients with genetic CJD did not reveal any significant riskfactor associated with transfusion. CONCLUSION This is the first case-control study showing a significantrisk of transfusion occurring more than 10 years before clinical onset in sporadic CJD patients. It remainsquestionable whether the significance of these data is biologically plausible or the consequence of biasesin the design of the study, but they counterbalance previous epidemiologic negative reports that mighthave overestimated the assessment of blood safety in sporadic CJD.", "metadata": {}}
+{"_id": "23206239", "title": "", "text": "Advantages and pitfalls of fructosamine and glycated albumin in the diagnosis and treatment ofdiabetes.The efficient diagnosis and accurate monitoring of diabetic patients are cornerstones forreducing the risk of diabetic complications. The current diagnostic and prognostic strategies in diabetesare mainly based on two tests, plasma (or capillary) glucose and glycated hemoglobin (HbA1c).Nevertheless, these measures are not foolproof, and their clinical usefulness is biased by a number ofclinical and analytical factors. The introduction of other indices of glucose homeostasis in clinical practicesuch as fructosamine and glycated albumin (GA) may be regarded as an attractive alternative, especiallyin patients in whom the measurement of HbA1c may be biased or even unreliable. These include patientswith rapid changes of glucose homeostasis and larger glycemic excursions, and patients with red bloodcell disorders and renal disease. According to available evidence, the overall diagnostic efficiency of GAseems superior to that of fructosamine throughout a broad range of clinical settings. The current methodfor measuring GA is also better standardized and less vulnerable to preanalytical variables than thoseused for assessing fructosamine. Additional advantages of GA over HbA1c are represented by lowerreagent cost and being able to automate the GA analysis on many conventional laboratory instruments.Although further studies are needed to definitely establish that GA can complement or even replaceconventional measures of glycemic control such as HbA1c, GA may help the clinical management ofpatients with diabetes in whom HbA1c values might be unreliable.", "metadata": {}}
+{"_id": "23208167", "title": "", "text": "Catalytic-Independent Functions of PARP-1 Determine Sox2 Pioneer Activity at Intractable GenomicLoci.Pioneer transcription factors (TFs) function as genomic first responders, binding to inaccessibleregions of chromatin to promote enhancer formation. The mechanism by which pioneer TFs gain accessto chromatin remains an important unanswered question. Here we show that PARP-1, anucleosome-binding protein, cooperates with intrinsic properties of the pioneer TF Sox2 to facilitate itsbinding to intractable genomic loci in embryonic stem cells. These actions of PARP-1 occur independentlyof its poly(ADP-ribosyl) transferase activity. PARP-1-dependent Sox2-binding sites reside in euchromaticregions of the genome with relatively high nucleosome occupancy and low co-occupancy by othertranscription factors. PARP-1 stabilizes Sox2 binding to nucleosomes at suboptimal sites throughcooperative interactions on DNA. Our results define intrinsic and extrinsic features that determine Sox2pioneer activity. The conditional pioneer activity observed with Sox2 at a subset of binding sites may be akey feature of other pioneer TFs operating at intractable genomic loci.", "metadata": {}}
+{"_id": "23237995", "title": "", "text": "Steroid regulation of C. elegans diapause, developmental timing, and longevity.Hormones play a criticalrole in driving major stage transitions and developmental timing events in many species. In thenematode C. elegans the steroid hormone receptor, DAF-12, works at the confluence of pathwaysregulating developmental timing, stage specification, and longevity. DAF-12 couples environmental andphysiologic signals to life history regulation, and it is embedded in a rich architecture governing diverseprocesses. Here, we highlight the molecular insights, extraordinary circuitry, and signaling pathwaysgoverning life stage transitions in the worm and how they have yielded fundamental insights into steroidregulation of biological time.", "metadata": {}}
+{"_id": "23244529", "title": "", "text": "A core subunit of Polycomb repressive complex 1 is broadly conserved in function but not primarysequence.Polycomb Group (PcG) proteins mediate heritable gene silencing by modifying chromatinstructure. An essential PcG complex, PRC1, compacts chromatin and inhibits chromatin remodeling. InDrosophila melanogaster, the intrinsically disordered C-terminal region of PSC (PSC-CTR) mediates thesenoncovalent effects on chromatin, and is essential for viability. Because the PSC-CTR sequence is poorlyconserved, the significance of its effects on chromatin outside of Drosophila was unclear. The absence offolded domains also made it difficult to understand how the sequence of PSC-CTR encodes its function. Todetermine the mechanistic basis and extent of conservation of PSC-CTR activity, we identified 17metazoan PSC-CTRs spanning chordates to arthropods, and examined their sequence features andbiochemical properties. PSC-CTR sequences are poorly conserved, but are all highly charged andstructurally disordered. We show that active PSC-CTRs--which bind DNA tightly and inhibit chromatinremodeling efficiently--are distinguished from less active ones by the absence of extended negativelycharged stretches. PSC-CTR activity can be increased by dispersing its contiguous negative charge,confirming the importance of this property. Using the sequence properties defined as important forPSC-CTR activity, we predicted the presence of active PSC-CTRs in additional diverse genomes. Ouranalysis reveals broad conservation of PSC-CTR activity across metazoans. This conclusion could not havebeen determined from sequence alignments. We further find that plants that lack active PSC-CTRsinstead possess a functionally analogous PcG protein, EMF1. Thus, our study suggests that a disordereddomain with dispersed negative charges underlies PRC1 activity, and is conserved across metazoans andplants.", "metadata": {}}
+{"_id": "23245050", "title": "", "text": "Dietary status of trained female cyclists.Dietary status was evaluated in eight highly trained femalecyclists. Each cyclist kept a 3-day weighed food record. Diets were analyzed for nutrient content using acomputerized software package. Blood was also obtained and evaluated for hemoglobin, hematocrit, andalbumin. For an athletic group, the cyclists' diets were found to be low in energy (85% RDA) andcarbohydrate (4.4 gm/kg body weight per day). Mean daily dietary intakes were well below the RDAs forfolacin (76% RDA), magnesium (81%), iron (59%), and zinc (48%). In addition, more than one-third ofthe cyclists failed to consume 67% of the RDA for the following micronutrients: pyridoxine, folacin,cobalamin, vitamin E, magnesium, iron, and zinc. Hemoglobin (135 gm/L), hematocrit (0.39), andalbumin (45 gm/L) values were all normal, although most hemoglobin values were in the lower 50% ofnormal range. Foods such as meats, poultry, fish, beans, peas, and nuts were low or absent from thediets of most athletes. Dietary quality in this group of female cyclists could have been greatly improvedwith the addition of more of those foods. These athletes could benefit from nutrition education and dietcounseling.", "metadata": {}}
+{"_id": "23253955", "title": "", "text": "Regulation of Pax-3 expression in the dermomyotome and its role in muscle development.The segmentedmesoderm in vertebrates gives rise to a variety of cell types in the embryo including the axial skeletonand muscle. A number of transcription factors containing a paired domain (Pax proteins) are expressed inthe segmented mesoderm during embryogenesis. These include Pax-3 and a closely related gene, Pax-7,both of which are expressed in the segmental plate and in the dermomyotome. In this paper, we showthat signals from the notochord pattern the expression of Pax-3, Pax-7 and Pax-9 in somites and thesubsequent differentiation of cell types that arise from the somitic mesoderm. We directly assess the roleof the Pax-3 gene in the differentiation of cell types derived from the dermomyotome by analyzing thedevelopment of muscle in splotch mouse embryos which lack a functional Pax-3 gene. A population ofPax-3-expressing cells derived from the dermomyotome that normally migrate into the limb are absent inhomozygous splotch embryos and, as a result, limb muscles are lost. No abnormalities were detected inthe trunk musculature of splotch embryos indicating that Pax-3 is necessary for the development of thelimb but not trunk muscle.", "metadata": {}}
+{"_id": "23260700", "title": "", "text": "Angiopoietin 2 is a partial agonist/antagonist of Tie2 signaling in the endothelium.Angiopoietin 2 (Ang2)was originally shown to be a competitive antagonist for Ang1 of the receptor tyrosine kinase Tie2 inendothelial cells (ECs). Since then, reports have conflicted on whether Ang2 is an agonist or antagonist ofTie2. Here we show that Ang2 functions as an agonist when Ang1 is absent but as a dose-dependentantagonist when Ang1 is present. Exogenous Ang2 activates Tie2 and the promigratory, prosurvivalPI3K/Akt pathway in ECs but with less potency and lower affinity than exogenous Ang1. ECs produceAng2 but not Ang1. This endogenous Ang2 maintains Tie2, phosphatidylinositol 3-kinase, and Aktactivities, and it promotes EC survival, migration, and tube formation. However, when ECs are stimulatedwith Ang1 and Ang2, Ang2 dose-dependently inhibits Ang1-induced Tie2 phosphorylation, Akt activation,and EC survival. We conclude that Ang2 is both an agonist and an antagonist of Tie2. Although Ang2 is aweaker agonist than Ang1, endogenous Ang2 maintains a level of Tie2 activation that is critical to aspectrum of EC functions. These findings may reconcile disparate reports of Ang2's effect on Tie2, impactour understanding of endogenous receptor tyrosine kinase signal transduction mechanisms, and affecthow Ang2 and Tie2 are targeted under conditions such as sepsis and cancer.", "metadata": {}}
+{"_id": "23262027", "title": "", "text": "Bacteremia caused by a strain of Desulfovibrio related to the provisionally named Desulfovibriofairfieldensis.Eight isolates of Desulfovibrio spp. have been obtained over 5 years from abdominal or brainabscesses or blood. Seven isolates were part of a mixed flora [corrected]. One strain was isolated in pureculture from the blood of a patient with peritonitis of appendicular origin. According to the 16S rRNA genesequences, this strain was close to Desulfovibrio fairfieldensis. The present report describes the fourthisolate of this recently described species to be isolated in pure culture or as a predominant part of theflora and to be associated with infectious processes. Thus, D. fairfieldensis may possess a higherpathogenic potential than other Desulfovibrio species.", "metadata": {}}
+{"_id": "23267371", "title": "", "text": "Vitamin D: The \"sunshine\" vitamin.Vitamin D insufficiency affects almost 50% of the populationworldwide. An estimated 1 billion people worldwide, across all ethnicities and age groups, have a vitaminD deficiency (VDD). This pandemic of hypovitaminosis D can mainly be attributed to lifestyle (forexample, reduced outdoor activities) and environmental (for example, air pollution) factors that reduceexposure to sunlight, which is required for ultraviolet-B (UVB)-induced vitamin D production in the skin.High prevalence of vitamin D insufficiency is a particularly important public health issue becausehypovitaminosis D is an independent risk factor for total mortality in the general population. Currentstudies suggest that we may need more vitamin D than presently recommended to prevent chronicdisease. As the number of people with VDD continues to increase, the importance of this hormone inoverall health and the prevention of chronic diseases are at the forefront of research. VDD is verycommon in all age groups. As few foods contain vitamin D, guidelines recommended supplementation atsuggested daily intake and tolerable upper limit levels. It is also suggested to measure the serum25-hydroxyvitamin D level as the initial diagnostic test in patients at risk for deficiency. Treatment witheither vitamin D2 or vitamin D3 is recommended for deficient patients. A meta-analysis published in 2007showed that vitamin D supplementation was associated with significantly reduced mortality. In thisreview, we will summarize the mechanisms that are presumed to underlie the relationship betweenvitamin D and understand its biology and clinical implications.", "metadata": {}}
+{"_id": "23269537", "title": "", "text": "Cyclin D1 activation in B-cell malignancy: association with changes in histone acetylation, DNAmethylation, and RNA polymerase II binding to both promoter and distal sequences.Cyclin D1 expressionis deregulated by chromosome translocation in mantle cell lymphoma and a subset of multiple myeloma.The molecular mechanisms involved in long-distance gene deregulation remain obscure, althoughchanges in acetylated histones and methylated CpG dinucleotides may be important. The patterns of DNAmethylation and histone acetylation were determined at the cyclin D1 locus on chromosome 11q13 inB-cell malignancies. The cyclin D1 promoter was hypomethylated and hyperacetylated in expressing celllines and patient samples, and methylated and hypoacetylated in nonexpressing cell lines. Domains ofhyperacetylated histones and hypomethylated DNA extended over 120 kb upstream of the cyclin D1gene. Interestingly, hypomethylated DNA and hyperacetylated histones were also located at the cyclin D1promoter but not the upstream major translocation cluster region in cyclin D1-nonexpressing,nontumorigenic B and T cells. RNA polymerase II binding was demonstrated both at the cyclin D1promoter and 3' immunoglobulin heavy-chain regulatory regions only in malignant B-cell lines withderegulated cyclin D1 expression. Our results suggest a model where RNA polymerase II bound at IgHregulatory sequences can activate the cyclin D1 promoter by either long-range polymerase transfer ortracking.", "metadata": {}}
+{"_id": "23273454", "title": "", "text": "The physiological regulation of toll-like receptor expression and function in humans.Eleven mammaliantoll-like receptors (TLRs 1-11) have been identified to date and are known to play a crucial role in theregulation of immune responses; however, the factors that regulate TLR expression and function in vivoare poorly understood. Therefore, in the present study, we investigated the physiological regulation ofTLR expression and function in humans. To examine the influence of diurnal rhythmicity on TLRexpression and function, peripheral venous blood samples were collected from healthy volunteers (n = 8)at time points coinciding with the peak and nadir in the endogenous circulating cortisol concentration.While no diurnal rhythmicity in the expression of TLRs 1, 2, 4 or 9 was observed, the upregulation ofcostimulatory (CD80 and CD86) and antigen-presenting (MHC class II) molecules on CD14(+) monocytesfollowing activation with specific TLR ligands was greater (P < 0.05) in samples obtained in the eveningcompared with the morning. To examine the influence of physical stress on TLR expression and function,peripheral venous blood samples were collected from healthy volunteers (n = 11) at rest and following1.5 h of strenuous exercise in the heat (34 degrees C). Strenuous exercise resulted in a decrease (P <0.005) in the expression of TLRs 1, 2 and 4 on CD14(+) monocytes. Furthermore, the upregulation ofCD80, CD86, MHC class II and interleukin-6 by CD14(+) monocytes following activation with specific TLRligands was decreased (P < 0.05) in samples obtained following exercise compared with at rest. Theseresults demonstrate that TLR function is subject to modulation under physiological conditions in vivo andprovide evidence for the role of immunomodulatory hormones in the regulation of TLR function.", "metadata": {}}
+{"_id": "23284774", "title": "", "text": "A review of psychosocial needs of breast-cancer patients and their relatives.AIM To identify thepsychosocial needs of breast-cancer patients and their relatives along with factors affecting these needsand to develop a tentative model to guide further research and need assessments in clinical practice.BACKGROUND Women experiencing breast cancer must deal with the diagnosis of a life-threateningillness. Treatment and the recovery process can be demanding for patients and their relatives. Needassessment may help clinicians focus on providing appropriate help. DESIGN Literature review. METHODUndertaken using electronic databases and specific research terms; 20 articles were identified andanalysed. RESULTS The needs identified by patients involve (1) treatment-related physical and socialimpairment like fatigue, menopausal symptoms and a changed body image and (2) emotional distresslike fear of recurrence, anxiety and depression. Partners need help to protect themselves and the patientfrom different threats. Women need information to maintain control and manage their illness. Partnerswant information concerning the patient's condition and both of them about the prognosis andperspectives. There is a lack of knowledge of relatives' needs. Mutual familial support, women's andpartners' health and emotional distress may affect the interaction between the patients and theirpartners. CONCLUSIONS A tentative family-based model to guide further research and clinical support isproposed. Further research is needed to determine precisely which psychosocial factors may influencefulfilment of the patients' and relatives' needs. RELEVANCE TO CLINICAL PRACTICE The proposed modelmay provide a framework for healthcare professionals to evaluate the patients' and relatives' met andunmet needs and the real demand for help, to guide care planning, counselling and education.", "metadata": {}}
+{"_id": "23286603", "title": "", "text": "Poly(ADP-ribose) Polymerase 1 Represses Liver X Receptor-mediated ABCA1 Expression and CholesterolEfflux in Macrophages.Liver X receptors (LXR) are oxysterol-activated nuclear receptors that play acentral role in reverse cholesterol transport through up-regulation of ATP-binding cassette transporters(ABCA1 and ABCG1) that mediate cellular cholesterol efflux. Mouse models of atherosclerosis exhibitreduced atherosclerosis and enhanced regression of established plaques upon LXR activation. However,the coregulatory factors that affect LXR-dependent gene activation in macrophages remain to beelucidated. To identify novel regulators of LXR that modulate its activity, we used affinity purification andmass spectrometry to analyze nuclear LXRα complexes and identified poly(ADP-ribose) polymerase-1(PARP-1) as an LXR-associated factor. In fact, PARP-1 interacted with both LXRα and LXRβ. Bothdepletion of PARP-1 and inhibition of PARP-1 activity augmented LXR ligand-induced ABCA1 expression inthe RAW 264.7 macrophage line and primary bone marrow-derived macrophages but did not affectLXR-dependent expression of other target genes, ABCG1 and SREBP-1c. Chromatin immunoprecipitationexperiments confirmed PARP-1 recruitment at the LXR response element in the promoter of the ABCA1gene. Further, we demonstrated that LXR is poly(ADP-ribosyl)ated by PARP-1, a potential mechanism bywhich PARP-1 influences LXR function. Importantly, the PARP inhibitor 3-aminobenzamide enhancedmacrophage ABCA1-mediated cholesterol efflux to the lipid-poor apolipoprotein AI. These findings shedlight on the important role of PARP-1 on LXR-regulated lipid homeostasis. Understanding the interplaybetween PARP-1 and LXR may provide insights into developing novel therapeutics for treatingatherosclerosis.", "metadata": {}}
+{"_id": "23294314", "title": "", "text": "Emergency contraception: advance provision in a young, high-risk clinic population.OBJECTIVE To assesswhether advance provision of emergency contraception increases its use and whether it has secondaryeffects on regular contraceptive use. METHODS We conducted a controlled trial of female clients, aged16-24 years, who attended a publicly funded family planning clinic. Women were systematically assignedto receive an advance provision of emergency contraception and education (treatment) or education only(control). Among 263 participants enrolled (133 treatment, 130 control), follow-up was completed in 213(111 treatment, 102 control). The main outcome measures were emergency contraception knowledgeand use, frequency of unprotected sex, and pattern of contraceptive use in the past 4 months. RESULTSParticipants were aware of emergency contraception at follow-up, but the treatment group was threetimes as likely to use it (P =.006). Although the treatment group did not report higher frequencies ofunprotected sex than the control group, women in the treatment group (28%) were more likely thanthose in the control group (17%) to report using less effective contraception at follow-up compared withenrollment (P =.05). The proportion of women in both groups who reported consistent pill use increasedfrom enrollment to follow-up (34% versus 45%); however, the control group (58%) was more likely thanthe treatment group (32%) to report consistent pill use at follow-up (P =.03). CONCLUSION Use ofemergency contraception was increased by providing it in advance, but not by education alone. Changesto less effective contraceptive methods and patterns of pill use were potentially negative effects that needto be explored in relation to observed benefits.", "metadata": {}}
+{"_id": "23304931", "title": "", "text": "Immunophenotypic analysis of AIDS-related diffuse large B-cell lymphoma and clinical implications inpatients from AIDS malignancies consortium clinical trials 010 and 034PURPOSE Diffuse large B-celllymphoma (DLBCL) represents a clinically heterogeneous disease. Models based onimmunohistochemistry predict clinical outcome. These include subdivision into germinal center (GC)versus non-GC subtypes; proliferation index (measured by expression of Ki-67), and expression of BCL-2,FOXP1, or B-lymphocyte-induced maturation protein (Blimp-1)/PRDM1. We sought to determine whetherimmunohistochemical analyses of biopsies from patients with DLBCL having HIV infection are similarlyrelevant for prognosis. PATIENTS AND METHODS We examined 81 DLBCLs from patients with AIDS inAMC010 (cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP] v CHOP-rituximab) andAMC034 (etoposide, doxorubicin, vincristine, prednisone, and dose-adjusted cyclophosphamide plusrituximab concurrent v sequential) clinical trials and compared the immunophenotype with survival data,Epstein-Barr virus (EBV) positivity, and CD4 counts. RESULTS The GC and non-GC subtypes of DLBCL didnot differ significantly with respect to overall survival or CD4 count at cancer presentation. EBV could befound in both subtypes of DLBCL, although less frequently in the GC subtype, and did not affect survival.Expression of FOXP1, Blimp-1/PRDM1, or BCL-2 was not correlated with the outcome in patients withAIDS-related DLBCL. CONCLUSION These data indicate that with current treatment strategies forlymphoma and control of HIV infection, commonly used immunohistochemical markers may not beclinically relevant in HIV-infected patients with DLBCL. The only predictive immunohistochemical markerwas found to be Ki-67, where a higher proliferation index was associated with better survival, suggestinga better response to therapy in patients whose tumors had higher proliferation rates.", "metadata": {}}
+{"_id": "23305547", "title": "", "text": "Prion-like activity of Cu/Zn superoxide dismutase: implications for amyotrophic lateralsclerosis.Neurodegenerative diseases belong to a larger group of protein misfolding disorders, known asproteinopathies. There is increasing experimental evidence implicating prion-like mechanisms in manycommon neurodegenerative disorders, including Alzheimer disease, Parkinson disease, the tauopathies,and amyotrophic lateral sclerosis (ALS), all of which feature the aberrant misfolding and aggregation ofspecific proteins. The prion paradigm provides a mechanism by which a mutant or wild-type protein candominate pathogenesis through the initiation of self-propagating protein misfolding. ALS, a lethal diseasecharacterized by progressive degeneration of motor neurons is understood as a classical proteinopathy;the disease is typified by the formation of inclusions consisting of aggregated protein within and aroundmotor neurons that can contribute to neurotoxicity. It is well established that misfolded/oxidized SOD1protein is highly toxic to motor neurons and plays a prominent role in the pathology of ALS. Recent workhas identified propagated protein misfolding properties in both mutant and wild-type SOD1, which mayprovide the molecular basis for the clinically observed contiguous spread of the disease through theneuroaxis. In this review we examine the current state of knowledge regarding the prion-like propertiesof SOD1 and comment on its proposed mechanisms of intercellular transmission.", "metadata": {}}
+{"_id": "23305884", "title": "", "text": "Analysis of Epstein-Barr virus-regulated host gene expression changes through primary B-cell outgrowthreveals delayed kinetics of latent membrane protein 1-mediated NF-κB activation.Epstein-Barr virus(EBV) is an oncogenic human herpesvirus that dramatically reorganizes host gene expression toimmortalize primary B cells. In this study, we analyzed EBV-regulated host gene expression changesfollowing primary B-cell infection, both during initial proliferation and through transformation intolymphoblastoid cell lines (LCLs). While most EBV-regulated mRNAs were changed during the transitionfrom resting, uninfected B cells through initial B-cell proliferation, a substantial number of mRNAschanged uniquely from early proliferation through LCL outgrowth. We identified constitutively anddynamically EBV-regulated biological processes, protein classes, and targets of specific transcriptionfactors. Early after infection, genes associated with proliferation, stress responses, and the p53 pathwaywere highly enriched. However, the transition from early to long-term outgrowth was characterized bygenes involved in the inhibition of apoptosis, the actin cytoskeleton, and NF-κB activity. It was previouslythought that the major viral protein responsible for NF-κB activation, latent membrane protein 1 (LMP1),is expressed within 2 days after infection. Our data indicate that while this is true, LCL-level LMP1expression and NF-κB activity are not evident until 3 weeks after primary B-cell infection. Furthermore,heterologous NF-κB activation during the first week after infection increased the transformationefficiency, while early NF-κB inhibition had no effect on transformation. Rather, inhibition of NF-κB wasnot toxic to EBV-infected cells until LMP1 levels and NF-κB activity were high. These data collectivelyhighlight the dynamic nature of EBV-regulated host gene expression and support the notion that earlyEBV-infected proliferating B cells have a fundamentally distinct growth and survival phenotype from thatof LCLs.", "metadata": {}}
+{"_id": "23326722", "title": "", "text": "Clinical and laboratory features of adult T-cell leukaemia lymphoma in Barbados.We describe the clinicaland pathological features of 23 Afro-Caribbean patients with adult T-cell leukaemia/lymphoma admittedto the Queen Elizabeth Hospital, Barbados over a 5 year period. There were 9 males and 14 females, witha median age of 38 years (range 14-84). Twelve had acute leukaemia, 10 lymphoma (including 4 withsolitary extra nodal lesions) and 1 smouldering subtype. Two patients had a past history of tropicalspastic paraparesis/HTLV I associated myelopathy (TSP/HAM). The prognosis was poor, with only 3complete responses to chemotherapy (CHOP) lasting from 9 to 36 months. We conclude that ATLL inBarbados is similar to the disease in the other Caribbean islands and Japan, except that in Barbados theage of onset is over a decade younger than in Japan.", "metadata": {}}
+{"_id": "23331269", "title": "", "text": "Acoustic landmarks drive delta-theta oscillations to enable speech comprehension by facilitatingperceptual parsing.A growing body of research suggests that intrinsic neuronal slow (<10 Hz) oscillationsin auditory cortex appear to track incoming speech and other spectro-temporally complex auditorysignals. Within this framework, several recent studies have identified critical-band temporal envelopes asthe specific acoustic feature being reflected by the phase of these oscillations. However, how thisalignment between speech acoustics and neural oscillations might underpin intelligibility is unclear. Herewe test the hypothesis that the 'sharpness' of temporal fluctuations in the critical band envelope acts as atemporal cue to speech syllabic rate, driving delta-theta rhythms to track the stimulus and facilitateintelligibility. We interpret our findings as evidence that sharp events in the stimulus cause corticalrhythms to re-align and parse the stimulus into syllable-sized chunks for further decoding. Usingmagnetoencephalographic recordings, we show that by removing temporal fluctuations that occur at thesyllabic rate, envelope-tracking activity is reduced. By artificially reinstating these temporal fluctuations,envelope-tracking activity is regained. These changes in tracking correlate with intelligibility of thestimulus. Together, the results suggest that the sharpness of fluctuations in the stimulus, as reflected inthe cochlear output, drive oscillatory activity to track and entrain to the stimulus, at its syllabic rate. Thisprocess likely facilitates parsing of the stimulus into meaningful chunks appropriate for subsequentdecoding, enhancing perception and intelligibility.", "metadata": {}}
+{"_id": "23342686", "title": "", "text": "Crystal structures of complexes of the small ribosomal subunit with tetracycline, edeine and IF3.The smallribosomal subunit is responsible for the decoding of genetic information and plays a key role in theinitiation of protein synthesis. We analyzed by X-ray crystallography the structures of three differentcomplexes of the small ribosomal subunit of Thermus thermophilus with the A-site inhibitor tetracycline,the universal initiation inhibitor edeine and the C-terminal domain of the translation initiation factor IF3.The crystal structure analysis of the complex with tetracycline revealed the functionally important siteresponsible for the blockage of the A-site. Five additional tetracycline sites resolve most of thecontroversial biochemical data on the location of tetracycline. The interaction of edeine with the smallsubunit indicates its role in inhibiting initiation and shows its involvement with P-site tRNA. The locationof the C-terminal domain of IF3, at the solvent side of the platform, sheds light on the formation of theinitiation complex, and implies that the anti-association activity of IF3 is due to its influence on theconformational dynamics of the small ribosomal subunit.", "metadata": {}}
+{"_id": "23342845", "title": "", "text": "Plasmid-encoded proinsulin preserves C-peptide while specifically reducing proinsulin-specific CD8\u0000 Tcells in type 1 diabetes.In type 1 diabetes (T1D), there is an intense inflammatory response that destroysthe β cells in the pancreatic islets of Langerhans, the site where insulin is produced and released. Atherapy for T1D that targets the specific autoimmune response in this disease while leaving theremainder of the immune system intact, has long been sought. Proinsulin is a major target of theadaptive immune response in T1D. We hypothesized that an engineered DNA plasmid encoding proinsulin(BHT-3021) would preserve β cell function in T1D patients through reduction of insulin-specific CD8\u0000 Tcells. We studied 80 subjects over 18 years of age who were diagnosed with T1D within the past 5 years.Subjects were randomized 2:1 to receive intramuscular injections of BHT-3021 or BHT-placebo, weeklyfor 12 weeks, and then monitored for safety and immune responses in a blinded fashion. Four dose levelsof BHT-3021 were evaluated: 0.3, 1.0, 3.0, and 6.0 mg. C-peptide was used both as an exploratoryefficacy measure and as a safety measure. Islet-specific CD8\u0000 T cell frequencies were assessed withmultimers of monomeric human leukocyte antigen class I molecules loaded with peptides from pancreaticand unrelated antigens. No serious adverse events related to BHT-3021 were observed. C-peptide levelsimproved relative to placebo at all doses, at 1 mg at the 15-week time point (+19.5% BHT-3021 versus-8.8% BHT-placebo, P < 0.026). Proinsulin-reactive CD8\u0000 T cells, but not T cells against unrelated isletor foreign molecules, declined in the BHT-3021 arm (P < 0.006). No significant changes were noted ininterferon-γ, interleukin-4 (IL-4), or IL-10 production in CD4 T cells. Thus, we demonstrate that aplasmid encoding proinsulin reduces the frequency of CD8\u0000 T cells reactive to proinsulin while preservingC-peptide over the course of dosing.", "metadata": {}}
+{"_id": "23349986", "title": "", "text": "Dexamethasone and risk of nausea and vomiting and postoperative bleeding after tonsillectomy inchildren: a randomized trial.CONTEXT Dexamethasone is widely used to prevent postoperative nauseaand vomiting (PONV) in pediatric tonsillectomy. OBJECTIVE To assess whether dexamethasonedose-dependently reduces the risk of PONV at 24 hours after tonsillectomy. DESIGN, SETTING, ANDPATIENTS Randomized placebo-controlled trial conducted among 215 children undergoing electivetonsillectomy at a major public teaching hospital in Switzerland from February 2005 to December 2007.INTERVENTIONS Children were randomly assigned to receive dexamethasone (0.05, 0.15, or 0.5 mg/kg)or placebo intravenously after induction of anesthesia. Acetaminophen-codeine and ibuprofen were givenas postoperative analgesia. Follow-up continued until the 10th postoperative day. MAIN OUTCOMEMEASURES The primary end point was prevention of PONV at 24 hours; secondary end points weredecrease in the need for ibuprofen at 24 hours and evaluation of adverse effects. RESULTS At 24 hours,24 of 54 participants who received placebo (44%; 95% confidence interval [CI], 31%-59%) hadexperienced PONV compared with 20 of 53 (38%; 95% CI, 25%-52%), 13 of 54 (24%; 95% CI,13%-38%), and 6 of 52 (12%; 95% CI, 4%-23%) who received dexamethasone at 0.05, 0.15, and 0.5mg/kg, respectively (P<.001 for linear trend). Children who received dexamethasone receivedsignificantly less ibuprofen. There were 26 postoperative bleeding episodes in 22 children. Two of 53(4%; 95% CI, 0.5%-13%) children who received placebo had bleeding compared with 6 of 53 (11%;95% CI, 4%-23%), 2 of 51 (4%; 95% CI, 0.5%-13%), and 12 of 50 (24%; 95% CI, 13%-38%) whoreceived dexamethasone at 0.05, 0.15, and 0.5 mg/kg, respectively (P = .003). Dexamethasone, 0.5mg/kg, was associated with the highest bleeding risk (adjusted relative risk, 6.80; 95% CI, 1.77-16.5).Eight children had to undergo emergency reoperation because of bleeding, all of whom had receiveddexamethasone. The trial was stopped early for safety reasons. CONCLUSION In this study of childrenundergoing tonsillectomy, dexamethasone decreased the risk of PONV dose dependently but wasassociated with an increased risk of postoperative bleeding. TRIAL REGISTRATION clinicaltrials.govIdentifier: NCT00403806.", "metadata": {}}
+{"_id": "23351136", "title": "", "text": "Detection of sweet and umami taste in the absence of taste receptor T1r3.The tastes of sugars (sweet)and glutamate (umami) are thought to be detected by T1r receptors expressed in taste cells. Moleculargenetics and heterologous expression implicate T1r2 plus T1r3 as a sweet-responsive receptor,and T1r1plus T1r3,as well as a truncated form of the type 4 metabotropic glutamate receptor (taste-mGluR4),asumami-responsive receptors. Here,we show that mice lacking T1r3 showed no preference for artificialsweeteners and had diminished but not abolished behavioral and nerve responses to sugars and umamicompounds. These results indicate that T1r3-independent sweet- and umami-responsive receptors and/orpathways exist in taste cells.", "metadata": {}}
+{"_id": "23356816", "title": "", "text": "Cyclin A1 is required for meiosis in the male mouseThe mammalian A-type cyclin family consists of twomembers, cyclin A1 (encoded by Ccna1) and cyclin A2 (encoded by Ccna2). Cyclin A2 promotes bothG1/S and G2/M transitions, and targeted deletion of Ccna2 in mouse is embryonic lethal. Cyclin A1 isexpressed in mice exclusively in the germ cell lineage and is expressed in humans at highest levels in thetestis and certain myeloid leukaemia cells. To investigate the role of cyclin A1 and possible redundancyamong the cyclins in vivo, we generated mice bearing a null mutation of Ccna1. Ccna1-/- males weresterile due to a block of spermatogenesis before the first meiotic division, whereas females were normal.Meiosis arrest in Ccna1–/– males was associated with increased germ cell apoptosis, desynapsisabnormalities and reduction of Cdc2 kinase activation at the end of meiotic prophase. Cyclin A1 istherefore essential for spermatocyte passage into the first meiotic division in male mice, a function thatcannot be complemented by the concurrently expressed B-type cyclins.", "metadata": {}}
+{"_id": "23369842", "title": "", "text": "Metabolic effects of isoenergetic nutrient exchange over 24 hours in relation to obesity inwomen.Twenty-four hour whole body indirect calorimetry has been used to study the effects of feeding,during a sedentary test day, isoenergetic diets which varied in fat (3 or 40 per cent of total energy) andcarbohydrate (82 or 45 per cent) content. Three groups of women were studied: lean, obese and'post-obese' after slimming. Energy expenditure was greater in absolute terms in the obese women.Twenty-four hour energy expenditure was lower by only 3-7 per cent when fasting compared to thatwhen fed to achieve energy balance. There were no large differences in energy expenditure between thetwo diets or between the groups but the thermogenic effect of the high carbohydrate diet wassignificantly greater than that of the high fat diet (5.8 vs 3.5 per cent of energy expenditure: P less than0.01). The post-obese tended to have lower energy expenditure per kg FFM than controls when fastingand when high-fat fed, but this pattern was not shown by the obese. Sleeping energy expenditure wasparticularly low in the post-obese group when high-fat fed. Dirunal variations in RQ appear to show moremarked rise in morning RQ from the nocturnal minimum in the obese and post-obese, which might beevidence for an energy-saving mechanism through greater availability of stored dietary carbohydrate.", "metadata": {}}
+{"_id": "23377475", "title": "", "text": "Acute kidney injury and chronic kidney disease: an integrated clinical syndrome.The previousconventional wisdom that survivors of acute kidney injury (AKI) tend to do well and fully recover renalfunction appears to be flawed. AKI can cause end-stage renal disease (ESRD) directly, and increase therisk of developing incident chronic kidney disease (CKD) and worsening of underlying CKD. In addition,severity, duration, and frequency of AKI appear to be important predictors of poor patient outcomes. CKDis an important risk factor for the development and ascertainment of AKI. Experimental data support theclinical observations and the bidirectional nature of the relationships between AKI and CKD. Reductions inrenal mass and nephron number, vascular insufficiency, cell cycle disruption, and maladaptive repairmechanisms appear to be important modulators of progression in patients with and without coexistentCKD. Distinction between AKI and CKD may be artificial. Consideration should be given to the integratedclinical syndrome of diminished GFR, with acute and chronic stages, where spectrum of disease state andoutcome is determined by host factors, including the balance of adaptive and maladaptive repairmechanisms over time. Physicians must provide long-term follow-up to patients with first episodes ofAKI, even if they presented with normal renal function.", "metadata": {}}
+{"_id": "23388442", "title": "", "text": "Fatty acids as modulators of the immune response.Research describing fatty acids as modulators ofinflammation and immune responses abounds. Many of these studies have focused on one particulargroup of fatty acids, omega-3. The data from animal studies have shown that these fatty acids can havepowerful anti-inflammatory and immunomodulatory activities in a wide array of diseases (e.g.,autoimmunity, arthritis, and infection). However, the evidence from human trials is more equivocal. Inthis review, a historical framework for understanding how and why fatty acids may affect the immunesystem is provided. Second, highlights of two recent landmark reports from the Agency for HealthcareResearch and Quality are presented. These reports critically evaluate the evidence from human clinicaltrials of omega-3 fatty acids and rheumatoid arthritis, asthma, and a few other immune-mediateddiseases. Third, the data from human clinical trials investigating the impact of various bioactive fattyacids on ex vivo and in vivo immune response are reviewed. Limitations in experimental design andimmune assays commonly used are discussed. The discordance between expectation and evidence in thisfield has been a disappointment. Recommendations for improving both animal-based and human studiesare provided.", "metadata": {}}
+{"_id": "23389795", "title": "", "text": "Common and rare variants in multifactorial susceptibility to common diseasesHere, we give a historicaloverview of the search for genetic variants that influence the susceptibility of an individual to a chronicdisease, from RA Fisher's seminal work to the current excitement of whole-genome association studies(WGAS). We then discuss the concepts behind the identification of common variants as disease causalfactors and contrast them to the basic ideas that underlie the rare variant hypothesis. The identificationof rare variants involves the careful selection of candidate genes to examine, the availability of highlyefficient resequencing techniques and the appropriate assessment of the functional consequences of theimplicated variant. We believe that this strategy can be successfully applied at present in order to unravelthe contribution of rare variants to the multifactorial inheritance of common diseases, which could lead tothe implementation of much needed preventative screening schemes.", "metadata": {}}
+{"_id": "23393712", "title": "", "text": "Cell-cell adhesion and signalling.Signalling pathways activated by Rho small GTPases have recently beenidentified that coordinate junction assembly, stability and function, as well as interactions of adhesivecomplexes with the underlying cortical cytoskeleton. Particularly exciting is the interplay betweenadherens junctions, activation of Rho proteins and the dynamics of microtubule, actin and intermediatefilaments. This interplay has important implications for functional regulation of cell-cell adhesion, andpoints to a more integrated view of signalling processes.", "metadata": {}}
+{"_id": "23397658", "title": "", "text": "Fibroblast growth factor 21 as an emerging metabolic regulator: clinical perspectives.Fibroblast growthfactor 21 (FGF21), a metabolic hormone predominantly produced by the liver, is also expressed inadipocytes and the pancreas. It regulates glucose and lipid metabolism through pleiotropic actions inthese tissues and the brain. In mice, fasting leads to increased PPAR-α mediated expression of FGF21 inthe liver where it stimulates gluconeogenesis, fatty acid oxidation, and ketogenesis, as an adaptiveresponse to fasting and starvation. In the fed state, FGF21 acts as an autocrine factor in adipocytes,regulating the activity of PPAR-γ through a feed-forward loop mechanism. Administration of recombinantFGF21 has been shown to confer multiple metabolic benefits on insulin sensitivity, blood glucose, lipidprofile and body weight in obese mice and diabetic monkeys, without mitogenic or other side effects.Such findings highlight the potential role of FGF21 as a therapeutic agent for obesity-related medicalconditions. However, in human studies, high circulating FGF21 levels are found in obesity and its relatedcardiometabolic disorders including the metabolic syndrome, type 2 diabetes, non-alcoholic fatty liverdisease and coronary artery disease. These findings may indicate the presence of FGF21 resistance orcompensatory responses to the underlying metabolic stress, and imply the need for supraphysiologicaldoses of FGF21 to achieve therapeutic efficacy. On the other hand, serum FGF21 has been implicated asa potential biomarker for the early detection of these cardiometabolic disorders. This review summarizesrecent developments in the understanding of FGF21, from physiological and clinical perspectives.", "metadata": {}}
+{"_id": "23400191", "title": "", "text": "Assessment of the cerebral circulation in adults with coarctation of the aorta.AIMS There is a fivefoldincrease in the frequency of intracranial aneurysm (IA) in adults with coarctation of the aorta (CoA).Current guidelines for management of adults with CoA recommend computed tomography angiography(CTA) or magnetic resonance imaging of the intracranial vessels. However, this recommendation has notbeen universally accepted. The purpose of our study was to prospectively perform CTA of the intracranialvessels in adults with CoA to evaluate the prevalence and identify high-risk features of this complication.METHODS AND RESULTS From January 2008 to February 2011, adults ≥18 years of age with CoA wereprospectively enrolled in a screening program with CTA of the intracranial vessels. Analyses of prognosticvariables were performed with both Fisher's exact and two sample t-test. Forty-three patients (58%female, 33.55 ± 10.21 years) with CoA completed CTA of the intracranial vessels. Five patients (11%)were found to have IA. Patients with IA were older than those without (45.6 ± 8.17 vs. 30.89 ± 7.89, P =0.0003). There were no statistically significant differences detected between measurements of fastinglipid profiles, C-reactive protein, brain natriuretic peptide, and homocysteine levels among CoA patientswith and without IA (P = not significant). CONCLUSION Prospective screening of adults with CoAconfirmed the increased prevalence of IA but also identified increased age as the sole risk factor. Thesedata suggested that screening is justified particularly in the fourth and fifth decades of life. Furtherstudies are required that focus on the development, natural history, and treatment of IA.", "metadata": {}}
+{"_id": "23403754", "title": "", "text": "Bioenergetic aspects of apoptosis, necrosis and mitoptosisIn this review I summarize interrelationsbetween bioenergetic processes and such programmed death phenomena as cell suicide (apoptosis andnecrosis) and mitochondrial suicide (mitoptosis). The following conclusions are made. (I) ATP and ratheroften mitochondrial hyperpolarization (i.e. an increase in membrane potential, ΔΨ) are required forcertain steps of apoptosis and necrosis. (II) Apoptosis, even if it is accompanied by ΔΨ and [ATP]increases at its early stage, finally results in a ΔΨ collapse and ATP decrease. (III) Moderate (aboutthree-fold) lowering of [ATP] for short and long periods of time induces apoptosis and necrosis,respectively. In some types of apoptosis and necrosis, the cell death is mediated by a ΔΨ-dependentoverproduction of ROS by the initial (Complex I) and the middle (Complex III) spans of the respiratorychain. ROS initiate mitoptosis which is postulated to rid the intracellular population of mitochondria fromthose that are ROS overproducing. Massive mitoptosis can result in cell death due to release to cytosol ofthe cell death proteins normally hidden in the mitochondrial intermembrane space.", "metadata": {}}
+{"_id": "23418635", "title": "", "text": "Embryonic stem cells require Wnt proteins to prevent differentiation to epiblast stem cellsPluripotentstem cells exist in naive and primed states, epitomized by mouse embryonic stem cells (ESCs) and thedevelopmentally more advanced epiblast stem cells (EpiSCs; ref. ). In the naive state of ESCs, thegenome has an unusual open conformation and possesses a minimum of repressive epigenetic marks. Incontrast, EpiSCs have activated the epigenetic machinery that supports differentiation towards theembryonic cell types. The transition from naive to primed pluripotency therefore represents a pivotalevent in cellular differentiation. But the signals that control this fundamental differentiation step remainunclear. We show here that paracrine and autocrine Wnt signals are essential self-renewal factors forESCs, and are required to inhibit their differentiation into EpiSCs. Moreover, we find that Wnt proteins incombination with the cytokine LIF are sufficient to support ESC self-renewal in the absence of anyundefined factors, and support the derivation of new ESC lines, including ones from non-permissivemouse strains. Our results not only demonstrate that Wnt signals regulate the naive-to-primedpluripotency transition, but also identify Wnt as an essential and limiting ESC self-renewal factor.", "metadata": {}}
+{"_id": "23420615", "title": "", "text": "CLIP identifies Nova-regulated RNA networks in the brain.Nova proteins are neuron-specific antigenstargeted in paraneoplastic opsoclonus myoclonus ataxia (POMA), an autoimmune neurologic diseasecharacterized by abnormal motor inhibition. Nova proteins regulate neuronal pre-messenger RNA splicingby directly binding to RNA. To identify Nova RNA targets, we developed a method to purify protein-RNAcomplexes from mouse brain with the use of ultraviolet cross-linking and immunoprecipitation(CLIP).Thirty-four transcripts were identified multiple times by Nova CLIP.Three-quarters of these encodeproteins that function at the neuronal synapse, and one-third are involved in neuronal inhibition. Splicingtargets confirmed in Nova-/- mice include c-Jun N-terminal kinase 2, neogenin, and gephyrin; the latterencodes a protein that clusters inhibitory gamma-aminobutyric acid and glycine receptors, two previouslyidentified Nova splicing targets. Thus, CLIP reveals that Nova coordinately regulates a biologicallycoherent set of RNAs encoding multiple components of the inhibitory synapse, an observation that mayrelate to the cause of abnormal motor inhibition in POMA.", "metadata": {}}
+{"_id": "23420807", "title": "", "text": "Anti-Angiogenic Activity of Selected Receptor Tyrosine Kinase Inhibitors, PD166285 and PD173074:Implications for Combination Treatment with Photodynamic TherapyAngiogenesis, the formation of newblood vessels from an existing vasculature, is requisite for tumor growth. It entails intercellularcoordination of endothelial and tumor cells through angiogenic growth factor signaling. Interruption ofthese events has implications in the suppression of tumor growth. PD166285, a broad-spectrum receptortyrosine kinase (RTK) inhibitor, and PD173074, a selective FGFR1TK inhibitor, were evaluated for theiranti-angiogenic activity and anti-tumor efficacy in combination with photodynamic therapy (PDT). Toevaluate the anti-angiogenic and anti-tumor activities of these compounds, RTK assays, in vitro tumorcell growth and microcapillary formation assays, in vivo murine angiogenesis and anti-tumor efficacystudies utilizing RTK inhibitors in combination with photodynamic therapy were performed. PD166285inhibited PDGFR-β-, EGFR-, and FGFR1TKs and c-src TK by 50% (IC50) at concentrations between7−85nM. PD173074 displayed selective inhibitory activity towards FGFR1TK at 26nM. PD173074demonstrated (>100 fold) selective growth inhibitory action towards human umbilical vein endothelialcells compared with a panel of tumor cell lines. Both PD166285 and PD173074 (at 10nM) inhibited theformation of microcapillaries on Matrigel-coated plastic. In vivo anti-angiogenesis studies in micerevealed that oral administration (p.o.) of either PD166285 (1−25 mg/kg) or PD173074 (25−100 mg/kg)generated dose dependent inhibition of angiogenesis. Against a murine mammary 16c tumor,significantly prolonged tumor regressions were achieved with daily p.o. doses of PD166285 (5−10 mg/kg)or PD173074 (30−60 mg/kg) following PDT compared with PDT alone (p<0.001). Many long-termsurvivors were also noted in combination treatment groups. PD166285 and PD173074 displayed potentanti-angiogenic and anti-tumor activity and prolonged the duration of anti-tumor response to PDT.Interference in membrane signal transduction by inhibitors of specific RTKs (e.g. FGFR1TK) should resultin new chemotherapeutic agents having the ability to limit tumor angiogenesis and regrowth followingcytoreductive treatments such as PDT.", "metadata": {}}
+{"_id": "23423230", "title": "", "text": "The VirB type IV secretion system of Bartonella henselae mediates invasion, proinflammatory activationand antiapoptotic protection of endothelial cells.Bartonella henselae is an arthropod-borne zoonoticpathogen causing intraerythrocytic bacteraemia in the feline reservoir host and a broad range of clinicalmanifestations in incidentally infected humans. Remarkably, B. henselae can specifically colonize thehuman vascular endothelium, resulting in inflammation and the formation of vasoproliferative lesionsknown as bacillary angiomatosis and bacillary peliosis. Cultured human endothelial cells provide an invitro system to study this intimate interaction of B. henselae with the vascular endothelium. However,little is known about the bacterial virulence factors required for this pathogenic process. Recently, weidentified the type IV secretion system (T4SS) VirB as an essential pathogenicity factor in Bartonella,required to establish intraerythrocytic infection in the mammalian reservoir. Here, we demonstrate thatthe VirB T4SS also mediates most of the virulence attributes associated with the interaction of B.henselae during the interaction with human endothelial cells. These include: (i) massive rearrangementsof the actin cytoskeleton, resulting in the formation of bacterial aggregates and their internalization bythe invasome structure; (ii) nuclear factor kappaB-dependent proinflammatory activation, leading to celladhesion molecule expression and chemokine secretion, and (iii) inhibition of apoptotic cell death,resulting in enhanced endothelial cell survival. Moreover, we show that the VirB system mediatescytostatic and cytotoxic effects at high bacterial titres, which interfere with a potent VirB-independentmitogenic activity. We conclude that the VirB T4SS is a major virulence determinant of B. henselae,required for targeting multiple endothelial cell functions exploited by this vasculotropic pathogen.", "metadata": {}}
+{"_id": "23439808", "title": "", "text": "Serum Cystatin C Is Related to Pulse Wave Velocity Even in Subjects with Normal Serum CreatinineWehypothesized that serum cystatin C can be a more predictable marker of arterial stiffness than serumcreatinine and creatinine-based glomerular filtration rate (GFR). The aim of this study is to evaluatewhether serum cystatin C is related to arterial stiffness independently of serum creatinine in subjects forwhom serum creatinine is normal. A total of 2,018 individuals (1,120 males, 898 females) were enrolled.Mean brachial-ankle pulse wave velocity (baPWV) was used as a marker of arterial stiffness andsex-specific analysis was performed. A positive relationship between baPWV and serum cystatin C(Y=1109.0548+329.9102X, r2=0.056, p<0.001) was found in males. Stepwise multivariate regressionanalysis in males showed that age, waist circumference, heart rate, cystatin C level, triglyceride level,and fasting glucose were independent contributors to baPWV. In females, a positive relationship betweenbaPWV and serum cystatin C (Y=1035.7828+402.2970X, r2=0.090, p<0.001) was found. Stepwisemultivariate regression analysis showed that age, heart rate, cystatin C level, fasting glucose and insulinlevel were independent contributors to baPWV. Age, heart rate, fasting glucose and serum cystatin Cwere the significant variables in both genders that contributed to baPWV. In conclusion, this studyconfirmed that serum cystatin C was related to pulse wave velocity even in subjects with normal serumcreatinine. This finding suggested that cystatin C could be a more predictable marker of arterial stiffnessthan serum creatinine and creatinine-based GFR.", "metadata": {}}
+{"_id": "23440856", "title": "", "text": "Screening for inhibition of Vibrio cholerae VipA-VipB interaction identifies small-molecule compoundsactive against type VI secretion.The type VI secretion system (T6SS) is the most prevalent bacterialsecretion system and an important virulence mechanism utilized by Gram-negative bacteria, either totarget eukaryotic cells or to combat other microbes. The components show much variability, but someappear essential for the function, and two homologues, denoted VipA and VipB in Vibrio cholerae, havebeen identified in all T6SSs described so far. Secretion is dependent on binding of an α-helical region ofVipA to VipB, and in the absence of this binding, both components are degraded within minutes andsecretion is ceased. The aim of the study was to investigate if this interaction could be blocked, and wehypothesized that such inhibition would lead to abrogation of T6S. A library of 9,600 small-moleculecompounds was screened for their ability to block the binding of VipA-VipB in a bacterial two-hybridsystem (B2H). After excluding compounds that showed cytotoxicity toward eukaryotic cells, that inhibitedgrowth of Vibrio, or that inhibited an unrelated B2H interaction, 34 compounds were further investigatedfor effects on the T6SS-dependent secretion of hemolysin-coregulated protein (Hcp) or of phospholipaseA1 activity. Two compounds, KS100 and KS200, showed intermediate or strong effects in both assays.Analogues were obtained, and compounds with potent inhibitory effects in the assays and desirablephysicochemical properties as predicted by in silico analysis were identified. Since the compoundsspecifically target a virulence mechanism without affecting bacterial replication, they have the potential tomitigate the virulence with minimal risk for development of resistance.", "metadata": {}}
+{"_id": "23460562", "title": "", "text": "Early life compartmentalization of human T cell differentiation and regulatory function in mucosal andlymphoid tissuesIt is unclear how the immune response in early life becomes appropriately stimulated toprovide protection while also avoiding excessive activation as a result of diverse new antigens. T cells areintegral to adaptive immunity; mouse studies indicate that tissue localization of T cell subsets isimportant for both protective immunity and immunoregulation. In humans, however, the earlydevelopment and function of T cells in tissues remain unexplored. We present here an analysis oflymphoid and mucosal tissue T cells derived from pediatric organ donors in the first two years of life, ascompared to adult organ donors, revealing early compartmentalization of T cell differentiation andregulation. Whereas adult tissues contain a predominance of memory T cells, in pediatric blood andtissues the main subset consists of naive recent thymic emigrants, with effector memory T cells (T(EM))found only in the lungs and small intestine. Additionally, regulatory T (T(reg)) cells comprise a highproportion (30-40%) of CD4(+) T cells in pediatric tissues but are present at much lower frequencies(1-10%) in adult tissues. Pediatric tissue T(reg) cells suppress endogenous T cell activation, and early Tcell functionality is confined to the mucosal sites that have the lowest T(reg):T(EM) cell ratios, whichsuggests control in situ of immune responses in early life.", "metadata": {}}
+{"_id": "23471400", "title": "", "text": "Circulating microRNAs as biomarkers for hepatocellular carcinoma.GOALS We investigated whethermeasurement of serum levels of the microRNAs (miRNAs) miR-16, miR-195, and miR-199a, alone or incombination with conventional serum markers, can help to differentiate hepatocellular carcinoma (HCC)from chronic liver diseases (CLDs). BACKGROUND Recent reports suggest a link between aberrantexpression of miRNA, and HCC. STUDY This retrospective analysis was conducted using sera from 105HCC patients, 107 CLD patients, and 71 normal control subjects. The miRNAs were measured usingreal-time reverse transcription-polymerase chain reaction. The conventional HCC markers α-fetoprotein(AFP), lens culinaris agglutinin-reactive AFP (AFP-L3%), and des-γ-carboxyprothrombin (DCP) weremeasured with commercial kits. RESULTS Serum levels of miR-16 and miR-199a were significantly lowerin HCC than in CLD patients or control subjects (P<0.01). As a single marker, miR-16 had the highestsensitivity for HCC, followed by miR-199a, AFP, DCP, AFP-L3%, and miR-195. The combination ofmiR-16, AFP, AFP-L3%, and DCP yielded the optimal combination of sensitivity (92.4%) and specificity(78.5%) for HCC, overall and when analysis was restricted to patients with tumors size smaller than 3cm. As a second-line HCC marker, miR-16 yielded positive HCC predictions in 18 of the 26 (69.2%) HCCpatients with negative results on all 3 conventional markers, most of whom had tumors size smaller than3 cm; miR-16 was falsely positive in only 12 of 96 (12.5%) CLD patients. CONCLUSIONS The addition ofmiR-16 to conventional serum markers improved sensitivity and specificity for HCC. Use of miR-16 forsecond-line testing in cases considered negative on the basis of conventional HCC markers should beexplored in larger, prospective studies.", "metadata": {}}
+{"_id": "23495058", "title": "", "text": "Mitochondrial haplogroups and hypervariable region polymorphisms in schizophrenia: a case-controlstudy.Previous studies have detected associations between mitochondrial haplogroups and schizophrenia(SZ). However, no study has examined the relationship between major mitochondrial DNA (mtDNA)haplogroups and SZ in the Chinese population. The aim of this study was to assess the associationbetween mtDNA haplogroups and SZ genesis in the Chinese Han population. We used a case-controlstudy and sequenced the mtDNA hypervariable regions (HVR1, HVR2, and HVR3) in the Han population.We analyzed mtDNA haplogroups and HVR polymorphisms in 298 SZ patients and 298 controls. Thehaplotypes were classified into 10 major haplogroups: A, B, CZ, D, F, G, M, N, N9a, and R. Statisticalanalysis revealed that only N9a showed a nominally significant association with protection from SZ[1.68% vs. 6.38%, p=0.004, OR=0.251 (0.092-0.680); after adjustment for age and sex: p=0.006,OR=0.246 (0.090-0.669)]. Three HVR polymorphisms were found to be nominally significantly differentbetween subjects with SZ and controls, and all except one (m.204T>C) are linked to the N9a haplogroup.Our results indicate that mtDNA haplogroup N9a might be a protective factor for SZ.", "metadata": {}}
+{"_id": "23509113", "title": "", "text": "Resolution of acute inflammation in the lung.Acute inflammation in the lung is essential to health. So toois its resolution. In response to invading microbes, noxious stimuli, or tissue injury, an acuteinflammatory response is mounted to protect the host. To limit inflammation and prevent collateral injuryof healthy, uninvolved tissue, the lung orchestrates the formation of specialized proresolving mediators,specifically lipoxins, resolvins, protectins, and maresins. These immunoresolvents are agonists forresolution that interact with specific receptors on leukocytes and structural cells to blunt furtherinflammation and promote catabasis. This process appears to be defective in several common lungdiseases that are characterized by excess or chronic inflammation. Here, we review the molecular andcellular effectors of resolution of acute inflammation in the lung.", "metadata": {}}
+{"_id": "23509593", "title": "", "text": "The calcium sensor STIM1 is regulated by androgens in prostate stromal cells.BACKGROUND Prostatedevelopment and maintenance in the adult results from an interaction of stromal and glandularcomponents. Androgens can drive this process by direct action on the stroma. We investigated whetherthere was a direct link between androgens and another key regulator of stromal cells, intracellular Ca2+([Ca2+ ]i ). METHODS Prostate stromal cells were freshly obtained and cultures derived from patientswith benign prostatic hyperplasia. Gene expression in dihydrotestosterone treated and untreated cellswas compared using Affymetrix gene expression arrays and Ca2+ regulated features were identified byGene Ontology (GO). Changes in [Ca2+]i were determined in Fluo-4 loaded cells. Androgen regulationwas confirmed by chromatin immunoprecipitaion. RESULTS Stromal cell cultures were sorted forexpression of integrin α1 β1 , which enriched for cells expressing the androgen receptor (AR). Weidentified key functional categories, within the androgen-induced gene expression signature, focusing ongenes involved in calcium signaling. From this analysis, stromal interaction molecule-1 (STIM1) wasidentified as a significantly differentially expressed gene with four relevant associated GO terms. DNAsequence analysis showed that the promoter region of STIM1 contained putative androgen responseelement sequences in which AR binding ability of STIM1 was confirmed. Androgens directly regulatedSTIM1 expression and STIM1 effects on store-operated calcium entry were inhibited by STIM1knock-down. Reduced STIM1 expression in prostate stromal cells led to a reduction in basal Ca2+ levels,the amount of Ca2+ released by thapsigargin and a reduction in store filling following TG-induced storedepletion. CONCLUSIONS These results indicate that androgens modulate [Ca2+]i through the directregulation of the STIM1 gene by AR binding to the STIM1 promoter.", "metadata": {}}
+{"_id": "23513718", "title": "", "text": "Role of soluble guanylate cyclase in dilator responses of the cerebral microcirculation.Responses ofcerebral blood vessels to nitric oxide (NO) are mediated by soluble guanylate cyclase (sGC)-dependentand potentially by sGC-independent mechanisms. One sGC-independent mechanism by which NO mayproduce vasodilatation is inhibition of formation of a vasoconstrictor metabolite produced through thecytochrome P450 pathway. In these experiments, we examined the hypothesis that dilatation of cerebralmicrovessels in response to NO is dependent on activation of sGC. Diameters of cerebral arterioles(baseline diameter=94+/-5 micrometers, mean+/-S.E.) were measured using a closed cranial window inanesthetized rabbits. Under control conditions, YC-1 [3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole],an NO-independent activator of sGC, produced vasodilation that was blocked by ODQ(1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one)(10 microM), an inhibitor of sGC. These findings indicatethat sGC is functionally important in cerebral arterioles. In addition, acetylcholine (which stimulatesendogenous production of NO by endothelium) produced dilatation of cerebral arterioles that wasinhibited by ODQ. For example, 1 microM acetylcholine dilated cerebral arterioles by 34+/-7 and 5+/-1%in the absence and presence of ODQ (10 microM), respectively. Increases in arteriolar diameter inresponse to sodium nitroprusside (1 microM, an NO donor) were inhibited by approximately 80% byODQ, but were not affected by 17-ODYA (10 microM) or clotrimazole (10 microM), inhibitors of thecytochrome P450 pathway. Thus, dilatation of the cerebral microcirculation in response to exogenouslyapplied and endogenously produced NO is dependent, in large part, on activation of sGC.", "metadata": {}}
+{"_id": "23513818", "title": "", "text": "Noxa controls Mule-dependent Mcl-1 ubiquitination through the regulation of the Mcl-1/USP9Xinteraction.The level of the Mcl-1 pro-survival protein is highly regulated, and the down-regulation ofMcl-1 expression favors the apoptotic process. Mcl-1 physically interacts with different BH3-only proteins;particularly, Noxa is involved in the modulation of Mcl-1 expression. In this study, we demonstrated thatNoxa triggers the degradation of Mcl-1 at the mitochondria according to the exclusive location of Noxa atthis compartment. The Noxa-induced degradation of Mcl-1 required the E3 ligase Mule, which isresponsible for the polyubiquitination of Mcl-1. Because the USP9X deubiquitinase was recentlydemonstrated to be involved in Mcl-1 protein turnover by preventing its degradation through the removalof conjugated ubiquitin, we investigated whether Noxa affected the deubiquitination process.Interestingly, Noxa over-expression caused a decrease in the USP9X/Mcl-1 interaction associated with anincrease in the Mcl-1 polyubiquitinated forms. Additionally, Noxa over-expression triggered an increase inthe Mule/Mcl-1 interaction in parallel with the decrease in Mule/USP9X complex formation. Takentogether, these modifications result in the degradation of Mcl-1 by the proteasome machinery. Theimplication of Noxa in the regulation of Mcl-1 proteasomal degradation adds complexity to this process,which is governed by multiple interactions.", "metadata": {}}
+{"_id": "23531592", "title": "", "text": "Paediatric HIV infection.By the year 2000 there will be six million pregnant women and five to ten millionchildren infected with HIV-1. Intervention strategies have been planned and in some instances alreadystarted. A timely and cost-effective strategy needs to take into account that most HIV-1 infectedindividuals reside in developing countries. Further studies are needed on immunological and virologicalfactors affecting HIV-1 transmission from mother to child, on differential disease progression in affectedchildren, and on transient infection.", "metadata": {}}
+{"_id": "23535770", "title": "", "text": "Potential role of NF-kappaB in adult neural stem cells: the underrated steersman?Neural stem cells areprecursors of neurons and glial cells. During brain development, these cells proliferate, migrate anddifferentiate into specific lineages. Recently neural stem cells within the adult central nervous systemwere identified. Informations are now emerging about regulation of stem cell proliferation, migration anddifferentiation by numerous soluble factors such as chemokines and cytokines. However, the signaltransduction mechanisms downstream of these factors are less clear. Here, we review potential evidencesfor a novel central role of the transcription factor nuclear factor kappa B (NF-kappaB) in these crucialsignal transduction processes. NF-kappaB is an inducible transcription factor detected in neurons, glia andneural stem cells. NF-kappaB was discovered by David Baltimore's laboratory as a transcription factor inlymphocytes. NF-kappaB is involved in many biological processes such as inflammation and innateimmunity, development, apoptosis and anti-apoptosis. It has been recently shown that members of theNF-kappaB family are widely expressed by neurons, glia and neural stem cells. In the nervous system,NF-kappaB plays a crucial role in neuronal plasticity, learning, memory consolidation, neuroprotectionand neurodegeneration. Recent data suggest an important role of NF-kappaB on proliferation, migrationand differentiation of neural stem cells. NF-kappaB is composed of three subunits: two DNA-binding andone inhibitory subunit. Activation of NF-kappaB takes place in the cytoplasm and results in degradation ofthe inhibitory subunit, thus enabling the nuclear import of the DNA-binding subunits. Within the nucleus,several target genes could be activated. In this review, we suggest a model explaining the multiple actionof NF-kappaB on neural stem cells. Furthermore, we discuss the potential role of NF-kappaB within theso-called brain cancer stem cells.", "metadata": {}}
+{"_id": "23557241", "title": "", "text": "Intrauterine factors and risk of breast cancer: a systematic review and meta-analysis of currentevidence.BACKGROUND Emerging evidence suggests an association between female prenatal experienceand her subsequent risk of developing breast cancer. Potential underlying mechanisms include variationin amounts of maternal endogenous sex hormones and growth hormones, germ-cell mutations, formationof cancer stem-cells, and other genetic or epigenetic events. We reviewed and summarised quantitativelythe available data on intrauterine exposures and risk of breast cancer. METHODS We systematicallysearched for studies that assessed association between perinatal factors and risk of breast cancer. Wereviewed separately each of the perinatal factors, including birthweight, birth length, parental age atdelivery, gestational age, intrauterine exposure to diethylstilbestrol, twin membership, maternalpre-eclampsia or eclampsia, and other factors. FINDINGS We identified 57 studies published between Oct1, 1980, and June 21, 2007. Increased risk of breast cancer was noted with increased birthweight(relative risk [RR] 1.15 [95% CI 1.09-1.21]), birth length (1.28 [1.11-1.48]), higher maternal age (1.13[1.02-1.25]), and paternal age (1.12 [1.05-1.19]). Decreased risk of breast cancer was noted formaternal pre-eclampsia and eclampsia (0.48 [0.30-0.78]) and twin membership (0.93 [0.87-1.00]). Noassociation was noted between risk of breast cancer and gestational age at birth (0.95 [0.71-1.26]) ormaternal diethylstilbestrol treatment (1.40 [0.86-2.28]). INTERPRETATION The intrauterine environmentcontributes to the predisposition of women to breast cancer in adulthood. The in-utero mechanismsresponsible for such predisposition need to be elucidated.", "metadata": {}}
+{"_id": "23573229", "title": "", "text": "Helicobacter hepaticus does not induce or potentiate colitis in interleukin-10-deficient mice.Helicobacterhepaticus has been reported to induce colitis, hepatitis, and hepatocellular carcinoma in several differentmurine models. The aim of this study was to determine if H. hepaticus will cause colitis inmonoassociated mice lacking the interleukin-10 gene (IL-10(-/-) mice) and potentiate colitis inspecific-pathogen-free (SPF) IL-10(-/-) mice. Germfree IL-10(-/-) mice on either a mixed (C57BL/6 x129/Ola) or inbred (129/SvEv) genetic background were monoassociated with H. hepaticus ATCC 51448by oral feeding and rectal enemas. In a second experiment, germfree IL-10(-/-) mice were colonized withstool from SPF mice that harbored or did not harbor endogenous H. hepaticus. After 7 to 9 weeks ofcolonization, weight loss and mortality were assessed, the colon was isolated for histology and IL-12secretion, and mesenteric lymph node cells were assessed for T-cell activation markers. It was found thatIL-10(-/-) mice monoassociated with H. hepaticus for up to 16 weeks showed almost no histologic colitisor increased IL-12 production. SPF IL-10-knockout mice had no significant difference in weight loss,mortality rate, histologic scores, colonic IL-12 secretion, or T-cell activation with or without H. hepaticus.We conclude that H. hepaticus does not induce or potentiate disease in our IL-10(-/-) mice and thereforeis not required to induce colitis in genetically susceptible hosts.", "metadata": {}}
+{"_id": "23576165", "title": "", "text": "Metabolic interplay between glycolysis and mitochondrial oxidation: The reverse Warburg effect and itstherapeutic implication.Aerobic glycolysis, i.e., the Warburg effect, may contribute to the aggressivephenotype of hepatocellular carcinoma. However, increasing evidence highlights the limitations of theWarburg effect, such as high mitochondrial respiration and low glycolysis rates in cancer cells. To explainsuch contradictory phenomena with regard to the Warburg effect, a metabolic interplay betweenglycolytic and oxidative cells was proposed, i.e., the \"reverse Warburg effect\". Aerobic glycolysis may alsooccur in the stromal compartment that surrounds the tumor; thus, the stromal cells feed the cancer cellswith lactate and this interaction prevents the creation of an acidic condition in the tumormicroenvironment. This concept provides great heterogeneity in tumors, which makes the diseasedifficult to cure using a single agent. Understanding metabolic flexibility by lactate shuttles offers newperspectives to develop treatments that target the hypoxic tumor microenvironment and overcome thelimitations of glycolytic inhibitors.", "metadata": {}}
+{"_id": "23576726", "title": "", "text": "Enhanced waterlogging tolerance in barley by manipulation of expression of the N\u0000end rule pathway E3ligase PROTEOLYSIS6Increased tolerance of crops to low oxygen (hypoxia) during flooding is a key targetfor food security. In Arabidopsis thaliana (L.) Heynh., the N-end rule pathway of targeted proteolysiscontrols plant responses to hypoxia by regulating the stability of group VII ethylene response factor(ERFVII) transcription factors, controlled by the oxidation status of amino terminal (Nt)-cysteine (Cys).Here, we show that the barley (Hordeum vulgare L.) ERFVII BERF1 is a substrate of the N-end rulepathway in vitro. Furthermore, we show that Nt-Cys acts as a sensor for hypoxia in vivo, as the stabilityof the oxygen-sensor reporter protein MCGGAIL-GUS increased in waterlogged transgenic plants.Transgenic RNAi barley plants, with reduced expression of the N-end rule pathway N-recognin E3 ligasePROTEOLYSIS6 (HvPRT6), showed increased expression of hypoxia-associated genes and altered seedgermination phenotypes. In addition, in response to waterlogging, transgenic plants showed sustainedbiomass, enhanced yield, retention of chlorophyll, and enhanced induction of hypoxia-related genes.HvPRT6 RNAi plants also showed reduced chlorophyll degradation in response to continued darkness,often associated with waterlogged conditions. Barley Targeting Induced Local Lesions IN Genomes(TILLING) lines, containing mutant alleles of HvPRT6, also showed increased expression ofhypoxia-related genes and phenotypes similar to RNAi lines. We conclude that the N-end rule pathwayrepresents an important target for plant breeding to enhance tolerance to waterlogging in barley andother cereals.", "metadata": {}}
+{"_id": "23577014", "title": "", "text": "A SUMO-Dependent Protein Network Regulates Chromosome Congression during Oocyte MeiosisDuringCaenorhabditis elegans oocyte meiosis, a multi-protein ring complex (RC) localized between homologouschromosomes, promotes chromosome congression through the action of the chromokinesin KLP-19.While some RC components are known, the mechanism of RC assembly has remained obscure. We showthat SUMO E3 ligase GEI-17/PIAS is required for KLP-19 recruitment to the RC, and proteomic analysisidentified KLP-19 as a SUMO substrate in vivo. In vitro analysis revealed that KLP-19 is efficientlysumoylated in a GEI-17-dependent manner, while GEI-17 undergoes extensive auto-sumoylation. GEI-17and another RC component, the kinase BUB-1, contain functional SUMO interaction motifs (SIMs),allowing them to recruit SUMO modified proteins, including KLP-19, into the RC. Thus, dynamic SUMOmodification and the presence of SIMs in RC components generate a SUMO-SIM network that facilitatesassembly of the RC. Our results highlight the importance of SUMO-SIM networks in regulating theassembly of dynamic protein complexes.", "metadata": {}}
+{"_id": "23577867", "title": "", "text": "Prediagnostic levels of C-peptide, IGF-I, IGFBP -1, -2 and -3 and risk of endometrial cancer.Conditionsrelated to chronic hyperinsulinemia, such as obesity, noninsulin dependent diabetes mellitus andpolycystic ovary syndrome, are associated with an increased risk of endometrial cancer. Elevated plasmaIGF-I and decreased levels of IGF-binding proteins have been shown to be associated with increased riskof several cancer types that are frequent in affluent societies. We investigated for the first time in aprospective study the association of pre-diagnostic blood concentrations of C-peptide (a marker ofpancreatic insulin production), IGF-I, IGFBP-1, -2 and -3 with endometrial cancer risk. A case-controlstudy was nested within 3 cohorts in New York (USA), Umeå (Sweden) and Milan (Italy). It included 166women with primary invasive endometrial cancer and 315 matched controls, of which 44 case and 78control subjects were premenopausal at recruitment. Endometrial cancer risk increased with increasinglevels of C-peptide (ptrend = 0.0002), up to an odds ratio (OR) of 4.76 [95% confidence interval (CI) =1.91-11.8] for the highest quintile. This association remained after adjustment for BMI and otherconfounders [OR for the top quintile = 4.40 (1.65-11.7)]. IGFBP-1 levels were inversely related toendometrial cancer [ptrend = 0.002; OR in the upper quintile = 0.30 (0.15-0.62)], but the associationwas weakened and lost statistical significance after adjustment for confounders [ptrend = 0.06; OR in theupper quintile = 0.49 (0.22-1.07)]. Risk was unrelated to levels of IGF-I, IGFBP-2 and IGFBP-3. Chronichyperinsulinemia, as reflected by increased circulating C-peptide, is associated with increasedendometrial cancer risk. Decrease in the prevalence of chronic hyperinsulinemia, through changes inlifestyle or medication, is expected to prevent endometrial cancer.", "metadata": {}}
+{"_id": "23581096", "title": "", "text": "Interactions between SRY and SOX genes in mammalian sex determination.The SRY gene on themammalian Y chromosome undoubtedly acts to determine testis, but it is still quite unclear how. It wasoriginally supposed that SRY acts directly to activate other genes in the testis-determining pathway. Thispaper presents an alternative hypothesis that SRY functions indirectly, by interacting with related genesSOX3 (from which SRY evolved) and SOX9 (which appears to be intimately involved in vertebrate gonaddifferentiation). Specifically, I propose that in females SOX3 inhibits SOX9 function, but in males, SRYinhibits SOX3 and permits SOX9 to enact its testis-determining role. This hypothesis makes testablepredictions of the phenotypes of XX and XY individuals with deficiencies or overproduction of any of thethree genes, and is able to account for the difficult cases of XX(SRY-) males and transdifferentiation inthe absence of SRY. The hypothesis also suggests a way that the dominant SRY sex-determining systemof present-day mammals may have evolved from an ancient system relying on SOX3 dosage.", "metadata": {}}
+{"_id": "23586085", "title": "", "text": "Chromatin immunoprecipitation and microarray-based analysis of protein locationGenome-wide locationanalysis, also known as ChIP-Chip, combines chromatin immunoprecipitation and DNA microarrayanalysis to identify protein-DNA interactions that occur in living cells. Protein-DNA interactions arecaptured in vivo by chemical crosslinking. Cell lysis, DNA fragmentation and immunoaffinity purification ofthe desired protein will co-purify DNA fragments that are associated with that protein. The enriched DNApopulation is then labeled, combined with a differentially labeled reference sample and applied to DNAmicroarrays to detect enriched signals. Various computational and bioinformatic approaches are thenapplied to normalize the enriched and reference channels, to connect signals to the portions of thegenome that are represented on the DNA microarrays, to provide confidence metrics and to generatemaps of protein-genome occupancy. Here, we describe the experimental protocols that we use fromcrosslinking of cells to hybridization of labeled material, together with insights into the aspects of theseprotocols that influence the results. These protocols require approximately 1 week to complete oncesufficient numbers of cells have been obtained, and have been used to produce robust, high-qualityChIP-chip results in many different cell and tissue types.", "metadata": {}}
+{"_id": "23594156", "title": "", "text": "Spatial and temporal clusters of Barmah Forest virus disease in Queensland, Australia.OBJECTIVE Toidentify the spatial and temporal clusters of Barmah Forest virus (BFV) disease in Queensland inAustralia, using geographical information systems and spatial scan statistic (SaTScan). METHODS Weobtained BFV disease cases, population and statistical local areas (SLAs) boundary data from QueenslandHealth and Australian Bureau of Statistics, respectively, during 1992-2008 for Queensland. Aretrospective Poisson-based analysis using SaTScan software and method was conducted to identify bothpurely spatial and space-time BFV disease high-rate clusters. A spatial cluster size of a proportion of thepopulation and a 200 km radius and varying time windows from 1 to 12 months were chosen (for thespace-time analysis). RESULTS The spatial scan statistic detected a most likely significant purely spatialcluster (including 23 SLAs) and a most likely significant space-time cluster (including 24 SLAs) inapproximately the same location. Significant secondary clusters were also identified from both theanalyses in several locations. CONCLUSIONS This study provides evidence of the existence of statisticallysignificant BFV disease clusters in Queensland, Australia. The study also demonstrated the relevance andapplicability of SaTScan in analysing ongoing surveillance data to identify clusters to facilitate thedevelopment of effective BFV disease prevention and control strategies in Queensland, Australia.", "metadata": {}}
+{"_id": "23599024", "title": "", "text": "Surfactant Protein B Suppresses Lung Cancer Progression by Inhibiting Secretory Phospholipase A2Activity and Arachidonic Acid ProductionBackground/Aims: Radiotherapy is applied to patients withinoperable cancer types including advanced stage non-small cell lung cancer (NSCLC) and radioresistancefunctions as a critical obstacle in radiotherapy. This study was aimed to investigate the mechanism ofradioresistance regulated by surfactant protein B (SP-B). Methods: To investigate the role of SP-B inradioresistance, ΔSFTPB A549 cell line was established and SP-B expression was analyzed. In response toionizing radiation (IR), the change of SP-B expression was analyzed in A549 and NCI-H441 cell lines.Conditioned media (CM) from NSCLC cells were utilized to evaluate the downstream signaling pathway.The in vivo effects of SP-B were assessed through mouse xenograft model with intratumoral injection ofCM. Results: In response to IR, NSCLC cell lines showed decreased SP-B regulated by the TGF-β signalingand decreased SP-B stimulated cell survival and epithelial-mesenchymal transition. Treatment with CMfrom irradiated cells activated sPLA2, enhanced protein kinase Cδ-MAPKs signaling pathway, andincreased arachidonic acid production. We confirmed the in vivo roles of SP-B through mouse xenograftmodel. Conclusion: Our results revealed that down-regulation of SP-B was involved in theradiation-induced metastatic conversion of NSCLC and provided evidence that SP-B acted as a suppressorof NSCLC progression.", "metadata": {}}
+{"_id": "23601616", "title": "", "text": "Liraglutide improves hippocampal synaptic plasticity associated with increased expression of Mash1 inob/ob miceObjective:Consumption of high-fat diet exerts adverse effects on learning and memoryformation, which is linked to impaired hippocampal function. Activation of glucagon-like peptide-1(GLP-1) signalling ameliorates detrimental effects of obesity-diabetes on cognitive function; however,mechanisms underlying these beneficial actions remain unclear. This study examined effects of dailysubcutaneous treatment with GLP-1 mimetic, Liraglutide, on synaptic plasticity, hippocampal geneexpression and metabolic control in adult obese diabetic (ob/ob) mice. Results:Long-term potentiation(LTP) induced by area CA1 was completely abolished in ob/ob mice compared with lean controls.Deleterious effects on LTP were rescued (P<0.001) with Liraglutide. Indeed, Liraglutide-treated miceexhibited superior LTP profile compared with lean controls (P<0.01). Expression of hippocampalbrain-derived neurotropic factor and neurotrophic tyrosine kinase receptor-type 2 were not significantlydifferent, but synaptophysin and Mash1 were decreased in ob/ob mice. Treatment with Liraglutide over21 days increased expression of Mash1 in ob/ob mice (2.0-fold; P<0.01). These changes were associatedwith significantly reduced plasma glucose (21% reduction; P<0.05) and markedly improved plasmainsulin concentrations (2.1- to 3.3-fold; P<0.05 to P<0.01). Liraglutide also significantly reduced theglycaemic excursion following an intraperitonal glucose load (area under curve (AUC) values: 22%;P<0.05) and markedly enhanced the insulin response to glucose (AUC values: 1.6-fold; P<0.05). O2consumption, CO2 production, respiratory exchange ratio and energy expenditure were not altered byLiraglutide therapy. On day 21, accumulated food intake (32% reduction; P<0.05) and number of feedingbouts (32% reduction; P<0.05) were significantly reduced but simple energy restriction was notresponsible for the beneficial actions of Liraglutide. Conclusion:Liraglutide elicits beneficial effects onmetabolic control and synaptic plasticity in mice with severe obesity and insulin resistance mediated inpart through increased expression of Mash1 believed to improve hippocampal neurogenesis and cellsurvival.", "metadata": {}}
+{"_id": "23604601", "title": "", "text": "Post-transcriptional regulation of IME1 determines initiation of meiosis in Saccharomyces cerevisiae.TheIME1 gene of Saccharomyces cerevisiae is required for initiation of meiosis. Transcription of IME1 isdetected under conditions which are known to induce initiation of meiosis, namely starvation for nitrogenand glucose, and the presence of MATa1 and MAT alpha 2 gene products. In this paper we show thatIME1 is also subject to translational regulation. Translation of IME1 mRNA is achieved either uponnitrogen starvation, or upon G1 arrest. In the presence of nutrients, constitutively elevated transcriptionof IME1 is also sufficient for the translation of IME1 RNA. Four different conditions were found to causeexpression of Ime1 protein in vegetative cultures: elevated transcription levels due to the presence ofIME1 on a multicopy plasmid; elevated transcription provided by a Gal-IME1 construct; G1 arrest due toalpha-factor treatment; G1 arrest following mild heat-shock treatment of cdc28 diploids. Using theseconditions, we obtained evidence that starvation is required not only for transcription and efficienttranslation of IME1, but also for either the activation of Ime1 protein or for the induction/activation ofanother factor that, either alone or in combination with Ime1, induces meiosis.", "metadata": {}}
+{"_id": "23618826", "title": "", "text": "Targeted proteomics reveals compositional dynamics of 60S pre-ribosomes after nuclearexportConstruction and intracellular targeting of eukaryotic pre-ribosomal particles involve a multitude ofdiverse transiently associating trans-acting assembly factors, energy-consuming enzymes, and transportfactors. The ability to rapidly and reliably measure co-enrichment of multiple factors with maturingpre-ribosomal particles presents a major biochemical bottleneck towards revealing their function and theprecise contribution of >50 energy-consuming steps that drive ribosome assembly. Here, we devised aworkflow that combines genetic trapping, affinity-capture, and selected reaction monitoring massspectrometry (SRM-MS), to overcome this deficiency. We exploited this approach to interrogate thedynamic proteome of pre-60S particles after nuclear export. We uncovered assembly factors that travelwith pre-60S particles to the cytoplasm, where they are released before initiating translation. Notably, weidentified a novel shuttling factor that facilitates nuclear export of pre-60S particles. Capturing andquantitating protein interaction networks of trapped intermediates of macromolecular complexes by ourworkflow is a reliable discovery tool to unveil dynamic processes that contribute to their in vivo assemblyand transport.", "metadata": {}}
+{"_id": "23627419", "title": "", "text": "Obstructive sleep apnea-hypopnea and incident stroke: the sleep heart health study.RATIONALE Althoughobstructive sleep apnea is associated with physiological perturbations that increase risk of hypertensionand are proatherogenic, it is uncertain whether sleep apnea is associated with increased stroke risk in thegeneral population. OBJECTIVES To quantify the incidence of ischemic stroke with sleep apnea in acommunity-based sample of men and women across a wide range of sleep apnea. METHODS Baselinepolysomnography was performed between 1995 and 1998 in a longitudinal cohort study. The primaryexposure was the obstructive apnea-hypopnea index (OAHI) and outcome was incident ischemic stroke.MEASUREMENTS AND MAIN RESULTS A total of 5,422 participants without a history of stroke at thebaseline examination and untreated for sleep apnea were followed for a median of 8.7 years. Onehundred ninety-three ischemic strokes were observed. In covariate-adjusted Cox proportional hazardmodels, a significant positive association between ischemic stroke and OAHI was observed in men (Pvalue for linear trend: P = 0.016). Men in the highest OAHI quartile (>19) had an adjusted hazard ratioof 2.86 (95% confidence interval, 1.1-7.4). In the mild to moderate range (OAHI, 5-25), each one-unitincrease in OAHI in men was estimated to increase stroke risk by 6% (95% confidence interval, 2-10%).In women, stroke was not significantly associated with OAHI quartiles, but increased risk was observed atan OAHI greater than 25. CONCLUSIONS The strong adjusted association between ischemic stroke andOAHI in community-dwelling men with mild to moderate sleep apnea suggests that this is an appropriatetarget for future stroke prevention trials.", "metadata": {}}
+{"_id": "23633726", "title": "", "text": "Reproducibility of 31P cardiac magnetic resonance spectroscopy at 3 T.The purpose of this work was totake advantage of the new clinical field strength of 3 T to implement and optimize a chemical shiftimaging (CSI) acquisition protocol to produce spectra of high quality with high specificity to themyocardium within a clinically feasible scan time. Further, an analysis method was implementeddependent purely on anatomical location of spectra, and as such free from any potential user bias causedby inference from spectral information. Twenty healthy male subjects were scanned on two separateoccasions using the optimized CSI protocol at 3 T. Data were analyzed for intra- and inter-subjectvariability, as well as intra- and inter-observer variability. The average phosphocreatine (PCr)/adenosinetriphosphate (ATP) value for scan 1 was 2.07 +/- 0.38 and for scan 2 was 2.14 +/- 0.46, showing nosignificant difference between scans. Intra-subject variability was 0.43 +/- 0.35 (percentage difference20%) and the inter-subject coefficient of variation was 18%. The intra-observer variability, assessed asthe absolute difference between analyses of the data by a single observer, was 0.14 +/- 0.24 with nosignificant difference between analyses. The inter-observer variability showed no significant differencesbetween the PCr/ATP value measured by four different observers as demonstrated by an intra-classcorrelation coefficient of 0.763. The increased signal available at 3 T has improved spatial resolution andthereby increased myocardial specificity without any significant decrease in reproducibility over previousstudies at 1.5 T. We present an acquisition protocol that routinely provides high quality spectra and arobust analysis method that is free from potential user bias.", "metadata": {}}
+{"_id": "23634484", "title": "", "text": "Nuclear HuR accumulation through phosphorylation by Cdk1.A predominantly nuclear RNA-bindingprotein, HuR translocates to the cytoplasm in response to stress and proliferative signals, where itstabilizes or modulates the translation of target mRNAs. Here, we present evidence that HuRphosphorylation at S202 by the G2-phase kinase Cdk1 influences its subcellular distribution. HuR wasspecifically phosphorylated in synchronous G2-phase cultures; its cytoplasmic levels increased byCdk1-inhibitory interventions and declined in response to Cdk1-activating interventions. In keeping withthe prominently cytoplasmic location of the nonphosphorylatable point mutant HuR(S202A),phospho-HuR(S202) was shown to be predominantly nuclear using a novel anti-phospho-HuR(S202)antibody. The enhanced cytoplasmic presence of unphosphorylated HuR was linked to its decreasedassociation with 14-3-3 and to its heightened binding to target mRNAs. Our findings suggest that Cdk1phosphorylates HuR during G2, thereby helping to retain it in the nucleus in association with 14-3-3 andhindering its post-transcriptional function and anti-apoptotic influence.", "metadata": {}}
+{"_id": "23639838", "title": "", "text": "Surgical Resection for Patients with Solid Brain Metastases: Current StatusBrain metastases occur in upto 40% of patients with cancer. Their management has been revolutionized in the last decade by threedevelopments: improved imaging and detection of metastases, better treatment of systemic disease withthe result that metastases occur more often; and improved surgical techniques including image-guidedsurgery to treat metastatic lesions. Class 1 data suggest that surgery is a better treatment formetastases than whole brain radiation. Other data suggest that metastases even in eloquent cortex canbe removed safely. The complication rate is low and the recurrence rate is less than 10%. In general,indications for surgery include a mass with an unknown primary; a symptomatic mass including one ineloquent areas; a mass with considerable edema requiring high dose steroids; a mass greater than 3 cm;or patient preference when radiosurgery may also be an option. The question of radiosurgery or wholebrain radiation as adjunct to surgical removal requires further evaluation.", "metadata": {}}
+{"_id": "23649163", "title": "", "text": "Clinical features and treatment of peristomal pyoderma gangrenosum.CONTEXT Peristomal pyodermagangrenosum (PPG), an unusual variant of pyoderma gangrenosum, has been reported almostexclusively in patients with inflammatory bowel disease (IBD) and is frequently misdiagnosed. OBJECTIVETo better characterize the clinical manifestations, diagnosis, and management of PPG. DESIGN, SETTING,AND PATIENTS Retrospective analysis of 7 patients with PPG observed in a university-affiliatedcommunity setting between 1988 and December 1999. MAIN OUTCOME MEASURES Clinical andhistopathologic features, associated disorders, and microbiologic findings. RESULTS Two patients hadCrohn disease, 2 had ulcerative colitis, and 3 had abdominal cancer. Five patients had at least 1 relapseof PPG after initial healing. Although 3 of 4 patients with IBD had active bowel disease, a parallel coursewith PPG occurred in only 1 patient. Both patients whose stoma was relocated developed an ulcer at thenew site. Effective therapies included topical superpotent corticosteroids; intralesional injection oftriamcinolone acetonide at the ulcer margin; topical cromolyn sodium; oral dapsone, prednisone,cyclosporine, mycophenolate mofetil; and intravenous infliximab. CONCLUSION Our experiencesdemonstrate that although PPG has been most often reported in patients with IBD, it may occur in theabsence of IBD. Biopsy of the skin lesion is not diagnostic but excludes other causes. Relocation of thestoma may be associated with a new ulceration and should be avoided. Trauma to the skin of apredisposed patient may elicit the pustules or ulcerations associated with pathergy. JAMA.2000;284:1546-1548.", "metadata": {}}
+{"_id": "23664875", "title": "", "text": "The Tof1p-Csm3p protein complex counteracts the Rrm3p helicase to control replication termination ofSaccharomyces cerevisiae.Termination of replication forks at the natural termini of the rDNA ofSaccharomyces cerevisiae is controlled in a sequence-specific and polar mode by the interaction of theFob1p replication terminator protein with the tandem Ter sites located in the nontranscribed spacers.Here we show, by both 2D gel analyses and chromatin immunoprecipitations (ChIP), that there exists asecond level of global control mediated by the intra-S-phase checkpoint protein complex of Tof1p andCsm3p that protect stalled forks at Ter sites against the activity of the Rrm3p helicase (\"sweepase\"). Thesweepase tends to release arrested forks presumably by the transient displacement of the Ter-boundFob1p. Consistent with this mechanism, very few replication forks were arrested at the natural replicationtermini in the absence of the two checkpoint proteins. In the absence of the Rrm3p helicase, there was aslight enhancement of fork arrest at the Ter sites. Simultaneous deletions of the TOF1 (or CSM3), and theRRM3 genes restored fork arrest by removing both the fork-releasing and fork-protection activities. Othergenes such as MRC1, WSS1, and PSY2 that are also involved in the MRC1 checkpoint pathway were notinvolved in this global control. This observation suggests that Tof1p-Csm3p function differently fromMRC1 and the other above-mentioned genes. This mechanism is not restricted to the natural Ter sites butwas also observed at fork arrest caused by the meeting of a replication fork with transcriptionapproaching from the opposite direction.", "metadata": {}}
+{"_id": "23665162", "title": "", "text": "Association of hypomethylation of LINE-1 repetitive element in blood leukocyte DNA with an increasedrisk of hepatocellular carcinomaGlobal DNA hypomethylation has been associated with increased risk forcancers of the colorectum, bladder, breast, head and neck, and testicular germ cells. The aim of thisstudy was to examine whether global hypomethylation in blood leukocyte DNA is associated with the riskof hepatocellular carcinoma (HCC). A total of 315 HCC cases and 356 age-, sex- and HBsAgstatus-matched controls were included. Global methylation in blood leukocyte DNA was estimated byanalyzing long interspersed element-1 (LINE-1) repeats using bisulfite-polymerase chain reaction (PCR)and pyrosequencing. We observed that the median methylation level in HCC cases (percentage of5-methylcytosine (5mC)=77.7%) was significantly lower than that in controls (79.5% 5mC) (P=0.004,Wilcoxon rank-sum test). The odds ratios (ORs) of HCC for individuals in the third, second, and first(lowest) quartiles of LINE-1 methylation were 1.1 (95% confidence interval (CI) 0.7–1.8), 1.4 (95% CI0.8–2.2), and 2.6 (95% CI 1.7–4.1) (P for trend <0.001), respectively, compared to individuals in thefourth (highest) quartile. A 1.9-fold (95% CI 1.4–2.6) increased risk of HCC was observed amongindividuals with LINE-1 methylation below the median compared to individuals with higher (>median)LINE-1 methylation. Our results demonstrate for the first time that individuals with globalhypomethylation measured in LINE-1 repeats in blood leukocyte DNA have an increased risk for HCC. Ourdata provide the evidence that global hypomethylation detected in the easily obtainable DNA source ofblood leukocytes may help identify individuals at risk of HCC.", "metadata": {}}
+{"_id": "23670644", "title": "", "text": "The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial.BACKGROUNDThe ketogenic diet has been widely and successfully used to treat children with drug-resistant epilepsysince the 1920s. The aim of this study was to test the efficacy of the ketogenic diet in a randomisedcontrolled trial. METHODS 145 children aged between 2 and 16 years who had at least daily seizures (ormore than seven seizures per week), had failed to respond to at least two antiepileptic drugs, and hadnot been treated previously with the ketogenic diet participated in a randomised controlled trial of itsefficacy to control seizures. Enrolment for the trial ran between December, 2001, and July, 2006.Children were seen at one of two hospital centres or a residential centre for young people with epilepsy.Children were randomly assigned to receive a ketogenic diet, either immediately or after a 3-monthdelay, with no other changes to treatment (control group). Neither the family nor investigators wereblinded to the group assignment. Early withdrawals were recorded, and seizure frequency on the diet wasassessed after 3 months and compared with that of the controls. The primary endpoint was a reduction inseizures; analysis was intention to treat. Tolerability of the diet was assessed by questionnaire at 3months. The trial is registered with ClinicalTrials.gov, number NCT00564915. FINDINGS 73 children wereassigned to the ketogenic diet and 72 children to the control group. Data from 103 children wereavailable for analysis: 54 on the ketogenic diet and 49 controls. Of those who did not complete the trial,16 children did not receive their intervention, 16 did not provide adequate data, and ten withdrew fromthe treatment before the 3-month review, six because of intolerance. After 3 months, the meanpercentage of baseline seizures was significantly lower in the diet group than in the controls (62.0%vs136.9%, 75% decrease, 95% CI 42.4-107.4%; p<0.0001). 28 children (38%) in the diet group hadgreater than 50% seizure reduction compared with four (6%) controls (p<0.0001), and five children(7%) in the diet group had greater than 90% seizure reduction compared with no controls (p=0.0582).There was no significant difference in the efficacy of the treatment between symptomatic generalised orsymptomatic focal syndromes. The most frequent side-effects reported at 3-month review wereconstipation, vomiting, lack of energy, and hunger. INTERPRETATION The results from this trial of theketogenic diet support its use in children with treatment-intractable epilepsy. FUNDING HSA CharitableTrust; Smiths Charity; Scientific Hospital Supplies; Milk Development Council.", "metadata": {}}
+{"_id": "23686039", "title": "", "text": "Building-in biosafety for synthetic biology.As the field of synthetic biology develops, real-worldapplications are moving from the realms of ideas and laboratory-confined research towardsimplementation. A pressing concern, particularly with microbial systems, is that self-replicatingre-engineered cells may produce undesired consequences if they escape or overwhelm their intendedenvironment. To address this biosafety issue, multiple mechanisms for constraining microbial replicationand horizontal gene transfer have been proposed. These include the use of host-construct dependenciessuch as toxin-antitoxin pairs, conditional plasmid replication or the requirement for a specific metaboliteto be present for cellular function. While refactoring of the existing genetic code or tailoring of orthogonalsystems, e.g. xeno nucleic acids, offers future promise of more stringent 'firewalls' between natural andsynthetic cells, here we focus on what can be achieved using existing technology. The state-of-the-art indesigning for biosafety is summarized and general recommendations are made (e.g. short environmentalretention times) for current synthetic biology projects to better isolate themselves against potentiallynegative impacts.", "metadata": {}}
+{"_id": "23698769", "title": "", "text": "Sustained active site rigidity during synthesis by human DNA polymerase μDNA polymerase μ (Pol μ) isthe only template-dependent human DNA polymerase capable of repairing double-strand DNA breaks(DSBs) with unpaired 3′ ends in nonhomologous end joining (NHEJ). To probe this function, westructurally characterized Pol μ's catalytic cycle for single-nucleotide incorporation. These structuresindicate that, unlike other template-dependent DNA polymerases, Pol μ shows no large-scaleconformational changes in protein subdomains, amino acid side chains or DNA upon dNTP binding orcatalysis. Instead, the only major conformational change is seen earlier in the catalytic cycle, when theflexible loop 1 region repositions upon DNA binding. Pol μ variants with changes in loop 1 have alteredcatalytic properties and are partially defective in NHEJ. The results indicate that specific loop 1 residuescontribute to Pol μ's unique ability to catalyze template-dependent NHEJ of DSBs with unpaired 3′ ends.", "metadata": {}}
+{"_id": "23700330", "title": "", "text": "Angiopoietin-1 requires p190 RhoGAP to protect against vascular leakage in vivo.Angiopoietin-1 (Ang-1),a ligand of the endothelium-specific receptor Tie-2, inhibits permeability in the mature vasculature, butthe mechanism remains unknown. Here we show that Ang-1 signals Rho family GTPases to organize thecytoskeleton into a junction-fortifying arrangement that enhances the permeability barrier function of theendothelium. Ang-1 phosphorylates Tie-2 and its downstream effector phosphatidylinositol 3-kinase. Thisinduces activation of one endogenous GTPase, Rac1, and inhibition of another, RhoA. Loss of either partof this dual effect abrogates the cytoskeletal and anti-permeability actions of Ang-1, suggesting thatcoordinated GTPase regulation is necessary for the vessel-sealing effects of Ang-1. p190 RhoGAP, aGTPase regulatory protein, provides this coordinating function as it is phosphorylated by Ang-1treatment, requires Rac1 activation, and is necessary for RhoA inhibition. Ang-1 prevents the cytoskeletaland pro-permeability effects of endotoxin but requires p190 RhoGAP to do so. Treatment with p190RhoGAP small interfering RNA completely abolishes the ability of Ang-1 to rescue endotoxemia-inducedpulmonary vascular leak and inflammation in mice. We conclude that Ang-1 prevents vascularpermeability by regulating the endothelial cytoskeleton through coordinated and opposite effects on theRho GTPases Rac1 and RhoA. By linking Rac1 activation and RhoA inhibition, p190 RhoGAP is critical tothe protective effects of Ang-1 against endotoxin. These results provide mechanistic evidence thattargeting the endothelium through Tie-2 may offer specific therapeutic strategies in life-threateningendotoxemic conditions such as sepsis and acute respiratory distress syndrome.", "metadata": {}}
+{"_id": "23702805", "title": "", "text": "Vesicular trafficking of semaphorin 3A is activity-dependent and differs between axons anddendrites.Secreted semaphorins act as guidance cues in the developing nervous system and may haveadditional functions in mature neurons. How semaphorins are transported and secreted by neurons ispoorly understood. We find that endogenous semaphorin 3A (Sema3A) displays a punctate distribution inaxons and dendrites of cultured cortical neurons. GFP-Sema3A shows a similar distribution andco-localizes with secretory vesicle cargo proteins. Live-cell imaging reveals highly dynamic trafficking ofGFP-Sema3A vesicles with distinct properties in axons and dendrites regarding directionality, velocity,mobility and pausing time. In axons, most GFP-Sema3A vesicles move fast without interruption, almostexclusively in the anterograde direction, while in dendrites many GFP-Sema3A vesicles are stationary andmove equally frequent in both directions. Disruption of microtubules, but not of actin filaments,significantly impairs GFP-Sema3A transport. Interestingly, depolarization induces a reversible arrest ofaxonal transport of GFP-Sema3A vesicles but has little effect on dendritic transport. Conversely, actionpotential blockade using tetrodotoxin (TTX) accelerates axonal transport, but not dendritic transport.These data indicate that axons and dendrites regulate trafficking of Sema3A and probably other secretoryvesicles in distinct ways, with axons specializing in fast, uninterrupted, anterograde transport.Furthermore, neuronal activity regulates secretory vesicle trafficking in axons by a depolarization-evokedtrafficking arrest.", "metadata": {}}
+{"_id": "23704559", "title": "", "text": "Frequency of Intracranial Aneurysms Determined by Magnetic Resonance Angiography in Children (MeanAge 16) Having Operative or Endovascular Treatment of Coarctation of the Aorta (Mean Age3).Coarctation of the aorta (CofA) has been associated with an increased risk of intracranial aneurysm(IA). This magnetic resonance angiography (MRA) study investigates the prevalence of IAs in 80 childrentreated in early life for CofA. MRA was performed at mean age of 15.7 ± 7.1 years, and surgical orendovascular treatment for CofA occurred at a mean age of 2.6 ± 4.4 years. No IA was found. In contrastwith earlier findings in adult patients with late treatment for CofA, this first systematic study of very earlytreated patients for CofA failed to confirm the association between CofA and IAs. Our results call theabnormal developmental relation between CofA and IAs into question and suggest that modifiable riskfactors like hypertension may be responsible for IA development in patients with CofA with adultdiagnosis and treatment. In conclusion, our data suggest that early treatment of CofA can reduce theformation of IAs in children so as to make MRA screening less valuable in this young population.", "metadata": {}}
+{"_id": "23716150", "title": "", "text": "Transcriptional profiling of the heart reveals chamber-specific gene expression patterns.Cardiacchamber-specific gene expression is critical for the normal development and function of the heart. Toinvestigate the genetic basis of cardiac anatomical specialization, we have undertaken a nearlygenome-wide transcriptional profiling of the four heart chambers and the interventricular septum.Rigorous statistical analysis has allowed the identification of known and novel members of gene familiesthat are felt to be important in cardiac development and function, including LIM proteins, homeoboxproteins, wnt and T-box pathway proteins, as well as structural proteins like actins and myosins. Inaddition, these studies have allowed the identification of thousands of additional differentially expressedgenes, for which there is little structural or functional information. Clustering of genes with known andunknown functions provides insights into signaling pathways that are essential for development andmaintenance of chamber-specific features. To facilitate future research in this area, a searchable internetdatabase has been constructed that allows study of the chamber-specific expression of any generepresented on this comprehensive microarray. It is anticipated that further study of genes identifiedthrough this effort will provide insights into the specialization of heart chamber tissues, and their specificroles in cardiac development, aging, and disease.", "metadata": {}}
+{"_id": "23727313", "title": "", "text": "CD34+ hematopoietic stem-progenitor cell microRNA expression and function: a circuit diagram ofdifferentiation control.MicroRNAs (miRNAs) are a recently identified class of epigenetic elementsconsisting of small noncoding RNAs that bind to the 3' untranslated region of mRNAs and down-regulatetheir translation to protein. miRNAs play critical roles in many different cellular processes includingmetabolism, apoptosis, differentiation, and development. We found 33 miRNAs expressed in CD34+hematopoietic stem-progenitor cells (HSPCs) from normal human bone marrow and mobilized humanperipheral blood stem cell harvests. We then combined these data with human HSPC mRNA expressiondata and with miRNA-mRNA target predictions, into a previously undescribed miRNA:mRNA interactiondatabase called the Transcriptome Interaction Database. The in silico predictions from the TranscriptomeInteraction Database pointed to miRNA control of hematopoietic differentiation through translationalcontrol of mRNAs critical to hematopoiesis. From these predictions, we formulated a model for miRNAcontrol of stages of hematopoiesis in which many of the genes specifying hematopoietic differentiationare expressed by HSPCs, but are held in check by miRNAs until differentiation occurs. We validatedmiRNA control of several of these target mRNAs by demonstrating that their translation in fact isdecreased by miRNAs. Finally, we chose miRNA-155 for functional characterization in hematopoiesis,because we predicted that it would control both myelopoiesis and erythropoiesis. As predicted,miRNA-155 transduction greatly reduced both myeloid and erythroid colony formation of normal humanHSPCs.", "metadata": {}}
+{"_id": "23737024", "title": "", "text": "Acute exercise activates nuclear factor (NF)-kappaB signaling pathway in rat skeletal muscle.Two studieswere performed to investigate the effects of an acute bout of physical exercise on the nuclear proteinkappaB (NF-kappaB) signaling pathway in rat skeletal muscle. In Study 1, a group of rats (n=6) was runon the treadmill at 25 m/min, 5% grade, for 1 h or until exhaustion (Ex), and compared with a secondgroup (n=6) injected with two doses of pyrrolidine dithiocarbamate (PDTC, 100 mg/kg, i.p.) 24 and 1 hprior to the acute exercise bout. Three additional groups of rats (n=6) were injected with either 8 mg/kg(i.p.) of lipopolysaccharide (LPS), 1 mmol/kg (i.p.) t-butylhydroperoxide (tBHP), or saline (C) and killedat resting condition. Ex rats showed higher levels of NF-kappaB binding and P50 protein content inmuscle nuclear extracts compared with C rats. Cytosolic IkappaBalpha and IkappaB kinase (IKK) contentswere decreased, whereas phospho-IkappaBalpha and phospho-IKK contents were increased, comparingEx vs. C. The exercise-induced activation of NF-kappaB signaling cascade was partially abolished by PDTCtreatment. LPS, but not tBHP, treatment mimicked and exaggerated the effects observed in Ex rats. InStudy 2, the time course of exercise-induced NF-kappaB activation was examined. Highest levels ofNF-kappaB binding were observed at 2 h postexercise. Decreased cytosolic IkappaBalpha and increasedphosphor-IkappaBalpha content were found 0-1 h postexercise whereas P65 reached peak levels at 2-4h. These data suggest that the NF-kappaB signaling pathway can be activated in a redox-sensitivemanner during muscular contraction, presumably due to increased oxidant production. The cascade ofintracellular events may be the overture to elevated gene expression of manganese superoxidedismutase reported earlier (Pfluegers Arch. 442, 426-434, 2001).", "metadata": {}}
+{"_id": "23746313", "title": "", "text": "Staphylococcus aureus RNAIII and the endoribonuclease III coordinately regulate spa geneexpression.Staphylococcus aureus RNAIII is one of the largest regulatory RNAs, which controls severalvirulence genes encoding exoproteins and cell-wall-associated proteins. One of the RNAIII effects is therepression of spa gene (coding for the surface protein A) expression. Here, we show that spa repressionoccurs not only at the transcriptional level but also by RNAIII-mediated inhibition of translation anddegradation of the stable spa mRNA by the double-strand-specific endoribonuclease III (RNase III). The3' end domain of RNAIII, partially complementary to the 5' part of spa mRNA, efficiently anneals to spamRNA through an initial loop-loop interaction. Although this annealing is sufficient to inhibit in vitro theformation of the translation initiation complex, the coordinated action of RNase III is essential in vivo todegrade the mRNA and irreversibly arrest translation. Our results further suggest that RNase III isrecruited for targeting the paired RNAs. These findings add further complexity to the expression of the S.aureus virulon.", "metadata": {}}
+{"_id": "23746332", "title": "", "text": "Fast calcium and voltage-sensitive dye imaging in enteric neurones reveal calcium peaks associated withsingle action potential discharge.Slow changes in [Ca(2+)](i) reflect increased neuronal activity. Ourstudy demonstrates that single-trial fast [Ca(2+)](i) imaging (≥200 Hz sampling rate) revealed peakseach of which are associated with single spike discharge recorded by consecutive voltage-sensitive dye(VSD) imaging in enteric neurones and nerve fibres. Fast [Ca(2+)](i) imaging also revealed subthresholdfast excitatory postsynaptic potentials. Nicotine-evoked [Ca(2+)](i) peaks were reduced by -conotoxinand blocked by ruthenium red or tetrodotoxin. Fast [Ca(2+)](i) imaging can be used to directly recordsingle action potentials in enteric neurones. [Ca(2+)](i) peaks required opening of voltage-gated sodiumand calcium channels as well as Ca(2+) release from intracellular stores.", "metadata": {}}
+{"_id": "23763738", "title": "", "text": "New colorimetric cytotoxicity assay for anticancer-drug screening.We have developed a rapid, sensitive,and inexpensive method for measuring the cellular protein content of adherent and suspension cultures in96-well microtiter plates. The method is suitable for ordinary laboratory purposes and for very large-scaleapplications, such as the National Cancer Institute's disease-oriented in vitro anticancer-drug discoveryscreen, which requires the use of several million culture wells per year. Cultures fixed with trichloroaceticacid were stained for 30 minutes with 0.4% (wt/vol) sulforhodamine B (SRB) dissolved in 1% acetic acid.Unbound dye was removed by four washes with 1% acetic acid, and protein-bound dye was extractedwith 10 mM unbuffered Tris base [tris (hydroxymethyl)aminomethane] for determination of opticaldensity in a computer-interfaced, 96-well microtiter plate reader. The SRB assay results were linear withthe number of cells and with values for cellular protein measured by both the Lowry and Bradford assaysat densities ranging from sparse subconfluence to multilayered supraconfluence. The signal-to-noise ratioat 564 nm was approximately 1.5 with 1,000 cells per well. The sensitivity of the SRB assay comparedfavorably with sensitivities of several fluorescence assays and was superior to those of both the Lowryand Bradford assays and to those of 20 other visible dyes. The SRB assay provides a colorimetric endpoint that is nondestructive, indefinitely stable, and visible to the naked eye. It provides a sensitivemeasure of drug-induced cytotoxicity, is useful in quantitating clonogenicity, and is well suited tohigh-volume, automated drug screening. SRB fluoresces strongly with laser excitation at 488 nm and canbe measured quantitatively at the single-cell level by static fluorescence cytometry.", "metadata": {}}
+{"_id": "23777820", "title": "", "text": "A murine model of human myeloma bone disease.Myeloma causes a devastating and unique form ofosteolytic bone disease. Although osteoclast activation is responsible for bone destruction, the precisemechanisms by which myeloma cells increase osteoclast activity have not been defined. An animal modelof human myeloma bone disease would help in clarification of these mechanisms. Multiple myelomaoccurs spontaneously in aging C57 BL/KaLwRij mice and has all of the features of the disease in humans,including the characteristic bone lesions. The disease can be induced in normal C57 BL/KaLwRij mice byinoculation of fresh marrow-derived cells from mice with myeloma, but this model is difficult to studybecause of variability in the number of myeloma cells in marrow-derived preparations. To develop abetter animal model of human myeloma bone disease, we have established and subcloned a cell line fromthis murine myeloma and found that it causes osteolytic bone lesions in mice characteristic of humanmyeloma bone disease. The cell line produces interleukin-6, but grows independent of exogenousinterleukin-6. Mice inoculated intravenously with the cultured cells predictably develop an identicaldisease to the mice injected intravenously with fresh bone-marrow-derived myeloma cells, includingmonoclonal gammopathy and radiologic bone lesions. We found that some of the mice becamehypercalcemic, and the bone lesions are characterized by increased osteoclast activity. We found identicalresults when we inoculated Nu/Bg/XID mice with cultured murine myeloma cells. Because we caninoculate mice with precise numbers of cells and predict accurately when the mice will develop bonelesions, become hypercalcemic, and die, this should be a convenient model for determining themechanisms by which the myeloma cells cause osteoclast activation in this model of human myelomabone disease.", "metadata": {}}
+{"_id": "23783727", "title": "", "text": "Ticagrelor vs. clopidogrel in patients with acute coronary syndromes and diabetes: a substudy from thePLATelet inhibition and patient Outcomes (PLATO) trialAIMS patients with diabetes mellitus (DM) havehigh platelet reactivity and are at increased risk of ischaemic events and bleeding post-acute coronarysyndromes (ACS). In the PLATelet inhibition and patient Outcomes (PLATO) trial, ticagrelor reduced theprimary composite endpoint of cardiovascular death, myocardial infarction, or stroke, but with similarrates of major bleeding compared with clopidogrel. We aimed to investigate the outcome with ticagrelorvs. clopidogrel in patients with DM or poor glycaemic control. METHODS AND RESULTS we analysedpatients with pre-existing DM (n = 4662), including 1036 patients on insulin, those without DM (n = 13951), and subgroups based on admission levels of haemoglobin A1c (HbA1c; n = 15 150). In patientswith DM, the reduction in the primary composite endpoint (HR: 0.88, 95% CI: 0.76-1.03), all-causemortality (HR: 0.82, 95% CI: 0.66-1.01), and stent thrombosis (HR: 0.65, 95% CI: 0.36-1.17) with noincrease in major bleeding (HR: 0.95, 95% CI: 0.81-1.12) with ticagrelor was consistent with the overallcohort and without significant diabetes status-by-treatment interactions. There was no heterogeneitybetween patients with or without ongoing insulin treatment. ticagrelor reduced the primary endpoint,all-cause mortality, and stent thrombosis in patients with HbA1c above the median (HR: 0.80, 95% CI:0.70-0.91; HR: 0.78, 95% CI: 0.65-0.93; and HR: 0.62, 95% CI: 0.39-1.00, respectively) with similarbleeding rates (HR: 0.98, 95% CI: 0.86-1.12). CONCLUSION ticagrelor, when compared with clopidogrel,reduced ischaemic events in ACS patients irrespective of diabetic status and glycaemic control, withoutan increase in major bleeding events.", "metadata": {}}
+{"_id": "23785605", "title": "", "text": "Cardiovascular risk factors and migraine: the GEM population-based study.BACKGROUND Migraine,particularly with aura, is a risk factor for early-onset ischemic stroke. The underlying mechanisms areunknown, but may in part be due to migraineurs having an increased risk profile for cardiovasculardisease. In this study, the authors compare the cardiovascular risk profile of adult migraineurs to that ofnonmigraineurs. METHODS Participants (n = 5,755, 48% men, age 20 to 65 years) are from the GeneticEpidemiology of Migraine (GEM) study, a population-based study in the Netherlands. A total of 620current migraineurs were identified: 31% with aura (MA), 64% without aura (MO), and 5% unclassified.Controls were 5,135 individuals without lifetime migraine. Measured cardiovascular risk factors includedblood pressure (BP), serum total and high-density lipoprotein cholesterol (TC, HDL), smoking, oralcontraceptive use, and the Framingham risk score for myocardial infarction or coronary heart disease(CHD) death. RESULTS Compared to controls, migraineurs were more likely to smoke (OR = 1.43 [1.1 to1.8]), less likely to consume alcohol (OR = 0.58 [0.5 to 0.7]), and more likely to report a parental historyof early myocardial infarction. Migraineurs with aura were more likely to have an unfavorable cholesterolprofile (TC > or = 240 mg/dL [OR = 1.43 (0.97 to 2.1)], TC:HDL ratio > 5.0 [OR = 1.64 (1.1 to 2.4)]),have elevated BP (systolic BP > 140 mm Hg or diastolic BP > 90 mm Hg [OR = 1.76 (1.04 to 3.0)]), andreport a history of early onset CHD or stroke (OR = 3.96 [1.1 to 14.3]); female migraineurs with aurawere more likely to be using oral contraceptives (OR = 2.06 [1.05 to 4.0]). The odds of having anelevated Framingham risk score for CHD were approximately doubled for the migraineurs with aura.CONCLUSIONS Migraineurs, particularly with aura, have a higher cardiovascular risk profile thanindividuals without migraine.", "metadata": {}}
+{"_id": "23801039", "title": "", "text": "Th2-mediated host protective immunity to intestinal nematode infections.Despite many years of study,relatively little is known about the effector mechanisms that operate against intestine-dwellingnematodes. Most of the current understanding comes from studies of laboratory model systems inrodents. It is clear that when an intestinal helminth infection takes place the immune system generates astrong Th2-mediated response, which regulates a variety of responses characteristic of helminthinfections such as eosinophilia, intestinal mastocytosis and elevated IgE production. The ability tomodulate the host's immune response in vivo with cytokine-specific monoclonal antibodies andrecombinant cytokines, together with the use of animals with disruption of key genes involved in theimmune response, have provided powerful tools with which to dissect the potential effector mechanismsoperating. In the absence of a T-cell compartment the host is unable to expel the parasite. If aTh1-dominated response is generated, protective immunity is almost universally compromised. Thus, it itwould appear that some aspect of a Th2-mediated response controls effector mechanisms. Although it isclear that for some infections the mast cell appears to be involved in protection, probably through thegeneration of a non-specific inflammatory response, how these cells become activated remains unclear.Data from infections in transgenic animals suggest that activation is not through the high-affinity receptorfor IgE. Such studies also call into doubt the importance of conventional interactions between effectorleucocytes and antibody. There is little evidence to support a protective role for eosinophilia in anysystem. New data also imply that, although interleukin 4 (IL-4) is generally important (and can exerteffects independent of an adaptive immune response), it is not always sufficient to mediate protection;other Th2 cytokines (e.g. IL-13) may warrant closer investigation. It is apparent that a number ofpotential Th2-controlled effector mechanisms (some of which may be particularly important at mucosalsurfaces) remain to be explored. Overall, it is likely that worm expulsion is the result of a combination ofmultiple mechanisms, some of which are more critical to some species of parasite than to others.", "metadata": {}}
+{"_id": "23804187", "title": "", "text": "Wnt/β-catenin signaling defines organizing centers that orchestrate growth and differentiation of theregenerating zebrafish caudal fin.Zebrafish regenerate their fins via the formation of a population ofprogenitor cells, the blastema. Wnt/β-catenin signaling is essential for blastemal cell proliferation andpatterning of the overlying epidermis. Yet, we find that β-catenin signaling is neither active in theepidermis nor the majority of the proliferative blastemal cells. Rather, tissue-specific pathwayinterference indicates that Wnt signaling in the nonproliferative distal blastema is required for cellproliferation in the proximal blastema, and signaling in cells lining the osteoblasts directs osteoblastdifferentiation. Thus, Wnt signaling regulates epidermal patterning, blastemal cell proliferation, andosteoblast maturation indirectly via secondary signals. Gene expression profiling, chromatinimmunoprecipitation, and functional rescue experiments suggest that Wnt/β-catenin signaling actsthrough Fgf and Bmp signaling to control epidermal patterning, whereas retinoic acid and Hedgehogsignals mediate its effects on blastemal cell proliferation. We propose that Wnt signaling orchestrates finregeneration by defining organizing centers that instruct cellular behaviors of adjacent tissues.", "metadata": {}}
+{"_id": "23816832", "title": "", "text": "The utility of cerebrospinal fluid analysis in patients with multiple sclerosisDiagnosis of multiple sclerosis(MS) requires the exclusion of other possible diagnoses. For this reason, the cerebrospinal fluid (CSF)should be routinely analysed in patients with a first clinical event suggestive of MS. CSF analysis is nolonger mandatory for diagnosis of relapsing–remitting MS, as long as MRI diagnostic criteria are fulfilled.However, caution is required in diagnosing MS in patients with negative MRI findings or in the absence ofCSF analysis, as CSF investigation is useful to eliminate other causes of disease. The detection ofoligoclonal IgG bands in CSF has potential prognostic value and is helpful for clinical decision-making. Inaddition, CSF analysis is important for research into the pathogenesis of MS. Pathophysiological andneurodegenerative findings of inflammation in MS have been derived from CSF investigations. Novel CSFbiomarkers, though not yet validated, have been identified for diagnosis of MS and for ascertainingdisease activity, prognosis and response to treatment, and are likely to increase in number with moderndetection techniques. In this Review, we summarize CSF findings that shed light on the differentialdiagnosis of MS, and highlight the potential of novel biomarkers for this disease that could advanceunderstanding of its pathophysiology.", "metadata": {}}
+{"_id": "23830488", "title": "", "text": "Expression of circadian genes correlates with liver metastasis and outcomes in colorectal cancer.Circadianrhythms are daily oscillations in various biological processes, generated by the feedback loops of eightcore circadian genes: Period1 (Per1), Period2 (Per2), Period3 (Per3), Cryptochrome1 (Cry1),Cryptochrome2 (Cry2), Clock, Bmal1 and Casein Kinase I ε (CKIε). Recent studies have suggested thatcircadian genes participate in the growth and development of various cancers. This study examined therelations of circadian gene expression to clinicopathological factors and outcomes in patients withcolorectal cancer. We studied surgical specimens of cancer tissue and adjacent normal mucosa obtainedfrom 202 patients with untreated colorectal cancer. The relative expression levels of the circadian genesin the specimens were measured by quantitative real-time, reverse-transcription polymerase chainreaction. Expression of the Clock gene and the CKIε gene in cancer tissue were significantly highercompared to that in adjacent normal mucosa. Expression of the Per1 and Per3 genes in cancer tissue wassignificantly lower compared to that in adjacent normal mucosa. Analysis of the relations betweenclinicopathological features and expression of the eight circadian genes in cancer tissue showed that highexpression of the Bmal1 gene and low expression of the Per1 gene correlated with liver metastasis. Onanalysis of the relations between outcomes and gene expression, high expression of the Per2 gene wasassociated with significantly better outcomes than low expression of the Per2 gene. Overexpression of theBmal1 gene and reduced expression of the Per1 gene may thus be useful predictors of liver metastasis.Moreover, reduced expression of the Per2 gene may be a predictor of outcomes in patients with colorectalcancer.", "metadata": {}}
+{"_id": "23841828", "title": "", "text": "The Danish prescription registries.The extensive computerisation of Danish pharmacies has permitted theestablishment of two large prescription registries: The Odense University PharmacoepidemiologicalDatabase (OPED) and the Pharmacoepidemiological Prescription Database of North Jutland (PDNJ). TheDanish prescription registries content, coverage, completeness and the quality of the data are discussedin this article. Furthermore, conditions for access to the data are presented. The two prescriptionregistries cover a background population of approximately one million or 18% of the Danish population.The populations covered by the registries are stable and representative of the Danish population ingeneral. The registries cover all reimbursed medicine at the level of the individual user. Registration of aunique and permanent personal identifier enables the compilation of longitudinal drug histories andallows the linking of prescription data to other population-based Danish registries. The degree ofcompleteness of the Danish prescription registries is excellent for reimbursed prescription drugs. A smallnumber of comparison studies also indicate high validity of the register information. The Danishprescription registries represent a useful new data source for pharmacoepidemiological studies.", "metadata": {}}
+{"_id": "23848916", "title": "", "text": "Oridonin, a diterpenoid purified from Rabdosia rubescens, inhibits the proliferation of cells from lymphoidmalignancies in association with blockade of the NF-kappa B signal pathways.This study found thatoridonin, a natural diterpenoid purified from Rabdosia rubescens, inhibited growth of multiple myeloma(MM; U266, RPMI8226), acute lymphoblastic T-cell leukemia (Jurkat), and adult T-cell leukemia (MT-1)cells with an effective dose that inhibited 50% of target cells (ED50) ranging from 0.75 to 2.7 microg/mL.Terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling staining showed that oridonincaused apoptosis of MT-1 cells in a time-dependent manner. We explored effects of oridonin onantiapoptotic Bcl-2 family members and found that it down-regulated levels of Mcl-1 and BCL-x(L), butnot Bcl-2 protein, in both MT-1 and RPMI8226 cells. Further studies found that oridonin inhibited nuclearfactor-kappa B (NF-kappa B) DNA-binding activity in these cells as measured by luciferase reporter gene,ELISA-based, and electrophoretic mobility shift assays. Oridonin also blocked tumor necrosisfactor-alpha- and lipopolysaccharide-stimulated NF-kappa B activity in Jurkat cells as well as RAW264.7murine macrophages. Of note, oridonin decreased survival of freshly isolated adult T-cell leukemia (threesamples), acute lymphoblastic leukemia (one sample), chronic lymphocytic leukemia (one sample),non-Hodgkin's lymphoma (three samples), and MM (four samples) cells from patients in association withinhibition of NF-kappa B DNA-binding activity. On the other hand, oridonin did not affect survival ofnormal lymphoid cells from healthy volunteers. Taken together, oridonin might be useful as adjunctivetherapy for individuals with lymphoid malignancies, including the lethal disease adult T-cell leukemia.", "metadata": {}}
+{"_id": "23851261", "title": "", "text": "Uncertainty in integrative structural modeling.Integrative structural modeling uses multiple types of inputinformation and proceeds in four stages: (i) gathering information, (ii) designing model representationand converting information into a scoring function, (iii) sampling good-scoring models, and (iv) analyzingmodels and information. In the first stage, uncertainty originates from data that are sparse, noisy,ambiguous, or derived from heterogeneous samples. In the second stage, uncertainty can originate froma representation that is too coarse for the available information or a scoring function that does notaccurately capture the information. In the third stage, the major source of uncertainty is insufficientsampling. In the fourth stage, clustering, cross-validation, and other methods are used to estimate theprecision and accuracy of the models and information.", "metadata": {}}
+{"_id": "23862975", "title": "", "text": "Moist occlusive dressing (Aquacel(®) Ag) versus moist open dressing (MEBO(®)) in the management ofpartial-thickness facial burns: a comparative study in Ain Shams University.INTRODUCTION The face isthe central point of the physical features; it transmits expressions and emotions, communicates feelingsand allows for individual identity. Facial burns are very common and are devastating to the affectedpatient and results into numerous physical, emotional and psychosocial sequels. Partial thickness facialburns are very common especially among children. This study compares the effect of standard moistopen technique management and a moist closed technique for partial thickness burns of the face.PATIENTS AND METHODS Patients with partial-thickness facial burns admitted in the burn unit, AinShams University, Cairo, Egypt in the period from April 2009 to December 2009 were included in thisstudy. They were divided into two groups to receive either open treatment with MEBO(®) (n=20) orcoverage with Aquacel(®) Ag (n=20). Demographics (age, gender, ethnicity, TBSA, burn areas), lengthof hospital stay (LOS), rate of infections, time to total healing, frequency of dressing changes, pain, costbenefit and patient discomfort were compared between the two groups. The long-term outcome(incidence of hypertrophic scarring) was assessed for up to 6 months follow-up period. RESULTS Therewere no significant differences in demographics between the two groups. In the group treated with theAquacel(®) Ag, the mean time for re-epithelialization was 10.5 days, while it was 12.4 days in theMEBO(®) group (p<0.05). Frequency of changes, pain and patient discomfort were less with Aquacel(®)Ag. Cost was of no significant difference between the two groups. Scar quality improved in theAquacel(®) Ag treatment group. Three and 6 months follow-up was done and long-term outcomes wererecorded in both groups. CONCLUSION Moist occlusive dressing (Aquacel(®) Ag) significantly improvesthe management and healing rate of partial thickness facial burns with better long-term outcomecompared to moist open dressing (MEBO(®)).", "metadata": {}}
+{"_id": "23863551", "title": "", "text": "Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3Kinhibitors.We examined the effects of an inhibitor of PI3K, XL147, against human breast cancer cell lineswith constitutive PI3K activation. Treatment with XL147 resulted in dose-dependent inhibition of cellgrowth and levels of pAKT and pS6, signal transducers in the PI3K/AKT/TOR pathway. InHER2-overexpressing cells, inhibition of PI3K was followed by up-regulation of expression andphosphorylation of multiple receptor tyrosine kinases, including HER3. Knockdown of FoxO1 and FoxO3atranscription factors suppressed the induction of HER3, InsR, IGF1R, and FGFR2 mRNAs upon inhibition ofPI3K. In HER2(+) cells, knockdown of HER3 with siRNA or cotreatment with the HER2 inhibitorstrastuzumab or lapatinib enhanced XL147-induced cell death and inhibition of pAKT and pS6.Trastuzumab and lapatinib each synergized with XL147 for inhibition of pAKT and growth of establishedBT474 xenografts. These data suggest that PI3K antagonists will inhibit AKT and relieve suppression ofreceptor tyrosine kinase expression and their activity. Relief of this feedback limits the sustainedinhibition of the PI3K/AKT pathway and attenuates the response to these agents. As a result, PI3Kpathway inhibitors may have limited clinical activity overall if used as single agents. In patients withHER2-overexpressing breast cancer, PI3K inhibitors should be used in combination with HER2/HER3antagonists.", "metadata": {}}
+{"_id": "23863576", "title": "", "text": "Developmental RacGAP α2-Chimaerin Signaling Is a Determinant of the Morphological Features ofDendritic Spines in Adulthood.UNLABELLED Morphological characteristics of dendritic spines form thebasis of cognitive ability. However, molecular mechanisms involved in fine-tuning of spine morphologyduring development are not fully understood. Moreover, it is unclear whether, and to what extent, thesedevelopmental mechanisms determine the normal adult spine morphological features. Here, we provideevidence that α2-isoform of Rac-specific GTPase-activating protein α-chimaerin (α2-chimaerin) isinvolved in spine morphological refinement during late postnatal period, and furthermore show that thisdevelopmental α2-chimaerin function affects adult spine morphologies. We used a series of mice withglobal and conditional knock-out of α-chimaerin isoforms (α1-chimaerin and α2-chimaerin). α2-Chimaerindisruption, but not α1-chimaerin disruption, in the mouse results in an increased size (and density) ofspines in the hippocampus. In contrast, overexpression of α2-chimaerin in developing hippocampalneurons induces a decrease of spine size. Disruption of α2-chimaerin suppressed EphA-mediated spinemorphogenesis in cultured developing hippocampal neurons. α2-Chimaerin disruption that begins duringthe juvenile stage results in an increased size of spines in the hippocampus. Meanwhile, spinemorphologies are unaltered when α2-chimaerin is deleted only in adulthood. Consistent with these spinemorphological results, disruption of α2-chimaerin beginning in the juvenile stage led to an increase incontextual fear learning in adulthood; whereas contextual learning was recently shown to be unaffectedwhen α2-chimaerin was deleted only in adulthood. Together, these results suggest that α2-chimaerinsignaling in developmental stages contributes to determination of the morphological features of adultspines and establishment of normal cognitive ability. SIGNIFICANCE STATEMENT Recent studies ofneurodevelopmental disorders in humans and their animal models have led to an attractive hypothesisthat spine morphogenesis during development forms the basis of adult cognition. In particular, the rolesof Rac and its regulators, such as Rac-specific GTPase-activating proteins (RacGAPs) and Rac guaninenucleotide exchange factors, are a topic of focus in spine morphogenesis and cognitive ability. Using aseries of mice with global and conditional knock-out (KO) of RacGAP α-chimaerin isoforms (α1-chimaerinand α2-chimaerin), we provide compelling evidence demonstrating that α2-chimaerin is involved in spinemorphological refinement during late postnatal development and that this developmental α2-chimaerinfunction affects adult spine morphologies. Furthermore, our results clearly showed that α2-chimaerinsignaling during late postnatal development contributes to normal cognitive ability in adult mice.", "metadata": {}}
+{"_id": "23865182", "title": "", "text": "Efficacy and tolerability of amitriptylinoxide in the treatment of chronic tension-type headache: amulti-centre controlled study.Amitriptyline is the medication of first choice in the treatment of chronictension-type headache. In 197 patients with chronic tension-type headache (87M and 110F with a meanage of 38 +/- 13 (18-68)) efficacy and tolerability of 60-90 mg amitriptylinoxide (AO) were comparedwith 50-75 mg amitriptyline (AM) and placebo (PL) in a double-blind, parallel-group trial consisting of afour weeks' baseline phase and 12 weeks of treatment. The primary study endpoint was a reduction of atleast 50% of the product of headache duration and frequency and a reduction of at least 50% inheadache intensity. Statistics used were Fisher's exact test and analysis of variance. No significantdifference emerged between AO, AM and PL with respect to the primary study endpoint. Treatmentresponse occurred in 30.3% of the AO, 22.4% of the AM and 21.9% of the PL group. A reduction inheadache duration and frequency of at least 50% was found in 39.4% on AO, in 25.4% on AM and in26.6% on PL (PAO-PL = .1384, PAM-PL = 1.000, PAO-AM = .0973). A reduction in headache intensity ofat least 50% was found in 31.8% on AO, in 26.9% on AM and in 26.6% on PL (PAO-PL = .5657, PAM-PL= 1.000, PAO-AM = .5715). Trend analysis with respect to a significant reduction of headache intensity (p< 0.05) and the product of headache duration and frequency revealed a superior effect of AO.(ABSTRACTTRUNCATED AT 250 WORDS)", "metadata": {}}
+{"_id": "23868856", "title": "", "text": "Downregulation of Superoxide Dismutase Activity and Gene Expression in Cultured Rat Brain Astrocytesafter Incubation with Vitamin CReactive oxygen species have been linked with neuropathological changesin the central nervous system. Epidemiological studies supported the beneficial effect of supplementationof antioxidants. Superoxide dismutase (SOD) is an endogenous enzyme which can scavenge reactiveoxygen species. This study investigated the effect of supplementation with ascorbic acid (vitamin C) onthe changes of SOD in cultured neurological cells. Rat brain astrocytes (RBA-1 cells) were incubated withvitamin C and divided into four groups: a control group (without vitamin C) and three treatment groupswith vitamin C at 40, 80, and 160 µmol/l. After short-term (2 days) and long-term (7 days) incubation,SOD activity, SOD mRNA level by Northern blotting, and SOD protein amounts by Western blotting weremeasured. After 2 days of incubation, vitamin C resulted in a decrease in the activity of SOD in aconcentration-dependent manner (Mn-SOD from 14.8 ± 1.2 to 13.2 ± 0.5 U/mg protein and Cu/Zn-SODfrom 64.8 ± 1.2 to 51.7 ± 0.9 U/mg protein; p < 0.05), and vitamin C also attenuated the Cu/Zn-SODmRNA level from 100 to 86.3 ± 6.7%; p < 0.01), whereas the protein amounts of these two SODsremained unchanged. After 7 days of incubation with vitamin C, the SOD activity of RBA-1 cells decreasedsignificantly (Mn-SOD from 14.9 ± 0.3 to 11.8 ± 0.3 U/mg protein and Cu/Zn SOD from 61.8 ± 1.8 to54.6 ± 0.9 U/mg protein; p < 0.01), and the mRNA level was also attenuated (Mn-SOD from 100 to 86.8± 8.7% and Cu/Zn-SOD from 100 to 84.7 ± 4.8%; p < 0.01). These results suggest that 2 and 7 days ofincubation with relatively high concentrations of vitamin C may downregulate activity and geneexpression of SOD in cultured RBA-1 cells.", "metadata": {}}
+{"_id": "23869951", "title": "", "text": "Lateral Hypothalamic Area Glutamatergic Neurons and Their Projections to the Lateral Habenula RegulateFeeding and Reward.UNLABELLED The overconsumption of calorically dense, highly palatable foods isthought to be a major contributor to the worldwide obesity epidemic; however, the precise neural circuitsthat directly regulate hedonic feeding remain elusive. Here, we show that lateral hypothalamic area (LHA)glutamatergic neurons, and their projections to the lateral habenula (LHb), negatively regulate theconsumption of palatable food. Genetic ablation of LHA glutamatergic neurons increased daily caloricintake and produced weight gain in mice that had access to a high-fat diet, while not altering generallocomotor activity. Anterior LHA glutamatergic neurons send a functional glutamatergic projection to theLHb, a brain region involved in processing aversive stimuli and negative reward prediction outcomes.Pathway-specific, optogenetic stimulation of glutamatergic LHA-LHb circuit resulted in detectableglutamate-mediated EPSCs as well as GABA-mediated IPSCs, although the net effect of neurotransmitterrelease was to increase the firing of most LHb neurons. In vivo optogenetic inhibition of LHA-LHbglutamatergic fibers produced a real-time place preference, whereas optogenetic stimulation of LHA-LHbglutamatergic fibers had the opposite effect. Furthermore, optogenetic inhibition of LHA-LHbglutamatergic fibers acutely increased the consumption of a palatable liquid caloric reward. Collectively,these results demonstrate that LHA glutamatergic neurons are well situated to bidirectionally regulatefeeding and potentially other behavioral states via their functional circuit connectivity with the LHb andpotentially other brain regions. SIGNIFICANCE STATEMENT In this study, we show that the geneticablation of LHA glutamatergic neurons enhances caloric intake. Some of these LHA glutamatergic neuronsproject to the lateral habenula, a brain area important for generating behavioral avoidance. Optogeneticstimulation of this circuit has net excitatory effects on postsynaptic LHb neurons. This is the first study tocharacterize the functional connectivity and behavioral relevance of this circuit within the context offeeding and reward-related behavior.", "metadata": {}}
+{"_id": "23887844", "title": "", "text": "Glucose Metabolism Inhibits Apoptosis in Neurons and Cancer Cells by Redox Inactivation of CytochromecNeurons and cancer cells use glucose extensively, yet the precise advantage of this adaptation remainsunclear. These two seemingly disparate cell types also show an increased regulation of the apoptoticpathway, which allows for their long-term survival. Here we show that both neurons and cancer cellsstrictly inhibit cytochrome c-mediated apoptosis by a mechanism dependent on glucose metabolism. Wereport that the pro-apoptotic activity of cytochrome c is influenced by its redox state and that increases inreactive oxygen species (ROS) following an apoptotic insult lead to the oxidation and activation ofcytochrome c. In healthy neurons and cancer cells, however, cytochrome c is reduced and held inactiveby intracellular glutathione (GSH), generated as a result of glucose metabolism by the pentose phosphatepathway. These results uncover a striking similarity in apoptosis regulation between neurons and cancercells and provide insight into an adaptive advantage offered by the Warburg effect for cancer cell evasionof apoptosis and for long-term neuronal survival.", "metadata": {}}
+{"_id": "23895668", "title": "", "text": "mTORC2 Regulates Amino Acid Metabolism in Cancer by Phosphorylation of the Cystine-GlutamateAntiporter xCT.Mutations in cancer reprogram amino acid metabolism to drive tumor growth, but themolecular mechanisms are not well understood. Using an unbiased proteomic screen, we identifiedmTORC2 as a critical regulator of amino acid metabolism in cancer via phosphorylation of thecystine-glutamate antiporter xCT. mTORC2 phosphorylates serine 26 at the cytosolic N terminus of xCT,inhibiting its activity. Genetic inhibition of mTORC2, or pharmacologic inhibition of the mammalian targetof rapamycin (mTOR) kinase, promotes glutamate secretion, cystine uptake, and incorporation intoglutathione, linking growth factor receptor signaling with amino acid uptake and utilization. These resultsidentify an unanticipated mechanism regulating amino acid metabolism in cancer, enabling tumor cells toadapt to changing environmental conditions.", "metadata": {}}
+{"_id": "23897346", "title": "", "text": "Bayesian models leveraging bioactivity and cytotoxicity information for drug discovery.Identification ofunique leads represents a significant challenge in drug discovery. This hurdle is magnified in neglecteddiseases such as tuberculosis. We have leveraged public high-throughput screening (HTS) data toexperimentally validate a virtual screening approach employing Bayesian models built with bioactivityinformation (single-event model) as well as bioactivity and cytotoxicity information (dual-event model).We virtually screened a commercial library and experimentally confirmed actives with hit rates exceedingtypical HTS results by one to two orders of magnitude. This initial dual-event Bayesian model identifiedcompounds with antitubercular whole-cell activity and low mammalian cell cytotoxicity from a publishedset of antimalarials. The most potent hit exhibits the in vitro activity and in vitro/in vivo safety profile of adrug lead. These Bayesian models offer significant economies in time and cost to drug discovery.", "metadata": {}}
+{"_id": "23901235", "title": "", "text": "A role for interleukin-1β in determining the lineage fate of embryonic rat hippocampal neural precursorcells.Neurogenesis occurs in the hippocampus of the developing and adult brain due to the presence ofmultipotent stem cells and restricted precursor cells at different stages of differentiation. It has beenproposed that they may be of potential benefit for use in cell transplantation approaches forneurodegenerative disorders and trauma. Prolonged release of interleukin-1β (IL-1β) from activatedmicroglia has a deleterious effect on hippocampal neurons and is implicated in the impaired neurogenesisand cognitive dysfunction associated with aging, Alzheimer's disease and depression. This study assessedthe effect of IL-1β on the proliferation and differentiation of embryonic rat hippocampal NPCs in vitro. Weshow that IL-1R1 is expressed on proliferating NPCs and that IL-1β treatment decreases cell proliferationand neurosphere growth. When NPCs were differentiated in the presence of IL-1β, a significant reductionin the percentages of newly-born neurons and post-mitotic neurons and a significant increase in thepercentage of astrocytes was observed in these cultures. These effects were attenuated by IL-1 receptorantagonist. These data reveal that IL-1β exerts an anti-proliferative, anti-neurogenic and pro-gliogeniceffect on embryonic hippocampal NPCs, which is mediated by IL-1R1. The present results emphasise theconsequences of an inflammatory environment during NPC development, and indicate that strategies toinhibit IL-1β signalling may be necessary to facilitate effective cell transplantation approaches or inconditions where endogenous hippocampal neurogenesis is impaired.", "metadata": {}}
+{"_id": "23908217", "title": "", "text": "Bone disease in pediatric patients undergoing dialysis with CAPD or CCPD.The histologic features of renalosteodystrophy and the prevalence of bone aluminum deposition in children receiving regular dialysishave not been described. Forty-four pediatric patients undergoing continuous ambulatory (CAPD) orcycling (CCPD) peritoneal dialysis had bone biopsies and deferoxamine (DFO) infusion tests; all werereceiving oral calcitriol. Osteitis fibrosa (OF) was found in 39%, mild lesions (M) in 25%, normal histology(NH) in 16%, aplastic lesions (AP) in 11%, and osteomalacia (OM) in 9%. Bone surface aluminum (SA)was present by histochemical staining in 10 out of 20 given aluminum-containing phosphate-bindingagents and in 0 of 24 treated with calcium carbonate; chi 2 = 15.5, P less than 0.0001. Serumbiochemistries and DFO infusion tests failed to predict bone histology, but plasma aluminum levels weremarkedly elevated and bone aluminum content was highest in patients with OM. Bone formation rate(BFR) correlated with serum parathyroid hormone (PTH), r = 0.55, P less than 0.001; BFR was inverselyrelated to bone aluminum content (r = -0.42, P less than 0.01), even in patients with OF (r = -0.66, Pless than 0.05). All patients with SA greater than 30% had normal or reduced BFR when compared tothose with SA less than 30%; chi 2 = 12.2, P less than 0.005. Based on SA greater than 30%, sixpatients were classified as aluminum-related bone disease: three OM, one AP, and two NH. Two-thirds ofpediatric patients undergoing CAPD/CCPD have persistent hyperparathyroidism despite treatment withcalcitriol, but aluminum can adversely affect BFR when SA exceeds 30% regardless of histologic lesion orserum PTH level.", "metadata": {}}
+{"_id": "23912923", "title": "", "text": "Disruption of the immune-checkpoint VISTA gene imparts a proinflammatory phenotype withpredisposition to the development of autoimmunity.V domain-containing Ig suppressor of T-cell activation(VISTA) is a negative checkpoint regulator that suppresses T cell-mediated immune responses. Previousstudies using a VISTA-neutralizing monoclonal antibody show that VISTA blockade enhances T-cellactivation. The current study describes a comprehensive characterization of mice in which the gene forVISTA has been deleted. Despite the apparent normal hematopoietic development in young mice, VISTAgenetic deficiency leads to a gradual accumulation of spontaneously activated T cells, accompanied by theproduction of a spectrum of inflammatory cytokines and chemokines. Enhanced T-cell responsivenesswas also observed upon immunization with neoantigen. Despite the presence of multiorgan chronicinflammation, aged VISTA-deficient mice did not develop systemic or organ-specific autoimmune disease.Interbreeding of the VISTA-deficient mice with 2D2 T-cell receptor transgenic mice, which arepredisposed to the development of experimental autoimmune encephalomyelitis, drastically enhanceddisease incidence and intensity. Disease development is correlated with the increase in the activation ofencephalitogenic T cells in the periphery and enhanced infiltration into the CNS. Taken together, our datasuggest that VISTA is a negative checkpoint regulator whose loss of function lowers the threshold forT-cell activation, allowing for an enhanced proinflammatory phenotype and an increase in the frequencyand intensity of autoimmunity under susceptible conditions.", "metadata": {}}
+{"_id": "23913146", "title": "", "text": "Molecular mechanisms that funnel RNA precursors into endogenous small-interfering RNA and microRNAbiogenesis pathways in Drosophila.In Drosophila, three types of endogenous small RNAs-microRNAs(miRNAs), PIWI-interacting RNAs (piRNAs), and endogenous small-interfering RNAs (endo-siRNAs oresiRNAs)-function as triggers in RNA silencing. Although piRNAs are produced independently of Dicer,miRNA and esiRNA biogenesis pathways require Dicer1 and Dicer2, respectively. Recent studies haveshown that among the four isoforms of Loquacious (Loqs), Loqs-PB and Loqs-PD are involved in miRNAand esiRNA processing pathways, respectively. However, how these Loqs isoforms function in theirrespective small RNA biogenesis pathways remains elusive. Here, we show that Loqs-PD associatesspecifically with Dicer2 through its C-terminal domain. The Dicer2-Loqs-PD complex contains R2D2,another known Dicer2 partner, and excises both exogenous siRNAs and esiRNAs from their correspondingprecursors in vitro. However, Loqs-PD, but not R2D2, enhanced Dicer2 activity. The Dicer2-Loqs-PDcomplex processes esiRNA precursor hairpins with long stems, which results in the production ofAGO2-associated small RNAs. Interestingly, however, small RNAs derived from terminal hairpins ofesiRNA precursors are loaded onto AGO1; thus, they are classified as a new subset of miRNAs. Theseresults suggest that the precursor RNA structure determines the biogenesis mechanism of esiRNAs andmiRNAs, thereby implicating hairpin structures with long stems as intermediates in the evolution ofDrosophila miRNA.", "metadata": {}}
+{"_id": "23915841", "title": "", "text": "Neutralizing antibody responses in acute human immunodeficiency virus type 1 subtype C infection.Thestudy of the evolution and specificities of neutralizing antibodies during the course of humanimmunodeficiency virus type 1 (HIV-1) infection may be important in the discovery of possible targets forvaccine design. In this study, we assessed the autologous and heterologous neutralization responses of14 HIV-1 subtype C-infected individuals, using envelope clones obtained within the first 2 monthspostinfection. Our data show that potent but relatively strain-specific neutralizing antibodies developwithin 3 to 12 months of HIV-1 infection. The magnitude of this response was associated with shorterV1-to-V5 envelope lengths and fewer glycosylation sites, particularly in the V1-V2 region. Anti-MPERantibodies were detected in 4 of 14 individuals within a year of infection, while antibodies to CD4-induced(CD4i) epitopes developed to high titers in 12 participants, in most cases before the development ofautologous neutralizing antibodies. However, neither anti-MPER nor anti-CD4i antibody specificityconferred neutralization breadth. These data provide insights into the kinetics, potency, breadth, andepitope specificity of neutralizing antibody responses in acute HIV-1 subtype C infection.", "metadata": {}}
+{"_id": "23918031", "title": "", "text": "The cell cycle in polyploid megakaryocytes is associated with reduced activity of cyclin B1-dependent cdc2kinase.The platelet precursor, the megakaryocyte, matures to a polyploid cell as a result of DNAreplication in the absence of mitosis (endomitosis). The factors controlling endomitosis are accessible toanalysis in our megakaryocytic cell line, MegT, generated by targeted expression oftemperature-sensitive simian virus 40 large T antigen to megakaryocytes of transgenic mice. We aimedto define whether endomitosis consists of a continuous phase of DNA synthesis (S) or of S phasesinterrupted by gaps. Analysis of the cell cycle in MegT cells revealed that, upon inactivation of large Tantigen, the cells shifted from a mitotic cell cycle to an endomitotic cell cycle consisting of S/Gap phases.The level of the G1/S cyclin, cyclin A, as well as of the G1 phase cyclin, cyclin D3, were elevated at theonset of DNA synthesis, either in MegT cells undergoing a mitotic cell cycle or during endomitosis. Incontrast, the level of the mitotic cyclin, cyclin B1, cycled in cells displaying a mitotic cell cycle while notdetectable during endomitosis. Comparable levels of the mitotic kinase protein, Cdc2, were detectedduring the mitotic cell cycle or during endomitosis; however, cyclin B1-dependent Cdc2 kinase activitywas largely abolished in the polyploid cells. Fibroblasts immortalized with the same heat-labile oncogenedo not display reduced levels of cyclin B1 upon shifting to high temperature nor do they becomepolyploid, indicating that reduced levels of cyclin B1 is a property of megakaryocytes and not of theT-antigen mutant. We conclude that cellular programming during endoreduplication in megakaryocytes isassociated with reduced levels of cyclin B1.", "metadata": {}}
+{"_id": "23929297", "title": "", "text": "Ghrelin secretion stimulated by {beta}1-adrenergic receptors in cultured ghrelinoma cells and in fastedmice.Ghrelin, an octanoylated peptide hormone produced in the stomach, rises dramatically in mouseplasma during chronic severe calorie deprivation, an event that is essential to maintain life. Themechanism for this increase is not understood. Here, we study the control of ghrelin secretion in tissueculture cells derived from mice bearing ghrelinomas induced by a tissue-specific SV40 T-antigentransgene. We found that the ghrelin-secreting cells express high levels of mRNA encodingbeta(1)-adrenergic receptors. Addition of norepinephrine or epinephrine to the culture medium stimulatedghrelin secretion, and this effect was blocked by atenolol, a selective beta(1)-adrenergic antagonist.When WT mice were treated with reserpine to deplete adrenergic neurotransmitters from sympatheticneurons, the fasting-induced increase in plasma ghrelin was blocked. Inhibition was also seen followingatenolol administration. We conclude that ghrelin secretion during fasting is induced by adrenergic agentsreleased by sympathetic neurons and acting directly on beta(1) receptors on the ghrelin-secreting cells ofthe stomach.", "metadata": {}}
+{"_id": "23932173", "title": "", "text": "Dominance relationships between S-alleles in self-incompatible Brassica campestris L.Dominancerelationships were studied for 249 out of 276 possible pair-wise combinations between 24 S-alleles ofBrassica campestris that had been isolated from two natural populations from Turkey and Japan. Each F1hybrid was test-crossed reciprocally against its respective parental S-homozygotes to determine thedominance relationships between the pair of S-alleles it contained. The 24 S-alleles were classified intotwo groups on the stigma side and three groups on the pollen side. In the stigma, codominance occurredfrequently, and dominance or recessiveness seemed to appear according to the combination of S-alleles.In the pollen, codominance was less frequent, and there seemed to be a certain hierarchy of thedominance relationships as a whole, although dominance appeared with certain specific combinations ofS-alleles. Interactions among 24 S-alleles were different in the stigma and in the pollen. Independentweakening of S-alleles was found between 20 pairs in the pollen, but only two in the stigma. Thisinteraction seems to be correlated with recessiveness of S-alleles.", "metadata": {}}
+{"_id": "23934390", "title": "", "text": "MicroRNA-203 inhibits cellular proliferation and invasion by targeting Bmi1 in non-small cell lungcancer.MicroRNAs are proposed to serve vital functions in the regulation of tumor progression andinvasion. However, the expression levels of miR-203 in non-small cell lung cancer (NSCLC) and its clinicalsignificance remain unknown. In the present study, the association between B-cell-specific moloneymurine leukemia virus insertion site 1 (Bmi1) and miR-203 was investigated. miR-203 was demonstratedto act as a tumor suppressor by regulating the expression of Bmi1. miR-203 expression levels weredownregulated in NSCLC tissues while Bmi1 expression was upregulated in NSCLC tissues and cell lines.Furthermore, downregulated Bmi1 or enhanced miR-203 expression inhibited NSCLC cell proliferation andinvasion in vitro. In addition, a dual-luciferase reporter assay was performed, which identified Bmi1 as anovel target of miR-203. In conclusion, the present study demonstrated that miR-203 functions as atumor suppressor and is important in inhibiting the proliferation of NSCLC cells through targeting Bmi1.These findings indicate that miR-203 may be useful as a novel potential therapeutic target for NSCLC.", "metadata": {}}
+{"_id": "23938319", "title": "", "text": "Characterization of the interaction between retinoic acid receptor/retinoid X receptor (RAR/RXR)heterodimers and transcriptional coactivators through structural and fluorescence anisotropystudies.Retinoid receptors (RARs and RXRs) are ligand-activated transcription factors that regulate thetranscription of target genes by recruiting coregulator complexes at cognate promoters. To understandthe effects of heterodimerization and ligand binding on coactivator recruitment, we solved the crystalstructure of the complex between the RARbeta/RXRalpha ligand-binding domain heterodimer, its 9-cisretinoic acid ligand, and an LXXLL-containing peptide (termed NR box 2) derived from the nuclearreceptor interaction domain (NID) of the TRAP220 coactivator. In parallel, we measured the bindingaffinities of the isolated NR box 2 peptide or the full-length NID of the coactivator SRC-1 for retinoidreceptors in the presence of various types of ligands. Our correlative analysis of three-dimensionalstructures and fluorescence data reveals that heterodimerization does not significantly alter the structureof individual subunits or their intrinsic capacity to interact with NR box 2. Similarly, we show that theability of a protomer to recruit NR box 2 does not vary as a function of the ligand binding status of thepartner receptor. In contrast, the strength of the overall association between the heterodimer and thefull-length SRC-1 NID is dictated by the combinatorial action of RAR and RXR ligands, the simultaneouspresence of the two receptor agonists being required for highest binding affinity. We identified an LXXLLpeptide-driven mechanism by which the concerted reorientation of three phenylalanine side chainsgenerates an \"aromatic clamp\" that locks the RXR activation helix H12 in the transcriptionally activeconformation. Finally, we show how variations of helix H11-ligand interactions can alter thecommunication pathway linking helices H11, H12, and the connecting loop L11-12 to thecoactivator-binding site. Together, our results reveal molecular and structural features that impact on theligand-dependent interaction of the RAR/RXR heterodimer with nuclear receptor coactivators.", "metadata": {}}
+{"_id": "23959496", "title": "", "text": "PRC2 complexes with JARID2, MTF2, and esPRC2p48 in ES cells to modulate ES cell pluripotency andsomatic cell reprogramming.Polycomb repressive complex two (PRC2) has been implicated in embryonicstem (ES) cell pluripotency; however, the mechanistic roles of this complex are unclear. It was assumedthat ES cells contain PRC2 with the same subunit composition as that identified in HeLa cells andDrosophila embryos. Here, we report that PRC2 in mouse ES cells contains at least three additionalsubunits: JARID2, MTF2, and a novel protein denoted esPRC2p48. JARID2, MTF2, and esPRC2p48 arehighly expressed in mouse ES cells compared to differentiated cells. Importantly, knockdowns of JARID2,MTF2, or esPRC2p48 alter the level of PRC2-mediated H3K27 methylation and result in the expression ofdifferentiation-associated genes in ES cells. Interestingly, expression of JARID2, MTF2, and esPRC2p48together, but not individually, enhances Oct4/Sox2/Klf4-mediated reprogramming of mouse embryonicfibroblasts (MEFs) into induced pluripotent stem cells, whereas knockdown or knockout of JARID2, MTF2,or esPRC2p48 significantly inhibits reprogramming. JARID2, MTF2, and esPRC2p48 modulate H3K27methylation and facilitate repression of lineage-associated gene expression when transduced into MEFs,and synergistically stimulate the histone methyltransferase activity of PRC2 in vitro. Therefore, thesestudies identify JARID2, MTF2, and esPRC2p48 as important regulatory subunits of PRC2 in ES cells andreveal critical functions of these subunits in modulating PRC2's activity and gene expression both in EScells and during somatic cell reprogramming.", "metadata": {}}
+{"_id": "23967973", "title": "", "text": "General and abdominal adiposity and risk of death in Europe.BACKGROUND Previous studies have reliedpredominantly on the body-mass index (BMI, the weight in kilograms divided by the square of the heightin meters) to assess the association of adiposity with the risk of death, but few have examined whetherthe distribution of body fat contributes to the prediction of death. METHODS We examined the associationof BMI, waist circumference, and waist-to-hip ratio with the risk of death among 359,387 participantsfrom nine countries in the European Prospective Investigation into Cancer and Nutrition (EPIC). We useda Cox regression analysis, with age as the time variable, and stratified the models according to studycenter and age at recruitment, with further adjustment for educational level, smoking status, alcoholconsumption, physical activity, and height. RESULTS During a mean follow-up of 9.7 years, 14,723participants died. The lowest risks of death related to BMI were observed at a BMI of 25.3 for men and24.3 for women. After adjustment for BMI, waist circumference and waist-to-hip ratio were stronglyassociated with the risk of death. Relative risks among men and women in the highest quintile of waistcircumference were 2.05 (95% confidence interval [CI], 1.80 to 2.33) and 1.78 (95% CI, 1.56 to 2.04),respectively, and in the highest quintile of waist-to-hip ratio, the relative risks were 1.68 (95% CI, 1.53to 1.84) and 1.51 (95% CI, 1.37 to 1.66), respectively. BMI remained significantly associated with therisk of death in models that included waist circumference or waist-to-hip ratio (P<0.001). CONCLUSIONSThese data suggest that both general adiposity and abdominal adiposity are associated with the risk ofdeath and support the use of waist circumference or waist-to-hip ratio in addition to BMI in assessing therisk of death.", "metadata": {}}
+{"_id": "23972114", "title": "", "text": "Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth.Selective autophagycan be mediated via receptor molecules that link specific cargoes to the autophagosomal membranesdecorated by ubiquitin-like microtubule-associated protein light chain 3 (LC3) modifiers. Although severalautophagy receptors have been identified, little is known about mechanisms controlling their functions invivo. In this work, we found that phosphorylation of an autophagy receptor, optineurin, promotedselective autophagy of ubiquitin-coated cytosolic Salmonella enterica. The protein kinase TANK bindingkinase 1 (TBK1) phosphorylated optineurin on serine-177, enhancing LC3 binding affinity and autophagicclearance of cytosolic Salmonella. Conversely, ubiquitin- or LC3-binding optineurin mutants and silencingof optineurin or TBK1 impaired Salmonella autophagy, resulting in increased intracellular bacterialproliferation. We propose that phosphorylation of autophagy receptors might be a general mechanism forregulation of cargo-selective autophagy.", "metadata": {}}
+{"_id": "23974474", "title": "", "text": "PKD1 Inhibits AMPKα2 through Phosphorylation of Serine 491 and Impairs Insulin Signaling in SkeletalMuscle Cells.AMP-activated protein kinase (AMPK) is an energy-sensing enzyme whose activity isinhibited in settings of insulin resistance. Exposure to a high glucose concentration has recently beenshown to increase phosphorylation of AMPK at Ser(485/491) of its α1/α2 subunit; however, themechanism by which it does so is not known. Diacylglycerol (DAG), which is also increased in muscleexposed to high glucose, activates a number of signaling molecules including protein kinase (PK)C andPKD1. We sought to determine whether PKC or PKD1 is involved in inhibition of AMPK by causingSer(485/491) phosphorylation in skeletal muscle cells. C2C12 myotubes were treated with the PKC/D1activator phorbol 12-myristate 13-acetate (PMA), which acts as a DAG mimetic. This caused dose- andtime-dependent increases in AMPK Ser(485/491) phosphorylation, which was associated with a \u000060%decrease in AMPKα2 activity. Expression of a phosphodefective AMPKα2 mutant (S491A) prevented thePMA-induced reduction in AMPK activity. Serine phosphorylation and inhibition of AMPK activity werepartially prevented by the broad PKC inhibitor Gö6983 and fully prevented by the specific PKD1 inhibitorCRT0066101. Genetic knockdown of PKD1 also prevented Ser(485/491) phosphorylation of AMPK.Inhibition of previously identified kinases that phosphorylate AMPK at this site (Akt, S6K, and ERK) didnot prevent these events. PMA treatment also caused impairments in insulin-signaling through Akt, whichwere prevented by PKD1 inhibition. Finally, recombinant PKD1 phosphorylated AMPKα2 at Ser(491) incell-free conditions. These results identify PKD1 as a novel upstream kinase of AMPKα2 Ser(491) thatplays a negative role in insulin signaling in muscle cells.", "metadata": {}}
+{"_id": "23983289", "title": "", "text": "Accuracy of ICD-9-CM codes for identifying cardiovascular and stroke risk factors.OBJECTIVES We soughtto determine which ICD-9-CM codes in Medicare Part A data identify cardiovascular and stroke riskfactors. DESIGN AND PARTICIPANTS This was a cross-sectional study comparing ICD-9-CM data tostructured medical record review from 23,657 Medicare beneficiaries aged 20 to 105 years who had atrialfibrillation. MEASUREMENTS Quality improvement organizations used standardized abstractioninstruments to determine the presence of 9 cardiovascular and stroke risk factors. Using the chartabstractions as the gold standard, we assessed the accuracy of ICD-9-CM codes to identify these riskfactors. MAIN RESULTS ICD-9-CM codes for all risk factors had high specificity (>0.95) and low sensitivity(< or =0.76). The positive predictive values were greater than 0.95 for 5 common, chronic riskfactors-coronary artery disease, stroke/transient ischemic attack, heart failure, diabetes, andhypertension. The sixth common risk factor, valvular heart disease, had a positive predictive value of0.93. For all 6 common risk factors, negative predictive values ranged from 0.52 to 0.91. The rare riskfactors-arterial peripheral embolus, intracranial hemorrhage, and deep venous thrombosis-had highnegative predictive value (> or =0.98) but moderate positive predictive values (range, 0.54-0.77) in thispopulation. CONCLUSIONS Using ICD-9-CM codes alone, heart failure, coronary artery disease, diabetes,hypertension, and stroke can be ruled in but not necessarily ruled out. Where feasible, review ofadditional data (eg, physician notes or imaging studies) should be used to confirm the diagnosis ofvalvular disease, arterial peripheral embolus, intracranial hemorrhage, and deep venous thrombosis.", "metadata": {}}
+{"_id": "23985464", "title": "", "text": "Modulation of cellular and viral promoters by mutant human p53 proteins found in tumor cells.Wild-typep53 has recently been shown to repress transcription from several cellular and viral promoters. Since p53mutations are the most frequently reported genetic defects in human cancers, it becomes important tostudy the effects of mutations of p53 on promoter functions. We, therefore, have studied the effects ofwild-type and mutant human p53 on the human proliferating-cell nuclear antigen (PCNA) promoter andon several viral promoters, including the herpes simplex virus type 1 UL9 promoter, the humancytomegalovirus major immediate-early promoter-enhancer, and the long terminal repeat promoters ofRous sarcoma virus and human T-cell lymphotropic virus type I. HeLa cells were cotransfected with awild-type or mutant p53 expression vector and a plasmid containing a chloramphenicol acetyltransferasereporter gene under viral (or cellular) promoter control. As expected, expression of the wild-type p53inhibited promoter function. Expression of a p53 with a mutation at any one of the four amino acidpositions 175, 248, 273, or 281, however, correlated with a significant increase of the PCNA promoteractivity (2- to 11-fold). The viral promoters were also activated, although to a somewhat lesser extent.We also showed that activation by a mutant p53 requires a minimal promoter containing a lone TATAbox. A more significant increase (25-fold) in activation occurs when the promoter contains a binding sitefor the activating transcription factor or cyclic AMP response element-binding protein. Using Saos-2 cellsthat do not express p53, we showed that activation by a mutant p53 was a direct enhancement. Themutant forms of p53 used in this study are found in various cancer cells. The activation of PCNA bymutant p53s may indicate a way to increase cell proliferation by the mutant p53s. Thus, our data indicatea possible functional role for the mutants of p53 found in cancer cells in activating several important loci,including PCNA.", "metadata": {}}
+{"_id": "24003461", "title": "", "text": "Valvular interstitial cells suppress calcification of valvular endothelial cells.BACKGROUND Calcific aorticvalve disease (CAVD) is the most common heart valve disease in the Western world. We previouslyproposed that valvular endothelial cells (VECs) replenish injured adult valve leaflets viaendothelial-to-mesenchymal transformation (EndMT); however, whether EndMT contributes to valvularcalcification is unknown. We hypothesized that aortic VECs undergo osteogenic differentiation via anEndMT process that can be inhibited by valvular interstitial cells (VICs). APPROACH AND RESULTS VECclones underwent TGF-β1-mediated EndMT, shown by significantly increased mRNA expression of theEndMT markers α-SMA (5.3 ± 1.2), MMP-2 (13.5 ± 0.6) and Slug (12 ± 2.1) (p < 0.05), (compared tounstimulated controls). To study the effects of VIC on VEC EndMT, clonal populations of VICs werederived from the same valve leaflets, placed in co-culture with VECs, and grown in control/TGF-β1supplemented media. In the presence of VICs, EndMT was inhibited, shown by decreased mRNAexpression of α-SMA (0.1 ± 0.5), MMP-2 (0.1 ± 0.1), and Slug (0.2 ± 0.2) (p < 0.05). When cultured inosteogenic media, VECs demonstrated osteogenic changes confirmed by increase in mRNA expression ofosteocalcin (8.6 ± 1.3), osteopontin (3.7 ± 0.3), and Runx2 (5.5 ± 1.5). The VIC presence inhibited VECosteogenesis, demonstrated by decreased expression of osteocalcin (0.4 ± 0.1) and osteopontin (0.2 ±0.1) (p < 0.05). Time course analysis suggested that EndMT precedes osteogenesis, shown by an initialincrease of α-SMA and MMP-2 (day 7), followed by an increase of osteopontin and osteocalcin (day 14).CONCLUSIONS The data indicate that EndMT may precede VEC osteogenesis. This study shows that VICsinhibit VEC EndMT and osteogenesis, indicating the importance of VEC-VIC interactions in valvehomeostasis.", "metadata": {}}
+{"_id": "24005548", "title": "", "text": "The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesisin normocholesterolemic animals.Recent studies suggest that statins can function to protect thevasculature in a manner that is independent of their lipid-lowering activity. We show here that statinsrapidly activate the protein kinase Akt/PKB in endothelial cells. Accordingly, simvastatin enhancedphosphorylation of the endogenous Akt substrate endothelial nitric oxide synthase (eNOS), inhibitedapoptosis and accelerated vascular structure formation in vitro in an Akt-dependent manner. Similar tovascular endothelial growth factor (VEGF) treatment, both simvastatin administration and enhanced Aktsignaling in the endothelium promoted angiogenesis in ischemic limbs of normocholesterolemic rabbits.Therefore, activation of Akt represents a mechanism that can account for some of the beneficial sideeffects of statins, including the promotion of new blood vessel growth.", "metadata": {}}
+{"_id": "24019260", "title": "", "text": "Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, selectively decreases ethanolconsumption and seeking.Alcohol dependence is a disease that impacts millions of individuals worldwide.There has been some progress with pharmacotherapy for alcohol-dependent individuals; however, thereremains a critical need for the development of novel and additional therapeutic approaches. Alcohol andnicotine are commonly abused together, and there is evidence that neuronal nicotinic acetylcholinereceptors (nAChRs) play a role in both alcohol and nicotine dependence. Varenicline, a partial agonist atthe alpha4beta2 nAChRs, reduces nicotine intake and was recently approved as a smoking cessation aid.We have investigated the role of varenicline in the modulation of ethanol consumption and seeking usingthree different animal models of drinking. We show that acute administration of varenicline, in dosesreported to reduce nicotine reward, selectively reduced ethanol but not sucrose seeking using an operantself-administration drinking paradigm and also decreased voluntary ethanol but not water consumption inanimals chronically exposed to ethanol for 2 months before varenicline treatment. Furthermore, chronicvarenicline administration decreased ethanol consumption, which did not result in a rebound increase inethanol intake when the varenicline was no longer administered. The data suggest that the alpha4beta2nAChRs may play a role in ethanol-seeking behaviors in animals chronically exposed to ethanol. Theselectivity of varenicline in decreasing ethanol consumption combined with its reported safety profile andmild side effects in humans suggest that varenicline may prove to be a treatment for alcohol dependence.", "metadata": {}}
+{"_id": "24042363", "title": "", "text": "Targeting TLR4 signaling by TLR4 Toll/IL-1 receptor domain-derived decoy peptides: identification of theTLR4 Toll/IL-1 receptor domain dimerization interface.Agonist-induced dimerization of TLR4 Toll/IL-1R(TIR) domains initiates intracellular signaling. Therefore, identification of the TLR4-TIR dimerizationinterface is one key to the rational design of therapeutics that block TLR4 signaling. A library ofcell-permeating decoy peptides, each of which represents a nonfragmented patch of the TLR4 TIRsurface, was designed such that the peptides entirely encompass the TLR4 TIR surface. Each peptide wassynthesized in tandem with a cell-permeating Antennapedia homeodomain sequence and tested for theability to inhibit early cytokine mRNA expression and MAPK activation in LPS-stimulated primary murinemacrophages. Five peptides--4R1, 4R3, 4BB, 4R9, and 4αE--potently inhibited all manifestations of TLR4,but not TLR2 signaling. When tested for their ability to bind directly to TLR4 TIR by Förster resonanceenergy transfer using time-resolved fluorescence spectroscopy, Bodipy-TMR-X-labeled 4R1, 4BB, and 4αEquenched fluorescence of TLR4-Cerulean expressed in HeLa or HEK293T cells, whereas 4R3 was partiallyactive, and 4R9 was least active. These findings suggest that the area between the BB loop of TLR4 andits fifth helical region mediates TLR4 TIR dimerization. Moreover, our data provide direct evidence for theutility of the decoy peptide approach, in which peptides representing various surface-exposed segmentsof a protein are initially probed for the ability to inhibit protein function, and then their specific targets areidentified by Förster resonance energy transfer to define recognition sites in signaling proteins that maybe targeted therapeutically to disrupt functional transient protein interactions.", "metadata": {}}
+{"_id": "24042919", "title": "", "text": "A paediatric case of sideroblastic anaemia. Ultrastructural studies of erythroblasts cultured from marrowBFU-E in a methylcellulose micromethod.We examined the morphological and functional characteristics oferythroblasts derived from marrow erythroid progenitor cells grown in a methylcellulose microculture,which were taken from a female child with rare atypical sideroblastic anaemia (SA) partially responsive topyridoxine. Colony formation was within the normal range in three successive cultures (median values:82.25 CFU-E and 16.4 BFU-E derived colonies/6.6 X 10(4) cells) compared to growth by normal cells(65-315 CFU-E and 9-40 BFU-E). We evaluated in vitro differentiation by biochemical microassay of acytosol enzyme involved in the haem pathway: uroporphyrinogen I synthase (UROS). The UROS values inthe erythroid colonies from SA marrow were at the lowere end of the normal range (median values: 6.7+/- 0.3 and 14.4 +/- 3.8 pmol uroporphyrinogen/h in CFU-E and BFU-E-derived colonies respectivelyversus 17.4 +/- 7.3 and 25 +/- 7.2 pmol/h in CFU-E and BFU-E colonies from normal subjects.Ultrastructural examination of the SA erythroblasts from non-cultured bone marrow or derived fromcultured BFU-E revealed the characteristic deposition of iron in mitochondria around the nucleus of mostcells (ringed sideroblasts). However, the majority of cultured cells had marked dyserythropoietic features,with a large number of bilobulated or trilobulated erythroblasts, multiple cytoplasmic vacuoles, numerousabnormalities of the nucleus, and excessive membrane material beneath the plasma membrane, allfeatures difficult to observe in non-cultured marrows.", "metadata": {}}
+{"_id": "24044977", "title": "", "text": "Innate lymphoid cells: emerging insights in development, lineage relationships, and function.Innatelymphoid cells (ILCs) are immune cells that lack a specific antigen receptor yet can produce an array ofeffector cytokines that in variety match that of T helper cell subsets. ILCs function in lymphoidorganogenesis, tissue remodeling, antimicrobial immunity, and inflammation, particularly at barriersurfaces. Their ability to promptly respond to insults inflicted by stress-causing microbes stronglysuggests that ILCs are critical in first-line immunological defenses. Here, we review current data ondevelopmental requirements, lineage relationships, and effector functions of two families of ILCs: (a)Rorγt-expressing cells involved in lymphoid tissue formation, mucosal immunity, and inflammation and(b) type 2 ILCs that are important for helminth immunity. We also discuss the potential roles of ILCs inthe pathology of immune-mediated inflammatory and infectious diseases including allergy.", "metadata": {}}
+{"_id": "24049225", "title": "", "text": "No net renal extraction of homocysteine in fasting humans.BACKGROUND The pathophysiologicalmechanism of hyperhomocysteinemia in chronic renal failure in humans is unknown. The loss of aputative renal homocysteine extraction in chronic renal failure has been hypothesized as significanthomocysteine uptake has been demonstrated in the normal rat kidney. We studied homocysteineextraction in the normal human kidney. METHODS We measured plasma total (free and protein-bound)and free homocysteine (tHcy and fHcy, respectively) in arterial and renal venous blood sampled from theaorta and right-side renal vein during cardiac catheterization in 20 fasting patients with normal renalfunction. Renal homocysteine extraction was calculated as the arteriovenous difference divided by thearterial levels times 100%. RESULTS No significant renal extraction was demonstrated either for tHcy:0.9% (SD 5.8; 95% CI -1.8 to +3.6) or for fHcy: -0.2% (11.0; -5.4 to +4.9). CONCLUSIONS Weconclude that no significant net renal uptake of homocysteine occurs in fasting humans with normal renalfunction. The loss of such uptake, therefore, cannot cause hyperhomocysteinemia in patients with renalfailure.", "metadata": {}}
+{"_id": "24055603", "title": "", "text": "Traditional Chinese acupuncture in tension-type headache: a controlled study.Thirty patients withtension-type headache were randomly chosen to undergo a trial of traditional Chinese acupuncture andsham acupuncture. Five measures were used to assess symptom severity and treatment response:intensity, duration and frequency of headache pain episodes, headache index and analgesic intake. Thefive measures were assessed during a 4 week baseline period, after 4 and 8 weeks of treatment, and 1, 6and 12 months thereafter. Before the start of the study, each patient was administered the MMPI.Split-plot ANOVAs showed that, compared to baseline, at 1 month after the end of treatment and for the12 month follow-up, the frequency of headache episodes, analgesic consumption and the headache index(but not the duration or intensity of headache episodes) significantly decreased over time; however, nodifference between acupuncture and placebo treatment was found. No single MMPI scale predicted theresponse to treatment, but the mean MMPI profile of acupuncture non-responders showed the presenceof 'Conversion V'.", "metadata": {}}
+{"_id": "24069089", "title": "", "text": "TCR stimulation with modified anti-CD3 mAb expands CD8+ T cell population and induces CD8+CD25+Tregs.Modified anti-CD3 mAbs are emerging as a possible means of inducing immunologic tolerance insettings including transplantation and autoimmunity such as in type 1 diabetes. In a trial of a modifiedanti-CD3 mAb [hOKT3gamma1(Ala-Ala)] in patients with type 1 diabetes, we identified clinicalresponders by an increase in the number of peripheral blood CD8+ cells following treatment with themAb. Here we show that the anti-CD3 mAb caused activation of CD8+ T cells that was similar in vitro andin vivo and induced regulatory CD8+CD25+ T cells. These cells inhibited the responses of CD4+ cells tothe mAb itself and to antigen. The regulatory CD8+CD25+ cells were CTLA4 and Foxp3 and requiredcontact for inhibition. Foxp3 was also induced on CD8+ T cells in patients during mAb treatment, whichsuggests a potential mechanism of the anti-CD3 mAb immune modulatory effects involving induction of asubset of regulatory CD8+ T cells.", "metadata": {}}
+{"_id": "24077493", "title": "", "text": "Interactions between Non-Physician Clinicians and Industry: A Systematic ReviewBACKGROUND Withincreasing restrictions placed on physician-industry interactions, industry marketing may target otherhealth professionals. Recent health policy developments confer even greater importance on the decisionmaking of non-physician clinicians. The purpose of this systematic review is to examine the types andimplications of non-physician clinician-industry interactions in clinical practice. METHODS AND FINDINGSWe searched MEDLINE and Web of Science from January 1, 1946, through June 24, 2013, according toPRISMA guidelines. Non-physician clinicians eligible for inclusion were: Registered Nurses, nurseprescribers, Physician Assistants, pharmacists, dieticians, and physical or occupational therapists; traineesamples were excluded. Fifteen studies met inclusion criteria. Data were synthesized qualitatively intoeight outcome domains: nature and frequency of industry interactions; attitudes toward industry;perceived ethical acceptability of interactions; perceived marketing influence; perceived reliability ofindustry information; preparation for industry interactions; reactions to industry relations policy; andmanagement of industry interactions. Non-physician clinicians reported interacting with thepharmaceutical and infant formula industries. Clinicians across disciplines met with pharmaceuticalrepresentatives regularly and relied on them for practice information. Clinicians frequently receivedindustry \"information,\" attended sponsored \"education,\" and acted as distributors for similar materialstargeted at patients. Clinicians generally regarded this as an ethical use of industry resources, and feltthey could detect \"promotion\" while benefiting from industry \"information. \" Free samples were amongthe most approved and common ways that clinicians interacted with industry. Included studies wereobservational and of varying methodological rigor; thus, these findings may not be generalizable. Thisreview is, however, the first to our knowledge to provide a descriptive analysis of this literature.CONCLUSIONS Non-physician clinicians' generally positive attitudes toward industry interactions, despitetheir recognition of issues related to bias, suggest that industry interactions are normalized in clinicalpractice across non-physician disciplines. Industry relations policy should address all disciplines and beimplemented consistently in order to mitigate conflicts of interest and address such interactions' potentialto affect patient care. Please see later in the article for the Editors' Summary.", "metadata": {}}
+{"_id": "24082820", "title": "", "text": "Emtricitabine-tenofovir concentrations and pre-exposure prophylaxis efficacy in men who have sex withmen.Drug concentrations associated with protection from HIV-1 acquisition have not been determined.We evaluated drug concentrations among men who have sex with men in a substudy of the iPrEx trial(1). In this randomized placebo-controlled trial, daily oral doses of emtricitabine/tenofovir disoproxilfumarate were used as pre-exposure prophylaxis (PrEP) in men who have sex with men. Drug wasdetected less frequently in blood plasma and in viable cryopreserved peripheral blood mononuclear cells(PBMCs) in HIV-infected cases at the visit when HIV was first discovered compared with controls at thematched time point of the study (8% versus 44%; P < 0.001) and in the 90 days before that visit (11%versus 51%; P < 0.001). An intracellular concentration of the active form of tenofovir,tenofovir-diphosphate (TFV-DP), of 16 fmol per million PBMCs was associated with a 90% reduction inHIV acquisition relative to the placebo arm. Directly observed dosing in a separate study, the STRANDtrial, yielded TFV-DP concentrations that, when analyzed according to the iPrEx model, corresponded toan HIV-1 risk reduction of 76% for two doses per week, 96% for four doses per week, and 99% for sevendoses per week. Prophylactic benefits were observed over a range of doses and drug concentrations,suggesting ways to optimize PrEP regimens for this population.", "metadata": {}}
+{"_id": "24088502", "title": "", "text": "Clinical outcomes following institution of the Canadian universal leukoreduction program for red blood celltransfusions.CONTEXT A number of countries have implemented a policy of universal leukoreduction oftheir blood supply, but the potential role of leukoreduction in decreasing postoperative mortality andinfection is unclear. OBJECTIVE To evaluate clinical outcomes following adoption of a national universalprestorage leukoreduction program for blood transfusions. DESIGN, SETTING, AND POPULATIONRetrospective before-and-after cohort study conducted from August 1998 to August 2000 in 23 academicand community hospitals throughout Canada, enrolling 14 786 patients who received red blood celltransfusions following cardiac surgery or repair of hip fracture, or who required intensive care following asurgical intervention or multiple trauma. INTERVENTION Universal prestorage leukoreduction programintroduced by 2 Canadian blood agencies. A total of 6982 patients were enrolled during the control periodand 7804 patients were enrolled following prestorage leukoreduction. MAIN OUTCOME MEASURESAll-cause in-hospital mortality and serious nosocomial infections (pneumonia, bacteremia, septic shock,all surgical site infections) occurring after first transfusion and at least 2 days after index procedure orintensive care unit admission. Secondary outcomes included rates of posttransfusion fever and antibioticuse. RESULTS Unadjusted in-hospital mortality rates were significantly lower following the introduction ofleukoreduction compared with the control period (6.19% vs 7.03%, respectively; P =.04). Compared withthe control period, the adjusted odds of death following leukoreduction were reduced (odds ratio [OR],0.87; 95% confidence interval [CI], 0.75-0.99), but serious nosocomial infections did not decrease(adjusted OR, 0.97; 95% CI, 0.87-1.09). The frequency of posttransfusion fevers decreased significantlyfollowing leukoreduction (adjusted OR, 0.86; 95% CI, 0.79-0.94), as did antibiotic use (adjusted OR,0.90; 95% CI, 0.82-0.99). CONCLUSION A national universal leukoreduction program is potentiallyassociated with decreased mortality as well as decreased fever episodes and antibiotic use after red bloodcell transfusion in high-risk patients.", "metadata": {}}
+{"_id": "24097933", "title": "", "text": "Failure of continuous venovenous hemofiltration to prevent death in paraquat poisoning.Paraquatpoisoning is characterized by multiorgan failure and pulmonary fibrosis with respiratory failure.Multiorgan failure with circulatory collapse is a major cause of early death within 3 days of paraquatingestion. Recent studies suggested that continuous venovenous hemofiltration (CVVH) had a role in thetreatment of multiorgan failure by promoting hemodynamic stability. We therefore evaluated the effect ofprophylactic CVVH in 80 patients with paraquat poisoning (August 1996 to February 1999). The amountingested was 2.1 +/- 1.0 mouthfuls (as 20% concentrate). All patients were treated with hemoperfusion(HP; duration, 6.4 +/- 3.0 hours) within 24 hours of ingestion and then randomly assigned to theHP-alone or HP-CVVH group. Forty-four patients underwent HP only, and 36 patients underwent CVVH(duration, 57.4 +/- 31.3 hours; ultrafiltration volume, 40.2 +/- 4.8 L/d) after HP. Although time to deathafter ingestion was significantly longer in the HP-CVVH than HP group (5.0 +/- 5.0 versus 2.5 +/- 2.1days; P < 0.05), there was no difference in mortality rates between the two groups (66.7% versus63.6%; P = 0.82). In the HP group, early circulatory collapse was a major cause of death compared withthe HP-CVVH group, in which late respiratory failure was a major cause of death. In conclusion,prophylactic CVVH after HP prevented early death caused by circulatory collapse and prolonged survivaltime. However, it could not prevent late death caused by respiratory failure and did not provide a survivalbenefit in acute paraquat poisoning.", "metadata": {}}
+{"_id": "24101431", "title": "", "text": "The antidiabetic effect of mesenchymal stem cells is unrelated to their transdifferentiation potential but totheir capability to restore Th1/Th2 balance and to modify the pancreatic microenvironment.Type 1diabetes mellitus (T1DM) is a chronic metabolic disease that results from cell-mediated autoimmunedestruction of insulin-producing cells. In T1DM animal models, it has been shown that the systemicadministration of multipotent mesenchymal stromal cells, also referred as to mesenchymal stem cells(MSCs), results in the regeneration of pancreatic islets. Mechanisms underlying this effect are still poorlyunderstood. Our aims were to assess whether donor MSCs (a) differentiate into pancreatic β-cells and (b)modify systemic and pancreatic pathophysiologic markers of T1DM. After the intravenous administrationof 5 × 10(5) syngeneic MSCs, we observed that mice with T1DM reverted their hyperglycemia andpresented no donor-derived insulin-producing cells. In contrast, 7 and 65 days post-transplantation,MSCs were engrafted into secondary lymphoid organs. This correlated with a systemic and local reductionin the abundance of autoaggressive T cells together with an increase in regulatory T cells. Additionally, inthe pancreas of mice with T1DM treated with MSCs, we observed a cytokine profile shift fromproinflammatory to antinflammatory. MSC transplantation did not reduce pancreatic cell apoptosis butrecovered local expression and increased the circulating levels of epidermal growth factor, a pancreatictrophic factor. Therefore, the antidiabetic effect of MSCs intravenously administered is unrelated to theirtransdifferentiation potential but to their capability to restore the balance between Th1 and Th2immunological responses along with the modification of the pancreatic microenvironment. Our datashould be taken into account when designing clinical trials aimed to evaluate MSC transplantation inpatients with T1DM since the presence of endogenous precursors seems to be critical in order to restoreglycemic control.", "metadata": {}}
+{"_id": "24142891", "title": "", "text": "Tmem27: a cleaved and shed plasma membrane protein that stimulates pancreatic beta cellproliferation.The signals and molecular mechanisms that regulate the replication of terminallydifferentiated beta cells are unknown. Here, we report the identification and characterization oftransmembrane protein 27 (Tmem27, collectrin) in pancreatic beta cells. Expression of Tmem27 isreduced in Tcf1(-/-) mice and is increased in islets of mouse models with hypertrophy of the endocrinepancreas. Tmem27 forms dimers and its extracellular domain is glycosylated, cleaved and shed from theplasma membrane of beta cells. This cleavage process is beta cell specific and does not occur in other celltypes. Overexpression of full-length Tmem27, but not the truncated or soluble protein, leads to increasedthymidine incorporation, whereas silencing of Tmem27 using RNAi results in a reduction of cellreplication. Furthermore, transgenic mice with increased expression of Tmem27 in pancreatic beta cellsexhibit increased beta cell mass. Our results identify a pancreatic beta cell transmembrane protein thatregulates cell growth of pancreatic islets.", "metadata": {}}
+{"_id": "24144677", "title": "", "text": "The ATM missense mutation p.Ser49Cys (c.146C>G) and the risk of breast cancer.Homozygous mutationin the ATM gene causes ataxia telangiectasia and heterozygous mutation carriers may be at increasedrisk of breast cancer. We studied a total of 22 ATM variants; 18 variants were analyzed in one of twolarge population-based studies from the U.S. and Poland, and four variants were analyzed in all 2,856breast cancer cases and 3,344 controls from the two studies. The missense mutation Ser49Cys(c.146C>G, p. S49C), carried by approximately 2% of subjects, was more common in cases than controlsin both study populations, combined odds ratio (OR) 1.69 (95% CI, 1.19-2.40; P=0.004). Anothermissense mutation at approximately 2% frequency, Phe858Leu (c.2572T>C, p. F858L), was associatedwith a significant increased risk in the U.S. study but not in Poland, and had a combined OR of 1.44 (95%CI, 0.98-2.11; P=0.06). These analyses provide the most convincing evidence thus far that missensemutations in ATM, particularly p. S49C, may be breast cancer susceptibility alleles. Because of their lowfrequency, even larger sample sizes are required to more firmly establish these associations.", "metadata": {}}
+{"_id": "24148722", "title": "", "text": "A diffusion tensor magnetic resonance imaging study of corpus callosum from adult patients withmigraine complicated with depressive/anxious disorder.OBJECTIVE The aim of this study was toinvestigate the possible microstructural abnormalities of the corpus callosum (CC) in adult patients withmigraine without aura complicated with depressive/anxious disorder. BACKGROUND Emotional disorders,especially depression and anxiety, are with relatively higher incidence in migraine population. However,the mechanism of migraine complicated with depressive/anxious disorder remains unclear. METHODSDiffusion tensor magnetic resonance imaging was carried out in 12 adult patients with simple migraine(without aura and without depressive/anxious disorder) (S-M group), 12 adult patients with complicatedmigraine (without aura but complicated with depressive/anxious disorder) (Co-M group), and 12 age- andsex-matched healthy subjects (Control group). Fractional anisotropy (FA) and apparent diffusioncoefficient were measured at genu, body, and splenium of the CC, respectively. RESULTS There weresignificant differences in FA values at all locations of the CC among the 3 groups. The FA values from boththe SM and Co-M groups were significantly lower than the control (P < .05 and P < .01, respectively). TheFA values from Co-M group were significantly lower than the SM group (P < .01). The apparent diffusioncoefficient values of the above regions had no significant differences among these groups (P > .05).There were negative correlations between FA value of genu of the CC and disease course as well as FAvalue of genu and body of the CC and headache frequency (P < .05). Negative correlations were alsofound between FA values at all locations of the CC and Hamilton anxiety and Hamilton depression scores(both P < .05). CONCLUSIONS There might be an integrity change of neurofibrotic microstructuresexisting as a possible neuroanatomical basis in the CC of migraine patients complicated withdepressive/anxious disorder.", "metadata": {}}
+{"_id": "24150328", "title": "", "text": "Peroxisome proliferator-activated receptor gamma agonists for the Prevention of Adverse eventsfollowing percutaneous coronary Revascularization--results of the PPAR study.BACKGROUND Patientswith metabolic syndrome are at increased risk for cardiovascular complications. We sought to determinewhether peroxisome proliferator-activated receptor gamma agonists had any beneficial effect on patientswith metabolic syndrome undergoing percutaneous coronary intervention (PCI). METHODS A total of 200patients with metabolic syndrome undergoing PCI were randomized to rosiglitazone or placebo andfollowed for 1 year. Carotid intima-medial thickness (CIMT), inflammatory markers, lipid levels, brainnatriuretic peptide, and clinical events were measured at baseline, 6 months, and 12 months. RESULTSThere was no significant difference in CIMT between the 2 groups. There was no difference in the12-month composite end point of death, myocardial infarction (MI), stroke, or any recurrent ischemia(31.4% vs 30.2%, P = .99). The rate of death, MI, or stroke at 12 months was numerically lower in therosiglitazone group (11.9% vs 6.4%, P = .19). There was a trend toward a greater decrease over time inhigh-sensitivity C-reactive protein values compared with baseline in the group randomized torosiglitazone versus placebo both at 6 months (-35.4% vs -15.8%, P = .059) and 12 months (-40.0% vs-20.9%, P = .089) and higher change in high-density lipoprotein (+15.5% vs +4.1%, P = .05) and lowertriglycerides (-13.9% vs +14.9%, P = .004) in the rosiglitazone arm. There was a trend toward less newonset diabetes in the rosiglitazone group (0% vs 3.3%, P = .081) and no episodes of symptomatichypoglycemia. There was no excess of new onset of clinical heart failure in the rosiglitazone group, norwas there a significant change in brain natriuretic peptide levels. CONCLUSIONS Patients with metabolicsyndrome presenting for PCI are at increased risk for subsequent cardiovascular events. Rosiglitazone for12 months did not appear to affect CIMT in this population, although it did have beneficial effects onhigh-sensitivity C-reactive protein, high-density lipoprotein, and triglycerides. Further study ofperoxisome proliferator-activated receptor agonism in patients with metabolic syndrome undergoing PCImay be warranted.", "metadata": {}}
+{"_id": "24155601", "title": "", "text": "Accumulation of hydroxyethyl starch in human and animal tissues: a systematic reviewTo systematicallyreview clinical and preclinical data on hydroxyethyl starch (HES) tissue storage. MEDLINE (PubMed) wassearched and abstracts were screened using defined criteria to identify articles containing original data onHES tissue accumulation. Forty-eight studies were included: 37 human studies with a total of 635patients and 11 animal studies. The most frequent indication for fluid infusion was surgery accounting for282 patients (45.9 %). HES localization in skin was shown by 17 studies, in kidney by 12, in liver by 8,and in bone marrow by 5. Additional sites of HES deposition were lymph nodes, spleen, lung, pancreas,intestine, muscle, trophoblast, and placental stroma. Among major organs the highest measured tissueconcentration of HES was in the kidney. HES uptake into intracellular vacuoles was observed by 30 minafter infusion. Storage was cumulative, increasing in proportion to dose, although in 15 % of patientsstorage and associated symptoms were demonstrated at the lowest cumulative doses (0.4 g kg−1).Some HES deposits were extremely long-lasting, persisting for 8 years or more in skin and 10 years inkidney. Pruritus associated with HES storage was described in 17 studies and renal dysfunction in tenstudies. In one included randomized trial, HES infusion produced osmotic nephrosis-like lesions indicativeof HES storage (p = 0.01) and also increased the need for renal replacement therapy (odds ratio, 9.50;95 % confidence interval, 1.09–82.7; p = 0.02). The tissue distribution of HES was generally similar inanimals and humans. Tissue storage of HES is widespread, rapid, cumulative, frequently long-lasting, andpotentially harmful.", "metadata": {}}
+{"_id": "24157077", "title": "", "text": "Cationic host defense (antimicrobial) peptides.Members of the cationic host defense (antimicrobial)peptide family are widely distributed in nature, existing in organisms from insects to plants to mammalsand non-mammalian vertebrates. Although many demonstrate direct antimicrobial activity againstbacteria, fungi, eukaryotic parasites and/or viruses, it has been established that cationic peptides have akey modulatory role in the innate immune response. More recent evidence suggests that host defensepeptides are effective adjuvants, are synergistic with other immune effectors, polarize the adaptiveresponse, and support wound healing. In addition, the mechanisms of action are being unraveled, whichsupport more effective implementation of derivatives of these endogenous peptides as therapeuticagents.", "metadata": {}}
+{"_id": "24159217", "title": "", "text": "A mental health intervention for schoolchildren exposed to violence: a randomized controlledtrial.CONTEXT No randomized controlled studies have been conducted to date on the effectiveness ofpsychological interventions for children with symptoms of posttraumatic stress disorder (PTSD) that hasresulted from personally witnessing or being personally exposed to violence. OBJECTIVE To evaluate theeffectiveness of a collaboratively designed school-based intervention for reducing children's symptoms ofPTSD and depression that has resulted from exposure to violence. DESIGN A randomized controlled trialconducted during the 2001-2002 academic year. SETTING AND PARTICIPANTS Sixth-grade students at 2large middle schools in Los Angeles who reported exposure to violence and had clinical levels ofsymptoms of PTSD. INTERVENTION Students were randomly assigned to a 10-session standardizedcognitive-behavioral therapy (the Cognitive-Behavioral Intervention for Trauma in Schools) earlyintervention group (n = 61) or to a wait-list delayed intervention comparison group (n = 65) conductedby trained school mental health clinicians. MAIN OUTCOME MEASURES Students were assessed beforethe intervention and 3 months after the intervention on measures assessing child-reported symptoms ofPTSD (Child PTSD Symptom Scale; range, 0-51 points) and depression (Child Depression Inventory;range, 0-52 points), parent-reported psychosocial dysfunction (Pediatric Symptom Checklist; range, 0-70points), and teacher-reported classroom problems using the Teacher-Child Rating Scale (acting out,shyness/anxiousness, and learning problems; range of subscales, 6-30 points). RESULTS Compared withthe wait-list delayed intervention group (no intervention), after 3 months of intervention students whowere randomly assigned to the early intervention group had significantly lower scores on symptoms ofPTSD (8.9 vs 15.5, adjusted mean difference, - 7.0; 95% confidence interval [CI], - 10.8 to - 3.2),depression (9.4 vs 12.7, adjusted mean difference, - 3.4; 95% CI, - 6.5 to - 0.4), and psychosocialdysfunction (12.5 vs 16.5, adjusted mean difference, - 6.4; 95% CI, -10.4 to -2.3). Adjusted meandifferences between the 2 groups at 3 months did not show significant differences for teacher-reportedclassroom problems in acting out (-1.0; 95% CI, -2.5 to 0.5), shyness/anxiousness (0.1; 95% CI, -1.5 to1.7), and learning (-1.1, 95% CI, -2.9 to 0.8). At 6 months, after both groups had received theintervention, the differences between the 2 groups were not significantly different for symptoms of PTSDand depression; showed similar ratings for psychosocial function; and teachers did not report significantdifferences in classroom behaviors. CONCLUSION A standardized 10-session cognitive-behavioral groupintervention can significantly decrease symptoms of PTSD and depression in students who are exposed toviolence and can be effectively delivered on school campuses by trained school-based mental healthclinicians.", "metadata": {}}
+{"_id": "24163770", "title": "", "text": "Knowledge gaps and misconceptions about coronary heart disease among U.S. SouthAsians.BACKGROUND Although South Asians are at higher risk for coronary heart disease (CHD) thanmost other U.S. racial/ethnic groups, very little research has addressed this disparity. PURPOSE As a firststep in developing culturally targeted CHD prevention messages for this rapidly growing community, thisstudy examined South Asians' knowledge and beliefs about CHD. METHODS Analyses, conducted in 2009,were based on data collected from January to July 2008 in a cross-sectional study population of 270South Asian adults in Illinois. Interviews were conducted in English, Hindi, or Urdu using a standardizedquestionnaire. Multivariate regression models were used to examine the associations betweensociodemographics and CHD knowledge and attitudes about preventability. RESULTS Eighty-one percentof respondents had one or more CHD risk factors. Most participants (89%) said they knew little ornothing about CHD. Stress was the most frequently mentioned risk factor (44%). Few mentionedcontrolling blood pressure (11%); cholesterol (10%); and diabetes (5%) for prevention. Fifty-threepercent said that heart attacks are not preventable. Low education level, being interviewed in Urdu orHindi, and low level of acculturation were associated with less knowledge and believing that CHD is notpreventable. CONCLUSIONS A majority of South Asians in this study believed that CHD is not preventableand had low awareness of modifiable risk factors. As a first step, CHD education should target theknowledge gaps that may affect risk factor control and behavior change. Educational messages may needto be somewhat different for subgroups (e.g., by education and language) to be maximally effective.", "metadata": {}}
+{"_id": "24177706", "title": "", "text": "Innate host defense requires TFEB-mediated transcription of cytoprotective and antimicrobialgenes.Animal host defense against infection requires the expression of defense genes at the right placeand the right time. Understanding such tight control of host defense requires the elucidation of thetranscription factors involved. By using an unbiased approach in the model Caenorhabditis elegans, wediscovered that HLH-30 (known as TFEB in mammals) is a key transcription factor for host defense.HLH-30 was activated shortly after Staphylococcus aureus infection, and drove the expression of close to80% of the host response, including antimicrobial and autophagy genes that were essential for hosttolerance of infection. TFEB was also rapidly activated in murine macrophages upon S. aureus infectionand was required for proper transcriptional induction of several proinflammatory cytokines andchemokines. Thus, our data suggest that TFEB is a previously unappreciated, evolutionarily ancienttranscription factor in the host response to infection.", "metadata": {}}
+{"_id": "24185667", "title": "", "text": "DAP kinase regulates JNK signaling by binding and activating protein kinase D under oxidative stressThestress-activated kinase JNK mediates key cellular responses to oxidative stress. Here we show that DAPkinase (DAPk), a cell death promoting Ser/Thr protein kinase, plays a main role in oxidativestress-induced JNK signaling. We identify protein kinase D (PKD) as a novel substrate of DAPk anddemonstrate that DAPk physically interacts with PKD in response to oxidative stress. We further showthat DAPk activates PKD in cells and that induction of JNK phosphorylation by ectopically expressed DAPkcan be attenuated by knocking down PKD expression or by inhibiting its catalytic activity. Moreover,knockdown of DAPk expression caused a marked reduction in JNK activation under oxidative stress,indicating that DAPk is indispensable for the activation of JNK signaling under these conditions. Finally,DAPk is shown to be required for cell death under oxidative stress in a process that displays thecharacteristics of caspase-independent necrotic cell death. Taken together, these findings establish amajor role for DAPk and its specific interaction with PKD in regulating the JNK signaling network underoxidative stress.", "metadata": {}}
+{"_id": "24186125", "title": "", "text": "The changes of antioxidant defense system caused by quercetin administration do not lead to DNAdamage and apoptosis in the spleen and bone marrow cells of rats.Quercetin may have the oppositeeffect, namely anti- as well as pro-oxidant. The aim of this study was to assess the results of quercetinanti- and/or pro-oxidant activity in the bone marrow and spleen cells of rats. The experimental rats weretreated daily, with quercetin in a dose of 8 or 80mg/kg b.w. by gavage for 40 days. The intracellularredox state in cells were assessed by measuring the ferric ion reducing antioxidant power (FRAP) leveland malonodialdehyde concentration. HO-1 mRNA expression was examined with real-time PCR. Theextent of DNA damage was determined by the alkaline-labile comet assay. A potential pro-apoptoticquercetin action was determined using the FITC-Annexin V kit. The quercetin and isorhamnetinconcentrations in serum were analyzed by HPLC-ECD. MDA concentration and FRAP values, weresignificantly decreased in the spleen and bone marrow cells of rats treated with quercetin, in a dose of80mg/kg b.w. in comparison with the control rats; no significant changes were observed after quercetinwas administered in a dose ten times as low. Treatment with quercetin dose-dependently upregulated theexpression of HO-1 mRNA in the bone marrow cells. Quercetin administration to the rats did not induceeither DNA damage or apoptosis in the examined cells. The results of our study prove that changes in theantioxidant state, caused by quercetin, do not lead to DNA damage or exert any pro-apoptotic activity invivo.", "metadata": {}}
+{"_id": "24190159", "title": "", "text": "Mutated KRAS results in overexpression of DUSP4, a MAP-kinase phosphatase, and SMYD3, a histonemethyltransferase, in rectal carcinomas.Mutations of the KRAS oncogene are predictive for resistance totreatment with antibodies against the epithelial growth factor receptor in patients with colorectal cancer.Overcoming this therapeutic dilemma could potentially be achieved by the introduction of drugs thatinhibit signaling pathways that are activated by KRAS mutations. To identify comprehensively suchsignaling pathways, we profiled pretreatment biopsies and normal mucosa from 65 patients with locallyadvanced rectal cancer-30 of which carried mutated KRAS-using global gene expression microarrays. Bycomparing all tumor tissues exclusively to matched normal mucosa, we could improve assay sensitivity,and identified a total of 22,297 features that were differentially expressed (adjusted P-value <0.05)between normal mucosa and cancer, including several novel potential rectal cancer genes. We then usedthis comprehensive description of the rectal cancer transcriptome as the baseline for identifyingKRAS-dependent alterations. The presence of activating KRAS mutations is significantly correlated to anupregulation of 13 genes (adjusted P-value <0.05), among them DUSP4, a MAP-kinase phosphatase, andSMYD3, a histone methyltransferase. Inhibition of the expression of both genes has previously beenshown using the MEK1-inhibitor PD98059 and the antibacterial compound Novobiocin, respectively. Thesefindings suggest a potential approach to overcome resistance to treatment with antibodies against theepithelial growth factor receptor in patients with KRAS-mutant rectal carcinomas.", "metadata": {}}
+{"_id": "24205118", "title": "", "text": "Clinicopathological and prognostic significance of Bmi-1 expression in human cervical cancer.OBJECTIVETo investigate the clinical significance of Bmi-1 expression as a prognostic marker for cervical cancer.Design. Retrospectively collected data from a population-based cohort. SETTING Jiangsu ProvinceHospital. Population. Eighty-eight women diagnosed with cervical carcinoma between 2000 and 2003.METHODS RT-PCR assay was performed to determine Bmi-1 mRNA expression in 18 cervical cancer andnoncancerous tissue samples and immunohistochemistry to detect Bmi-1 protein expression in 88cervical cancer samples. The correlation between Bmi-1 expression and clinicopathological factors wasanalyzed. Additionally, statistical analyses were applied to test for prognostic associations. RNAinterference was used to downregulate Bmi-1 expression in a cervical cancer cell line (HeLa). In vitrocytotoxicity was measured by the methylthiazoletetrazolium and colony formation assays. Effects ofBmi-1 inhibition on in vivo growth of cancer cells was detected by the tumorigenicity assay. Cell cycledistribution and cell apoptosis were measured by flow cytometry. MAIN OUTCOME MEASURES The levelsof Bmi-1 mRNA and protein expression in tissues were evaluated by RT-PCR and Western Blot assays.RESULTS The level of Bmi-1 mRNA expression in cervical cancer tissues was significantly higher than thatin corresponding noncancerous tissues. High Bmi-1 expression was significantly correlated with poortumor differentiation, advanced International Federation of Gynecology and Obstetrics stage and positivelymph node metastasis. Patients with high Bmi-1 expression showed shorter overall survival than thosewith low expression. Univariate and multivariate analyses showed that high Bmi-1 expression was anindependent prognostic factor. CONCLUSIONS RNA interference-mediated Bmi-1 inhibition could inhibit invitro and in vivo growth, enhance apoptosis and induce cell cycle arrest of cervical cancer cells. Bmi-1might be an independent prognostic marker for cervical cancer patients.", "metadata": {}}
+{"_id": "24211561", "title": "", "text": "Dexamethasone decreases vomiting by children after tonsillectomy.We evaluated the effect ofdexamethasone on vomiting after elective tonsillectomy in 133 healthy children aged 2-12 yr in arandomized, stratified, blocked, double-blind, placebo-controlled study. General anesthesia was inducedby inhalation of N2O and halothane or intravenously (IV) with propofol. Anesthesia was maintained withN2O and halothane. Dexamethasone 150 micrograms/kg up to a maximum dose of 8 mg, or placebo, wasadministered IV before surgery. All patients received 1.5 mg/kg codeine intramuscularly (IM)intraoperatively. Perioperative IV fluids, management of emesis, postoperative pain and hospitaldischarge criteria were all standardized. The groups were similar with respect to number, age, weight,length of surgery, and estimated intraoperative blood loss. Dexamethasone reduced the overall incidenceof vomiting from 72% (placebo) to 40% (P < 0.001). Vomiting, both in-hospital and postdischarge, wasdecreased by the prophylactic administration of dexamethasone. Each episode of in-hospital vomitingprolonged discharge by 13 +/- 2 min, mean +/- SD (P < 0.001). In conclusion, dexamethasone markedlydecreased vomiting by healthy children after elective tonsillectomy in an ambulatory hospital setting.", "metadata": {}}
+{"_id": "24221369", "title": "", "text": "A Conserved Histidine in the RNA Sensor RIG-I Controls Immune Tolerance to N1-2'O-Methylated SelfRNA.The cytosolic helicase retinoic acid-inducible gene-I (RIG-I) initiates immune responses to most RNAviruses by detecting viral 5'-triphosphorylated RNA (pppRNA). Although endogenous mRNA is also5'-triphosphorylated, backbone modifications and the 5'-ppp-linked methylguanosine ((m7)G) capprevent immunorecognition. Here we show that the methylation status of endogenous capped mRNA atthe 5'-terminal nucleotide (N1) was crucial to prevent RIG-I activation. Moreover, we identified a singleconserved amino acid (H830) in the RIG-I RNA binding pocket as the mediator of steric exclusion ofN1-2'O-methylated RNA. H830A alteration (RIG-I(H830A)) restored binding of N1-2'O-methylatedpppRNA. Consequently, endogenous mRNA activated the RIG-I(H830A) mutant but not wild-type RIG-I.Similarly, knockdown of the endogenous N1-2'O-methyltransferase led to considerable RIG-I stimulationin the absence of exogenous stimuli. Studies involving yellow-fever-virus-encoded 2'O-methyltransferaseand RIG-I(H830A) revealed that viruses exploit this mechanism to escape RIG-I. Our data reveal a newrole for cap N1-2'O-methylation in RIG-I tolerance of self-RNA.", "metadata": {}}
+{"_id": "24234341", "title": "", "text": "lumi: a pipeline for processing Illumina microarray.UNLABELLED Illumina microarray is becoming apopular microarray platform. The BeadArray technology from Illumina makes its preprocessing andquality control different from other microarray technologies. Unfortunately, most other analyses have nottaken advantage of the unique properties of the BeadArray system, and have just incorporatedpreprocessing methods originally designed for Affymetrix microarrays. lumi is a Bioconductor packageespecially designed to process the Illumina microarray data. It includes data input, quality control,variance stabilization, normalization and gene annotation portions. In specific, the lumi package includesa variance-stabilizing transformation (VST) algorithm that takes advantage of the technical replicatesavailable on every Illumina microarray. Different normalization method options and multiple qualitycontrol plots are provided in the package. To better annotate the Illumina data, a vendor independentnucleotide universal identifier (nuID) was devised to identify the probes of Illumina microarray. The nuIDannotation packages and output of lumi processed results can be easily integrated with otherBioconductor packages to construct a statistical data analysis pipeline for Illumina data. AVAILABILITYThe lumi Bioconductor package, www.bioconductor.org", "metadata": {}}
+{"_id": "24237492", "title": "", "text": "Large scale replication and meta-analysis of variants on chromosome 4q25 associated with atrialfibrillation.AIMS A recent genome-wide association study identified a haplotype block on chromosome4q25 associated with atrial fibrillation (AF). We sought to replicate this association in four independentcohorts. METHODS AND RESULTS The Framingham Heart Study and Rotterdam Study arecommunity-based longitudinal studies. The Vanderbilt AF Registry and German AF Network (AFNet) arecase-control studies. Participants with AF (n = 3508) were more likely to be male and were older thanreferent participants (n = 12 173; Framingham 82 +/- 10 vs. 71 +/- 13 years; Rotterdam 73 +/- 8 vs. 69+/- 9 years; Vanderbilt 54 +/- 14 vs. 57 +/- 14 years; AFNet 62 +/- 12 vs. 49 +/- 14 years). Singlenucleotide polymorphism (SNP) rs2200733 was associated with AF in all four cohorts, with odds ratios(ORs) ranging from 1.37 in Rotterdam [95% confidence interval (CI) 1.18-1.59; P = 3.1 x 10(-5)] to 2.52in AFNet (95% CI 2.22-2.8; P = 1.8 x 10(-49)). There also was a significant association between AF andrs10033464 in Framingham (OR 1.34; 95% CI 1.03-1.75; P = 0.031) and AFNet (OR 1.30; 95% CI1.13-1.51; P = 0.0002), but not Vanderbilt (OR 1.16; 95% CI 0.86-1.56; P = 0.33). A meta-analysis ofthe current and prior AF studies revealed an OR of 1.90 (95% CI 1.60-2.26; P = 3.3 x 10(-13)) forrs2200733 and of 1.36 (95% CI 1.26-1.47; P = 6.7 x 10(-15)) for rs10033464. CONCLUSION Thenon-coding SNPs rs2200733 and rs10033464 are strongly associated with AF in four cohorts of Europeandescent. These results confirm the significant relations between AF and intergenic variants onchromosome 4.", "metadata": {}}
+{"_id": "24241932", "title": "", "text": "Ecological analysis of ethnic differences in relation between tuberculosis and poverty.OBJECTIVE Toexamine the effect of ethnicity on the relation between tuberculosis and deprivation. DESIGNRetrospective ecological study comparing incidence of tuberculosis in white and south Asian residents ofthe 39 electoral wards in Birmingham with ethnic specific indices of deprivation. SETTING Birmingham,1989-93. SUBJECTS 1516 notified cases of tuberculosis. MAIN OUTCOME MEASURES Rates oftuberculosis and measures of deprivation. RESULTS Univariate analysis showed significant associations oftuberculosis rates for the whole population with several indices of deprivation (P<0.01) and with theproportion of the population of south Asian origin (P<0.01). All deprivation covariates were positivelyassociated with each other but on multiple regression, higher level of overcrowding was independentlyassociated with tuberculosis rates. For the white population, overcrowding was associated withtuberculosis rates independently of other variables (P=0.0036). No relation with deprivation was foundfor the south Asian population in either single or multivariable analyses. CONCLUSIONS Poverty issignificantly associated with tuberculosis in the white population, but no such relation exists for those ofAsian ethnicity. These findings suggest that causal factors, and therefore potential interventions, will alsodiffer by ethnic group.", "metadata": {}}
+{"_id": "24249915", "title": "", "text": "Reduced expression of oestrogen receptor beta in invasive breast cancer and its re-expression using DNAmethyl transferase inhibitors in a cell line model.To gain insights into the possible role of oestrogenreceptor (ER) beta in breast carcinogenesis, immunohistochemical analysis of ER beta was performed on512 breast specimens encompassing normal (n = 138), pure ductal carcinoma in situ (n = 16), invasivecancers (n = 319), lymph node metastases (n = 31), and recurrences (n = 8). Real-time polymerasechain reaction (PCR) was used to investigate the methylation status of the ER beta gene in the ER betanegative breast cancer cell lines SkBr3 and MDA-MB-435. A gradual reduction in, but not a complete lossof, ER beta expression was observed during the transition from normal and pre-invasive lesions toinvasive cancers, where ER beta was lost in 21% of cases. This was more pronounced in invasive ductalthan in lobular carcinomas, a significantly higher proportion of which were ER beta-positive (74%compared with 91%, respectively, p = 0.0004). Examination of paired primary cancers with their axillarylymph node metastases showed that if ER beta was present in the primary tumour, it persisted in themetastasis. Treatment of ER beta-negative cell lines with DNA methyl transferase inhibitors restored ERbeta expression, providing experimental evidence that silencing of ER beta in breast carcinomas could bedue to promoter hypermethylation. These results suggest that loss of ER beta expression is one of thehallmarks of breast carcinogenesis and that it may be a reversible process involving methylation.", "metadata": {}}
+{"_id": "24269361", "title": "", "text": "Atopy risk in infants and children in relation to early exposure to fish, oily fish, or long-chain omega-3fatty acids: a systematic review.There are two main families of polyunsaturated fatty acids (PUFAs), then-6 and the n-3 families. It has been suggested that there is a causal relationship between n-6 PUFAintake and allergic disease, and there are biologically plausible mechanisms, involving eicosanoidmediators of the n-6 PUFA arachidonic acid, that could explain this. Fish and fish oils are sources oflong-chain n-3 PUFAs and these fatty acids act to oppose the actions of n-6 PUFAs. Thus, it is consideredthat n-3 PUFAs will protect against atopic sensitization and against the clinical manifestations of atopy.Evidence to examine this has been acquired from epidemiologic studies investigating associationsbetween fish intake in pregnancy, lactation, infancy, and childhood, and atopic outcomes in infants andchildren and from intervention studies with fish oil supplements in pregnancy, lactation, infancy, andchildhood, and atopic outcomes in infants and children. All five epidemiological studies investigating theeffect of maternal fish intake during pregnancy on atopic or allergic outcomes in infants/children of thosepregnancies concluded protective associations. One study investigating the effects of maternal fish intakeduring lactation did not observe any significant associations. The evidence from epidemiological studiesinvestigating the effects of fish intake during infancy and childhood on atopic outcomes in those infants orchildren is inconsistent, although the majority of the studies (nine of 14) showed a protective effect offish intake during infancy or childhood on atopic outcomes in those infants/children. Fish oilsupplementation during pregnancy and lactation or during infancy or childhood results in a higher n-3PUFA status in the infants or children. Fish oil provision to pregnant women is associated withimmunologic changes in cord blood and such changes may persist. Studies performed to date indicatethat provision of fish oil during pregnancy may reduce sensitization to common food allergens and reduceprevalence and severity of atopic dermatitis in the first year of life, with a possible persistence untiladolescence with a reduction in eczema, hay fever, and asthma. Fish oil provision to infants or childrenmay be associated with immunologic changes in the blood but it is not clear if these are of clinicalsignificance and whether they persist. Fish oil supplementation in infancy may decrease the risk ofdeveloping some manifestations of allergic disease, but this benefit may not persist as other factors comeinto play. It is not clear whether fish oil can be used to treat children with asthma as the two studiesconducted to date give divergent results. Further studies of increased long-chain n-3 PUFA provision induring pregnancy, lactation, and infancy are needed to more clearly identify the immunologic and clinicaleffects in infants and children and to identify protective and therapeutic effects and their persistence.", "metadata": {}}
+{"_id": "24273592", "title": "", "text": "Dietary quality among men and women in 187 countries in 1990 and 2010: a systematicassessmentBACKGROUND Healthy dietary patterns are a global priority to reduce non-communicablediseases. Yet neither worldwide patterns of diets nor their trends with time are well established. Weaimed to characterise global changes (or trends) in dietary patterns nationally and regionally and toassess heterogeneity by age, sex, national income, and type of dietary pattern. METHODS In thissystematic assessment, we evaluated global consumption of key dietary items (foods and nutrients) byregion, nation, age, and sex in 1990 and 2010. Consumption data were evaluated from 325 surveys(71·7% nationally representative) covering 88·7% of the global adult population. Two types of dietarypattern were assessed: one reflecting greater consumption of ten healthy dietary items and the otherbased on lesser consumption of seven unhealthy dietary items. The mean intakes of each dietary factorwere divided into quintiles, and each quintile was assigned an ordinal score, with higher scores beingequivalent to healthier diets (range 0-100). The dietary patterns were assessed by hierarchical linearregression including country, age, sex, national income, and time as exploratory variables. FINDINGSFrom 1990 to 2010, diets based on healthy items improved globally (by 2·2 points, 95% uncertaintyinterval (UI) 0·9 to 3·5), whereas diets based on unhealthy items worsened (-2·5, -3·3 to -1·7). In 2010,the global mean scores were 44·0 (SD 10·5) for the healthy pattern and 52·1 (18·6) for the unhealthypattern, with weak intercorrelation (r=-0·08) between countries. On average, better diets were seen inolder adults compared with younger adults, and in women compared with men (p<0·0001 each).Compared with low-income nations, high-income nations had better diets based on healthy items (+2·5points, 95% UI 0·3 to 4·1), but substantially poorer diets based on unhealthy items (-33·0, -37·8 to-28·3). Diets and their trends were very heterogeneous across the world regions. For example, bothtypes of dietary patterns improved in high-income countries, but worsened in some low-income countriesin Africa and Asia. Middle-income countries showed the largest improvement in dietary patterns based onhealthy items, but the largest deterioration in dietary patterns based on unhealthy items.INTERPRETATION Consumption of healthy items improved, while consumption of unhealthy itemsworsened across the world, with heterogeneity across regions and countries. These global data providethe best estimates to date of nutrition transitions across the world and inform policies and priorities forreducing the health and economic burdens of poor diet quality. FUNDING The Bill & Melinda GatesFoundation and Medical Research Council.", "metadata": {}}
+{"_id": "24276304", "title": "", "text": "The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication(NCS-R).CONTEXT Uncertainties exist about prevalence and correlates of major depressive disorder(MDD). OBJECTIVE To present nationally representative data on prevalence and correlates of MDD byDiagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, and on studypatterns and correlates of treatment and treatment adequacy from the recently completed NationalComorbidity Survey Replication (NCS-R). DESIGN Face-to-face household survey conducted fromFebruary 2001 to December 2002. SETTING The 48 contiguous United States. PARTICIPANTS Householdresidents ages 18 years or older (N = 9090) who responded to the NCS-R survey. MAIN OUTCOMEMEASURES Prevalence and correlates of MDD using the World Health Organization's (WHO) CompositeInternational Diagnostic Interview (CIDI), 12-month severity with the Quick Inventory of DepressiveSymptomatology Self-Report (QIDS-SR), the Sheehan Disability Scale (SDS), and the WHO disabilityassessment scale (WHO-DAS). Clinical reinterviews used the Structured Clinical Interview for DSM-IV.RESULTS The prevalence of CIDI MDD for lifetime was 16.2% (95% confidence interval [CI], 15.1-17.3)(32.6-35.1 million US adults) and for 12-month was 6.6% (95% CI, 5.9-7.3) (13.1-14.2 million USadults). Virtually all CIDI 12-month cases were independently classified as clinically significant using theQIDS-SR, with 10.4% mild, 38.6% moderate, 38.0% severe, and 12.9% very severe. Mean episodeduration was 16 weeks (95% CI, 15.1-17.3). Role impairment as measured by SDS was substantial asindicated by 59.3% of 12-month cases with severe or very severe role impairment. Most lifetime (72.1%)and 12-month (78.5%) cases had comorbid CIDI/DSM-IV disorders, with MDD only rarely primary.Although 51.6% (95% CI, 46.1-57.2) of 12-month cases received health care treatment for MDD,treatment was adequate in only 41.9% (95% CI, 35.9-47.9) of these cases, resulting in 21.7% (95% CI,18.1-25.2) of 12-month MDD being adequately treated. Sociodemographic correlates of treatment werefar less numerous than those of prevalence. CONCLUSIONS Major depressive disorder is a commondisorder, widely distributed in the population, and usually associated with substantial symptom severityand role impairment. While the recent increase in treatment is encouraging, inadequate treatment is aserious concern. Emphasis on screening and expansion of treatment needs to be accompanied by aparallel emphasis on treatment quality improvement.", "metadata": {}}
+{"_id": "24276902", "title": "", "text": "The Pain Catastrophizing Scale: Further Psychometric Evaluation with Adult SamplesPrevious studies withundergraduates have provided support for the reliability and oblique three-factor structure of a newscale, the Pain Catastrophizing Scale (PCS). We examined the reliability and validity of the PCS in adultcommunity and pain outpatient samples. The PCS showed a high internal consistency in both groups.Using data from the community sample, confirmatory factor analyses showed that the PCS taps a singleconstruct characterized by three related dimensions. Gender differences were obtained on the PCS totalscore in the community and the outpatient samples. The analyses also showed significant differencesbetween the community and the outpatient samples on the PCS total and subscales. Overall, the resultsshowed strong evidence of criterion-related, concurrent, and discriminant validity for the PCS in thecommunity sample. Limitations of the present study are discussed.", "metadata": {}}
+{"_id": "24278870", "title": "", "text": "Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma.BACKGROUND Interferon alfa iswidely used for metastatic renal-cell carcinoma but has limited efficacy and tolerability. Temsirolimus, aspecific inhibitor of the mammalian target of rapamycin kinase, may benefit patients with this disease.METHODS In this multicenter, phase 3 trial, we randomly assigned 626 patients with previouslyuntreated, poor-prognosis metastatic renal-cell carcinoma to receive 25 mg of intravenous temsirolimusweekly, 3 million U of interferon alfa (with an increase to 18 million U) subcutaneously three timesweekly, or combination therapy with 15 mg of temsirolimus weekly plus 6 million U of interferon alfathree times weekly. The primary end point was overall survival in comparisons of the temsirolimus groupand the combination-therapy group with the interferon group. RESULTS Patients who receivedtemsirolimus alone had longer overall survival (hazard ratio for death, 0.73; 95% confidence interval[CI], 0.58 to 0.92; P=0.008) and progression-free survival (P<0.001) than did patients who receivedinterferon alone. Overall survival in the combination-therapy group did not differ significantly from that inthe interferon group (hazard ratio, 0.96; 95% CI, 0.76 to 1.20; P=0.70). Median overall survival times inthe interferon group, the temsirolimus group, and the combination-therapy group were 7.3, 10.9, and 8.4months, respectively. Rash, peripheral edema, hyperglycemia, and hyperlipidemia were more common inthe temsirolimus group, whereas asthenia was more common in the interferon group. There were fewerpatients with serious adverse events in the temsirolimus group than in the interferon group (P=0.02).CONCLUSIONS As compared with interferon alfa, temsirolimus improved overall survival among patientswith metastatic renal-cell carcinoma and a poor prognosis. The addition of temsirolimus to interferon didnot improve survival. (ClinicalTrials.gov number, NCT00065468 [ClinicalTrials.gov].).", "metadata": {}}
+{"_id": "24282306", "title": "", "text": "Macrophage Diversity Enhances Tumor Progression and MetastasisThere is persuasive clinical andexperimental evidence that macrophages promote cancer initiation and malignant progression. Duringtumor initiation, they create an inflammatory environment that is mutagenic and promotes growth. Astumors progress to malignancy, macrophages stimulate angiogenesis, enhance tumor cell migration andinvasion, and suppress antitumor immunity. At metastatic sites, macrophages prepare the target tissuefor arrival of tumor cells, and then a different subpopulation of macrophages promotes tumor cellextravasation, survival, and subsequent growth. Specialized subpopulations of macrophages mayrepresent important new therapeutic targets.", "metadata": {}}
+{"_id": "24285403", "title": "", "text": "Ankle brachial index as a predictor of cognitive impairment in the general population: ten-year follow-upof the Edinburgh Artery Study.OBJECTIVES To determine whether the ankle brachial index (ABI, a markerof generalized atherosclerosis) is associated with cognitive impairment after 10 years in older people.DESIGN Cohort study (Edinburgh Artery Study). SETTING Eleven general practices in Edinburgh,Scotland. PARTICIPANTS Seven hundred seventeen men and women aged 55 to 74 from the generalpopulation, followed for 10 years. MEASUREMENTS ABI measured at baseline and major cognitivefunctions (including premorbid function using the National Adult Reading Test, NART) tested after 10years. RESULTS After adjustment for age and sex, a low ABI was associated with lower scoring (bottomtertile vs top tertile) on Raven's Matrices (odds ratio (OR)=1.6, 95% confidence interval (CI) =1.0-2.6),Verbal Fluency (OR =1.8, 95% CI =1.1-3.0), and Digit Symbol Test (OR =2.3, 95% CI =1.3-4.2),suggesting that the ABI is predictive of poorer performance in nonverbal reasoning, verbal fluency, andinformation processing speed. The association between ABI and the Digit Symbol Test remainedsignificant after further adjustment for premorbid cognitive function (tested using the NART), suggestingthat the ABI is also predictive of decline in information processing speed (from premorbid ability to thatmeasured here in older age). CONCLUSION The ABI may be useful in identifying older individuals athigher risk of cognitive impairment. In the future, preventive measures developed to target individualswith a low ABI should consider measures to reduce vascular-related cognitive decline as well ascardiovascular events, in an effort to reduce the incidence and consequences of subsequent cognitiveimpairment and dementia.", "metadata": {}}
+{"_id": "24294572", "title": "", "text": "PTEN Regulates PI(3,4)P2 Signaling Downstream of Class I PI3KThe PI3K signaling pathway regulates cellgrowth and movement and is heavily mutated in cancer. Class I PI3Ks synthesize the lipid messengerPI(3,4,5)P3. PI(3,4,5)P3 can be dephosphorylated by 3- or 5-phosphatases, the latter producingPI(3,4)P2. The PTEN tumor suppressor is thought to function primarily as a PI(3,4,5)P3 3-phosphatase,limiting activation of this pathway. Here we show that PTEN also functions as a PI(3,4)P2 3-phosphatase,both in vitro and in vivo. PTEN is a major PI(3,4)P2 phosphatase in Mcf10a cytosol, and loss of PTEN andINPP4B, a known PI(3,4)P2 4-phosphatase, leads to synergistic accumulation of PI(3,4)P2, whichcorrelated with increased invadopodia in epidermal growth factor (EGF)-stimulated cells. PTEN deletionincreased PI(3,4)P2 levels in a mouse model of prostate cancer, and it inversely correlated with PI(3,4)P2levels across several EGF-stimulated prostate and breast cancer lines. These results point to a role forPI(3,4)P2 in the phenotype caused by loss-of-function mutations or deletions in PTEN.", "metadata": {}}
+{"_id": "24307695", "title": "", "text": "Genetic analysis of an ARS element from the fission yeast Schizosaccharomyces pombe.ARS(autonomously replicating sequence) elements are DNA fragments that can function as origins of DNAreplication in yeast. We report the first fine-structure analysis of ars1, an ARS element of the fission yeastSchizosaccharomyces pombe. Characterization of a series of nested deletion mutations indicated that theminimal fragment of DNA encompassing ars1 is surprisingly large. No fragment < 650 bp retainedsignificant ARS activity. Analysis of deletion and substitution mutations scanning the entire minimal ars1identified a single essential 50 bp fragment (segment 1). Only one other 50 bp mutation reduced activityas much as 5-fold and most deletions were without effect. Thus, the minimal ars1 is composed of twogeneral types of genetic elements, a small segment that is absolutely required for efficient ARS activityand a much larger region that is tolerant of internal structural alterations. Higher resolution analysis ofsegment 1 defined a critical 30 bp A/T-rich segment which appears to contain redundant geneticelements. Schizosaccharomyces pombe ars1 promoted high frequency transformation in the buddingyeast S.cerevisiae but this heterologous activity was not dependent on segment 1. Our analysis indicatesthat the functional elements required for ARS function in S.pombe and S.cerevisiae are clearly different.", "metadata": {}}
+{"_id": "24311787", "title": "", "text": "N terminus of Swr1 binds to histone H2AZ and provides a platform for subunit assembly in the chromatinremodeling complex.Variant histone H2AZ-containing nucleosomes are involved in the regulation of geneexpression. In Saccharomyces cerevisiae, chromatin deposition of histone H2AZ is mediated by thefourteen-subunit SWR1 complex, which catalyzes ATP-dependent exchange of nucleosomal histone H2Afor H2AZ. Previous work defined the role of seven SWR1 subunits (Swr1 ATPase, Swc2, Swc3, Arp6,Swc5, Yaf9, and Swc6) in maintaining complex integrity and H2AZ histone replacement activity. Here weexamined the function of three additional SWR1 subunits, bromodomain containing Bdf1, actin-relatedprotein Arp4 and Swc7, by analyzing affinity-purified mutant SWR1 complexes. We observed thatdepletion of Arp4 (arp4-td) substantially impaired the association of Bdf1, Yaf9, and Swc4. In contrast,loss of either Bdf1 or Swc7 had minimal effects on overall complex integrity. Furthermore, the basic H2AZhistone replacement activity of SWR1 in vitro required Arp4, but not Bdf1 or Swc7. Thus, three out offourteen SWR1 subunits, Bdf1, Swc7, and previously noted Swc3, appear to have roles auxiliary to thebasic histone replacement activity. The N-terminal region of the Swr1 ATPase subunit is necessary andsufficient to direct association of Bdf1 and Swc7, as well as Arp4, Act1, Yaf9 and Swc4. This same regioncontains an additional H2AZ-H2B specific binding site, distinct from the previously identified Swc2subunit. These findings suggest that one SWR1 enzyme might be capable of binding two H2AZ-H2Bdimers, and provide further insight on the hierarchy and interdependency of molecular interactions withinthe SWR1 complex.", "metadata": {}}
+{"_id": "24315156", "title": "", "text": "Role of the cytoskeleton during leukocyte responsesThe cytoskeleton is a cellular network of structural,adaptor and signalling molecules that regulates most cellular functions that are related to the immuneresponse, including migration, extravasation, antigen recognition, activation and phagocytosis bydifferent subsets of leukocytes. Recently, a large number of regulatory elements and structuralconstituents of the leukocyte cytoskeleton have been identified. In this review, we discuss thecomposition and regulation of the different cytoskeletal elements and their role in immune responses.", "metadata": {}}
+{"_id": "24318630", "title": "", "text": "Integration of mental health into primary healthcare in low-income countries: avoidingmedicalization.Since 2008 the World Health Organization (WHO), through its mental health Gap ActionProgramme, has attempted to revitalize efforts to integrate mental health into non-specialized (e.g.primary) healthcare. While this has led to renewed interest in this potential method of mental healthservice delivery, it has also prompted criticism. Some concerns raised are that it would contribute to themedicalization of social and psychological problems, and narrowly focus on primary care without sufficientattention given to strengthening other levels of the healthcare system, notably community-based careand care on district levels. This paper discusses seven elements that may be critical to preventinginadvertently contributing to increasing a narrow biomedical approach to mental healthcare whenintegrating mental health into non-specialized healthcare: (1) using task shifting approaches within asystem of stepped care, (2) ensuring primary mental healthcare also includes brief psychotherapeuticinterventions, (3) promote community-based recovery-oriented interventions for people with disablingchronic mental disorders, (4) conceptualizing training as a continuous process of strengthening clinicalcompetencies through supervision, (5) engaging communities as partners in psychosocial interventions,(6) embedding shifts to primary mental healthcare within wider health policy reforms, and (7) promotinginter-sectoral approaches to address social determinants of mental health.", "metadata": {}}
+{"_id": "24323369", "title": "", "text": "Comparison of clomiphene citrate, metformin, or the combination of both for first-line ovulation inductionand achievement of pregnancy in 154 women with polycystic ovary syndrome.OBJECTIVE To determinewhich first-line medication is more effective in polycystic ovary syndrome (PCOS) patients for ovulationinduction and pregnancy achievement and to verify whether any patient characteristic is associated witha better response to therapy. DESIGN Observational comparative study. SETTING Fertility clinic.PATIENT(S) One hundred fifty-four infertile women with oligomenorrhea and hyperandrogenism.INTERVENTION(S) Group 1 (56 patients) received clomiphene citrate (CC) 50 mg from days 5-9 of thecycle. Group 2 (57 patients) received 500 mg of metformin 3 times a day. Group 3 (41 patients) receivedboth medications. MAIN OUTCOME MEASURE(S) Ovulation and pregnancy. RESULT(S) Patients receivingmetformin alone had an increased ovulation rate compared with those receiving CC alone (75.4% vs.50%). Patients on metformin had similar ovulation rates compared with those in the combination group(75.4% vs. 63.4%). Pregnancy rates were equivalent in the 3 groups. Response to metformin wasindependent of body weight and dose. Finally, nonsmoking predicted better ovulatory response overall aswell as lower fasting glucose for CC and lower androgens for metformin. CONCLUSION(S) Metformin isbetter for ovulation induction than CC alone and equivalent for pregnancy achievement. We suggest thatmetformin can be used first for ovulation induction in patients with PCOS regardless of their weight andinsulin levels because of its efficacy and known safety profile.", "metadata": {}}
+{"_id": "24323695", "title": "", "text": "Pulmonologist involvement, stage-specific treatment, and survival in adults with non-small cell lungcancer and chronic obstructive pulmonary disease.RATIONALE Up to 80% of patients with lung cancerhave comorbid chronic obstructive pulmonary disease (COPD). Many of them are poor candidates forstage-specific lung cancer treatment due to diminished lung function and poor functional status, andmany forego treatment. The negative effect of COPD may be moderated by pulmonologist-guidedmanagement. OBJECTIVES This study examined the association between pulmonologist management andthe probability of receiving the recommended stage-specific treatment modality and overall survivalamong patients with non-small cell lung cancer (NSCLC) with preexisting COPD. METHODS Early- andadvanced-stage NSCLC cases diagnosed between 2002 and 2005 with a prior COPD diagnosis (3-24months before NSCLC diagnosis) were identified in Surveillance, Epidemiology, and End Results tumorregistry data linked to Medicare claims. Study outcomes included receipt of recommended stage-specifictreatment (surgical resection for early-stage NSCLC and chemotherapy for advanced-stage NSCLC[advNSCLC]) and overall survival. Pulmonologist management was considered present if one or moreEvaluation and Management visit claims with pulmonologist specialty were observed within 6 monthsafter NSCLC diagnosis. Stage-specific multivariate logistic regression tested association betweenpulmonologist management and treatment received. Cox proportional hazard models examined theindependent association between pulmonologist care and mortality. Two-stage residual inclusioninstrumental variable (2SRI-IV) analyses tested and adjusted for potential confounding based onunobserved factors or measurement error. MEASUREMENTS AND MAIN RESULTS The cohorts included5,488 patients with early-stage NSCLC and 6,426 patients with advNSCLC disease with preexisting COPD.Pulmonologist management was recorded for 54.9% of patients with early stage NSCLC and 35.7% ofpatients with advNSCLC. Of those patients with pulmonologist involvement, 58.5% of patients with earlyNSCLC received surgical resection, and 43.6% of patients with advNSCLC received chemotherapy.Pulmonologist management post NSCLC diagnosis was associated with increased surgical resection rates(odds ratio, 1.26; 95% confidence interval, 1.11-1.45) for early NSCLC and increased chemotherapyrates (odds ratio, 1.88; 95% confidence interval, 1.67-2.10) for advNSCLC. Pulmonologist managementwas also associated with reduced mortality risk for patients with early-stage NSCLC but not AdvNSCLC.CONCLUSIONS Pulmonologist management had a positive association with rates of stage-specifictreatment in both groups and overall survival in early-stage NSCLC. These results provide preliminarysupport for the recently published guidelines emphasizing the role of pulmonologists in lung cancermanagement.", "metadata": {}}
+{"_id": "24335068", "title": "", "text": "Divalent cations differentially regulate integrin alphaIIb cytoplasmic tail binding to beta3 and to calcium-and integrin-binding protein.We have used recombinant or synthetic alphaIIb and beta3 integrincytoplasmic peptides to study their in vitro complexation and ligand binding capacity by surface plasmonresonance. alpha.beta heterodimerization occurred in a 1:1 stoichiometry with a weak KD in themicromolar range. Divalent cations were not required for this association but stabilized the alpha.betacomplex by decreasing the dissociation rate. alpha.beta complexation was impaired by the R995Asubstitution or the KVGFFKR deletion in alphaIIb but not by the beta3 S752P mutation. Recombinantcalcium- and integrin-binding protein (CIB), an alphaIIb-specific ligand, bound to the alphaIIbcytoplasmic peptide in a Ca2+- or Mn2+-independent, one-to-one reaction with a KD value of 12 microM.In contrast, in vitro liquid phase binding of CIB to intact alphaIIbbeta3 occurred preferentially withMn2+-activated alphaIIbbeta3 conformers, as demonstrated by enhanced coimmunoprecipitation of CIBwith PAC-1-captured Mn2+-activated alphaIIbbeta3, suggesting that Mn2+ activation of intactalphaIIbbeta3 induces the exposure of a CIB-binding site, spontaneously exposed by the free alphaIIbpeptide. Since CIB did not stimulate PAC-1 binding to inactive alphaIIbbeta3 nor prevented activatedalphaIIbbeta3 occupancy by PAC-1, we conclude that CIB does not regulate alphaIIbbeta3 inside-outsignaling, but rather is involved in an alphaIIbbeta3 post-receptor occupancy event.", "metadata": {}}
+{"_id": "24338780", "title": "", "text": "Lethal autoimmune myocarditis in interferon-gamma receptor-deficient mice: enhanced disease severityby impaired inducible nitric oxide synthase induction.BACKGROUND Interferon-gamma (IFN-gamma) isan essential cytokine in the regulation of inflammatory responses in autoimmune diseases. Little is knownabout its role in inflammatory heart disease. METHODS AND RESULTS We showed that IFN-gammareceptor-deficient mice (IFN-gammaR(-/-)) on a BALB/c background immunized with a peptide derivedfrom cardiac alpha-myosin heavy chain develop severe myocarditis with high mortality. Althoughmyocarditis subsided in wild-type mice after 3 weeks, IFN-gammaR(-/-) mice showed persistent disease.The persistent inflammation was accompanied by vigorous in vitro CD4 T-cell responses and impairedinducible nitric oxide synthase expression, together with evidence of impaired nitric oxide production inIFN-gammaR(-/-) hearts. Treatment of wild-type mice with the nitric oxide synthetase inhibitorN:-nitro-l-arginine-methyl-ester enhanced in vitro CD4 T-cell proliferation and prevented healing ofmyocarditis. CONCLUSIONS Our data provide evidence that IFN-gamma protects mice from lethalautoimmune myocarditis by inducing the expression of inducible nitric oxide synthase followed by thedownregulation of T-cell responses.", "metadata": {}}
+{"_id": "24341590", "title": "", "text": "Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancertreated with tamoxifen.CONTEXT The growth inhibitory effect of tamoxifen, which is used for thetreatment of hormone receptor-positive breast cancer, is mediated by its metabolites,4-hydroxytamoxifen and endoxifen. The formation of active metabolites is catalyzed by the polymorphiccytochrome P450 2D6 (CYP2D6) enzyme. OBJECTIVE To determine whether CYP2D6 variation isassociated with clinical outcomes in women receiving adjuvant tamoxifen. DESIGN, SETTING, ANDPATIENTS Retrospective analysis of German and US cohorts of patients treated with adjuvant tamoxifenfor early stage breast cancer. The 1325 patients had diagnoses between 1986 and 2005 of stage Ithrough III breast cancer and were mainly postmenopausal (95.4%). Last follow-up was in December2008; inclusion criteria were hormone receptor positivity, no metastatic disease at diagnosis, adjuvanttamoxifen therapy, and no chemotherapy. DNA from tumor tissue or blood was genotyped for CYP2D6variants associated with reduced (*10, *41) or absent (*3, *4, *5) enzyme activity. Women wereclassified as having an extensive (n=609), heterozygous extensive/intermediate (n=637), or poor (n=79)CYP2D6 metabolism. MAIN OUTCOME MEASURES Time to recurrence, event-free survival, disease-freesurvival, and overall survival. RESULTS Median follow-up was 6.3 years. At 9 years of follow-up, therecurrence rates were 14.9% for extensive metabolizers, 20.9% for heterozygous extensive/intermediatemetabolizers, and 29.0% for poor metabolizers, and all-cause mortality rates were 16.7%, 18.0%, and22.8%, respectively. Compared with extensive metabolizers, there was a significantly increased risk ofrecurrence for heterozygous extensive/intermediate metabolizers (time to recurrence adjusted hazardratio [HR], 1.40; 95% confidence interval [CI], 1.04-1.90) and for poor metabolizers (time to recurrenceHR, 1.90; 95% CI, 1.10-3.28). Compared with extensive metabolizers, those with decreased CYP2D6activity (heterozygous extensive/intermediate and poor metabolism) had worse event-free survival (HR,1.33; 95% CI, 1.06-1.68) and disease-free survival (HR, 1.29; 95% CI, 1.03-1.61), but there was nosignificant difference in overall survival (HR, 1.15; 95% CI, 0.88-1.51). CONCLUSION Among womenwith breast cancer treated with tamoxifen, there was an association between CYP2D6 variation andclinical outcomes, such that the presence of 2 functional CYP2D6 alleles was associated with betterclinical outcomes and the presence of nonfunctional or reduced-function alleles with worse outcomes.", "metadata": {}}
+{"_id": "24346598", "title": "", "text": "Long-term, nightly benzodiazepine treatment of injurious parasomnias and other disorders of disruptednocturnal sleep in 170 adults.PURPOSE To assess the efficacy, dose stability, safety, and abuse potentialof long-term, nightly benzodiazepine treatment of chronic disorders of disrupted nocturnal sleep.PATIENTS AND METHODS During a 12-year period, one author evaluated and treated 170 adult referralsfor > or = 6 months with nightly benzodiazepine therapy for longstanding, sleep-disruptive disorders:injurious sleepwalking and sleep terrors (69); rapid eye movement sleep behavior disorder (52); chronic,severe insomnia (25); and restless legs syndrome/periodic limb movement disorder (24). RESULTSComplete/substantial control of the sleep disorders was achieved by 146 patients (86%); 8% hadadverse effects requiring medication changes; 2% had relapses of alcohol or chemical abuse requiringhospitalization; another 2% at times misused their medications. A total of 136 patients receivedclonazepam nightly for a mean 3.5 (+/- 2.4) years, with no significant difference in inital versus finalmean dose: 0.77 mg (+/- 0.46) versus 1.10 mg (+/- 0.96). Similar results were obtained with chronicalprazolam treatment and with other benzodiazepine treatments. CONCLUSION Long-term, nightlybenzodiazepine treatment of injurious parasomnias and other disorders of disrupted nocturnal sleepresulted in sustained efficacy in most cases, with low risk of dosage tolerance, adverse effects, or abuse.Data from this study on the treatment of chronic, severe insomnia (a small subset of all insomnia) are notgeneralizable to the typical insomnia patient.", "metadata": {}}
+{"_id": "24347647", "title": "", "text": "Decreased proteasomal activity causes age-related phenotypes and promotes the development ofmetabolic abnormalities.The proteasome is a multicatalytic enzyme complex responsible for thedegradation of both normal and damaged proteins. An age-related decline in proteasomal activity hasbeen implicated in various age-related pathologies. The relevance of decreased proteasomal activity toaging and age-related diseases remains unclear, however, because suitable animal models are notavailable. In the present study, we established a transgenic (Tg) mouse model with decreasedproteasomal chymotrypsin-like activity. Tg mice exhibited a shortened life span and developedage-related phenotypes. In Tg mice, polyubiquitinated and oxidized proteins accumulated, and theexpression levels of cellular proteins such as Bcl-xL and RNase L were altered. When Tg mice were fed ahigh-fat diet, they developed more pronounced obesity and hepatic steatosis than did wild-type mice.Consistent with its role in lipid droplet formation, the expression of adipose differentiation-related protein(ADRP) was elevated in the livers of Tg mice. Of note, obesity and hepatic steatosis induced by a high-fatdiet were more pronounced in aged than in young wild-type mice, and aged wild-type mice had elevatedlevels of ADRP, suggesting that the metabolic abnormalities present in Tg mice mimic those in aged mice.Our results provide the first in vivo evidence that decreased proteasomal chymotrypsin-like activityaffects longevity and aggravates age-related metabolic disorders, such as obesity and hepatic steatosis.", "metadata": {}}
+{"_id": "24349430", "title": "", "text": "Orai1/CRACM1 overexpression suppresses cell proliferation via attenuation of the store-operated calciuminflux-mediated signalling pathway in A549 lung cancer cells.BACKGROUND Orai1/CRACM1 is a principalcomponent of the store-operated calcium channels. Store-operated calcium influx is highly correlatedwith inflammatory reactions, immunological regulation, and cell proliferation. Epidermal growth factor(EGF), which plays an important role in the regulation of cell proliferation, can activate store-operatedcalcium channels. However, the consequences of Orai1/CRACM1 overexpression in EGF-mediated lungcancer cells growth are not known. METHODS To investigate the role of Orai1/CRACM1 in EGF-mediatedlung cancer cell proliferation, Orai1/CRACM1 plasmids were transfected into cells by lipofection. A cellproliferation assay, immunofluorescence staining, flow cytometry, and real-time polymerase chainreaction were employed to monitor cell proliferation. The calcium influx signals were investigated using afluorescent-based calcium assay. RESULTS Transfection of Orai1/CRACM1 plasmids resulted in theinhibition of EGF-mediated cell proliferation. ERK1/2 and Akt phosphorylation were inhibited byOrai1/CRACM1 overexpression. Expression of the cell cycle modulator p21 was induced in theOrai1/CRACM1-overexpressing cells, whereas the expression of cyclin D3 was reduced. Flow cytometryrevealed that overexpression of Orai1/CRACM1 resulted in G0/G1 cell cycle arrest. Importantly,Orai1/CRACM1 overexpression significantly attenuated EGF-mediated store-operated calcium influx. Inaddition, application of 2-APB, a store-operated calcium channel inhibitor, resulted in the inhibition ofEGF-mediated cancer cell proliferation. CONCLUSIONS We conclude that Orai1/CRACM1 overexpressionattenuates store-operated Ca(2+) influx that in turn blocks EGF-mediated proliferative signaling anddrives cell cycle arrest.", "metadata": {}}
+{"_id": "24349992", "title": "", "text": "Oxidative stress in cancer associated fibroblasts drives tumor-stroma co-evolution: A new paradigm forunderstanding tumor metabolism, the field effect and genomic instability in cancer cells.Loss of stromalfibroblast caveolin-1 (Cav-1) is a powerful single independent predictor of poor prognosis in humanbreast cancer patients, and is associated with early tumor recurrence, lymph node metastasis andtamoxifen-resistance. We developed a novel co-culture system to understand the mechanism(s) by whicha loss of stromal fibroblast Cav-1 induces a \"lethal tumor micro-environment. \" Here, we propose a newparadigm to explain the powerful prognostic value of stromal Cav-1. In this model, cancer cells induceoxidative stress in cancer-associated fibroblasts, which then acts as a \"metabolic\" and \"mutagenic\" motorto drive tumor-stroma co-evolution, DNA damage and aneuploidy in cancer cells. More specifically, weshow that an acute loss of Cav-1 expression leads to mitochondrial dysfunction, oxidative stress andaerobic glycolysis in cancer associated fibroblasts. Also, we propose that defective mitochondria areremoved from cancer-associated fibroblasts by autophagy/mitophagy that is induced by oxidative stress.As a consequence, cancer associated fibroblasts provide nutrients (such as lactate) to stimulatemitochondrial biogenesis and oxidative metabolism in adjacent cancer cells (the \"Reverse WarburgEffect\"). We provide evidence that oxidative stress in cancer-associated fibroblasts is sufficient to inducegenomic instability in adjacent cancer cells, via a bystander effect, potentially increasing their aggressivebehavior. Finally, we directly demonstrate that nitric oxide (NO) over-production, secondary to Cav-1loss, is the root cause for mitochondrial dysfunction in cancer associated fibroblasts. In support of thisnotion, treatment with anti-oxidants (such as N-acetyl-cysteine, metformin and quercetin) or NOinhibitors (L-NAME) was sufficient to reverse many of the cancer-associated fibroblast phenotypes thatwe describe. Thus, cancer cells use \"oxidative stress\" in adjacent fibroblasts (i) as an \"engine\" to fueltheir own survival via the stromal production of nutrients and (ii) to drive their own mutagenic evolutiontowards a more aggressive phenotype, by promoting genomic instability. We also present evidence thatthe \"field effect\" in cancer biology could also be related to the stromal production of ROS and NO species.eNOS-expressing fibroblasts have the ability to downregulate Cav-1 and induce mitochondrial dysfunctionin adjacent fibroblasts that do not express eNOS. As such, the effects of stromal oxidative stress can belaterally propagated, amplified and are effectively \"contagious\"--spread from cell-to-cell like avirus--creating an \"oncogenic/mutagenic\" field promoting widespread DNA damage.", "metadata": {}}
+{"_id": "24351680", "title": "", "text": "Telomeres and telomerase: more than the end of the lineEarly studies of telomerase suggested thattelomeres are maintained by an elegant but relatively simple and highly conserved mechanism oftelomerase-mediated replication. As we learn more, it has become clear that the mechanism is elegantbut not as simple as first thought. It is also evident that, although many species use similar, sometimesidentical, DNA sequences for telomeres, these species express their own individuality in the way theyregulate these sequences and, perhaps, in the additional tasks that they have imposed on their telomericDNA. The striking similarities between telomeres in different species have revealed much aboutchromosome ends; the differences are proving to be equally informative. In addition to the differencesbetween species that use telomerase, there are also a few exceptional organisms with atypical telomeresfor which no telomerase activity has been detected. This review addresses recent studies, the insightsthey offer, and, perhaps more importantly, the questions they raise.", "metadata": {}}
+{"_id": "24356383", "title": "", "text": "Reduced osteoblastic population and defective mineralization in osteopetrotic (op/op) mice.Osteopetrotic(op/op) mice fail to exhibit bone remodeling because of a defective osteoclast formation due to a lack ofmacrophage colony-stimulating factor. In this study, we investigated the femora of op/op mice to clarifywhether the osteoblastic population and bone mineralization are involved in osteoclasts or their boneresorption. The op/op mice extended the meshwork of trabecular bones from the chondro-osseousjunction to the diaphyseal region. In the femoral metaphyses of op/op mice, intense alkaline phosphatase(ALPase)-positive osteoblasts were observed on the metaphyseal bone in close proximity to the erosionzone of the growth plates. Von Kossa's staining revealed scattered mineralized nodules and a finemeshwork of mineralized bone matrices while the wild-type littermates developed well-mineralizedtrabeculae parallel to the longitudinal axis. In contrast to the metaphysis, some op/op diaphyses showedflattened osteoblasts with weak ALPase-positivity, and the other diaphyses displayed bone surfaceswithout a covering by osteoblasts. It is likely, therefore, that the osteoblastic population and activity werelessened in the op/op diaphyses. Despite the osteopetrotic model, von Kossa's staining demonstratedpatchy unmineralized areas in the op/op diaphyses, indicating that a lower population and/or the activityof osteoblasts resulted in defective mineralization in the bone. Transmission electron microscopydisclosed few osteoblasts on the diaphyseal bones, and instead, bone marrow cells and vascularendothelial cells were often attached to the unmineralized bone. Osteocytes were embedded in theunmineralized bone matrix. Thus, osteoclasts appear to be involved in the osteoblastic population andactivity as well as subsequent bone mineralization.", "metadata": {}}
+{"_id": "24384587", "title": "", "text": "Interleukin 18 function in atherosclerosis is mediated by the interleukin 18 receptor and the Na-Clco-transporterInterleukin-18 (IL18) participates in atherogenesis through several putative mechanisms.Interruption of IL18 action reduces atherosclerosis in mice. Here, we show that absence of the IL18receptor (IL18r) does not affect atherosclerosis in apolipoprotein E–deficient (Apoe−/−) mice, nor does itaffect IL18 cell surface binding to or signaling in endothelial cells. As identified initially byco-immunoprecipitation with IL18, we found that IL18 interacts with the Na-Cl co-transporter (NCC; alsoknown as SLC12A3), a 12-transmembrane-domain ion transporter protein preferentially expressed in thekidney. NCC is expressed in atherosclerotic lesions, where it colocalizes with IL18r. In Apoe−/− mice,combined deficiency of IL18r and NCC, but not single deficiency of either protein, protects mice fromatherosclerosis. Peritoneal macrophages from Apoe−/− mice or from Apoe−/− mice lacking IL18r or NCCshow IL18 binding and induction of cell signaling and cytokine and chemokine expression, butmacrophages from Apoe−/− mice with combined deficiency of IL18r and NCC have a blunted response.An interaction between NCC and IL18r on macrophages was detected by co-immunoprecipitation. IL18binds to the cell surface of NCC-transfected COS-7 cells, which do not express IL18r, and induces cellsignaling and cytokine expression. This study identifies NCC as an IL18-binding protein that collaborateswith IL18r in cell signaling, inflammatory molecule expression, and experimental atherogenesis.", "metadata": {}}
+{"_id": "24387017", "title": "", "text": "Notch promotes survival of pre–T cells at the β-selection checkpoint by regulating cellularmetabolismNotch signals are necessary for the functional outcomes of T cell receptor β-selection,including differentiation, proliferation and rescue from apoptosis. The mechanism underlying thisrequirement for T cell development is unknown. Here we show that Notch receptor and Delta-like 1 ligandinteractions promoted the survival of CD4−CD8− pre–T cells through the maintenance of cell size,glucose uptake and metabolism. Furthermore, the trophic effects of Notch signaling were mediated by thepathway of phosphatidylinositol-3-OH kinase and the kinase Akt, such that expression of active Atkovercame the requirement for Notch in β-selection. Collectively, our results demonstrate involvement ofNotch receptor–ligand interactions in the regulation of cellular metabolism, thus enabling the autonomoussignaling capacity of the pre–T cell receptor complex.*Note: In the version of this article initiallypublished online, in the fourth sentence of the abstract, the term \"Atk\" was a misspelling; this should be\"Akt. \" In the fourth sentence of the second paragraph of the introduction, the name of the second kinasementioned, \"PI(3)K-dependent kinase 1,\" was incorrect; this should read \"phosphoinositide-dependentkinase 1. \" These errors have been corrected for the HTML and print versions of the article.", "metadata": {}}
+{"_id": "24396137", "title": "", "text": "Blood pressure, salivary cortisol, and inflammatory cytokine outcomes in senior female cancer survivorsenrolled in a tai chi chih randomized controlled trialOlder cancer survivors are a vulnerable population dueto an increased risk for chronic diseases (e.g., cardiovascular disease) compounded with treatmentlate-effects and declines in physical functioning. Therefore, interventions that reduce chronic disease riskfactors (i.e., blood pressure, chronic inflammation, and cortisol) are important in this population. Tai chichih (TCC) is a mind-body exercise associated with reductions in chronic disease risk factors, but has notbeen examined with older cancer survivors. In a feasibility randomized controlled trial of TCC, weexamined secondary outcomes of blood pressure, salivary cortisol, and inflammatory cytokines(interleukin (IL)-6, IL-12, tumor necrosis factor-α, IL-10, IL-4) due to their implications in chronicdiseases. Sixty-three senior female cancer survivors (M age = 67 years, SD = 7.15) with physicalfunctioning limitations (SF-12 physical functioning ≤80 or role-physical ≤72) were randomized to12-weeks (60-min, three times a week) of TCC or Health Education control (HEC) classes. Resting bloodpressure, 1-day salivary cortisol samples, and fasting plasma samples for cytokine multiplex assays werecollected at baseline and 1-week post-intervention. Controlling for baseline values, the TCC group hadsignificantly lower systolic blood pressure (SBP, p = 0.002) and cortisol area-under-curve (AUC, p =0.02) at post-intervention than the HEC group. There was no intervention effect on inflammatorycytokines (p’s > 0.05). This TCC feasibility trial was associated with significant reductions in SBP andcortisol AUC in senior female cancer survivors. Larger, definitive trials are needed to confirm thesefindings. Senior survivors’ have an increased risk for chronic diseases; however, TCC interventions mayhelp reduce associated risk factors.", "metadata": {}}
+{"_id": "24408040", "title": "", "text": "Heart failure admissions in adults with congenital heart disease; risk factors and prognosis.BACKGROUNDHeart failure (HF) is a serious complication and often the cause of death in adults with congenital heartdisease (CHD). Therefore, our aims were to determine the frequency of HF-admissions, and to assess riskfactors of first HF-admission and of mortality after first HF-admission in adults with CHD. METHODS TheDutch CONCOR registry was linked to the Hospital Discharge Registry and National Mortality Registry toobtain data on HF-admissions and mortality. Risk factors for both HF-admission and mortality wereassessed using Cox regression models. RESULTS Of 10,808 adult patients (49% male), 274 (2.5%) wereadmitted for HF during a median follow-up period of 21 years. The incidence of first HF-admission was 1.2per 1000 patient-years, but the incidence of HF itself will be higher. Main defect, multiple defects, andsurgical interventions in childhood were identified as independent risk factors of HF-admission. Patientsadmitted for HF had a five-fold higher risk of mortality than patients not admitted (hazard ratio(HR)=5.3; 95% confidence interval 4.2-6.9). One- and three-year mortality after first HF-admission were24% and 35% respectively. Independent risk factors for three-year mortality after first HF-admissionwere male gender, pacemaker implantation, admission duration, non-cardiac medication use and highserum creatinine. CONCLUSIONS The incidence of HF-admission in adults with CHD is 1.2 per 1000patient-years. Mortality risk is substantially increased after HF-admission, which emphasises theimportance to identify patients at high risk of HF-admission. These patients might benefit from closerfollow-up and earlier medical interventions. The presented risk factors may facilitate surveillance.", "metadata": {}}
+{"_id": "24414345", "title": "", "text": "New pathologic classification of lung cancer: relevance for clinical practice and clinical trials.Wesummarize significant changes in pathologic classification of lung cancer resulting from the 2011International Association for the Study of Lung Cancer/American Thoracic Society/European RespiratorySociety (IASLC/ATS/ERS) lung adenocarcinoma classification. The classification was developed by aninternational core panel of experts representing IASLC, ATS, and ERS with oncologists/pulmonologists,pathologists, radiologists, molecular biologists, and thoracic surgeons. Because 70% of patients with lungcancer present with advanced stages, a new approach to small biopsies and cytology with specificterminology and criteria focused on the need for distinguishing squamous cell carcinoma fromadenocarcinoma and on molecular testing for EGFR mutations and ALK rearrangement. Tumorspreviously classified as non-small-cell carcinoma, not otherwise specified, because of the lack of clearsquamous or adenocarcinoma morphology should be classified further by using a limitedimmunohistochemical workup to preserve tissue for molecular testing. The terms \"bronchioloalveolarcarcinoma\" and \"mixed subtype adenocarcinoma\" have been discontinued. For resectedadenocarcinomas, new concepts of adenocarcinoma in situ and minimally invasive adenocarcinoma definepatients who, if they undergo complete resection, will have 100% disease-free survival. Invasiveadenocarcinomas are now classified by predominant pattern after using comprehensive histologicsubtyping with lepidic, acinar, papillary, and solid patterns; micropapillary is added as a new histologicsubtype with poor prognosis. Former mucinous bronchioloalveolar carcinomas are now called \"invasivemucinous adenocarcinoma. \" Because the lung cancer field is now rapidly evolving with new advancesoccurring on a frequent basis, particularly in the molecular arena, this classification provides a muchneeded standard for pathologic diagnosis not only for patient care but also for clinical trials and TNMclassification.", "metadata": {}}
+{"_id": "24423427", "title": "", "text": "Polymorphisms in EGFR and IL28B are associated with spontaneous clearance in an HCV-infected iranianpopulationAlthough most hepatitis C virus (HCV)-infected individuals develop chronic infection, about25% of them are able to clear the virus spontaneously without any therapeutic intervention. The aim ofthe present study was to identify genes associated with spontaneous HCV clearance in a population ofIranian patients. We genotyped 110 single-nucleotide polymorphisms (SNPs) in 59selected—candidate—genes in a cohort of 107 HCV-infected participants who spontaneously cleared theinfection and 176 participants whose infection persisted. Three out of the 110 SNPs were found to beassociated with HCV outcome (P-values<0.03). rs11506105 in EGFR (epidermal growth factor receptorgene), and rs11881222 and rs12979860 in IL28B (interferon-λ3 gene). Multivariate logistic regression ofthe three markers showed that the A/A genotypes in both rs11506105 (EFGR) and rs11881222 (IL28B),and the C/C genotype in rs12979860 (IL28B) are associated with HCV clearance (recessive model: oddsratio (OR)=2.06, 95% confidence interval (95% CI)=1.09–3.88, P=0.025; OR=2.09, 95% CI=1.23–3.60,P=0.007; and OR=1.95, 95% CI=1.15–3.35, P=0.014 for rs11506105, rs12979860 and rs11881222,respectively). In conclusion, EGFR and IL28B SNPs are strong independent predictive markers ofspontaneous viral clearance.", "metadata": {}}
+{"_id": "24443043", "title": "", "text": "Cardiopulmonary exercise testing variables reflect the degree of diastolic dysfunction in patients withheart failure-normal ejection fraction.PURPOSE Previous investigations have reported a relationshipbetween variables obtained from echocardiography with tissue Doppler imaging (TDI) andcardiopulmonary exercise testing (CPX) in systolic heart failure (HF) cohorts. The purpose of the presentinvestigation was to perform a comparative analysis between echocardiography with TDI and CPX inpatients with HF and normal ejection fraction (NEF). METHODS Patients with HF-NEF (N = 32) underwentechocardiography with TDI and CPX to determine the following variables: (1) the ratio between mitralearly velocity (E) and mitral annular velocity (E'), (2) ejection fraction, (3) left ventricular (LV) mass, (4)left ventricular end systolic volume, (5) peak oxygen uptake (.VO2), (6) ventilatory efficiency, (7) thepartial pressure of end-tidal carbon dioxide (P(ET)CO2) at rest and peak exercise, and (8) heart raterecovery at 1 minute (HRR1). RESULTS Pearson correlation revealed that E/E' was significantly correlatedwith peak oxygen uptake (r = -0.55, P = .001), the ventilatory efficiency slope (r = 0.60, P < .001),resting P(ET)CO2 (r = -0.39, P = .03), peak P(ET)CO2 (r = -0.50, P = .004), and HRR1 (r = -0.63, P <.001). Left ventricular mass and left ventricular end systolic volume were not correlated with any CPXvariable. Ejection fraction was correlated with HRR1 (r = -0.55, P = .001). An HRR1 threshold of less than16 and/or 16 or more beats per minute (higher value positive) effectively identified subjects with an E/E'> 10 (positive likelihood ratio: 13:2). DISCUSSION E/E' provides an accurate reflection of LV fillingpressure and thus, insight into diastolic function. The results of the present investigation indicate CPXprovides insight into cardiac dysfunction in patients with HF-NEF and thus, may eventually prove to be avaluable and accepted clinical assessment.", "metadata": {}}
+{"_id": "24450344", "title": "", "text": "Radical prostatectomy for pathological Gleason 8 or greater prostate cancer: influence of concomitantpathological variables.PURPOSE We evaluated the long-term outcome of radical prostatectomy forpathological Gleason score 8 or greater prostate cancer and characterized the prognostic significance ofother pathological variables. MATERIALS AND METHODS A total of 6,419 patients underwent radicalprostatectomy between 1987 and 1996. There were 407 patients classified as having pathologicalGleason 8 or greater, including 8 in 48%, 9 in 49% and 10 in 3%. Adjuvant treatment was used in 45%of patients and adjuvant hormonal therapy was administered to 155 (38%). Progression-free, includinglocal or systemic, and/or prostate specific antigen (PSA) 0.4 ng./ml. or greater, and cancer specificsurvival were determined by the Kaplan-Meier method. The effect of pathological grade and stage,preoperative PSA, DNA ploidy, margin status, tumor dimension, seminal vesicle invasion, and adjuvanttreatment was assessed with the univariate and multivariate analyses. RESULTS Pathological stagedistribution was pT2 in 26% of patients, pT3 48% and pTxN+ 27%. Overall and progression-free survivalat 10 years was 67% and 36%, respectively, compared to cancer specific survival 85%. Adjuvanttreatment, pathological stage, preoperative PSA and pathological grade were significant (less than 0.05)univariate predictors of progression-free survival. Pathological stage, margin status and ploidy wereunivariately associated with cancer specific survival. Progression-free survival at 10 years of thosepatients who did and did not receive adjuvant treatment was 52% and 23%, respectively. In themultivariate analysis pathological grade (p=0.02), preoperative PSA (p <0.0001), adjuvant therapy (p<0.0001) and pathological stage (p=0.036) were significant independent predictors of progression-freesurvival. CONCLUSIONS High grade prostate cancer can be controlled with radical prostatectomy in somepatients with disease confined pathologically, and 10-year cause specific survival is 96%. Predictors ofoutcome in patients with Gleason 8 disease or greater are similar to established predictors derived byusing all grades. Although adjuvant hormonal therapy appears to improve disease progression rates afterradical prostatectomy on the basis of this nonrandomized study, it may not affect prostate cancer deathrates within 10 years in patients with high grade cancer.", "metadata": {}}
+{"_id": "24466904", "title": "", "text": "Successful establishment of long-term bone marrow cultures in 103 patients with myelodysplasticsyndromes.We used bone marrow biopsies instead of mononuclear cells to maintain long-term culturesfrom 103 patients belonging to all five sub-categories of myelodysplastic syndromes (MDS), as well as 12normal controls. By week 4, 30-50% confluency was reached and could be maintained for up to 12 weekswith 100% confluency. The four prominent cells were fibroblasts, macrophages, endothelial cells andadipocytes. Immunohistochemical and electron microscopic studies provided lineage confirmation.Normal hematopoiesis was well supported by MDS stroma. Neither the FAB nor cytogenetics wasco-related with the potency of growth. MDS stroma appears to be both morphologically and functionallynormal.", "metadata": {}}
+{"_id": "24494539", "title": "", "text": "[Acupuncture combined with auricular point sticking therapy for post stroke depression:a randomizedcontrolled trial].OBJECTIVE To observe the clinical effects of acupuncture combined with auricular pointsticking based on the western medication for post stroke depression (PSD). METHODS Sixty patients withPSD were randomly assigned into an acupuncture plus auricular application group (a combination group)and a medication group, 30 cases in each one. 20 mg paroxetine hydrochloride was prescribed orally inthe medication group, once a day for continuous 8 weeks. Based on the above treatment, 30-minuteacupuncture was used in the combination group for 8 weeks at Baihui (GV 20), Sishencong (EX-HN 1),Shenting (GV 24), Yintang (GV 29), Shenmen (HT 7), Neiguan (PC 6), Taichong (LR 3), Hegu (LI 4),Zusanli (ST 36), Sanyinjiao (SP 6) and Fenglong (ST 40), once the other day and three times a week.Auricular point sticking therapy for 8 weeks was applied at shenmen (TF4), pizhixia (AT4), xin (CO15),and gan (CO12), with pressing 3 times a day and once 3-5 days. The total score and each factor scores ofHamilton's depression scale (HAMD) were observed in the two groups before and after treatment, andAsberg's antidepressant side-effect rating scale (SERS) and clinical effect were evaluated. RESULTS Aftertreatment, the total HAMD scores of the two groups decreased compared with those before treatment(both P<0.05), with better effect in the combination group (P<0.05). The scores of the combinationgroup after treatment were lower than those in the medication group, including the anxiety/somatizationfactor, sleep disturbance factor, hopelessness factor (all P<0.05). The total effective rate of thecombination group was 86.7% (26/30), which was better than 66.7% (20/30) of the medication group(P<0.05). The SERS score of the combination group was lower than that of the medication group(P<0.05). CONCLUSIONS Acupuncture combined with auricular point sticking can improve the clinicalsymptoms and are effective and safe for PSD.", "metadata": {}}
+{"_id": "24496245", "title": "", "text": "Selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterialhypertensionGenetic evidence implicates the loss of bone morphogenetic protein type II receptor(BMPR-II) signaling in the endothelium as an initiating factor in pulmonary arterial hypertension (PAH).However, selective targeting of this signaling pathway using BMP ligands has not yet been explored as atherapeutic strategy. Here, we identify BMP9 as the preferred ligand for preventing apoptosis andenhancing monolayer integrity in both pulmonary arterial endothelial cells and blood outgrowthendothelial cells from subjects with PAH who bear mutations in the gene encoding BMPR-II, BMPR2. Micebearing a heterozygous knock-in allele of a human BMPR2 mutation, R899X, which we generated as ananimal model of PAH caused by BMPR-II deficiency, spontaneously developed PAH. Administration ofBMP9 reversed established PAH in these mice, as well as in two other experimental PAH models, in whichPAH develops in response to either monocrotaline or VEGF receptor inhibition combined with chronichypoxia. These results demonstrate the promise of direct enhancement of endothelial BMP signaling as anew therapeutic strategy for PAH.", "metadata": {}}
+{"_id": "24498673", "title": "", "text": "Coordinated actions of SLX1-SLX4 and MUS81-EME1 for Holliday junction resolution in humancells.Holliday junctions (HJs) are four-way DNA intermediates that form during homologousrecombination, and their efficient resolution is essential for chromosome segregation. Here, we show thatthree structure-selective endonucleases, namely SLX1-SLX4, MUS81-EME1, and GEN1, define twopathways of HJ resolution in human cells. One pathway is mediated by GEN1, whereas SLX1-SLX4 andMUS81-EME1 provide a second and genetically distinct pathway (SLX-MUS). Cells depleted for SLX-MUSor GEN1 pathway proteins exhibit severe defects in chromosome segregation and reduced survival. Inresponse to CDK-mediated phosphorylation, SLX1-SLX4 and MUS81-EME1 associate at the G2/Mtransition to form a stable SLX-MUS holoenzyme, which can be reconstituted in vitro. Biochemical studiesshow that SLX-MUS is a HJ resolvase that coordinates the active sites of two distinct endonucleasesduring HJ resolution. This cleavage reaction is more efficient and orchestrated than that mediated bySLX1-SLX4 alone, which exhibits a potent nickase activity that acts promiscuously upon DNA secondarystructures.", "metadata": {}}
+{"_id": "24510595", "title": "", "text": "Prevalence of frequent headache in a population sample.PURPOSE Patients with daily or near-dailyheadaches are commonly seen in neurology practices and in headache subspecialty centers, but there islittle information on the prevalence of this condition in the general population. We present the firstUS-based study describing the prevalence and characteristics of frequent headache in the generalpopulation. METHODS In Baltimore County, Maryland, 13 343 individuals 18 to 65 years of age wereselected by random-digit dialing and interviewed by telephone about their headaches. Subjects reporting180 or more headaches per year were classified as having frequent headache. Three mutually exclusivesubtypes of frequent headache were identified: frequent headache with migrainous features, chronictension-type headache, and unclassified frequent headache. RESULTS The overall prevalence of frequentheadache was 4.1% (5.0% female, 2.8% male; 1.8:1 female to male ratio). Frequent headache was 33%more common in Caucasians (4.4%) than in African Americans (3.3%). In both males and females,prevalence was highest in the lowest educational category. Among frequent headache sufferers, morethan half (52% female, 56% male) met criteria for chronic tension-type headache, almost one third (33%female, 25% male) met criteria for frequent headache with migrainous features, and the remainder (15%female, 19% male) were unclassified. Overall, 30% of female and 25% of male frequent headachesufferers met International Headache Society (IHS) criteria for migraine (with or without aura).CONCLUSIONS Frequent headache is common in the general population and is more prevalent inCaucasians and in those with less than a high school education. Chronic tension-type headache is morecommon than frequent headache with migrainous features, though the latter is more disabling. Althoughmore common in females than males, the female preponderance of frequent headache is less markedthan in migraine. The sex ratio varies by frequent headache subtype.", "metadata": {}}
+{"_id": "24512064", "title": "", "text": "HTLV-I/II associated disease in England and Wales, 1993-7: retrospective review of serologyrequests.Apart from HIV two exogenous retroviruses (human T cell leukaemia viruses type I (HTLV-I) andtype II (HTLV-II)) infect humans. HTLV-I infection is endemic in Japan, the Caribbean, Africa, andMelanesia and is found among immigrants from these regions in Europe. HTLV-I infection is associatedwith a 1-5% lifetime risk of adult T cell leukaemia/lymphoma, 1 a 0.25% lifetime risk of HTLV-Iassociated myelopathy, 2 and other inflammatory conditions (uveitis, alveolitis, and arthritis).1 HTLV-IIinfection is endemic in some native American and African peoples and among injecting drug users andhas been associated with neurological disease.1 Between 1986 and 1992, 100 cases of HTLV-I associatedmyelopathy and 44 cases of adult T cell leukaemia/lymphoma were diagnosed in the United Kingdom.3Adult T cell leukaemia/lymphoma was first described in 1977 and patients with it have a mean lifeexpectancy of only six months, so most of the 44 cases were probably incident cases. …", "metadata": {}}
+{"_id": "24512417", "title": "", "text": "Lentiviral vector design and imaging approaches to visualize the early stages of cellularreprogramming.Induced pluripotent stem cells (iPSCs) can be derived from somatic cells by gene transferof reprogramming transcription factors. Expression levels of these factors strongly influence the overallefficacy to form iPSC colonies, but additional contribution of stochastic cell-intrinsic factors has beenproposed. Here, we present engineered color-coded lentiviral vectors in which codon-optimizedreprogramming factors are co-expressed by a strong retroviral promoter that is rapidly silenced in iPSC,and imaged the conversion of fibroblasts to iPSC. We combined fluorescence microscopy with long-termsingle cell tracking, and used live-cell imaging to analyze the emergence and composition of early iPSCclusters. Applying our engineered lentiviral vectors, we demonstrate that vector silencing typically occursprior to or simultaneously with the induction of an Oct4-EGFP pluripotency marker. Around 7 dayspost-transduction (pt), a subfraction of cells in clonal colonies expressed Oct4-EGFP and rapidlyexpanded. Cell tracking of single cell-derived iPSC colonies supported the concept that stochasticepigenetic changes are necessary for reprogramming. We also found that iPSC colonies may emerge as agenetic mosaic originating from different clusters. Improved vector design with continuous cell trackingthus creates a powerful system to explore the subtle dynamics of biological processes such as earlyreprogramming events.", "metadata": {}}
+{"_id": "24521894", "title": "", "text": "EIF2AK3, encoding translation initiation factor 2-α kinase 3, is mutated in patients with Wolcott-RallisonsyndromeWolcott-Rallison syndrome (WRS) is a rare, autosomal recessive disorder characterized bypermanent neonatal or early infancy insulin-dependent diabetes. Epiphyseal dysplasia, osteoporosis andgrowth retardation occur at a later age. Other frequent multisystemic manifestations include hepatic andrenal dysfunction, mental retardation and cardiovascular abnormalities. On the basis of twoconsanguineous families, we mapped WRS to a region of less than 3 cM on chromosome 2p12, withmaximal evidence of linkage and homozygosity at 4 microsatellite markers within an interval ofapproximately 1 cM. The gene encoding the eukaryotic translation initiation factor 2-α kinase 3 (EIF2AK3)resides in this interval; thus we explored it as a candidate. We identified distinct mutations of EIF2AK3that segregated with the disorder in each of the families. The first mutation produces a truncated proteinin which the entire catalytic domain is missing. The other changes an amino acid, located in the catalyticdomain of the protein, that is highly conserved among kinases from the same subfamily. Our resultsprovide evidence for the role of EIF2AK3 in WRS. The identification of this gene may provide insight intothe understanding of the more common forms of diabetes and other pathologic manifestations of WRS.", "metadata": {}}
+{"_id": "24523573", "title": "", "text": "Beta oscillations in a large-scale sensorimotor cortical network: directional influences revealed byGranger causality.Previous studies have shown that synchronized beta frequency (14-30 Hz) oscillationsin the primary motor cortex are involved in maintaining steady contractions of contralateral arm andhand muscles. However, little is known about the role of postcentral cortical areas in motor maintenanceand their patterns of interaction with motor cortex. We investigated the functional relations ofbeta-synchronized neuronal assemblies in pre- and postcentral areas of two monkeys as they pressed ahand lever during the wait period of a visual discrimination task. By using power and coherence spectralanalysis, we identified a beta-synchronized large-scale network linking pre- and postcentral areas. Wethen used Granger causality spectra to measure directional influences among recording sites. In bothmonkeys, strong Granger causal influences were observed from primary somatosensory cortex to bothmotor cortex and inferior posterior parietal cortex, with the latter area also exerting Granger causalinfluences on motor cortex. Granger causal influences from motor cortex to postcentral sites, however,were weak in one monkey and not observed in the other. These results are the first, to our knowledge, todemonstrate in awake monkeys that synchronized beta oscillations bind multiple sensorimotor areas intoa large-scale network during motor maintenance behavior and carry Granger causal influences fromprimary somatosensory and inferior posterior parietal cortices to motor cortex.", "metadata": {}}
+{"_id": "24524403", "title": "", "text": "Aging, frailty and age-related diseasesThe concept of frailty as a medically distinct syndrome has evolvedbased on the clinical experience of geriatricians and is clinically well recognizable. Frailty is a nonspecificstate of vulnerability, which reflects multisystem physiological change. These changes underlying frailtydo not always achieve disease status, so some people, usually very elderly, are frail without a specific lifethreatening illness. Current thinking is that not only physical but also psychological, cognitive and socialfactors contribute to this syndrome and need to be taken into account in its definition and treatment.Together, these signs and symptoms seem to reflect a reduced functional reserve and consequentdecrease in adaptation (resilience) to any sort of stressor and perhaps even in the absence of extrinsicstressors. The overall consequence is that frail elderly are at higher risk for accelerated physical andcognitive decline, disability and death. All these characteristics associated with frailty can easily beapplied to the definition and characterization of the aging process per se and there is little consensus inthe literature concerning the physiological/biological pathways associated with or determining frailty. It isprobably true to say that a consensus view would implicate heightened chronic systemic inflammation asa major contributor to frailty. This review will focus on the relationship between aging, frailty andage-related diseases, and will highlight possible interventions to reduce the occurrence and effects offrailty in elderly people.", "metadata": {}}
+{"_id": "24525112", "title": "", "text": "A case of paraquat intoxication caused by intravenous injection.Paraquat intoxication is a fatal problem.Most paraquat intoxications happen through oral administration. We report a case of death afterintravenous paraquat injection. There is little clinical data on parenteral paraquat exposure, and wedescribe this case and fatal progression. Toxic symptoms and severe organ function impairmentdeveloped soon after injection. Treatment with repeated activated charcoal hemoperfusion with pulsesteroids, cyclophosphamide, and antioxidants was attempted. The patient died from multiple organfailure 3 days after intoxication. This case indicates that paraquat intoxication via intravenous injection,even in very small amounts, has an extremely poor prognosis.", "metadata": {}}
+{"_id": "24530130", "title": "", "text": "Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer'sdiseaseThe gene encoding apolipoprotein E (APOE) on chromosome 19 is the only confirmed susceptibilitylocus for late-onset Alzheimer's disease. To identify other risk loci, we conducted a large genome-wideassociation study of 2,032 individuals from France with Alzheimer's disease (cases) and 5,328 controls.Markers outside APOE with suggestive evidence of association (P < 10−5) were examined in collectionsfrom Belgium, Finland, Italy and Spain totaling 3,978 Alzheimer's disease cases and 3,297 controls. Twoloci gave replicated evidence of association: one within CLU (also called APOJ), encoding clusterin orapolipoprotein J, on chromosome 8 (rs11136000, OR = 0.86, 95% CI 0.81–0.90, P = 7.5 × 10−9 forcombined data) and the other within CR1, encoding the complement component (3b/4b) receptor 1, onchromosome 1 (rs6656401, OR = 1.21, 95% CI 1.14–1.29, P = 3.7 × 10−9 for combined data). Previousbiological studies support roles of CLU and CR1 in the clearance of β amyloid (Aβ) peptide, the principalconstituent of amyloid plaques, which are one of the major brain lesions of individuals with Alzheimer'sdisease.", "metadata": {}}
+{"_id": "24530633", "title": "", "text": "Identification and characterization of subpopulations in undifferentiated ES cell culture.Embryonic stem(ES) cells are pluripotent cells derived from the inner cell mass (ICM) and the epiblast, and have beensuggested to be a homogeneous population with characteristics intermediate between them. These cellsexpress Oct3/4 and Rex1 genes, which have been used as markers to indicate the undifferentiated stateof ES cells. Whereas Oct3/4 is expressed in totipotent and pluripotent cells in the mouse life cycle, Rex1expression is restricted to the ICM, and is downregulated in pluripotent cell populations in the laterstages, i.e. the epiblast and primitive ectoderm (PrE). To address whether ES cells comprise ahomogeneous population equivalent to a certain developmental stage of pluripotent cells or aheterogeneous population composed of cells corresponding to various stages of differentiation, weestablished knock-in ES cell lines in which genes for fluorescent proteins were inserted into the Rex1 andOct3/4 gene loci to visualize the expression of these genes. We found that undifferentiated ES cellsincluded at least two different populations, Rex1(+)/Oct3/4(+) cells and Rex1(-)/Oct3/4(+) cells. TheRex1(-)/Oct3/4(+) and Rex1(+)/Oct3/4(+) populations could convert into each other in the presence ofLIF. In accordance with our assumption that Rex1(+)/Oct3/4(+) cells and Rex1(-)/Oct3/4(+) cells havecharacteristics similar to those of ICM and early-PrE cells, Rex1(+)/Oct3/4(+) cells predominantlydifferentiated into primitive ectoderm and contributed to chimera formation, whereas Rex1(-)/Oct3/4(+)cells differentiated into cells of the somatic lineage more efficiently than non-fractionated ES cells in vitroand showed poor ability to contribute to chimera formation. These results confirmed that undifferentiatedES cell culture contains subpopulations corresponding to ICM, epiblast and PrE.", "metadata": {}}
+{"_id": "24541180", "title": "", "text": "Isolation of intact nuclei of high purity from mouse liver.Current methods of nuclear isolation from liverdisrupt the plasmalemmae via homogenization and separation of the nuclei by high centrifugal force(HCF) through gradients of sucrose or other substances for up to 80 min. The use of HCF for such a longtime increases the potential for nuclear damage and degradation by endogenous proteases. We comparedfour combinations of alterations to classical nuclear isolation methods as follows. Mouse liver was gentlycrushed through a fine mesh with and without in vivo perfusion with collagenase. The cell suspension wascentrifuged at 600 g to remove gross debris and then at moderate centrifugal force (MCF, 16,000 g) orhigh centrifugal force (HCF, 70,000 g) through sucrose gradients for 30 min. The purity of the isolatednuclei was assessed biologically and morphologically, including analyses of representative markerproteins for nuclei and cytoplasm. The results indicate that MCF and no collagenase provided the highestnuclear integrity and purity, whereas MCF with collagenase is a viable option if priority is given to yield.The method is especially suited for small samples and so should facilitate studies with human liverbiopsies and livers from mice, the most widely used species for gene targeting.", "metadata": {}}
+{"_id": "24550453", "title": "", "text": "Two structurally independent domains of E. coli NusG create regulatory plasticity via distinct interactionswith RNA polymerase and regulators.NusG is a conserved regulatory protein that interacts withelongation complexes (ECs) of RNA polymerase, DNA, and RNA to modulate transcription in multiple andsometimes opposite ways. In Escherichia coli, NusG suppresses pausing and increases elongation rate,enhances termination by E. coli rho and phage HK022 Nun protein, and promotes antitermination bylambdaN and in ribosomal RNA operons. We report NMR studies that suggest that E. coli NusG consists oftwo largely independent N- and C-terminal structural domains, NTD and CTD, respectively. Based ontests of the functions of the NTD and CTD and variants of NusG in vivo and in vitro, we find that NTDalone is sufficient to suppress pausing and enhance transcript elongation in vitro. However, neitherdomain alone can enhance rho-dependent termination or support antitermination, indicating thatinteractions of both domains with ECs are required for these processes. We propose that the two domainsof NusG mediate distinct interactions with ECs: the NTD interacts with RNA polymerase and the CTDinteracts with rho and other regulators, providing NusG with different combinations of interactions toeffect different regulatory outcomes.", "metadata": {}}
+{"_id": "24552097", "title": "", "text": "Cytochemistry and C-values: the less-well-known world of nuclear DNA amounts.BACKGROUND In theplant sciences there are two widely applied technologies for measuring nuclear DNA content: Feulgenabsorbance cytophotometry and flow cytometry (FCM). While FCM is, with good reasons, increasinglypopular among plant scientists, absorbance-cytophotometric techniques lose ground. This results in anarrowing of the methodological repertoire, which is neither desirable nor beneficial. Both approacheshave their advantages, but static cytophotometry seems to pose more instrumental difficulties andmaterial-based problems than FCM, so that Feulgen-based data in the literature are often less reliablethan one would expect. SCOPE The purpose of this article is to present a selective overview of the field ofnuclear DNA content measurement, and C-values in particular, with a focus on the technical difficultiesimposed by the characteristics of the biological material and with some comments on the photometricalaspects of the work. For over 20 years it has been known that plant polyphenols cause problems inFeulgen DNA cytophotometry, since they act as major staining inhibitors leading to unreliable results.However, little information is available about the chemical classes of plant metabolites capable of DNAstaining interference and the mechanisms of their inhibition. Plant slimes are another source of concern.CONCLUSIONS In FCM research to uncover the effects of secondary metabolites on measurement resultshas begun only recently. In particular, the analysis of intraspecific genome size variation demands astringent methodology which accounts for inhibitors. FCM tests for inhibitory effects of endogenousmetabolites should become obligatory. The use of dry seeds for harvesting embryo and endosperm nucleifor FCM and Feulgen densitometry may often provide a means of circumventing staining inhibitors. Theimportance of internal standardization is highlighted. Our goal is a better understanding ofphytochemical/cytochemical interactions in plant DNA photometry for the benefit of an ever-growing listof plant genome sizes.", "metadata": {}}
+{"_id": "24554740", "title": "", "text": "Integrins and cell proliferation: regulation of cyclin-dependent kinases via cytoplasmic signalingpathways.Cell cycle progression in mammalian cells is strictly regulated by both integrin-mediatedadhesion to the extracellular matrix and by binding of growth factors to their receptors. This regulation ismediated by G1 phase cyclin-dependent kinases (CDKs), which are downstream of signaling pathwaysunder the integrated control of both integrins and growth factor receptors. Recent advances demonstratea surprisingly diverse array of integrin-dependent signals that are channeled into the regulation of the G1phase CDKs. Regulation of cyclin D1 by the ERK pathway may provide a paradigm for understanding howcell adhesion can determine cell cycle progression.", "metadata": {}}
+{"_id": "24555417", "title": "", "text": "Interplay between microtubule bundling and sorting factors ensures acentriolar spindle stability during C.elegans oocyte meiosisIn many species, oocyte meiosis is carried out in the absence of centrioles. As aresult, microtubule organization, spindle assembly, and chromosome segregation proceed by uniquemechanisms. Here, we report insights into the principles underlying this specialized form of cell division,through studies of C. elegans KLP-15 and KLP-16, two highly homologous members of the kinesin-14family of minus-end-directed kinesins. These proteins localize to the acentriolar oocyte spindle andpromote microtubule bundling during spindle assembly; following KLP-15/16 depletion, microtubulebundles form but then collapse into a disorganized array. Surprisingly, despite this defect we found thatduring anaphase, microtubules are able to reorganize into a bundled array that facilitates chromosomesegregation. This phenotype therefore enabled us to identify factors promoting microtubule organizationduring anaphase, whose contributions are normally undetectable in wild-type worms; we found thatSPD-1 (PRC1) bundles microtubules and KLP-18 (kinesin-12) likely sorts those bundles into a functionalorientation capable of mediating chromosome segregation. Therefore, our studies have revealed aninterplay between distinct mechanisms that together promote spindle formation and chromosomesegregation in the absence of structural cues such as centrioles.", "metadata": {}}
+{"_id": "24555878", "title": "", "text": "Development of a questionnaire to measure heart disease risk knowledge in people with diabetes: theHeart Disease Fact Questionnaire.This paper describes a paper and pencil questionnaire that measuresheart disease risk knowledge in people with diabetes. The Heart Disease Fact Questionnaire (HDFQ) is a25-item questionnaire that was developed to tap into respondents' knowledge of major risk factors forthe development of CHD. Approximately half of these items specifically address diabetes-related CHD riskfactors. Based on extensive pilot data, the current study analyzed responses from 524 people withdiabetes to assess the psychometric properties. The HDFQ is readable to an average 13-year old andimposes little burden. It shows good content and face validity. It demonstrates adequate internalconsistency, with Kuder-Richardson-20 formula = 0.77 and good item-total correlations. Item analysisshowed a desirable range in P-values. In discriminant function analyses, HDFQ scores differentiatedrespondents by knowledge of their own cardiovascular health, use of lipid lowering medications, healthinsurance status, and educational attainment, thus indicating good criterion related validity. This measureof heart disease risk knowledge is brief, understandable to respondents, and easy to administer andscore. Its potential for use in research and practice is discussed. Future research should establish normsas well as investigate its test-retest reliability and predictive validity.", "metadata": {}}
+{"_id": "24557631", "title": "", "text": "Prevalence of Multiple Sclerosis in Isfahan, IranBackground: The prevalence of multiple sclerosis (MS)shows considerable variability all over the world. According to Kurtzke, Iran is considered to have a lowprevalence. Objective: To estimate the period prevalence and risk factors of MS in Isfahan, central part ofIran. Methods: A cross-sectional case register study conducted between 2004 and 2005. In the provinceof Isfahan, Iran, all patients known to have definite MS during 2004 and 2005, being alive and residentwithin Isfahan as well as being a member of the Isfahan MS Association were included in the study.Demographic and case-related information was recorded. 1,391 definite MS patients (308 men and 1,083women) from the Isfahan MS Association, Iran, have been identified. The disease was confirmed usingclinical information and MRI findings by a neurologist and radiologist. The patients were evaluated byinterview and a questionnaire. Population data were obtained from the year 1999 Iran Census. The mean(SD) age of the participants was 32.5 (9.3) years with a mean (SD) duration of the disease of 6.4 (5.1)years for men and 6.9 (5.3) years for women. Results: The period prevalence of MS was 35.5 per100,000 [95% confidence interval (CI) 33.6–37.3] in a population of 3,923,255, with a higher rate inwomen than men [54.5 (95% CI: 51.1–57.8) for women and 14.9 (95% CI: 13.3–16.6) for men]. Thefemale/male ratio was 3.6 (95% CI: 3.2–4.1). The direct age-adjusted period prevalence was 59.5 per100,000 (95% CI: 44.8–75.2) for women and 17.0 per 100,000 (95% CI: 8.9–25.1) for men. MS rateswere highest among 30- to 39-year-olds and decreased with increasing age. Sensory and visualdisturbances were the most common initial presentations with a prevalence of 51.1% (95% CI:48.4–53.7) and 47.0% (95% CI: 44.4–49.7), respectively. Conclusion: Isfahan could be considered as anarea with a medium to high risk of MS. This is in sharp contrast with the gradient hypothesis.", "metadata": {}}
+{"_id": "24558930", "title": "", "text": "A kinetochore-independent mechanism drives anaphase chromosome separation during acentrosomalmeiosisAlthough assembly of acentrosomal meiotic spindles has been extensively studied, little is knownabout the segregation of chromosomes on these spindles. Here, we show in Caenorhabditis elegansoocytes that the kinetochore protein, KNL-1, directs assembly of meiotic kinetochores that orientchromosomes. However, in contrast to mitosis, chromosome separation during meiotic anaphase iskinetochore-independent. Before anaphase, meiotic kinetochores and spindle poles disassemble alongwith the microtubules on the poleward side of chromosomes. During anaphase, microtubules then formbetween the separating chromosomes. Functional analysis implicated a set of proteins that localize to aring-shaped domain between kinetochores during pre-anaphase spindle assembly and anaphaseseparation. These proteins are localized by the chromosomal passenger complex, which regulates the lossof meiotic chromosome cohesion. Thus, meiotic segregation in C. elegans is a two-stage process, wherekinetochores orient chromosomes, but are then dispensable for their separation. We suggest thatseparation is controlled by a meiosis-specific chromosomal domain to coordinate cohesin removal andchromosome segregation.", "metadata": {}}
+{"_id": "24575065", "title": "", "text": "Association between the Medicare Modernization Act of 2003 and patient wait times and travel distancefor chemotherapy.CONTEXT The Medicare Prescription Drug, Improvement, and Modernization Act of2003 (MMA) altered reimbursements for outpatient chemotherapy drugs and drug administrationservices. Anecdotal reports suggest that these adjustments may have negatively affected access tochemotherapy for Medicare beneficiaries. OBJECTIVE To compare patient wait times and travel distancesfor chemotherapy before and after the enactment of the MMA. DESIGN, SETTING, AND PATIENTSAnalysis of a nationally representative 5% sample of claims from the Centers for Medicare & MedicaidServices for the period 2003 through 2006. Patients were Medicare beneficiaries with incident breastcancer, colorectal cancer, leukemia, lung cancer, or lymphoma who received chemotherapy in inpatienthospital, institutional outpatient, or physician office settings. MAIN OUTCOME MEASURES Days fromincident diagnosis to first chemotherapy visit and distance traveled for treatment, controlling for age, sex,race/ethnicity, cancer type, geographic region, comorbid conditions, and year of diagnosis and treatment.RESULTS There were 5082 incident cases of breast cancer, colorectal cancer, leukemia, lung cancer, orlymphoma in 2003; 5379 cases in 2004; 5116 cases in 2005; and 5288 cases in 2006. Approximately70% of patients received treatment in physician office settings in each year. Although the distribution oftreatment settings in 2004 and 2005 was not significantly different from 2003 (P = .24 and P = .72,respectively), there was a small but significant change from 2003 to 2006 (P = .02). The proportion ofpatients receiving chemotherapy in inpatient settings decreased from 10.2% in 2003 to 8.8% in 2006 (P= .03), and the proportion in institutional outpatient settings increased from 21.1% to 22.5% (P = .004).The proportion in physician offices remained at 68.7% (P = .29). The median time from diagnosis toinitial chemotherapy visit was 28 days in 2003, 27 days in 2004, 29 days in 2005, and 28 days in 2006.In multivariate analyses, average wait times for chemotherapy were 1.96 days longer in 2005 than in2003 (95% confidence interval [CI], 0.11-3.80 days; P = .04) but not significantly different in 2006 (0.88days; 95% CI, -0.96 to 2.71 days; P = .35). Median travel distance was 7 miles (11.2 km) in 2003 and 8miles (12.8 km) in 2004 through 2006. After adjustment, average travel distance remained slightlylonger in 2004 (1.47 miles [2.35 km]; 95% CI, 0.87-2.07 miles [1.39-3.31 km]; P < .001), 2005 (1.19miles [1.90 km]; 95% CI, 0.58-1.80 miles [0.93-2.88 km]; P < .001), and 2006 (1.30 miles [2.08 km];95% CI, 0.69-1.90 miles [1.10-3.04 km]; P < .001) compared with 2003. CONCLUSION There have notbeen major changes in travel distance and patient wait times for chemotherapy in the Medicarepopulation since 2003, the year before MMA-related changes in reimbursement.", "metadata": {}}
+{"_id": "24581365", "title": "", "text": "20-year outcomes following conservative management of clinically localized prostate cancer.CONTEXTThe appropriate therapy for men with clinically localized prostate cancer is uncertain. A recent studysuggested an increasing prostate cancer mortality rate for men who are alive more than 15 yearsfollowing diagnosis. OBJECTIVE To estimate 20-year survival based on a competing risk analysis of menwho were diagnosed with clinically localized prostate cancer and treated with observation or androgenwithdrawal therapy alone, stratified by age at diagnosis and histological findings. DESIGN, SETTING, ANDPATIENTS A retrospective population-based cohort study using Connecticut Tumor Registry datasupplemented by hospital record and histology review of 767 men aged 55 to 74 years with clinicallylocalized prostate cancer diagnosed between January 1, 1971, and December 31, 1984. Patients weretreated with either observation or immediate or delayed androgen withdrawal therapy, with a medianobservation of 24 years. MAIN OUTCOME MEASURES Probability of mortality from prostate cancer orother competing medical conditions, given a patient's age at diagnosis and tumor grade. RESULTS Theprostate cancer mortality rate was 33 per 1000 person-years during the first 15 years of follow-up (95%confidence interval [CI], 28-38) and 18 per 1000 person-years after 15 years of follow-up (95% CI,10-29). The mortality rates for these 2 follow-up periods were not statistically different, after adjustingfor differences in tumor histology (rate ratio, 1.1; 95% CI, 0.6-1.9). Men with low-grade prostate cancershave a minimal risk of dying from prostate cancer during 20 years of follow-up (Gleason score of 2-4, 6deaths per 1000 person-years; 95% CI, 2-11). Men with high-grade prostate cancers have a highprobability of dying from prostate cancer within 10 years of diagnosis (Gleason score of 8-10, 121 deathsper 1000 person-years; 95% CI, 90-156). Men with Gleason score of 5 or 6 tumors have an intermediaterisk of prostate cancer death. CONCLUSION The annual mortality rate from prostate cancer appears toremain stable after 15 years from diagnosis, which does not support aggressive treatment for localizedlow-grade prostate cancer.", "metadata": {}}
+{"_id": "24586989", "title": "", "text": "Role of beta adrenergic receptor polymorphisms in heart failure: systematic review andmeta-analysis.Heart Failure (HF) is a common disorder associated with substantial morbidity andmortality. beta adrenergic receptors (betaAR) are the primary pathway through which cardiac function isinfluenced. Chronic beta(1)AR activation is implicated in the pathogenesis of HF and betaAR blockadeimproves survival in left ventricular systolic dysfunction. Common functional polymorphisms in betaadrenergic receptor genes (ADRB) have been associated with HF phenotypes, and with pharmacogeneticinteraction with beta adrenergic receptor blockers (beta blockers). However, these associations have notbeen consistently replicated. The evidence for ADRB variant involvement in pathogenesis, progressionand response to beta blockers in HF is reviewed. In addition, a meta-analysis of three studies analysingthe effect of ADRB1 Arg389Gly polymorphism on left ventricular remodelling with the use of betablockers, demonstrating a 5% improvement in left ventricular ejection fraction in Arg389 homozygotes, ispresented. There is now accumulating molecular evidence for a different functional response to betablockers associated with this polymorphism. In the future, confirmed genotypic associations may enablepatients to be identified who are either at greater risk of developing HF, whose HF may rapidly progress,or who are unlikely to benefit from beta blockers, and such patients may benefit from targeted aggressivetherapy.", "metadata": {}}
+{"_id": "24594624", "title": "", "text": "New development of the yolk sac theory in diabetic embryopathy: molecular mechanism and link tostructural birth defects.Maternal diabetes mellitus is a significant risk factor for structural birth defects,including congenital heart defects and neural tube defects. With the rising prevalence of type 2 diabetesmellitus and obesity in women of childbearing age, diabetes mellitus-induced birth defects have becomean increasingly significant public health problem. Maternal diabetes mellitus in vivo and high glucose invitro induce yolk sac injuries by damaging the morphologic condition of cells and altering the dynamics oforganelles. The yolk sac vascular system is the first system to develop during embryogenesis; therefore,it is the most sensitive to hyperglycemia. The consequences of yolk sac injuries include impairment ofnutrient transportation because of vasculopathy. Although the functional relationship between yolk sacvasculopathy and structural birth defects has not yet been established, a recent study reveals that thequality of yolk sac vasculature is related inversely to embryonic malformation rates. Studies in animalmodels have uncovered key molecular intermediates of diabetic yolk sac vasculopathy, which includehypoxia-inducible factor-1α, apoptosis signal-regulating kinase 1, and its inhibitor thioredoxin-1,c-Jun-N-terminal kinases, nitric oxide, and nitric oxide synthase. Yolk sac vasculopathy is also associatedwith abnormalities in arachidonic acid and myo-inositol. Dietary supplementation with fatty acids thatrestore lipid levels in the yolk sac lead to a reduction in diabetes mellitus-induced malformations.Although the role of the human yolk in embryogenesis is less extensive than in rodents, nevertheless,human embryonic vasculogenesis is affected negatively by maternal diabetes mellitus. Mechanisticstudies have identified potential therapeutic targets for future intervention against yolk sac vasculopathy,birth defects, and other complications associated with diabetic pregnancies.", "metadata": {}}
+{"_id": "24596228", "title": "", "text": "Hepatitis B and C in HIV-infected patients. Prevalence and prognostic value.BACKGROUND/AIMS There isonly limited information on the prevalence and influence of coinfection with either hepatitis B or C on theclinical course in patients infected with the human immunodeficiency virus (HIV). METHODS Follow-upwas available in 232 HIV-infected patients (age 37+/-8 years, CD4 count 167+/-167 microl; 46% hadAIDS). Samples were investigated for markers of HBV and HCV infection (HBsAg, HBeAg, HBV-DNA,Anti-HBs, anti-HBc, anti-HCV, HCV-RNA). RESULTS 60/232 patients (23%) were anti-HCV positive. 78%of these sera were positive for HCV-RNA. 22/232 patients (9%) suffered from chronic HBV infection(HBsAg positive), 18/22 (82%) of these sera had detectable HBeAg and 19/22 (86%) HBV-DNA.Presence of HCV-RNA, HBeAg and amount of HBV-DNA were related to the degree of immunodeficiency.In contrast to the control group without HBV or HCV infection, patients infected with HIV and either HBVor HCV showed a direct correlation between a reduction in CD4 counts and decreased cholinesteraseactivity. In patients with AIDS, coinfection with HBV or HCV was associated with a reduced survivalcompared to controls (HBV: 212 days, 95%CI, 106-317; HCV: 267, 95%CI, 112-396; controls: 439 days,95%CI, 364-513). CONCLUSIONS Coinfection of HIV and HBV or HCV is frequently observed. Our resultssuggest that with prolonged survival of HIV-infected patients, coinfection with either HBV or HCVcorrelates with a reduced survival rate.", "metadata": {}}
+{"_id": "24612804", "title": "", "text": "Requirement of endogenous stem cell factor and granulocyte-colony-stimulating factor forIL-17-mediated granulopoiesis.IL-17 is a novel, CD4+ T cell-restricted cytokine. In vivo, it stimulateshematopoiesis and causes neutrophilia consisting of mature granulocytes. In this study, we show thatIL-17-mediated granulopoiesis requires G-CSF release and the presence or induction of thetransmembrane form of stem cell factor (SCF) for optimal granulopoiesis. However, IL-17 also protectsmice from G-CSF neutralization-induced neutropenia. G-CSF neutralization completely reversedIL-17-induced BM progenitor expansion, whereas splenicCFU-GM/CFU-granulocyte-erythrocyte-megakaryocyte-monocyte was only reduced by 50% in both Sl/Sldand littermate control mice. Thus, there remained a significant SCF/G-CSF-independent effect of IL-17 onsplenic granulopoiesis, resulting in a preservation of mature circulating granulocytes. IL-17 is a cytokinethat potentially interconnects lymphocytic and myeloid host defense and may have potential fortherapeutic development.", "metadata": {}}
+{"_id": "24624992", "title": "", "text": "The expression of immediate early gene X-1 (IEX-1) is differentially induced by retinoic acids in NB4 andKG1 cells: possible implication in the distinct phenotype of retinoic acid-responsive and -resistantleukemic cellsIn a cell-type- and stimulus-dependent fashion, the early response gene immediate earlygene X-1 (IEX-1) is involved in growth control and modulation of apoptosis. The present studydemonstrates that, in the two acute promyelocytic leukemia (APL) cell lines NB4 and KG1, exhibitingdistinct responsiveness to retinoic acids (RAs), IEX-1 expression is rapidly (30–60 min) induced byall-trans- or cis-RA and independently of other signal transduction mediators, such as TNFα, NF-κB orMAP kinases. In NB4 cells (expressing PML–RARα), this increase is transient and completely reversible,along with a cell cycle arrest, ongoing differentiation and lower sensitivity to anti-cancer-drug-inducedapoptosis. In contrast, the RA-induced IEX-1 expression in KG1 cells (expressing PLZF–RARα) persistsover days, along with continued cell cycle progression and increased apoptotic sensitivity. Furthermore,two functional RA-response elements in the IEX-1 promoter were identified by gel shift and luciferasereporter gene assays. IEX-1 might be a rather unique transcriptional target of the two X–RARα fusionreceptors exhibiting distinct responsiveness to RAs. Following a different time course of directtranscriptional induction by PML–RARα and PLZF–RARα in NB4 and KG1 cells, respectively, IEX-1expression may be involved in the modified actions of these receptors and the distinct phenotypes of APLcells.", "metadata": {}}
+{"_id": "24625323", "title": "", "text": "Comorbidity between ADHD and obesity: exploring shared mechanisms and clinical implications.Recentstudies suggest an association between attention-deficit/hyperactivity disorder (ADHD) and obesity. Inthis article, we systematically review and critically discuss evidence on the prevalence of ADHD in obesepatients as well as the weight status of individuals with ADHD. Relevant articles were searched inPubMed, PsychInfo, and ISI Web of Science (January 1980 to June 2010). We found that currentevidence indicates a high prevalence of ADHD in clinical samples of patients seeking treatment for theirobesity. Moreover, available studies show that individuals with ADHD have higher-than-average bodymass index z scores and/or a significantly higher prevalence of obesity compared with subjects withoutADHD. Three mechanisms underlying the association between ADHD and obesity have been proposed: 1)it is possible that obesity and/or factors associated with it (such as sleep-disordered breathing) manifestas ADHD-like symptoms; 2) ADHD and obesity share common biological dysfunctions; and 3) ADHDcontributes to obesity. With regards to the possible clinical implications, our findings suggest that it isnoteworthy to screen for ADHD in patients with obesity and to look for abnormal eating behaviors aspossible contributing factors of obesity in patients with ADHD. Based on preliminary findings, appropriatetreatment of ADHD may improve the weight status of individuals with both obesity and ADHD.", "metadata": {}}
+{"_id": "24632480", "title": "", "text": "Rapamycin treatment augments motor neuron degeneration in SOD1(G93A) mouse model ofamyotrophic lateral sclerosis.Aberrant protein misfolding may contribute to the pathogenesis ofamyotrophic lateral sclerosis (ALS) but the detailed mechanisms are largely unknown. Our previous studyhas shown that autophagy is altered in the mouse model of ALS. In the present study, we systematicallyinvestigated the correlation of the autophagic alteration with the motor neurons (MNs) degeneration inthe ALS mice. We have demonstrated that the autophagic protein marker LC3-II is markedly andspecifically increased in the spinal cord MNs of the ALS mice. Electron microscopy and immunochemistrystudies have shown that autophagic vacuoles are significantly accumulated in the dystrophic axons ofspinal cord MNs of the ALS mice. All these changes in the ALS mice appear at the age of 90 d when theALS mice display modest clinical symptoms; and they become prominent at the age of 120 d. The clinicalsymptoms are correlated with the progression of MNs degeneration. Moreover, we have found thatp62/SQSTM1 is accumulated progressively in the spinal cord, indicating that the possibility of impairedautophagic flux in the SOD1(G93A) mice. Furthermore, to our surprise, we have found that treatmentwith autophagy enhancer rapamycin accelerates the MNs degeneration, shortens the life span of the ALSmice, and has no obvious effects on the accumulation of SOD1 aggregates. In addition, we havedemonstrated that rapamycin treatment in the ALS mice causes more severe mitochondrial impairment,higher Bax levels and greater caspase-3 activation. These findings suggest that selective degeneration ofMNs is associated with the impairment of the autophagy pathway and that rapamycin treatment mayexacerbate the pathological processing through apoptosis and other mechanisms in the ALS mice.", "metadata": {}}
+{"_id": "24634621", "title": "", "text": "Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients withadvanced pancreas cancer: a randomized trial.PURPOSE Most patients with advanced pancreas cancerexperience pain and must limit their daily activities because of tumor-related symptoms. To date, notreatment has had a significant impact on the disease. In early studies with gemcitabine, patients withpancreas cancer experienced an improvement in disease-related symptoms. Based on those findings, adefinitive trial was performed to assess the effectiveness of gemcitabine in patients with newly diagnosedadvanced pancreas cancer. PATIENTS AND METHODS One hundred twenty-six patients with advancedsymptomatic pancreas cancer completed a lead-in period to characterize and stabilize pain and wererandomized to receive either gemcitabine 1,000 mg/m2 weekly x 7 followed by 1 week of rest, thenweekly x 3 every 4 weeks thereafter (63 patients), or to fluorouracil (5-FU) 600 mg/m2 once weekly (63patients). The primary efficacy measure was clinical benefit response, which was a composite ofmeasurements of pain (analgesic consumption and pain intensity), Karnofsky performance status, andweight. Clinical benefit required a sustained (> or = 4 weeks) improvement in at least one parameterwithout worsening in any others. Other measures of efficacy included response rate, time to progressivedisease, and survival. RESULTS Clinical benefit response was experienced by 23.8% ofgemcitabine-treated patients compared with 4.8% of 5-FU-treated patients (P = .0022). The mediansurvival durations were 5.65 and 4.41 months for gemcitabine-treated and 5-FU-treated patients,respectively (P = .0025). The survival rate at 12 months was 18% for gemcitabine patients and 2% for5-FU patients. Treatment was well tolerated. CONCLUSION This study demonstrates that gemcitabine ismore effective than 5-FU in alleviation of some disease-related symptoms in patients with advanced,symptomatic pancreas cancer. Gemcitabine also confers a modest survival advantage over treatmentwith 5-FU.", "metadata": {}}
+{"_id": "24640046", "title": "", "text": "Endothelial-myofibroblast transition contributes to the early development of diabetic renal interstitialfibrosis in streptozotocin-induced diabetic mice.Diabetic nephropathy is the leading cause of chronic renalfailure. Myofibroblasts play a major role in the synthesis and secretion of extracellular matrix in diabeticrenal fibrosis. Increasing evidence suggests that endothelial cells may undergo endothelial-myofibroblasttransition under physiological and pathophysiological circumstances. Therefore, this study investigateswhether endothelial-myofibroblast transition occurs and contributes to the development of diabetic renalinterstitial fibrosis. Diabetes was induced by administration of streptozotocin to Tie2-Cre;LoxP-EGFP mice,an endothelial lineage-traceable mouse line generated by crossbreeding B6.Cg-Tg(Tek-cre)12F1v/J micewith B6.Cg-Tg(ACTB-Bgeo/GFP)21Lbe/J mice. The endothelial-myofibroblast transition was also studiedin MMECs (a mouse pancreatic microvascular endothelial cell line) and primary cultures of CD31+/EYFP-(enhanced yellow fluorescent protein) endothelial cells isolated from adult normal alpha-smooth muscleactin promoter-driven-EYFP (alpha-SMA/EYFP) mouse kidneys. Confocal microscopy demonstrated that10.4 +/- 4.2 and 23.5 +/- 7.4% of renal interstitial myofibroblasts (alpha-SMA+) in 1- and 6-monthstreptozotocin-induced diabetic kidneys were of endothelial origin (EGFP+/alpha-SMA+ cells), comparedwith just 0.2 +/- 0.1% of myofibroblasts in vehicle-treated Tie2-Cre;LoxP-EGFP mice (P < 0.01).Confocal microscopy and real-time PCR showed that transforming growth factor (TGF)-beta1 induced denovo expression of alpha-SMA and loss of expression of VE-cadherin and CD31 in MMECs and primarycultures of renal endothelial cells in a time- and dose-dependent fashion. These findings demonstrate thatthe endothelial-myofibroblast transition occurs and contributes to the early development and progressionof diabetic renal interstitial fibrosis and suggest that the endothelial-myofibroblast transition may be atherapeutic target.", "metadata": {}}
+{"_id": "24645237", "title": "", "text": "Effect of phosducin silencing on the photokinetic motile response of Blepharisma japonicum.The colouredciliate Blepharisma japonicum changes swimming velocity (positive photokinesis) and elongates its bodyin response to a prolonged illumination. We have recently proposed that alterations in thephosphorylation level of the ciliate phosducin (Pdc) may be involved in light-induced cell elongation,which in turn affects the interaction of βγ-dimer of G-proteins (Gβγ) with β-tubulin and subsequentcytoskeletal remodelling. The cellular mechanism that governs the photokinetic effect in this ciliate hasnot been elucidated. In the present study, we utilise real-time PCR to demonstrate that the levels ofciliate Pdc mRNA are significantly reduced in Pdc-RNAi-treated cells compared to cells fed with bacteriacarrying the empty vector (control cells). Using western immunoblotting, we confirmed that these cellstreated with Pdc-RNAi expressed a substantially lower level of the Pdc protein. The assay also revealedthat in ciliates treated with Pdc-RNAi and exposed to light, the cytosolic level of Gβ (~36 kDa) wasreduced, whereas the level of Gβ localized to the membrane (~32 kDa) was increased compared tocontrol cells. In addition, behavioural analysis of the cells indicated a substantial reduction ofphotokinesis. The findings in this study provide additional characterization of the functional properties ofthe ciliate Pdc protein and we discuss a likely role for this phosphoprotein in the photokineticphenomenon of the ciliate protist Blepharisma.", "metadata": {}}
+{"_id": "24652030", "title": "", "text": "Alzheimer’s disease and NGF signalingAge-related degeneration of basal forebrain cholinergic neurons(BFCNs) occurs early and contributes significantly to cognitive decline in Alzheimer’s disease (AD). Properfunction and morphology of BFCNs depends on the supply of nerve growth factor (NGF) from the cortexand the hippocampus. A large number of experiments have shown that decreased supply of NGF at thelevel of BFCN cell bodies leads to loss of neuronal markers and shrinkage, mimicking what is observed inAD. The delivery of sufficient amounts of NGF signal to BFCN cell bodies depends on the effectiveparticipation of several factors including sufficient synthesis and release of NGF, adequate synthesis andexpression of NGF receptors by BFCNs, normal signaling and retrograde transport of NGF-receptorcomplex, and finally effective induction of gene expression by NGF. In the past few years it has becomeclear that decreased amounts of NGF at the level of BFCN cell bodies is largely due to failed retrogradetransport rather than decreased synthesis, binding or expression of NGF receptors in the BFCN terminals.We will discuss in vivo evidence supporting decreased retrograde transport of NGF in a mouse model withBFCN degeneration, and will attempt to match these findings with our studies in postmortem human ADbrain. We will speculate about the possible mechanisms of failed NGF retrograde transport and itsrelationship to AD pathology.", "metadata": {}}
+{"_id": "24660385", "title": "", "text": "Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings.Todetermine the accuracy of echocardiographic left ventricular (LV) dimension and mass measurements fordetection and quantification of LV hypertrophy, results of blindly read antemortem echocardiograms werecompared with LV mass measurements made at necropsy in 55 patients. LV mass was calculated usingM-mode LV measurements by Penn and American Society of Echocardiography (ASE) conventions andcube function and volume correction formulas in 52 patients. Penn-cube LV mass correlated closely withnecropsy LV mass (r = 0.92, p less than 0.001) and overestimated it by only 6%; sensitivity in 18patients with LV hypertrophy (necropsy LV mass more than 215 g) was 100% (18 of 18 patients) andspecificity was 86% (29 of 34 patients). ASE-cube LV mass correlated similarly to necropsy LV mass (r =0.90, p less than 0.001), but systematically overestimated it (by a mean of 25%); the overestimationcould be corrected by the equation: LV mass = 0.80 (ASE-cube LV mass) + 0.6 g. Use of ASEmeasurements in the volume correction formula systematically underestimated necropsy LV mass (by amean of 30%). In a subset of 9 patients, 3 of whom had technically inadequate M-modeechocardiograms, 2-dimensional echocardiographic (echo) LV mass by 2 methods was also significantlyrelated to necropsy LV mass (r = 0.68, p less than 0.05 and r = 0.82, p less than 0.01). Among otherindexes of LV anatomy, only measurement of myocardial cross-sectional area was acceptably accurate forquantitation of LV mass (r = 0.80, p less than 0.001) or diagnosis of LV hypertrophy (sensitivity = 72%,specificity = 94%).(ABSTRACT TRUNCATED AT 250 WORDS)", "metadata": {}}
+{"_id": "24670522", "title": "", "text": "R93W mutation in Orai1 causes impaired calcium influx in platelets.The intracellular Ca(2+) concentrationof many nonexcitable cells is regulated by calcium store release and store-operated calcium entry(SOCE). In platelets, STIM1 was recently identified as the main calcium sensor expressed in theendoplasmic reticulum. To evaluate the role of the SOC channel moiety, Orai1, in platelet SOCE, wegenerated mice expressing a mutated, inactive form of Orai1 in blood cells only (Orai1(R93W)). Plateletsexpressing Orai1(R93W) were characterized by markedly reduced SOCE and impaired agonist-inducedincreases in [Ca(2+)](i). Orai1(R93W) platelets showed reduced integrin activation and impaireddegranulation when stimulated with low agonist concentrations under static conditions. This defect,however, did not significantly affect the ability of Orai1(R93W) platelets to aggregate or to adhere tocollagen under arterial flow conditions ex vivo. In contrast, these adherent Orai1(R93W) platelets weredefective in surface phosphatidylserine exposure, suggesting that Orai1 is crucial for the platelets'procoagulant response rather than for other Ca(2+)-dependent cellular responses.", "metadata": {}}
+{"_id": "24697979", "title": "", "text": "[Efficacy on post-stroke depression treated with acupuncture at the acupoints based on ziwuliuzhu andprozac].OBJECTIVE To observe the effects on post-stroke depression treated with acupuncture at the acupoints based on ziwuliuzhu (the midnight-noon ebb-flow theory). METHODS Ninety-three patients wererandomized into a comprehensive group, a ziwuliuzhu group and a prozac group, 31 cases in each group.In the ziwuliuzhu group, acupuncture was applied to the acupoints based on ziwuliuzhu, once a day, 5times in a week. In the prozac group, fluoxertine hydrochloride (prozac) was prescribed for oraladministration, once a day, 20 mg each time. In the comprehensive group, acupuncture based onziwuliuzhu combined with the oral administration of prozac were adopted and the treatment frequencywas the same as the ziwuliuzhu group and the prozac group. The 4-week treatment was taken as onesession in the three groups and 6 sessions were required totally. The clinical efficacy and the Hamiltondepression rating scale (HAMD) score and the adverse reaction were compared among the 3 groups.RESULTS The total effective rate was 96.8% (30/31) in the comprehensive group, better than 83.9%(26/31) in the ziwuliuzhu group and 80. 6% (25/31) in the prozac group (both P<0.05). In 4, 12 and 24weeks of treatment, HAMD score was lower significantly than that before the treatment in the threegroups (all P<0.05), and the score in the comprehensive group at each time point after treatment waslower than the other two groups (all P<0.05). In 4 and 12 weeks of treatment, there were not differentsignificantly between the ziwuliuzhu group and the prozac group (both P>0.05). In 24 weeks oftreatment, HAMD score in the ziwuliuzhu group was lower than that in the prozac group (P<0.05). For theadverse reaction, there were 2 cases in the comprehensive group, 6 cases in the prozac group and 0 casein the ziwzuliuzhu group. CONCLUSION The comprehensive therapy of acupuncture at the acupointsbased on ziwuliuzhu and oral administration of prozac is superior to either the simple oral administrationof prozac or the ziwuliuzhu acu-puncture in terms of clinical efficacy and the improvements in depressivestate. Regarding the clinical efficacy, the impact of simple ziwuliuzhu acupuncture is not differentsignificantly as compared with the simple oral administration of prozac, but it is better than the simpleoral administration of prozac in terms of the long-term HAMD score and safety.", "metadata": {}}
+{"_id": "24700152", "title": "", "text": "Linkage with methadone treatment upon release from incarceration: a promising opportunity.Injectiondrug users (IDUs) are at increased risk for HIV, viral hepatitis, and tuberculosis, and making up morethan a quarter of the incarcerated population in the United States. Methadone maintenance treatment ofopiate addiction is highly effective at reducing drug use, drug-related criminal activity, and risk of HIVtransmission. Recently released inmates are at particularly high risk for overdose and diseasetransmission. Linkage to methadone treatment immediately upon release from incarceration is apromising opportunity to combat disease transmission, facilitate reentry into the community, and reducerecidivism.", "metadata": {}}
+{"_id": "24704139", "title": "", "text": "The Diabetes Prevention Program: baseline characteristics of the randomized cohort. The DiabetesPrevention Program Research Group.OBJECTIVE The Diabetes Prevention Program (DPP) is a 27-centerrandomized clinical trial designed to evaluate the safety and efficacy of interventions that may delay orprevent development of diabetes in people at increased risk for type 2 diabetes. RESEARCH DESIGN ANDMETHODS Eligibility requirements were age > or = 25 years, BMI > or = 24 kg/m2 (> or = 22 kg/m2 forAsian-Americans), and impaired glucose tolerance plus a fasting plasma glucose of 5.3-6.9 mmol/l (or <or = 6.9 mmol for American Indians). Randomization of participants into the DPP over 2.7 years ended inJune 1999. Baseline data for the three treatment groups--intensive lifestyle modification, standard careplus metformin, and standard care plus placebo--are presented for the 3,234 participants who have beenrandomized. RESULTS Of all participants , 55% were Caucasian, 20% were African-American, 16% wereHispanic, 5% were American Indian, and 4% were Asian-American. Their average age at entry was 51+/- 10.7 years (mean +/- SD), and 67.7% were women. Moreover, 16% were < 40 years of age, and20% were > or = 60 years of age. Of the women, 48% were postmenopausal. Men and women hadsimilar frequencies of history of hypercholesterolemia (37 and 33%, respectively) or hypertension (29and 26%, respectively). On the basis of fasting lipid determinations, 54% of men and 40% of women fitNational Cholesterol Education Program criteria for abnormal lipid profiles. More men than women werecurrent or former cigarette smokers or had a history of coronary heart disease. Furthermore, 66% of menand 71% of women had a first-degree relative with diabetes. Overall, BMI averaged 34.0 +/- 6.7 kg/m2at baseline with 57% of the men and 73% of women having a BMI > or = 30 kg/m2. Average fastingplasma glucose (6.0 +/- 0.5 mmol/l) and HbA1c (5.9 +/- 0.5%) in men were comparable with values inwomen (5.9 +/- 0.4 mmol/l and 5.9 +/- 0.5%, respectively). CONCLUSIONS The DPP has successfullyrandomized a large cohort of participants with a wide distribution of age, obesity, and ethnic and racialbackgrounds who are at high risk for developing type 2 diabetes. The study will examine the effects ofinterventions on the development of diabetes.", "metadata": {}}
+{"_id": "24705390", "title": "", "text": "Chronic Helicobacter pylori infections induce gastric mutations in mice.BACKGROUND & AIMSHelicobacter pylori is an important etiologic factor in the development of gastric cancer. The aim of thisstudy was to analyze the role of H. pylori infections in the induction of mutagenic events in gastricepithelial cells. The effect of a high-salt diet as a genotoxic risk factor was also investigated. METHODSBig Blue transgenic male mice (C57Bl/6) were inoculated with H. pylori (strain SS1) or Helicobacter felis(strain CS1) for 6 and 12 months. The frequency and spectrum of mutations at the stomach level wereassessed. Inflammatory host response and inducible nitric oxide synthase (iNOS) expression byreverse-transcription polymerase chain reaction and immunohistochemistry analysis were alsoperformed. RESULTS After 6 months, the gastric mutant frequency was 4-fold and 1.7-fold higher in miceinfected with H. pylori and H. felis, respectively, than in uninfected mice. It was associated with a highfrequency of transversions (AT --> CG and GC --> TA) known to result from oxidative damages. TheHelicobacter-infected mice exhibited severe gastritis and a high level of iNOS messenger RNA expression.Hyperplasia developed 12 months after inoculation, and both the mutagenic effects and iNOS expressiondecreased in H. pylori- and H. felis-infected mice. No synergistic effects of a high-salt diet andHelicobacter infection were observed regarding the frequency of gastric mutation. CONCLUSIONS A directgastric mutagenic effect due to H. pylori infection in the Big Blue transgenic mouse model has beenshown 6 months after inoculation. This genotoxicity can be attributable to oxidative DNA damageinvolving the inflammatory host response.", "metadata": {}}
+{"_id": "24706198", "title": "", "text": "A minimal Tat system from a gram-positive organism: a bifunctional TatA subunit participates in discreteTatAC and TatA complexes.The Tat system transports folded proteins across bacterial and thylakoidmembranes. In Gram-negative organisms, a TatABC substrate-binding complex and separate TatAcomplex are believed to coalesce to form an active translocon, with all three subunits essential fortranslocation. Most Gram-positive organisms lack a tatB gene, indicating major differences inorganization and possible differences in mode of action. Here, we have studied Tat complexes encoded bythe tatAdCd genes of Bacillus subtilis. Expression of tatAdCd in an Escherichia coli tat null mutant resultsin efficient export of a large, cofactor-containing E. coli Tat substrate, TorA. We show that the tatAd genecomplements E. coli mutants lacking either tatAE or tatB, indicating a bifunctional role for this subunit inB. subtilis. Second, we have identified and characterized two distinct Tat complexes that are novel in keyrespects: a TatAdCd complex of approximately 230 kDa that is significantly smaller than the analogous E.coli TatABC complex (approximately 370 kDa on BN gels) and a separate TatAd complex. The latter is adiscrete entity of approximately 270 kDa as judged by gel filtration chromatography, very different fromthe highly heterogeneous E. coli TatA complex that ranges in size from approximately 50 kDa to over 600kDa. TatA heterogeneity has been linked to the varying size of Tat substrates being translocated, but thesingular nature of the B. subtilis TatAd complex suggests that discrete TatAC and TatA complexes mayform a single form of translocon.", "metadata": {}}
+{"_id": "24707550", "title": "", "text": "A systemic granulomatous response to Schistosoma mansoni eggs alters responsiveness ofbone-marrow-derived macrophages to Toll-like receptor agonists.Macrophages play a pivotal role ininnate and acquired immune responses to Schistosoma mansoni. Classical (M1) or alternative (M2)activation states of these cells further delineate their roles in tissue damage through innate immunity orfibrotic remodeling, respectively. In the present study, we addressed the following question: Doessystemic Th2-type cytokine polarization evoked by S. mansoni affect macrophage differentiation andactivation? To this end, we analyzed bone marrow-derived macrophages from mice with S. mansoniegg-induced pulmonary granulomas and unchallenged (or naïve) mice to determine their activation stateand their response to specific TLR agonists, including S. mansoni egg antigens. Unlike naïvemacrophages, macrophages from Th2-polarized mice constitutively expressed significantly higher \"foundin inflammatory zone-1\" (FIZZ1) and ST2 (M2 markers) and significantly lower NO synthase 2, CCL3,MIP-2, TNF-alpha, and IL-12 (M1 markers). Also, compared with naïve macrophages, Th2-polarizedmacrophages exhibited enhanced responses to the presence of specific TLR agonists, which consistentlyinduced significantly higher levels of gene and protein levels for M2 and M1 markers in these cells.Together, these data show that signals received by bone marrow precursors during S. mansoniegg-induced granuloma responses dynamically alter the development of macrophages and enhance theTLR responsiveness of these cells, which may ultimately have a significant effect on the pulmonarygranulomatous response.", "metadata": {}}
+{"_id": "24712186", "title": "", "text": "Orai1 and STIM reconstitute store-operated calcium channel function.The two membrane proteins, STIM1and Orai1, have each been shown to be essential for the activation of store-operated channels (SOC).Yet, how these proteins functionally interact is not known. Here, we reveal that STIM1 and Orai1expressed together reconstitute functional SOCs. Expressed alone, Orai1 strongly reduces store-operatedCa(2+) entry (SOCE) in human embryonic kidney 293 cells and the Ca(2+) release-activated Ca(2+)current (I(CRAC)) in rat basophilic leukemia cells. However, expressed along with the store-sensingSTIM1 protein, Orai1 causes a massive increase in SOCE, enhancing the rate of Ca(2+)entry by up to103-fold. This entry is entirely store-dependent since the same coexpression causes no measurablestore-independent Ca(2+) entry. The entry is completely blocked by the SOC blocker,2-aminoethoxydiphenylborate. Orai1 and STIM1 coexpression also caused a large gain in CRAC channelfunction in rat basophilic leukemia cells. The close STIM1 homologue, STIM2, inhibited SOCE whenexpressed alone but coexpressed with Orai1 caused substantial constitutive (store-independent) Ca(2+)entry. STIM proteins are known to mediate Ca(2+) store-sensing and endoplasmic reticulum-plasmamembrane coupling with no intrinsic channel properties. Our results revealing a powerful gain in SOCfunction dependent on the presence of both Orai1 and STIM1 strongly suggest that Orai1 contributes thePM channel component responsible for Ca(2+) entry. The suppression of SOC function by Orai1overexpression likely reflects a required stoichiometry between STIM1 and Orai1.", "metadata": {}}
+{"_id": "24713020", "title": "", "text": "Tet and TDG mediate DNA demethylation essential for mesenchymal-to-epithelial transition in somaticcell reprogramming.Tet-mediated DNA oxidation is a recently identified mammalian epigeneticmodification, and its functional role in cell-fate transitions remains poorly understood. Here, we derivemouse embryonic fibroblasts (MEFs) deleted in all three Tet genes and examine their capacity forreprogramming into induced pluripotent stem cells (iPSCs). We show that Tet-deficient MEFs cannot bereprogrammed because of a block in the mesenchymal-to-epithelial transition (MET) step.Reprogramming of MEFs deficient in TDG is similarly impaired. The block in reprogramming is caused atleast in part by defective activation of key miRNAs, which depends on oxidative demethylation promotedby Tet and TDG. Reintroduction of either the affected miRNAs or catalytically active Tet and TDG restoresreprogramming in the knockout MEFs. Thus, oxidative demethylation to promote gene activation appearsto be functionally required for reprogramming of fibroblasts to pluripotency. These findings providemechanistic insight into the role of epigenetic barriers in cell-lineage conversion.", "metadata": {}}
+{"_id": "24721347", "title": "", "text": "The last and the next hundred years of malariology.The founding fathers of malariology combinedscientific originality, perseverance in research, strong characters, breadth of interest and social concern.A hundred years later research and understanding has made immense progress but the world still bears ahuge burden of malaria. For the next century research requires both more specialism and a holistic rangeif it is to be used in control, requiring multidisciplinary team work. Environmental changes andinterventions produce a dynamic and changing pattern of malaria, not the static one of the past. From theoriginal parasite life cycle, research has analysed a series of other cycles at electron microscope,biochemical and genome levels on decreasing size scales and quantitative epidemiological cycles forcontrol. Recent additions to these concepts have been stage-specific antigens, cycles of disease ratherthan parasites alone, considering populations of parasites rather than just cases, and also geneticvariation in each component of the parasite-human host-vector triad. In this volume there emerges forthe first time a coherent overall picture of the biomedical aspects of basic malariology as the interactingpopulation genetics of malaria parasites, anophelines and people. This provides a coherent model for thenew century dealing with the great biological malaria problems of drug resistance, vaccine development,insecticidal and net control and can feed, with socio-economic work, into the gathering renewal of controlefforts. New work on large-scale changes of malaria in space and time enables us to be precise abouteffects of local and global environmental changes to predict epidemics. Future research will be as muchabout linking these different scales of understanding as control will be about linking different levels of thehealth system. The grim situation in poor holoendemic countries also requires practical support of thetype that the founders of malariology were involved in. A coherent understanding needs to feed into thenew control efforts, from Roll Back Malaria onwards, for the next century.", "metadata": {}}
+{"_id": "24721866", "title": "", "text": "Activation of AMP-activated protein kinase suppresses oxidized low-density lipoprotein-inducedmacrophage proliferation.Macrophage-derived foam cells play important roles in the progression ofatherosclerosis. We reported previously that ERK1/2-dependent granulocyte/macrophagecolony-stimulating factor (GM-CSF) expression, leading to p38 MAPK/ Akt signaling, is important foroxidized low density lipoprotein (Ox-LDL)-induced macrophage proliferation. Here, we investigatedwhether activation of AMP-activated protein kinase (AMPK) could suppress macrophage proliferation.Ox-LDL-induced proliferation of mouse peritoneal macrophages was assessed by [(3)H]thymidineincorporation and cell counting assays. The proliferation was significantly inhibited by the AMPK activator5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) and restored by dominant-negativeAMPKalpha1, suggesting that AMPK activation suppressed macrophage proliferation. AICAR partiallysuppressed Ox-LDL-induced ERK1/2 phosphorylation and GM-CSF expression, suggesting that anothermechanism is also involved in the AICAR-mediated suppression of macrophage proliferation. AICARsuppressed GM-CSF-induced macrophage proliferation without suppressing p38 MAPK/Akt signaling.GM-CSF suppressed p53 phosphorylation and expression and induced Rb phosphorylation.Overexpression of p53 or p27(kip) suppressed GM-CSF-induced macrophage proliferation. AICAR inducedcell cycle arrest, increased p53 phosphorylation and expression, and suppressed GM-CSF-induced Rbphosphorylation via AMPK activation. Moreover, AICAR induced p21(cip) and p27(kip) expression viaAMPK activation, and small interfering RNA (siRNA) of p21(cip) and p27(kip) restored AICAR-mediatedsuppression of macrophage proliferation. In conclusion, AMPK activation suppressed Ox-LDL-inducedmacrophage proliferation by suppressing GM-CSF expression and inducing cell cycle arrest. These effectsof AMPK activation may represent therapeutic targets for atherosclerosis.", "metadata": {}}
+{"_id": "24724242", "title": "", "text": "Evaluation of cortical bone by peripheral quantitative computed tomography in renal transplantrecipients.BACKGROUND The absolute risk of fractures in renal transplant patients is 3 times that ofmatched controls. Most of the symptomatic fractures are peripheral, suggesting a greater compromise ofcortical bone. Peripheral quantitative computed tomography (pQCT) is a new imaging technique thatallows separate noninvasive evaluations of cortical and trabecular bones. We investigated cortical boneby pQCT in 12 renal transplant patients (seven men and five women) for comparison with 27 normalcontrols. METHODS pQCT (XCT 960, Stratec, Pforheim, Germany) was performed upon the distal radiusof the nondominant forearm (15% the length of the ulna, proximal from the radius end plate). Weevaluated total and cortical bone mineral density (TBMD, cBMD), total (cross-sectional) and cortical area(TA, cA), cortical thickness (cThk), endosteal and periosteal circumferences, and the buckling ratio(r/cThK). RESULTS Compared with normal controls transplant patients as a whole showed a significantincrease in TA, in endosteal circumference (P < .001), and in the buckling ratio (P < .001) with asignificant reduction in cThK (P < .001). Female patients had a marked decrease in cA (51.4 vs 69.3[pixel n]; P < .0001) and cThK (2.08 vs 2.78 mm; P < .0001). Male patients also had a decrease in cThK(2.54 vs 3.30 mm; P = .0001) and an increase in endosteal perimeter (31.2 vs 26.4 mm; P < .0001).Total time on dialysis prior to renal graft correlated negatively with cortical thickness (r = .62; P < .01).CONCLUSIONS Our results suggest that a marked thinning of cortical bone may explain the increasedincidence of peripheral fractures among renal transplant patients.", "metadata": {}}
+{"_id": "24725136", "title": "", "text": "Ataxia, dementia, and hypogonadotropism caused by disordered ubiquitination.BACKGROUND Thecombination of ataxia and hypogonadism was first described more than a century ago, but its geneticbasis has remained elusive. METHODS We performed whole-exome sequencing in a patient with ataxiaand hypogonadotropic hypogonadism, followed by targeted sequencing of candidate genes in similarlyaffected patients. Neurologic and reproductive endocrine phenotypes were characterized in detail. Theeffects of sequence variants and the presence of an epistatic interaction were tested in a zebrafish model.RESULTS Digenic homozygous mutations in RNF216 and OTUD4, which encode a ubiquitin E3 ligase and adeubiquitinase, respectively, were found in three affected siblings in a consanguineous family. Additionalscreening identified compound heterozygous truncating mutations in RNF216 in an unrelated patient andsingle heterozygous deleterious mutations in four other patients. Knockdown of rnf216 or otud4 inzebrafish embryos induced defects in the eye, optic tectum, and cerebellum; combinatorial suppression ofboth genes exacerbated these phenotypes, which were rescued by nonmutant, but not mutant, humanRNF216 or OTUD4 messenger RNA. All patients had progressive ataxia and dementia. Neuronal loss wasobserved in cerebellar pathways and the hippocampus; surviving hippocampal neurons containedubiquitin-immunoreactive intranuclear inclusions. Defects were detected at the hypothalamic andpituitary levels of the reproductive endocrine axis. CONCLUSIONS The syndrome of hypogonadotropichypogonadism, ataxia, and dementia can be caused by inactivating mutations in RNF216 or by thecombination of mutations in RNF216 and OTUD4. These findings link disordered ubiquitination toneurodegeneration and reproductive dysfunction and highlight the power of whole-exome sequencing incombination with functional studies to unveil genetic interactions that cause disease. (Funded by theNational Institutes of Health and others.).", "metadata": {}}
+{"_id": "24726600", "title": "", "text": "Combination cancer immunotherapies tailored to the tumour microenvironmentEvidence suggests thatcancer immunotherapy will be a major part of the combination treatment plan for many patients withmany cancer types in the near future. There are many types of immune processes involving differentantitumour and tumour-promoting leucocytes, and tumour cells use many strategies to evade theimmune response. The tumour microenvironment can help determine which immune suppressivepathways become activated to restrain antitumour immunity. This includes immune checkpoint receptorson effector T-cells and myeloid cells, and release of inhibitory cytokines and metabolites. Therapeuticapproaches that target these pathways, particularly immune-checkpoint receptors, can induce durableantitumour responses in patients with advanced-stage cancers, including melanoma. Nevertheless, manypatients do not have a good response to monotherapy approaches and alternative strategies are requiredto achieve optimal therapeutic benefit. These strategies include eliminating the bulk of tumour cells toprovoke tumour-antigen release and antigen-presenting cell (APC) function, using adjuvants to enhanceAPC function, and using agents that enhance effector-cell activity. In this Review, we discuss thestratification of the tumour microenvironment according to tumour-infiltrating lymphocytes and PD-L1expression in the tumour, and how this stratification enables the design of optimal combination cancertherapies tailored to target different tumour microenvironments.", "metadata": {}}
+{"_id": "24730100", "title": "", "text": "Cyclic AMP-dependent phosphorylation of thromboxane A(2) receptor-associated Galpha(13).Although itis well established that cAMP inhibits platelet activation induced by all agonists, the thromboxane A(2)signal transduction pathway was found to be particularly sensitive to such inhibition. Therefore, weexamined whether cAMP-dependent kinase mediates phosphorylation of the thromboxane A(2)receptor-G-protein complex. It was found that cAMP induces protein kinase A-dependent[gamma-(32)P]ATP labeling of solubilized membrane proteins in the region of Galpha subunits, i.e. 38-45kDa. Moreover, ligand affinity chromatography purification of thromboxane A(2) receptor-G-proteincomplexes from these membranes revealed that 38-45-kDa phosphoproteins co-purify with thromboxaneA(2) receptors. Immunoprecipitation of the affinity column eluate with a Galpha(13) antibodydemonstrated that 8-Br-cAMP increased phosphorylation of thromboxane A(2) receptor-associatedGalpha(13) by 87 +/- 27%. In separate experiments, immunopurification of Galpha(13) on microtiterwells coated with a different Galpha(13) antibody revealed that 8-Br-cAMP increased Galpha(13)phosphorylation by 53 +/- 19%. Finally, treatment of (32)P-labeled whole platelets with prostacyclinresulted in a 90 +/- 14% increase in phosphorylated Galpha(13) that was abolished by pretreatment withthe adenylate cyclase inhibitor MDL-12. These results provide the first evidence that protein kinase Amediates phosphorylation of Galpha(13) both in vitro and in vivo and provides a basis for the preferentialinhibition of thromboxane A(2)-mediated signaling in platelets by cAMP.", "metadata": {}}
+{"_id": "24731248", "title": "", "text": "Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine.5-methylcytosine(5mC) in DNA plays an important role in gene expression, genomic imprinting, and suppression oftransposable elements. 5mC can be converted to 5-hydroxymethylcytosine (5hmC) by the Tet (teneleven translocation) proteins. Here, we show that, in addition to 5hmC, the Tet proteins can generate5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) from 5mC in an enzymatic activity-dependentmanner. Furthermore, we reveal the presence of 5fC and 5caC in genomic DNA of mouse embryonic stemcells and mouse organs. The genomic content of 5hmC, 5fC, and 5caC can be increased or reducedthrough overexpression or depletion of Tet proteins. Thus, we identify two previously unknown cytosinederivatives in genomic DNA as the products of Tet proteins. Our study raises the possibility that DNAdemethylation may occur through Tet-catalyzed oxidation followed by decarboxylation.", "metadata": {}}
+{"_id": "24735908", "title": "", "text": "Long-term use of aspirin and age-related macular degeneration.CONTEXT Aspirin is widely used for reliefof pain and for cardioprotective effects. Its use is of concern to ophthalmologists when ocular surgery isbeing considered and also in the presence of age-related macular degeneration (AMD). OBJECTIVE Toexamine the association of regular aspirin use with incidence of AMD. DESIGN, SETTING, ANDPARTICIPANTS The Beaver Dam Eye Study, a longitudinal population-based study of age-related eyediseases conducted in Wisconsin. Examinations were performed every 5 years over a 20-year period(1988-1990 through 2008-2010). Study participants (N = 4926) were aged 43 to 86 years at thebaseline examination. At subsequent examinations, participants were asked if they had regularly usedaspirin at least twice a week for more than 3 months. MAIN OUTCOME MEASURE Incidence of early AMD,late AMD, and 2 subtypes of late AMD (neovascular AMD and pure geographic atrophy), assessed inretinal photographs according to the Wisconsin Age-Related Maculopathy Grading System. RESULTS Themean duration of follow-up was 14.8 years. There were 512 incident cases of early AMD (of 6243person-visits at risk) and 117 incident cases of late AMD (of 8621 person-visits at risk) over the course ofthe study. Regular aspirin use 10 years prior to retinal examination was associated with late AMD (hazardratio [HR], 1.63 [95% CI, 1.01-2.63]; P = .05), with estimated incidence of 1.76% (95% CI,1.17%-2.64%) in regular users and 1.03% (95% CI, 0.70%-1.51%) in nonusers. For subtypes of lateAMD, regular aspirin use 10 years prior to retinal examination was significantly associated withneovascular AMD (HR, 2.20 [95% CI, 1.20-4.15]; P = .01) but not pure geographic atrophy (HR, 0.66[95% CI, 0.25-1.95]; P = .45). Aspirin use 5 years (HR, 0.86 [95% CI, 0.71-1.05]; P = .13) or 10 years(HR, 0.86 [95% CI, 0.65-1.13]; P = .28) prior to retinal examination was not associated with incidentearly AMD. CONCLUSIONS Among an adult cohort, aspirin use 5 years prior to observed incidence wasnot associated with incident early or late AMD. However, regular aspirin use 10 years prior wasassociated with a small but statistically significant increase in the risk of incident late and neovascularAMD.", "metadata": {}}
+{"_id": "24737389", "title": "", "text": "Growth control and ribosomopathies.Ribosome biogenesis and protein synthesis are two of the mostenergy consuming processes in a growing cell. Moreover, defects in their molecular components can alterthe pattern of gene expression. Thus it is understandable that cells have developed a surveillance systemto monitor the status of the translational machinery. Recent discoveries of causative mutations anddeletions in genes linked to ribosome biogenesis have defined a group of similar pathologies termedribosomopathies. Over the past decade, much has been learned regarding the relationship betweengrowth control and ribosome biogenesis. The discovery of extra-ribosomal functions of several ribosomeproteins and their regulation of p53 levels has provided a link from ribosome impairment to cell cycleregulation. Yet, evidence suggesting p53 and/or Hdm2 independent pathways also exists. In this review,we summarize recent advances in understanding the mechanisms underlying the pathologies ofribosomopathies and discuss the relationship between ribosome production and tumorigenesis.", "metadata": {}}
+{"_id": "24742375", "title": "", "text": "Tunable signal processing through modular control of transcription factor translocation.Signalingpathways can induce different dynamics of transcription factor (TF) activation. We explored how TFsprocess signaling inputs to generate diverse dynamic responses. The budding yeast generalstress-responsive TF Msn2 acted as a tunable signal processor that could track, filter, or integrate signalsin an input-dependent manner. This tunable signal processing appears to originate from dual regulationof both nuclear import and export by phosphorylation, as mutants with one form of regulation sustainedonly one signal-processing function. Versatile signal processing by Msn2 is crucial for generating distinctdynamic responses to different natural stresses. Our findings reveal how complex signal-processingfunctions are integrated into a single molecule and provide a guide for the design of TFs with\"programmable\" signal-processing functions.", "metadata": {}}
+{"_id": "24746892", "title": "", "text": "Killing by bactericidal antibiotics does not depend on reactive oxygen species.Bactericidal antibiotics killby modulating their respective targets. This traditional view has been challenged by studies that proposean alternative, unified mechanism of killing, whereby toxic reactive oxygen species (ROS) are produced inthe presence of antibiotics. We found no correlation between an individual cell's probability of survival inthe presence of antibiotic and its level of ROS. An ROS quencher, thiourea, protected cells fromantibiotics present at low concentrations, but the effect was observed under anaerobic conditions as well.There was essentially no difference in survival of bacteria treated with various antibiotics under aerobic oranaerobic conditions. This suggests that ROS do not play a role in killing of bacterial pathogens byantibiotics.", "metadata": {}}
+{"_id": "24760136", "title": "", "text": "A naturally occurring mouse model of X-linked congenital stationary night blindness.PURPOSE To describea naturally occurring X-linked recessive mutation, no b-wave (nob), that compromises visualtransmission between photoreceptors and second-order neurons in mice. METHODS Affected mice wereidentified by recording the light-evoked response of the retina, the electroretinogram (ERG). To evaluatevisual transmission, cortical potentials were recorded with a scalp electrode. The inheritance pattern fornob was defined by breeding nob animals with normal mice. Retinal histologic analysis was performed bylight microscopy. RESULTS Although the photoreceptor-mediated ERG component (a-wave) was normalin nob mice, the major response component reflecting postreceptoral neuronal activity (b-wave) wasmissing. Visually-driven cortical activity was also abnormal in nob animals. At the light microscopic level,the nob retina appeared to have a normal cytoarchitecture. CONCLUSIONS These findings suggest thatthe nob defect interferes with the transmission of visual information through the retina and that thesemice are a useful model for the study of outer retinal synaptic function. In addition, this mutant mouseseems to provide an animal model for the complete form of congenital stationary night blindness, ahuman disorder in which patients have a profound loss of rod-mediated visual sensitivity.", "metadata": {}}
+{"_id": "24766509", "title": "", "text": "Differentiation of mesenchymal stem cells and embryonic stem cells into steroidogenic cells usingsteroidogenic factor-1 and liver receptor homolog-1.Previously, we have demonstrated that mesenchymalstem cells could be differentiated into steroidogenic cells through steroidogenic factor-1 and8bromo-cAMP treatment. Use of liver receptor homolog-1, another of the nuclear receptor 5A familynuclear receptors, with 8bromo-cAMP also resulted in the differentiation of human mesenchymal stemcells into steroid hormone-producing cells. The same approaches could not be applied to otherundifferentiated cells such as embryonic stem cells or embryonal carcinoma cells, because theover-expression of the nuclear receptor 5A family is cytotoxic to these cells. We established embryonicstem cells carrying tetracycline-regulated steroidogenic factor-1 gene at the ROSA26 locus. Theembryonic stem cells were first differentiated into a mesenchymal cell lineage by culturing on collagenIV-coated dishes and treating with pulse exposures of retinoic acid before expression of steroidogenicfactor-1. Although the untreated embryonic stem cells could not be converted into steroidogenic cells byexpression of steroidogenic factor-1 in the absence of leukemia inhibitory factor due to inability of thecells to survive, the differentiated cells could be successfully converted into steroidogenic cells whenexpression of steroidogenic factor-1 was induced. They exhibited characteristics of adrenocortical-likecells and produced a large amount of corticosterone. These results indicated that pluripotent stem cellscould be differentiated into steroidogenic cells by the nuclear receptor 5A family of protein via themesenchymal cell lineage. This approach may provide a source of cells for future gene therapy fordiseases caused by steroidogenesis deficiencies.", "metadata": {}}
+{"_id": "24770122", "title": "", "text": "Chronic daily headache. A clinical and psychological profile before and after treatment.To assess theclinical and personality characteristics of patients with chronic daily headache before and after treatment,20 patients were examined and the Minnesota Multiphasic Personality Inventory (MMPI [Italian 356-itemabbreviated version]) and the Strait and Trait Anxiety Index 1,2 (STAI) administered. There were twogroups: group 1 (n = 6), with a \"conversion V\" configuration (with elevation of hypochondria and hysteriascales, the depression scale being somewhat lower); and group 2 (n = 13) with elevation of depressionand of other MMPI scales. One patient had no scale elevation. STAI 1,2 scores were high in both groups.Several psychosomatic symptoms and some migraine features were present in almost all patients.Occurrence, severity, and duration of headache were recorded regularly and the MMPI and the STAIadministered again after treatment. Improvement of headaches and a decrease of several MMPI and STAI2 scores were observed. However, 12 of 20 patients showed a conversion V configuration after treatment.It is concluded that chronic daily headache was transformed migraine in most cases and wasaccompanied by anxiety levels in all patients and hysteric traits in some. With time, these patients maydevelop a depressive disorder. After treatment, hysterical traits are still present at a lower level in thoseshowing these traits before treatment and may be unmasked in those that had depression.", "metadata": {}}
+{"_id": "24770913", "title": "", "text": "Potassium channel structure and function as reported by a single glycosylation sequon.Inwardly rectifyingK+ channels (IRKs) are highly K(+)-selective, integral membrane proteins that help maintain resting themembrane potential and cell volume. Integral membrane proteins as a class are frequentlyN-glycosylated with the attached carbohydrate being extracellular and perhaps modulating function.However, dynamic effects of glycosylation have yet to be demonstrated at the molecular level. ROMK1, amember of the IRK family is particularly suited to the study of glycosylation because it has a singleN-glycosylation consensus sequence (Ho, K., Nichols, C. G., Lederer, W. J., Lytton, J., Vassilev, P. M.,Kanazirska, M. V., and Herbert, S. C. (1993) Nature 362, 31-38). We show that ROMK1 is expressed in afunctional state in the plasmalemma of an insect cell line (Spodoptera frugiperda, Sf9) and has twostructures, glycosylated and unglycosylated. To test functionality, glycosylation was abolished by anN117Q mutation or by treatment with tunicamycin. Whole cell currents were greatly reduced in both ofthe unglycosylated forms compared to wild-type. Single channel currents revealed a dramatic decrease inopening probability, po, as the causative factor. Thus we have shown biochemically that theN-glycosylation sequon is extracellular, a result consistent with present topological models of IRKs, andwe conclude that sequon occupancy by carbohydrate stabilizes the open state of ROMK1.", "metadata": {}}
+{"_id": "24783597", "title": "", "text": "Role of the novel Th17 cytokine IL-17F in inflammatory bowel disease (IBD): upregulated colonic IL-17Fexpression in active Crohn's disease and analysis of the IL17F p.His161Arg polymorphism inIBD.BACKGROUND Interleukin (IL)-17F, produced in IL-23R-expressing Th17 cells, is a novel member ofthe IL-17 cytokine family. Given the association of IL23R with inflammatory bowel disease (IBD), wecharacterized the role of IL-17F in IBD including its intestinal gene expression and the effect of the IL17Fp. His161Arg polymorphism on disease susceptibility and phenotype of Crohn's disease (CD) andulcerative colitis (UC). In addition, we analyzed the IL17F p. His161Arg polymorphism for potentialepistasis with IL23R and NOD2/CARD15 variants. METHODS Intestinal IL-17F mRNA expression wasmeasured by quantitative polymerase chain reaction (PCR). Genomic DNA from 1682 individuals (CD: n =499; UC: n = 216; controls: n = 967) was analyzed for the presence of the IL17F p. His161Argpolymorphism, the 3 NOD2 variants, p. Arg702Trp, p. Gly908Arg, and p. Leu1007fsX1008, and 10CD-associated IL23R variants. RESULTS Intestinal IL-17F mRNA expression was 4.4-fold increased ininflamed colonic lesions compared to uninflamed biopsies in CD (P = 0.016) but not in UC. However, themean intestinal IL-17F mRNA expression was higher in UC than in CD (P < 0.0001). The IL17F p.His161Arg substitution was observed with similar frequencies in IBD patients and controls and was notassociated with a certain disease phenotype, but weakly associated with a low body mass index (BMI; P= 0.009) and an earlier age of disease onset (P = 0.039) in UC. There was no evidence for epistasisbetween the IL17F p. His161Arg polymorphism and IBD-associated single nucleotide polymorphismswithin the IL23R gene. CONCLUSIONS Intestinal IL17F gene expression is increased in active CD. TheIL17F p. His161Arg polymorphism is not associated with IBD susceptibility and has no epistaticinteraction with CD-associated IL23R variants.", "metadata": {}}
+{"_id": "24790460", "title": "", "text": "Targeting brain cancer: advances in the molecular pathology of malignant glioma andmedulloblastomaMalignant brain tumours continue to be the cause of a disproportionate level ofmorbidity and mortality across a wide range of individuals. The most common variants in the adult andpaediatric populations — malignant glioma and medulloblastoma, respectively — have been the subject ofincreasingly intensive research over the past two decades that has led to considerable advances in theunderstanding of their basic biology and pathogenesis. This Review summarizes these developments inthe context of the evolving notion of molecular pathology and discusses the implications that this workhas on the design of new treatment regimens.", "metadata": {}}
+{"_id": "24795767", "title": "", "text": "Rapid helper T-cell recovery above 200 × 106/l at 3 months correlates to successful transplant outcomesafter allogeneic stem cell transplantationThe current study evaluates the role of quantitativemeasurement of peripheral lymphocyte subsets, especially CD4+ helper T-cell recovery, in predictingtransplant outcomes including overall survival (OS) and non-relapse mortality (NRM) after allogeneicstem cell transplantation. A total of 69 allogeneic recipients were included with following diagnoses: acutemyeloid leukemia 42, acute lymphoblastic leukemia 5, chronic myeloid leukemia 15, non-Hodgkin'slymphoma 5 and high-risk myelodysplastic syndrome 2. The peripheral lymphocyte subset counts (CD3+T cells, CD3+4+ helper T cells, CD3+8+ cytotoxic T cells, CD19+ B cells, and CD56+ natural killer cells)were measured at 3, 6 and 12 months. The CD4+ helper T-cell reconstitution at 3 months was stronglycorrelated with OS (P<0.0001), NRM (P=0.0007), and opportunistic infections (P=0.0108) at the cutoffvalue of 200 × 106/l CD4+ helper T cells. Rapid CD4+ helper T-cell recovery was also associated with ahigher CD4+ helper T-cell transplant dose (P=0.006) and donor type (P<0.001). An early CD4+ helperT-cell recovery at 3 months correlated with a subsequent faster helper T-cell recovery until 12 months,yet not with B-cell recovery. In a multivariate analysis, rapid recovery of CD4+ helper T cells at 3 monthswas a favorable prognostic factor together with higher CD34+ cell transplant dose in terms of OS(P=0.001) and NRM (P=0.005).", "metadata": {}}
+{"_id": "24825841", "title": "", "text": "Generating an iPSC bank for HLA-matched tissue transplantation based on known donor and recipientHLA types.The likelihood for immunological rejection of Human Leukocyte Antigens (HLA)-mismatchedinduced pluripotent stem cells (iPSCs) limits their therapeutic potential. Here we show how a tissue bankfrom 150 selected homozygous HLA-typed volunteers could match 93% of the UK population with aminimal requirement for immunosuppression. Our model provides a practical approach for using existingHLA-typed samples to generate an iPSC stem cell bank that circumvents prospective typing of a largenumber of individuals.", "metadata": {}}
+{"_id": "24828165", "title": "", "text": "Promiscuous gene expression and the developmental dynamics of medullary thymic epithelialcells.Thymic epithelial cells (TEC) form the structural and functional microenvironment necessary for theestablishment and quality control of the T cell repertoire. In addition, they provide an ectopic source ofnumerous tissue-restricted antigens (TRA), a feature called promiscuous gene expression (pGE). How theregulation of pGE is related to the cell biology of TEC subset(s), e.g. their turnover and developmentalinterrelationship is still poorly understood. The observation that pGE is foremost a property ofphenotypically and functionally mature medullary TEC (mTEC) implies that the full implementation of pGEis contingent on mTEC differentiation. Here, we show that the emergence of TEC subsets and pGE istightly correlated during ontogeny and we provide evidence that mature CD80pos mTEC develop from animmature CD80neg subset. This differentiation step proceeds continuously in the postnatal thymus. Whilemature mTEC turnover in 2 to 3 weeks, immature mTEC encompass a smaller cycling and a largernon-cycling pool. The latter might serve as a reservoir of committed precursors, which sustain thisrenewal process. Our data document that mTEC represent a highly dynamic cell population, and theyimply that the availability and display of TRA in the thymus undergoes a perpetual temporal and spatialreorganization.", "metadata": {}}
+{"_id": "24834968", "title": "", "text": "Evaluation of HER-2/neu amplification and other biological markers as predictors of response toneoadjuvant anthracycline-based chemotherapy in primary breast cancer: the role of anthracycline doseintensity.OBJECTIVES The value of HER-2/neu status as a predictor of response to anthracycline-basedchemotherapy is still a matter of debate. We evaluated the contribution of HER-2/neu gene amplificationand other biologic markers in predicting response to different doses of neoadjuvant anthracycline-basedchemotherapy. METHODS Clinical and pathologic records of 115 primary breast cancer patients werereviewed. Forty-eight and 67 patients received high (doxorubicin > or =20 mg/m2/wk; epirubicin > or=30 mg/m2/wk) and moderate-low anthracycline dose intensity regimens, respectively. Pathologicdiagnosis, hormonal receptor status (HR), Ki67, and HER-2/neu status were assessed on tumor samplesbefore neoadjuvant chemotherapy. HER-2/neu was determined by fluorescence in situ hybridization(FISH). RESULTS HER-2/neu amplification was observed in 29/115 (25%) tumors, 18 frommoderate-low-dose and 11 from high-dose group. In the univariate analysis, a high Ki67 index (> or=20%) and positive clinical axillary nodes were predictive of an objective tumor response (P = 0.033 and0.001, respectively). In the multivariate analysis, Ki67 was the only factor predictive of response (OR =3.08, 95% CI = 1.1-8.5, P = 0.03). HER-2/neu status was not a factor in predicting objective response todifferent anthracycline dose intensities. The same finding was observed with regards to HR and Ki67.CONCLUSIONS In our series, no significant dose-response relationship was found according to HER-2/neustatus.", "metadata": {}}
+{"_id": "24863571", "title": "", "text": "Radioactive labeling of mitochondrial translation products in cultured cells.The mammalian mitochondrialgenome contains 37 genes, 13 of which encode polypeptide subunits in the enzyme complexes of theoxidative phosphorylation system. The other genes encode the rRNAs and tRNAs necessary for theirtranslation. The mitochondrial translation machinery is located in the mitochondrial matrix, and isexclusively dedicated to the synthesis of these 13 enzyme subunits. Mitochondrial disease in humans isoften associated with defects in mitochondrial translation. This can manifest as a global decrease in therate of mitochondrial protein synthesis, a decrease in the synthesis of specific polypeptides, the synthesisof abnormal polypeptides, or in altered stability of specific translation products. All of these changes inthe normal pattern of mitochondrial translation can be assessed by a straightforward technique that takesadvantage of the insensitivity of the mitochondrial translation machinery to antibiotics that completelyinhibit cytoplasmic translation. Thus, specific radioactive labeling of the mitochondrial translationproducts can be achieved in cultured cells, and the results can be visualized on gradient gels. Theanalysis of mitochondrial translation in cells cultured from patient biopsies is useful in the study ofdisease-causing mutations in both the mitochondrial and the nuclear genomes.", "metadata": {}}
+{"_id": "24864273", "title": "", "text": "Caenorhabditis elegans cyclin A- and B-type genes: a cyclin A multigene family, an ancestral cyclin B3and differential germline expression.We have cloned cDNAs for Caenorhabditis elegans cyclins A1, B andB3. While cyclins A1 and B are most closely related to either A- or B-type cyclins of other species, cyclinB3 is less related to these cyclins. However, this cyclin is most similar to the recently identified chickencyclin B3. Our identification of a Caenorhabditis homolog demonstrates that cyclin B3 has been conservedin evolution. Cyclin A1 is a member of an A-type multigene family; however the cyclin A1 cDNA onlyrecognizes a single band on northern blots. A single-sized RNA is also observed for the cyclin B3 cDNA. Incontrast, three different transcripts are observed for the cyclin B cDNA. Based on our analyses usingRNAs from germline-defective mutants and from populations enriched for males, one cyclin B transcript isspecific to the paternal germline. The two other cyclin B transcripts, as well as the cyclin A1 and cyclin B3transcripts, are most abundant in the maternal germline and are only present at low levels in othertissues. Moreover, the 3' untranslated regions of each Caenorhabditis cyclin cDNA possess several copiesof potential translational control elements shown in Xenopus and Drosophila maternal cyclin mRNAs tofunction during oogenesis and early embryogenesis.", "metadata": {}}
+{"_id": "24865781", "title": "", "text": "A comparison of pharmacological (amitriptyline HCL) and nonpharmacological (cognitive-behavioral)therapies for chronic tension headaches.Forty-one recurrent tension headache sufferers were randomlyassigned to either cognitive-behavioral therapy (administered in a primarily home-based treatmentprotocol) or to amitriptyline therapy (with dosage individualized at 25, 50, or 75 mg/day).Cognitive-behavioral therapy and amitriptyline each yielded clinically significant improvements inheadache activity, both when improvement was assessed with patient daily recordings (56% and 27%reduction in headache index, respectively), and when improvement was assessed with neurologist ratingsof clinical improvement (94% and 69% of patients rated at least moderately improved, respectively). Ininstances where differences in treatment effectiveness were observed (headache index, somaticcomplaints, perceptions of control of headache activity), cognitive-behavioral therapy yielded somewhatmore positive outcomes than did amitriptyline. Neither treatment, however, eliminated headacheproblems.", "metadata": {}}
+{"_id": "24872571", "title": "", "text": "Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose andinsulin concentrations in manThe steady-state basal plasma glucose and insulin concentrations aredetermined by their interaction in a feedback loop. A computer-solved model has been used to predict thehomeostatic concentrations which arise from varying degrees of β-cell deficiency and insulin resistance.Comparison of a patient's fasting values with the model's predictions allows a quantitative assessment ofthe contributions of insulin resistance and deficient β-cell function to the fasting hyperglycaemia(homeostasis model assessment, HOMA). The accuracy and precision of the estimate have beendetermined by comparison with independent measures of insulin resistance and β-cell function usinghyperglycaemic and euglycaemic clamps and an intravenous glucose tolerance test. The estimate ofinsulin resistance obtained by homeostasis model assessment correlated with estimates obtained by useof the euglycaemic clamp (Rs = 0.88, p < 0.0001), the fasting insulin concentration (Rs = 0.81, p <0.0001), and the hyperglycaemic clamp, (Rs = 0.69, p < 0.01). There was no correlation with any aspectof insulin-receptor binding. The estimate of deficient β-cell function obtained by homeostasis modelassessment correlated with that derived using the hyperglycaemic clamp (Rs = 0.61, p < 0.01) and withthe estimate from the intravenous glucose tolerance test (Rs = 0.64, p < 0.05). The low precision of theestimates from the model (coefficients of variation: 31% for insulin resistance and 32% for β-cell deficit)limits its use, but the correlation of the model's estimates with patient data accords with the hypothesisthat basal glucose and insulin interactions are largely determined by a simple feed back loop.", "metadata": {}}
+{"_id": "24873253", "title": "", "text": "Clinical benefits and considerations of bisphosphonate treatment in metastatic bone disease.Patients withmetastatic bone disease are at risk for developing skeletal-related events that can negatively influencequality of life, contributing to loss of autonomy and functional capabilities. Bisphosphonates have becomean important component in the treatment of patients with bone metastases as they delay the onset andreduce the risk of skeletal-related events and also palliate or control bone pain in multiple cancer types,thus preserving quality of life. Zoledronic acid has proven efficacy and safety in patients with bone lesionsfrom breast cancer, prostate cancer, lung cancer, and other solid tumors, as well as in patients withmultiple myeloma. Current data suggest that early treatment with zoledronic acid (before the onset ofbone pain) may provide additional clinical benefits and also positive effects on survival in subsets ofpatients who have elevated levels of N-telopeptide of type I collagen (NTX), a biochemical marker of boneresorption. Studies have shown that in patients with breast cancer, prostate cancer, lung cancer, or othersolid tumors, normalization of elevated levels of NTX was observed in the majority of patients whoreceived zoledronic acid. Furthermore, normalization of NTX values correlated with extended survival.", "metadata": {}}
+{"_id": "24879055", "title": "", "text": "Distinct memory CD4+ T cells with commitment to T follicular helper- and T helper 1-cell lineages aregenerated after acute viral infection.CD4(+) T follicular helper (Tfh) cells provide the required signals to Bcells for germinal center reactions that are necessary for long-lived antibody responses. However, itremains unclear whether there are CD4(+) memory T cells committed to the Tfh cell lineage after antigenclearance. By using adoptive transfer of antigen-specific memory CD4(+) T cell subpopulations in thelymphocytic choriomeningitis virus infection model, we found that there are distinct memory CD4(+) Tcell populations with commitment to either Tfh- or Th1-cell lineages. Our conclusions are based on geneexpression profiles, epigenetic studies, and phenotypic and functional analyses. Our findings indicate thatCD4(+) memory T cells \"remember\" their previous effector lineage after antigen clearance, being poisedto reacquire their lineage-specific effector functions upon antigen reencounter. These findings haveimportant implications for rational vaccine design, where improving the generation and engagement ofmemory Tfh cells could be used to enhance vaccine-induced protective immunity.", "metadata": {}}
+{"_id": "24881307", "title": "", "text": "Control of synapse development and plasticity by Rho GTPase regulatory proteinsSynapses arespecialized cell-cell contacts that mediate communication between neurons. Most excitatory synapses inthe brain are housed on dendritic spines, small actin-rich protrusions extending from dendrites. Duringdevelopment and in response to environmental stimuli, spines undergo marked changes in shape andnumber thought to underlie processes like learning and memory. Improper spine development, incontrast, likely impedes information processing in the brain, since spine abnormalities are associated withnumerous brain disorders. Elucidating the mechanisms that regulate the formation and plasticity ofspines and their resident synapses is therefore crucial to our understanding of cognition and disease.Rho-family GTPases, key regulators of the actin cytoskeleton, play essential roles in orchestrating thedevelopment and remodeling of spines and synapses. Precise spatio-temporal regulation of Rho GTPaseactivity is critical for their function, since aberrant Rho GTPase signaling can cause spine and synapsedefects as well as cognitive impairments. Rho GTPases are activated by guanine nucleotide exchangefactors (GEFs) and inhibited by GTPase-activating proteins (GAPs). We propose that Rho-family GEFs andGAPs provide the spatiotemporal regulation and signaling specificity necessary for proper Rho GTPasefunction based on the following features they possess: (i) existence of multiple GEFs and GAPs per RhoGTPase, (ii) developmentally regulated expression, (iii) discrete localization, (iv) ability to bind to andorganize specific signaling networks, and (v) tightly regulated activity, perhaps involving GEF/GAPinteractions. Recent studies describe several Rho-family GEFs and GAPs that uniquely contribute tospinogenesis and synaptogenesis. Here, we highlight several of these proteins and discuss how theyoccupy distinct biochemical niches critical for synaptic development.", "metadata": {}}
+{"_id": "24896957", "title": "", "text": "Rate and molecular spectrum of spontaneous mutations in the bacterium Escherichia coli as determinedby whole-genome sequencing.Knowledge of the rate and nature of spontaneous mutation is fundamentalto understanding evolutionary and molecular processes. In this report, we analyze spontaneousmutations accumulated over thousands of generations by wild-type Escherichia coli and a derivativedefective in mismatch repair (MMR), the primary pathway for correcting replication errors. The majorconclusions are (i) the mutation rate of a wild-type E. coli strain is ~1 × 10(-3) per genome pergeneration; (ii) mutations in the wild-type strain have the expected mutational bias for G:C > A:Tmutations, but the bias changes to A:T > G:C mutations in the absence of MMR; (iii) during replication,A:T > G:C transitions preferentially occur with A templating the lagging strand and T templating theleading strand, whereas G:C > A:T transitions preferentially occur with C templating the lagging strandand G templating the leading strand; (iv) there is a strong bias for transition mutations to occur at5'ApC3'/3'TpG5' sites (where bases 5'A and 3'T are mutated) and, to a lesser extent, at 5'GpC3'/3'CpG5'sites (where bases 5'G and 3'C are mutated); (v) although the rate of small (≤4 nt) insertions anddeletions is high at repeat sequences, these events occur at only 1/10th the genomic rate of base-pairsubstitutions. MMR activity is genetically regulated, and bacteria isolated from nature often lack MMRcapacity, suggesting that modulation of MMR can be adaptive. Thus, comparing results from the wild-typeand MMR-defective strains may lead to a deeper understanding of factors that determine mutation ratesand spectra, how these factors may differ among organisms, and how they may be shaped byenvironmental conditions.", "metadata": {}}
+{"_id": "24906548", "title": "", "text": "Apolipoprotein E4 as a predictor of outcomes in pediatric mild traumatic brain injury.The epsilon4 allele ofthe apolipoprotein E (APOE) gene has been linked to negative outcomes among adults with traumaticbrain injury (TBI) across the spectrum of severity, with preliminary evidence suggesting a similar patternamong children. This study investigated the relationship of the APOE epsilon4 allele to outcomes inchildren with mild TBI. Participants in this prospective, longitudinal study included 99 children with mildTBI between the ages of 8 and 15 recruited from consecutive admissions to Emergency Departments attwo large children's hospitals. Outcomes were assessed acutely in the Emergency Department and atfollow-ups at 2 weeks, 3 months, and 12 months post-injury. Among the 99 participants, 28 had at leastone epsilon4 allele. Children with and without an epsilon4 allele did not differ demographically. Childrenwith an epsilon4 allele were significantly more likely than those without an epsilon4 allele to have aGlasgow Coma Scale score of less than 15, but the groups did not differ on any other measures of injuryseverity. Those with an epsilon4 allele exhibited better performance than children without an epsilon4allele on a test of constructional skill, but the groups did not differ on any other neuropsychological tests.Children with and without an epsilon4 allele also did not differ on measures of post-concussivesymptoms. Overall, the findings suggest that the APOE epsilon4 allele is not consistently related to theoutcomes of mild TBI in children.", "metadata": {}}
+{"_id": "24916604", "title": "", "text": "Do physicians follow systemic treatment and funding policy guidelines?BACKGROUND The use ofbisphosphonates for the prevention of skeletal related events in women with bone metastases frombreast cancer is well established. We undertook an evaluation of bisphosphonate use in clinical practice inthree Canadian cancer centres. In addition we assessed whether or not physicians at these centres arefollowing their local treatment guidelines and funding policies. METHODS Charts and electronic files ofpatients who had received either clodronate or pamidronate at any time between January 2000 andDecember 2001 at three Canadian cancer centres were retrospectively reviewed. RESULTS There hasbeen a marked improvement in the time between the diagnosis of bone metastases and thecommencement of bisphosphonates from a median of 155 days in 1998 to 24 days in 2001. However,despite a local funding policy requiring that oral clodronate be the first bisphosphonate used, this was thecase in only 67% of patients. In addition, despite one centre's guidelines recommending thatbisphosphonates be stopped once the patient was progressing, 90% of their patients remained onbisphosphonates until they died. CONCLUSIONS A considerable amount of effort is spent on the creationof \"evidence based\" treatment guidelines. Funding agencies develop policies based on these treatmentguidelines, but often funding is more restrictive than the treatment guideline would suggest. It is clearfrom this review that physicians still appear to manage a substantial proportion of patients outside offunding policies, but within evidence based recommendations. Therefore, a need exists for either thecreation of guidelines and policies that physicians will follow or the implementation of methods to ensurethat restrictive policies are actually followed.", "metadata": {}}
+{"_id": "24917562", "title": "", "text": "Increased resting energy expenditure and weight loss are related to a systemic inflammatory response inlung cancer patients.PURPOSE To determine whether an increased resting energy expenditure (REE) andweight loss in lung cancer patients are related to a systemic inflammatory response. MATERIALS ANDMETHODS REE was measured by indirect calorimetry using a ventilated hood system. Soluble tumornecrosis factor receptor 55 (sTNF-R55) and sTNF-R75, soluble intercellular adhesion molecule (sICAM)-1,soluble E (sE)-selectin, lipopolysaccharide (LPS)-binding protein (LBP), interleukin (IL)-6, and TNF-alphawere measured using sandwich enzyme-linked immunosorbent assay (ELISA), and C-reactive protein(CRP) was measured by turbidimetry. A cross-sectional study was performed to compare inflammatorymediators between hypermetabolic (REE/Harris Benedict [HB] equation > or = 110%) versusnormometabolic (REE/HB < 110%) patients and between patients who lost weight (more than 10% lossof preillness weight) versus those whose weight remained stable. RESULTS Eighty-seven patients withprimary non-small-cell lung cancer were consecutively entered onto the study. Mean REE expressed as apercentage of the HB reference values was 118% +/- 12%; 67 patients were considered hypermetabolic.Twenty-six patients had a substantial loss of more than 10% of their preillness weight. Hypermetabolicpatients were found to have significantly increased levels of sTNF-R55, sE-selectin, LBP, and CRPcompared with normometabolic patients. Weight loss was related with increased levels of the sTNF-Rs,sICAM-1, IL-6, LBP, and CRP. CONCLUSION Hypermetabolism and weight loss are related to the presenceof a systemic inflammatory response as reflected by enhanced levels of inflammatory mediators andacute phase proteins in patients with primary non-small-cell lung cancer.", "metadata": {}}
+{"_id": "24918110", "title": "", "text": "Exercise capacity and body mass as predictors of mortality among male veterans with type 2diabetes.OBJECTIVE To demonstrate the relation of exercise capacity and BMI to mortality in a populationof male veterans with type 2 diabetes. RESEARCH DESIGN AND METHODS After excluding twounderweight patients (BMI <18.5 kg/m2), the study population comprised 831 consecutive patients withtype 2 diabetes (mean age 61 +/- 9 years) referred for exercise testing for clinical reasons between 1995and 2006. Exercise capacity was determined from a maximal exercise test and measured in metabolicequivalents (METs). Patients were classified both according to BMI category (18.5-24.9, 25.0-29.9, and >or =30 kg/m2) and by exercise capacity (<5.0 or > or =5.0 maximal METs). The association amongexercise capacity, BMI, other clinical variables, and all-cause mortality was assessed by Cox proportionalhazards. Study participants were followed for mortality up to 30 June 2006. RESULTS During a meanfollow-up of 4.8 +/- 3.0 years, 112 patients died, for an average annual mortality rate of 2.2%. Each1-MET increase in exercise capacity conferred a 10% survival benefit (hazard ratio 0.90 [95% CI0.82-0.98]; P = 0.01), but BMI was not significantly associated with mortality. After adjustment for age,ethnicity, examination year, BMI, presence of cardiovascular disease (CVD), and CVD risk factors,diabetic patients achieving <5 maximal METs were 70% more likely to die (1.70 [1.13-2.54]) than thoseachieving > or =5 maximal METs. CONCLUSIONS There was a strong inverse association betweenexercise capacity and mortality in this cohort of men with documented diabetes, and this relationship wasindependent of BMI.", "metadata": {}}
+{"_id": "24921368", "title": "", "text": "Impaired awareness of hypoglycaemia: a review.Impaired awareness of hypoglycaemia (IAH) is anacquired complication of insulin therapy, which affects people with type 1 and insulin-treated type 2diabetes mellitus, whereby the ability to perceive the onset of hypoglycaemia becomes diminished orabsent. Deficiencies of the counter-regulatory hormonal responses to hypoglycaemia usually co-exist.The development of IAH and counter-regulatory failure greatly increases the risk of severehypoglycaemia. Scoring systems have been developed that can be used in the clinical setting and assistwith identification of this group of individuals at risk of severe hypoglycaemia. The mainstay of treatmentof IAH is the scrupulous avoidance of hypoglycaemia.", "metadata": {}}
+{"_id": "24922825", "title": "", "text": "A chikungunya fever vaccine utilizing an insect-specific virus platformTraditionally, vaccine developmentinvolves tradeoffs between immunogenicity and safety. Live-attenuated vaccines typically offer rapid anddurable immunity but have reduced safety when compared to inactivated vaccines. In contrast, theinability of inactivated vaccines to replicate enhances safety at the expense of immunogenicity, oftennecessitating multiple doses and boosters. To overcome these tradeoffs, we developed the insect-specificalphavirus, Eilat virus (EILV), as a vaccine platform. To address the chikungunya fever (CHIKF)pandemic, we used an EILV cDNA clone to design a chimeric virus containing the chikungunya virus(CHIKV) structural proteins. The recombinant EILV/CHIKV was structurally identical at 10 Å to wild-typeCHIKV, as determined by single-particle cryo-electron microscopy, and it mimicked the early stages ofCHIKV replication in vertebrate cells from attachment and entry to viral RNA delivery. Yet therecombinant virus remained completely defective for productive replication, providing a high degree ofsafety. A single dose of EILV/CHIKV produced in mosquito cells elicited rapid (within 4 d) and long-lasting(>290 d) neutralizing antibodies that provided complete protection in two different mouse models. Innonhuman primates, EILV/CHIKV elicited rapid and robust immunity that protected against viremia andtelemetrically monitored fever. Our EILV platform represents the first structurally native application of aninsect-specific virus in preclinical vaccine development and highlights the potential application of suchviruses in vaccinology.", "metadata": {}}
+{"_id": "24923605", "title": "", "text": "Molecular elements of low-oxygen signaling in plants.Oxygen and its limitation are emerging as a crucialfactor in plant fitness, growth and development. Recent studies revealed the mechanisms by whichoxygen is perceived by plant cells. This sensory system partly relies on an oxygen-mediated branch of theN-end rule pathway for protein degradation acting on a specific clade of ethylene responsive transcriptionfactors (ERF-VII). A complementary regulative step is provided by aerobic sequestration of an ERF-VIIprotein at the plasma membrane and its timely release when hypoxia occurs. Complete absence ofoxygen triggers the transient accumulation of reactive hydrogen peroxide and induces an additional set ofreactive oxygen species-related genes involved in both signaling and attenuation of oxidative stress.Moreover, temporary hypoxic environments that are built up as consequence of dense cell packing havebeen demonstrated to trigger cell-fate determination in maize anthers. Similarly, limited oxygen deliveryin bulky fruit or tuber tissues growing in aerobic conditions were shown to stimulate anaerobic-likeresponses. These advances in low-oxygen signaling and its effect on cell development highlight theimportance of taking hypoxia into account in agronomical practices as well as in breeding programs.", "metadata": {}}
+{"_id": "24928817", "title": "", "text": "Purification, characterization, and sequence analysis of a potential virulence factor from Porphyromonasgingivalis, peptidylarginine deiminase.The initiation and progression of adult-onset periodontitis has beenassociated with infection of the gingival sulcus by Porphyromonas gingivalis. This organism utilizes amultitude of virulence factors to evade host defenses as it establishes itself as one of the predominantpathogens in periodontal pockets. A feature common to many other oral pathogens is the production ofammonia due to its protective effect during acidic cleansing cycles in the mouth. Additionally, ammoniaproduction by P. gingivalis has been proposed as a virulence factor due to its negative effects onneutrophil function. In this study, we describe the first purification of a peptidylarginine deiminase (PAD)from a prokaryote. PAD exhibits biochemical characteristics and properties that suggest that it may be avirulence agent. PAD deiminates the guanidino group of carboxyl-terminal arginine residues on a varietyof peptides, including the vasoregulatory peptide-hormone bradykinin, to yield ammonia and a citrullineresidue. The soluble protein has an apparent mass of 46 kDa, while the DNA sequence predicts afull-length protein of 61.7 kDa. PAD is optimally active at 55 degrees C, stable at low pH, and shows thegreatest activity above pH 9.0. Interestingly, in the presence of stabilizing factors, PAD is resistant tolimited proteolysis and retains significant activity after short-term boiling. We propose that PAD, acting inconcert with arginine-specific proteinases from P. gingivalis, promotes the growth of the pathogen in theperiodontal pocket, initially by enhancing its survivability and then by assisting the organism in itscircumvention of host humoral defenses.", "metadata": {}}
+{"_id": "24942840", "title": "", "text": "Traumatic encephalopathy: review and provisional research diagnostic criteria.OBJECTIVES To determinethe frequency of neurobehavioral signs and symptoms reported in every published case of traumaticencephalopathy with a view toward the development of clinical diagnostic criteria with predictive validity.INTRODUCTION Cases of persistent or progressive neurological or neurobehavioral change followingexposure to one or more head injuries have been reported since 1928. This condition is often referred toas traumatic encephalopathy (TE). To date, however, no diagnostic criteria have been advanced oraccepted for the clinical diagnosis of TE. Provisional research diagnostic criteria are required not only formeaningful diagnosis but also to facilitate research to determine the epidemiology, etiology, course,prognosis, imaging and biomarkers, neuropathological features and potentially effective treatments of TE.METHODS All 436 published cases of TE in all languages were reviewed. All symptoms and signs reportedin these cases were classified and enumerated. RESULTS Ninety-seven cases met inclusion criteria basedon sufficient documentation of the history and neurobehavioral examination. Provisional researchdiagnostic criteria for clinically probable and clinically possible TE were developed based on the mostfrequently reported clinical features. CONCLUSION The provisional diagnostic criteria for TE presentedhere are the first published criteria for this condition based upon a systematic analysis of its clinicalcharacteristics. This is the first a step toward scientifically derived consensus criteria, which are essentialto accelerate progress in the investigation of this important condition.", "metadata": {}}
+{"_id": "24943534", "title": "", "text": "Hepatitis C and human immunodeficiency virus infection.In the United States, an estimated 200,000persons are infected with both hepatitis C virus (HCV) and human immunodeficiency virus (HIV). As thelives of HIV-infected persons have been prolonged by use of highly active antiretroviral therapy, liverdisease has emerged as an important, and in some settings, the leading cause of morbidity and mortality.Human immunodeficiency virus infection appears to adversely affect all stages of hepatitis C infection,leading to increased viral persistence and accelerated progression of HCV-related liver disease. In turn,hepatitis C may affect the management of HIV infection, increasing the incidence of liver toxicity causedby antiretroviral medications. The medical management of hepatitis C in HIV-infected persons remainscontroversial, in part because of the complexity of both infections and potential drug interactions, butchiefly because there is so little published information. Nonetheless, the burden of liver disease is toohigh to delay management of HIV/HCV-coinfected persons while awaiting better data. Instead, themanagement of hepatitis C today must be based on data generated on persons without HIV and anunderstanding of both infections. Properly designed studies of therapy in HIV/HCV-coinfected persons areneeded to help guide management of these patients in the future.", "metadata": {}}
+{"_id": "24974080", "title": "", "text": "Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis.New bloodvessel formation (angiogenesis) is a fundamental event in the process of tumor growth and metastaticdissemination. Hence, the molecular basis of tumor angiogenesis has been of keen interest in the field ofcancer research. The vascular endothelial growth factor (VEGF) pathway is well established as one of thekey regulators of this process. The VEGF/VEGF-receptor axis is composed of multiple ligands andreceptors with overlapping and distinct ligand-receptor binding specificities, cell-type expression, andfunction. Activation of the VEGF-receptor pathway triggers a network of signaling processes that promoteendothelial cell growth, migration, and survival from pre-existing vasculature. In addition, VEGF mediatesvessel permeability, and has been associated with malignant effusions. More recently, an important rolefor VEGF has emerged in mobilization of endothelial progenitor cells from the bone marrow to distantsites of neovascularization. The well-established role of VEGF in promoting tumor angiogenesis and thepathogenesis of human cancers has led to the rational design and development of agents that selectivelytarget this pathway. Studies with various anti-VEGF/VEGF-receptor therapies have shown that theseagents can potently inhibit angiogenesis and tumor growth in preclinical models. Recently, an anti-VEGFantibody (bevacizumab), when used in combination with chemotherapy, was shown to significantlyimprove survival and response rates in patients with metastatic colorectal cancer and thus, validate VEGFpathway inhibitors as an important new treatment modality in cancer therapy.", "metadata": {}}
+{"_id": "24979644", "title": "", "text": "Frozen robust multiarray analysis (fRMA).Robust multiarray analysis (RMA) is the most widely usedpreprocessing algorithm for Affymetrix and Nimblegen gene expression microarrays. RMA performsbackground correction, normalization, and summarization in a modular way. The last 2 steps requiremultiple arrays to be analyzed simultaneously. The ability to borrow information across samples providesRMA various advantages. For example, the summarization step fits a parametric model that accounts forprobe effects, assumed to be fixed across arrays, and improves outlier detection. Residuals, obtainedfrom the fitted model, permit the creation of useful quality metrics. However, the dependence on multiplearrays has 2 drawbacks: (1) RMA cannot be used in clinical settings where samples must be processedindividually or in small batches and (2) data sets preprocessed separately are not comparable. Wepropose a preprocessing algorithm, frozen RMA (fRMA), which allows one to analyze microarraysindividually or in small batches and then combine the data for analysis. This is accomplished by utilizinginformation from the large publicly available microarray databases. In particular, estimates ofprobe-specific effects and variances are precomputed and frozen. Then, with new data sets, these areused in concert with information from the new arrays to normalize and summarize the data. We find thatfRMA is comparable to RMA when the data are analyzed as a single batch and outperforms RMA whenanalyzing multiple batches. The methods described here are implemented in the R package fRMA and arecurrently available for download from the software section of http://rafalab.jhsph.edu.", "metadata": {}}
+{"_id": "24980622", "title": "", "text": "Hypoxia in relation to vasculature and proliferation in liver metastases in patients with colorectalcancer.PURPOSE To investigate hypoxia measured by pimonidazole binding, glucose transporter 1(GLUT1) and carbonic anhydrase IX (CA-IX) expression, proliferation, and vascularity in liver metastasesof colorectal cancer and to compare GLUT1 and CA-IX expression in corresponding primary tumors.METHODS AND MATERIALS Twenty-five patients with liver metastases of colorectal cancer, planned formetastasectomy, were included. The hypoxia marker pimonidazole and proliferation markeriododeoxyuridine were administered before surgery. After immunofluorescent staining of the frozenmetastases, pimonidazole binding, vascularity, and proliferation were analyzed quantitatively. Thirteenparaffin-embedded primary tumors were stained immunohistochemically for GLUT1 and CA-IXexpression, which was analyzed semiquantitatively in primary tumors and corresponding livermetastases. RESULTS In liver metastases, pimonidazole binding showed a pattern consistent withdiffusion-limited hypoxia. The mean pimonidazole-positive fraction was 0.146; the mean distance fromvessels to pimonidazole-positive areas was 80 microm. When expressed, often co-localization wasobserved between pimonidazole binding and GLUT1 or CA-IX expression, but microregional areas ofmismatch were also observed. No correlation between the level of pimonidazole binding and GLUT1 orCA-IX expression was observed. In some patients, a large fraction (up to 30%) of proliferating cells waspresent in pimonidazole-stained areas. Expression of CA-IX in primary tumors and metastases showed asignificant correlation, which was absent for GLUT1 expression. CONCLUSIONS Compared with othertumor types, liver metastases of colorectal cancer contain large amounts of hypoxic cells. The lack ofcorrelation with pimonidazole binding brings into question the value of GLUT1 and CA-IX as endogenousmarkers of hypoxia.", "metadata": {}}
+{"_id": "24988745", "title": "", "text": "Unmet needs mediate the relationship between symptoms and quality of life in breast cancersurvivorsThis study aimed to compare the symptoms, unmet needs, and QoL reported by women at 6months to <2 years and 2 to 5 years following surgery and adjuvant treatment for breast cancer. It alsoevaluated the relationships among symptoms, unmet needs, and QoL using structural equation modeling.In this study, 113 and 137 survivors following breast cancer treatment 6 months to <2 years and 2 to 5years, respectively, completed the Memorial Symptom Assessment Scale, the Supportive Care NeedsSurvey-34, and the Medical Outcomes Study 12-item Short Form Health Survey version 2.0 during theirmedical follow-up. The mean numbers of symptoms and unmet needs were 5.43 and 3.0, respectively,for survivors at <2 years, and 5.24 and 2.42, respectively, for survivors at 2 to 5 years followingtreatment. The most common reported symptoms were related primarily to physical domains. Nosignificant differences were found between the two survivor groups on the MSAS scores. Survivors at <2years reported significantly higher scores in Psychological and Health Care System/Information needs (p< 0.01), and lower composite scores in physical and mental QoL (p < 0.05) than those at 2 to 5 yearspost-treatment. Significant direct and indirect effects were found of symptom burden through unmetneeds on survivors’ physical and mental QoL after adjustment for survival time, and the models showed agood fit. Results suggest that breast cancer survivors continue to endure many symptoms independent ofthe survivorship period. The unmet needs mediate the relationship between symptom burden andsurvivors’ QoL.", "metadata": {}}
+{"_id": "24989194", "title": "", "text": "Phagocytosis and deposition of vascular beta-amyloid in rat brains injected with Alzheimerbeta-amyloid.The presence of extracellular deposits of beta-amyloid protein in the brain is a hallmark ofAlzheimer's disease (AD). In an effort to determine the effect of amyloid in an animal model, the authorsinjected amyloid cores isolated from AD brains into the cortex and hippocampus of rats. Lipofuscin, amajor contaminant of the plaque core preparation, was injected on the contralateral side and used as acontrol to induce an analogous phagocytic cell response. Rats were sacrificed 2 days, 7 days, and 1month after injection and amyloid located by four histochemical techniques. Amyloid and lipofuscin movefrom the site of injection into otherwise undamaged neuropil, persist for at least 1 month and are bothassociated with increases in glial fibrillary acidic protein and microglia (OX-42) staining. By 1 week, manyof the amyloid cores are ingested by phagocytes. Some of the beta-amyloid-containing phagocytesmigrate to the vessels and to the ventricles, and by 1 month, a significant amount of the amyloid isdirectly associated with the vessels. This suggests that phagocytic cells can internalize exogenousamyloid and attempt to clear it from the central nervous system (CNS). Therefore, the observeddistribution of amyloid is not necessarily the initial site of deposition.", "metadata": {}}
+{"_id": "24995939", "title": "", "text": "Specific sites in the C terminus of CTCF interact with the SA2 subunit of the cohesin complex and arerequired for cohesin-dependent insulation activity.Recent studies have shown that the protein CTCF,which plays an important role in insulation and in large-scale organization of chromatin within theeukaryotic nucleus, depends for both activities on recruitment of the cohesin complex. We show here thatthe interaction of CTCF with the cohesin complex involves direct contacts between the cohesin subunitSA2 and specific regions of the C-terminal tail of CTCF. All other cohesin components are recruitedthrough their interaction with SA2. Expression in vivo of CTCF mutants lacking the C-terminal domain, orwith mutations at sites within it required for SA2 binding, disrupts the normal expression profile of theimprinted genes IGF2-H19 and also results in a loss of insulation activity. Taken together, our resultsdemonstrate that specific sites on the C terminus of CTCF are essential for cohesin binding and insulatorfunction. The only direct interaction between CTCF and cohesin involves contact with SA2, which isexternal to the cohesin ring. This suggests that in recruiting cohesin to CTCF, SA2 could bind first and thering could assemble subsequently.", "metadata": {}}
+{"_id": "24998637", "title": "", "text": "Interleukin 6 plays a key role in the development of antigen-induced arthritis.To investigate the directrole of interleukin (IL) 6 in the development of rheumatoid arthritis, IL-6-deficient (IL-6 -/-) mice werebackcrossed for eight generations into C57BL/6 mice, a strain of mice with a genetic background ofsusceptibility for antigen-induced arthritis (AIA). Both histological and immunological comparisons weremade between IL-6-deficient (IL-6 -/-) mice and wild-type (IL-6 +/+) littermates after the induction ofAIA. Although all IL-6 +/+ mice developed severe arthritis, only mild arthritis was observed in IL-6 -/-mice. Safranin O staining demonstrated that articular cartilage was well preserved in IL-6 -/- mice,whereas it was destroyed completely in IL-6 +/+ mice. In addition, comparable mRNA expression forboth IL-1beta and tumor necrosis factor alpha, but not for IL-6, was detected in the inflamed joints ofIL-6 -/- mice, suggesting that IL-6 may play a more crucial role in cartilage destruction than eitherIL-1beta or tumor necrosis factor alpha. In immunological comparisons, both antigen-specific in vitroproliferative response in lymph node cells and in vivo antibody production were elicited in IL-6 -/- mice,but they were reduced to less than half of that found in IL-6 +/+ mice. Lymph node cells of IL-6 -/- miceproduced many more Th2 cytokines than did IL-6 +/+ mice with either antigen-specific or nonspecificstimulation in in vitro culture. Taken together, these results indicate that IL-6 may play a key role in thedevelopment of AIA at the inductive as well as the effector phase, and the blockade of IL-6 is possiblybeneficial in the treatment of rheumatoid arthritis.", "metadata": {}}
+{"_id": "24998764", "title": "", "text": "Relation between renal function within the normal range and central and peripheral arterial stiffness inhypertension.Chronic kidney disease is accompanied by increased large-artery stiffness, but the relationbetween glomerular filtration rate within the reference range and central or peripheral arterial stiffnesshas been understudied. The link between renal function and arterial stiffness was assessed in 305patients with never-treated essential hypertension (men: 58%; age: 48+/-11 years, blood pressure:151/95+/-20/11 mm Hg), free from overt cardiovascular disease and with serum creatinine values <1.4mg/dL (men) and <1.2 mg/dL (women), who underwent noninvasive aortic and upper-limb pulse wavevelocity (PWV) determination. Aortic PWV was strongly related to age (r=0.55; P<0.001), whereasupper-limb PWV had a weaker nonlinear relation with age (beta=1.392; P<0.001 for age; beta=-1.312;P<0.001 for age squared) and a weak relation with aortic PWV (r=0.22; P<0.001). Glomerular filtrationrate (GFR), estimated according to the Mayo clinic equation for healthy subjects, was inversely correlatedwith large-artery stiffness, as assessed by aortic PWV (r=-0.34; P<0.001), and with peripheral arterystiffness, as assessed by upper-limb PWV (r=-0.25; P<0.001). In a multivariate linear regression, aorticPWV was independently predicted by age (beta=0.48; P<0.001), mean arterial pressure (beta=0.14;P=0.013), and GFR (beta=-0.13, P=0.029). Upper-limb PWV was predicted by GFR (beta=-0.24;P<0.001) and mean arterial pressure (beta=0.20; P<0.001). We conclude that, in hypertensive patientswith normal renal function, an inverse relationship exists between GFR and stiffness of both centralelastic and peripheral muscular arteries. These relations are in part independent from the effect ofseveral confounders, including age, sex, and blood pressure values.", "metadata": {}}
+{"_id": "25001628", "title": "", "text": "Comparative gene expression profiling of in vitro differentiated megakaryocytes and erythroblastsidentifies novel activatory and inhibitory platelet membrane proteins.To identify previously unknownplatelet receptors we compared the transcriptomes of in vitro differentiated megakaryocytes (MKs) anderythroblasts (EBs). RNA was obtained from purified, biologically paired MK and EB cultures andcompared using cDNA microarrays. Bioinformatical analysis of MK-up-regulated genes identified 151transcripts encoding transmembrane domain-containing proteins. Although many of these were knownplatelet genes, a number of previously unidentified or poorly characterized transcripts were also detected.Many of these transcripts, including G6b, G6f, LRRC32, LAT2, and the G protein-coupled receptorSUCNR1, encode proteins with structural features or functions that suggest they may be involved in themodulation of platelet function. Immunoblotting on platelets confirmed the presence of the encodedproteins, and flow cytometric analysis confirmed the expression of G6b, G6f, and LRRC32 on the surfaceof platelets. Through comparative analysis of expression in platelets and other blood cells wedemonstrated that G6b, G6f, and LRRC32 are restricted to the platelet lineage, whereas LAT2 andSUCNR1 were also detected in other blood cells. The identification of the succinate receptor SUCNR1 inplatelets is of particular interest, because physiologically relevant concentrations of succinate were shownto potentiate the effect of low doses of a variety of platelet agonists.", "metadata": {}}
+{"_id": "25007443", "title": "", "text": "Topographic mapping of VMH \u0000 arcuate nucleus microcircuits and their reorganization by fastingIn thehypothalamic arcuate nucleus (ARC), pro-opiomelanocortin (POMC) neurons inhibit feeding andneuropeptide-Y (NPY) neurons stimulate feeding. We tested whether neurons in the ventromedialhypothalamic nucleus (VMH), a known satiety center, activate anorexigenic neuronal pathways in theARC by projecting either excitatory synaptic inputs to POMC neurons and/or inhibitory inputs to NPYneurons. Using laser scanning photostimulation in brain slices from transgenic mice, we found that POMCand NPY neurons, which are interspersed in the ARC, are nevertheless regulated by anatomically distinctsynaptic inputs. POMC neurons received strong excitatory input from the medial VMH (mVMH), whereasNPY neurons did not and, instead, received weak inhibitory input only from within the ARC. The strengthof the excitatory input from the mVMH to POMC neurons was diminished by fasting. These data identify anew molecularly defined circuit that is dynamically regulated by nutritional state in a manner consistentwith the known role of the VMH as a satiety center.", "metadata": {}}
+{"_id": "25014337", "title": "", "text": "The human immunodeficiency virus type 1 nonnucleoside reverse transcriptase inhibitor resistancemutation I132M confers hypersensitivity to nucleoside analogs.We previously identified a rare mutation inhuman immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT), I132M, which confershigh-level resistance to the nonnucleoside RT inhibitors (NNRTIs) nevirapine and delavirdine. In thisstudy, we have further characterized the role of this mutation in viral replication capacity and inresistance to other RT inhibitors. Surprisingly, our data show that I132M confers markedhypersusceptibility to the nucleoside analogs lamivudine (3TC) and tenofovir at both the virus andenzyme levels. Subunit-selective mutagenesis studies revealed that the mutation in the p51 subunit of RTwas responsible for the increased sensitivity to the drugs, and transient kinetic analyses showed that thishypersusceptibility was due to I132M decreasing the enzyme's affinity for the natural dCTP substrate butincreasing its affinity for 3TC-triphosphate. Furthermore, the replication capacity of HIV-1 containingI132M is severely impaired. This decrease in viral replication capacity could be partially or completelycompensated for by the A62V or L214I mutation, respectively. Taken together, these results help toexplain the infrequent selection of I132M in patients for whom NNRTI regimens are failing andfurthermore demonstrate that a single mutation outside of the polymerase active site and inside of thep51 subunit of RT can significantly influence nucleotide selectivity.", "metadata": {}}
+{"_id": "25022826", "title": "", "text": "AFF1 and AFF4 differentially regulate the osteogenic differentiation of human MSCsAFF1 and AFF4 belongto the AFF (AF4/FMR2) family of proteins, which function as scaffolding proteins linking two differenttranscription elongation factors, positive elongation factor b (P-TEFb) and ELL1/2, in super elongationcomplexes (SECs). Both AFF1 and AFF4 regulate gene transcription through elongation and chromatinremodeling. However, their function in the osteogenic differentiation of mesenchymal stem cells (MSCs)is unknown. In this study, we show that small interfering RNA (siRNA)-mediated depletion of AFF1 inhuman MSCs leads to increased alkaline phosphatase (ALP) activity, enhanced mineralization andupregulated expression of osteogenic-related genes. On the contrary, depletion of AFF4 significantlyinhibits the osteogenic potential of MSCs. In addition, we confirm that overexpression of AFF1 and AFF4differentially affects osteogenic differentiation in vitro and MSC-mediated bone formation in vivo.Mechanistically, we find that AFF1 regulates the expression of DKK1 via binding to its promoter region.Depletion of DKK1 in HA-AFF1-overexpressing MSCs abrogates the impairment of osteogenicdifferentiation. Moreover, we detect that AFF4 is enriched in the promoter region of ID1. AFF4 knockdownblunts the BRE luciferase activity, SP7 expression and ALP activity induced by BMP2 treatment. Inconclusion, our data indicate that AFF1 and AFF4 differentially regulate the osteogenic differentiation ofhuman MSCs.", "metadata": {}}
+{"_id": "25028913", "title": "", "text": "Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronaryartery disease. FRISC Study Group. Fragmin during Instability in Coronary Artery Disease.BACKGROUNDIn patients with unstable coronary artery disease, there is a relation between the short-term risk of deathand blood levels of troponin T (a marker of myocardial damage) and C-reactive protein and fibrinogen(markers of inflammation). Using information obtained during an extension of the follow-up period in theFragmin during Instability in Coronary Artery Disease trial, we evaluated the usefulness of troponin T,C-reactive protein, and fibrinogen levels and other indicators of risk as predictors of the long-term risk ofdeath from cardiac causes. METHODS Levels of C-reactive protein and fibrinogen at enrollment and themaximal level of troponin T during the first 24 hours after enrollment were analyzed in 917 patientsincluded in a clinical trial of low-molecular-weight heparin in unstable coronary artery disease. Thepatients were followed for a mean of 37.0 months (range, 1.6 to 50.6). RESULTS During follow-up, 1.2percent of the 173 patients with maximal blood troponin T levels of less than 0.06 microg per liter died ofcardiac causes, as compared with 8.7 percent of the 367 patients with levels of 0.06 to 0.59 microg perliter and 15.4 percent of the 377 patients with levels of at least 0.60 microg per liter (P=0.007 andP=0.001, respectively). The rates of death from cardiac causes were 5.7 percent among the 314 patientswith blood C-reactive protein levels of less than 2 mg per liter, 7.8 percent among the 294 with levels of2 to 10 mg per liter, and 16.5 percent among the 309 with levels of more than 10 mg per liter (P=0.29and P=0.001, respectively). The rates of death from cardiac causes were 5.4 percent among the 314patients with blood fibrinogen levels of less than 3.4 g per liter, 12.0 percent among the 300 with levelsof 3.4 to 3.9 g per liter, and 12.9 percent among the 303 with levels of at least 4.0 g per liter (P=0.004and P=0.69, respectively). In a multivariate analysis, levels of troponin T and C-reactive protein wereindependent predictors of the risk of death from cardiac causes. CONCLUSIONS In unstable coronaryartery disease, elevated levels of troponin T and C-reactive protein are strongly related to the long-termrisk of death from cardiac causes. These markers are independent risk factors, and their effects areadditive with respect to each other and other clinical indicators of risk.", "metadata": {}}
+{"_id": "25036988", "title": "", "text": "Loss of lamin B1 results in prolongation of S phase and decondensation of chromosometerritories.Nuclear lamin B1 (LMNB1) constitutes one of the major structural proteins in the lamina mesh.We silenced the expression of LMNB1 by RNA interference in the colon cancer cell line DLD-1 and showeda dramatic redistribution of H3K27me3 from the periphery to a more homogeneous nuclear dispersion. Inaddition, we observed telomere attrition and an increased frequency of micronuclei and nuclear blebs. By3D-FISH analyses, we demonstrated that the volume and surface of chromosome territories weresignificantly larger in LMNB1-depleted cells, suggesting that LMNB1 is required to maintain chromatincondensation in interphase nuclei. These changes led to a prolonged S phase due to activation of Chk1.Finally, silencing of LMNB1 resulted in extensive changes in alternative splicing of multiple genes and in ahigher number of enlarged nuclear speckles. Taken together, our results suggest a mechanistic role ofthe nuclear lamina in the organization of chromosome territories, maintenance of genome integrity andproper gene splicing.", "metadata": {}}
+{"_id": "25041967", "title": "", "text": "Human artificial chromosomes with alpha satellite-based de novo centromeres show increased frequencyof nondisjunction and anaphase lag.Human artificial chromosomes have been used to modelrequirements for human chromosome segregation and to explore the nature of sequences competent forcentromere function. Normal human centromeres require specialized chromatin that consists of alphasatellite DNA complexed with epigenetically modified histones and centromere-specific proteins. Whileseveral types of alpha satellite DNA have been used to assemble de novo centromeres in artificialchromosome assays, the extent to which they fully recapitulate normal centromere function has not beenexplored. Here, we have used two kinds of alpha satellite DNA, DXZ1 (from the X chromosome) andD17Z1 (from chromosome 17), to generate human artificial chromosomes. Although artificialchromosomes are mitotically stable over many months in culture, when we examined their segregation inindividual cell divisions using an anaphase assay, artificial chromosomes exhibited more segregationerrors than natural human chromosomes (P < 0.001). Naturally occurring, but abnormal small ringchromosomes derived from chromosome 17 and the X chromosome also missegregate more than normalchromosomes, implicating overall chromosome size and/or structure in the fidelity of chromosomesegregation. As different artificial chromosomes missegregate over a fivefold range, the data suggest thatvariable centromeric DNA content and/or epigenetic assembly can influence the mitotic behavior ofartificial chromosomes.", "metadata": {}}
+{"_id": "25045244", "title": "", "text": "Identification of a human HLA-E-restricted CD8+ T cell subset in volunteers immunized with Salmonellaenterica serovar Typhi strain Ty21a typhoid vaccine.Our previous studies in volunteers immunized withSalmonella enterica serovar Typhi (S. Typhi) have suggested an important role for CD8+ T cells in hostdefense. In this study we describe a novel subset of nonclassical human HLA-E-restricted S.Typhi-specific CD8+ T cells derived from PBMC of Ty21a typhoid vaccinees. CD3+CD8+CD4-CD56- T cellseffectively killed S. Typhi-infected targets regardless of whether they share classical HLA class Imolecules with them, by a FAS-independent, granule-dependent mechanism, as evidenced by inductionof granzyme B release and the blocking effects of concanamycin and strontium ions. The expression ofHLA-E Ags, but not CD1-a, -b, or -c, on the membrane of S. Typhi-infected targets rendered themsusceptible to lysis. Moreover, anti-HLA-E Abs partially blocked these responses. We also demonstratedthat presentation of S. Typhi Ags via HLA-E could stimulate IFN-gamma production. Increases in the netfrequency of IFN-gamma spot-forming cells were observed in the presence of targets coated withpeptides that contain S. Typhi GroEL HLA-E binding motifs. These results demonstrate that HLA-E bindsnonamer peptides derived from bacterial proteins and trigger CD8+-mediated lysis and IFN-gammaproduction when exposed to infected targets, raising the possibility that this novel effector mechanismmight contribute to host defense against intracellular bacterial infections.", "metadata": {}}
+{"_id": "25049067", "title": "", "text": "Costs and cost-effectiveness of alternative tuberculosis management strategies in SouthAfrica--implications for policy.OBJECTIVE To conduct an economic analysis of the Hlabisacommunity-based directly observed therapy management strategy for tuberculosis and to project costs ofthree alternative strategies. SETTING Hlabisa health district, KwaZulu-Natal, South Africa. METHODS Aneconomic analysis comparing the current tuberculosis management strategy in Hlabisa with threealternative strategies (the Hlabisa strategy prior to 1991 based on hospitalisation, the national strategyand sanatorium care) in terms of costs to both health service and patient and of cost-effectiveness.RESULTS The current Hlabisa strategy was the most cost-effective (R3799 per patient cured), comparedwith R98307 for the strategy used prior to 1991, R9940 for the national strategy, and R11145 forsanatorium care. Between 71% and 88% of treatment costs lie with the health service, andhospitalisation (R119 per day) is the most expensive item. Prolonged hospitalisation is extremelyexpensive, but community care is cheaper (community clinic visit, R28; community health worker visit,R7). The total cost of supervising a patient in the community under the current Hlabisa strategy wasR503, equivalent to 4.2 days in hospital. Drug costs (R157) are equivalent to just 1.3 days in hospital.CONCLUSION Cost to both health service and patient can be substantially reduced by usingcommunity-based directly observed therapy for tuberculosis, a strategy that is cheap and cost-effectivein Hlabisa. These findings have important national implications, supporting the goals of the newtuberculosis control programme.", "metadata": {}}
+{"_id": "25050364", "title": "", "text": "Interleukin-18 null mutation increases weight and food intake and reduces energy expenditure and lipidsubstrate utilization in high-fat diet fed miceOBJECTIVE The proinflammatory cytokine interleukin-18(IL-18) putatively modulates food intake and energy metabolism, but the effects of IL-18 in high-fat dietfed animals are unknown. Whether IL-18 alters basal metabolic rate or metabolic processes of living isunknown. Here, we tested the hypothesis that IL-18 modulates weight gain, energy intake, whole-bodyenergy expenditure, and utilization of lipid as a fuel substrate in high-fat diet fed mice. METHODS Foodintake, whole-body metabolism, and motor activity of IL-18 knockout mice were compared to those ofwildtype littermates; anorectic effects of intracerebroventricular IL-18 administration were comparedbetween IL-18 receptor knockout, IL-18/IL-18R knockout and wildtype mice. RESULTS Chow-rearedIL-18 knockout mice were overweight at 6 months of age and then gained excess weight on both low-fatand high-fat diets, ate more high-fat diet, and showed reduced whole-body energy expenditure andincreased respiratory exchange ratios. Reductions in energy expenditure of IL-18 knockout mice wereseen across fasting vs. feeding conditions, low- vs. high-fat diets, high vs. low levels of physical activityand times of day, suggesting actions on basal metabolic rate. The circadian amplitude of energyexpenditure, but not respiratory exchange ratio, food intake, or motor activity, also was blunted in IL-18knockout mice. Central IL-18 administration reduced high-fat diet intake in wildtype mice, but not in micelacking the IL-18 receptor. CONCLUSION The loss-of-function results support the hypothesis thatendogenous IL-18 suppresses appetite and promote energy expenditure and lipid fuel substrateutilization not only during sickness, but also in healthy adults consuming high-fat diets.", "metadata": {}}
+{"_id": "25050969", "title": "", "text": "Notch activation promotes cell proliferation and the formation of neural stem cell-like colonies in humanglioma cellsSince Notch signaling plays a critical role in stem cells and oncogenesis, we hypothesized thatNotch signaling might play roles in cancer stem cells and cancer cells with a stem cell phenotype. In thisstudy, we accessed potential functions of the Notch pathway in the formation of cancer stem cells usinghuman glioma. Using RT-PCR, we found that most human astrogliomas of different grades expressedmoderate to high level of Notch receptors and ligands. mRNA of Hes5 but not Hes1, both of which aremajor downstream molecules of the Notch pathway, was also detected. In human glioma cell lines BT325,U251, SHG-44, and U87, mRNA encoding different types of Notch receptors were detected, but activeform of Notch1 (NIC) was only detected in SHG-44 and U87 by Western blot. Interestingly, proliferationof these two glioma cell lines appeared faster than that of the other two lines in which NIC was notdetected. We have over-expressed NIC of Notch1 in SHG-44 cells by constitutive transfection to evaluatethe effects of Notch signaling on glioma cells. Our results showed that over-expression of NIC in SHG-44cells promoted the growth and the colony-forming activity of SHG-44 cells. Interestingly, over-expressionof NIC increased the formation neurosphere-like colonies in the presence of growth factors. Thesecolonies expressed nestin, and could be induced to cells expressing neuron-, astrocyte-, oroligodendrocyte-specific markers, consistent with phenotypes of neural stem cells. These data suggestthat Notch signaling promote the formation of cancer stem cell-like cells in human glioma.", "metadata": {}}
+{"_id": "25052749", "title": "", "text": "Rodent models in bone-related research: the relevance of calvarial defects in the assessment of boneregeneration strategies.In vivo research with animal models has been a preferred experimental system inbone-related biomedical research since, by approximation, it allows relevant data gathering regardingphysiological and pathological conditions that could be of use to establish more effective clinicalinterventions. Animal models, and more specifically rodent models, have been extensively used and havecontributed greatly to the development and establishment of a wide range of translational approachesaiming to regenerate the bone tissue. In this regard, the calvarial defect model has found greatapplication in basic and applied research, nonetheless the controversial rationalization for the use ofcritical size defects - defects that are unable to report spontaneous healing - or subcritical size defects inthe proposed applications. Accordingly, this work aims to review the advantages and limitations of theuse of rodent models in biomedical bone-related research, emphasizing the problematic issues of the useof calvarial critical and subcritical size defects. Additionally, surgical protocols for the establishment ofboth defects in rat calvarial bone, as well as the description and exemplification of the most frequentlyused techniques to access the bone tissue repair, are portrayed.", "metadata": {}}
+{"_id": "25062868", "title": "", "text": "The transcriptional responses of Mycobacterium tuberculosis to inhibitors of metabolism: novel insightsinto drug mechanisms of action.The differential transcriptional response of Mycobacterium tuberculosis todrugs and growth-inhibitory conditions was monitored to generate a data set of 430 microarray profiles.Unbiased grouping of these profiles independently clustered agents of known mechanism of actionaccurately and was successful at predicting the mechanism of action of several unknown agents. Thesepredictions were validated biochemically for two agents of previously uncategorized mechanism,pyridoacridones and phenothiazines. Analysis of this data set further revealed 150 underlying clusters ofcoordinately regulated genes offering the first glimpse at the full metabolic potential of this organism. Asignature subset of these gene clusters was sufficient to classify all known agents as to mechanism ofaction. Transcriptional profiling of both crude and purified natural products can provide criticalinformation on both mechanism and detoxification prior to purification that can be used to guide the drugdiscovery process. Thus, the transcriptional profile generated by a crude marine natural productrecapitulated the mechanistic prediction from the pure active component. The underlying gene clustersfurther provide fundamental insights into the metabolic response of bacteria to drug-induced stress andprovide a rational basis for the selection of critical metabolic targets for screening for new agents withimproved activity against this important human pathogen.", "metadata": {}}
+{"_id": "25068298", "title": "", "text": "Electron microscopic studies of macrophages in early human yolk sacs.Distribution and fine structure ofmacrophages were studied in 10 human embryos in the 6th and 7th week of gestation, 5.5 to 12 mm incrown-rump length. The yolk sac macrophages were found in the extravascular mesenchymal tissues andintravascular spaces long before the first appearance of bone marrow and lymphatic tissues in theembryos. In addition to the macrophages, the fibroblastic cells and the cells of erythropoietic series werealso present in the extravascular space. The macrophages showed a variety of cellular structuressuggesting transition from immature cell type with no heterophagolysosomes to mature cell type inphagocytosis. The mature macrophages avidly phagocytized the primitive erythroblasts and occasionallyplatelets. They were positively stained for lysosomal enzymes and were characterized by numerouspleomorphic heterophagolysosomes which exhibited various stages of digestion of phagocytized bloodcells. The origin of intravascular macrophages may be in either migrated extravascular macrophages orphagocytic endothelial cells. The phagocytosis and degradation of erythroblasts appear to be one of themain functions of yolk sac macrophages. The presence of the macrophages in mitosis indicates theirproliferation in situ.", "metadata": {}}
+{"_id": "25069745", "title": "", "text": "Urban malaria and anaemia in children: a cross-sectional survey in two cities of Ghana.OBJECTIVE Todescribe the epidemiology of urban malaria, an emerging problem in sub-Saharan Africa. METHODCross-sectional surveys of communities in Accra and Kumasi, Ghana, determining risk factors for malariainfection and anaemia in children aged 6-60 months. RESULTS Malaria prevalence rates ranged from 2%to 33% between urban communities. 47.1% of children were anaemic (Hb<11.0 g/dl). Factors associatedwith malaria prevalence were low socio-economic status, age and anaemia. The attributable risks ofanaemia and severe anaemia (Hb<8.0 g/dl) caused by malaria were 5% and 23% respectively.CONCLUSIONS Malaria in urban areas displayed a heterogeneity and complexity that differed from therural environment, which has important implications for malaria control. Marked intra-city variationindicates the importance of targeting specific areas or districts. The most vulnerable group, the urbanpoor, should be prioritized when designing control measures. This would require careful assessment ofthe malaria risk pattern in any city to guide an integrated control program.", "metadata": {}}
+{"_id": "25079962", "title": "", "text": "Nitrite infusions to prevent delayed cerebral vasospasm in a primate model of subarachnoidhemorrhage.CONTEXT Delayed cerebral vasospasm causes permanent neurological deficits or death in atleast 15% of patients following otherwise successful treatment for ruptured intracranial aneurysm.Decreased bioavailability of nitric oxide has been associated with the development of cerebral vasospasm.OBJECTIVE To determine whether infusions of nitrite will prevent delayed cerebral vasospasm. DESIGN,SETTING, AND SUBJECTS A total of 14 anesthetized cynomolgus monkeys had an autologous blood clotplaced around the right middle cerebral artery. Cerebral arteriography was performed before clotplacement and on days 7 and 14 to assess vasospasm. The study was conducted from August 2003 toFebruary 2004. INTERVENTIONS A 90-mg sodium nitrite intravenous solution infused over 24 hours plusa 45-mg sodium nitrite bolus daily (n = 3); a 180-mg sodium nitrite intravenous solution infused over 24hours (n = 3); or a control saline solution infusion (n = 8). Each was infused continuously for 14 days.MAIN OUTCOME MEASURES Nitrite, S-nitrosothiol, and methemoglobin levels in blood and cerebrospinalfluid and degree of arteriographic vasospasm. RESULTS In control monkeys, mean (SD) cerebrospinalfluid nitrite levels decreased from 3.1 (1.5) micromol/L to 0.4 (0.1) micromol/L at day 7 and to 0.4 (0.4)micromol/L at day 14 (P = .03). All 8 control monkeys developed significant vasospasm of the rightmiddle cerebral artery, which was complicated by stroke and death in 1 animal. Sodium nitrite infusionsincreased the nitrite and methemoglobin levels (<2.1% of total hemoglobin) in the blood andcerebrospinal fluid without evoking systemic hypotension. Nitrite infusion prevented development ofvasospasm (no animals developed significant vasospasm; mean [SD] reduction in right middle cerebralartery area on day 7 after subarachnoid hemorrhage of 8% [9%] in nitrite-treated monkeys vs 47%[5%] in saline-treated controls; P<.001). There was a negative correlation between the concentration ofnitrite in cerebrospinal fluid and the degree of cerebral vasospasm (P<.001). Pharmacological effects ofnitrite infusion were also associated with the formation of S-nitrosothiol in cerebrospinal fluid. There wasno clinical or pathological evidence of nitrite toxicity. CONCLUSION Subacute sodium nitrite infusionsprevented delayed cerebral vasospasm in a primate model of subarachnoid hemorrhage.", "metadata": {}}
+{"_id": "25085979", "title": "", "text": "Developmental gene networks: a triathlon on the course to T cell identityCells acquire their ultimateidentities by activating combinations of transcription factors that initiate and sustain expression of theappropriate cell type-specific genes. T cell development depends on the progression of progenitor cellsthrough three major phases, each of which is associated with distinct transcription factor ensembles thatcontrol the recruitment of these cells to the thymus, their proliferation, lineage commitment andresponsiveness to T cell receptor signals, all before the allocation of cells to particular effectorprogrammes. All three phases are essential for proper T cell development, as are the mechanisms thatdetermine the boundaries between each phase. Cells that fail to shut off one set of regulators before thenext gene network phase is activated are predisposed to leukaemic transformation.", "metadata": {}}
+{"_id": "25089501", "title": "", "text": "A tumor necrosis factor-α–mediated pathway promoting autosomal dominant polycystic kidneydiseaseAutosomal dominant polycystic kidney disease (ADPKD) is caused by heterozygous mutations ineither PKD1 or PKD2, genes that encode polycystin-1 and polycystin-2, respectively. We show here thattumor necrosis factor-α (TNF-α), an inflammatory cytokine present in the cystic fluid of humans withADPKD, disrupts the localization of polycystin-2 to the plasma membrane and primary cilia through ascaffold protein, FIP2, which is induced by TNF-α. Treatment of mouse embryonic kidney organ cultureswith TNF-α resulted in formation of cysts, and this effect was exacerbated in the Pkd2+/− kidneys. TNF-αalso stimulated cyst formation in vivo in Pkd2+/− mice. In contrast, treatment of Pkd2+/− mice with theTNF-α inhibitor etanercept prevented cyst formation. These data reveal a pathway connecting TNF-αsignaling, polycystins and cystogenesis, the activation of which may reduce functional polycystin-2 belowa critical threshold, precipitating the ADPKD cellular phenotype.", "metadata": {}}
+{"_id": "25098790", "title": "", "text": "Inappropriate inhaler use: assessment of use and patient preference of seven inhalation devices.EDICI.Inefficient inhaler technique is a common problem resulting in poor drug delivery, decreaseddisease control and increased inhaler use. The aim of this study was to assess patients' use of differentinhaler devices and to ascertain whether patient preference is indicative of ease of use and whethercurrent inhaler use has any influence on either technique or preference. We also wished to define themost appropriate method of selecting an inhaler for a patient, taking into account observed technique anddevice cost. One hundred patients received instruction, in randomized order, in the use of seven differentinhaler devices. After instruction they were graded (using predetermined criteria) in their inhalertechnique. After assessment patients were asked which three inhalers they most preferred and which, ifany, they currently used. Technique was best using the breath-actuated inhalers; the Easi-Breathe andAutohaler, with 91% seen to have good technique. The pressurized metered dose inhaler (pMDI) faredpoorly, in last position with only 79% of patients showing good technique, despite being the mostcommonly prescribed. The Easi-Breathe was by far the most popular device with the patients. TheAutohaler came in second position closely followed by the Clickhaler and Accuhaler. The majority ofpatients (55%) currently used the pMDI but the pMDI did not score highly for preference or achievebetter grades than the other devices. Only 79% of patients tested could use the pMDI effectively evenafter expert instruction yet it continues to be commonly prescribed. This has important repercussions fordrug delivery and hence disease control. Prescribing a patient's preferred device increases cost but canimprove efficiency and therefore be cost effective in the long term. Using an inexpensive device (pMDI)when technique is good and the patient's preferred inhaler device when not is one way to optimizedelivery and may even reduce cost.", "metadata": {}}
+{"_id": "25104843", "title": "", "text": "Hemoperfusion-hemodialysis ineffective for paraquat removal in life-threatening poisoning?We report ona patient treated with hemoperfusion-hemodialysis (HP-HD) for severe paraquat poisoning. Thisprocedure was adopted since the combination of adsorption and dialysis may improve overall drugremoval. On admission blood paraquat was 15.8 micrograms/ml. He received conventional treatment andcombined HP-HD which started within 3 hours after ingestion of the chemical and lasted 5 hours. Bloodsamples were obtained during and after HP-HD. The samples during HP-HD were taken before thecharcoal column, between the charcoal column and the artificial kidney and after the artificial kidney.Blood clearances of paraquat were 116 +/- 32 ml/min (n=6) for the charcoal column (HP), 90 +/- 54ml/min (n=6) for the artificial kidney (HD) and 151 +/- 37 ml/min (n=6) for the combined systems(HP-HD). After HP-HD a limited rebound of blood paraquat level was seen. One day after admission renaland hepatic failure had developed, and the patient died after 5 days. Tissue paraquat levels (microgram/gwet tissue) were: skeletal muscle 9.4, pancreas 6.0, prostate 5.6, thyroid 4.2, lungs 4.0, bone marrow4.0, kidney 3.1, spleen 2.9, adrenal 2.9, heart 2.8, liver 2.3, stomach and testis below 1.0.Measurements of blood levels demonstrated the efficient clearances of paraquat with HP-HD from thecentral (plasma) compartment. However, the present results confirmed those previously reported whichsuggest that the efficiency of short HP-HD in treating severe paraquat poisoning is questionable sinceparaquat levels in the peripheral (tissue) compartment remain elevated.", "metadata": {}}
+{"_id": "25121903", "title": "", "text": "Cancer treatment and survivorship statistics, 2014.The number of cancer survivors continues to increasedue to the aging and growth of the population and improvements in early detection and treatment. Inorder for the public health community to better serve these survivors, the American Cancer Society andthe National Cancer Institute collaborated to estimate the number of current and future cancer survivorsusing data from the Surveillance, Epidemiology, and End Results (SEER) program registries. In addition,current treatment patterns for the most common cancer types are described based on information in theNational Cancer Data Base and the SEER and SEER-Medicare linked databases; treatment-related sideeffects are also briefly described. Nearly 14.5 million Americans with a history of cancer were alive onJanuary 1, 2014; by January 1, 2024, that number will increase to nearly 19 million. The 3 most commonprevalent cancers among males are prostate cancer (43%), colorectal cancer (9%), and melanoma (8%),and those among females are cancers of the breast (41%), uterine corpus (8%), and colon and rectum(8%). The age distribution of survivors varies substantially by cancer type. For example, the majority ofprostate cancer survivors (62%) are aged 70 years or older, whereas less than one-third (32%) ofmelanoma survivors are in this older age group. It is important for clinicians to understand the uniquemedical and psychosocial needs of cancer survivors and to proactively assess and manage these issues.There are a growing number of resources that can assist patients, caregivers, and health care providersin navigating the various phases of cancer survivorship.", "metadata": {}}
+{"_id": "25124117", "title": "", "text": "Massive activation of archaeal defense genes during viral infection.Archaeal viruses display unusually highgenetic and morphological diversity. Studies of these viruses proved to be instrumental for the expansionof knowledge on viral diversity and evolution. The Sulfolobus islandicus rod-shaped virus 2 (SIRV2) is amodel to study virus-host interactions in Archaea. It is a lytic virus that exploits a unique egressmechanism based on the formation of remarkable pyramidal structures on the host cell envelope. Usingwhole-transcriptome sequencing, we present here a global map defining host and viral gene expressionduring the infection cycle of SIRV2 in its hyperthermophilic host S. islandicus LAL14/1. This informationwas used, in combination with a yeast two-hybrid analysis of SIRV2 protein interactions, to advancecurrent understanding of viral gene functions. As a consequence of SIRV2 infection, transcription of morethan one-third of S. islandicus genes was differentially regulated. While expression of genes involved incell division decreased, those genes playing a role in antiviral defense were activated on a large scale.Expression of genes belonging to toxin-antitoxin and clustered regularly interspaced short palindromicrepeat (CRISPR)-Cas systems was specifically pronounced. The observed different degree of activation ofvarious CRISPR-Cas systems highlights the specialized functions they perform. The information onindividual gene expression and activation of antiviral defense systems is expected to aid future studiesaimed at detailed understanding of the functions and interplay of these systems in vivo.", "metadata": {}}
+{"_id": "25134146", "title": "", "text": "Impact of human immunodeficiency virus infection on the histological features of chronic hepatitis C: acase-control study. The MULTIVIRC group.Hepatitis C virus (HCV) is frequently encountered in humanimmunodeficiency virus (HIV)-infected patients because of common routes of transmission. Previousstudies suggested that HIV infection impaired the natural course of chronic hepatitis C, with a more rapidprogression to cirrhosis. However, these studies did not assess the HIV infection impact on chronichepatitis C by taking into account the risk factors for liver fibrosis progression: alcohol, sex, age at thecontamination, and duration of HCV infection. We studied liver biopsy specimens of 2 groups of 58patients that were infected by both HCV and HIV or by HCV alone. The 2 groups were matched accordingthose risk factors, and liver biopsy responses were evaluated with the METAVIR items. The METAVIRactivity was higher in HIV-positive than HIV-negative patients. Cirrhosis was more frequent: (1) inHIV-positive patients with CD4 < or = 200 cells/microL (45%) than in HIV-negative patients (10%) (P =.003), (2) in HIV-positive patients with CD4 < or = 200 cells/microL (45%) than in HIV-positive patientswith CD4 > 200 cells/microL (17%) (P = .04). These differences, which were linked to HIV status, mightbe related to the enhanced HCV replication during HIV infection or other immune mechanisms that needfurther studies.", "metadata": {}}
+{"_id": "25135304", "title": "", "text": "Relation of plasma leptin concentrations to sex, body fat, dietary intake, and peak oxygen uptake inyoung adult women and men.The purpose of this study was to examine the relation of leptin to metabolicand dietary factors in college-age adults. Young adult women and men (n = 32) were recruited andunderwent testing for measurement of body mass index, body composition, peak oxygen consumption(VO2peak), dietary intake, and plasma levels of leptin and insulin. Ln leptin was significantly greater forwomen than for men (2.1 versus 1.2 ng/mL, respectively). This difference remained significant even afteradjusting ln leptin for fat mass and fat-free mass as covariates in separate analyses. VO2peak was higherfor men than for women and this remained significant after adjustment for differences in fat-free massand total body mass. Significant correlations were found between ln leptin and indicators of fat mass inwomen and men, with higher correlations for similar variables observed in men (r = 0.548, 0.674, and0.732 for body mass index, percentage of body fat, and fat mass [kg] for women, respectively, and r =0.740, 0.888, 0.858 for body mass index, percentage of body fat, and fat mass [kg] for men,respectively). Ln leptin showed a significant inverse relationship with VO2peak (r = -0.751) in men only.After adjusting ln leptin for body fat mass using partial correlations, ln leptin was not significantlyassociated with any of the measured variables. Alternatively, after normalization of ln leptin using fatmass as the divisor, a less adequate statistical analysis method, men showed statistical significantcorrelations between ln leptin and dietary intake and VO2peak. Although plasma leptin values werehigher in women, stronger associations were evident for men than for women between leptin andmetabolic and dietary factors.", "metadata": {}}
+{"_id": "25141908", "title": "", "text": "Expression of a human cytomegalovirus latency-associated homolog of interleukin-10 during theproductive phase of infection.The human cytomegalovirus UL111A region is active during both productiveand latent phases of infection. During productive infection, the virus expresses ORF79, a protein withoncogenic properties, and cmvIL-10, a functional homolog of human IL-10. During latent infection ofmyeloid progenitor cells, an alternately spliced variant of cmvIL-10, termed latency-associated (LA)cmvIL-10 has previously been identified. To determine whether LAcmvIL-10 transcription occurs duringproductive infection, we performed 5' and 3' RACE to map UL111A-region transcripts in productivelyinfected human foreskin fibroblasts (HFFs). This analysis revealed the presence of a singly splicedUL111A-region transcript predicted to encode LAcmvIL-10. This transcript was expressed in HFFs withearly (beta) kinetics, a temporal class that differs from that of ORF79 (alpha kinetics) and cmvIL-10(gamma kinetics). These data identify and map a transcript encoding a latency-associated homolog ofIL-10 which is expressed by the virus during the productive phase of infection.", "metadata": {}}
+{"_id": "25148216", "title": "", "text": "Kruppel-like factor 4 is essential for inflammatory monocyte differentiation in vivo.Several members ofthe Kruppel-like factor (KLF) family of transcription factors play important roles in differentiation,survival, and trafficking of blood and immune cell types. We demonstrate in this study that hematopoieticcells from KLF4(-/-) fetal livers (FL) contained normal numbers of functional hematopoietic progenitorcells, were radioprotective, and performed as well as KLF4(+/+) cells in competitive repopulation assays.However, hematopoietic \"KLF4(-/-) chimeras\" generated by transplantation of KLF4(-/-) fetal livers cellsinto lethally irradiated wild-type mice completely lacked circulating inflammatory (CD115(+)Gr1(+))monocytes, and had reduced numbers of resident (CD115(+)Gr1(-)) monocytes. Although the numbersand function of peritoneal macrophages were normal in KLF4(-/-) chimeras, bone marrow monocytic cellsfrom KLF4(-/-) chimeras expressed lower levels of key trafficking molecules and were more apoptotic.Thus, our in vivo loss-of-function studies demonstrate that KLF4, previously shown to mediateproinflammatory signaling in human macrophages in vitro, is essential for differentiation of mouseinflammatory monocytes, and is involved in the differentiation of resident monocytes. In addition,inducible expression of KLF4 in the HL60 human acute myeloid leukemia cell line stimulated monocyticdifferentiation and enhanced 12-O-tetradecanoylphorbol 13-acetate induced macrophage differentiation,but blocked all-trans-retinoic acid induced granulocytic differentiation of HL60 cells. Theinflammation-selective effects of loss-of-KLF4 and the gain-of-KLF4-induced monocytic differentiation inHL60 cells identify KLF4 as a key regulator of monocytic differentiation and a potential target fortranslational immune modulation.", "metadata": {}}
+{"_id": "25157790", "title": "", "text": "A population-based, case–control study of green tea consumption and leukemia risk in southwesternTaiwanThis study investigated the association between green tea consumption and leukemia. A total of252 cases (90.3% response) and 637 controls (53.4% response) were enrolled. Controls were matchedfor cases on age and gender. Information was collected on participants’ living habits, including teaconsumption. Green tea was used as a standard to estimate the total amount of individual catechinconsumption. We stratified individual consumption of catechins into four levels. Conditional logisticregression models were fit to subjects aged 0–15 and 16–29 years to evaluate separate associationsbetween leukemia and catechin consumption. A significant inverse association between green teaconsumption and leukemia risk was found in individuals aged 16–29 years, whereas no significantassociation was found in the younger age groups. For the older group with higher amounts of teaconsumption (>550 units of catechins), the adjusted odds ratio (OR) compared with the group withouttea consumption was 0.47 [95% confidence interval (CI) = 0.23–0.97]. After we adjusted for smokingstatus and medical irradiation exposure, the overall OR for all participants was 0.49 (95% CI =0.27–0.91), indicating an inverse relation between large amounts of catechins and leukemia. Drinkingsufficient amounts of tea, especially green tea, which contains more catechins than oolong tea and blacktea, may reduce the risk of leukemia.", "metadata": {}}
+{"_id": "25175223", "title": "", "text": "Specific HDV RNA-templated transcription by pol II in vitro.RNA polymerase II is implicated in theRNA-templated RNA synthesis during replication of viroids and Hepatitis Delta Virus (HDV); however,neither the RNA template nor protein factor requirements for this process are well defined. We havedeveloped an in vitro transcription system based on HeLa cell nuclear extract (NE), in which a segment ofantigenomic RNA corresponding to the left-hand tip region of the HDV rod-like structure serves as atemplate for efficient and highly specific RNA synthesis. Accumulation of the unique RNA product is highlysensitive to alpha-amanitin in HeLa NE and only partially sensitive to this drug in NE from PMG cells thatcontain an allele of the alpha-amanitin-resistant subunit of pol II, strongly suggesting pol II involvementin this reaction. Detailed analysis of the RNA product revealed that it represents a chimeric moleculecomposed of a newly synthesized transcript covalently attached to the 5' half of the RNA template.Selection of the start site for transcription is remarkably specific and depends on the secondary structureof the RNA template, rather than on its primary sequence. Some features of this reaction resemble theRNA cleavage-extension process observed for pol II-arrested complexes in vitro. A possible involvementof the described reaction in HDV replication is discussed.", "metadata": {}}
+{"_id": "25175997", "title": "", "text": "Pulmonary vascular lesions in end-stage idiopathic pulmonary fibrosis: Histopathologic study on lungexplant specimens and correlations with pulmonary hemodynamics.In patients presenting with idiopathicpulmonary fibrosis (IPF), modifications of pulmonary vessels are well defined in fibrotic areas but havenot been accurately assessed in the intervening patches of preserved lung. Moreover, the relationbetween pulmonary vessel lesions and pulmonary hemodynamics is not well known. We thereforedesigned a retrospective study on lung explant specimens from 26 patients with a firm diagnosis of IPFwho had undergone lung transplantation. Our aim was to (1) describe the vascular lesions, especially inpreserved lung areas, and (2) correlate them with pulmonary hemodynamics. In dense fibrotic zones,thickening of the arterial and venous wall with severe luminal narrowing was present in each patient. Inarchitecturally preserved lung zones, occlusion of venules and small pulmonary veins was observed in65% of the patients, although there were only mild changes of muscular pulmonary arteries. We found asignificant positive correlation between the macroscopic extent of lung fibrosis and mean pulmonaryartery pressure, but we failed to find a relation between mean pulmonary artery pressure andvenous/venular lesions in nonfibrotic areas. Our study points out that in many patients with IPF,nonfibrotic lung areas demonstrate an occlusive venopathy, the signification of which remainsundetermined.", "metadata": {}}
+{"_id": "25182647", "title": "", "text": "Maternal and perinatal outcome in severe pregnancy-related liver disease.Acute fatty liver of pregnancy(AFLP) and the syndrome of hemolysis, elevated liver enzyme levels, and low platelet count (HELLP) arerare but major disorders of the third trimester of pregnancy. Over a 10-year period, 46 women (medianage, 30 years; range, 17-41 years) developed hepatic dysfunction severe enough to require transfer toour Liver Failure Unit. Three quarters of the women were nulliparous, and 5 had twin pregnancies; themedian gestational age was 35 weeks (range, 24-40 weeks). At admission, 32 patients (70%) werepreeclamptic and 21 (46%) were encephalopathic and/or ventilated. Thirty-two patients (70%) hadclinical features and laboratory values consistent with AFLP, and 7 (15%) had HELLP syndrome. Onepatient had preeclamptic liver rupture requiring liver transplantation. In 6 other patients, causes ofsevere liver dysfunction unrelated to pregnancy were found. Infectious complications occurred in 17 ofthe patients with AFLP (53%) and in 2 of those with HELLP syndrome (29%). Major intra-abdominalbleeding occurred in 12 women (10 with AFLP), 9 of whom required laparotomies for clot evacuation.Four patients with AFLP (12.5%) had a fatal outcome, with a corresponding perinatal mortality rate of9%. There were no maternal or perinatal deaths associated with HELLP syndrome. In contrast to resultsof many previous studies, the results of this large series suggest a relatively favorable maternal andperinatal outcome in severe AFLP and HELLP syndrome. Further improvements in outcome are likely to beachieved through the prevention of the bleeding and infectious complications associated with thesedisorders.", "metadata": {}}
+{"_id": "25183830", "title": "", "text": "Circadian rhythms and the regulation of metabolic tissue function and energy homeostasis.Circadianoscillators play an indispensable role in the coordination of physiological processes with the cyclicchanges in the physical environment. A significant number of recent clinical and molecular studiessuggest that circadian biology may play an important role in the regulation of adipose and othermetabolic tissue functions. In this discussion, we present the hypothesis that circadian dysfunction maybe involved in the pathogenesis of obesity, type 2 diabetes, and the metabolic syndrome.", "metadata": {}}
+{"_id": "25186412", "title": "", "text": "Large-scale gene function analysis with the PANTHER classification systemThe PANTHER (proteinannotation through evolutionary relationship) classification system (http://www.pantherdb.org/) is acomprehensive system that combines gene function, ontology, pathways and statistical analysis toolsthat enable biologists to analyze large-scale, genome-wide data from sequencing, proteomics or geneexpression experiments. The system is built with 82 complete genomes organized into gene families andsubfamilies, and their evolutionary relationships are captured in phylogenetic trees, multiple sequencealignments and statistical models (hidden Markov models or HMMs). Genes are classified according totheir function in several different ways: families and subfamilies are annotated with ontology terms (GeneOntology (GO) and PANTHER protein class), and sequences are assigned to PANTHER pathways. ThePANTHER website includes a suite of tools that enable users to browse and query gene functions, and toanalyze large-scale experimental data with a number of statistical tests. It is widely used by benchscientists, bioinformaticians, computer scientists and systems biologists. In the 2013 release of PANTHER(v.8.0), in addition to an update of the data content, we redesigned the website interface to improve bothuser experience and the system's analytical capability. This protocol provides a detailed description ofhow to analyze genome-wide experimental data with the PANTHER classification system.", "metadata": {}}
+{"_id": "25191216", "title": "", "text": "Periostin, a novel marker of intramembranous ossification, is expressed in fibrous dysplasia and inc-Fos-overexpressing bone lesions.Fibrous dysplasia is a benign bone disease caused by a mutation in thegene for the stimulatory guanine nucleotide-binding protein Gs alpha, leading to high cyclic adenosinemonophosphate levels. Histologically, fibrous dysplasia is characterized by the production of fibroustissue accompanied by the deposition of ectopic type I collagen and other bone-associated extracellularmatrix proteins, as well as by irregular woven intramembranous bone onto which type Icollagen-containing Sharpey fibers are often attached. Fibrous dysplasia is also characterized by highexpression of c-Fos/c-Jun, known targets for cyclic adenosine monophosphate signaling. In this study, weexamined the expression of the bone-related extracellular matrix protein, periostin, and its knownreceptor, integrin alpha v beta 3 (CD51/61), in normal bones as well as in fibrous dysplasia.Immunohistochemistry and in situ hybridization studies revealed that periostin was expressed in theextracellular matrix during intramembranous but not endochondral ossification, as well as in the fibrouscomponent of fibrous dysplasia; and all cells adjacent to periostin-positive regions expressed CD51/61.Importantly, periostin was abundantly localized to Sharpey fibers. To investigate the contribution ofc-Fos, we examined transgenic mice overexpressing c-fos, which develop sclerotic lesions closelyresembling those found in fibrous dysplasia. In all lesions, transformed osteoblasts expressed high levelsof periostin, whereas normal osteoblasts did not. Our results show that periostin is a novel marker forintramembranous ossification, and is a good candidate as a diagnostic tool and/or a therapeutic target infibrous dysplasia. Moreover, the Gs alpha-cyclic adenosine monophosphate-c-Fos pathway mightrepresent one mechanism of periostin up-regulation in fibrous dysplasia, resulting in altered collagenfibrillogenesis characteristic of this disease.", "metadata": {}}
+{"_id": "25238950", "title": "", "text": "FGF-2 enhances intestinal stem cell survival and its expression is induced after radiation injury.Fibroblastgrowth factors (FGFs) have mitogenic activity toward a wide variety of cells of mesenchymal, neuronal,and epithelial origin and regulate events in normal embryonic development, angiogenesis, wound repair,and neoplasia. FGF-2 is expressed in many normal adult tissues and can regulate migration andreplication of intestinal epithelial cells in culture. However, little is known about the effects of FGF-2 onintestinal epithelial stem cells during either normal epithelial renewal or regeneration of a functionalepithelium after injury. In this study, we investigated the expression of FGF-2 in the mouse smallintestine after irradiation and determined the effect of exogenous FGF-2 on crypt stem cell survival afterradiation injury. Expression of FGF-2 mRNA and protein began to increase at 12 h aftergamma-irradiation, and peak levels were observed from 48 to 120 h after irradiation. At all times afterirradiation, the higher molecular mass isoform ( approximately 24 kDa) of FGF-2 was the predominantform expressed in the small intestine. Immunohistochemical analysis of FGF-2 expression after radiationinjury demonstrated that FGF-2 was predominantly found in the mesenchyme surrounding regeneratingcrypts. Exogenous recombinant human FGF-2 (rhFGF-2) markedly enhanced crypt stem cell survivalwhen given before irradiation. We conclude that expression of FGF-2 is induced by radiation injury andthat rhFGF-2 can enhance crypt stem cell survival after subsequent injury.", "metadata": {}}
+{"_id": "25251625", "title": "", "text": "Caspase inhibitors promote alternative cell death pathways.The use of caspase inhibitors has revealed theexistence of alternative backup cell death programs for apoptosis. The broad-spectrum caspase inhibitorzVAD-fmk modulates the three major types of cell death. Addition of zVAD-fmk blocks apoptotic celldeath, sensitizes cells to necrotic cell death, and induces autophagic cell death. Several studies haveshown a crucial role for the kinase RIP1 and the adenosine nucleotide translocator (ANT)-cyclophilin D(CypD) complex in necrotic cell death. The underlying mechanism of zVAD-fmk-mediated sensitization tonecrotic cell death involves the inhibition of caspase-8-mediated proteolysis of RIP1 and disturbance ofthe ANT-CypD interaction. RIP1 is also involved in autophagic cell death. Caspase inhibitors andknockdown studies have revealed negative roles for catalase and caspase-8 in autophagic cell death. Thepositive role of RIP1 and the negative role of caspase-8 in both necrotic and autophagic cell deathsuggest that the pathways of these two types of cell death are interconnected. Necrotic cell deathrepresents a rapid cellular response involving mitochondrial reactive oxygen species (ROS) production,decreased adenosine triphosphate concentration, and other cellular insults, whereas autophagic cell deathfirst starts as a survival attempt by cleaning up ROS-damaged mitochondria. However, when this processoccurs in excess, autophagy itself becomes cytotoxic and eventually leads to autophagic cell death. Abetter understanding of the molecular mechanisms of these alternative cell death pathways may providetherapeutic tools to combat cell death associated with neurodegenerative diseases, ischemia-reperfusionpathologies, and infectious diseases, and may also facilitate the development of alternative cytotoxicstrategies in cancer treatment.", "metadata": {}}
+{"_id": "25254425", "title": "", "text": "Nucleosome stability mediated by histone variants H3.3 and H2A.Z.Nucleosomes containing the histonevariant H3.3 tend to be clustered in vivo in the neighborhood of transcriptionally active genes and overregulatory elements. It has not been clear, however, whether H3.3-containing nucleosomes possessunique properties that would affect transcription. We report here that H3.3 nucleosomes isolated fromvertebrates, regardless of whether they are partnered with H2A or H2A.Z, are unusually sensitive tosalt-dependent disruption, losing H2A/H2B or H2A.Z/H2B dimers. Immunoprecipitation studies ofnucleosome core particles (NCPs) show that NCPs that contain both H3.3 and H2A.Z are even less stablethan NCPs containing H3.3 and H2A. Intriguingly, NCPs containing H3 and H2A.Z are at least as stable asH3/H2A NCPs. These results establish an hierarchy of stabilities for native nucleosomes carrying differentcomplements of variants, and suggest how H2A.Z could play different roles depending on its partnerswithin the NCP. They also are consistent with the idea that H3.3 plays an active role in maintainingaccessible chromatin structures in enhancer regions and transcribed regions. Consistent with this idea,promoters and enhancers at transcriptionally active genes and coding regions at highly expressed geneshave nucleosomes that simultaneously carry both H3.3 and H2A.Z, and should therefore be extremelysensitive to disruption.", "metadata": {}}
+{"_id": "25259746", "title": "", "text": "Increased growth after long-term oral 1alpha,25-vitamin D3 in childhood renal osteodystrophy.Weevaluated oral 1,25-vitamin D3 for as long as 26 months in six prepubescent children with renalosteodystrophy previously treated with vitamin D2. Therapy was given at 14 to 41 ng per kilogram perday to correct hypocalcemia and reverse bone disease. Serum levels of 1,25-vitamin D3 were initiallyreduced at 15 +/- 5 pg per milliliter (mean +/- S.E.M.) and after treatment rose to 54 +/- 13. Serumcalcium rose from 7.5 +/- 1.6 mg per deciliter (mean +/- S.D.) to 9.8 +/- 0.6 after one month (P lessthan 0.02). Alkaline phosphatase activity fell from 536 +/- 298 to 208 +/- 91 IU per liter after 12 months(P less than 0.05). Serum immunoreactive parathyroid levels fell from 900 +/- 562 microliter eq permilliliter 411 +/- 377. Healing of rickets and subperiosteal erosions was found. Remineralization of bonewas demonstrated by the photon absorption technic. In four patients growth velocity, evaluated for 12months before and after therapy, increased from 2.6 +/- 0.8 to 8.0 +/- 3.2 cm per year. Growth velocityper year increased from less than third percentile in each to the 10th to 97th percentile after therapy.Height increment ranged from 27 to 113 per cent of that expected for change in chronologic age and 40to 114 per cent expected for change in bone age after therapy. This trial demonstrates that oral1,25-vitamin D3 can reverse renal bone disease and increase growth in uremic children.", "metadata": {}}
+{"_id": "25261168", "title": "", "text": "Rapid progression of familial amyloidotic polyneuropathy: a multinational natural historystudy.OBJECTIVES To assess the association between severity of neuropathy and disease stage, andestimate the rate of neuropathy progression in a retrospective cross-sectional analysis of a multinationalpopulation of patients with familial amyloidotic polyneuropathy (FAP). METHODS We characterizeneuropathy severity and rate of progression in available patients with FAP in France, the United States,Portugal, and Italy. Neuropathy Impairment Scores (NIS), time from symptom onset to NISmeasurement, polyneuropathy disability (PND) scores, FAP disease stage, and manual grip strength datawere collected. We estimated neuropathy progression using Loess Fit and Gompertz Fit models. RESULTSFor the 283 patients studied (mean age, 56.4 years), intercountry genotypic variation in the transthyretin(TTR) mutation was observed, with the majority of patients in Portugal (92%) having early-onsetVal30Met-FAP. There was also marked intercountry variation in PND score, FAP stage, and TTR stabilizeruse. NIS was associated with PND score (NIS 10 and 99 for scores I and IV, respectively; p < 0.0001)and FAP stage (NIS 14 and 99 for stages 1 and 3, respectively; p < 0.0001). In addition, there was anassociation between NIS and TTR genotype. The estimated rate of NIS progression for a population with amedian NIS of 32 was 14.3 points/year; the corresponding estimated rate for the modified NIS+7 is 17.8points/year. CONCLUSIONS In a multinational population of patients with FAP, rapid neuropathicprogression is observed and the severity of neuropathy is associated with functional scales of locomotion.", "metadata": {}}
+{"_id": "25263810", "title": "", "text": "The BRRF1 early gene of Epstein-Barr virus encodes a transcription factor that enhances induction of lyticinfection by BRLF1.The switch from the latent to the lytic form of Epstein-Barr virus (EBV) infection ismediated by expression of the viral immediate-early (IE) proteins, BZLF1 (Z) and BRLF1 (R). An EBVearly protein, BRRF1 (Na), is encoded by the opposite strand of the BRLF1 intron, but the function of thisnuclear protein in the viral life cycle is unknown. Here we demonstrate that Na enhances the R-mediatedinduction of lytic EBV infection in 293 cells latently infected with a recombinant EBV (R-KO) defective forthe expression of both R and Na. Na also enhances R-induced lytic infections in a gastric carcinoma line(AGS) carrying the R-KO virus, although it has no effect in a Burkitt lymphoma line (BL-30) stablyinfected with the same mutant virus. We show that Na is a transcription factor that increases the abilityof R to activate Z expression from the R-KO viral genome in 293 cells and that Na by itself activates the Zpromoter (Zp) in EBV-negative cells. Na activation of Zp requires a CRE motif (ZII), and a consensus CREmotif is sufficient to transfer Na responsiveness to the heterologous E1b promoter. Furthermore, we showthat Na enhances the transactivator function of a Gal4-c-Jun fusion protein but does not increase thetransactivator function of other transcription factors (including ATF-1, ATF-2, and CREB) known to bindCRE motifs. Na expression in cells results in increased levels of a hyperphosphorylated form of c-Jun,suggesting a mechanism by which Na activates c-Jun. Our results indicate that Na is a transcription factorthat activates the EBV Zp IE promoter through its effects on c-Jun and suggest that Na cooperates withBRLF1 to induce the lytic form of EBV infection in certain cell types.", "metadata": {}}
+{"_id": "25263942", "title": "", "text": "Stromal p16 expression differentiates endometrial polyp from endometrial hyperplasiaEndometrial polypsare very common benign endometrial lesions, but their pathogenesis is poorly understood, except for afew studies indicating the possibility of benign stromal neoplasm. Although the histopathologicaldiagnosis of endometrial polyp on a surgical specimen is straightforward, it is often difficult todifferentiate endometrial polyp from endometrial hyperplasia on a biopsy or curettage specimen.Presently, there is no immunohistochemical marker helpful in this differential diagnosis. In this study, weexamined p16 expression in 35 endometrial polyps and 33 cases of endometrial hyperplasia that included16 simple hyperplasias, 14 complex atypical hyperplasias, and 3 complex hyperplasias without atypia.Stromal p16 expression differed significantly between the two groups; it was seen in 31 (89 %)endometrial polyps, but in only 1 (3 %) endometrial hyperplasia. The percentage of p16-positive stromalcells ranged from 10 to 90 % (mean, 47 %) and the positive cells tended to be distributed around glands.Six cases of endometrial hyperplasia within an endometrial polyp were also examined and all casesshowed stromal p16 expression. There was no difference in glandular p16 expression betweenendometrial polyps 33 (94 %) and hyperplasia 27 (82 %). The p16-immunoreactivity was mostlyconfined to metaplastic epithelial cells in both groups. Stromal p16 expression might be a peculiarcharacteristic of endometrial polyp and constitute a useful marker for the diagnosis, especially infragmented specimens from biopsy or curettage. Stromal p16 expression might be a reflection ofp16-induced cellular senescence, which has been documented in several benign mesenchymalneoplasms.", "metadata": {}}
+{"_id": "25293616", "title": "", "text": "A systematic review of mortality in schizophrenia: is the differential mortality gap worsening overtime?CONTEXT Despite improvements in mental health services in recent decades, it is unclear whetherthe risk of mortality in schizophrenia has changed over time. OBJECTIVE To explore the distribution ofstandardized mortality ratios (SMRs) for people with schizophrenia. DATA SOURCES Broad search termswere used in MEDLINE, PsychINFO, Web of Science, and Google Scholar to identify all studies thatinvestigated mortality in schizophrenia, published between January 1, 1980, and January 31, 2006.References were also identified from review articles, reference lists, and communication with authors.STUDY SELECTION Population-based studies that reported primary data on deaths in people withschizophrenia. DATA EXTRACTION Operationalized criteria were used to extract key study features andmortality data. DATA SYNTHESIS We examined the distribution of SMRs and pooled selected estimatesusing random-effects meta-analysis. We identified 37 articles drawn from 25 different nations. Themedian SMR for all persons for all-cause mortality was 2.58 (10%-90% quantile, 1.18-5.76), with acorresponding random-effects pooled SMR of 2.50 (95% confidence interval, 2.18-2.43). No sexdifference was detected. Suicide was associated with the highest SMR (12.86); however, most of themajor causes-of-death categories were found to be elevated in people with schizophrenia. The SMRs forall-cause mortality have increased during recent decades (P = .03). CONCLUSIONS With respect tomortality, a substantial gap exists between the health of people with schizophrenia and the generalcommunity. This differential mortality gap has worsened in recent decades. In light of the potential forsecond-generation antipsychotic medications to further adversely influence mortality rates in the decadesto come, optimizing the general health of people with schizophrenia warrants urgent attention.", "metadata": {}}
+{"_id": "25293721", "title": "", "text": "Antioxidant Defenses in the Rat Placenta in Late Gestation: Increased Labyrinthine Expression ofSuperoxide Dismutases, Glutathione Peroxidase 3, and Uncoupling Protein 21Placental oxidative stressplays a key role in the pathophysiology of placenta-related disorders, most notably preeclampsia (PE) andintrauterine growth restriction (IUGR). Oxidative stress occurs when accumulation of reactive oxygenspecies (ROS) damages DNA, proteins and lipids, an outcome that is limited by antioxidant enzymes;mitochondrial uncoupling protein 2 (UCP2) may also limit oxidative stress by reducing ROS production.Here we characterized placental antioxidant defenses during normal gestation and followingglucocorticoid-induced IUGR. Placentas were collected on Days 16 and 22 of normal rat pregnancy (term= Day 23) and at Day 22 after dexamethasone treatment from Day 13. Expression of several genesencoding antioxidant enzymes (Sod1, Sod2, Sod3, Cat, Gpx3, Txn1, Txnrd1, Txnrd2, and Txnrd3) andUcp2 was measured by quantitative RT-PCR in the labyrinth (LZ) and junctional zones (JZ) of theplacenta. Expression of Sod1 and Ucp2 mRNAs and the activity of xanthine oxidase, a source of ROS, allincreased from Days 16 to 22 in both placental zones, whereas Sod2 and Gpx3 increased only in therapidly growing LZ. In contrast, Sod3 and Txnrd1 expression fell in the LZ over this period, whereas totalsuperoxide dismutase activity remained stable. Dexamethasone treatment reduced fetal-placental growthand LZ expression of Ucp2 but increased JZ expression of Txn1. Indices of placental oxidative damage(TBARS, F2-isoprostanes, and 8-OHdG) did not change with gestational age or dexamethasone, indicativeof adequate antioxidant protection. Overall, our data suggest that the rat placenta is protected fromoxidative stress by the dynamic zone- and stage-dependent expression of antioxidant defense genes.", "metadata": {}}
+{"_id": "25298276", "title": "", "text": "Emerging role of bisphosphonates in the clinic--antitumor activity and prevention of metastasis tobone.Bisphosphonates are currently used for the treatment of bone metastases, and emerging datasuggest that they may also have antitumor properties. Preclinical studies have demonstrated thatzoledronic acid can inhibit angiogenesis, invasion and adhesion of tumor cells, and overall tumorprogression, and emerging evidence suggests that the use of these agents may impede the developmentof skeletal metastases. In a recent clinical study in patients with metastatic bone disease, basal levels ofvascular endothelial growth factor, a factor essential for angiogenesis, were significantly reduced inpatients receiving zoledronic acid, suggesting that zoledronic acid may have clinically relevantantiangiogenic properties. Early clinical data on prevention of bone metastases by the early-generationbisphosphonate clodronate have yielded promising results in patients with breast cancer, and trials arecurrently ongoing to assess the efficacy of clodronate in this setting. Similarly, the new-generationbisphosphonate zoledronic acid has demonstrated activity in the prevention of bone metastases in small,18-month pilot studies in patients with high-risk solid tumors (N=40; P=0.0002). Similarly, in a separate5-year trial, the overall survival of patients with multiple myeloma was greater in patients whosestandard treatment regimens included zoledronic acid compared with standard treatment alone (P<0.01).These encouraging early clinical results supported the initiation of larger randomized trials that arecurrently ongoing.", "metadata": {}}
+{"_id": "25300426", "title": "", "text": "LIF/STAT3 controls ES cell self-renewal and pluripotency by a Myc-dependent mechanism.Murine ES cellscan be maintained as a pluripotent, self-renewing population by LIF/STAT3-dependent signaling. Thedownstream effectors of this pathway have not been previously defined. In this report, we identify a keytarget of the LIF self-renewal pathway by showing that STAT3 directly regulates the expression of theMyc transcription factor. Murine ES cells express elevated levels of Myc and following LIF withdrawal, MycmRNA levels collapse and Myc protein becomes phosphorylated on threonine 58 (T58), triggering itsGSK3beta dependent degradation. Maintained expression of stable Myc (T58A) renders self-renewal andmaintenance of pluripotency independent of LIF. By contrast, expression of a dominant negative form ofMyc antagonizes self-renewal and promotes differentiation. Transcriptional control by STAT3 andsuppression of T58 phosphorylation are crucial for regulation of Myc activity in ES cells and therefore inpromoting self-renewal. Together, our results establish a mechanism for how LIF and STAT3 regulate EScell self-renewal and pluripotency.", "metadata": {}}
+{"_id": "25300664", "title": "", "text": "Chronic renal failure accelerates atherogenesis in apolipoprotein E-deficient mice.Cardiovascular mortalityis 10 to 20 times increased in patients with chronic renal failure (CRF). Risk factors for atherosclerosis areabundant in patients with CRF. However, the pathogenesis of cardiovascular disease in CRF remains to beelucidated. The effect of CRF on the development of atherosclerosis in apolipoprotein E-deficient malemice was examined. Seven-week-old mice underwent 5/6 nephrectomy (CRF, n = 28), unilateralnephrectomy (UNX, n = 24), or no surgery (n = 23). Twenty-two weeks later, CRF mice showedincreased aortic plaque area fraction (0.266 +/- 0.033 versus 0.045 +/- 0.006; P < 0.001), aorticcholesterol content (535 +/- 62 versus 100 +/- 9 nmol/cm(2) intimal surface area; P < 0.001), andaortic root plaque area (205,296 +/- 22,098 versus 143,662 +/- 13,302 micro m(2); P < 0.05) ascompared with no-surgery mice; UNX mice showed intermediate values. The plaques from uremic micecontained CD11b-positive macrophages and showed strong staining for nitrotyrosine. Systolic BP andplasma homocysteine concentrations were similar in uremic and nonuremic mice. Plasma urea andcholesterol concentrations were elevated 2.6-fold (P < 0.001) and 1.5-fold (P < 0.001) in CRF comparedwith no-surgery mice. Both variables correlated with aortic plaque area fraction (r(2) = 0.5, P < 0.001and r(2) = 0.3, P < 0.001, respectively) and with each other (r(2) = 0.5, P < 0.001). On multiple linearregression analysis, only plasma urea was a significant predictor of aortic plaque area fraction. Inconclusion, the present findings suggest that uremia markedly accelerates atherogenesis inapolipoprotein E-deficient mice. This effect could not be fully explained by changes in BP, plasmahomocysteine levels, or total plasma cholesterol concentrations. Thus, the CRF apolipoprotein E-deficientmouse is a new model for studying the pathogenesis of accelerated atherosclerosis in uremia.", "metadata": {}}
+{"_id": "25301182", "title": "", "text": "Left ventricular function and exercise capacity.CONTEXT Limited information exists regarding the role ofleft ventricular function in predicting exercise capacity and impact on age- and sex-related differences.OBJECTIVES To determine the impact of measures of cardiac function assessed by echocardiography onexercise capacity and to determine if these associations are modified by sex or advancing age. DESIGNCross-sectional study of patients undergoing exercise echocardiography with routine measurements ofleft ventricular systolic and diastolic function by 2-dimensional and Doppler techniques. Analyses wereconducted to determine the strongest correlates of exercise capacity and the age and sex interactions ofthese variables with exercise capacity. SETTING Large tertiary referral center in Rochester, Minnesota, in2006. PARTICIPANTS Patients undergoing exercise echocardiography using the Bruce protocol (N =2867). Patients with echocardiographic evidence of exercise-induced ischemia, ejection fractions lowerthan 50%, or significant valvular heart disease were excluded. MAIN OUTCOME MEASURE Exercisecapacity in metabolic equivalents (METs). RESULTS Diastolic dysfunction was strongly and inverselyassociated with exercise capacity. Compared with normal function, after multivariate adjustment, thosewith moderate/severe resting diastolic dysfunction (-1.30 METs; 95% confidence interval [CI], -1.52 to-0.99; P < .001) and mild resting diastolic dysfunction (-0.70 METs; 95% CI, -0.88 to -0.46; P < .001)had substantially lower exercise capacity. Variation of left ventricular systolic function within the normalrange was not associated with exercise capacity. Left ventricular filling pressures measured by restingE/e' of 15 or greater (-0.41 METs; 95% CI, -0.70 to -0.11; P = .007) or postexercise E/e' of 15 or greater(-0.41 METs; 95% CI, -0.71 to -0.11; P = .007) were similarly associated with a reduction in exercisecapacity, each in separate multivariate analyses. Individuals with impaired relaxation (mild dysfunction)or resting E/e' of 15 or greater had a progressive increase in the magnitude of reduction in exercisecapacity with advancing age (P < .001 and P = .02, respectively). Other independent correlates ofexercise capacity were age (unstandardized beta coefficient, -0.85 METs; 95% CI, -0.92 to -0.77, per10-year increment; P < .001), female sex (-1.98 METs; 95% CI, -2.15 to -1.84; P < .001), and bodymass index greater than 30 (-1.24 METs; 95% CI, -1.41 to -1.10; P < .001). CONCLUSION In this largecross-sectional study of those referred for exercise echocardiography and not limited by ischemia,abnormalities of left ventricular diastolic function were independently associated with exercise capacity.", "metadata": {}}
+{"_id": "25308734", "title": "", "text": "A dynamic population model to investigate effects of climate on geographic range and seasonality of thetick Ixodes scapularis.A dynamic population model of Ixodes scapularis, the vector of a number oftick-borne zoonoses in North America, was developed to simulate effects of temperature on tick survivaland seasonality. Tick development rates were modelled as temperature-dependent time delays,calculated using mean monthly normal temperature data from specific meteorological stations.Temperature also influenced host-finding success in the model. Using data from stations near endemicpopulations of I. scapularis, the model reached repeatable, stable, cyclical equilibria with seasonal activityof different instars being very close to that observed in the field. In simulations run using data frommeteorological stations in central and eastern Canada, the maximum equilibrium numbers of ticksdeclined the further north was the station location, and simulated populations died out at more northerlystations. Tick die-out at northern latitudes was due to a steady increase in mortality of all life stages withdecreasing temperature rather than a specific threshold event in phenology of one life stage. By linearregression we investigated mean annual numbers of degree-days >0 degrees C (DD>0 degrees C) as areadily mapped index of the temperature conditions at the meteorological stations providing temperaturedata for the model. Maximum numbers of ticks at equilibrium were strongly associated with the meanDD>0 degrees C (r2>0.96, P<0.001), when the Province of origin of the meteorological station wasaccounted for (Quebec>Ontario, beta=103, P<0.001). The intercepts of the regression models providedtheoretical limits for the establishment of I. scapularis in Canada. Maps of these limits suggested that therange of southeast Canada where temperature conditions are currently suitable for the tick, is muchwider than the existing distribution of I. scapularis, implying that there is potential for spread. Futureapplications of the model in investigating climate change effects on I. scapularis are discussed.", "metadata": {}}
+{"_id": "25315295", "title": "", "text": "Inflammatory cytokines in depression: neurobiological mechanisms and therapeuticimplications.Mounting evidence indicates that inflammatory cytokines contribute to the development ofdepression in both medically ill and medically healthy individuals. Cytokines are important fordevelopment and normal brain function, and have the ability to influence neurocircuitry andneurotransmitter systems to produce behavioral alterations. Acutely, inflammatory cytokineadministration or activation of the innate immune system produces adaptive behavioral responses thatpromote conservation of energy to combat infection or recovery from injury. However, chronic exposureto elevated inflammatory cytokines and persistent alterations in neurotransmitter systems can lead toneuropsychiatric disorders and depression. Mechanisms of cytokine behavioral effects involve activationof inflammatory signaling pathways in the brain that results in changes in monoamine, glutamate, andneuropeptide systems, and decreases in growth factors, such as brain-derived neurotrophic factor.Furthermore, inflammatory cytokines may serve as mediators of both environmental (e.g. childhoodtrauma, obesity, stress, and poor sleep) and genetic (functional gene polymorphisms) factors thatcontribute to depression's development. This review explores the idea that specific gene polymorphismsand neurotransmitter systems can confer protection from or vulnerability to specific symptom dimensionsof cytokine-related depression. Additionally, potential therapeutic strategies that target inflammatorycytokine signaling or the consequences of cytokines on neurotransmitter systems in the brain to preventor reverse cytokine effects on behavior are discussed.", "metadata": {}}
+{"_id": "25319221", "title": "", "text": "Sputum inflammation predicts exacerbations after cessation of inhaled corticosteroids inCOPD.INTRODUCTION The GOLD guidelines advocate not to institute inhaled corticosteroids (ICS) inpatients with mild-to-moderate COPD. However, many patients do use ICS and in some patients,withdrawal is associated with deteriorating lung function and increased exacerbation rates. Unfortunately,physicians do not know in which patients they can stop ICS treatment safely. AIM To identify predictors ofCOPD exacerbations after ICS withdrawal. METHODS During ICS treatment, post-bronchodilatorspirometry, body plethysmography, and health status assessment were performed in 68 COPD patientsusing ICS. Additionally, sputum cell differentials, supernatant leukotriene B(4), eosinophilic cationicprotein, and myeloperoxidase, serum C-reactive protein and soluble intracellular adhesion molecule, andurinary desmosine were assessed. Sputum was also analysed for mRNA levels of haemoxygenase-1,tumour necrosis factor-α, RANTES, interleukin 5(IL-5), IL-10, IL-12, IL-13, transforming growth factor-β,and interferon-γ. STATISTICS Cox regression analyses were performed using time to exacerbation asoutcome variable to identify significant hazards for a COPD exacerbation after ICS withdrawal. RESULTSHigher sputum % eosinophils, higher sputum MPO/neutrophil level, longer duration of COPD symptoms,<40 packyears smoking, and ICS withdrawal in November, December or January were significant hazards(all p<0.05) for experiencing a COPD exacerbation after ICS withdrawal in a monovariate model. In amultivariate model, all factors proved independent predictors except for sputum MPO/neutrophil level.CONCLUSIONS Decisions on whether or not inhaled corticosteroids can be safely withdrawn inmild-to-moderate COPD can be facilitated by assessment of sputum inflammation, particularly eosinophilnumbers, next to packyears smoking, season, and duration of COPD symptoms.", "metadata": {}}
+{"_id": "25328476", "title": "", "text": "Peroxisome proliferator-activated receptor alpha activation decreases metastatic potential of melanomacells in vitro via down-regulation of Akt.PURPOSE Peroxisome proliferator-activated receptors (PPAR)regulate lipid and glucose metabolism but their anticancer properties have been recently studied as well.We previously reported the antimetastatic activity of the PPARalpha ligand, fenofibrate, againstmelanoma tumors in vivo. Here we investigated possible molecular mechanisms of fenofibrate antimetastatic action. EXPERIMENTAL DESIGN Monolayer cultures of mouse (B16F10) and human (SkMell88)melanoma cell lines, soft agar assay, and cell migration assay were used in this study. In addition, weanalyzed PPARalpha expression and its transcriptional activity in response to fenotibrate by usingWestern blots and liciferase-based reporter system. RESULTS Fenofibrate inhibited migration of B16F10and SkMel188 cells in Transwell chambers and colony formation in soft agar. These effects were reversedby PPAR inhibitor, GW9662. Western blot analysis revealed time-dependent down-regulation of Akt andextracellular signal-regulated kinase l/2 phosphorylation in fenofibrate-treated cells. A B16F10 cell linestably expressing constitutively active Akt mutant was resistant to fenofibrate. In contrast, Akt genesilencing with siRNA mimicked the fenofibrate action and reduced the migratory ability of B16F1O cells. Inaddition, fenofibrate strongly sensitized BI6FIO cells to the proapoptotic drug staurosporine, furthersupporting the possibility that fenofibrate-induced down-regulation of Akt function contributes tofenofibrate-mediated inhibition of metastatic potential in this experimental model. CONCLUSIONS Ourresults show that the PPAR-dependent antimetastatic activity of fenofibrate involves down-regulation ofAkt phosphorylation and suggest that supplementation with this drug may improve the effectiveness ofmelanoma chemotherapy.", "metadata": {}}
+{"_id": "25344732", "title": "", "text": "PHC3, a component of the hPRC-H complex, associates with E2F6 during G0 and is lost in osteosarcomatumorsPolyhomeotic-like 3 (PHC3) is a ubiquitously expressed member of the polycomb gene family andpart of the human polycomb complex hPRC-H. We found that in normal cells PHC3 associated with bothhPRC-H complex components and with the transcription factor E2F6. In differentiating and confluent cells,PHC3 and E2F6 showed nuclear colocalization in a punctate pattern that resembled the binding ofpolycomb bodies to heterochromatin. This punctate pattern was not seen in proliferating cells suggestingthat PHC3 may be part of an E2F6-polycomb complex that has been shown to occupy and silence targetpromoters in G0. Previous loss of heterozygosity (LoH) analyses had shown that the region containingPHC3 underwent frequent LoH in primary human osteosarcoma tumors. When we examined normal boneand human osteosarcoma tumors, we found loss of PHC3 expression in 36 of 56 osteosarcoma tumors.Sequence analysis revealed that PHC3 was mutated in nine of 15 primary osteosarcoma tumors. Thesefindings suggest that loss of PHC3 may favor tumorigenesis by potentially disrupting the ability of cells toremain in G0.", "metadata": {}}
+{"_id": "25353658", "title": "", "text": "Germinal center T follicular helper cell IL-4 production is dependent on signaling lymphocytic activationmolecule receptor (CD150).CD4 T cell help is critical for the generation and maintenance of germinalcenters (GCs), and T follicular helper (T(FH)) cells are the CD4 T cell subset required for this process.Signaling lymphocytic activation molecule (SLAM)-associated protein (SAP [SH2D1A]) expression in CD4T cells is essential for GC development. However, SAP-deficient mice have only a moderate defect inT(FH) differentiation, as defined by common T(FH) surface markers. CXCR5(+) T(FH) cells are foundwithin the GC, as well as along the boundary regions of T/B cell zones. In this study, we show thatGC-associated T follicular helper (GC T(FH)) cells can be identified by their coexpression of CXCR5 andthe GL7 epitope, allowing for phenotypic and functional analysis of T(FH) and GC T(FH) populations. GCT(FH) cells are a functionally discrete subset of further polarized T(FH) cells, with enhanced B cell helpcapacity and a specialized ability to produce IL-4 in a T(H)2-independent manner. Strikingly,SAP-deficient mice have an absence of the GC T(FH) cell subset and SAP(-) T(FH) cells are defective inIL-4 and IL-21 production. We further demonstrate that SLAM (Slamf1, CD150), a surface receptor thatuses SAP signaling, is specifically required for IL-4 production by GC T(FH) cells. GC T(FH) cells requireIL-4 and -21 production for optimal help to B cells. These data illustrate complexities of SAP-dependentSLAM family receptor signaling, revealing a prominent role for SLAM receptor ligation in IL-4 productionby GC CD4 T cells but not in T(FH) cell and GC T(FH) cell differentiation.", "metadata": {}}
+{"_id": "25355575", "title": "", "text": "High cardiovascular mortality in Russia cannot be explained by the classical risk factors. The Arkhangelskstudy 2000Since the beginning of the 1990s the public health situation in Russia has been characterizedby an extremely high mortality and a significant reduction in life expectancy. Cardiovascular diseasesremained the major cause of death. Only a few large population studies were conducted in Russia duringthis period. A total of 1968 men and 1737 women aged 18–75 years participated in a health survey inArkhangelsk, Russia, over the period 1999–2000. Investigation included assessment of classiccardiovascular risk factors (family history, smoking, blood pressure, and blood lipids) along with generalhealth variables. The paper presents sex specific data on risk factors for coronary heart disease. Thoughthe cardiovascular mortality is high in Russia, the calculated risk for coronary heart disease (theFramingham risk score and the Norwegian risk score) was lower in all age groups of men and women inArkhangelsk compared with studies from the Western Europe and USA. Our data suggest that highcardiovascular mortality in Russia may be driven not only by the classic risk factors for coronary heartdisease.", "metadata": {}}
+{"_id": "25365522", "title": "", "text": "Wnt7a/Fzd7 Signalling Directly Activates the Akt/mTOR Anabolic Growth Pathway in SkeletalMuscleWnt7a signals through its receptor Fzd7 to activate the planar-cell-polarity pathway and drive thesymmetric expansion of satellite stem cells resulting in enhanced repair of skeletal muscle. Indifferentiated myofibres, we observed that Wnt7a binding to Fzd7 directly activates the Akt/mTOR growthpathway, thereby inducing myofibre hypertrophy. Notably, the Fzd7 receptor complex was associatedwith Gα(s) and PI(3)K and these components were required for Wnt7a to activate the Akt/mTOR growthpathway in myotubes. Wnt7a-Fzd7 activation of this pathway was completely independent ofIGF-receptor activation. Together, these experiments demonstrate that Wnt7a-Fzd7 activates distinctpathways at different developmental stages during myogenic lineage progression, and identify anon-canonical anabolic signalling pathway for Wnt7a and its receptor Fzd7 in skeletal muscle.", "metadata": {}}
+{"_id": "25373397", "title": "", "text": "Four newly located pseudouridylate residues in Escherichia coli 23S ribosomal RNA are all at thepeptidyltransferase center: analysis by the application of a new sequencing technique.A new techniquehas been developed for the facile location of pseudouridylate (psi) residues in any RNA molecule. Themethod uses two known modification procedures which in combination uniquely identify U residues whichhave been converted into psi. The first procedure involves reaction of all U-like and G-like residues withN-cyclohexyl-N'-beta-(4-methylmorpholinium)ethylcarbodiimide p-tosylate (CMC), followed by alkalineremoval of all CMC groups except those linked to the N3 of psi. This stops reverse transcription, resultingin a gel band which identifies the U residue. The second procedure is uridine-specific hydrazinolysis whichcleaves the RNA chain at all U residues and produces a gel band upon reverse transcription. psi residues,being resistant to hydrazinolysis, are not cleaved and do not stop reverse transcription. This leads to theabsence of a band at psi residues. The combined method can also distinguish psi from 5-methyluridine,4-thiouridine, uridine-5-oxyacetic acid, and 2-thio-5-methylaminomethyluridine as shown by treatingrRNA and tRNA species known to contain these modified bases at defined sites. By this procedure, fournew sites for psi in Escherichia coli 23S RNA were discovered, and one was disproven. The four new sitesare at positions 2457, 2504, 2580, and 2605. The erroneous site is at position 2555. These four new psiresidues, which are all in or within 2-3 residues of the peptidyltransferase ring, are thus in a position toplay a functional and/or structural role at the peptidyltransferase center.(ABSTRACT TRUNCATED AT 250WORDS)", "metadata": {}}
+{"_id": "25388309", "title": "", "text": "Pharmacological characterization of1-(5-chloro-6-(trifluoromethoxy)-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid (JNJ-42041935),a potent and selective hypoxia-inducible factor prolyl hydroxylase inhibitor.The hypoxia-inducible factor(HIF) prolyl hydroxylase (PHD) enzymes represent novel targets for the treatment of anemia, ulcerativecolitis, and ischemic and metabolic disease inter alia. We have identified a novel small-molecule inhibitorof PHD, 1-(5-chloro-6-(trifluoromethoxy)-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid(JNJ-42041935), through structure-based drug design methods. The pharmacology of JNJ-42041935 wasinvestigated in enzyme, cellular, and whole-animal systems and was compared with other compoundsdescribed in the literature as PHD inhibitors. JNJ-42041935, was a potent (pK(I) = 7.3-7.9),2-oxoglutarate competitive, reversible, and selective inhibitor of PHD enzymes. In addition,JNJ-42041935 was used to compare the effect of selective inhibition of PHD to intermittent, high doses(50 μg/kg i.p.) of an exogenous erythropoietin receptor agonist in an inflammation-induced anemiamodel in rats. JNJ-42041935 (100 μmol/kg, once a day for 14 days) was effective in reversinginflammation-induced anemia, whereas erythropoietin had no effect. The results demonstrate thatJNJ-42041935 is a new pharmacological tool, which can be used to investigate PHD inhibition anddemonstrate that PHD inhibitors offer great promise for the treatment of inflammation-induced anemia.", "metadata": {}}
+{"_id": "25404036", "title": "", "text": "Three-Dimensional Modeling and Quantitative Analysis of Gap Junction Distributions in Cardiac TissueGapjunctions play a fundamental role in intercellular communication in cardiac tissue. Various types of heartdisease including hypertrophy and ischemia are associated with alterations of the spatial arrangement ofgap junctions. Previous studies applied two-dimensional optical and electron-microscopy to visualize gapjunction arrangements. In normal cardiomyocytes, gap junctions were primarily found at cell ends, butcan be found also in more central regions. In this study, we extended these approaches towardthree-dimensional reconstruction of gap junction distributions based on high-resolution scanning confocalmicroscopy and image processing. We developed methods for quantitative characterization of gapjunction distributions based on analysis of intensity profiles along the principal axes of myocytes. Theanalyses characterized gap junction polarization at cell ends and higher-order statistical image momentsof intensity profiles. The methodology was tested in rat ventricular myocardium. Our analysis yieldednovel quantitative data on gap junction distributions. In particular, the analysis demonstrated that thedistributions exhibit significant variability with respect to polarization, skewness, and kurtosis. Wesuggest that this methodology provides a quantitative alternative to current approaches based on visualinspection, with applications in particular in characterization of engineered and diseased myocardium.Furthermore, we propose that these data provide improved input for computational modeling of cardiacconduction.", "metadata": {}}
+{"_id": "25413327", "title": "", "text": "Clonally derived human embryonic stem cell lines maintain pluripotency and proliferative potential forprolonged periods of culture.Embryonic stem (ES) cell lines derived from human blastocysts have thedevelopmental potential to form derivatives of all three embryonic germ layers even after prolongedculture. Here we describe the clonal derivation of two human ES cell lines, H9.1 and H9.2. At the time ofthe clonal derivation of the H9.1 and H9.2 ES cell lines, the parental ES cell line, H9, had already beencontinuously cultured for 6 months. After an additional 8 months of culture, H9.1 and H9.2 ES cell linescontinued to: (1) actively proliferate, (2) express high levels of telomerase, and (3) retain normalkaryotypes. Telomere lengths, while somewhat variable, were maintained between 8 and 12 kb inhigh-passage H9.1 and H9.2 cells. High-passage H9.1 and H9.2 cells both formed teratomas inSCID-beige mice that included differentiated derivatives of all three embryonic germ layers. These resultsdemonstrate the pluripotency of single human ES cells, the maintenance of pluripotency during anextended period of culture, and the long-term self-renewing properties of cultured human ES cells. Theremarkable developmental potential, proliferative capacity, and karyotypic stability of human ES cellsdistinguish them from adult cells.", "metadata": {}}
+{"_id": "25416944", "title": "", "text": "Autosomal dominant lateral temporal epilepsy: two families with novel mutations in the LGI1gene.PURPOSE Mutations in the leucine rich, glioma inactivated gene (LGI1) were recently described in asmall number of families with autosomal dominant lateral temporal epilepsy (ADLTE). ADLTE ischaracterized by partial seizures with symptoms suggestive of a lateral temporal onset, includingfrequent auditory aura. Here we report the results of clinical and genetic analyses of two newly identifiedfamilies with ADTLE. METHODS We identified two families whose seizure semiology was suggestive ofADLTE. Evaluation included a detailed history and neurologic examination, as well as collection of DNA.The coding sequence of the LGI1 gene from affected subjects from both families was analyzed forevidence of mutation. RESULTS Each patient had a history of partial seizures, often with secondarygeneralization earlier in the course. Auditory aura was reported by approximately two thirds of affectedpatients in each pedigree. Novel mutations in LGI1 were detected in both families. A heterozygoussingle-nucleotide deletion at position 329 (del 329C) was detected in affected individuals from one family,whereas patients from the second family had a nonsynonymous variation, corresponding to C435G.CONCLUSIONS We identified two novel mutations in the LGI1 gene. The phenotype of these two familieswas similar to that of other kindreds with ADLTE, as auditory aura was absent in one third of affectedindividuals. Our results further support that LGI1 mutations should be considered in patients with ahistory of partial seizures if the semiology of seizures is consistent with the onset in the lateral temporallobe.", "metadata": {}}
+{"_id": "25419778", "title": "", "text": "Identification of Senescent Cells in the Bone Microenvironment.Cellular senescence is a fundamentalmechanism by which cells remain metabolically active yet cease dividing and undergo distinct phenotypicalterations, including upregulation of p16Ink4a , profound secretome changes, telomere shortening, anddecondensation of pericentromeric satellite DNA. Because senescent cells accumulate in multiple tissueswith aging, these cells and the dysfunctional factors they secrete, termed the senescence-associatedsecretory phenotype (SASP), are increasingly recognized as promising therapeutic targets to preventage-related degenerative pathologies, including osteoporosis. However, the cell type(s) within the bonemicroenvironment that undergoes senescence with aging in vivo has remained poorly understood, largelybecause previous studies have focused on senescence in cultured cells. Thus in young (age 6 months)and old (age 24 months) mice, we measured senescence and SASP markers in vivo in highly enriched cellpopulations, all rapidly isolated from bone/marrow without in vitro culture. In both females and males,p16Ink4a expression by real-time quantitative polymerase chain reaction (rt-qPCR) was significantlyhigher with aging in B cells, T cells, myeloid cells, osteoblast progenitors, osteoblasts, and osteocytes.Further, in vivo quantification of senescence-associated distension of satellites (SADS), ie, large-scaleunraveling of pericentromeric satellite DNA, revealed significantly more senescent osteocytes in oldcompared with young bone cortices (11% versus 2%, p < 0.001). In addition, primary osteocytes fromold mice had sixfold more (p < 0.001) telomere dysfunction-induced foci (TIFs) than osteocytes fromyoung mice. Corresponding with the age-associated accumulation of senescent osteocytes wassignificantly higher expression of multiple SASP markers in osteocytes from old versus young mice,several of which also showed dramatic age-associated upregulation in myeloid cells. These data showthat with aging, a subset of cells of various lineages within the bone microenvironment becomesenescent, although senescent myeloid cells and senescent osteocytes predominantly develop the SASP.Given the critical roles of osteocytes in orchestrating bone remodeling, our findings suggest thatsenescent osteocytes and their SASP may contribute to age-related bone loss. © 2016 American Societyfor Bone and Mineral Research.", "metadata": {}}
+{"_id": "25420421", "title": "", "text": "Changes in white blood cells and platelets in children with falciparum malaria: relationship to diseaseoutcome.Little is known about the changes in white blood cells and platelets in children with falciparummalaria in endemic areas. We measured the white cell count (WCC) and platelets of 230 healthy childrenfrom the community, 1369 children admitted to hospital with symptomatic malaria, and 1461 childrenwith other medical conditions. Children with malaria had a higher WCC compared with communitycontrols, and leucocytosis was strongly associated with younger age, deep breathing, severe anaemia,thrombocytopenia and death. The WCC was not associated with a positive blood culture. In children withmalaria, high lymphocyte and low monocyte counts were independently associated with mortality. Aplatelet count of less than 150 x 109/l was found in 56.7% of children with malaria, and was associatedwith age, prostration and parasite density, but not with bleeding problems or mortality. The mean plateletvolume was also higher in children with malaria compared with other medical conditions. This may reflectearly release from the bone marrow in response to peripheral platelet destruction. Thus, leucocytosis wasassociated with both severity and mortality in children with falciparum malaria, irrespective ofbacteraemia, whereas thrombocytopenia, although very common, was not associated with adverseoutcome.", "metadata": {}}
+{"_id": "25435456", "title": "", "text": "Microenvironmental regulation of biomacromolecular therapiesThere is currently great interest inmolecular therapies to treat various diseases, and this has prompted extensive efforts to achievetarget-specific and controlled delivery of bioactive macromolecules (for example, proteins, antibodies,DNA and small interfering RNA) through the design of smart drug carriers. By contrast, the influence ofthe microenvironment in which the target cell resides and the effect it might have on the success ofbiomacromolecular therapies has been under-appreciated. The extracellular matrix (ECM) component ofthe cellular niche may be particularly important, as many diseases and injury disrupt the normal ECMarchitecture, the cell adhesion to ECM, and the subsequent cellular activities. This Review will discuss theimportance of the ECM and the ECM–cell interactions on the cell response to bioactive macromolecules,and suggest how this information could lead to new criteria for the design of novel drug delivery systems.", "metadata": {}}
+{"_id": "25439264", "title": "", "text": "Homocysteine Induces Trophoblast Cell Death with Apoptotic Features1Abstract Hyperhomocysteinemiahas been suggested as a possible risk factor in women suffering from habitual abortions, placentalabruption or infarcts, preeclampsia, and/or intrauterine growth retardation. However, little is knownabout the pathogenic mechanisms underlying the action of homocysteine. The present study investigatedthe in vitro ability of homocysteine to affect trophoblast gonadotropin secretion and to induce cell death.In primary human trophoblast cells, homocysteine treatment (20 μmol/L) resulted in cellular flatteningand enlargement, extension of pseudopodia, and cellular vacuolization. Cellular detachment, apoptosis,and necrosis were favored. With in situ nick end labeling, we investigated DNA degradation, and we usedM30 CytoDEATH to selectively stain the cytoplasm of apoptotic cells. Cytochrome c release frommitochondria to the cytosol and DNA cleavage in agarose gel have been investigated. Homocysteine, butnot cysteine, induced trophoblast apoptosis and significantly reduced human chorionic gonadotropinsecretion. These findings suggest that trophoblast cell death might represent a pathogenic mechanism bywhich homocysteine may cause pregnancy complications related to placental diseases.", "metadata": {}}
+{"_id": "25440070", "title": "", "text": "Intrahippocampal administration of an androgen receptor antagonist, flutamide, can increase anxiety-likebehavior in intact and DHT-replaced male rats.Testosterone (T) and its 5alpha-reduced metabolite,dihydrotestosterone (DHT), can decrease anxiety-like behavior; however, the mechanisms underlyingthese effects have not been established. First, we hypothesized that if T reduces anxiety-like behaviorthrough actions of its 5alpha-reduced metabolite, DHT, then gonadectomy (GDX) would increaseanxiety-like behavior, an effect which would be reversed by systemic administration of DHT. Second, wehypothesized that if T and DHT reduce anxiety-like behavior in part through actions at intracellularandrogen receptors in the hippocampus, then administration of an androgen receptor antagonist,flutamide, directly to the hippocampus should increase anxiety-like behavior of intact and DHT-replaced,but not GDX, male rats. Inserts that were empty or contained flutamide were applied directly to thedorsal hippocampus of intact, GDX, or GDX and DHT-replaced rats 2 h prior to testing in the open field,elevated plus maze, or defensive freezing tasks. GDX rats exhibited significantly more anxiety-likebehaviors than intact or DHT-replaced rats. Intact and DHT-replaced rats administered flutamide to thehippocampus showed significantly more anxiety-like behavior than did intact and DHT-replaced controls.However, flutamide alone did not increase anxiety-like behavior of GDX rats. Together, these findingssuggest that androgens can decrease anxiety-like behavior of male rats in part through DHT's actions atandrogen receptors in the hippocampus.", "metadata": {}}
+{"_id": "25451374", "title": "", "text": "Cardiovascular risk and events in 17 low-, middle-, and high-income countries.BACKGROUND More than80% of deaths from cardiovascular disease are estimated to occur in low-income and middle-incomecountries, but the reasons are unknown. METHODS We enrolled 156,424 persons from 628 urban andrural communities in 17 countries (3 high-income, 10 middle-income, and 4 low-income countries) andassessed their cardiovascular risk using the INTERHEART Risk Score, a validated score for quantifyingrisk-factor burden without the use of laboratory testing (with higher scores indicating greater risk-factorburden). Participants were followed for incident cardiovascular disease and death for a mean of 4.1 years.RESULTS The mean INTERHEART Risk Score was highest in high-income countries, intermediate inmiddle-income countries, and lowest in low-income countries (P<0.001). However, the rates of majorcardiovascular events (death from cardiovascular causes, myocardial infarction, stroke, or heart failure)were lower in high-income countries than in middle- and low-income countries (3.99 events per 1000person-years vs. 5.38 and 6.43 events per 1000 person-years, respectively; P<0.001). Case fatality rateswere also lowest in high-income countries (6.5%, 15.9%, and 17.3% in high-, middle-, and low-incomecountries, respectively; P=0.01). Urban communities had a higher risk-factor burden than ruralcommunities but lower rates of cardiovascular events (4.83 vs. 6.25 events per 1000 person-years,P<0.001) and case fatality rates (13.52% vs. 17.25%, P<0.001). The use of preventive medications andrevascularization procedures was significantly more common in high-income countries than in middle- orlow-income countries (P<0.001). CONCLUSIONS Although the risk-factor burden was lowest inlow-income countries, the rates of major cardiovascular disease and death were substantially higher inlow-income countries than in high-income countries. The high burden of risk factors in high-incomecountries may have been mitigated by better control of risk factors and more frequent use of provenpharmacologic therapies and revascularization. (Funded by the Population Health Research Institute andothers.).", "metadata": {}}
+{"_id": "25452937", "title": "", "text": "Increased density of tumor-associated macrophages is associated with decreased survival in advancedthyroid cancer.Thyroid cancers are infiltrated with tumor-associated macrophages (TAMs), yet their rolein cancer progression is not known. The objectives of this study were to characterize the density of TAMsin well-differentiated (WDTC), poorly differentiated (PDTC), and anaplastic thyroid cancers (ATC) and tocorrelate TAM density with clinicopathologic parameters. Immunohistochemistry was performed on tissuemicroarray sections from WDTC (n=33), PDTC (n=37), and ATC (n=20) using macrophage-specificmarkers. Electronic medical records were used to gather clinical and pathologic data. Follow-upinformation of PDTC patients was available for 0-12 years. In total, 9 out of 33 WDTC (27%), 20 out of37 PDTC (54%), and 19 out of 20 ATC (95%) had an increased density of CD68(+) TAMs (> or = 10 per0.28 mm(2); WDTC versus PDTC, P=0.03; WDTC versus ATC, P<0.0001; PDTC versus ATC, P<0.002).Increased TAMs in PDTC was associated with capsular invasion (P=0.034), extrathyroidal extension(P=0.009), and decreased cancer-related survival (P=0.009) compared with PDTC with a low density ofTAMs. In conclusion, the density of TAMs is increased in advanced thyroid cancers. The presence of a highdensity of TAMs in PDTC correlates with invasion and decreased cancer-related survival. These resultssuggest that TAMs may facilitate tumor progression. As novel therapies directed against thyroid tumorcell-specific targets are being tested, the potential role of TAMs as potential modulators of the thyroidcancer behavior will need to be considered.", "metadata": {}}
+{"_id": "25453683", "title": "", "text": "Blockade of Tim-1 and Tim-4 Enhances Atherosclerosis in Low-Density Lipoprotein Receptor-DeficientMice.OBJECTIVE T cell immunoglobulin and mucin domain (Tim) proteins are expressed by numerousimmune cells, recognize phosphatidylserine on apoptotic cells, and function as costimulators orcoinhibitors. Tim-1 is expressed by activated T cells but is also found on dendritic cells and B cells. Tim-4,present on macrophages and dendritic cells, plays a critical role in apoptotic cell clearance, regulates thenumber of phosphatidylserine-expressing activated T cells, and is genetically associated with lowlow-density lipoprotein and triglyceride levels. Because these functions of Tim-1 and Tim-4 could affectatherosclerosis, their modulation has potential therapeutic value in cardiovascular disease. APPROACHAND RESULTS ldlr(-/-) mice were fed a high-fat diet for 4 weeks while being treated with control (ratimmunoglobulin G1) or anti-Tim-1 (3D10) or -Tim-4 (21H12) monoclonal antibodies that blockphosphatidylserine recognition and phagocytosis. Both anti-Tim-1 and anti-Tim-4 treatments enhancedatherosclerosis by 45% compared with controls by impairment of efferocytosis and increasing aorticCD4(+)T cells. Consistently, anti-Tim-4-treated mice showed increased percentages of activated T cellsand late apoptotic cells in the circulation. Moreover, in vitro blockade of Tim-4 inhibited efferocytosis ofoxidized low-density lipoprotein-induced apoptotic macrophages. Although anti-Tim-4 treatmentincreased T helper cell (Th)1 and Th2 responses, anti-Tim-1 induced Th2 responses but dramaticallyreduced the percentage of regulatory T cells. Finally, combined blockade of Tim-1 and Tim-4 increasedatherosclerotic lesion size by 59%. CONCLUSIONS Blockade of Tim-4 aggravates atherosclerosis likely byprevention of phagocytosis of phosphatidylserine-expressing apoptotic cells and activated T cells byTim-4-expressing cells, whereas Tim-1-associated effects on atherosclerosis are related to changes inTh1/Th2 balance and reduced circulating regulatory T cells.", "metadata": {}}
+{"_id": "25462689", "title": "", "text": "Genetic and physical analysis of double-strand break repair and recombination in Saccharomycescerevisiae.We have investigated HO endonuclease-induced double-strand break (DSB) recombination andrepair in a LACZ duplication plasmid in yeast. A 117-bp MATa fragment, embedded in one copy of LACZ,served as a site for initiation of a DSB when HO endonuclease was expressed. The DSB could be repairedusing wild-type sequences located on a second, promoterless, copy of LACZ on the same plasmid. Incontrast to normal mating-type switching, crossing-over associated with gene conversion occurred atleast 50% of the time. The proportion of conversion events accompanied by exchange was greater whenthe two copies of LACZ were in direct orientation (80%), than when inverted (50%). In addition, thefraction of plasmids lost was significantly greater in the inverted orientation. The kinetics of appearanceof intermediates and final products were also monitored. The repair of the DSB is slow, requiring at leastan hour from the detection of the HO-cut fragments to completion of repair. Surprisingly, the appearanceof the two reciprocal products of crossing over did not occur with the same kinetics. For example, whenthe two LACZ sequences were in the direct orientation, the HO-induced formation of a large circulardeletion product was not accompanied by the appearance of a small circular reciprocal product. Wesuggest that these differences may reflect two kinetically separable processes, one involving only one cutend and the other resulting from the concerted participation of both ends of the DSB.", "metadata": {}}
+{"_id": "25475802", "title": "", "text": "Nitroxergic nerves mediate vagally induced relaxation in the isolated stomach of the guinea pig.Here weshow that the relaxation induced by stimulation of the vagus nerve in the presence of cholinergic(muscarinic) and adrenergic blockade in the isolated stomach of the guinea pig is mediated by nitric oxide(NO). This is substantiated by inhibition of vagal relaxation by NG-monomethyl-L-arginine, an inhibitor ofNO synthesis. The effect of NG-monomethyl-L-arginine was partially reversed by coincubation withL-arginine but not with D-arginine. NO activates soluble guanylate cyclase, and relaxation of the stomachinduced by vagal stimulation was prevented by an inhibitor of soluble guanylate cyclase, methylene blue,further supporting our conclusions. The relaxant effect of vagal stimulation was also ablated byhexamethonium, an inhibitor of ganglionic nicotinic receptors, thereby showing that ganglionictransmission did not rely on NO, through its release from preganglionic neurons. However,hexamethonium did not inhibit the gastric relaxation brought about by increasing the intragastricpressure, which is also mediated by NO as previously described by us. The selective inhibition byhexamethonium of only the vagally mediated relaxation but not of the pressure-induced relaxation of thestomach indicates the existence of at least two separate neuronal pathways able to generate NO andbring about gastric accommodation of food or fluid.", "metadata": {}}
+{"_id": "25479072", "title": "", "text": "Efficient T cell activation requires an optimal dwell-time of interaction between the TCR and the pMHCcomplexCytotoxic T cell (CTL) activation by antigen requires the specific detection of peptide–majorhisto-compatibility class I (pMHC) molecules on the target-cell surface by the T cell receptor (TCR). Weexamined the effect of mutations in the antigen-binding site of a Kb-restricted TCR on T cell activation,antigen binding and dissociation from antigen. These parameters were also examined for variants derivedfrom a Kd-restricted peptide that was recognized by a CTL clone. Using these two independent systems,we show that T cell activation can be impaired by mutations that either decrease or increase the bindinghalf-life of the TCR-pMHC interaction. Our data indicate that efficient T cell activation occurs within anoptimal dwell-time range of TCR-pMHC interaction. This restricted dwell-time range is consistent with theexclusion of either extremely low or high affinity T cells from the expanded population during immuneresponses.", "metadata": {}}
+{"_id": "25483562", "title": "", "text": "Crystal structure of human insulin-regulated aminopeptidase with specificity for cyclicpeptides.Insulin-regulated aminopeptidase (IRAP or oxytocinase) is a membrane-boundzinc-metallopeptidase that cleaves neuroactive peptides in the brain and produces memory enhancingeffects when inhibited. We have determined the crystal structure of human IRAP revealing a closed, fourdomain arrangement with a large, mostly buried cavity abutting the active site. The structure reveals thatthe GAMEN exopeptidase loop adopts a very different conformation from other aminopeptidases, thusexplaining IRAP's unique specificity for cyclic peptides such as oxytocin and vasopressin. Computationaldocking of a series of IRAP-specific cognitive enhancers into the crystal structure provides a molecularbasis for their structure-activity relationships and demonstrates that the structure will be a powerful toolin the development of new classes of cognitive enhancers for treating a variety of memory disorders suchas Alzheimer's disease.", "metadata": {}}
+{"_id": "25488034", "title": "", "text": "Glutathione and glutathione-dependent enzymes represent a co-ordinately regulated defence againstoxidative stress.Increases in the intracellular levels of reactive oxygen species (ROS), frequently referredto as oxidative stress, represents a potentially toxic insult which if not counteracted will lead tomembrane dysfunction, DNA damage and inactivation of proteins. Chronic oxidative stress has numerouspathological consequences including cancer, arthritis and neurodegenerative disease.Glutathione-associated metabolism is a major mechanism for cellular protection against agents whichgenerate oxidative stress. It is becoming increasingly apparent that the glutathione tripeptide is central toa complex multifaceted detoxification system, where there is substantial inter-dependence betweenseparate component members. Glutathione participates in detoxification at several different levels, andmay scavenge free radicals, reduce peroxides or be conjugated with electrophilic compounds. Thus,glutathione provides the cell with multiple defences not only against ROS but also against their toxicproducts. This article discusses how glutathione biosynthesis, glutathione peroxidases, glutathioneS-transferases and glutathione S-conjugate efflux pumps function in an integrated fashion to allowcellular adaption to oxidative stress. Co-ordination of this response is achieved, at least in part, throughthe antioxidant responsive element (ARE) which is found in the promoters of many of the genes that areinducible by oxidative and chemical stress. Transcriptional activation through this enhancer appears to bemediated by basic leucine zipper transcription factors such as Nrf and small Maf proteins. The nature ofthe intracellular sensor(s) for ROS and thiol-active chemicals which induce genes through the ARE isdescribed. Gene activation through the ARE appears to account for the enhanced antioxidant anddetoxification capacity of normal cells effected by many cancer chemopreventive agents. In certaininstances it may also account for acquired resistance of tumours to cancer chemotherapeutic drugs. It istherefore clear that determining the mechanisms involved in regulation of ARE-driven gene expressionhas enormous medical implications.", "metadata": {}}
+{"_id": "25493293", "title": "", "text": "Does socioeconomic status matter? A meta-analysis on parent training effectiveness for disruptive childbehavior.Disadvantaged family socioeconomic status (SES) is often assumed to diminish parent trainingprogram effectiveness. In examining effects of SES, influences of initial problem severity have beenlargely ignored. In the present meta-analysis, we examined (a) whether there is a differential influence ofSES on parent training effectiveness at immediate posttreatment and at 1-year follow-up-controlling forlevels of initial problem severity--and (b) whether SES interacts with initial problem severity in its effecton program effectiveness. Seventy-five studies on parent training program effectiveness to reducedisruptive child behavior were included. Separate analyses were conducted for immediate posttreatmentand approximately 1-year follow-up assessments. Immediately posttreatment, disadvantaged samplesbenefited less from parent training, but only when they had low levels of initial problem severity. Atfollow-up, disadvantaged samples benefited less from parent training regardless of initial problemseverity. Initial problem severity was a strong predictor of effect sizes both immediately posttreatmentand at follow-up. Parent training programs are equally effective for disadvantaged and nondisadvantagedfamilies immediately posttreatment, at least when initial problems are severe. Maintenance of treatmentgain, however, seems harder for disadvantaged families, suggesting that more sustained family supportmay be needed.", "metadata": {}}
+{"_id": "25499612", "title": "", "text": "Infectiousness of malaria-endemic human populations to vectors.Despite its key role in determining thestability and intensity of malaria transmission, the infectiousness of human populations to mosquitoes hasrarely been estimated. Field-based analyses of malaria transmission have frequently relied on theprevalence of asexual parasites or gametocytes as proxies for infectiousness. We now summarizeempirical data on human infectiousness from Africa and Papua New Guinea. Over a wide range oftransmission intensities there is little relationship between the infectiousness of human populations tovector mosquitoes and mosquito-to-human transmission intensity. We compare these data with thepredictions of a stochastic simulation model of Plasmodium falciparum epidemiology. This modelpredicted little variation in the infectiousness of the human population for entomologic inoculation rates(EIRs) greater than approximately 10 infectious bites per year, demonstrating that the lack ofrelationship between the EIR and the infectious reservoir can be explained without invoking any effects ofacquired transmission-blocking immunity. The near absence of field data from areas with an EIR < 10 peryear precluded validation of the model predictions for low EIR values. These results suggest thatinterventions reducing mosquito-to-human transmission will have little or no effect on humaninfectiousness at the levels of transmission found in most rural areas of sub-Saharan Africa. Unless verylarge reductions in transmission can be achieved, measures to prevent mosquito-to-human transmissionneed to be complemented with interventions that reduce the density or infectiousness of blood stageparasites.", "metadata": {}}
+{"_id": "25504006", "title": "", "text": "Molecular analysis of circulating tumour cells—biology and biomarkersGrowing evidence for intratumourheterogeneity informs us that single-site biopsies fall short of revealing the complete genomic landscapeof a tumour. With an expanding repertoire of targeted agents entering the clinic, screening tumours forgenomic aberrations is increasingly important, as is interrogating the tumours for resistance mechanismsupon disease progression. Multiple biopsies separated spatially and temporally are impractical,uncomfortable for the patient and not without risk. Here, we describe how circulating tumour cells(CTCs), captured from a minimally invasive blood test—and readily amenable to serial sampling—havethe potential to inform intratumour heterogeneity and tumour evolution, although it remains to bedetermined how useful this will be in the clinic. Technologies for detecting and isolating CTCs include thevalidated CellSearch® system, but other technologies are gaining prominence. We also discuss howrecent CTC discoveries map to mechanisms of haematological spread, previously described in preclinicalmodels, including evidence for epithelial–mesenchymal transition, collective cell migration and cells withtumour-initiating capacity within the circulation. Advances in single-cell molecular analysis are enhancingour ability to explore mechanisms of metastasis, and the combination of CTC and cell-free DNA assaysare anticipated to provide invaluable blood-borne biomarkers for real-time patient monitoring andtreatment stratification.", "metadata": {}}
+{"_id": "25510546", "title": "", "text": "Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetesIncreased lipid supplycauses beta cell death, which may contribute to reduced beta cell mass in type 2 diabetes. Weinvestigated whether endoplasmic reticulum (ER) stress is necessary for lipid-induced apoptosis in betacells and also whether ER stress is present in islets of an animal model of diabetes and of humans withtype 2 diabetes. Expression of genes involved in ER stress was evaluated in insulin-secreting MIN6 cellsexposed to elevated lipids, in islets isolated from db/db mice and in pancreas sections of humans withtype 2 diabetes. Overproduction of the ER chaperone heat shock 70 kDa protein 5 (HSPA5, previouslyknown as immunoglobulin heavy chain binding protein [BIP]) was performed to assess whetherattenuation of ER stress affected lipid-induced apoptosis. We demonstrated that the pro-apoptotic fattyacid palmitate triggers a comprehensive ER stress response in MIN6 cells, which was virtually absentusing non-apoptotic fatty acid oleate. Time-dependent increases in mRNA levels for activatingtranscription factor 4 (Atf4), DNA-damage inducible transcript 3 (Ddit3, previously known as C/EBPhomologous protein [Chop]) and DnaJ homologue (HSP40) C3 (Dnajc3, previously known as p58)correlated with increased apoptosis in palmitate- but not in oleate-treated MIN6 cells. Attenuation of ERstress by overproduction of HSPA5 in MIN6 cells significantly protected against lipid-induced apoptosis. Inislets of db/db mice, a variety of marker genes of ER stress were also upregulated. Increased processing(activation) of X-box binding protein 1 (Xbp1) mRNA was also observed, confirming the existence of ERstress. Finally, we observed increased islet protein production of HSPA5, DDIT3, DNAJC3 andBCL2-associated X protein in human pancreas sections of type 2 diabetes subjects. Our results provideevidence that ER stress occurs in type 2 diabetes and is required for aspects of the underlying beta cellfailure.", "metadata": {}}
+{"_id": "25513319", "title": "", "text": "Coactivator SRC-2-dependent metabolic reprogramming mediates prostate cancer survival andmetastasis.Metabolic pathway reprogramming is a hallmark of cancer cell growth and survival andsupports the anabolic and energetic demands of these rapidly dividing cells. The underlying regulators ofthe tumor metabolic program are not completely understood; however, these factors have potential ascancer therapy targets. Here, we determined that upregulation of the oncogenic transcriptionalcoregulator steroid receptor coactivator 2 (SRC-2), also known as NCOA2, drives glutamine-dependent denovo lipogenesis, which supports tumor cell survival and eventual metastasis. SRC-2 was highly elevatedin a variety of tumors, especially in prostate cancer, in which SRC-2 was amplified and overexpressed in37% of the metastatic tumors evaluated. In prostate cancer cells, SRC-2 stimulated reductivecarboxylation of α-ketoglutarate to generate citrate via retrograde TCA cycling, promoting lipogenesisand reprogramming of glutamine metabolism. Glutamine-mediated nutrient signaling activated SRC-2 viamTORC1-dependent phosphorylation, which then triggered downstream transcriptional responses bycoactivating SREBP-1, which subsequently enhanced lipogenic enzyme expression. Metabolic profiling ofhuman prostate tumors identified a massive increase in the SRC-2-driven metabolic signature inmetastatic tumors compared with that seen in localized tumors, further implicating SRC-2 as a prominentmetabolic coordinator of cancer metastasis. Moreover, SRC-2 inhibition in murine models severelyattenuated the survival, growth, and metastasis of prostate cancer. Together, these results suggest thatthe SRC-2 pathway has potential as a therapeutic target for prostate cancer.", "metadata": {}}
+{"_id": "25515662", "title": "", "text": "In vitro substrate specificity of protein tyrosine kinasesSynthetic peptides such as P60stcautophosphorylation site peptides and angiotensin are indiscriminately phosphorylated by proteintyrosine kinases. The observation has led to the general belief that protein tyrosine kinases are highlypromiscuous, displaying littlein vitro site specificity. In recent years, evidence has been accumulating toindicate that such a belief requires close examination. Synthetic peptides showing high substrate activityfor specific groups of protein tyrosine kinases have been obtained. Systematic modification of certainsubstrate peptides suggests that kinase substrate determinants reside with specific amino acid residuesproximal to the target tyrosine. A number of protein kinases have been shown to be regulated by tyrosinephosphorylation at specific sites by highly specific protein tyrosine kinases. These and other selectedbiochemical studies that contribute to the evolving view ofin vitro substrate specificity of protein tyrosinekinases are reviewed.", "metadata": {}}
+{"_id": "25515907", "title": "", "text": "Relative effectiveness of clinic and home blood pressure monitoring compared with ambulatory bloodpressure monitoring in diagnosis of hypertension: systematic reviewOBJECTIVE To determine the relativeaccuracy of clinic measurements and home blood pressure monitoring compared with ambulatory bloodpressure monitoring as a reference standard for the diagnosis of hypertension. DESIGN Systematicreview with meta-analysis with hierarchical summary receiver operating characteristic models.Methodological quality was appraised, including evidence of validation of blood pressure measurementequipment. DATA SOURCES Medline (from 1966), Embase (from 1980), Cochrane Database ofSystematic Reviews, DARE, Medion, ARIF, and TRIP up to May 2010. Eligibility criteria for selectingstudies Eligible studies examined diagnosis of hypertension in adults of all ages using home and/or clinicblood pressure measurement compared with those made using ambulatory monitoring that clearlydefined thresholds to diagnose hypertension. RESULTS The 20 eligible studies used various thresholds forthe diagnosis of hypertension, and only seven studies (clinic) and three studies (home) could be directlycompared with ambulatory monitoring. Compared with ambulatory monitoring thresholds of 135/85 mmHg, clinic measurements over 140/90 mm Hg had mean sensitivity and specificity of 74.6% (95%confidence interval 60.7% to 84.8%) and 74.6% (47.9% to 90.4%), respectively, whereas homemeasurements over 135/85 mm Hg had mean sensitivity and specificity of 85.7% (78.0% to 91.0%) and62.4% (48.0% to 75.0%). CONCLUSIONS Neither clinic nor home measurement had sufficient sensitivityor specificity to be recommended as a single diagnostic test. If ambulatory monitoring is taken as thereference standard, then treatment decisions based on clinic or home blood pressure alone might resultin substantial overdiagnosis. Ambulatory monitoring before the start of lifelong drug treatment might leadto more appropriate targeting of treatment, particularly around the diagnostic threshold.", "metadata": {}}
+{"_id": "25516011", "title": "", "text": "Purification and characterization of mouse hematopoietic stem cells.Mouse bone marrow hematopoieticstem cells were isolated with the use of a variety of phenotypic markers. These cells can proliferate anddifferentiate with approximately unit efficiency into myelomonocytic cells, B cells, or T cells. Thirty ofthese cells are sufficient to save 50 percent of lethally irradiated mice, and to reconstitute all blood celltypes in the survivors.", "metadata": {}}
+{"_id": "25519138", "title": "", "text": "Regulation of arabinose and xylose metabolism in Escherichia coli.Bacteria such as Escherichia coli willoften consume one sugar at a time when fed multiple sugars, in a process known as carbon cataboliterepression. The classic example involves glucose and lactose, where E. coli will first consume glucose,and only when it has consumed all of the glucose will it begin to consume lactose. In addition to that oflactose, glucose also represses the consumption of many other sugars, including arabinose and xylose. Inthis work, we characterized a second hierarchy in E. coli, that between arabinose and xylose. We showthat, when grown in a mixture of the two pentoses, E. coli will consume arabinose before it consumesxylose. Consistent with a mechanism involving catabolite repression, the expression of the xylosemetabolic genes is repressed in the presence of arabinose. We found that this repression is AraCdependent and involves a mechanism where arabinose-bound AraC binds to the xylose promoters andrepresses gene expression. Collectively, these results demonstrate that sugar utilization in E. coli involvesmultiple layers of regulation, where cells will consume first glucose, then arabinose, and finally xylose.These results may be pertinent in the metabolic engineering of E. coli strains capable of producingchemical and biofuels from mixtures of hexose and pentose sugars derived from plant biomass.", "metadata": {}}
+{"_id": "25523969", "title": "", "text": "MicroRNA expression profiling of human metastatic cancers identifies cancer gene targets.Smallnon-coding microRNAs (miRNAs) contribute to cancer development and progression, and are differentiallyexpressed in normal tissues and cancers. However, the specific role of miRNAs in the metastatic processis still unknown. To seek a specific miRNA expression signature characterizing the metastatic phenotypeof solid tumours, we performed a miRNA microarray analysis on 43 paired primary tumours (ten colon,ten bladder, 13 breast, and ten lung cancers) and one of their related metastatic lymph nodes. Weidentified a metastatic cancer miRNA signature comprising 15 overexpressed and 17 underexpressedmiRNAs. Our results were confirmed by qRT-PCR analysis. Among the miRNAs identified, some have awell-characterized association with cancer progression, eg miR-10b, miR-21, miR-30a, miR-30e,miR-125b, miR-141, miR-200b, miR-200c, and miR-205. To further support our data, we performed animmunohistochemical analysis for three well-defined miRNA gene targets (PDCD4, DHFR, and HOXD10genes) on a small series of paired colon, breast, and bladder cancers, and one of their metastatic lymphnodes. We found that the immunohistochemical expression of these targets significantly follows thecorresponding miRNA deregulation. Our results suggest that specific miRNAs may be directly involved incancer metastasis and that they may represent a novel diagnostic tool in the characterization ofmetastatic cancer gene targets.", "metadata": {}}
+{"_id": "25536577", "title": "", "text": "Circos: an information aesthetic for comparative genomics.We created a visualization tool called Circos tofacilitate the identification and analysis of similarities and differences arising from comparisons ofgenomes. Our tool is effective in displaying variation in genome structure and, generally, any other kindof positional relationships between genomic intervals. Such data are routinely produced by sequencealignments, hybridization arrays, genome mapping, and genotyping studies. Circos uses a circularideogram layout to facilitate the display of relationships between pairs of positions by the use of ribbons,which encode the position, size, and orientation of related genomic elements. Circos is capable ofdisplaying data as scatter, line, and histogram plots, heat maps, tiles, connectors, and text. Bitmap orvector images can be created from GFF-style data inputs and hierarchical configuration files, which can beeasily generated by automated tools, making Circos suitable for rapid deployment in data analysis andreporting pipelines.", "metadata": {}}
+{"_id": "25543207", "title": "", "text": "Pharmacokinetic, pharmacodynamic and clinical profile of novel antiplatelet drugs targeting vasculardiseases.Platelet inhibitors are the mainstay treatment for patients with vascular diseases. The current'gold standard' antiplatelet agent clopidogrel has several pharmacological and clinical limitations thathave prompted the search for more effective platelet antagonists. The candidates include various blockersof the purinergic P2Y12 receptor such as prasugrel, an oral irreversible thienopyridine; two adenosinetriphosphate analogues that bind reversibly to the P2Y12 receptor: ticagrelor (oral) and cangrelor(intravenous); elinogrel, a direct-acting reversible P2Y12 receptor inhibitor (the only antiplateletcompound that can be administered both intravenously and orally); BX 667, an orally active andreversible small-molecule P2Y12 receptor antagonist; SCH 530348, SCH 205831, SCH 602539 andE5555, highly selective and orally active antagonists on the protease-activated receptor 1. A number ofdrugs also hit new targets: terutroban, an oral, selective and specific inhibitor of the thromboxanereceptor; ARC1779, a second-generation, nuclease resistant aptamer which inhibits von Willebrandfactor-dependent platelet aggregation; ALX-0081, a bivalent humanized nanobody targeting the GPIbbinding site of von Willebrand factor and AJW200, an IgG4 monoclonal antibody of von Willebrand factor.The pharmacology and clinical profiles of new platelet antagonists indicate that they provide moreconsistent, more rapid and more potent platelet inhibition than agents currently used. Whether thesepotential advantages will translate into clinical advantages will require additional comparisons in properlypowered, randomized, controlled trials.", "metadata": {}}
+{"_id": "25550665", "title": "", "text": "BLM is required for faithful chromosome segregation and its localization defines a class of ultrafineanaphase bridges.Mutations in BLM cause Bloom's syndrome, a disorder associated with cancerpredisposition and chromosomal instability. We investigated whether BLM plays a role in ensuring thefaithful chromosome segregation in human cells. We show that BLM-defective cells display a higherfrequency of anaphase bridges and lagging chromatin than do isogenic corrected derivatives thateptopically express the BLM protein. In normal cells undergoing mitosis, BLM protein localizes toanaphase bridges, where it colocalizes with its cellular partners, topoisomerase IIIalpha and hRMI1(BLAP75). Using BLM staining as a marker, we have identified a class of ultrafine DNA bridges inanaphase that are surprisingly prevalent in the anaphase population of normal human cells. Theseso-called BLM-DNA bridges, which also stain for the PICH protein, frequently link centromeric loci, andare present at an elevated frequency in cells lacking BLM. On the basis of these results, we propose thatsister-chromatid disjunction is often incomplete in human cells even after the onset of anaphase. Wepresent a model for the action of BLM in ensuring complete sister chromatid decatenation in anaphase.", "metadata": {}}
+{"_id": "25562234", "title": "", "text": "Association Between High Serum Soluble Corin and Hypertension: A Cross-Sectional Study in a GeneralPopulation of China.BACKGROUND Corin has been suggested to be associated with hypertension by cell-and animal-based studies. However, the association still lacks population-based evidence which criticallypromotes translation from basic research to clinical and preventive practice. Here, we aimed to explorethe association in a general population of China. METHODS From January to May 2010, we conducted across-sectional study in 2,498 participants aged above 30 years, residing in Gusu district of Suzhou.Serum soluble corin and blood pressure were measured. RESULTS Hypertensive participants had a higherlevel of serum corin than nonhypertensive participants (median (interquartile range): 1,836.83(1,497.85-2,327.87) pg/ml vs. 1,579.14 (1,322.18-1,956.82) pg/ml, P < 0.001). Higher serum corin waspositively associated with prevalent hypertension (odds ratio (OR) = 2.01, P < 0.001). In the multipleanalysis, participants in the third (OR = 1.43, P = 0.007) and fourth (OR = 1.96, P < 0.001) quartiles hadsignificantly increased odds of hypertension compared to those in the lowest quartile of serum corin. ORsof hypertension positively and significantly increased with serum corin levels (P for trend <0.001).Further subgroup analysis showed that ORs of hypertension associated with high corin (over the medianlevel of serum corin: 1,689.20 pg/ml) were still significant in subgroups by age, body mass index, totalcholesterol, low-density lipoprotein cholesterol, and fasting plasma glucose (all P < 0.05). CONCLUSIONSOur study showed that hypertensive participants had an increased serum corin level compared to thosewithout hypertension. This finding suggests that corin may play a role in the pathology of hypertension.", "metadata": {}}
+{"_id": "25571386", "title": "", "text": "Shared and distinct genetic variants in type 1 diabetes and celiac disease.BACKGROUND Twoinflammatory disorders, type 1 diabetes and celiac disease, cosegregate in populations, suggesting acommon genetic origin. Since both diseases are associated with the HLA class II genes on chromosome6p21, we tested whether non-HLA loci are shared. METHODS We evaluated the association between type1 diabetes and eight loci related to the risk of celiac disease by genotyping and statistical analyses of DNAsamples from 8064 patients with type 1 diabetes, 9339 control subjects, and 2828 families providing3064 parent-child trios (consisting of an affected child and both biologic parents). We also investigated18 loci associated with type 1 diabetes in 2560 patients with celiac disease and 9339 control subjects.RESULTS Three celiac disease loci--RGS1 on chromosome 1q31, IL18RAP on chromosome 2q12, andTAGAP on chromosome 6q25--were associated with type 1 diabetes (P<1.00x10(-4)). The 32-bpinsertion-deletion variant on chromosome 3p21 was newly identified as a type 1 diabetes locus(P=1.81x10(-8)) and was also associated with celiac disease, along with PTPN2 on chromosome 18p11and CTLA4 on chromosome 2q33, bringing the total number of loci with evidence of a shared associationto seven, including SH2B3 on chromosome 12q24. The effects of the IL18RAP and TAGAP alleles conferprotection in type 1 diabetes and susceptibility in celiac disease. Loci with distinct effects in the twodiseases included INS on chromosome 11p15, IL2RA on chromosome 10p15, and PTPN22 onchromosome 1p13 in type 1 diabetes and IL12A on 3q25 and LPP on 3q28 in celiac disease.CONCLUSIONS A genetic susceptibility to both type 1 diabetes and celiac disease shares common alleles.These data suggest that common biologic mechanisms, such as autoimmunity-related tissue damage andintolerance to dietary antigens, may be etiologic features of both diseases.", "metadata": {}}
+{"_id": "25576204", "title": "", "text": "Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene.Malignant cellsoften display defects in autophagy, an evolutionarily conserved pathway for degrading long-lived proteinsand cytoplasmic organelles. However, as yet, there is no genetic evidence for a role of autophagy genesin tumor suppression. The beclin 1 autophagy gene is monoallelically deleted in 40-75% of cases ofhuman sporadic breast, ovarian, and prostate cancer. Therefore, we used a targeted mutant mousemodel to test the hypothesis that monoallelic deletion of beclin 1 promotes tumorigenesis. Here we showthat heterozygous disruption of beclin 1 increases the frequency of spontaneous malignancies andaccelerates the development of hepatitis B virus-induced premalignant lesions. Molecular analyses oftumors in beclin 1 heterozygous mice show that the remaining wild-type allele is neither mutated norsilenced. Furthermore, beclin 1 heterozygous disruption results in increased cellular proliferation andreduced autophagy in vivo. These findings demonstrate that beclin 1 is a haplo-insufficienttumor-suppressor gene and provide genetic evidence that autophagy is a novel mechanism of cell-growthcontrol and tumor suppression. Thus, mutation of beclin 1 or other autophagy genes may contribute tothe pathogenesis of human cancers.", "metadata": {}}
+{"_id": "25589047", "title": "", "text": "Treatment-related mortality with bevacizumab in cancer patients: a meta-analysis.CONTEXT Fataladverse events (FAEs) have been reported in cancer patients treated with the widely used angiogenesisinhibitor bevacizumab in combination with chemotherapy. Currently, the role of bevacizumab intreatment-related mortality is not clear. OBJECTIVE To perform a systematic review and meta-analysis ofpublished randomized controlled trials (RCTs) to determine the overall risk of FAEs associated withbevacizumab. DATA SOURCES PubMed, EMBASE, and Web of Science databases as well as abstractspresented at American Society of Clinical Oncology conferences from January 1966 to October 2010 weresearched to identify relevant studies. STUDY SELECTION AND DATA EXTRACTION Eligible studiesincluded prospective RCTs in which bevacizumab in combination with chemotherapy or biological therapywas compared with chemotherapy or biological therapy alone. Summary incidence rates, relative risks(RRs), and 95% confidence intervals (CIs) were calculated using fixed- or random-effects models. DATASYNTHESIS A total of 10,217 patients with a variety of advanced solid tumors from 16 RCTs wereincluded in the analysis. The overall incidence of FAEs with bevacizumab was 2.5% (95% CI,1.7%-3.9%). Compared with chemotherapy alone, the addition of bevacizumab was associated with anincreased risk of FAEs, with an RR of 1.46 (95% CI, 1.09-1.94; P = .01; incidence, 2.5% vs 1.7%). Thisassociation varied significantly with chemotherapeutic agents (P = .045) but not with tumor types (P =.13) or bevacizumab doses (P = .16). Bevacizumab was associated with an increased risk of FAEs inpatients receiving taxanes or platinum agents (RR, 3.49; 95% CI, 1.82-6.66; incidence, 3.3% vs 1.0%)but was not associated with increased risk of FAEs when used in conjunction with other agents (RR, 0.85;95% CI, 0.25-2.88; incidence, 0.8% vs 0.9%). The most common causes of FAEs were hemorrhage(23.5%), neutropenia (12.2%), and gastrointestinal tract perforation (7.1%). CONCLUSION In ameta-analysis of RCTs, bevacizumab in combination with chemotherapy or biological therapy, comparedwith chemotherapy alone, was associated with increased treatment-related mortality.", "metadata": {}}
+{"_id": "25597580", "title": "", "text": "Quiescent and active hippocampal neural stem cells with distinct morphologies respond selectively tophysiological and pathological stimuli and aging.New neurons are generated in the adult hippocampusthroughout life by neural stem/progenitor cells (NSCs), and neurogenesis is a plastic process responsiveto external stimuli. We show that canonical Notch signaling through RBP-J is required for hippocampalneurogenesis. Notch signaling distinguishes morphologically distinct Sox2(+) NSCs, and within thesepools subpopulations can shuttle between mitotically active or quiescent. Radial and horizontal NSCsrespond selectively to neurogenic stimuli. Physical exercise activates the quiescent radial populationwhereas epileptic seizures induce expansion of the horizontal NSC pool. Surprisingly, reducedneurogenesis correlates with a loss of active horizontal NSCs in aged mice rather than a total loss of stemcells, and the transition to a quiescent state is reversible to rejuvenate neurogenesis in the brain. Thediscovery of multiple NSC populations with Notch dependence but selective responses to stimuli andreversible quiescence has important implications for the mechanisms of adaptive learning and also forregenerative therapy.", "metadata": {}}
+{"_id": "25599283", "title": "", "text": "Low serum vitamin D is associated with high risk of diabetes in Korean adults.Vitamin D may play a rolein glucose metabolism. A low vitamin D level has been associated with increased risk of diabetes mellitus,but the association has not been confirmed in Asians. Our objective was to examine the association ofserum 25-hydroxyvitamin D [25(OH)D] levels with insulin resistance and diabetes mellitus in Koreanadults based on a large population-based survey. Cross-sectional analyses were carried out on 5787Korean adults (2453 men and 3334 women) who were 20 y or older and participated in the Fourth KoreaNHANES conducted in 2008. Diabetes mellitus was defined as fasting plasma glucose ≥7 mmol/L orcurrent use of oral hypoglycemic agents or insulin. Insulin resistance was estimated by homeostaticmodel assessment for insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index(QUICKI). Compared to individuals with a sufficient serum 25(OH)D concentration ≥75 nmol/L, the OR(95% CI) for diabetes mellitus were 1.73 (1.09-2.74), 1.30 (0.91-1.84), and 1.40 (0.99-1.98) for serum25(OH)D concentrations <25, 25 to <50, and 50 to <75 nmol/L, respectively, after multiple adjustments(P-trend < 0.0001). Furthermore, the serum 25(OH)D level was inversely associated with HOMA-IR (β =-0.061; P = 0.001) and positively associated with QUICKI (β = 0.059; P = 0.001) in overweight or obeseparticipants. In conclusion, a low serum vitamin D concentration is associated with a high risk of diabetesmellitus in Korean adults and the concentration is inversely associated with insulin resistance in thosewho are overweight or obese.", "metadata": {}}
+{"_id": "25602549", "title": "", "text": "When NK cells overcome their lack of education.Cells of the immune system have evolved variousmolecular mechanisms to sense their environment and react to alterations of self. NK cells arelymphocytes with effector and regulatory functions, which are remarkably adaptable to changes in self. Ina study published in this issue of the JCI, Tarek and colleagues report the clinical benefits of manipulatingNK cell adaptation to self in an innovative mAb-based therapy against neuroblastoma (NB). This noveltherapeutic strategy should stimulate further research on NK cell therapies.", "metadata": {}}
+{"_id": "25606339", "title": "", "text": "Toll-like receptor-3 mediates HIV-1 transactivation via NFκB and JNK pathways and histone acetylation,but prolonged activation suppresses Tat and HIV-1 replication.TLR3 has been implicated in thepathogenesis of several viral infections, including SIV- and HIV-1-induced inflammation and AIDS.However the molecular mechanisms of these TLR3-mediated effects are not known, and it is not knownwhether HIV interacts with cellular TLR3 to affect disease process. Here we investigate the effects of TLR3ligands on HIV-1 transactivation using both primary human macrophages and cells containing integratedcopies of the HIV-1 promoter. We demonstrate that TLR3 activation induced upregulation of transcriptionfactors such as c-Jun, CCAAT/enhancer-binding protein alpha (CEBPA), signal transducer and activator oftranscription (STAT)-1, STAT-2, RELB, and nuclear factor kappa-B1 (NFκB1), most of which are known toregulate the HIV promoter activity. We also demonstrate that TLR3 activation increased HIV-1transactivation via the c-Jun N-terminal kinase (JNK) and NFκB pathways. This was associated withepigenetic modifications, including decreased histone deacetylase activity, increased histone acetyltransferase (HAT) activity, and increased acetylation of histones H3 and H4 at lysine residues in thenucleosome-0 and nucleosome-1 of the HIV-1 promoter. However, prolonged TLR3 activation decreasedHIV-1 transactivation, decreased HAT activity and Tat transcription, and suppressed viral replication.Overall, data suggests that TLR3 can act as viral sensor to mediate viral transactivation, cellularsignaling, innate immune response, and inflammation in HIV-infected humans. Our study provides novelinsights into the molecular basis for these TLR3-mediated effects.", "metadata": {}}
+{"_id": "25612629", "title": "", "text": "Patent ductus arteriosus: are current neonatal treatment options better or worse than no treatment atall?Although a moderate-sized patent ductus arteriosus (PDA) needs to be closed by the time a child is1-2 years old, there is great uncertainty about whether it needs to be closed during the neonatal period.Although 95% of neonatologists believe that a moderate-sized PDA should be closed if it persists ininfants (born before 28 weeks) who still require mechanical ventilation, the number of neonatologists whotreat a PDA when it occurs in infants who do not require mechanical ventilation varies widely. Both thehigh likelihood of spontaneous ductus closure and the absence of randomized controlled trials, specificallyaddressing the risks and benefits of neonatal ductus closure, add to the current uncertainty. Newinformation suggests that early pharmacologic treatment has several important short-term benefits forthe preterm newborn. By contrast, ductus ligation, while eliminating the detrimental effects of a PDA onlung development, may create its own set of morbidities that counteract many of the benefits derivedfrom ductus closure.", "metadata": {}}
+{"_id": "25623469", "title": "", "text": "A conserved phosphatase cascade that regulates nuclear membrane biogenesis.A newly emerging familyof phosphatases that are members of the haloacid dehalogenase superfamily contains the catalytic motifDXDX(T/V). A member of this DXDX(T/V) phosphatase family known as Dullard was recently shown to bea potential regulator of neural tube development in Xenopus [Satow R, Chan TC, Asashima M (2002)Biochem Biophys Res Commun 295:85-91]. Herein, we demonstrate that human Dullard and the yeastprotein Nem1p perform similar functions in mammalian cells and yeast cells, respectively. In addition tosimilarity in primary sequence, Dullard and Nem1p possess similar domains and show similar substratepreferences, and both localize to the nuclear envelope. Additionally, we show that human Dullard canrescue the aberrant nuclear envelope morphology of nem1Delta yeast cells, functionally replacingNem1p. Finally, Nem1p, has been shown to deposphorylate the yeast phosphatidic acid phosphataseSmp2p [Santos-Rosa H, Leung J, Grimsey N, Peak-Chew S, Siniossoglou S (2005) EMBO J24:1931-1941], and we show that Dullard dephosphorylates the mammalian phospatidic acidphosphatase, lipin. Therefore, we propose that Dullard participates in a unique phosphatase cascaderegulating nuclear membrane biogenesis, and that this cascade is conserved from yeast to mammals.", "metadata": {}}
+{"_id": "25628793", "title": "", "text": "Increased expression of CYP1A1 and CYP1B1 in ovarian/peritoneal endometriotic lesions.Endometriosis isan estrogen-dependent disease affecting up to 10% of all premenopausal women. There is evidence thatdifferent endometriosis sites show distinct local estrogen concentration, which, in turn, might be due to aunique local estrogen metabolism. We aimed to investigate whether there was a site-specific regulation ofselected enzymes responsible for the oxidative metabolism of estrogens in biopsy samples andendometrial and endometriotic stromal cells. Cytochrome P450 (CYP) 1A1 and CYP1B1 mRNA and proteinexpressions in deep-infiltrating (rectal, retossigmoidal, and uterossacral) lesions, superficial (ovarian andperitoneal) lesions, and eutopic and healthy (control) endometrium were evaluated by real-time PCR andwestern blot. Using a cross-sectional study design with 58 premenopausal women who were not underhormonal treatment, we were able to identify an overall increased CYP1A1 and CYP1B1 mRNA expressionin superficial lesions compared with the healthy endometrium. CYP1A1 mRNA expression in superficiallesions was also greater than in the eutopic endometrium. Interestingly, we found a similar pattern ofCYP1A1 and CYP1B1 expression in in vitro stromal cells isolated from ovarian lesions (n=3) whencompared with stromal cells isolated from either rectum lesions or eutopic endometrium. In contradiction,there was an increased half-life of estradiol (measured by HPLC-MS-MS) in ovarian endometriotic stromalcells compared with paired eutopic stromal endometrial cells. Our results indicate that there is asite-dependent regulation of CYP1A1 and CYP1B1 in ovarian/peritoneal lesions and ovarian endometrioticstromal cells, whereas a slower metabolism is taking place in these cells.", "metadata": {}}
+{"_id": "25629722", "title": "", "text": "Eset partners with Oct4 to restrict extraembryonic trophoblast lineage potential in embryonic stemcells.The histone H3 Lys 9 (H3K9) methyltransferase Eset is an epigenetic regulator critical for thedevelopment of the inner cell mass (ICM). Although ICM-derived embryonic stem (ES) cells are normallyunable to contribute to the trophectoderm (TE) in blastocysts, we find that depletion of Eset by shRNAsleads to differentiation with the formation of trophoblast-like cells and induction of trophoblast-associatedgene expression. Using chromatin immmunoprecipitation (ChIP) and sequencing (ChIP-seq) analyses, weidentified Eset target genes with Eset-dependent H3K9 trimethylation. We confirmed that genes that arepreferentially expressed in the TE (Tcfap2a and Cdx2) are bound and repressed by Eset. Single-cell PCRanalysis shows that the expression of Cdx2 and Tcfap2a is also induced in Eset-depleted morula cells.Importantly, Eset-depleted cells can incorporate into the TE of a blastocyst and, subsequently, placentaltissues. Coimmunoprecipitation and ChIP assays further demonstrate that Eset interacts with Oct4, whichin turn recruits Eset to silence these trophoblast-associated genes. Our results suggest that Eset restrictsthe extraembryonic trophoblast lineage potential of pluripotent cells and links an epigenetic regulator tokey cell fate decision through a pluripotency factor.", "metadata": {}}
+{"_id": "25641414", "title": "", "text": "Suicides after pregnancy in Finland, 1987-94: register linkage study.OBJECTIVE To determine rates ofsuicide associated with pregnancy by the type of pregnancy. DESIGN Register linkage study. Informationon suicides in women of reproductive age was linked with the Finnish birth, abortion, and hospitaldischarge registers to find out how many women who committed suicide had had a completed pregnancyduring her last year of life. SETTING Nationwide data from Finland. SUBJECTS Women who committedsuicide in 1987-94. RESULTS There were 73 suicides associated with pregnancy, representing 5.4% of allsuicides in women in this age group. The mean annual suicide rate was 11.3 per 100,000. The suiciderate associated with birth was significantly lower (5.9) and the rates associated with miscarriage (18.1)and induced abortion (34.7) were significantly higher than in the population. The risk associated withbirth was higher among teenagers and that associated with abortion was increased in all age groups.Women who had committed a suicide tended to come from lower social classes and were more likely tobe unmarried than other women who had had a completed pregnancy. CONCLUSIONS The increased riskof suicide after an induced abortion indicates either common risk factors for both or harmful effects ofinduced abortion on mental health.", "metadata": {}}
+{"_id": "25643818", "title": "", "text": "Metformin-associated lactic acidosis: a rare or very rare clinical entity?AIMS Lactic acidosis is a wellrecognized complication of biguanide therapy which is potentially serious. Although the prevalence ofmetformin-associated lactic acidosis (MALA) is much lower than that associated with phenformin, it is stillbeing reported sporadically which raises concerns for the practising clinicians. We review the currentlyavailable world-wide data of the prevalence of MALA, the risk factors for its development and the currentpractical guidelines on the use of metformin to minimize the risk of this potential hazard. METHODS Anextensive literature search was conducted from both Medline and Ovid (1965-98) using the followingkeywords: 'Type 2 diabetes mellitus', 'oral hypoglycaemic drugs', 'biguanides', 'metformin-associatedlactic acidosis' and 'renal impairment'. RESULTS MALA was found to be a very rare clinical entity, being20 times less common than phenformin-associated lactic acidosis. Amongst all the risk factors, renalimpairment appears to be the major precipitating factor for the development of MALA inmetformin-treated patients. We also found cases of MALA where no precipitating factors were identifiedand the underlying mechanism in these cases remains unclear. Practical recommendations of metforminuse to minimize the risk of MALA have been listed based on previous reports. CONCLUSIONS The lowprevalence of MALA is comparable to the prevalence of sulphonylurea-induced hypoglycaemia. Metforminhas many beneficial metabolic effects in the management of Type 2 diabetes mellitus. Provided that therecommended guidelines for metformin use are strictly adhered to, its widespread use would be safe andthe incidence of MALA will be further reduced.", "metadata": {}}
+{"_id": "25649545", "title": "", "text": "Inborn errors of human JAKs and STATs.Inborn errors of the genes encoding two of the four human JAKs(JAK3 and TYK2) and three of the six human STATs (STAT1, STAT3, and STAT5B) have been described.We review the disorders arising from mutations in these five genes, highlighting the way in which themolecular and cellular pathogenesis of these conditions has been clarified by the discovery of inbornerrors of cytokines, hormones, and their receptors, including those interacting with JAKs and STATs. Thephenotypic similarities between mice and humans lacking individual JAK-STAT components suggest thatthe functions of JAKs and STATs are largely conserved in mammals. However, a wide array of phenotypicdifferences has emerged between mice and humans carrying biallelic null alleles of JAK3, TYK2, STAT1, orSTAT5B. Moreover, the high degree of allelic heterogeneity at the human JAK3, TYK2, STAT1, and STAT3loci has revealed highly diverse immunological and clinical phenotypes, which had not been anticipated.", "metadata": {}}
+{"_id": "25649714", "title": "", "text": "Mental health problems of homeless children and families: longitudinal study.OBJECTIVE To establish themental health needs of homeless children and families before and after rehousing. DESIGN Crosssectional, longitudinal study. SETTING City of Birmingham. SUBJECTS 58 rehoused families with 103children aged 2-16 years and 21 comparison families of low socioeconomic status in stable housing, with54 children. MAIN OUTCOME MEASURES Children's mental health problems and level of communication;mothers' mental health problems and social support one year after rehousing. RESULTS Mental healthproblems remained significantly higher in rehoused mothers and their children than in the comparisongroup (mothers 26% v 5%, P = 0.04; children 39% v 11%, P = 0.0003). Homeless mothers continued tohave significantly less social support at follow up. Mothers with a history of abuse and poor socialintegration were more likely to have children with persistent mental health problems. CONCLUSIONSHomeless families have a high level of complex needs that cannot be met by conventional health servicesand arrangements. Local strategies for rapid rehousing into permanent accommodation, effective socialsupport and health care for parents and children, and protection from violence and intimidation should bedeveloped and implemented.", "metadata": {}}
+{"_id": "25653703", "title": "", "text": "The flip side of perception-action coupling: locomotor experience and the ontogeny of visual-posturalcoupling.The possible role of motor development on psychological function is once again a topic of greattheoretical and practical importance. The revival of this issue has stemmed from a different approach tothe topic, away from Gesell's interest in the long-term prediction of psychological functions from earlymotoric assessments, toward an attempt to understand how the acquisition of motor skills orchestratespsychological changes. This paper describes how the acquisition of one motor skill, prone locomotion, hasbeen linked to developmental changes in an infant's ability to regulate posture based on informationavailable in patterns of optic flow. It is argued that the onset of prone locomotion presses the infant todifferentiate spatially delimited regions of optic flow to effectively and efficiently control the importantsubtasks nested within the larger task of locomotion, namely, steering, attending to the surface ofsupport, and maintaining postural control. Following this argument, a research program is described thataims to determine if locomotor experience is causally linked to improvements in the ability tofunctionalize peripheral optic flow for postural control or whether locomotor experience is merely amaturational forecaster of such improvements. Finally, a hypothesis is put forward that links theemergence of wariness of heights to infants' ability to regulate posture on the basis of peripheral opticflow. The paper's overarching theoretical point is the principle of probabilistic epigenesis, which statesthat one developmental acquisition produces experiences that bring about a host of new developmentalchanges in the same and different domains.", "metadata": {}}
+{"_id": "25657127", "title": "", "text": "Crystal structure of the first plant urease from jack bean: 83 years of journey from its first crystal tomolecular structure.Urease, a nickel-dependent metalloenzyme, is synthesized by plants, some bacteria,and fungi. It catalyzes the hydrolysis of urea into ammonia and carbon dioxide. Although the amino acidsequences of plant and bacterial ureases are closely related, some biological activities differ significantly.Plant ureases but not bacterial ureases possess insecticidal properties independent of its ureolyticactivity. To date, the structural information is available only for bacterial ureases although the jack beanurease (Canavalia ensiformis; JBU), the best-studied plant urease, was the first enzyme to be crystallizedin 1926. To better understand the biological properties of plant ureases including the mechanism ofinsecticidal activity, we initiated the structural studies on some of them. Here, we report the crystalstructure of JBU, the first plant urease structure, at 2.05 A resolution. The active-site architecture of JBUis similar to that of bacterial ureases containing a bi-nickel center. JBU has a bound phosphate andcovalently modified residue (Cys592) by beta-mercaptoethanol at its active site, and the concomitantbinding of multiple inhibitors (phosphate and beta-mercaptoethanol) is not observed so far in bacterialureases. By correlating the structural information of JBU with the available biophysical and biochemicaldata on insecticidal properties of plant ureases, we hypothesize that the amphipathic beta-hairpin locatedin the entomotoxic peptide region of plant ureases might form a membrane insertion beta-barrel as foundin beta-pore-forming toxins.", "metadata": {}}
+{"_id": "25670099", "title": "", "text": "Studies of nuclear and cytoplasmic behaviour during the five mitotic cycles that precede gastrulation inDrosophila embryogenesis.Using differential interference contrast optics, combined with cinematography,we have studied the morphological changes that the living, syncytial embryo undergoes from stage 10through 14 of Drosophila embryogenesis, that is just prior to and during formation of the cellularblastoderm. We have supplemented these studies with data collected from fixed, stained, whole embryos.The following information has been obtained. The average duration of nuclear cycles 10, 11, 12 and 13 isabout 9, 10, 12 and 21 min, respectively (25 degrees C). In these four cycles, the duration of that portionof the mitotic period that lacks a discrete nuclear envelope is 3, 3, 3 and 5 min, respectively. The lengthof nuclear cycle 14 varies in a position-specific manner throughout the embryo, the shortest cycles beingof 65 min duration. During nuclear cycles 10 through 13, it is commonly observed in living embryos thatthe syncytial blastoderm nuclei enter (and leave) mitosis in one of two waves that originate nearlysimultaneously from the opposite anterior and posterior poles of the embryo, and terminate in itsmidregion. From our preparations of quick-frozen embryos, we estimate that these mitotic waves take onaverage about half a minute to travel over the embryonic surface from pole to equator. The yolk nuclei,which remain in the core of the embryo when the rest of the nuclei migrate to the periphery, divide insynchrony with the migrating nuclei at nuclear cycles 8 and 9, and just after the now peripherally locatednuclei at nuclear cycle 10. After cycle 10, these yolk nuclei cease dividing and become polyploid. Thesyncytial embryo has at least three distinct levels of cytoskeletal organization: structured domains ofcytoplasm are organized around each blastoderm nucleus; radially directed tracks orientcolchicine-sensitive saltatory transport throughout the peripheral cytoplasm; and a long-rangeorganization of the core of the embryo makes possible coherent movements of the large inner yolk massin concert with each nuclear cycle. This highly organized cytoplasm may be involved in providingpositional information for the important process of nuclear determination that is known to occur duringthese stages.", "metadata": {}}
+{"_id": "25677651", "title": "", "text": "Activation of liver X receptors and retinoid X receptors prevents bacterial-induced macrophageapoptosis.Microbe-macrophage interactions play a central role in the pathogenesis of many infections.The ability of some bacterial pathogens to induce macrophage apoptosis has been suggested tocontribute to their ability to elude innate immune responses and successfully colonize the host. Here, weprovide evidence that activation of liver X receptors (LXRs) and retinoid X receptors (RXRs) inhibitsapoptotic responses of macrophages to macrophage colony-stimulating factor (M-CSF) withdrawal andseveral inducers of apoptosis. In addition, combined activation of LXR and RXR protected macrophagesfrom apoptosis caused by infection with Bacillus anthracis, Escherichia coli, and Salmonella typhimurium.Expression-profiling studies demonstrated that LXR and RXR agonists induced the expression ofantiapoptotic regulators, including AIM/CT2, Bcl-X(L), and Birc1a. Conversely, LXR and RXR agonistsinhibited expression of proapoptotic regulators and effectors, including caspases 1, 4/11, 7, and 12; Fasligand; and Dnase1l3. The combination of LXR and RXR agonists was more effective than either agonistalone at inhibiting apoptosis in response to various inducers of apoptosis, and it acted synergistically toinduce expression of AIM/CT2. Inhibition of AIM/CT2 expression in response to LXR/RXR agonists partiallyreversed their antiapoptotic effects. These findings reveal unexpected roles of LXRs and RXRs in thecontrol of macrophage survival and raise the possibility that LXR/RXR agonists may be exploited toenhance innate immunity to bacterial pathogens that induce apoptotic programs as a strategy for evadinghost responses.", "metadata": {}}
+{"_id": "25682129", "title": "", "text": "p53 binding to nucleosomal DNA depends on the rotational positioning of DNA response element.Thesequence-specific binding to DNA is crucial for the p53 tumor suppressor function. To investigate theconstraints imposed on p53-DNA recognition by nucleosomal organization, we studied binding of the p53DNA binding domain (p53DBD) and full-length wild-type p53 protein to a single p53 response element(p53RE) placed near the nucleosomal dyad in six rotational settings. We demonstrate that the strongestp53 binding occurs when the p53RE in the nucleosome is bent in the same direction as observed for thep53-DNA complexes in solution and in co-crystals. The p53RE becomes inaccessible, however, if itsorientation in the core particle is changed by approximately 180 degrees. Our observations indicate thatthe orientation of the binding sites on a nucleosome may play a significant role in the initial p53-DNArecognition and subsequent cofactor recruitment.", "metadata": {}}
+{"_id": "25687558", "title": "", "text": "Diminished sympathetic nervous system activity in genetically obese (ob/ob) mouse.The geneticallyobese (ob/ob) mouse exhibits defective thermoregulatory responses to cold exposure. Pathophysiologicalexplanations for this phenomenon have focused on abnormalities in intracellular metabolism orinsensitivity of peripheral tissues to the thermogenic effects of catecholamines. Because the sympatheticnervous system (SNS) is subject to feedback regulation, a peripheral impairment in thermogenesisshould be associated with a compensatory increase in SNS activity. To examine SNS activity in the ob/obmouse, norepinephrine (NE) turnover was measured in heart and interscapular brown adipose tissue(IBAT) of ob/ob and lean mice. The results from studies utilizing radiolabeled NE or inhibition of NEbiosynthesis with alpha-methyl-p-tyrosine to measure NE turnover demonstrated reductions in SNSactivity of 33-56% in heart and of 45-73% in IBAT in ob/ob mice at ambient temperature (22 degrees C)compared with measurements in lean controls. During cold exposure (4 degrees C) NE turnover increasedin heart and IBAT to a similar extent in both ob/ob and lean mice, but NE turnover rates in heart, andprobably in IBAT as well, remained lower in the obese mice than in the lean despite the gradualdevelopment of hypothermia in the ob/ob mice during this period. Administration of naltrexone, along-acting opiate antagonist, failed to reverse the suppression of SNS activity observed in the ob/obmice. These data indicate that diminished SNS activity in ob/ob mice may be an additional factorcontributing to the defective thermogenesis characteristic of these animals.", "metadata": {}}
+{"_id": "25690516", "title": "", "text": "Quality of life of young adults with idiopathic short stature: effect of growth hormone treatment. DutchGrowth Hormone Working Group.The aim of the study was to evaluate whether treatment withrecombinant human growth hormone (rhGH) affects the quality of life of young adults who werediagnosed as idiopathic short stature (ISS) during childhood, and whether their quality of life and aspectsof the personality are different from normal. Experiences and expectations concerning rhGH treatment ofthe subjects and their parents were also investigated. Eighty-nine subjects were included into the study:24 subjects (16M, 8F) were treated with rhGH from childhood, whereas 65 subjects (40M, 25F) werenever treated. At the time of the interview all subjects had attained final height [mean (SD) -2.3 (0.9)SDS for Dutch references], and the age of the treated subjects was 20.5 (1.0) y, and 25.7 (3.5) y of thecontrol subjects (p < 0.001). The level of education was similar, but the treated subjects had less often apartner compared to the control subjects (adjusted for age and gender, p < 0.001). The NottinghamHealth Profile and Short Form 36 Health Survey showed no difference in general health state betweentreated and control subjects, and the healthy Dutch age-specific references (norm group). Although 74%of the subjects reported one or more negative events related to their height, and 61% would like to betaller, only 22% and 11% were willing to trade-off at Time Trade-Off and Standard Gamble, respectively.The personality of the subjects, which was measured by the Minnesota Multiphasic Personality Inventory,was not different from the norm group. The satisfaction with the rhGH treatment was high, as it hadcaused 12 (8) cm and 13 (7) cm gain in final height according to the subjects and parents, respectively.Based on initial predicted adult height (Bayley & Pinneau), this gain was only 3.3 (5.6) cm. We concludedthat although the treated subjects had a partner less often when compared to the control subjects, thequality of life of subjects with ISS at adult age is normal and appears not to be affected by rhGH therapy,The treated subjects were very satisfied with the treatment, probably by overestimation of the finalheight gain.", "metadata": {}}
+{"_id": "25690564", "title": "", "text": "Neighborhood Racial/Ethnic Concentration, Social Disadvantage, and Homicide Risk: An EcologicalAnalysis of 10 U.S. CitiesHomicide is one of the leading causes of death among African-American andHispanic men. We investigated how neighborhood characteristics associated with social disadvantageexplain racial/ethnic homicide gaps in 10 U.S. cities. The test hypotheses were that (1) higherconcentrations of African-Americans and Hispanics would be associated with higher homicide rates and(2) the relationship between racial/ethnic concentration and homicide would be attenuated afteradjusting for neighborhood characteristics (e.g., unemployment, median household income, loweducational attainment, and female headship). The test hypotheses were examined using separatePoisson regression models, which adjusted for spatial autocorrelation. Homicide rates were greater inneighborhoods with higher concentrations of African-Americans and Hispanics than in other groups, andthe association of neighborhood racial/ethnic concentration with homicide was reduced after adjusting forneighborhood social disadvantage variables, especially percent female head of household and percentpersons with less than a high school education. We also found that the relationship betweenneighborhood racial/ethnic concentration and homicide was explained more by social disadvantagevariables in some cities than in others. Based on our findings, policy makers may wish to considerimplementation of policies that (1) expand early childhood education programs and higher educationopportunities and (2) encourage economic and community development initiatives in sociallydisadvantaged neighborhoods.", "metadata": {}}
+{"_id": "25691541", "title": "", "text": "Preterm patent ductus arteriosus: A continuing conundrum for the neonatologist?How to manage thepreterm patent ductus arteriosus (PDA) remains a conundrum. On the one hand, physiology andstatistical association with adverse outcomes suggest that it is pathological. On the other hand, clinicaltrials of treatment strategies have failed to show any long-term benefit. Ultrasound studies of PDA havesuggested that the haemodynamic impact may be much earlier after birth than previously thought (in thefirst hours); however, we still do not know when to treat PDA. Studies that have tested symptomatic orpre-symptomatic treatment are mainly historical and have not tested the effect of no treatment.Prophylactic treatment is the best-studied regimen but improvements in some short-term outcomes donot translate to any difference in longer-term outcomes. Neonatologists have been reluctant to engage intrials that test treatment against almost never treating. Observations of very early postnatalhaemodynamic significance suggest that targeting treatment on the basis of the early postnatalconstrictive response of the duct may optimize benefits. A pilot trial of this strategy showed reduction inthe incidence of pulmonary haemorrhage but more trials of this strategy are needed.", "metadata": {}}
+{"_id": "25691878", "title": "", "text": "Political and economic aspects of the transition to universal health coverage.Countries have reacheduniversal health coverage by different paths and with varying health systems. Nonetheless, the trajectorytoward universal health coverage regularly has three common features. The first is a political processdriven by a variety of social forces to create public programmes or regulations that expand access tocare, improve equity, and pool financial risks. The second is a growth in incomes and a concomitant risein health spending, which buys more health services for more people. The third is an increase in theshare of health spending that is pooled rather than paid out-of-pocket by households. This pooled shareis sometimes mobilised as taxes and channelled through governments that provide or subsidise care--inother cases it is mobilised in the form of contributions to mandatory insurance schemes. Thepredominance of pooled spending is a necessary condition (but not sufficient) for achieving universalhealth coverage. This paper describes common patterns in countries that have successfully provideduniversal access to health care and considers how economic growth, demographics, technology, politics,and health spending have intersected to bring about this major development in public health.", "metadata": {}}
+{"_id": "25725663", "title": "", "text": "Wedelolactone protects human bronchial epithelial cell injury against cigarette smoke extract-inducedoxidant stress and inflammation responses through Nrf2 pathway.Cigarette smoke is the leading cause ofthe development of various lung diseases including lung cancer through triggering oxidant stress andinflammatory responses which contributed to the lesions of normal human bronchial epithelial (NHBE)cell. Wedelolactone (WEL), a natural compound from Eclipta prostrata L., has been found to possess theinhibitive effects on the proliferation and growth of cancers. In the present study, we investigated theeffects of WEL on NHBE cell injury induced by cigarette smoke extract (CSE) in vitro. It showed that thepretreatment WEL (2.5-20μM) resulted in a significant protective effect on 10% CSE-induced cell death inNHBE cells. The pretreatment with WEL dose-dependently and significantly reversed the activities of SOD,CAT, GSH and the level of MDA to normal level. We also found that the protein expression levels of COX-2and ICAM-1 which are related to inflammatory response were remarkably reduced by WEL compared with10% CSE treatment. Additionally, WEL also reduced the expressions of antioxidases including NAD(P)Hdehydrogenase:Quinone 1 (NQO1) and heme oxygenase-1 (HO-1). Moreover, Nrf2 inhibitorall-trans-retinoic acid (ATRA) decreased remarkably their expressions. These results suggest that WELprotects NHBE cell against CSE-induced injury through modulating Nrf2 pathway. Our study indicates thatWEL may be a new potential protective agent against CSE-induced lung injury.", "metadata": {}}
+{"_id": "25726838", "title": "", "text": "IL-17 promotes tumor development through the induction of tumor promoting microenvironments attumor sites and myeloid-derived suppressor cells.The role of immune responses in tumor development isa central issue for tumor biology and immunology. IL-17 is an important cytokine for inflammatory andautoimmune diseases. Although IL-17-producing cells are detected in cancer patients and tumor-bearingmice, the role of IL-17 in tumor development is controversial, and mechanisms remain to be fullyelucidated. In the current study, we found that the development of tumors was inhibited inIL-17R-deficient mice. A defect in IFN-gammaR increased tumor growth, whereas tumor growth wasinhibited in mice that were deficient in both IL-17R and IFN-gammaR compared with wild-type animals.Further experiments showed that neutralization of IL-17 by Abs inhibited tumor growth in wild-type mice,whereas systemic administration of IL-17 promoted tumor growth. The IL-17R deficiency increased CD8 Tcell infiltration, whereas it reduced the infiltration of myeloid-derived suppressor cells (MDSCs) in tumors.In contrast, administration of IL-17 inhibited CD8 T cell infiltration and increased MDSCs in tumors.Further analysis indicated that IL-17 was required for the development and tumor-promoting activity ofMDSCs in tumor-bearing mice. These data demonstrate that IL-17-mediated responses promote tumordevelopment through the induction of tumor-promoting microenvironments at tumor sites.IL-17-mediated regulation of MDSCs is a primary mechanism for its tumor-promoting effects. The studyprovides novel insights into the role of IL-17 in tumor development and has major implications fortargeting IL-17 in treatment of tumors.", "metadata": {}}
+{"_id": "25732836", "title": "", "text": "Circulating tumor cells and [18F]fluorodeoxyglucose positron emission tomography/computedtomography for outcome prediction in metastatic breast cancer.PURPOSE Circulating tumor cells (CTCs)and [(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT)are two new promising tools for therapeutic monitoring. In this study, we compared the prognostic valueof CTC and FDG-PET/CT monitoring during systemic therapy for metastatic breast cancer (MBC).PATIENTS AND METHODS A retrospective analyses of 115 MBC patients who started a new line of therapyand who had CTC counts and FDG-PET/CT scans performed at baseline and at 9 to 12 weeks duringtherapy (midtherapy) was performed. Patients were categorized according to midtherapy CTC counts asfavorable (ie, < five CTCs/7.5 mL blood) or unfavorable (> or = five CTCs/7.5 mL blood) outcomes. CTCcounts and FDG-PET/CT response at midtherapy were compared, and univariate and multivariateanalyses were performed to identify factors associated with survival. RESULTS In 102 evaluable patients,the median overall survival time was 14 months (range, 1 to > 41 months). Midtherapy CTC levelscorrelated with FDG-PET/CT response in 68 (67%) of 102 evaluable patients. In univariate analysis,midtherapy CTC counts and FDG-PET/CT response predicted overall survival (P < .001 and P = .001,respectively). FDG-PET/CT predicted overall survival (P = .0086) in 31 (91%) of 34 discordant patientswho had fewer than five CTCs at midtherapy. Only midtherapy CTC levels remained significant in amultivariate analysis (P = .004). CONCLUSION Detection of five or more CTCs during therapeuticmonitoring can accurately predict prognosis in MBC beyond metabolic response. FDG-PET/CT deserves arole in patients who have fewer than five CTCs at midtherapy. Prospective trials should evaluate the mostsensitive and cost-effective modality for therapeutic monitoring in MBC.", "metadata": {}}
+{"_id": "25737507", "title": "", "text": "Phylogenetic analysis of Portuguese Feline Immunodeficiency Virus sequences reveals high geneticdiversity.Feline Immunodeficiency Virus (FIV) is a Lentivirus responsible for an immunodeficiency likedisease in domestic cats. Based on the genetic diversity of the V3-V5 region of env gene FIV is divided infive phylogenetic subtypes (A, B, C, D and E) with a world-wide distribution. To understand the subtypediversity of FIV in Portugal a serological survey was conducted during 1 year in the Veterinary FacultyHospital, Lisbon, Portugal to identify seropositive animals. Two viral genomic regions were amplified by anested PCR, sequenced and the phylogenetic relationships between 24 new Portuguese FIV sequencesand other previously published FIV isolates were assessed. The introduction of these sequences induced asubclustering in subtype B including most of the new Portuguese sequences. Moreover, a new clusteremerged, with two highly divergent new sequences that might represent a new subtype. The study ofthese new FIV isolates showed the presence in Portugal of a unique viral population subclustering withinsubtype B and of sequences clearly divergent from the five known subtypes, providing a contribution forthe understanding of FIV's genetic diversity.", "metadata": {}}
+{"_id": "25738896", "title": "", "text": "Aire deficiency promotes TRP-1-specific immune rejection of melanoma.The thymic transcription factorautoimmune regulator (Aire) prevents autoimmunity in part by promoting expression of tissue-specificself-antigens, which include many cancer antigens. For example, AIRE-deficient patients are predisposedto vitiligo, an autoimmune disease of melanocytes that is often triggered by efficacious immunotherapiesagainst melanoma. Therefore, we hypothesized that Aire deficiency in mice may elevate immuneresponses to cancer and provide insights into how such responses might be triggered. In this study, weshow that Aire deficiency decreases thymic expression of TRP-1 (TYRP1), which is a self-antigen inmelanocytes and a cancer antigen in melanomas. Aire deficiency resulted in defective negative selectionof TRP-1-specific T cells without affecting thymic numbers of regulatory T cells. Aire-deficient micedisplayed elevated T-cell immune responses that were associated with suppression of melanomaoutgrowth. Furthermore, transplantation of Aire-deficient thymic stroma was sufficient to confer moreeffective immune rejection of melanoma in an otherwise Aire wild-type host. Together, our work showedhow Aire deficiency can enhance immune responses against melanoma and how manipulatingTRP-1-specific T-cell negative selection may offer a logical strategy to enhance immune rejection ofmelanoma.", "metadata": {}}
+{"_id": "25742130", "title": "", "text": "Mass screening programmes and trends in cervical cancer in Finland and the Netherlands.With respect tocervical cancer management, Finland and the Netherlands are comparable in relevant characteristics,e.g., fertility rate, age-of-mother at first birth and a national screening programme for several years. Theaim of this study is to compare trends in incidence of and mortality from cervical cancer in Finland andthe Netherlands in relation to the introduction and intensity of the screening programmes. Therefore,incidence and mortality rates were calculated using the Cancer Registries of Finland and the Netherlands.Data on screening intensity were obtained from the Finnish Cancer Registry and the Dutch evaluationcentre at ErasmusMC-Rotterdam. Women aged 30-60 have been screened every 5 years, in Finland since1992 and in the Netherlands since 1996. Screening protocols for smear taking and referral to thegynaecologist are comparable. Incidence and mortality rates have declined more in Finland. In 2003,age-adjusted incidence and mortality in Finland were 4.0 and 0.9 and in the Netherlands 4.9 and 1.4 per100,000 woman-years, respectively. Excess smear use in the Netherlands was estimated to be 24 per1,000 women during a 5-year interval compared to 121 in Finland. The decline in mortality in Finlandseems to be almost completely related to the screening programme whereas in the Netherlands it wasinitially considered to be a natural decline. Differences in risk factors might also play a role: theNetherlands has higher population density and higher percentages of immigrants and (female) smokers.The greater excess smear use in Finland might also have affected incidence.", "metadata": {}}
+{"_id": "25742205", "title": "", "text": "Biochemical characterization of the Ran-RanBP1-RanGAP system: are RanBP proteins and the acidic tailof RanGAP required for the Ran-RanGAP GTPase reaction?RanBP type proteins have been reported toincrease the catalytic efficiency of the RanGAP-mediated GTPase reaction on Ran. Since the structure ofthe Ran-RanBP1-RanGAP complex showed RanBP1 to be located away from the active site, wereinvestigated the reaction using fluorescence spectroscopy under pre-steady-state conditions. We canshow that RanBP1 indeed does not influence the rate-limiting step of the reaction, which is the cleavageof GTP and/or the release of product P(i). It does, however, influence the dynamics of the Ran-RanGAPinteraction, its most dramatic effect being the 20-fold stimulation of the already very fast associationreaction such that it is under diffusion control (4.5 x 10(8) M(-1) s(-1)). Having established a valuablekinetic system for the interaction analysis, we also found, in contrast to previous findings, that the highlyconserved acidic C-terminal end of RanGAP is not required for the switch-off reaction. Rather, geneticexperiments in Saccharomyces cerevisiae demonstrate a profound effect of the acidic tail on microtubuleorganization during mitosis. We propose that the acidic tail of RanGAP is required for a process duringmitosis.", "metadata": {}}
+{"_id": "25747721", "title": "", "text": "Concomitant induction of CD4+ and CD8+ T cell responses in volunteers immunized with Salmonellaenterica serovar typhi strain CVD 908-htrA.Type 1 cell-mediated immunity might play an important rolein protection from typhoid fever. We evaluated whether immunization with Salmonella enterica serovarTyphi (S. Typhi) strain CVD 908-htrA (a Delta aroC Delta aroD Delta htrA mutant), a leading live oraltyphoid vaccine candidate, elicits specific CD4(+) and CD8(+) S. Typhi immune responses. Potent CTLresponses and IFN-gamma secretion by CD8(+) T cells were detected following immunization with CVD908-htrA in high (4.5 x 10(8) CFU) and low (5 x 10(7) CFU) dosages. S. Typhi-specific CTL were observedin six of eight vaccinees (four high and two low dose) after immunization. Mean increases in thefrequency of IFN-gamma spot-forming cells (SFC) in the presence of S. Typhi-infected targets were 221+/- 41 SFC/10(6) PBMC and 233 +/- 87 SFC/10(6) PBMC, in the high and low dose groups, respectively.Strong CD4(+) T cell responses were also observed. Increases in the IFN-gamma production to soluble S.Typhi flagella (STF) occurred in 82 and 38% of the volunteers who received the high and low doses,respectively. Robust correlations were observed between volunteers that responded with IFN-gamma SFCto stimulation with S. Typhi-infected cells and IFN-gamma released in response to stimulation with STFAgs (r = 0.822, p < 0.001) and between CTL and IFN-gamma production to STF (r = 0.818, p = 0.013).These data demonstrating the concomitant induction of both CD4- and CD8-mediated CMI are consistentwith a significant role for type 1 immunity in controlling typhoid infection and support the continuingevaluation of CVD 908-htrA as a typhoid vaccine candidate.", "metadata": {}}
+{"_id": "25748308", "title": "", "text": "The diverse functions of GAPDH: views from different subcellular compartments.Multiple roles forglyceraldehyde-3-phosphate dehydrogenase (GAPDH) have been recently appreciated. In addition to thecytoplasm where the majority of GAPDH is located under the basal condition, GAPDH is also found in theparticulate fractions, such as the nucleus, the mitochondria, and the small vesicular fractions. When cellsare exposed to various stressors, dynamic subcellular re-distribution of GAPDH occurs. Here we reviewthese multifunctional properties of GAPDH, especially linking them to its oligomerization, posttranslationalmodification, and subcellular localization. This includes mechanistic descriptions of how S-nitrosylation ofGAPDH under oxidative stress may lead to cell death/dysfunction via nuclear translocation of GAPDH,which is counteracted by a cytosolic GOSPEL. GAPDH is also involved in various diseases, especiallyneurodegenerative disorders and cancers. Therapeutic strategies to these conditions based on molecularunderstanding of GAPDH are discussed.", "metadata": {}}
+{"_id": "25761154", "title": "", "text": "Exercise-induced asthma: a practical guide to definitions, diagnosis, prevalence, andtreatment.Exercise-induced asthma is defined as an intermittent narrowing of the airways, demonstratedby a decrease in some measure of flow, that the patient experiences as wheezing, chest tightness,coughing, and difficulty breathing that is triggered by exercise. Exercise will trigger asthma in mostindividuals who have chronic asthma, as well as in some who do not otherwise have asthma. Definitivediagnosis requires demonstration of a drop in flow rate, typically > or = 13-15% for forced expiratoryvolume in one second (FEV1) and > or = 15-20% for peak expiratory flow rate (PEFR), after exercise,associated with symptoms. Prevalence data indicate that this disorder is very common in those whoparticipate in recreational sports as well as in highly competitive athletes, with at least 12-15% ofunselected athletes having positive exercise challenges. Treatment of exercise induced asthma involvesuse of nonpharmacological measures (such as the use of the refractory period after exercise andprewarming air) as well as use of medications (beta-agonists, cromolyn, and nedocromil). Withtreatment, those who suffer from exercise-induced asthma may be able to participate and compete at thehighest levels of performance.", "metadata": {}}
+{"_id": "25786167", "title": "", "text": "Effect of sample quality on the sensitivity of endoscopic biopsy for detecting gastric and duodenal lesionsin dogs and cats.BACKGROUND The quality of histopathology slides of endoscopic biopsies from differentlaboratories varies, but the effect of biopsy quality on outcome is unknown. HYPOTHESIS The ability todemonstrate a histologic lesion in the stomach or duodenum of a dog or cat is affected by the quality ofendoscopic biopsy samples submitted. More endoscopic samples are needed to find a lesion inpoor-quality tissue specimens. ANIMALS Tissues from 99 dogs and 51 cats were examined as clinicalcases at 8 veterinary institutions or practices in 5 countries. METHODS Histopathology slides fromsequential cases that underwent endoscopic biopsy were submitted by participating institutions. Qualityof the histologic section of tissue (inadequate, marginal, adequate), type of lesion (lymphangiectasia,crypt lesion, villus blunting, cellular infiltrate), and severity of lesion (normal, mild, moderate, severe)were determined. Sensitivity of different quality tissue samples for finding different lesions wasdetermined. RESULTS Fewer samples were required from dogs for diagnosis as the quality of the sampleimproved from inadequate to marginal to adequate. Duodenal lesions in cats displayed the same trendexcept for moderate duodenal infiltrates for which quality of tissue sample made no difference. Gastriclesions in dogs and mild gastric lesions in cats had the same trend, whereas the number of tissuesamples needed to diagnose moderately severe gastric lesions in cats was not affected by the quality oftissue sample. CONCLUSIONS AND CLINICAL IMPORTANCE The quality of endoscopically obtained tissuesamples has a profound effect on their sensitivity for identifying certain lesions, and there are differencesbetween biopsies of canine and feline tissues.", "metadata": {}}
+{"_id": "25787749", "title": "", "text": "G-quadruplexes significantly stimulate Pif1 helicase-catalyzed duplex DNA unwinding.The evolutionarilyconserved G-quadruplexes (G4s) are faithfully inherited and serve a variety of cellular functions such astelomere maintenance, gene regulation, DNA replication initiation, and epigenetic regulation. Differentfrom the Watson-Crick base-pairing found in duplex DNA, G4s are formed via Hoogsteen base pairing andare very stable and compact DNA structures. Failure of untangling them in the cell impedes DNA-basedtransactions and leads to genome instability. Cells have evolved highly specific helicases to resolve G4structures. We used a recombinant nuclear form of Saccharomyces cerevisiae Pif1 to characterizePif1-mediated DNA unwinding with a substrate mimicking an ongoing lagging strand synthesis stalled byG4s, which resembles a replication origin and a G4-structured flap in Okazaki fragment maturation. Wefind that the presence of G4 may greatly stimulate the Pif1 helicase to unwind duplex DNA. Furtherstudies reveal that this stimulation results from G4-enhanced Pif1 dimerization, which is required forduplex DNA unwinding. This finding provides new insights into the properties and functions of G4s. Wediscuss the observed activation phenomenon in relation to the possible regulatory role of G4s in the rapidrescue of the stalled lagging strand synthesis by helping the replicator recognize and activate thereplication origin as well as by quickly removing the G4-structured flap during Okazaki fragmentmaturation.", "metadata": {}}
+{"_id": "25789730", "title": "", "text": "Diffusion tensor imaging detects and differentiates axon and myelin degeneration in mouse optic nerveafter retinal ischemia.Both axon and myelin degeneration have significant impact on the long-termdisability of patients with white matter disorder. However, the clinical manifestations of the neurologicaldysfunction caused by white matter disorders are not sufficient to determine the origin of neurologicaldeficits. A noninvasive biological marker capable of detecting and differentiating axon and myelindegeneration would be a significant addition to currently available tools. Directional diffusivities derivedfrom diffusion tensor imaging (DTI) have been previously proposed by this group as potential biologicalmarkers to detect and differentiate axon and myelin degeneration. To further test the hypothesis thataxial (lambdaparallel) and radial (lambdaperpendicular) diffusivities reflect axon and myelin pathologies,respectively, the optic nerve was examined serially using DTI in a mouse model of retinal ischemia. Asignificant decrease of lambdaparallel, the putative DTI axonal marker, was observed 3 days afterischemia without concurrently detectable changes in lambdaperpendicular, the putative myelin marker.This result is consistent with histological findings of significant axonal degeneration with no detectabledemyelination at 3 days after ischemia. The elevation of lambdaperpendicular observed 5 days afterischemia is consistent with histological findings of myelin degeneration at this time. These results supportthe hypothesis that lambdaparallel and lambdaperpendicular hold promise as specific markers of axonaland myelin injury, respectively, and, further, that the coexistence of axonal and myelin degenerationdoes not confound this utility.", "metadata": {}}
+{"_id": "25799020", "title": "", "text": "Direct isolation and identification of promoters in the human genome.Transcriptional regulatory elementsplay essential roles in gene expression during animal development and cellular response to environmentalsignals, but our knowledge of these regions in the human genome is limited despite the availability of thecomplete genome sequence. Promoters mark the start of every transcript and are an important class ofregulatory elements. A large, complex protein structure known as the pre-initiation complex (PIC) isassembled on all active promoters, and the presence of these proteins distinguishes promoters fromother sequences in the genome. Using components of the PIC as tags, we isolated promoters directlyfrom human cells as protein-DNA complexes and identified the resulting DNA sequences using genomictiling microarrays. Our experiments in four human cell lines uncovered 252 PIC-binding sites in 44semirandomly selected human genomic regions comprising 1% (30 megabase pairs) of the humangenome. Nearly 72% of the identified fragments overlap or immediately flank 5' ends of known cDNAsequences, while the remainder is found in other genomic regions that likely harbor putative promoters ofunannotated transcripts. Indeed, molecular analysis of the RNA isolated from one cell line uncoveredtranscripts initiated from over half of the putative promoter fragments, and transient transfection assaysrevealed promoter activity for a significant proportion of fragments when they were fused to a luciferasereporter gene. These results demonstrate the specificity of a genome-wide analysis method for mappingtranscriptional regulatory elements and also indicate that a small, yet significant number of human genesremains to be discovered.", "metadata": {}}
+{"_id": "25806385", "title": "", "text": "Attempted suicide in Europe: rates, trends and sociodemographic characteristics of suicide attemptersduring the period 1989-1992. Results of the WHO/EURO Multicentre Study on Parasuicide.The WorldHealth Organization/EURO Multicentre Project on Parasuicide is part of the action to implement target 12of the WHO programme, \"Health for All by the Year 2000', for the European region. Sixteen centres in 13European countries are participating in the monitoring aspect of the project, in which trends in theepidemiology of suicide attempts are assessed. The highest average male age-standardized rate ofsuicide attempts was found for Helsinki, Finland (314/100,000), and the lowest rate (45/100,000) wasfor Guipuzcoa, Spain, representing a sevenfold difference. The highest average female age-standardizedrate was found for Cergy-Pontoise, France (462/100,000), and the lowest (69/100,000) again forGuipuzcoa, Spain. With only one exception (Helsinki), the person-based suicide attempt rates werehigher among women than among men. In the majority of centres, the highest person-based rates werefound in the younger age groups. The rates among people aged 55 years or over were generally thelowest. For the majority of the centres, the rates for individuals aged 15 years or over decreased between1989 and 1992. The methods used were primarily \"soft' (poisoning) or cutting. More than 50% of thesuicide attempters made more than one attempt, and nearly 20% of the second attempts were madewithin 12 months after the first attempt. Compared with the general population, suicide attempters moreoften belong to the social categories associated with social destabilization and poverty.", "metadata": {}}
+{"_id": "25811797", "title": "", "text": "Recurrent outbreaks of Salmonella Enteritidis infections in a Texas restaurant: phage type 4 arrives in theUnited States.In recent years infection caused by Salmonella serotype Enteritidis (SE) phage type 4 hasspread through Europe but has been uncommon in the USA. The first recognized outbreak of this strain inthe USA occurred in a Chinese restaurant in EI Paso, Texas, in April 1993; no source was identified. InSeptember 1993, a second outbreak caused by SE phage type 4 was associated with the samerestaurant. To determine the cause of the second outbreak, we compared food exposures of the 19patients with that of two control groups. Egg rolls were the only item significantly associated with illnessin both analyses (first control group: odds ratio [OR] 8.2, 95% confidence interval [CI] 2.3-31.6; secondcontrol group: OR 13.1, 95% CI 2.1-97.0). Retrospective analysis of the April outbreak also implicatedegg rolls (OR 32.4, 95% CI 9.1-126.6). Egg roll batter was made from pooled shell eggs and was left atroom temperature throughout the day. These two outbreaks of SE phage type 4 likely could have beenprevented by using pasteurized eggs and safe food preparation practices.", "metadata": {}}
+{"_id": "25813706", "title": "", "text": "Strand-specific mismatch correction in nuclear extracts of human and Drosophila melanogaster celllines.Nuclear extracts derived from HeLa and Drosophila melanogaster KC cell lines have been found tocorrect single base-base mispairs within open circular DNA heteroduplexes containing a strand-specific,site-specific incision located 808 base pairs from the mismatch. Correction in both extract systems isstrand specific, being highly biased to the incised DNA strand. Different mispairs within a homologous setof heteroduplexes were processed with different efficiencies (G.T greater than G.G approximately equal toA.C greater than C.C), and correction was accompanied by mismatch-dependent DNA synthesis localizedto the region spanning the mispair and the strand break, thus demonstrating that mismatch recognition isassociated with the repair reaction. Correction of each of these heteroduplexes was abolished byaphidicolin but was relatively insensitive to the presence of high concentrations of ddTTP, indicatingprobable involvement of alpha and/or delta class DNA polymerase(s). These findings suggest that highereukaryotic cells possess a general, strand-specific mismatch repair system analogous to the Escherichiacoli mutHLS and the Streptococcus pneumoniae hexAB pathways, systems that contribute in a major wayto the genetic stability of these bacterial species.", "metadata": {}}
+{"_id": "25816994", "title": "", "text": "Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGETstudy): a multicentre, randomised, double-blind, controlled trial.BACKGROUND Angiotensin receptorblockers (ARB) and angiotensin converting enzyme (ACE) inhibitors are known to reduce proteinuria.Their combination might be more effective than either treatment alone, but long-term data forcomparative changes in renal function are not available. We investigated the renal effects of ramipril (anACE inhibitor), telmisartan (an ARB), and their combination in patients aged 55 years or older withestablished atherosclerotic vascular disease or with diabetes with end-organ damage. METHODS The trialran from 2001 to 2007. After a 3-week run-in period, 25 620 participants were randomly assigned toramipril 10 mg a day (n=8576), telmisartan 80 mg a day (n=8542), or to a combination of both drugs(n=8502; median follow-up was 56 months), and renal function and proteinuria were measured. Theprimary renal outcome was a composite of dialysis, doubling of serum creatinine, and death. Analysis wasby intention to treat. This study is registered with ClinicalTrials.gov, number NCT00153101. FINDINGS784 patients permanently discontinued randomised therapy during the trial because of hypotensivesymptoms (406 on combination therapy, 149 on ramipril, and 229 on telmisartan). The number of eventsfor the composite primary outcome was similar for telmisartan (n=1147 [13.4%]) and ramipril (1150[13.5%]; hazard ratio [HR] 1.00, 95% CI 0.92-1.09), but was increased with combination therapy (1233[14.5%]; HR 1.09, 1.01-1.18, p=0.037). The secondary renal outcome, dialysis or doubling of serumcreatinine, was similar with telmisartan (189 [2.21%]) and ramipril (174 [2.03%]; HR 1.09, 0.89-1.34)and more frequent with combination therapy (212 [2.49%]: HR 1.24, 1.01-1.51, p=0.038). Estimatedglomerular filtration rate (eGFR) declined least with ramipril compared with telmisartan (-2.82 [SD 17.2]mL/min/1.73 m(2)vs -4.12 [17.4], p<0.0001) or combination therapy (-6.11 [17.9], p<0.0001). Theincrease in urinary albumin excretion was less with telmisartan (p=0.004) or with combination therapy(p=0.001) than with ramipril. INTERPRETATION In people at high vascular risk, telmisartan's effects onmajor renal outcomes are similar to ramipril. Although combination therapy reduces proteinuria to agreater extent than monotherapy, overall it worsens major renal outcomes.", "metadata": {}}
+{"_id": "25817686", "title": "", "text": "Hypothermic preservation up-regulates calpain expression and increases ubiquitination in culturedvascular endothelial cells: influence of dopamine pretreatment.BACKGROUND Prolonged hypothermia, asoccurs during solid organ transplantation, negatively influences transplantation outcome. Proteolysis isone of the deleterious events implicated in preservation injury of organ allografts. This strongly affectsgraft quality and hence immediate organ function. Since donor catecholamine treatment improvestransplantation outcome after renal transplantation, the present study was conducted to examine theinfluence of dopamine (DA) pretreatment on hypothermia induced proteolysis in endothelial cellssubjected to prolonged cold storage. MATERIALS AND METHODS Lactate dehydrogenase (LDH) assay,two-dimensional electrophoresis, ubiquitination analysis, intracellular calcium measurement, and Westernblot analysis were performed on human umbilical vein endothelial cells (HUVEC) subjected tohypothermic preservation or not. RESULTS HUVEC were highly susceptible to cold storage, which wasreflected by morphological changes, loss of viability, and by significant changes in cellular proteome. DApretreatment prevented cell death during cold storage. Western blot analysis demonstrated a timedependent up-regulation of calpain 1 and 2 during cold storage, which could be prevented by addition ofEDTA. DA pretreatment abolished autoproteolysis of calpain 1. Analysis of ubiquitination revealed asignificant increase in ubiquitinated conjugates after cold storage. This was not prevented by DApretreatment. Neither proteasome nor calpain inhibitors prevented cell death during cold storage.CONCLUSION In endothelial cells subjected to cold preservation, activation of the calpain pathway andthe ubiquitin proteasome system occur. Although DA pretreatment inhibits the former, calpain inhibitiondid not protect endothelial cells during cold storage. DA pretreatment might influence proteolysis, butproteolysis is not the major cause of endothelial cell death.", "metadata": {}}
+{"_id": "25821556", "title": "", "text": "The three 'C' s of chromosome conformation capture: controls, controls, controlsTranscription regulationin higher eukaryotes is controlled by regulatory elements such as enhancers that are recognized bytranscription factors. In many cases regulatory elements can be located at distances up to severalmegabases from their target genes. Recent evidence shows that long-range control of gene expressioncan be mediated through direct physical interactions between genes and these regulatory elements. Suchlooping interactions can be detected using the chromosome conformation capture (3C) methodology.Although 3C is experimentally straightforward, to draw meaningful conclusions one must carefully design3C experiments and implement the conscientious use of controls. The general guidelines presented hereshould help experimental design and minimize misinterpretation of 3C experiments.", "metadata": {}}
+{"_id": "25822299", "title": "", "text": "Effects of exercise training of 8 weeks and detraining on plasma levels of endothelium-derived factors,endothelin-1 and nitric oxide, in healthy young humans.Vascular endothelial cells produce nitric oxide(NO), which is a potent vasodilator substance and has been proposed as having antiatheroscleroticproperty. Vascular endothelial cells also produce endothelin-1 (ET-1), which is a potent vasoconstrictorpeptide and has potent proliferating activity on vascular smooth muscle cells. Therefore, ET-1 has beenimplicated in the progression of atheromatous vascular disease. Because exercise training has beenreported to produce an alteration in the function of vascular endothelial cells in animals, we hypothesizedthat exercise training influences the production of NO and ET-1 in humans. The purpose of the presentstudy was to examine whether chronic exercise could influence the plasma levels of NO (measured as thestable end product of NO, i.e., nitrite/nitrate [NOx]) and ET-1 in humans. Eight healthy young subjects(20.3 +/- 0.5 yr old) participated in the study and exercised by cycling on a leg ergometer (70% VO2maxfor 1 hour, 3-4 days/week) for 8 weeks. Venous plasma concentrations of NOx and ET-1 were measuredbefore and after (immediately before the end of 8-week exercise training) the exercise training, and alsoafter the 4th and 8th week after the cessation of training. The VO2max significantly increased afterexercise training. After the exercise training, the plasma concentration of NOx significantly increased(30.69 +/- 3.20 vs. 48.64 +/- 8.16 micromol/L, p < 0.05), and the plasma concentration of ET-1significantly decreased (1.65 +/- 0.14 vs. 1.23 +/- 0.12 pg/mL, p < 0.05). The increase in NOx level andthe decrease in ET-1 level lasted to the 4th week after the cessation of exercise training and these levels(levels of NOx and ET-1) returned to the basal levels (the levels before the exercise training) in the 8thweek after the cessation of exercise training. There was a significant negative correlation between plasmaNOx concentration and plasma ET-1 concentration. The present study suggests that chronic exercisecauses an increase in production of NO and a decrease in production of ET-1 in humans, which mayproduce beneficial effects (i.e., vasodilative and antiatherosclerotic) on the cardiovascular system.", "metadata": {}}
+{"_id": "25827024", "title": "", "text": "Neuron-specific expression of CuZnSOD prevents the loss of muscle mass and function that occurs inhomozygous CuZnSOD-knockout mice.Deletion of copper-zinc superoxide dismutase (CuZnSOD) inSod1(-/-) mice leads to accelerated loss of muscle mass and force during aging, but the losses do notoccur with muscle-specific deletion of CuZnSOD. To determine the role of motor neurons in the muscledecline, we generated transgenic Sod1(-/-) mice in which CuZnSOD was expressed under control of thesynapsin 1 promoter (SynTgSod1(-/-) mice). SynTgSod1(-/-) mice expressed CuZnSOD in brain, spinalcord, and peripheral nerve, but not in other tissues. Sciatic nerve CuZnSOD content in SynTgSod1(-/-)mice was ~20% that of control mice, but no reduction in muscle mass or isometric force was observed inSynTgSod1(-/-) mice compared with control animals, whereas muscles of age-matched Sod1(-/-) micedisplayed 30-40% reductions in mass and force. In addition, increased oxidative damage and adaptationsin stress responses observed in muscles of Sod1(-/-) mice were absent in SynTgSod1(-/-) mice, anddegeneration of neuromuscular junction (NMJ) structure and function occurred in Sod1(-/-) mice but notin SynTgSod1(-/-) mice. Our data demonstrate that specific CuZnSOD expression in neurons is sufficientto preserve NMJ and skeletal muscle structure and function in Sod1(-/-) mice and suggest that redoxhomeostasis in motor neurons plays a key role in initiating sarcopenia during aging.", "metadata": {}}
+{"_id": "25830701", "title": "", "text": "A developmental transition in definitive erythropoiesis: erythropoietin expression is sequentially regulatedby retinoic acid receptors and HNF4.The cytokine erythropoietin (Epo) promotes erythropoietic progenitorcell proliferation and is required for erythropoietic differentiation. We have found that the Epo gene is adirect transcriptional target gene of retinoic acid signaling during early erythropoiesis (prior to embryonicday E12.5) in the fetal liver. Mouse embryos lacking the retinoic acid receptor gene RXR alpha have amorphological and histological phenotype that is comparable with embryos in which the Epo gene itselfhas been mutated, and flow cytometric analysis indicates that RXR alpha-deficient embryos are deficientin erythroid differentiation. Epo mRNA levels are reduced substantially in the fetal livers of RXR alpha(-/-)embryos at E10.25 and E11.25, and genetic analysis shows that the RXR alpha and Epo genes arecoupled in the same pathway. We furthermore show that the Epo gene is retinoic acid inducible inembryos, and that the Epo gene enhancer contains a DR2 sequence that represents a retinoic acidreceptor-binding site and a retinoic acid receptor transcriptional response element. However, unlikeEpo-deficient embryos that die from anemia, the erythropoietic deficiency in RXR alpha(-/-) embryos istransient; Epo mRNA is expressed at normal levels by E12.5, and erythropoiesis and liver morphology arenormal by E14.5. We show that HNF4, like RXR alpha a member of the nuclear receptor family, isabundantly expressed in fetal liver hepatocytes, and is competitive with retinoic acid receptors foroccupancy of the Epo gene enhancer DR2 element. We propose that Epo expression is regulated duringthe E9.5--E11.5 phase of fetal liver erythropoiesis by RXR alpha and retinoic acid, and that expressionthen becomes dominated by HNF4 activity from E11.5 onward. This transition may be responsible forswitching regulation of Epo expression from retinoic acid control to hypoxic control, as is foundthroughout the remainder of life.", "metadata": {}}
+{"_id": "25832301", "title": "", "text": "Tetraspanin 7 (TSPAN7) expression is upregulated in multiple myeloma patients and inhibits myelomatumour development in vivo.BACKGROUND Increased expression of the tetraspanin TSPAN7 has beenobserved in a number of cancers; however, it is unclear how TSPAN7 plays a role in cancer progression.METHODS We investigated the expression of TSPAN7 in the haematological malignancy multiple myleoma(MM) and assessed the consequences of TSPAN7 expression in the adhesion, migration and growth of MMplasma cells (PC) in vitro and in bone marrow (BM) homing and tumour growth in vivo. Finally, wecharacterised the association of TSPAN7 with cell surface partner molecules in vitro. RESULTS TSPAN7was found to be highly expressed at the RNA and protein level in CD138(+) MM PC from approximately50% of MM patients. TSPAN7 overexpression in the murine myeloma cell line 5TGM1 significantly reducedtumour burden in 5TGM1/KaLwRij mice 4 weeks after intravenous adminstration of 5TGM1 cells. WhileTSPAN7 overexpression did not affect cell proliferation in vitro, TSPAN7 increased 5TGM1 cell adhesion toBM stromal cells and transendothelial migration. In addition, TSPAN7 was found to associate with themolecular chaperone calnexin on the cell surface. CONCLUSION These results suggest that elevatedTSPAN7 may be associated with better outcomes for up to 50% of MM patients.", "metadata": {}}
+{"_id": "25837950", "title": "", "text": "Association of body mass index with outcomes in patients with CKD.Obesity is associated with highermortality in the general population, but this association is reversed in patients on dialysis. The nature ofthe relationship of obesity with adverse clinical outcomes in nondialysis-dependent CKD and the putativeinteraction of the severity of disease with this association are unclear. We analyzed data from a nationallyrepresentative cohort of 453,946 United States veterans with eGFR<60 ml/min per 1.73 m(2). Theassociations of body mass index categories (<20, 20 to <25, 25 to <30, 30 to <35, 35 to <40, 40 to<45, 45 to <50, and ≥50 kg/m(2)) with all-cause mortality and disease progression (using multipledefinitions, including incidence of ESRD, doubling of serum creatinine, and the slopes of eGFR) wereexamined in Cox proportional hazards models and logistic regression models. Multivariable adjustmentswere made for age, race, comorbidities and medications, and baseline eGFR. Body mass index showed arelatively consistent U-shaped association with clinical outcomes, with the best outcomes observed inoverweight and mildly obese patients. Body mass index levels <25 kg/m(2) were associated with worseoutcomes in all patients, independent of severity of CKD. Body mass index levels ≥35 kg/m(2) wereassociated with worse outcomes in patients with earlier stages of CKD, but this association wasattenuated in those patients with eGFR<30 ml/min per 1.73 m(2). Thus, until clinical trials establish theideal body mass index, a cautious approach to weight management is warranted in this patientpopulation.", "metadata": {}}
+{"_id": "25838286", "title": "", "text": "WRN, the protein deficient in Werner syndrome, plays a critical structural role in optimizing DNArepair.Werner syndrome (WS) predisposes patients to cancer and premature aging, owing to mutations inWRN. The WRN protein is a RECQ-like helicase and is thought to participate in DNA double-strand break(DSB) repair by non-homologous end joining (NHEJ) or homologous recombination (HR). It has beenpreviously shown that non-homologous DNA ends develop extensive deletions during repair in WS cells,and that this WS phenotype was complemented by wild-type (wt) WRN. WRN possesses both 3' --> 5'exonuclease and 3' --> 5' helicase activities. To determine the relative contributions of each of thesedistinct enzymatic activities to DSB repair, we examined NHEJ and HR in WS cells (WRN-/-)complemented with either wtWRN, exonuclease-defective WRN (E-), helicase-defective WRN (H-) orexonuclease/helicase-defective WRN (E-H-). The single E-and H- mutants each partially complementedthe NHEJ abnormality of WRN-/- cells. Strikingly, the E-H- double mutant complemented the WSdeficiency nearly as efficiently as did wtWRN. Similarly, the double mutant complemented the moderateHR deficiency of WS cells nearly as well as did wtWRN, whereas the E- and H- single mutants increasedHR to levels higher than those restored by either E-H- or wtWRN. These results suggest that balancedexonuclease and helicase activities of WRN are required for optimal HR. Moreover, WRN appears to play astructural role, independent of its enzymatic activities, in optimizing HR and efficient NHEJ repair. Anotherhuman RECQ helicase, BLM, suppressed HR but had little or no effect on NHEJ, suggesting thatmammalian RECQ helicases have distinct functions that can finely regulate recombination events.", "metadata": {}}
+{"_id": "25842866", "title": "", "text": "In vitro generated antibodies specific for telomeric guanine-quadruplex DNA react with Stylonychialemnae macronuclei.Most eukaryotic telomeres contain a repeating motif with stretches of guanineresidues that form a 3'-terminal overhang extending beyond the telomeric duplex region. The telomericrepeat of hypotrichous ciliates, d(T(4)G(4)), forms a 16-nucleotide 3'-overhang. Such sequences canadopt parallel-stranded as well as antiparallel-stranded quadruplex conformations in vitro. Although it hasbeen proposed that guanine-quadruplex conformations may have important cellular roles includingtelomere function, recombination, and transcription, evidence for the existence of this DNA structure invivo has been elusive to date. We have generated high-affinity single-chain antibody fragment (scFv)probes for the guanine-quadruplex formed by the Stylonychia telomeric repeat, by ribosome display fromthe Human Combinatorial Antibody Library. Of the scFvs selected, one (Sty3) had an affinity of K(d) =125 pM for the parallel-stranded guanine-quadruplex and could discriminate with at least 1,000-foldspecificity between parallel or antiparallel quadruplex conformations formed by the same sequence motif.A second scFv (Sty49) bound both the parallel and antiparallel quadruplex with similar (K(d) = 3--5 nM)affinity. Indirect immunofluorescence studies show that Sty49 reacts specifically with the macronucleusbut not the micronucleus of Stylonychia lemnae. The replication band, the region where replication andtelomere elongation take place, was also not stained, suggesting that the guanine-quadruplex is resolvedduring replication. Our results provide experimental evidence that the telomeres of Stylonychiamacronuclei adopt in vivo a guanine-quadruplex structure, indicating that this structure may have animportant role for telomere functioning.", "metadata": {}}
+{"_id": "25853741", "title": "", "text": "Incidence of skin cancer after renal transplantation in The Netherlands.The incidence of squamous cellcarcinoma (SCC) and basal cell carcinoma (BCC) was analyzed separately in all 764 patients who receiveda renal allograft between 1966 and 1988 at the Leiden University Hospital. The mean follow-up periodwas 8.7 posttransplant years (range 1-21 years). During this time period 176 skin cancers werediagnosed in 47 patients. The overall risk to develop a first tumor increased from 10% after 10 years to40% after 20 years of graft survival. The overall incidence of SCC was 250 times higher and that of BCC10 times higher when compared with the general Dutch population. Moreover the localization of SCCs andBCCs differed considerably. Solar radiation is thought to be an important risk factor for the developmentof skin cancer. However, the occurrence of skin cancer in long-term graft survivors forms also a majorproblem in a country with a higher geographical latitude and a moderate amount of sun-exposure, suchas the Netherlands.", "metadata": {}}
+{"_id": "25858295", "title": "", "text": "Myogenic and morphogenetic defects in the heart tubes of murine embryos lacking the homeo box geneNkx2-5.The murine homeo box gene Nkx2-5 is expressed in precardiac mesoderm and in themyocardium of embryonic and fetal hearts. Targeted interruption of Nkx2-5 resulted in abnormal heartmorphogenesis, growth retardation and embryonic lethality at approximately 9-10 days postcoitum(p.c.). Heart tube formation occurred normally in mutant embryos, but looping morphogenesis, a criticaldeterminant of heart form, was not initiated at the linear heart tube stage (8.25-8.5 days p.c.).Commitment to the cardiac muscle lineage, expression of most myofilament genes and myofibrillogenesiswere not compromised. However, the myosin light-chain 2V gene (MLC2V) was not expressed in mutanthearts nor in mutant ES cell-derived cardiocytes. MLC2V expression normally occurs only in ventricularcells and is the earliest known molecular marker of ventricular differentiation. The regional expression inmutant hearts of two other ventricular markers, myosin heavy-chain beta and cyclin D2, indicated thatnot all ventricle-specific gene expression is dependent on Nkx2-5. The data demonstrate that Nkx2-5 isessential for normal heart morphogenesis, myogenesis, and function. Furthermore, this gene is acomponent of a genetic pathway required for myogenic specialization of the ventricles.", "metadata": {}}
+{"_id": "25878014", "title": "", "text": "Hygiene hypothesis in inflammatory bowel disease: a critical review of the literature.The hygienehypothesis is thought to be a significant contributor to the growing incidence of inflammatory boweldisease (IBD) around the world, although the evidence for specific factors that underlie the hygienehypothesis in IBD is unclear. We aimed to systematically review the literature to determine whichhygiene-related factors are associated with the development of IBD. Publications identified from a broadbased MEDLINE and Current Contents search between 1966 and 2007 on key terms relevant to the'hygiene hypothesis' and IBD including H pylori exposure, helminths, cold chain hypothesis, measlesinfection and vaccination, antibiotic use, breastfeeding, family size, sibship, urban upbringing, day careattendance and domestic hygiene were reviewed. The literature suggests that the hygiene hypothesis andits association with decreased microbial exposure in childhood probably plays an important role in thedevelopment of IBD, although the strength of the supporting data for each of the factors variesconsiderably. The most promising factors that may potentially be associated with development of IBDinclude H pylori exposure, helminths, breastfeeding and sibship. However, the vast majority of studies inthis area are plagued by serious methodological shortcomings, particularly the reliance on retrospectiverecall of information making it difficult to truly ascertain the importance of a 'hygiene hypothesis' in IBD.The 'hygiene hypothesis' in IBD is an important area of research that may give clues to the aetiology ofthis disease. Directions for future research are recommended.", "metadata": {}}
+{"_id": "25886725", "title": "", "text": "Are dual eligibles admitted to poorer quality skilled nursing facilities?BACKGROUND Dual eligibles,persons who qualify for both Medicare and Medicaid coverage, often receive poorer quality care relativeto other Medicare beneficiaries. OBJECTIVES To determine whether dual eligibles are discharged to lowerquality post-acute skilled nursing facilities (SNFs) compared with Medicare-only beneficiaries. RESEARCHDESIGN Following the random utility maximization model, we specified a discharge function using aconditional logit model and tested how this discharge rule varied by dual-eligibility status. SUBJECTS Atotal of 692,875 Medicare fee-for-service patients (22% duals) who were discharged for Medicare paidSNF care between July 2004 and June 2005. MEASURES Medicare enrollment and the Medicaid AnalyticExtract files were used to determine dual eligibility. The proportion of Medicaid patients and nursing staffcharacteristics provided measures of SNF quality. RESULTS Duals are more likely to be discharged toSNFs with a higher share of Medicaid patients and fewer nurses. These results are robust to estimationwith an alternative subsample of patients based on primary diagnoses, propensity of being dual eligible,and likelihood of remaining in the nursing home. CONCLUSIONS Disparities exist in access to quality SNFcare for duals. Strategies to improve discharge planning processes are required to redirect patients tohigher quality providers, regardless of Medicaid eligibility.", "metadata": {}}
+{"_id": "25895285", "title": "", "text": "Quantitative phosphoproteomic analysis of acquired cancer drug resistance to pazopanib anddasatinibAcquired drug resistance impacts the majority of patients being treated with tyrosine kinaseinhibitors (TKIs) and remains a key challenge in modern anti-cancer therapy. The lack of clinicallyeffective therapies to overcome resistance represents an unmet need. Understanding the signalling thatdrives drug resistance will facilitate the development of new salvage therapies to treat patients withsecondary TKI resistance. In this study, we utilise mass spectrometry to characterise the globalphosphoproteomic alterations that accompany the acquisition of resistance to two FDA-approved TKIs,pazopanib and dasatinib, in the A204 rhabdoid tumour cell line. Our analysis finds that only 6% and 9.7%of the quantified phosphoproteome is altered upon the acquisition of pazopanib and dasatinib resistance,respectively. Pazopanib resistant cells display elevated phosphorylation in cytoskeletal regulatorypathways while dasatinib resistant cells show an upregulation of the insulin receptor/IGF-1R signallingpathway. Drug response profiling rediscovers several previously reported vulnerabilities associated withpazopanib and dasatinib resistance and identifies a new dependency to the second generation HSP90inhibitor NVP-AUY-922. This study provides a useful resource detailing the candidate signallingdeterminants of acquired TKI resistance; and reveals a therapeutic approach of inhibiting HSP90 functionas a means of salvage therapy to overcome pazopanib and dasatinib resistance. SIGNIFICANCEPazopanib and dasatinib are tyrosine kinase inhibitors (TKIs) approved for the treatment of multiplecancer types. Patients who are treated with these drugs are prone to the development of drug resistanceand consequently tumour relapse. Here we use quantitative phosphoproteomics to characterise thesignalling pathways which are enriched in cells that have acquired resistance to these two drugs.Furthermore, targeted drug screens were used to identify salvage therapies capable of overcomingpazopanib and dasatinib resistance. This data advances our understanding of the mechanisms of TKIresistance and highlights candidate targets for cancer therapy.", "metadata": {}}
+{"_id": "25897733", "title": "", "text": "Pandemic H1N12009 influenza and HIV: a review of natural history, management and vaccineimmunogenicity.PURPOSE OF REVIEW The 2009 pandemic HIN1 influenza strain (H1N12009) producedmore severe disease and increased risk for mortality. As an at-risk population for more severe influenzaillness, particular concern regarding HIV patients triggered a focused effort to evaluate disease burdenand vaccine efficacy in these populations. RECENT FINDINGS As with other immune-compromisedindividuals, most HIV-infected individuals recovered without major consequence. Although HIV infectionwas assumed to be a risk factor for more severe disease and death, the published literature does notindicate this to be so. Neuraminadase inhibitors were well tolerated by this population and there was noevidence of clinically significant pharmacokinetic interactions with antiretroviral therapy. Immunogenicitywas increased with H1N12009 vaccine compared to the historical results of nonpandemic vaccines andoptimized by the use of adjuvants. Booster dosing was also of benefit. H1N12009 vaccine was generallywell tolerated without evidence of detrimental effect on HIV status. SUMMARY The worse case scenariowas not realized for H1N12009 in the general population or in those with HIV. Immunization withadjuvant represents a key measure to protect this population from H1N12009 and other future novelinfluenza strains.", "metadata": {}}
+{"_id": "25900857", "title": "", "text": "Population genomics of the honey bee reveals strong signatures of positive selection on workertraits.Most theories used to explain the evolution of eusociality rest upon two key assumptions: mutationsaffecting the phenotype of sterile workers evolve by positive selection if the resulting traits benefit fertilekin, and that worker traits provide the primary mechanism allowing social insects to adapt to theirenvironment. Despite the common view that positive selection drives phenotypic evolution of workers, weknow very little about the prevalence of positive selection acting on the genomes of eusocial insects. Wemapped the footprints of positive selection in Apis mellifera through analysis of 40 individual genomes,allowing us to identify thousands of genes and regulatory sequences with signatures of adaptive evolutionover multiple timescales. We found Apoidea- and Apis-specific genes to be enriched for signatures ofpositive selection, indicating that novel genes play a disproportionately large role in adaptive evolution ofeusocial insects. Worker-biased proteins have higher signatures of adaptive evolution relative toqueen-biased proteins, supporting the view that worker traits are key to adaptation. We also found genesregulating worker division of labor to be enriched for signs of positive selection. Finally, genes associatedwith worker behavior based on analysis of brain gene expression were highly enriched for adaptiveprotein and cis-regulatory evolution. Our study highlights the significant contribution of workerphenotypes to adaptive evolution in social insects, and provides a wealth of knowledge on the loci thatinfluence fitness in honey bees.", "metadata": {}}
+{"_id": "25901598", "title": "", "text": "An acetylation switch in p53 mediates holo-TFIID recruitment.Posttranslational modifications mediateimportant regulatory functions in biology. The acetylation of the p53 transcription factor, for example,promotes transcriptional activation of target genes including p21. Here we show that the acetylation oftwo lysine residues in p53 promotes recruitment of the TFIID subunit TAF1 to the p21 promoter throughits bromodomains. UV irradiation of cells diacetylates p53 at lysines 373 and 382, which in turn recruitsTAF1 to a distal p53-binding site on the p21 promoter prior to looping to the core promoter. Disruption ofacetyl-p53/bromodomain interaction inhibits TAF1 recruitment to both the distal p53-binding site and thecore promoter. Further, the TFIID subunits TAF4, TAF5, and TBP are detected on the core promoter priorto TAF1, suggesting that, upon DNA damage, distinct subunits of TFIID may be recruited separately tothe p21 promoter and that the transcriptional activation depends on posttranslational modification of thep53 transcription factor.", "metadata": {}}
+{"_id": "25915873", "title": "", "text": "Dasatinib inhibits both osteoclast activation and prostate cancer PC-3-cell-induced osteoclastformation.PURPOSE Therapies to target prostate cancer bone metastases have only limited effects. Newtreatments are focused on the interaction between cancer cells, bone marrow cells and the bone matrix.Osteoclasts play an important role in the development of bone tumors caused by prostate cancer. SinceSrc kinase has been shown to be necessary for osteoclast function, we hypothesized that dasatinib, a Srcfamily kinase inhibitor, would reduce osteoclast activity and prostate cancer (PC-3) cell-inducedosteoclast formation. RESULTS Dasatinib inhibited RANKL-induced osteoclast differentiation of bonemarrow-derived monocytes with an EC(50) of 7.5 nM. PC-3 cells, a human prostate cancer cell line, wereable to differentiate RAW 264.7 cells, a murine monocytic cell line, into osteoclasts, and dasatinibinhibited this differentiation. In addition, conditioned medium from PC-3 cell cultures was able todifferentiate RAW 264.7 cells into osteoclasts and this too, was inhibited by dasatinib. Even the lowestconcentration of dasatinib, 1.25 nmol, inhibited osteoclast differentiation by 29%. Moreover, dasatinibinhibited osteoclast activity by 58% as measured by collagen 1 release. EXPERIMENTAL DESIGN Weperformed in vitro experiments utilizing the Src family kinase inhibitor dasatinib to target osteoclastactivation as a means of inhibiting prostate cancer bone metastases. CONCLUSION Dasatinib inhibitsosteoclast differentiation of mouse primary bone marrow-derived monocytes and PC-3 cell-inducedosteoclast differentiation. Dasatinib also inhibits osteoclast degradation activity. Inhibiting osteoclastdifferentiation and activity may be an effective targeted therapy in patients with prostate cancer bonemetastases.", "metadata": {}}
+{"_id": "25928548", "title": "", "text": "BMP receptor ALK3 controls collecting system development.The molecular signals that regulate growthand branching of the ureteric bud during formation of the renal collecting system are largely undefined.Members of the bone morphogenetic protein (BMP) family signal through the type I BMP receptor ALK3 toinhibit ureteric bud and collecting duct cell morphogenesis in vitro. We investigated the function of theBMP signaling pathway in vivo by generating a murine model of ALK3 deficiency restricted to the uretericbud lineage (Alk3(UB-/-) mice). At the onset of branching morphogenesis, Alk3(UB-/-) kidneys arecharacterized by an abnormal primary (1 degrees ) ureteric bud branch pattern and an increased numberof ureteric bud branches. However, during later stages of renal development, Alk3(UB-/-) kidneys havefewer ureteric bud branches and collecting ducts than wild-type kidneys. Postnatal Alk3(UB-/-) miceexhibit a dysplastic renal phenotype characterized by hypoplasia of the renal medulla, a decreasednumber of medullary collecting ducts, and abnormal expression of beta-catenin and c-MYC in medullarytubules. In summary, normal kidney development requires ALK3-dependent BMP signaling, whichcontrols ureteric bud branching.", "metadata": {}}
+{"_id": "25937484", "title": "", "text": "Increased release of ferritin and iron by iron-loaded alveolar macrophages in cigarette smokers.The lowerrespiratory tract of cigarette smokers contains an increased amount of iron that is predominantlysequestered within alveolar macrophages (AM), but is also present in alveolar epithelial fluid.Extracellular ferritin-bound iron could potentially be released by reductants present in cigarette smokeand catalyze generation of highly reactive hydroxyl radicals capable of causing oxidant injury. Todetermine whether AM are a source of alveolar extracellular ferritin and iron, we assessed in vitro releaseof iron, ferritin, and transferrin by AM recovered by bronchoalveolar lavage (BAL) of 27 healthy subjectsincluding nine nonsmokers (NS), nine light smokers (LS), and nine heavy smokers (HS). Release of ironin vitro over 20 h was increased in AM recovered from LS (2.24 +/- 0.21 nmol/10(6) AM/20 h, p < 0.001)and HS (3.11 +/- 0.32 nmol/10(6) AM, p < 0.001) compared with NS (1.28 +/- 0.08 nmol/10(6) AM).Release of ferritin in vitro over 20 h was also increased in AM recovered from LS (71 +/- 24 ng/10(6) AM,p < 0.05) and HS (176 +/- 35 ng/10(6), p < 0.001) compared with NS (18 +/- 3 ng/10(6) AM). AMrecovered from 12 smokers (8 HS, 4 LS) contained greater than 10 nmol of iron per 10(6) cells. Theseiron-loaded AM released a greater percentage of cell ferritin stores in vitro over 4 h (8.4% +/- 1.1, p <0.01) than did AM from NS (3.2% +/- 0.6). Release of lactate dehydrogenase (LDH) over 4 h wassubstantially less (2.9% +/- 0.3, p < 0.001) than ferritin release.(ABSTRACT TRUNCATED AT 250WORDS)", "metadata": {}}
+{"_id": "25938221", "title": "", "text": "The spectrum of retinopathy in adults with Plasmodium falciparum malariaA specific retinopathy has beendescribed in African children with cerebral malaria, but in adults this has not been extensively studied.Since the structure and function of the retinal vasculature greatly resembles the cerebral vasculature,study of retinal changes can reveal insights into the pathophysiology of cerebral malaria. A detailedobservational study of malarial retinopathy in Bangladeshi adults was performed using high-definitionportable retinal photography. Retinopathy was present in 17/27 adults (63%) with severe malaria and14/20 adults (70%) with cerebral malaria. Moderate or severe retinopathy was more frequent in cerebralmalaria (11/20, 55%) than in uncomplicated malaria (3/15, 20%; P=0.039), bacterial sepsis (0/5, 0%;P=0.038) or healthy controls (0/18, 0%; P<0.001). The spectrum of malarial retinopathy was similar tothat previously described in African children, but no vessel discolouration was observed. The severity ofretinal whitening correlated with admission venous plasma lactate (P=0.046), suggesting that retinalischaemia represents systemic ischaemia. In conclusion, retinal changes related to microvascularobstruction were common in adults with severe falciparum malaria and correlated with disease severityand coma, suggesting that a compromised microcirculation has important pathophysiological significancein severe and cerebral malaria. Portable retinal photography has potential as a valuable tool to studymalarial retinopathy.", "metadata": {}}
+{"_id": "25938251", "title": "", "text": "Prospective randomized open blinded end-point (PROBE) study. A novel design for intervention trials.Prospective Randomized Open Blinded End-Point.A novel design for intervention studies is presented, theso called PROBE study (Prospective Randomized Open, Blinded End-point). This design is compared to theclassical double-blind design. Among the advantages of the PROBE design are lower cost and greatersimilarity to standard clinical practice, which should make the results more easily applicable in routinemedical care. Since end-points are evaluated by a blinded end-point committee it is obvious that thereshould be no difference between the two types of trials in this regard.", "metadata": {}}
+{"_id": "25942757", "title": "", "text": "PSGL-1 function in immunity and steady state homeostasis.The substantial importance of P-selectinglycoprotein ligand 1 (PSGL-1) in leukocyte trafficking has continued to emerge beyond its initialidentification as a selectin ligand. PSGL-1 seemed to be a relatively simple molecule with an extracellularmucin domain extended as a flexible rod, teleologically consistent with its primary role in tetheringleukocytes to endothelial selectins. The rolling interaction between leukocyte and endothelium mediatedby this selectin-PSGL-1 interaction requires branched O-glycan extensions on specific PSGL-1 amino acidresidues. In some cells, such as neutrophils, the glycosyltransferases involved in formation of theO-glycans are constitutively expressed, while in other cells, such as T cells, they are expressed only afterappropriate activation. Thus, PSGL-1 supports leukocyte recruitment in both innate and adaptive arms ofthe immune response. A complex array of amino acids within the selectins engage multiple sugarresidues of the branched O-glycans on PSGL-1 and provide the molecular interactions responsible for thevelcro-like catch bonds that support leukocyte rolling. Such binding of PSGL-1 can also induce signalingevents that influence cell phenotype and function. Scrutiny of PSGL-1 has revealed a betterunderstanding of how it performs as a selectin ligand and yielded unexpected insights that extend itsscope from supporting leukocyte rolling in inflammatory settings to homeostasis including stem cellhoming to the thymus and mature T-cell homing to secondary lymphoid organs. PSGL-1 has been foundto bind homeostatic chemokines CCL19 and CCL21 and to support the chemotactic response to thesechemokines. Surprisingly, the O-glycan modifications of PSGL-1 that support rolling mediated by selectinsin inflammatory conditions interfere with PSGL-1 binding to homeostatic chemokines and thereby limitresponsiveness to the chemotactic cues used in steady state T-cell traffic. The multi-level influence ofPSGL-1 on cell traffic in both inflammatory and steady state settings is therefore substantially determinedby the orchestrated addition of O-glycans. However, central as specific O-glycosylation is to PSGL-1function, in vivo regulation of PSGL-1 glycosylation in T cells remains poorly understood. It is our purposeherein to review what is known, and not known, of PSGL-1 glycosylation and to update understanding ofPSGL-1 functional scope.", "metadata": {}}
+{"_id": "25946292", "title": "", "text": "Ligand binding determines whether CD46 is internalized by clathrin-coated pits or macropinocytosis.CD46is a ubiquitous human cell surface receptor for the complement components C3b and C4b and for variouspathogens, including the measles virus and human herpes virus 6. Ligand binding to CD46 affects (i)protection of autologous cells from complement attack by breakdown of complement components, (ii)intracellular signals that affect the regulation of immune cell function, (iii) antigen presentation, and (iv)down-regulation of cell surface CD46. Recent evidence indicates that CD46 signaling can link innate andacquired immune function. The molecular mechanisms for these processes and the importance ofintracellular trafficking of the receptor have not yet been elucidated. We demonstrate here that, innonlymphoid cells, CD46 is constitutively internalized via clathrin-coated pits, traffics to multivesicularbodies, and is recycled to the cell surface. However, cross-linking of CD46 at the cell surface, by eithermultivalent antibody or by measles virus, induces pseudopodia that engulf the ligand in a process similarto macropinocytosis, and leads to the degradation of cell surface CD46. Thus, we have elucidated twopathways for CD46 internalization, which are regulated by the valence of cross-linking of CD46 and whichutilize either clathrin-coated pits or pseudopodial extension. This has important implications for CD46signaling, antigen presentation, CD46 down-regulation, and engulfment of pathogens.", "metadata": {}}
+{"_id": "25950264", "title": "", "text": "A three-dimensional cell biology model of human hepatocellular carcinoma in vitroWe established an invitro 3-D model of metastatic hepatocellular carcinoma (HCC) by culturing MHCC97H cells on molecularscaffolds within a rotating wall vessel bioreactor. Morphological and biochemical analyses revealed thatthe 3-D HCC model mirrored many clinical pathological features of HCC in vivo, including cancer cellmorphology, tissue ultrastructure, protein production and secretion, glucose metabolism, tissue-specificgene expression, and apoptosis. Xenografts into livers of nude mice resulted in tumorigenesis and distantmetastasis. This 3-D HCC spheroid is a promising model for HCC tumor biology, anticancer drugscreening, and for the establishment of HCC animal models.", "metadata": {}}
+{"_id": "25953438", "title": "", "text": "Patterns of age-specific mortality in children in endemic areas of sub-Saharan Africa.Understanding of theage- and season- dependence of malaria mortality is an important prerequisite for epidemiologic modelsof malaria immunity. However, most studies of malaria mortality have aggregated their results into broadage groups and across seasons, making it hard to predict the likely impact of interventions targeted atspecific age groups of children. We present age-specific mortality rates for children aged < 15 years forthe period of 2001-2005 in 7 demographic surveillance sites in areas of sub-Saharan Africa with stableendemic Plasmodium falciparum malaria. We use verbal autopsies (VAs) to estimate the proportion ofdeaths by age group due to malaria, and thus calculate malaria-specific mortality rates for each site,age-group, and month of the year. In all sites a substantial proportion of deaths (ranging from 20.1% ina Mozambican site to 46.2% in a site in Burkina Faso) were attributed to malaria. The overall agepatterns of malaria mortality were similar in the different sites. Deaths in the youngest children (< 3months old) were only rarely attributed to malaria, but in children over 1 year of age the proportion ofdeaths attributed to malaria was only weakly age-dependent. In most of the sites all-cause mortalityrates peaked during the rainy season, but the strong seasonality in malaria transmission in these siteswas not reflected in strong seasonality in the proportion of deaths attributed to malaria, except in the twosites in Burkina Faso. Improvement in the specificity of malaria verbal autopsies would make it easier tointerpret the age and season patterns in such data.", "metadata": {}}
+{"_id": "25969485", "title": "", "text": "Obesity due to melanocortin 4 receptor (MC4R) deficiency is associated with increased linear growth andfinal height, fasting hyperinsulinemia, and incompletely suppressed growth hormone secretion.CONTEXTMelanocortin receptor 4 (MC4R) deficiency is characterized by increased linear growth greater thanexpected for the degree of obesity. OBJECTIVE The objective of the investigation was to study thesomatotroph axis in obese MC4R-deficient patients and equally obese controls. PATIENTS AND METHODSWe obtained anthropometric measurements and insulin concentrations in 153 MC4R-deficient subjectsand 1392 controls matched for age and severity of obesity. We measured fasting IGF-I, IGF-II, IGFbinding protein (IGFBP)-1, IGFBP-3, and acid-labile subunit levels in a subset of 33 MC4R-deficientpatients and 36 control subjects. We examined pulsatile GH secretion in six adult MC4R-deficient subjectsand six obese controls. RESULTS Height sd score was significantly greater in MC4R-deficient childrenunder 5 yr of age compared with controls (mean ± SEM: 2.3 ± 0.06 vs. 1.8 ± 0.04, P < 0.001), an effectthat persisted throughout childhood. Final height (cm) was greater in MC4R-deficient men (mean ± SEM173 ± 2.5 vs. 168 ± 2.1, P < 0.001) and women (mean 165 ± 2.1 vs. 158 ± 1.9, P < 0.001). FastingIGF-I, IGF-II, acid-labile subunit, and IGFBP-3 concentrations were similar in the two groups. GH levelswere markedly suppressed in obese controls, but pulsatile GH secretion was retained in MC4R deficiency.The mean maximal GH secretion rate per burst (P < 0.05) and mass per burst (P < 0.05) were increasedin MC4R deficiency, consistent with increased pulsatile and total GH secretion. Fasting insulin levels weremarkedly elevated in MC4R-deficient children. CONCLUSIONS In MC4R deficiency, increased lineargrowth in childhood leads to increased adult final height, greater than predicted by obesity alone. GHpulsatility is maintained in MC4R deficiency, a finding consistent with animal studies, suggesting a role forMC4R in controlling hypothalamic somatostatinergic tone. Fasting insulin levels are significantly higher inchildren carrying MC4R mutations. Both of these factors may contribute to the accelerated growthphenotype characteristic of MC4R deficiency.", "metadata": {}}
+{"_id": "25970224", "title": "", "text": "The selectivity of beta-adrenoceptor antagonists on isoprenaline-induced changes in heart rate, bloodpressure, soleus muscle contractility and airways function in anaesthetized cats.The beta-adrenoceptorantagonist of propranolol, metoprolol, atenolol and butoxamine in anaesthetized cats has been measuredand compared with the activity of four synthetic phenylethanolamine derivatives. The effects ofisoprenaline on four parameters in the anaesthetized cat: heart rate, blood pressure, soleus musclecontractility and airway reactance, were measured and the modification of the isoprenaline dose-responserelation by each of the antagonist drugs assessed. Parallel shifts in log dose-response curves forisoprenaline were caused by propranolol for all parameters, by metoprolol and atenolol for eachparameter except blood pressure, and butoxamine for each except soleus muscle and heart rate.Selectivity of action of the antagonists between different organs was measured by comparing DR10values, computed from isoprenaline dose-ratios. Propranolol was the most potent antagonist and showedslight selectivity of action on soleus muscle compared with heart. Atenolol and metoprolol wereapproximately equipotent and were cardioselective at low doses only. Butoxamine was the least potentantagonist and possessed non-beta-adrenoceptor effects on the parameters measured. Each of the newcompounds, 4'-bromo-2'-methoxy-N-isopropyl phenylethanolamine, the 4'-chloro- and 4'-methylanalogues, and 4'-methoxy-N-t-butyl phenylethanolamine, was a potent antagonist but did not exhibitany selectivity of action. The results suggest no clear separation of beta-adrenoceptors into beta 1- andbeta 2-subclasses in organs of the cat. There is no apparent separation of beta-adrenoceptor-mediatedeffects on skeletal muscle and airways.", "metadata": {}}
+{"_id": "25973484", "title": "", "text": "Breast cancer and obesity: an update.Obesity has a complicated relationship to both breast cancer riskand the clinical behavior of the established disease. In postmenopausal women, particularly the elderly,various measures of obesity have been positively associated with risk. However, before menopauseincreased body weight is inversely related to breast cancer risk. In both premenopausal andpostmenopausal breast cancer, the mechanisms by which body weight and obesity affect risk have beenrelated to estrogenic activity. Obesity has also been related to advanced disease at diagnosis and with apoor prognosis in both premenopausal and postmenopausal breast cancer. Breast cancer inAfrican-American women, considering its relationship to obesity, exhibits some important differencesfrom those described in white women, although the high prevalence of obesity in African-Americanwomen may contribute to the relatively poor prognosis compared with white American women. Despitethe emphasis on estrogens to explain the effects of obesity on breast cancer, other factors may prove tobe equally or more important, particularly as they relate to expression of an aggressive tumor phenotype.Among these, this review serves to stress insulin, insulin-like growth factor-I, and leptin, and theirrelationship to angiogenesis, and transcriptional factors.", "metadata": {}}
+{"_id": "25974070", "title": "", "text": "Dietary saturated and unsaturated fats as determinants of blood pressure and vascular function.Theamount and type of dietary fat have long been associated with the risk of CVD. Arterial stiffness andendothelial dysfunction are important risk factors in the aetiology of CHD. A range of methods exists toassess vascular function that may be used in nutritional science, including clinic and ambulatory bloodpressure monitoring, pulse wave analysis, pulse wave velocity, flow-mediated dilatation and venousocclusion plethysmography. The present review focuses on the quantity and type of dietary fat andeffects on blood pressure, arterial compliance and endothelial function. Concerning fat quantity, theamount of dietary fat consumed habitually appears to have little influence on vascular functionindependent of fatty acid composition, although single high-fat meals postprandially impair endothelialfunction compared with low-fat meals. The mechanism is related to increased circulating lipoproteins andNEFA which may induce pro-inflammatory pathways and increase oxidative stress. Regarding the type offat, cross-sectional data suggest that saturated fat adversely affects vascular function whereaspolyunsaturated fat (mainly linoleic acid (18 : 2n-6) and n-3 PUFA) are beneficial. EPA (20 : 5n-3) andDHA (22 : 6n-3) can reduce blood pressure, improve arterial compliance in type 2 diabetics anddyslipidaemics, and augment endothelium-dependent vasodilation. The mechanisms for this vascularprotection, and the nature of the separate physiological effects induced by EPA and DHA, are priorities forfuture research. Since good-quality observational or interventional data on dietary fatty acid compositionand vascular function are scarce, no further recommendations can be suggested in addition to currentguidelines at the present time.", "metadata": {}}
+{"_id": "25985964", "title": "", "text": "Very small embryonic-like stem cells with maximum regenerative potential get discarded during cordblood banking and bone marrow processing for autologous stem cell therapy.Very small embryonic-likestem cells (VSELs) are possibly lost during cord blood banking and bone marrow (BM) processing forautologus stem cell therapy mainly because of their small size. The present study was conducted onhuman umbilical cord blood (UCB, n=6) and discarded red blood cells (RBC) fraction obtained afterseparation of mononuclear cells from human BM (n=6), to test this hypothesis. The results show thatVSELs, which are pluripotent stem cells with maximum regenerative potential, settle along with the RBCsduring Ficoll-Hypaque density separation. These cells are very small in size (3-5 μm), have highnucleo-cytoplasmic ratio, and express nuclear Oct-4, cell surface protein SSEA-4, and other pluripotentmarkers such as Nanog, Sox-2, Rex-1, and Tert as indicated by immunolocalization and quantitativepolymerase chain reaction (Q-PCR) studies. Interestingly, a distinct population of slightly larger, roundhematopoietic stem cells (HSCs) with cytoplasmic Oct-4 were detected in the \"buffy\" coat, which usuallygets banked or used during autologus stem cell therapy. Immunohistochemical studies on the umbilicalcord tissue (UCT) sections (n=3) showed the presence of nuclear Oct-4-positive VSELs and manyfibroblast-like mesenchymal stem cells (MSCs) with cytoplasmic Oct-4. These VSELs with nuclear Oct-4,detected in UCB, UCT, and discarded RBC fraction obtained after BM processing, may persist throughoutlife, maintain tissue homeostasis, and undergo asymmetric cell division to self-renew as well as producelarger progenitor stem cells, viz. HSCs or MSCs, which follow differentiation trajectories depending on thesomatic niche. Hence, it can be concluded that the true stem cells in adult body tissues are the VSELs,whereas the HSCs and MSCs are actually progenitor stem cells that arise by asymmetric cell division ofVSELs. The results of the present study may help explain low efficacy reported during adult autologousstem cell trials, wherein unknowingly progenitor stem cells are injected rather than the pluripotent stemcells with maximum regenerative potential.", "metadata": {}}
+{"_id": "25988622", "title": "", "text": "CNS repair requires both effector and regulatory T cells with distinct temporal and spatialprofiles.Monocyte-derived macrophages (mo-MΦs) and T cells have been shown to contribute to spinalcord repair. Recently, the remote brain choroid plexus epithelium (CP) was identified as a portal formonocyte recruitment, and its activation for leukocyte trafficking was found to be IFN-γ-dependent. Here,we addressed how the need for effector T cells can be reconciled with the role of inflammation-resolvingimmune cells in the repair process. Using an acute spinal cord injury model, we show that in micedeficient in IFN-γ-producing T cells, the CP was not activated, and recruitment of inflammation-resolvingmo-MΦ to the spinal cord parenchyma was limited. We further demonstrate that mo-MΦ locally regulatedrecruitment of thymic-derived Foxp3(+) regulatory T (Treg) cells to the injured spinal cord parenchymaat the subacute/chronic phase. Importantly, an ablation protocol that resulted in reduced Tregs at thisstage interfered with tissue remodeling, in contrast to Treg transient ablation, restricted to the 4 d periodbefore the injury, which favored repair. The enhanced functional recovery observed following such acontrolled decrease of Tregs suggests that reduced systemic immunosuppression at the time of the insultcan enhance CNS repair. Overall, our data highlight a dynamic immune cell network needed for repair,acting in discrete compartments and stages, and involving effector and regulatory T cells, interconnectedby mo-MΦ. Any of these populations may be detrimental to the repair process if their level or activitybecome dysregulated. Accordingly, therapeutic interventions must be both temporally and spatiallycontrolled.", "metadata": {}}
+{"_id": "25993718", "title": "", "text": "Sperm function tests and fertility.Traditionally, the diagnosis of male infertility has depended upon adescriptive evaluation of human semen with emphasis on the number of spermatozoa that are present inthe ejaculate, their motility and their morphology. The fundamental tenet underlying this approach is thatmale fertility can be defined by reference to a threshold concentration of motile, morphologically normalspermatozoa that must be exceeded in order to achieve conception. Many independent studies havedemonstrated that this fundamental concept is flawed and, in reality, it is not so much the absolutenumber of spermatozoa that determines fertility, but their functional competence. In the light of thisconclusion, a range of in vitro tests have been developed to monitor various aspects of sperm functionincluding their potential for movement, cervical mucus penetration, capacitation, zona recognition, theacrosome reaction and sperm-oocyte fusion. Such functional assays have been found to predict thefertilizing capacity of human spermatozoa in vitro and in vivo with some accuracy. Recent developmentsin this field include the introduction of tests to assess the degree to which human spermatozoa havesuffered oxidative stress as well as the integrity of their nuclear and mitochondrial DNA. Suchassessments not only yield information on the fertilizing capacity of human spermatozoa but also theirability to support normal embryonic development.", "metadata": {}}
+{"_id": "25994317", "title": "", "text": "Isolation and characterization of the cDNA encoding BKLF/TEF-2, a major CACCC-box-binding protein inerythroid cells and selected other cells.CACCC boxes are among the critical sequences present inregulatory elements of genes expressed in erythroid cells, as well as in selected other cell types. While anerythroid cell-specific CACCC-box-binding protein, EKLF, has been shown to be required in vivo for properexpression of the adult beta-globin gene, it is dispensable for the regulation of several other globin andnonglobin erythroid cell-expressed genes. In the work described here, we searched for additionalCACCC-box transcription factors that might be active in murine erythroid cells. We identified a major gelshift activity (termed BKLF), present in yolk sac and fetal liver erythroid cells, that could be distinguishedfrom EKLF by specific antisera. Through relaxed-stringency hybridization, we obtained the cDNA encodingBKLF, a highly basic, novel zinc finger protein that is related to EKLF and other Krüppel-like members inits DNA-binding domain but unrelated elsewhere. BKLF, which is widely but not ubiquitously expressed incell lines, is highly expressed in the midbrain region of embryonic mice and appears to correspond to thegel shift activity TEF-2, a transcriptional activator implicated in regulation of the simian virus 40 enhancerand other CACCC-box-containing regulatory elements. Because BKLF binds with high affinity andpreferentially over Sp1 to many CACCC sequences of erythroid cell expressed genes, it is likely toparticipate in the control of many genes whose expression appears independent of the action of EKLF.", "metadata": {}}
+{"_id": "26000593", "title": "", "text": "Effect of osteoporosis treatments on risk of non-vertebral fractures: review and meta-analysis ofintention-to-treat studiesMost osteoporosis treatments have proven efficacy in reducing the risk ofvertebral fractures, whereas evidence is less straightforward for prevention of non-vertebral fractures.Conclusions as to the efficacy of a treatment should be based primarily on analyses of the intention totreat (ITT) population rather than on exploratory subgroup analyses; however, non-vertebralanti-fracture efficacy has been largely derived by post-hoc subgroup analyses. This review andmeta-analysis was performed to assess non-vertebral anti-fracture efficacy of several osteoporosistherapies, including a more stringent assessment of the ITT populations. Data on non-vertebralanti-fracture efficacy, a defined endpoint of the ITT analyses and confirmed by radiographs, wereobtained from randomized, placebo-controlled, phase III clinical trials of at least 3-year duration.Meta-analyses were performed for the two bisphosphonates, alendronate and risedronate. Relative risks(RR), 95% confidence intervals (CI) and statistical significance for active treatment compared withplacebo were calculated. Eleven clinical trials met the criteria for review, three of which showedstatistically significant ( P ≤0.05) non-vertebral anti-fracture efficacy in the ITT population: two trials withrisedronate and one trial with strontium. A meta-analysis showed significant reductions in the relative riskof non-vertebral fracture for both alendronate (RR=0.86; 95% CI: 0.76–0.97, P =0.012) and risedronate(RR=0.81; 95% CI: 0.71–0.92, P =0.001). Risedronate and strontium ranelate were the only treatmentsto show non-vertebral anti-fracture efficacy in this robust assessment of anti-fracture efficacy ofosteoporosis therapy using ITT populations in trials of 3 years or more in duration. Risedronate was theonly agent shown to demonstrate efficacy in more than one trial. Meta-analysis showed that bothalendronate and risedronate provide non-vertebral anti-fracture efficacy.", "metadata": {}}
+{"_id": "26008063", "title": "", "text": "Islet1 deletion causes kidney agenesis and hydroureter resembling CAKUT.Islet1 (Isl1) is a transcriptionfactor transiently expressed in a subset of heart and limb progenitors. During studies of limbdevelopment, conditional Isl1 deletion produced unexpected kidney abnormalities. Here, we studied therenal expression of Isl1 and whether it has a role in kidney development. In situ hybridization revealedIsl1 expression in the mesenchymal cells surrounding the base of the ureteric bud in mice. Conditionaldeletion of Isl1 caused kidney agenesis or hypoplasia and hydroureter, a phenotype resembling humancongenital anomalies of the kidney and urinary tract (CAKUT). The absence of Isl1 led to ectopicbranching of the ureteric bud out from the nephric duct or to the formation of accessory buds, both ofwhich could lead to obstruction of the ureter-bladder junction and consequent hydroureter. The abnormalelongation and poor branching of the ureteric buds were the likely causes of the kidney agenesis orhypoplasia. Furthermore, the lack of Isl1 reduced the expression of Bmp4, a gene implicated in theCAKUT-like phenotype, in the metanephric region before ureteric budding. In conclusion, Isl1 is essentialfor proper development of the kidney and ureter by repressing the aberrant formation of the ureteric bud.These observations call for further studies to investigate whether Isl1 may be a causative gene for humanCAKUT.", "metadata": {}}
+{"_id": "26008462", "title": "", "text": "Tissue transglutaminase (TG2)--a wound response enzyme.Repair of tissue after injury depends on aseries of concerted but overlapping events including, inflammation, re-epithelialization,neovascularization and synthesis and stabilization of a fibrous extracellular matrix (ECM) that isremodeled to emulate normal tissue over time. Particular members of the transglutaminase (TG) familyare upregulated during wound healing and act as a novel class of wound-healing mediators during therepair process. This group of enzymes which crosslink proteins via epsilon(gamma-glutamyl) lysinebridges are involved in wound healing through their ability to stabilize proteins and also by regulating thebehavior of a wide variety of cell types that are recruited to the damaged area in order to carry out tissuerepair. In this article we discuss the function of the most widely expressed member of the TG family\"tissue transglutaminase\" (TG2) in wound repair. Using both early and recent evidence from the literaturewe demonstrate how the multifunctional TG2 affects the stability of the ECM, cell-ECM interactions and asa consequence cell behavior within the different phases of wound healing, and highlight how TG2 itselfmight be exploited for therapeutic use.", "metadata": {}}
+{"_id": "26011884", "title": "", "text": "Crystal structures of the glutamate receptor ion channel GluK3 and GluK5 amino-terminaldomains.Ionotropic glutamate receptors (iGluRs) mediate the majority of fast excitatory synapticneurotransmission in the central nervous system. The selective assembly of iGluRs into AMPA, kainate,and N-methyl-d-aspartic acid (NMDA) receptor subtypes is regulated by their extracellularamino-terminal domains (ATDs). Kainate receptors are further classified into low-affinity receptor families(GluK1-GluK3) and high-affinity receptor families (GluK4-GluK5) based on their affinity for the neurotoxinkainic acid. These two families share a 42% sequence identity for the intact receptor but only a 27%sequence identity at the level of ATD. We have determined for the first time the high-resolution crystalstructures of GluK3 and GluK5 ATDs, both of which crystallize as dimers but with a strikingly differentdimer assembly at the R1 interface. By contrast, for both GluK3 and GluK5, the R2 domain dimerassembly is similar to those reported previously for other non-NMDA iGluRs. This observation isconsistent with the reports that GluK4-GluK5 cannot form functional homomeric ion channels and requireobligate coassembly with GluK1-GluK3. Our analysis also reveals that the relative orientation of domainsR1 and R2 in individual non-NMDA receptor ATDs varies by up to 10°, in contrast to the 50° differencereported for the NMDA receptor GluN2B subunit. This restricted domain movement in non-NMDA receptorATDs seems to result both from extensive intramolecular contacts between domain R1 and domain R2and from their assembly as dimers, which interact at both R1 and R2 domains. Our results provide thefirst insights into the structure and function of GluK4-GluK5, the least understood family of iGluRs.", "metadata": {}}
+{"_id": "26016929", "title": "", "text": "Effectiveness of screening older people for impaired vision in community setting: systematic review ofevidence from randomised controlled trials.OBJECTIVE To assess whether population screening forimpaired vision among older people in the community leads to improvements in vision. DESIGNSystematic review of randomised controlled trials of population screening in the community that includedany assessment of vision or visual function with at least 6 months' follow up. SUBJECTS Adults aged 65 orover. MAIN OUTCOME MEASURE Proportions with visual impairment in intervention and control groupswith any method of assessing visual impairment. RESULTS There were no trials that primarily assessedvisual screening. Outcome data on vision were available for 3494 people in five trials of multiphasicassessment. All the trials used self reported measures for vision impairment, both as screening tools andas outcome measures. The inclusion of a visual screening component in the assessment did not result inimprovements in self reported visual problems (pooled odds ratio 1.04:95% confidence interval 0.89 to1.22). A small reduction (11%) in the number of older people with self reported visual problems cannotbe excluded. CONCLUSIONS Screening of asymptomatic older people in the community is not justified onpresent evidence. Visual impairment in this age group can usually be reduced with treatment. It isunclear why no benefit was seen. Further work is needed to clarify what interventions are appropriate forolder people with unreported impairment of vision.", "metadata": {}}
+{"_id": "26019505", "title": "", "text": "Protein interaction network of the mammalian Hippo pathway reveals mechanisms of kinase-phosphataseinteractions.The Hippo pathway regulates organ size and tissue homeostasis in response to multiplestimuli, including cell density and mechanotransduction. Pharmacological inhibition of phosphatases canalso stimulate Hippo signaling in cell culture. We defined the Hippo protein-protein interaction networkwith and without inhibition of serine and threonine phosphatases by okadaic acid. We identified 749protein interactions, including 599 previously unrecognized interactions, and demonstrated that severalinteractions with serine and threonine phosphatases were phosphorylation-dependent. Mutation of theT-loop of MST2 (mammalian STE20-like protein kinase 2), which prevented autophosphorylation,disrupted its association with STRIPAK (striatin-interacting phosphatase and kinase complex). Deletion ofthe amino-terminal forkhead-associated domain of SLMAP (sarcolemmal membrane-associated protein),a component of the STRIPAK complex, prevented its association with MST1 and MST2. Phosphataseinhibition produced temporally distinct changes in proteins that interacted with MOB1A and MOB1B (Mpsone binder kinase activator-like 1A and 1B) and promoted interactions with upstream Hippo pathwayproteins, such as MST1 and MST2, and with the trimeric protein phosphatase 6 complex (PP6). Mutationof three basic amino acids that are part of a phospho-serine- and phospho-threonine-binding domain inhuman MOB1B prevented its interaction with MST1 and PP6 in cells treated with okadaic acid.Collectively, our results indicated that changes in phosphorylation orchestrate interactions betweenkinases and phosphatases in Hippo signaling, providing a putative mechanism for pathway regulation.", "metadata": {}}
+{"_id": "26025370", "title": "", "text": "Differential Effects of N-Acetylcysteine, Theophylline or Bicarbonate on Contrast-Induced Rat RenalVasoconstrictionBackground: Vasoconstriction and reactive oxygen species (ROS) accumulation followingcontrast media (CM) injection are the key factors triggering CM-induced nephropathy. We compared theeffects of N-acetylcysteine (NAC), theophylline or sodium bicarbonate on intrarenal vasoconstriction andROS generation in a rat model of CM-induced nephropathy. Methods: Following a 3-day dehydration,Sprague-Dawley rats received CM (Telebrix) or sham ‘CM’ injection of 0.9% saline. Part of them receivedNAC, theophylline or bicarbonate prior to CM. Medullar renal blood flow was estimated by laser Doppler.The animals were sacrificed 1, 15 or 30 min after the respective treatments, their kidneys allocated andintrarenal STAT-8 isoprostane, PGE2 and NO assessed. Results: Vasoconstriction was significantlyattenuated by NAC. Theophylline only mildly attenuated the perfusion drop at 15 min, and was ineffectivefollowing 30 min. Unlike theophylline or bicarbonate, NAC significantly augmented intrarenal PGE2. NAC,theophylline but not bicarbonate, gradually increased intrarenal NO. In all experimental variables,CM-induced ROS accumulation, represented by STAT-8 isoprostane estimation, progressed undisturbed.Conclusions: (1) CM-induced intrarenal vasoconstriction was efficiently prohibited by NAC but notbicarbonate or theophylline; (2) the vasodilatory effect of NAC was mediated via increased PGE2synthesis, and (3) ROS accumulation was a primary renal response to CM-induced injury, not affected byany pharmacologic manipulations.", "metadata": {}}
+{"_id": "26025820", "title": "", "text": "Induction of AMPK activity corrects early pathophysiological alterations in the subtotal nephrectomymodel of chronic kidney disease.The rat kidney ablation and infarction (A/I) model of subtotal or 5/6thnephrectomy is the most commonly studied model of nondiabetic chronic kidney disease (CKD). The A/Ikidney at 1 wk exhibits reductions in kidney function, as determined by glomerular filtration rate, anddiminished metabolic efficiency as determined by oxygen consumption per sodium transport (QO2/TNa).As renoprotective AMPK activity is affected by metabolic changes and cellular stress, we evaluated AMPKactivity in this model system. We show that these early pathophysiological changes are accompanied by aparadoxical decrease in AMPK activity. Over time, these kidney parameters progressively worsen withextensive kidney structural, functional, metabolic, and fibrotic changes observed at 4 wk after A/I. Weshow that induction of AMPK activity with either metformin or 5-aminoimidazole-4-carboxamideribonucleotide increases AMPK activity in this model and also corrects kidney metabolic inefficiency,improves kidney function, and ameliorates kidney fibrosis and structural alterations. We conclude thatAMPK activity is reduced in the subtotal nephrectomy model of nondiabetic CKD, that altered regulationof AMPK is coincident with the progression of disease parameters, and that restoration of AMPK activitycan suppress the progressive loss of function characteristic of this model. We propose that induction ofAMPK activity may prove an effective therapeutic target for the treatment of nondiabetic CKD.", "metadata": {}}
+{"_id": "26026009", "title": "", "text": "Magnetic resonance imaging for volume estimation of large multinodular goitres: a comparison withscintigraphy.As a result of increasing interest in non-surgical treatment for the reduction of goitre size theuse of magnetic resonance (MR) imaging for volume estimation of large multinodular goitres wasevaluated in 20 patients (three males and 17 females; age 61 +/- 21 years) with a multinodular goitrelarger than 100 ml. In addition, MR measurements were compared with scintigraphic (SC) volumeestimations. Intraobserver coefficient of variation (CV) of MR measurements was 2.2 +/- 2.0% (Observer1) and interobserver CV 4.1 +/- 2.2% (Observers 1 and 2). In all 20 patients signs of mechanicalcomplications were shown on MR images. For SC measurements intraobserver CV was 7.5 +/- 5.7%(Observer 3) and 5.4 +/- 5.1% (Observer 4). Interobserver CV was 10.1 +/- 6.1%. The correlationbetween measurements with both methods was not strong (r = 0.665) and the resulting CV was 17.3 +/-14.2%. Underestimation of SC volumes could not be explained by the presence of cysts on the surface ofthe thyroid. It is concluded that MR imaging can be used for in vivo thyroid volume estimation in largemultinodular goitres. The high precision of MR measurements makes this technique potentially useful forthe evaluation of thyroid growth and non-surgical treatment for reducing goitre size. Scintigraphic volumemeasurements do not suffice for this purpose. An additional advantage of MR imaging is the detailedanatomical information it provides with regard to mechanical complications of large goitres.", "metadata": {}}
+{"_id": "26030079", "title": "", "text": "Differential role of CbpA and PspA in modulation of in vitro CXC chemokine responses of respiratoryepithelial cells to infection with Streptococcus pneumoniae.Respiratory epithelial cells play an active partin the host response to respiratory pathogens, such as Streptococcus pneumoniae, by releasingchemokines responsible for neutrophil recruitment. In order to investigate the role of specificpneumococcal virulence factors in eliciting CXC chemokine responses, type II pneumocytes (A549) andnasopharyngeal cells (Detroit-562) were infected with S. pneumoniae D39 or mutants lackingcholine-binding protein A (CbpA), pneumococcal surface protein A (PspA), or specific domains thereof. Inresponse to wild-type D39, both A549 and Detroit-562 cells showed a significant increase in CXCchemokine mRNA and interleukin-8 protein. This response was increased twofold when a cbpA deletionmutant (DeltaCbpA) was used, suggesting that CbpA inhibits CXC chemokine induction. All threeN-terminal domains of CbpA are required for this effect, as in-frame deletion of the respective region ofcbpA had the same effect on the CXC chemokine response as deletion of cbpA altogether. Infection with apspA deletion mutant (DeltaPspA) led to a twofold decrease in the CXC chemokine response of A549 butnot Detroit-562 cells, compared to infection with D39 at 2 h. Thus, PspA appears to have the ability tostimulate early CXC chemokine release from A549 cells. Deletion of the region of pspA encoding the firstN-terminal alpha-helical domain reduced the ability of S. pneumoniae to elicit a chemokine response tothe same degree as deletion of pspA altogether. Thus, the N termini of CbpA and PspA exert differentialeffects on CXC chemokine induction in epithelial cells infected with S. pneumoniae.", "metadata": {}}
+{"_id": "26038789", "title": "", "text": "HIV-1 therapy with monoclonal antibody 3BNC117 elicits host immune responses against HIV-13BNC117is a broad and potent neutralizing antibody to HIV-1 that targets the CD4 binding site on the viralenvelope spike. When administered passively, this antibody can prevent infection in animal models andsuppress viremia in HIV-1–infected individuals. Here we report that HIV-1 immunotherapy with a singleinjection of 3BNC117 affects host antibody responses in viremic individuals. In comparison to untreatedcontrols that showed little change in their neutralizing activity over a 6-month period, 3BNC117 infusionsignificantly improved neutralizing responses to heterologous tier 2 viruses in nearly all studyparticipants. We conclude that 3BNC117-mediated immunotherapy enhances host humoral immunity toHIV-1.", "metadata": {}}
+{"_id": "26045237", "title": "", "text": "Safety and efficacy of RNAi therapy for transthyretin amyloidosis.BACKGROUND Transthyretinamyloidosis is caused by the deposition of hepatocyte-derived transthyretin amyloid in peripheral nervesand the heart. A therapeutic approach mediated by RNA interference (RNAi) could reduce the productionof transthyretin. METHODS We identified a potent antitransthyretin small interfering RNA, which wasencapsulated in two distinct first- and second-generation formulations of lipid nanoparticles, generatingALN-TTR01 and ALN-TTR02, respectively. Each formulation was studied in a single-dose,placebo-controlled phase 1 trial to assess safety and effect on transthyretin levels. We first evaluatedALN-TTR01 (at doses of 0.01 to 1.0 mg per kilogram of body weight) in 32 patients with transthyretinamyloidosis and then evaluated ALN-TTR02 (at doses of 0.01 to 0.5 mg per kilogram) in 17 healthyvolunteers. RESULTS Rapid, dose-dependent, and durable lowering of transthyretin levels was observedin the two trials. At a dose of 1.0 mg per kilogram, ALN-TTR01 suppressed transthyretin, with a meanreduction at day 7 of 38%, as compared with placebo (P=0.01); levels of mutant and nonmutant forms oftransthyretin were lowered to a similar extent. For ALN-TTR02, the mean reductions in transthyretinlevels at doses of 0.15 to 0.3 mg per kilogram ranged from 82.3 to 86.8%, with reductions of 56.6 to67.1% at 28 days (P<0.001 for all comparisons). These reductions were shown to be RNAi-mediated.Mild-to-moderate infusion-related reactions occurred in 20.8% and 7.7% of participants receivingALN-TTR01 and ALN-TTR02, respectively. CONCLUSIONS ALN-TTR01 and ALN-TTR02 suppressed theproduction of both mutant and nonmutant forms of transthyretin, establishing proof of concept for RNAitherapy targeting messenger RNA transcribed from a disease-causing gene. (Funded by AlnylamPharmaceuticals; ClinicalTrials.gov numbers, NCT01148953 and NCT01559077.).", "metadata": {}}
+{"_id": "26047921", "title": "", "text": "The mechanosensitive ion channel Piezo1 is inhibited by the peptide GsMTx4.Cells can respond tomechanical stress by gating mechanosensitive ion channels (MSCs). The cloning of Piezo1, a eukaryoticcation selective MSC, defines a new system for studying mechanical transduction at the cellular level.Because Piezo1 has electrophysiological properties similar to those of endogenous cationic MSCs that areselectively inhibited by the peptide GsMTx4, we tested whether the peptide targets Piezo1 activity.Extracellular GsMTx4 at micromolar concentrations reversibly inhibited \u000080% of the mechanicallyinduced current of outside-out patches from transfected HEK293 cells. The inhibition was voltageinsensitive, and as seen with endogenous MSCs, the mirror image d enantiomer inhibited like the l. Therate constants for binding and unbinding based on Piezo1 current kinetics provided association anddissociation rates of 7.0 × 10(5) M(-1) s(-1) and 0.11 s(-1), respectively, and a K(D) of \u0000155 nM, similarto values previously reported for endogenous MSCs. Consistent with predicted gating modifier behavior,GsMTx4 produced an \u000030 mmHg rightward shift in the pressure-gating curve and was active on closedchannels. In contrast, streptomycin, a nonspecific inhibitor of cationic MSCs, showed the use-dependentinhibition characteristic of open channel block. The peptide did not block currents of the mechanicalchannel TREK-1 on outside-out patches. Whole-cell Piezo1 currents were also reversibly inhibited byGsMTx4, and although the off rate was nearly identical to that of outside-out patches, differences wereobserved for the on rate. The ability of GsMTx4 to target the mechanosensitivity of Piezo1 supports theuse of this channel in high-throughput screens for pharmacological agents and diagnostic assays.", "metadata": {}}
+{"_id": "26058927", "title": "", "text": "Thiazolidinediones improve beta-cell function in type 2 diabetic patients.Thiazolidinediones (TZDs)improve glycemic control and insulin sensitivity in patients with type 2 diabetes mellitus (T2DM). There isgrowing evidence from in vivo and in vitro studies that TZDs improve pancreatic beta-cell function. Theaim of this study was to determine whether TZD-induced improvement in glycemic control is associatedwith improved beta-cell function. We studied 11 normal glucose-tolerant and 53 T2DM subjects [age53+/-2 yr; BMI 29.4+/-0.8 kg/m2; fasting plasma glucose (FPG) 10.3+/-0.4 mM; Hb A1c 8.2+/-0.3%].Diabetic patients were randomized to receive placebo or TZD for 4 mo. Subjects received 1) 2-h OGTTwith determination of plasma glucose, insulin, and C-peptide concentrations and 2) two-step euglycemicinsulin (40 and 160 mU.m-2.min-1) clamp with [3-(3)H]glucose. T2DM patients were then randomized toreceive 4 mo of treatment with pioglitazone (45 mg/day), rosiglitazone (8 mg/day), or placebo.Pioglitazone and rosiglitazone similarly improved FPG, mean plasma glucose during OGTT, Hb A1c, andinsulin-mediated total body glucose disposal (Rd) and decreased mean plasma FFA during OGTT (allP<0.01, ANOVA). The insulin secretion/insulin resistance (disposition) index[DeltaISR(AUC)/Deltaglucose(AUC)/IR] was significantly improved in all TZD-treated groups: +1.8+/-0.7(PIO+drug-naïve diabetics), +0.7+/-0.3 (PIO+sulfonylurea-treated diabetics), and 0.7+/-0.2(ROSI+sulfonylurea-withdrawn diabetics) vs. -0.2+/-0.3 in the two placebo groups (P<0.01, all TZDs vs.placebo, ANOVA). Improved insulin secretion correlated positively with increased body weight, fat mass,and Rd and inversely with decreased plasma glucose and FFA during the OGTT. In T2DM patients, TZDtreatment leads to improved beta-cell function, which correlates strongly with improved glycemic control.", "metadata": {}}
+{"_id": "26059876", "title": "", "text": "A novel Ku70 function in colorectal homeostasis separate from nonhomologous end joiningKu70, a knownnonhomologous end-joining (NHEJ) factor, also functions in tumor suppression, although this molecularmechanism remains uncharacterized. Previously, we showed that mice deficient for DNA ligase IV (Lig4),another key NHEJ factor, succumbed to aggressive lymphoma in the absence of tumor suppressor p53.However, the tumor phenotype is abrogated by the introduction of a hypomorphic mutant p53R172P,which impaired p53-mediated apoptosis but not cell-cycle arrest. However, Lig4−/−p53R172P micesuccumbed to severe diabetes. To further elucidate the role of NHEJ and p53-mediated apoptosis in vivo,we bred Ku70−/− p53R172P mice. Unexpectedly, these mice were free of diabetes, although 80% of themutant mice had abnormally enlarged colons with pronounced inflammation. Remarkably, most of thesemutant mice progressed to dysplasia, adenoma and adenocarcinoma; this is in contrast to theLig4−/−p53R172P phenotype, strongly suggesting an NHEJ-independent function of Ku70. Significantly,our analyses of Ku70−/−p53R172P colonic epithelial cells show nuclear stabilization of β-cateninaccompanied by higher expression of cyclin D1 and c-Myc in affected colon sections than in controlsamples. This is not due to the p53 mutation, as Ku70−/− mice share this phenotype. Our results notonly unravel a novel function of Ku70 essential for colon homeostasis, but also establish an excellent invivo model in which to study how chronic inflammation and abnormal cellular proliferation underlietumorigenesis and tumor progression in the colon.", "metadata": {}}
+{"_id": "26064662", "title": "", "text": "Association of Sickle Cell Trait With Hemoglobin A1c in African AmericansImportance Hemoglobin A1c(HbA1c) reflects past glucose concentrations, but this relationship may differ between those with sicklecell trait (SCT) and those without it. Objective To evaluate the association between SCT and HbA1c forgiven levels of fasting or 2-hour glucose levels among African Americans. Design, Setting, andParticipants Retrospective cohort study using data collected from 7938 participants in 2 community-basedcohorts, the Coronary Artery Risk Development in Young Adults (CARDIA) study and the Jackson HeartStudy (JHS). From the CARDIA study, 2637 patients contributed a maximum of 2 visits (2005-2011);from the JHS, 5301 participants contributed a maximum of 3 visits (2000-2013). All visits were scheduledat approximately 5-year intervals. Participants without SCT data, those without any concurrent HbA1cand glucose measurements, and those with hemoglobin variants HbSS, HbCC, or HbAC were excluded.Analysis of the primary outcome was conducted using generalized estimating equations (GEE) to examinethe association of SCT with HbA1c levels, controlling for fasting or 2-hour glucose measures. ExposuresPresence of SCT. Main Outcomes and Measures Hemoglobin A1c stratified by the presence or absence ofSCT was the primary outcome measure. Results The analytic sample included 4620 participants (meanage, 52.3 [SD, 11.8] years; 2835 women [61.3%]; 367 [7.9%] with SCT) with 9062 concurrentmeasures of fasting glucose and HbA1c levels. In unadjusted GEE analyses, for a given fasting glucose,HbA1c values were statistically significantly lower in those with (5.72%) vs those without (6.01%) SCT(mean HbA1c difference, −0.29%; 95% CI, −0.35% to −0.23%). Findings were similar in modelsadjusted for key risk factors and in analyses using 2001 concurrent measures of 2-hour glucose andHbA1c concentration for those with SCT (mean, 5.35%) vs those without SCT (mean, 5.65%) for a meanHbA1c difference of −0.30% (95% CI, −0.39% to −0.21%). The HbA1c difference by SCT was greater athigher fasting (P = .02 for interaction) and 2-hour (P = .03) glucose concentrations. The prevalence ofprediabetes and diabetes was statistically significantly lower among participants with SCT when definedusing HbA1c values (29.2% vs 48.6% for prediabetes and 3.8% vs 7.3% for diabetes in 572 observationsfrom participants with SCT and 6877 observations from participants without SCT; P<.001 for bothcomparisons). Conclusions and Relevance Among African Americans from 2 large, well-establishedcohorts, participants with SCT had lower levels of HbA1c at any given concentration of fasting or 2-hourglucose compared with participants without SCT. These findings suggest that HbA1c may systematicallyunderestimate past glycemia in black patients with SCT and may require further evaluation.", "metadata": {}}
+{"_id": "26064942", "title": "", "text": "PGAP2 mutations, affecting the GPI-anchor-synthesis pathway, cause hyperphosphatasia with mentalretardation syndrome.Recently, mutations in genes involved in the biosynthesis of theglycosylphosphatidylinositol (GPI) anchor have been identified in a new subclass of congenital disordersof glycosylation (CDGs) with a distinct spectrum of clinical features. To date, mutations have beenidentified in six genes (PIGA, PIGL, PIGM, PIGN, PIGO, and PIGV) encoding proteins in theGPI-anchor-synthesis pathway in individuals with severe neurological features, including seizures,muscular hypotonia, and intellectual disability. We developed a diagnostic gene panel for targeting allknown genes encoding proteins in the GPI-anchor-synthesis pathway to screen individuals matchingthese features, and we detected three missense mutations in PGAP2, c.46C>T, c.380T>C, and c.479C>T,in two unrelated individuals with hyperphosphatasia with mental retardation syndrome (HPMRS). Themutations cosegregated in the investigated families. PGAP2 is involved in fatty-acid GPI-anchorremodeling, which occurs in the Golgi apparatus and is required for stable association betweenGPI-anchored proteins and the cell-surface membrane rafts. Transfection of the altered proteinconstructs, p. Arg16Trp (NP_001243169.1), p. Leu127Ser, and p. Thr160Ile, into PGAP2-null cellsshowed only partial restoration of GPI-anchored marker proteins, CD55 and CD59, on the cell surface. Inthis work, we show that an impairment of GPI-anchor remodeling also causes HPMRS and conclude thattargeted sequencing of the genes encoding proteins in the GPI-anchor-synthesis pathway is an effectivediagnostic approach for this subclass of CDGs.", "metadata": {}}
+{"_id": "26067999", "title": "", "text": "Screening for Lung Cancer: U.S. Preventive Services Task Force Recommendation StatementThe U.S.Preventive Services Task Force (USPSTF) makes recommendations about the effectiveness of specificpreventive care services for patients without related signs or symptoms. It bases its recommendations onthe evidence of both the benefits and harms of the service and an assessment of the balance. TheUSPSTF does not consider the costs of providing a service in this assessment. The USPSTF recognizesthat clinical decisions involve more considerations than evidence alone. Clinicians should understand theevidence but individualize decision making to the specific patient or situation. Similarly, the USPSTF notesthat policy and coverage decisions involve considerations in addition to the evidence of clinical benefitsand harms. Summary of Recommendation and Evidence The USPSTF recommends annual screening forlung cancer with low-dose computed tomography (LDCT) in adults aged 55 to 80 years who have a 30pack-year smoking history and currently smoke or have quit within the past 15 years. Screening shouldbe discontinued once a person has not smoked for 15 years or develops a health problem thatsubstantially limits life expectancy or the ability or willingness to have curative lung surgery. (Brecommendation) See the Clinical Considerations section for suggestions for implementation in practice.See the Figure for a summary of the recommendation and suggestions for clinical practice. Figure.Screening for lung cancer: clinical summary of U.S. Preventive Services Task Force recommendation.Appendix Table 1 describes the USPSTF grades, and Appendix Table 2 describes the USPSTF classificationof levels of certainty about net benefit. Appendix Table 1. What the USPSTF Grades Mean andSuggestions for Practice Appendix Table 2. USPSTF Levels of Certainty Regarding Net BenefitSupplement. Consumer Fact Sheet. Rationale Importance Lung cancer is the third most common cancerand the leading cause of cancer-related death in the United States (1). The most important risk factor forlung cancer is smoking, which results in approximately 85% of all U.S. lung cancer cases (2). Althoughthe prevalence of smoking has decreased, approximately 37% of U.S. adults are current or formersmokers (2). The incidence of lung cancer increases with age and occurs most commonly in persons aged55 years or older. Increasing age and cumulative exposure to tobacco smoke are the 2 most common riskfactors for lung cancer. Lung cancer has a poor prognosis, and nearly 90% of persons with lung cancerdie of the disease. However, early-stage nonsmall cell lung cancer (NSCLC) has a better prognosis andcan be treated with surgical resection. Detection Most lung cancer cases are NSCLC, and most screeningprograms focus on the detection and treatment of early-stage NSCLC. Although chest radiography andsputum cytologic evaluation have been used to screen for lung cancer, LDCT has greater sensitivity fordetecting early-stage cancer (3). Benefits of Detection and Early Treatment Although lung cancerscreening is not an alternative to smoking cessation, the USPSTF found adequate evidence that annualscreening for lung cancer with LDCT in a defined population of high-risk persons can prevent a substantialnumber of lung cancerrelated deaths. Direct evidence from a large, well-conducted, randomized,controlled trial (RCT) provides moderate certainty of the benefit of lung cancer screening with LDCT inthis population (4). The magnitude of benefit to the person depends on that person's risk for lung cancerbecause those who are at highest risk are most likely to benefit. Screening cannot prevent most lungcancerrelated deaths, and smoking cessation remains essential. Harms of Detection and EarlyIntervention and Treatment The harms associated with LDCT screening include false-negative andfalse-positive results, incidental findings, overdiagnosis, and radiation exposure. False-positive LDCTresults occur in a substantial proportion of screened persons; 95% of all positive results do not lead to adiagnosis of cancer. In a high-quality screening program, further imaging can resolve most false-positiveresults; however, some patients may require invasive procedures. The USPSTF found insufficientevidence on the harms associated with incidental findings. Overdiagnosis of lung cancer occurs, but itsprecise magnitude is uncertain. A modeling study performed for the USPSTF estimated that 10% to 12%of screen-detected cancer cases are overdiagnosedthat is, they would not have been detected in thepatient's lifetime without screening. Radiation harms, including cancer resulting from cumulativeexposure to radiation, vary depending on the age at the start of screening; the number of scans received;", "metadata": {}}
+{"_id": "26068103", "title": "", "text": "Dual role of interleukin-10 in the regulation of respiratory syncitial virus (RSV)-induced lunginflammation.RSV lower respiratory tract infections (LRTI) are among the most common diseasesnecessitating hospital admission in children. In addition to causing acute respiratory failure, RSVinfections are associated with sequelae such as secondary bacterial infections and reactive airwaydisease. One characteristic host response observed in severe RSV-induced LRTI and/or subsequentdevelopment of asthma is increased expression of interleukin (IL)-10. However, contradictory resultshave been reported regarding whether IL-10 inhibits asthmatic responses or intensifies the disease. Weaimed to reconcile these discordant observations by elucidating the role of IL-10 in regulating the hostresponse to RSV LRTI. In this study, we used a lung-specific, inducible IL-10 over-expression (OE)transgenic mouse model to address this question. Our results showed that the presence of IL-10 at thetime of RSV infection not only attenuated acute inflammatory process (i.e. 24 h post-infection), but alsolate inflammatory changes [characterized by T helper type 2 (Th2) cytokine and chemokine expression].While this result appears contradictory to some clinical observations where elevated IL-10 levels areobserved in asthmatic patients, we also found that delaying IL-10 OE until the late immune response toRSV infection, additive effects rather than inhibitory effects were observed. Importantly, in non-infected,IL-10 OE mice, IL-10 OE alone induced up-regulation of Th2 cytokine (IL-13 and IL-5) and Th2-relatedchemokine [monocyte chemoattractant protein 1 (MCP-1), chemokine (C-C motif) ligand 3 (CCL3) andregulated upon activation normal T cell expressed and secreted (RANTES)] expression. We identified asubset of CD11b(+)CD11c(+)CD49b(+)F4/80(-)Gr-1(-) myeloid cells as a prinicipal source ofIL-10-induced IL-13 production. Therefore, the augmented pathological responses observed in our'delayed' IL-10 over-expression model could be attributed to IL-10 OE alone. Taken together, our studyindicated dual roles of IL-10 on RSV-induced lung inflammation which appear to depend upon the timingof when elevated IL-10 is expressed in the lung.", "metadata": {}}
+{"_id": "26071782", "title": "", "text": "Latent membrane protein 1 of Epstein–Barr virus coordinately regulates proliferation with control ofapoptosisLatent membrane protein 1 (LMP1), an oncoprotein encoded by Epstein–Barr virus (EBV), is anintegral membrane protein, which acts like a constitutively active receptor. LMP1 is critical for some facetof EBV's induction and maintenance of proliferation of infected B cells. It, in part, mimics signaling by theCD40 receptor and has been implicated in regulating proliferation, survival, or both properties ofEBV-infected cells. We established a conditional LMP1 allele in the context of the intact EBV genome todefine the immediate-early cellular target genes regulated by LMP1 in order to assess its contributions toinfected human B cells. The functional analysis of this conditional system indicated that LMP1 specificallyinduces mitogenic B-cell activation through c-myc and Jun/AP1 family members and confirms its directrole in upregulating expression of multiple genes with opposing activities involved in cell survival. LMP1'ssignals were found to be essential for the G1/S transition in human B cells; cells lacking LMP1's signalsare cell cycle arrested and survive quiescently. LMP1's activities are therefore not required to maintainsurvival in nonproliferating cells. LMP1 does induce both pro- and antiapoptotic genes whose balanceseems to permit survival during LMP1's induction and maintenance of proliferation.", "metadata": {}}
+{"_id": "26079071", "title": "", "text": "Crizotinib in ROS1-rearranged non-small-cell lung cancer.BACKGROUND Chromosomal rearrangements ofthe gene encoding ROS1 proto-oncogene receptor tyrosine kinase (ROS1) define a distinct molecularsubgroup of non-small-cell lung cancers (NSCLCs) that may be susceptible to therapeutic ROS1 kinaseinhibition. Crizotinib is a small-molecule tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK),ROS1, and another proto-oncogene receptor tyrosine kinase, MET. METHODS We enrolled 50 patientswith advanced NSCLC who tested positive for ROS1 rearrangement in an expansion cohort of the phase 1study of crizotinib. Patients were treated with crizotinib at the standard oral dose of 250 mg twice dailyand assessed for safety, pharmacokinetics, and response to therapy. ROS1 fusion partners wereidentified with the use of next-generation sequencing or reverse-transcriptase-polymerase-chain-reactionassays. RESULTS The objective response rate was 72% (95% confidence interval [CI], 58 to 84), with 3complete responses and 33 partial responses. The median duration of response was 17.6 months (95%CI, 14.5 to not reached). Median progression-free survival was 19.2 months (95% CI, 14.4 to notreached), with 25 patients (50%) still in follow-up for progression. Among 30 tumors that were tested,we identified 7 ROS1 fusion partners: 5 known and 2 novel partner genes. No correlation was observedbetween the type of ROS1 rearrangement and the clinical response to crizotinib. The safety profile ofcrizotinib was similar to that seen in patients with ALK-rearranged NSCLC. CONCLUSIONS In this study,crizotinib showed marked antitumor activity in patients with advanced ROS1-rearranged NSCLC. ROS1rearrangement defines a second molecular subgroup of NSCLC for which crizotinib is highly active.(Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.).", "metadata": {}}
+{"_id": "26083387", "title": "", "text": "The S. cerevisiae Rrm3p DNA helicase moves with the replication fork and affects replication of all yeastchromosomes.The Saccharomyces cerevisiae DNA helicase Rrm3p is needed for normal fork progressionthrough >1000 discrete sites scattered throughout the genome. Here we show that replication of all yeastchromosomes was markedly delayed in rrm3 cells. Delayed replication was seen even in a region thatlacks any predicted Rrm3p-dependent sites. Based on the pattern of replication intermediates intwo-dimensional gels, the rate of fork movement in rrm3 cells appeared similar to wild-type except atknown Rrm3p-dependent sites. These data suggest that although Rrm3p has a global role in DNAreplication, its activity is needed only or primarily at specific, difficult-to-replicate sites. By the criterion ofchromatin immunoprecipitation, Rrm3p was associated with both Rrm3p-dependent and -independentsites, and moved with the replication fork through both. In addition, Rrm3p interacted with Pol2p, thecatalytic subunit of DNA polymerase epsilon, in vivo. Thus, rather than being recruited to its sites ofaction when replication forks stall at these sites, Rrm3p is likely a component of the replication forkapparatus.", "metadata": {}}
+{"_id": "26089649", "title": "", "text": "The pathophysiology of protein-overload proteinuria.Alterations in glomerular function and structure werestudied in protein-overload nephrosis in the rat induced by intraperitoneal administration of bovine serumalbumin (BSA). Fractional clearance (C/GFR) studies using inulin and tracer proteins of differentmolecular size and charge revealed in proteinuric rats 1) unchanged glomerular filtration rate and renalplasma flow; 2) a 34-fold increase in C/GFR of rat serum albumin, reaching values similar to BSA; 3) a2-fold increase in C/GFR for anionic horse radish peroxidase (HRP), but normal values for neutral andcationic HRP, and 4) an 11- and 3-fold increase for heterologous IgG and IgM, respectively. Glomerularepithelial cells showed degenerative changes, but the distribution of anionic sites in the glomerularbasement membrane was found to be unaltered, as determined by polyethyleneimine binding studies. Insummary, an elevation of serum albumin concentration resulted in an increased transcapillary albumintransport. This was found to lead to degenerative changes of glomerular epithelial cells with developmentof large pore defects, which were completely reversible.", "metadata": {}}
+{"_id": "26099680", "title": "", "text": "Effects of aging on central and peripheral mammalian clocks.Circadian organization changes with age, butwe do not know the extent to which age-related changes are the result of alterations in the centralpacemakers, the peripheral oscillators, or the coupling mechanisms that hold the system together. Byusing transgenic rats with a luciferase (luc) reporter, we assessed the effects of aging on the rhythm ofexpression of the Period 1 (Per1) gene in the suprachiasmatic nucleus (SCN) and in peripheral tissues.Young (2 months) and aged (24-26 months) Per1-luc transgenic rats, entrained to light-dark cycles, werekilled, and tissues were removed and cultured. Per1-luc expression was measured from 10 tissues. In theSCN, the central mammalian pacemaker, Per1-luc expression was robustly rhythmic for more than 7weeks in culture. The only difference between SCN rhythmicity in young and old rats was a small butsignificant age-related shortening of the free-running period. Circadian rhythmicity in some peripheraltissues was unaffected by aging, whereas rhythmicity in other tissues was either phase advanced relativeto the light cycle or absent. Those tissues that were arrhythmic could be induced to oscillate byapplication of forskolin, suggesting that they retained the capacity to oscillate but were not beingappropriately driven in vivo. Overall, the results provide new insights into the effects of aging on themammalian circadian system. Aging seems to affect rhythms in some but not in all tissues and may actprimarily on interactions among circadian oscillators, perhaps attenuating the ability of the SCN to drivedamped oscillators in the periphery.", "metadata": {}}
+{"_id": "26104554", "title": "", "text": "CtBP3/BARS drives membrane fission in dynamin-independent transport pathwaysMembrane fission is afundamental step in membrane transport. So far, the only fission protein machinery that has beenimplicated in in vivo transport involves dynamin, and functions in several, but not all, transport pathways.Thus, other fission machineries may exist. Here, we report that carboxy-terminal binding protein3/brefeldin A-ribosylated substrate (CtBP3/BARS) controls fission in basolateral transport from the Golgito the plasma membrane and in fluid-phase endocytosis, whereas dynamin is not involved in these steps.Conversely, CtBP3/BARS protein is inactive in apical transport to the plasma membrane and inreceptor-mediated endocytosis, both steps being controlled by dynamin. This indicates that CtBP3/BARScontrols membrane fission in endocytic and exocytic transport pathways, distinct from those that requiredynamin.", "metadata": {}}
+{"_id": "26105746", "title": "", "text": "Influenza A myocarditis developing in an adult liver transplant recipient despite vaccination: a case reportand review of the literature.Solid organ transplant recipients receiving chronic immunosuppressive agentsare at increased risk to acquire influenza virus despite vaccination. Myocarditis is a known but rarecomplication of influenza infection. We present the first adult liver transplant recipient who receivedprophylactic vaccination but developed influenza A myocarditis. This may occur in solid organ transplantrecipients, because they have reduced response to protein vaccines, which may leave them vulnerable toinfections. Studies are needed to evaluate if antiviral chemoprophylaxis in solid organ transplantrecipients during influenza season would be an effective preventive therapy against influenza in thishigh-risk population.", "metadata": {}}
+{"_id": "26107000", "title": "", "text": "Extrapulmonary effects of chronic obstructive pulmonary disease on physical activity: a cross-sectionalstudy.RATIONALE Physical activity is reduced in patients with chronic obstructive pulmonary disease(COPD). COPD has a systemic component that includes significant extrapulmonary effects that maycontribute to its severity in individual patients. OBJECTIVES To investigate the association ofextrapulmonary effects of the disease and its comorbidities with reduced physical activity in patients withCOPD. METHODS In a cross-sectional study, 170 outpatients with COPD (GOLD [Global Initiative forChronic Obstructive Lung Disease] stages I-IV; BODE [body mass index, airway obstruction, dyspnea,and exercise capacity] score 0-10) underwent a series of tests. Physical activity was assessed over 5 to 6consecutive days by using a multisensor accelerometer armband that records steps per day and thephysical activity level (total daily energy expenditure divided by whole-night sleeping energyexpenditure). Cardiovascular status was assessed by echocardiography, vascular Doppler sonography,and levels of N-terminal pro-B-type natriuretic peptide. Mental status, metabolic/muscular status,systemic inflammation, and anemia were assessed by Beck Depression Inventory, bioelectricalimpedance analysis, handgrip strength, high-sensitivity C-reactive protein/fibrinogen, and hemoglobin,respectively. MEASUREMENTS AND MAIN RESULTS In a multivariate linear regression analysis usingeither steps per day or physical activity level as a dependent variable, the extrapulmonary parametersthat were associated with reduced physical activity in patients with COPD independently of GOLD stagesor BODE score were N-terminal pro-B-type natriuretic peptide levels, echocardiographically measured leftventricular diastolic function, and systemic inflammation. CONCLUSIONS Higher values of systemicinflammation and left cardiac dysfunction are associated with reduced physical activity in patients withCOPD.", "metadata": {}}
+{"_id": "26108767", "title": "", "text": "Cleavage efficient 2A peptides for high level monoclonal antibody expression in CHO cells.Linking theheavy chain (HC) and light chain (LC) genes required for monoclonal antibodies (mAb) production on asingle cassette using 2A peptides allows control of LC and HC ratio and reduces non-expressing cells.Four 2A peptides derived from the foot-and-mouth disease virus (F2A), equine rhinitis A virus (E2A),porcine teschovirus-1 (P2A) and Thosea asigna virus (T2A), respectively, were compared for expressionof 3 biosimilar IgG1 mAbs in Chinese hamster ovary (CHO) cell lines. HC and LC were linked by different2A peptides both in the absence and presence of GSG linkers. Insertion of a furin recognition siteupstream of 2A allowed removal of 2A residues that would otherwise be attached to the HC. Different 2Apeptides exhibited different cleavage efficiencies that correlated to the mAb expression level. The relativecleavage efficiency of each 2A peptide remains similar for expression of different IgG1 mAbs in differentCHO cells. While complete cleavage was not observed for any of the 2A peptides, GSG linkers didenhance the cleavage efficiency and thus the mAb expression level. T2A with the GSG linker (GT2A)exhibited the highest cleavage efficiency and mAb expression level. Stably amplified CHO DG44 poolsgenerated using GT2A had titers 357, 416 and 600 mg/L for the 3 mAbs in shake flask batch cultures.Incomplete cleavage likely resulted in incorrectly processed mAb species and aggregates, which wereremoved with a chromatin-directed clarification method and protein A purification. The vector andmethods presented provide an easy process beneficial for both mAb development and manufacturing.", "metadata": {}}
+{"_id": "26112624", "title": "", "text": "The complexity of human ribosome biogenesis revealed by systematic nucleolar screening of Pre-rRNAprocessing factors.Mature ribosomal RNAs (rRNAs) are produced from polycistronic precursors followingcomplex processing. Precursor (pre)-rRNA processing has been extensively characterized in yeast andwas assumed to be conserved in humans. We functionally characterized 625 nucleolar proteins in HeLacells and identified 286 required for processing, including 74 without a yeast homolog. For selectedcandidates, we demonstrated that pre-rRNA processing defects are conserved in different cell types(including primary cells), defects are not due to activation of a p53-dependent nucleolar tumorsurveillance pathway, and they precede cell-cycle arrest and apoptosis. We also investigated theexosome's role in processing internal transcribed spacers (ITSs) and report that 3' end maturation of 18SrRNA involves EXOSC10/Rrp6, a yeast ITS2 processing factor. We conclude that human cells adoptunique strategies and recruit distinct trans-acting factors to carry out essential processing steps, posingfundamental implications for understanding ribosomopathies at the molecular level and developingeffective therapeutic agents.", "metadata": {}}
+{"_id": "26112696", "title": "", "text": "Maximal aerobic capacity in African-American and Caucasian prepubertal children.The purpose of thisstudy was to examine differences in resting, submaximal, and maximal (VO2max) oxygen consumption(VO2) in African-American (n = 44) and Caucasian (n = 31) prepubertal children aged 5-10 yr. RestingVO2 was measured via indirect calorimetry in the fasted state. Submaximal VO2 and VO2max weredetermined during an all out, progressive treadmill exercise test appropriate for children. Dual-energyX-ray absorptiometry was used to determine total fat mass (FM), soft lean tissue mass (LTM), and legsoft LTM. Doubly labeled water was used to determine total energy expenditure (TEE) and activity energyexpenditure (AEE). A significant effect of ethnicity (P < 0.01) was found for VO2max but not resting orsubmaximal VO2, with African-American children having absolute VO2max approximately 15% lowerthan Caucasian children (1.21 +/- 0.032 vs. 1.43 +/- 0.031 l/min, respectively). The lower VO2maxpersisted in African-American children after adjustment for soft LTM (1.23 +/- 0.025 vs. 1.39 +/- 0.031l/min; P < 0.01), leg soft LTM (1.20 +/- 0.031 vs. 1.43 +/- 0.042 l/min; P < 0.01), and soft LTM and FM(1.23 +/- 0.025 vs. 1.39 +/- 0.031 l/min; P < 0.01). The lower VO2max persisted also after adjustmentfor TEE (1.20 +/- 0.02 vs. 1.38 +/- 0.0028 l/min P < 0.001) and AEE (1.20 +/- 0.024 vs. 1.38 +/- 0.028l/min; P < 0.001). In conclusion, our data indicate that African-American and Caucasian children havesimilar rates of VO2 at rest and during submaximal exercise, but VO2max is approximately 15% lower inAfrican-American children, independent of soft LTM, FM, leg LTM, TEE, and AEE.", "metadata": {}}
+{"_id": "26117607", "title": "", "text": "Penaeus monodon Dscam (PmDscam) has a highly diverse cytoplasmic tail and is the firstmembrane-bound shrimp Dscam to be reported.Down syndrome cell adhesion molecule (Dscam) seemslikely to play a key role in the \"alternative adaptive immunity\" that has been reported in invertebrates.Dscam consists of a cytoplasmic tail that is involved in signal transduction and a hypervariableextracellular region that might use a pathogen recognition mechanism similar to that used by thevertebrate antibodies. In our previous paper, we isolated a unique tail-less form of Dscam fromLitopenaeus vannamei. In this study, we report the first membrane-bound form of shrimp Dscam:PmDscam was isolated from Penaeus monodon, and it occurred in both membrane-bound and tail-lessforms. Phylogenetic analysis showed that while the crustacean Dscams from shrimp and water flea didnot share a single subclade, they were distinct from the invertebrate Dscam-like molecules and from theinsecta Dscams. In the extracellular region, the variable regions of PmDscam were located in N-terminalIg2, N-terminal Ig3 and the entire Ig7 domain. The PmDscam extracellular variants and transmembranedomain variants were produced by mutually exclusive alternative splicing events. The cytoplasmic tailvariants were produced by exon inclusion/exclusion. Based on the genomic organization of DaphniaDscam's cytoplasmic tail, we propose a model of how the shrimp Dscam genomic locus might use TypeIII polyadenylation to generate both the tail-less and membrane-bound forms.", "metadata": {}}
+{"_id": "26118532", "title": "", "text": "The different biological effects of telomestatin and TMPyP4 can be attributed to their selectivity forinteraction with intramolecular or intermolecular G-quadruplex structures.Demonstration of the existenceof G-quadruplex structures in telomeres of Stylonychia macronuclei and in the promoter of c-myc inhuman cells has validated these secondary DNA structures as potential targets for drug design. The nextimportant issue is the selectivity of G-quadruplex-interactive agents for the different types ofG-quadruplex structures. In this study, we have taken an important step in associating specific biologicaleffects of these drugs with selective interaction with either intermolecular or intramolecular G-quadruplexstructures formed in telomeres. Telomestatin is a natural product isolated from Streptomyces anulatus3533-SV4 and has been shown to be a very potent telomerase inhibitor through its G-quadruplexinteraction. We have demonstrated that telomestatin interacts preferentially with intramolecular versusintermolecular G-quadruplex structures and also has a 70-fold selectivity for intramolecular G-quadruplexstructures over duplex DNA. Telomestatin is able to stabilize G-quadruplex structures that are formedfrom duplex human telomeric DNA as well as from single-stranded DNA. Importantly, telomestatinstabilizes these G-quadruplex structures in the absence of monovalent cations, which is a uniquecharacteristic among G-quadruplex-interactive compounds. At noncytotoxic concentrations, telomestatinsuppresses the proliferation of telomerase-positive cells within several weeks. In contrast, TMPyP4, acompound that preferentially facilitates the formation of intermolecular G-quadruplex structures,suppresses the proliferation of alternative lengthening of telomeres (ALT)-positive cells as well astelomerase-positive cells. We have also demonstrated that TMPyP4 induces anaphase bridges in seaurchin embryos, whereas telomestatin did not have this effect, leading us to conclude that the selectivityof telomestatin for intramolecular G-quadruplex structures and TMPyP4 for intermolecular G-quadruplexstructures is important in mediating different biological effects: stabilization of intramolecularG-quadruplex structures produces telomerase inhibition and accelerated telomere shortening, whereasfacilitation of the formation of intermolecular G-quadruplex structures induces the formation of anaphasebridges.", "metadata": {}}
+{"_id": "26121646", "title": "", "text": "Targeting oxidative stress to treat endometriosis.INTRODUCTION Endometriosis affects 10% of women ofreproductive age. It is defined as the presence of implanted active endometrial tissue outside the uterinecavity. The exact pathophysiology of endometriosis is still uncertain, although several optional etiologicaltheories have been suggested. Being so common, a novel treatment for endometriosis is widely quested.Recent studies addressing the pathological characteristics of endometriosis have revealed a vicious cyclein which oxidative stress (OS) is generated, which in turn facilitates the implantation of the ectopicendometrium. At the same time, the generation of high amounts of reactive oxygen species furthertriggers a state of OS. AREAS COVERED The author examined the evidence associating OS andendometriosis. After establishing an association, a search for antioxidant agents that were investigatedspecifically on endometriosis patients are described including Vitamins C and E, melatonin, resveratrol,xanthohumol and epigallocatechin-3-gallate. A significant effect of all the reviewed antioxidants onendometriosis is reported. EXPERT OPINION Aiming for the reduction of OS as the treatment goal forendometriosis looks promising. However, since most of the studies are either in vitro or are animal based,further studies on human subjects are deemed necessary to elucidate the impact of OS reduction onpatients with endometriosis.", "metadata": {}}
+{"_id": "26124606", "title": "", "text": "Interferon alpha for the treatment of chronic hepatitis C in patients infected with humanimmunodeficiency virus. Hepatitis-HIV Spanish Study Group.Liver disease secondary to hepatitis C virus(HCV) infection is a rising cause of morbidity and mortality among individuals who have been infectedparenterally with human immunodeficiency virus (HIV) such as injection drug users, hemophiliacs, andtransfused patients. We analyzed both the efficacy of interferon (IFN) alpha therapy in these patients andthe predictors of response to this agent. A total of 119 patients with chronic hepatitis C (90 of whom wereinfected with HIV and 29 of whom were not) were included in a multicenter, prospective, open,nonrandomized observational study. IFN-alpha was given subcutaneously in a dosage of 5 million unitsthree times a week during a 3-month period; those patients who responded received a dose of 3 millionunits given subcutaneously three times a week for an additional 9 months. One hundred seven patientscompleted the study; the level of aminotransferases returned to normal and sera became negative(complete response) for HCV RNA in 26 (32.5%) of 80 HIV-infected patients and 10 (37.0%) of 27non-HIV-infected patients (P = .666) after completion of the treatment. Two variables wereindependently associated with a response in HIV-infected patients: a CD4+ T lymphocyte count of > 500x 10(6)/L and a baseline HCV viremia level of < 10(7) copies/mL. In the 12 months following treatment,relapses occurred in 30.8% of the HIV-infected patients and 12.5% of non-HIV-infected patients (P =.403).", "metadata": {}}
+{"_id": "26132041", "title": "", "text": "Vanishing cerebellar infarcts in a migraine patient.Recent population-based studies have suggested thatmigraine is a risk factor for the development of infarct-like lesions in the territory of the posteriorcirculation. These lesions are thought to be true vascular infarcts based on their size, location andmagnetic resonance imaging (MRI) characteristics. However, as there are no postmortem studiesidentifying the pathology of these MRI findings, their true aetiology is unknown. A case patient withmigraine is presented, who developed what appeared to be cerebellar infarcts on MRI, but these lesionsvanished on repeat imaging 16 days later, questioning their aetiology as vascular ischaemic basedinfarcts.", "metadata": {}}
+{"_id": "26133404", "title": "", "text": "A novel viral transcript with homology to human interleukin-10 is expressed during latent humancytomegalovirus infection.Human cytomegalovirus (CMV) establishes latent infections in hematopoieticcells such as granulocyte-macrophage progenitors (GM-Ps). During latency the virus is sequestered in anonreplicating state, although limited transcriptional activity has been previously reported. In this studywe sought to further examine viral gene expression during the latent phase of infection. Using anexperimental model of latency, primary human GM-Ps were latently infected with CMV strain Toledo andextracted RNA subjected to reverse transcription-PCR by using CMV gene-specific primers. Using thisapproach, we detected transcription from the UL111.5A region of the viral genome. This transcription wasalso detected in GM-Ps latently infected with AD169 and Towne strains, indicating that expression wasCMV strain independent. Significantly, we detected UL111.5A-region transcripts in mononuclear cellsfrom healthy bone marrow and mobilized peripheral blood allograft donors, demonstrating expressionduring natural latent infection. Mapping experiments with RNA extracted from latently infected GM-Psrevealed the expression of a novel UL111.5A region transcript with a splicing pattern that differed fromthat reported during productive infection of permissive cells. This UL111.5A region transcript expressedduring latent infection is predicted to encode a 139-amino-acid protein with homology to the potentimmunosuppressor interleukin-10 (IL-10) and to the viral IL-10 homolog that is expressed duringproductive CMV infection. Expression of a latency-associated cmvIL-10 may confer upon the virus anability to avoid immune recognition and clearance during the latent phase of infection.", "metadata": {}}
+{"_id": "26150367", "title": "", "text": "Treatments for somnambulism in adults: assessing the evidence.Somnambulism, or sleepwalking, is aparasomnia of non-rapid eye movement (NREM) sleep where movement behaviours usually confined towakefulness are displayed during sleep. Generally, if sleepwalking is causing distress or danger in spite ofsafety measures, medical or psychological treatment is indicated. Clinicians will need to assess theevidence for treatment options. MEDLINE, EMBASE, PsycINFO and the Ovid Evidence-Based MedicineReviews (EBM) multifile databases were searched. No properly powered rigorous controlled trials werefound for treatment of sleepwalking in adults. Seven reports described small trials with some kind ofcontrol arm, or retrospective case series which included 30 or more patients. With no high qualityevidence to underpin recommendations for treatments of somnambulism, full discussion with patients isadvised. Adequately powered, well-designed clinical trials are now needed, and multi-centrecollaborations may be required to obtain the sample sizes required.", "metadata": {}}
+{"_id": "26182390", "title": "", "text": "Premature chromosome condensation: evidence for in vivo cell fusion in human malignanttumours.Premature chromosome condensation (PCC) was studied in direct preparations of tissues frompatients with haematological diseases and carcinomas of various histological types. PCC was found in 6out of 166 malignancies (128 haematological cases, 35 carcinomas and 3 malignant effusions) analysedwith the GTG-technique. Chromosome analysis revealed S-phase and G1-phase PCC in each case; thefrequency of PCC varied between 1, 4 and 8.6% of the metaphases analysed. It is suggested that PCCchromosomes, which represent cell fusion in vivo, are not very rare in naturally-occurring humanmalignancies, and that cell fusion may affect the malignant phenotype. In conjunction with other factorsthey may also explain the heterogeneity of tumour cell populations.", "metadata": {}}
+{"_id": "26199970", "title": "", "text": "Blockade of the angiotensin system improves mental health domain of quality of life: A meta-analysis ofrandomized clinical trialsObjective: It is unclear whether blockade of the angiotensin system has effectson mental health. Our objective was to determine the impact of angiotensin converting enzyme inhibitorsand angiotensin II type 1 receptor (AT1R) blockers on mental health domain of quality of life. Studydesign: Meta-analysis of published literature. Data sources: PubMed and clinicaltrials.gov databases. Thelast search was conducted in January 2017. Study selection: Randomized controlled trials comparing anyangiotensin converting enzyme inhibitor or AT1R blocker versus placebo or non-angiotensin convertingenzyme inhibitor or non-AT1R blocker were selected. Study participants were adults without any majorphysical symptoms. We adhered to meta-analysis reporting methods as per PRISMA and the CochraneCollaboration. Data synthesis: Eleven studies were included in the analysis. When compared with placeboor other antihypertensive medications, AT1R blockers and angiotensin converting enzyme inhibitors wereassociated with improved overall quality of life (standard mean difference = 0.11, 95% confidenceinterval = [0.08, 0.14], p < 0.0001), positive wellbeing (standard mean difference = 0.11, 95%confidence interval = [0.05, 0.17], p < 0.0001), mental (standard mean difference = 0.15, 95%confidence interval = [0.06, 0.25], p < 0.0001), and anxiety (standard mean difference = 0.08, 95%confidence interval = [0.01, 0.16], p < 0.0001) domains of QoL. No significant difference was found forthe depression domain (standard mean difference = 0.05, 95% confidence interval = [0.02, 0.12], p =0.15). Conclusions: Use of angiotensin blockers and inhibitors for the treatment of hypertension inotherwise healthy adults is associated with improved mental health domains of quality of life. Mentalhealth quality of life was a secondary outcome in the included studies. Research specifically designed toanalyse the usefulness of drugs that block the angiotensin system is necessary to properly evaluate thisnovel psychiatric target.", "metadata": {}}
+{"_id": "26230669", "title": "", "text": "The role of epigenetics in aging and autoimmunity.The decline in immunocompetence with age isaccompanied by the increase in the incidence of autoimmune diseases. Aging of the immune system, orimmunosenescence, is characterized by a decline of both T and B cell function, and paradoxically thepresence of low-grade chronic inflammation. There is growing evidence that epigenetics, the study ofinherited changes in gene expression that are not encoded by the DNA sequence itself, changes withaging. Interestingly, emerging evidence suggests a key role for epigenetics in human pathologies,including inflammatory and neoplastic disorders. Here, we will review the potential mechanisms thatcontribute to the increase in autoimmune responses in aging. In particular, we will discuss how epigeneticalterations, especially DNA methylation and histone acetylation, are accumulated during aging and howthese events contribute to autoimmunity risk.", "metadata": {}}
+{"_id": "26231129", "title": "", "text": "A framework for understanding and targeting residual disease in oncogene-driven solid cancersMoleculartargeted therapy has the potential to dramatically improve survival in patients with cancer. However,complete and durable responses to targeted therapy are rare in individuals with advanced-stage solidcancers. Even the most effective targeted therapies generally do not induce a complete tumor response,resulting in residual disease and tumor progression that limits patient survival. We discuss the emergingneed to more fully understand the molecular basis of residual disease as a prelude to designingtherapeutic strategies to minimize or eliminate residual disease so that we can move from temporary tochronic control of disease, or a cure, for patients with advanced-stage solid cancers. Ultimately, wepropose a shift from the current reactive paradigm of analyzing and treating acquired drug resistance to apre-emptive paradigm of defining the mechanisms that result in residual disease, to target and limit thisdisease reservoir.", "metadata": {}}
+{"_id": "26244918", "title": "", "text": "Long-term inhibition of dipeptidyl peptidase-4 in Alzheimer's prone mice.We tested here the impact of along-term inhibition of dipeptidyl peptidase-4 (DPP-4) with sitagliptin on the deposition of amyloid-betawithin the brain and deficits in memory-related behavioral paradigms in a model of Alzheimer's disease(AD): double transgenic mice B6*Cg-Tg(APPswe,PSEN1dE9)85Dbo/J. Mice began to receive sitagliptin at7 months of age. Three different dose of sitagliptin (5, 10 and 20 mg/kg), were administered daily for 12weeks by gastric gavage. The treatments counteracted: (i) the memory impairment in the contextual fearconditioning test; (ii) increased the brain levels of GLP-1; (iii) produced significant reductions ofnitrosative stress and inflammation hallmarks within the brain, as well as (iv) a significant diminution inthe ultimate number and total area of betaAPP and Abeta deposits. All these effects much more evidentfor the dose of 20 mg/kg sitagliptin. The long-term inhibition of the endogenous DPP-4 enzymes withsitagliptin can significantly delay some forms of AD pathology, including amyloid deposition, whenadministered early in the disease course of a transgenic mouse model of AD.", "metadata": {}}
+{"_id": "26283293", "title": "", "text": "Structural and mechanistic insights into phospholipid transfer by Ups1–Mdm35 in mitochondriaEukaryoticcells are compartmentalized into membrane-bounded organelles whose functions rely on lipid traffickingto achieve membrane-specific compositions of lipids. Here we focused on the Ups1-Mdm35 system, whichmediates phosphatidic acid (PA) transfer between the outer and inner mitochondrial membranes, anddetermined the X-ray structures of Mdm35 and Ups1-Mdm35 with and without PA. The Ups1-Mdm35complex constitutes a single domain that has a deep pocket and flexible Ω-loop lid. Structure-basedmutational analyses revealed that a basic residue at the pocket bottom and the Ω-loop lid are importantfor PA extraction from the membrane following Ups1 binding. Ups1 binding to the membrane is enhancedby the dissociation of Mdm35. We also show that basic residues around the pocket entrance areimportant for Ups1 binding to the membrane and PA extraction. These results provide a structural basisfor understanding the mechanism of PA transfer between mitochondrial membranes.", "metadata": {}}
+{"_id": "26297042", "title": "", "text": "Redox regulation of cell migration and adhesion.Reactive oxygen species (ROS), particularly hydrogenperoxide, and the proteins that regulate them play important roles in the migration and adhesion of cells.Stimulation of cell surface receptors with growth factors and chemoattractants generates ROS, whichrelay signals from the cell surface to key signaling proteins inside the cell. ROS act within cells to promotemigration and also in nonmigrating cells to influence the behavior of migrating cells. Hydrogen peroxidehas also been suggested to act as a chemoattractant in its own right, drawing immune cells to wounds.We discuss recent progress made towards understanding how organisms use ROS, and to what degreethey depend on them, during the related processes of cell migration and adhesion.", "metadata": {}}
+{"_id": "26314743", "title": "", "text": "Systemic Inflammatory Response Syndrome, Quick Sequential Organ Function Assessment, and OrganDysfunction: Insights From a Prospective Database of ED Patients With InfectionBACKGROUND: Aproposed revision of sepsis definitions has abandoned the systemic inflammatory response syndrome(SIRS), defined organ dysfunction as an increase in total Sequential Organ Function Assessment (SOFA)score of ≥ 2, and conceived “qSOFA” (quick SOFA) as a bedside indicator of organ dysfunction. We aimedto (1) determine the prognostic impact of SIRS, (2) compare the diagnostic accuracy of SIRS and qSOFAfor organ dysfunction, and (3) compare standard (Sepsis\u00002) and revised (Sepsis\u00003) definitions fororgan dysfunction in ED patients with infection. METHODS: Consecutive ED patients admitted withpresumed infection were prospectively enrolled over 3 years. Sufficient observational data were collectedto calculate SIRS, qSOFA, SOFA, comorbidity, and mortality. RESULTS: We enrolled 8,871 patients, withSIRS present in 4,176 (47.1%). SIRS was associated with increased risk of organ dysfunction (relativerisk [RR] 3.5) and mortality in patients without organ dysfunction (OR 3.2). SIRS and qSOFA showedsimilar discrimination for organ dysfunction (area under the receiver operating characteristic curve, 0.72vs 0.73). qSOFA was specific but poorly sensitive for organ dysfunction (96.1% and 29.7%, respectively).Mortality for patients with organ dysfunction was similar for Sepsis\u00002 and Sepsis\u00003 (12.5% and 11.4%,respectively), although 29% of patients with Sepsis\u00003 organ dysfunction did not meet Sepsis\u00002 criteria.Increasing numbers of Sepsis\u00002 organ system dysfunctions were associated with greater mortality.CONCLUSIONS: SIRS was associated with organ dysfunction and mortality, and abandoning the conceptappears premature. A qSOFA score ≥ 2 showed high specificity, but poor sensitivity may limit utility as abedside screening method. Although mortality for organ dysfunction was comparable between Sepsis\u00002and Sepsis\u00003, more prognostic and clinical information is conveyed using Sepsis\u00002 regarding numberand type of organ dysfunctions. The SOFA score may require recalibration.", "metadata": {}}
+{"_id": "26330861", "title": "", "text": "Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomycescerevisiae.Calorie restriction extends life-span in a wide variety of organisms. Although it has beensuggested that calorie restriction may work by reducing the levels of reactive oxygen species producedduring respiration, the mechanism by which this regimen slows aging is uncertain. Here, we mimickedcalorie restriction in yeast by physiological or genetic means and showed a substantial extension inlife-span. This extension was not observed in strains mutant for SIR2 (which encodes the silencingprotein Sir2p) or NPT1 (a gene in a pathway in the synthesis of NAD, the oxidized form of nicotinamideadenine dinucleotide). These findings suggest that the increased longevity induced by calorie restrictionrequires the activation of Sir2p by NAD.", "metadata": {}}
+{"_id": "26336593", "title": "", "text": "Pathways disrupted in human ALS motor neurons identified through genetic correction of mutantSOD1.Although many distinct mutations in a variety of genes are known to cause Amyotrophic LateralSclerosis (ALS), it remains poorly understood how they selectively impact motor neuron biology andwhether they converge on common pathways to cause neuronal degeneration. Here, we have combinedreprogramming and stem cell differentiation approaches with genome engineering and RNA sequencing todefine the transcriptional and functional changes that are induced in human motor neurons by mutantSOD1. Mutant SOD1 protein induced a transcriptional signature indicative of increased oxidative stress,reduced mitochondrial function, altered subcellular transport, and activation of the ER stress and unfoldedprotein response pathways. Functional studies demonstrated that these pathways were perturbed in amanner dependent on the SOD1 mutation. Finally, interrogation of stem-cell-derived motor neuronsproduced from ALS patients harboring a repeat expansion in C9orf72 indicates that at least a subset ofthese changes are more broadly conserved in ALS.", "metadata": {}}
+{"_id": "26341063", "title": "", "text": "Effect of enalapril on 12-year survival and life expectancy in patients with left ventricular systolicdysfunction: a follow-up study.BACKGROUND In the studies of left ventricular dysfunction (SOLVD),enalapril reduced mortality in patients with symptomatic but not asymptomatic left ventricular systolicdysfunction during the trial. We did a 12-year follow-up of SOLVD to establish if the mortality reductionwith enalapril among patients with heart failure was sustained, and whether a subsequent reduction inmortality would emerge among those with asymptomatic ventricular dysfunction. METHODS Of the 6797patients previously enrolled in the SOLVD prevention and treatment trials, we ascertained the subsequentvital status of 5165 individuals who were alive when the trials had been completed. Follow-up was donethrough direct contacts in Belgium and linkages with national death registries and federal beneficiary orhistoric tax summary files in the USA and Canada. FINDINGS Follow-up was 99.8% (6784/6797)complete. In the prevention trial, 50.9% (1074/2111) of the enalapril group had died compared with56.4% (1195/2117) of the placebo group (generalised Wilcoxon p=0.001). In the treatment trial, 79.8%(1025/1285) of the enalapril group had died compared with 80.8% (1038/1284) of the placebo group(generalised Wilcoxon p=0.01). The reductions in cardiac deaths were significant and similar in bothtrials. When data for the prevention and treatment trials were combined, the hazard ratio for death was0.90 for the enalapril group compared with the placebo group (95% CI 0.84-0.95, generalised Wilcoxonp=0.0003). Enalapril extended median survival by 9.4 months in the combined trials (95% CI 2.8-16.5,p=0.004). INTERPRETATION Treatment with enalapril for 3-4 years led to a sustained improvement insurvival beyond the original trial period in patients with left ventricular systolic dysfunction, with animportant increase in life expectancy.", "metadata": {}}
+{"_id": "26374799", "title": "", "text": "TGFbeta/activin/nodal signaling is necessary for the maintenance of pluripotency in human embryonicstem cells.Human embryonic stem cells (hESCs) self-renew indefinitely and give rise to derivatives of allthree primary germ layers, yet little is known about the signaling cascades that govern their pluripotentcharacter. Because it plays a prominent role in the early cell fate decisions of embryonic development, wehave examined the role of TGFbeta superfamily signaling in hESCs. We found that, in undifferentiatedcells, the TGFbeta/activin/nodal branch is activated (through the signal transducer SMAD2/3) while theBMP/GDF branch (SMAD1/5) is only active in isolated mitotic cells. Upon early differentiation, SMAD2/3signaling is decreased while SMAD1/5 signaling is activated. We next tested the functional role ofTGFbeta/activin/nodal signaling in hESCs and found that it is required for the maintenance of markers ofthe undifferentiated state. We extend these findings to show that SMAD2/3 activation is requireddownstream of WNT signaling, which we have previously shown to be sufficient to maintain theundifferentiated state of hESCs. Strikingly, we show that in ex vivo mouse blastocyst cultures, SMAD2/3signaling is also required to maintain the inner cell mass (from which stem cells are derived). These datareveal a crucial role for TGFbeta signaling in the earliest stages of cell fate determination anddemonstrate an interconnection between TGFbeta and WNT signaling in these contexts.", "metadata": {}}
+{"_id": "26378103", "title": "", "text": "The structure and expression of a novel gene activated in early mouse embryogenesis.We report thecloning and sequence determination of the mouse H19 gene. This gene is under the genetic control of twotrans-acting loci in the mouse, termed raf and Rif. These loci determine the adult basal and induciblelevels, respectively, of H19 mRNA, as well as the mRNA for alpha-fetoprotein. By elucidating thesequence and structure of the H19 gene we show that it is unrelated to the alpha-fetoprotein gene, andtherefore must have acquired its regulation by raf and Rif independently. The sequence also indicatesthat the H19 gene has a very unusual structure. It is composed of five exons, 1307, 135, 119, 127 and560 bp in size, along with four very small introns whose combined lengths are 270 bases. The largestopen reading frame of the gene, sufficient to encode a protein of approximately 14 kd, is containedentirely within the first large exon, 680 bases downstream of the cap site of the mRNA. Preceding thetranslation initiation codon are four ATG codons, each of which is followed shortly thereafter bytranslation terminator codons. The rest of the gene, which encompasses all five exons, is presumed to beuntranslated. That the long 5' untranslated region may be used to regulate the translation of the mRNA issuggested from in vitro translation studies. Experiments which utilized tissue culture cell lines of themesodermal lineage suggest that the gene is activated very early during muscle cell differentiation.", "metadata": {}}
+{"_id": "26409363", "title": "", "text": "Diminished linear growth during intermittent calcitriol therapy in children undergoing CCPD.Daily calcitrioltherapy has been reported to improve linear growth in children with renal bone disease, and1,25-dihydroxyvitamin D is a key regultor of chondrocyte proliferation and differentiation. Whereas largeintermittent doses of calcitriol can lower serum parathyroid hormone (PTH) levels and reverse theskeletal changes of secondary hyperparathyroidism, the impact of intermittent calcitriol therapy on lineargrowth in children is not known. Thus, we studied 16 pre-pubertal patients with bone biopsy-provensecondary hyperparathyroidism who completed a 12-month prospective clinical trial of intermittentcalcitriol therapy. Biochemical results and growth data obtained during intermittent calcitriol therapy werecompared to values determined during the preceding 12 months of daily calcitriol therapy in each studysubject; changes in bone histology were assessed after one year of intermittent calcitriol therapy.Z-scores for height did not change during 12 months of daily calcitriol therapy. Although the skeletallesions of secondary hyperparathyroidism improved in most patients, Z-scores for height decreased from-1.8 +/- 0.32 to -2.0 +/- 0.33, P < 0.01, during intermittent calcitriol therapy. The largest reductionswere seen in patients who developed adynamic bone lesions after 12 months of treatment. Delta Z-scoresfor height correlated with serum PTH, r = 0.71, P < 0.01, and alkaline phosphatase levels, r = 0.67, P <0.01, during intermittent calcitriol therapy but not during daily calcitriol therapy. The data suggest thathigh dose intermittent calcitriol therapy adversely affects linear growth, particularly in patients with theadynamic lesion. The higher doses of calcitriol or the intermittent schedule of calcitriol administrationmay directly inhibit chondrocyte activity within growth plate cartilage of children with end-stage renaldisease.", "metadata": {}}
+{"_id": "26445118", "title": "", "text": "Comparison of pain syndromes associated with nervous or somatic lesions and development of a newneuropathic pain diagnostic questionnaire (DN4)Few studies have directly compared the clinical featuresof neuropathic and non-neuropathic pains. For this purpose, the French Neuropathic Pain Groupdeveloped a clinician-administered questionnaire named DN4 consisting of both sensory descriptors andsigns related to bedside sensory examination. This questionnaire was used in a prospective study of 160patients presenting with pain associated with a definite neurological or somatic lesion. The most commonaetiologies of nervous lesions (n=89) were traumatic nerve injury, post herpetic neuralgia and poststroke pain. Non-neurological lesions (n=71) were represented by osteoarthritis, inflammatoryarthropathies and mechanical low back pain. Each patient was seen independently by two experts inorder to confirm the diagnosis of neuropathic or non-neuropathic pain. The prevalence of pain descriptorsand sensory dysfunctions were systematically compared in the two groups of patients. The analysis of thepsychometric properties of the DN4 questionnaire included: face validity, inter-rater reliability, factoranalysis and logistic regression to identify the discriminant properties of items or combinations of itemsfor the diagnosis of neuropathic pain. We found that a relatively small number of items are sufficient todiscriminate neuropathic pain. The 10-item questionnaire developed in the present study constitutes anew diagnostic instrument, which might be helpful both in clinical research and daily practice.", "metadata": {}}
+{"_id": "26456326", "title": "", "text": "Changing the density of alcohol outlets to reduce alcohol-related problems.Increasingly, it seems, legaland political debates regarding the granting of new liquor licences are turning to the issue of whether thenumber and density of alcohol outlets makes a difference in rates of alcohol consumption andalcohol-related harm. But what is the state of the evidence on this question? In this Harm ReductionDigest Livingston, Chikritzhs and Room review the research literature on the effects of density of alcoholsales outlets on alcohol consumption and alcohol-related problems; suggest a new way of conceptualisingthe relationships; and discuss the implications for reducing alcohol-related harm.", "metadata": {}}
+{"_id": "26461066", "title": "", "text": "[Pharmacokinetics and biotransformation of the antimycotic drug ciclopiroxolamine in animals and manafter topical and systemic administration].1. Following the dermal application of the carbon-14 labelledbroad spectrum antimycotic 6-cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridone, 2-aminoethanol salt(ciclopiroxolamine, Hoe 296, Batrafen) in the form of a 1% aqueous cream to healthy human dorsal skin(penetration time: 6 h; occlusive dressing for 5 h), percutaneous absorption accounted on average for1.3% of the dose applied. Excretion occurred via the kidney, with biological half-lives of 1.7 h. As can beseen from penetration studies of cadaverous skin, the horny layer contained the highest concentrations,with values of 2300-4500 microgram/cm3. The levels determined in the corium were still above theminimum inhibitory concentrations. These concentrations were already obtained at the first test stage(1.5 h after application) and did not change virtually at all over the longer penetration period. Accordingto studies using histoautoradiography, ciclopirox can penetrate the skin via the epidermis and the hairfollicles. When ciclopirox-14C-olamine aqueous cream was spread on the surface of fingernails, theradioactive-labelled compound penetrated right through the nail. The percutaneous absorption in dogswas higher, at 5-15% of the dose, than it was in humans. 2. After vaginal application (1 mg/kg) ofciclopirox-14C-olamine in the form of a 1% aqueous cream to bitches, between 42 and 97% of the dose(depending on the animal) was recovered in the urine and faeces, the remainder having penetrated intothe tampon used to close the vagina. 3. Ciclopirox is excreted by dogs and man in the urine, primarily asa glucuronide. In humans another glucuronide with properties similar to those of the original substancewas detected. Two conjugated, relatively non-polar metabolites were also present in small amounts. Themetabolite patterns after oral and dermal application were similar. The binding of ciclopirox to serumproteins in humans was 96 +/- 2% in a concentration range of 0.01-11.0 microgram/ml. 4. Placentaltransfer was low in the rats studied. Though there was good absorption by the mother animal, theradioactivity in the foetal tissues was always lower than that of the maternal blood.", "metadata": {}}
+{"_id": "26462632", "title": "", "text": "Maximizing the diagnostic utility of endoscopic biopsy in dogs and cats with gastrointestinaldisease.Flexible endoscopy has become a valuable tool for the diagnosis of many small animalgastrointestinal (GI) diseases, but the techniques must be performed carefully so that the results aremeaningful. This article reviews the current diagnostic utility of flexible endoscopy, includingpractical/technical considerations for endoscopic biopsy, optimal instrumentation for mucosal specimencollection, the correlation of endoscopic indices to clinical activity and to histopathologic findings, and newdevelopments in the endoscopic diagnosis of GI disease. Recent studies have defined endoscopic biopsyguidelines for the optimal number and quality of diagnostic specimens from different regions of the gut.They also have shown the value of ileal biopsy in the diagnosis of canine and feline chronic enteropathies,and have demonstrated the utility of endoscopic biopsy specimens beyond routine hematoxylin and eosinhistopathological analysis, including their use in immunohistochemical, microbiological, and molecularstudies.", "metadata": {}}
+{"_id": "26474812", "title": "", "text": "Age-structured red blood cell susceptibility and the dynamics of malaria infections.Malaria parasites andimmune responses in an infected human interact on a dynamic landscape, in which a population ofreplicating parasites depletes a population of replenishing red blood cells (RBCs). These underlyingdynamics receive relatively little attention, but they offer unique insights into the processes that controlmost malaria infections. Here, we focus on the observation that three of the four malaria-parasite speciesthat infect humans are restricted to particular age classes of RBC. We explicitly incorporate thisobservation in models of infection dynamics to distinguish common from species-specific pressures onhost immune responses, and we find that age structuring has profound effects on the course of infection.For all four species conditions exist under which the parasites may persist at low densities, or may clear,even in the absence of an immune response. Catastrophic anemia can occur even with the two speciesthat attack only the youngest RBCs, although only a small fraction of cells are parasitized at any point.Furthermore, with these two, compensatory erythropoetic responses in the host accelerate parasitepopulation growth. A \"basic reproduction rate\" characterizes these differences in outcomes.", "metadata": {}}
+{"_id": "26488879", "title": "", "text": "Helicobacter pylori AlpA and AlpB bind host laminin and influence gastric inflammation ingerbils.Helicobacter pylori persistently colonizes humans, causing gastritis, ulcers, and gastric cancer.Adherence to the gastric epithelium has been shown to enhance inflammation, yet only a few H. pyloriadhesins have been paired with targets in host tissue. The alpAB locus has been reported to encodeadhesins involved in adherence to human gastric tissue. We report that abrogation of H. pylori AlpA andAlpB reduces binding of H. pylori to laminin while expression of plasmid-borne alpA or alpB conferslaminin-binding ability to Escherichia coli. An H. pylori strain lacking only AlpB is also deficient in lamininbinding. Thus, we conclude that both AlpA and AlpB contribute to H. pylori laminin binding. Contrary toexpectations, the H. pylori SS1 mutant deficient in AlpA and AlpB causes more severe inflammation thanthe isogenic wild-type strain in gerbils. Identification of laminin as the target of AlpA and AlpB willfacilitate future investigations of host-pathogen interactions occurring during H. pylori infection.", "metadata": {}}
+{"_id": "26491450", "title": "", "text": "A quantitative analysis of kinase inhibitor selectivityKinase inhibitors are a new class of therapeutics witha propensity to inhibit multiple targets. The biological consequences of multi-kinase activity are poorlydefined, and an important step toward understanding the relationship between selectivity, efficacy andsafety is the exploration of how inhibitors interact with the human kinome. We present interaction mapsfor 38 kinase inhibitors across a panel of 317 kinases representing >50% of the predicted human proteinkinome. The data constitute the most comprehensive study of kinase inhibitor selectivity to date andreveal a wide diversity of interaction patterns. To enable a global analysis of the results, we introduce theconcept of a selectivity score as a general tool to quantify and differentiate the observed interactionpatterns. We further investigate the impact of panel size and find that small assay panels do not providea robust measure of selectivity.", "metadata": {}}
+{"_id": "26495128", "title": "", "text": "Ribosomal protein S9 is a novel B23/NPM-binding protein required for normal cell proliferation.B23(NPM/nucleophosmin) is a multifunctional nucleolar protein and a member of the nucleoplasminsuperfamily of acidic histone chaperones. B23 is essential for normal embryonic development and playsan important role in genomic stability, ribosome biogenesis, and anti-apoptotic signaling. Altered proteinexpression or genomic mutation of B23 is encountered in many different forms of cancer. Althoughdescribed as multifunctional, a genuine molecular function of B23 is not fully understood. Here we showthat B23 is associated with a protein complex consisting of ribosomal proteins and ribosome-associatedRNA helicases. A novel, RNA-independent interaction between ribosomal protein S9 (RPS9) and B23 wasfurther investigated. We found that S9 binding requires an intact B23 oligomerization domain. Depletionof S9 by small interfering RNA resulted in decreased protein synthesis and G(1) cell cycle arrest, inassociation with induction of p53 target genes. We determined that S9 is a short-lived protein in theabsence of ribosome biogenesis, and proteasomal inhibition significantly increased S9 protein level.Overexpression of B23 facilitated nucleolar storage of S9, whereas knockdown of B23 led to diminishedlevels of nucleolar S9. Our results suggest that B23 selectively stores, and protects ribosomal protein S9in nucleoli and therefore could facilitate ribosome biogenesis.", "metadata": {}}
+{"_id": "26501027", "title": "", "text": "Vasculature-associated cells expressing nestin in developing bones encompass early cells in theosteoblast and endothelial lineage.Nestin-positive (Nes(+)) cells are important hematopoiesis-supportingconstituents in adult bone marrow. However, how these cells originate during endochondral bonedevelopment is unknown. Studies using mice expressing GFP under the direction of nestinpromoter/enhancer (Nes-GFP) revealed distinct endothelial and nonendothelial Nes(+) cells in theembryonic perichondrium; the latter were early cells of the osteoblast lineage immediately descendedfrom their progenitors upon Indian hedgehog action and Runx2 expression. During vascular invasion andformation of ossification centers, these Nes(+) cells were closely associated with each other andincreased in number progressively. Interestingly, cells targeted by tamoxifen-inducible cre recombinasedriven by nestin enhancer (Nes-creER) in developing bone marrow were predominantly endothelial cells.Furthermore, Nes(+) cells in postnatal bones were heterogeneous populations, including a range of cellsin the osteoblast and endothelial lineage. These findings reveal an emerging complexity of stromalpopulations, accommodating Nes(+) cells as vasculature-associated early cells in the osteoblast andendothelial lineage.", "metadata": {}}
+{"_id": "26532518", "title": "", "text": "Public health, academic medicine, and the alcohol industry's corporate social responsibility activities.Weexplored the emerging relationships among the alcohol industry, academic medicine, and the publichealth community in the context of public health theory dealing with corporate social responsibility. Wereviewed sponsorship of scientific research, efforts to influence public perceptions of research,dissemination of scientific information, and industry-funded policy initiatives. To the extent that thescientific evidence supports the reduction of alcohol consumption through regulatory and legal measures,the academic community has come into increasing conflict with the views of the alcohol industry. Weconcluded that the alcohol industry has intensified its scientific and policy-related activities under thegeneral framework of corporate social responsibility initiatives, most of which can be described asinstrumental to the industry's economic interests.", "metadata": {}}
+{"_id": "26561572", "title": "", "text": "RET, ROS1 and ALK fusions in lung cancerThrough an integrated molecular- and histopathology-basedscreening system, we performed a screening for fusions of anaplastic lymphoma kinase (ALK) and c-rosoncogene 1, receptor tyrosine kinase (ROS1) in 1,529 lung cancers and identified 44 ALK-fusion–positiveand 13 ROS1-fusion–positive adenocarcinomas, including for unidentified fusion partners for ROS1. Inaddition, we discovered previously unidentified kinase fusions that may be promising formolecular-targeted therapy, kinesin family member 5B (KIF5B)-ret proto-oncogene (RET) and coiled-coildomain containing 6 (CCDC6)-RET, in 14 adenocarcinomas. A multivariate analysis of 1,116adenocarcinomas containing these 71 kinase-fusion–positive adenocarcinomas identified fourindependent factors that are indicators of poor prognosis: age ≥50 years, male sex, high pathologicalstage and negative kinase-fusion status.", "metadata": {}}
+{"_id": "26596106", "title": "", "text": "Genetic and biochemical interactions among Yar1, Ltv1 and Rps3 define novel links betweenenvironmental stress and ribosome biogenesis in Saccharomyces cerevisiae.In the yeast S. cerevisiae,ribosome assembly is linked to environmental conditions by the coordinate transcriptional regulation ofgenes required for ribosome biogenesis. In this study we show that two nonessential stress-responsivegenes, YAR1 and LTV1, function in 40S subunit production. We provide genetic and biochemical evidencethat Yar1, a small ankyrin-repeat protein, physically interacts with RpS3, a component of the 40Ssubunit, and with Ltv1, a protein recently identified as a substoichiometric component of a 43Spreribosomal particle. We demonstrate that cells lacking YAR1 or LTV1 are hypersensitive to particularprotein synthesis inhibitors and exhibit aberrant polysome profiles, with a reduced absolute number of40S subunits and an excess of free 60S subunits. Surprisingly, both mutants are also hypersensitive to avariety of environmental stress conditions. Overexpression of RPS3 suppresses both the stress sensitivityand the ribosome biogenesis defect of Deltayar1 mutants, but does not suppress either defect inDeltaltv1 mutants. We propose that YAR1 and LTV1 play distinct, nonessential roles in 40S subunitproduction. The stress-sensitive phenotypes of strains lacking these genes reveal a hitherto unknown linkbetween ribosome biogenesis factors and environmental stress sensitivity.", "metadata": {}}
+{"_id": "26607366", "title": "", "text": "Rational design of acridine-based ligands with selectivity for human telomericquadruplexes.Structure-based modeling methods have been used to design a series of disubstitutedtriazole-linked acridine compounds with selectivity for human telomeric quadruplex DNAs. A focusedlibrary of these compounds was prepared using click chemistry and the selectivity concept was validatedagainst two promoter quadruplexes from the c-kit gene with known molecular structures, as well as withduplex DNA using a FRET-based melting method. Lead compounds were found to have reduced effects onthe thermal stability of the c-kit quadruplexes and duplex DNA structures. These effects were furtherexplored with a series of competition experiments, which confirmed that binding to duplex DNA is verylow even at high duplex:telomeric quadruplex ratios. Selectivity to the c-kit quadruplexes is morecomplex, with some evidence of their stabilization at increasing excess over human telomeric quadruplexDNA. Selectivity is a result of the dimensions of the triazole-acridine compounds, and in particular theseparation of the two alkyl-amino terminal groups. Both lead compounds also have selective inhibitoryeffects on the proliferation of cancer cell lines compared to a normal cell line, and one has been shown toinhibit the activity of the telomerase enzyme, which is selectively expressed in tumor cells, where it playsa role in maintaining telomere integrity and cellular immortalization.", "metadata": {}}
+{"_id": "26611094", "title": "", "text": "Hospital volume and the outcomes of mechanical ventilation.BACKGROUND An increased volume ofpatients is associated with improved survival in numerous high-risk medical and surgical conditions. Therelationship between the number of patients admitted (hospital volume) and outcome among patientswith critical illnesses is unknown. METHODS We analyzed data from 20,241 nonsurgical patients receivingmechanical ventilation at 37 acute care hospitals in the Acute Physiology and Chronic Health Evaluationclinical information system from 2002 through 2003. Multivariate analyses were performed to adjust forthe severity of illness and other differences in the case mix. RESULTS An increase in hospital volume wasassociated with improved survival among patients receiving mechanical ventilation in the intensive careunit (ICU) and in the hospital. Admission to a hospital in the highest quartile according to volume (i.e.,>400 patients receiving mechanical ventilation per year) was associated with a 37 percent reduction inthe adjusted odds of death in the ICU as compared with admission to hospitals in the lowest quartile (<or =150 patients receiving mechanical ventilation per year, P<0.001). In-hospital mortality was similarlyreduced (adjusted odds ratio, 0.66; 95 percent confidence interval, 0.52 to 0.83; P<0.001). A typicalpatient in a hospital in a low-volume quartile would have an adjusted in-hospital mortality of 34.2 percentas compared with 25.5 percent in a hospital in a high-volume quartile. Among survivors, there were nosignificant trends in the length of stay in the ICU or the hospital. CONCLUSIONS Mechanical ventilation ofpatients in a hospital with a high case volume is associated with reduced mortality. Further research isneeded to determine the mechanism of the relationship between volume and outcome among patientswith a critical illness.", "metadata": {}}
+{"_id": "26611834", "title": "", "text": "A meta-analysis of depression during pregnancy and the risk of preterm birth, low birth weight, andintrauterine growth restriction.CONTEXT Maternal depressive symptoms during pregnancy have beenreported in some, but not all, studies to be associated with an increased risk of preterm birth (PTB), lowbirth weight (LBW), and intrauterine growth restriction (IUGR). OBJECTIVE To estimate the risk of PTB,LBW, and IUGR associated with antenatal depression. DATA SOURCES AND STUDY SELECTION Wesearched for English-language and non-English-language articles via the MEDLINE, PsycINFO, CINAHL,Social Work Abstracts, Social Services Abstracts, and Dissertation Abstracts International databases(January 1980 through December 2009). We aimed to include prospective studies reporting data onantenatal depression and at least 1 adverse birth outcome: PTB (<37 weeks' gestation), LBW (<2500 g),or IUGR (<10th percentile for gestational age). Of 862 reviewed studies, 29 US-published andnon-US-published studies met the selection criteria. DATA EXTRACTION Information was extracted onstudy characteristics, antenatal depression measurement, and other biopsychosocial risk factors and wasreviewed twice to minimize error. DATA SYNTHESIS Pooled relative risks (RRs) for the effect of antenataldepression on each birth outcome were calculated using random-effects methods. In studies of PTB, LBW,and IUGR that used a categorical depression measure, pooled effect sizes were significantly larger(pooled RR [95% confidence interval] = 1.39 [1.19-1.61], 1.49 [1.25-1.77], and 1.45 [1.05-2.02],respectively) compared with studies that used a continuous depression measure (1.03 [1.00-1.06], 1.04[0.99-1.09], and 1.02 [1.00-1.04], respectively). The estimates of risk for categorically defined antenataldepression and PTB and LBW remained significant when the trim-and-fill procedure was used to correctfor publication bias. The risk of LBW associated with antenatal depression was significantly larger indeveloping countries (RR = 2.05; 95% confidence interval, 1.43-2.93) compared with the United States(RR = 1.10; 95% confidence interval, 1.01-1.21) or European social democracies (RR = 1.16; 95%confidence interval, 0.92-1.47). Categorically defined antenatal depression tended to be associated withan increased risk of PTB among women of lower socioeconomic status in the United States.CONCLUSIONS Women with depression during pregnancy are at increased risk for PTB and LBW,although the magnitude of the effect varies as a function of depression measurement, country location,and US socioeconomic status. An important implication of these findings is that antenatal depressionshould be identified through universal screening and treated.", "metadata": {}}
+{"_id": "26612216", "title": "", "text": "ES cell pluripotency and germ-layer formation require the SWI/SNF chromatin remodeling componentBAF250a.ATP-dependent chromatin remodeling complexes are a notable group of epigenetic modifiersthat use the energy of ATP hydrolysis to change the structure of chromatin, thereby altering itsaccessibility to nuclear factors. BAF250a (ARID1a) is a unique and defining subunit of the BAF chromatinremodeling complex with the potential to facilitate chromosome alterations critical during development.Our studies show that ablation of BAF250a in early mouse embryos results in developmental arrest(about embryonic day 6.5) and absence of the mesodermal layer, indicating its critical role in earlygerm-layer formation. Moreover, BAF250a deficiency compromises ES cell pluripotency, severely inhibitsself-renewal, and promotes differentiation into primitive endoderm-like cells under normal feeder-freeculture conditions. Interestingly, this phenotype can be partially rescued by the presence of embryonicfibroblast cells. DNA microarray, immunostaining, and RNA analyses revealed that BAF250a-mediatedchromatin remodeling contributes to the proper expression of numerous genes involved in ES cellself-renewal, including Sox2, Utf1, and Oct4. Furthermore, the pluripotency defects in BAF250a mutantES cells appear to be cell lineage-specific. For example, embryoid body-based analyses demonstratedthat BAF250a-ablated stem cells are defective in differentiating into fully functional mesoderm-derivedcardiomyocytes and adipocytes but are capable of differentiating into ectoderm-derived neurons. Ourresults suggest that BAF250a is a key component of the gene regulatory machinery in ES cells controllingself-renewal, differentiation, and cell lineage decisions.", "metadata": {}}
+{"_id": "26625002", "title": "", "text": "Metabolic shutdown in Escherichia coli cells lacking the outer membrane channel TolC.The outermembrane channel TolC is a key component of multidrug efflux and type I secretion transporters inEscherichia coli. Mutational inactivation of TolC renders cells highly susceptible to antibiotics and leads todefects in secretion of protein toxins. Despite impairment of various transport functions, no growthdefects were reported in cells lacking TolC. Unexpectedly, we found that the loss of TolC notably impairscell division and growth in minimal glucose medium. The TolC-dependent phenotype was furtherexacerbated by the loss of ygiB and ygiC genes expressed in the same operon as tolC and theirhomologues yjfM and yjfC located elsewhere on the chromosome. Our results show that this growthdeficiency is caused by depletion of the critical metabolite NAD(+) and high NADH/NAD(+) ratios. Theincreased amounts of PspA and decreased rates of NADH oxidation in Delta tolC membranes indicatedstress on the membrane and dissipation of a proton motive force. We conclude that inactivation of TolCtriggers metabolic shutdown in E. coli cells grown in minimal glucose medium. The Delta tolC phenotypeis partially rescued by YgiBC and YjfMC, which have parallel functions independent from TolC.", "metadata": {}}
+{"_id": "26652147", "title": "", "text": "Acyl and total ghrelin are suppressed strongly by ingested proteins, weakly by lipids, and biphasically bycarbohydrates.CONTEXT Ghrelin is an orexigenic hormone that can increase body weight. Its circulatinglevels increase before meals and are suppressed after food ingestion. Understanding the effects ofspecific types of ingested macronutrients on ghrelin regulation could facilitate the design ofweight-reducing diets. OBJECTIVE We sought to understand how ingestion of carbohydrates, proteins, orlipids affect acyl (bioactive) and total ghrelin levels among human subjects, hypothesizing that lipidsmight suppress ghrelin levels less effectively than do either carbohydrates or proteins. DESIGN This wasa randomized, within-subjects cross-over study. SETTING The study was conducted at a UniversityClinical Research Center. PARTICIPANTS There were 16 healthy human subjects included in the study.INTERVENTIONS Isocaloric, isovolemic beverages composed primarily of carbohydrates, proteins, orlipids were provided. MAIN OUTCOME MEASURES The magnitude of postprandial suppression of total andacyl ghrelin levels (measured with a novel acyl-selective, two-site ELISA) was determined. RESULTS Allbeverages suppressed plasma acyl and total ghrelin levels. A significant effect of macronutrient class ondecremental area under the curve for both acyl and total ghrelin was observed; the rank order formagnitude of suppression was protein more than carbohydrate more than lipid. Total ghrelin nadir levelswere significantly lower after both carbohydrate and protein, compared with lipid beverages. In the first 3postprandial hours, the rank order for acyl and total ghrelin suppression was carbohydrate more thanprotein more than lipid. In the subsequent 3 h, there was a marked rebound above preprandial values ofacyl and total ghrelin after carbohydrate ingestion alone. CONCLUSIONS These findings suggest possiblemechanisms contributing to the effects of high-protein/low-carbohydrate diets to promote weight loss,and high-fat diets to promote weight gain.", "metadata": {}}
+{"_id": "26658659", "title": "", "text": "Hydrogen sulfide increases nitric oxide production with calcium-dependent activation of endothelial nitricoxide synthase in endothelial cells.Hydrogen sulfide (H(2)S) was recently discovered to be synthesized inmammalian tissues by several different enzymes. Numerous studies have shown that H(2)S hasvasodilator and antihypertensive effects in the cardiovascular system. However, intracellular mechanismsof the H(2)S-induced vasodilation and its interactions with other endothelium-derived relaxing factors,such as nitric oxide (NO), remain unclear. We investigated whether H(2)S directly regulates endothelialNO synthase (eNOS) activity and NO production in endothelial cells. NaHS, a H(2)S donor,dose-dependently increased NO production in cultured endothelial cells. This effect was abolished by acalcium chelator (BAPTA-AM), but not by the absence of extracellular calcium. The NaHS-induced NOproduction was partially blocked by inhibitors of ryanodine receptor (dantrolene) or inositol1,4,5-triphosphate receptor (xestospongin C). NaHS significantly increased intracellular calciumconcentrations, and this effect was attenuated by dantrolene or xestospongin C. NaHS inducedphosphorylation of eNOS at the activating phosphoserine residue 1179. The NaHS-induced eNOSphosphorylation and NO production were not affected by a PI3K/Akt inhibitor (wortmannin). The data ofthis study suggest that H(2)S directly acts on endothelial cells to induce eNOS activation and NOproduction by releasing calcium from the intracellular store in endoplasmic reticulum, which may explainone of mechanisms of its vasodilator function.", "metadata": {}}
+{"_id": "26668245", "title": "", "text": "Fear of falling and visual field loss from glaucoma.OBJECTIVE To determine if visual field (VF) lossresulting from glaucoma is associated with greater fear of falling. DESIGN Prospective, observationalstudy. PARTICIPANTS Fear of falling was compared between 83 glaucoma subjects with bilateral VF lossand 60 control subjects with good visual acuity and without significant VF loss recruited from patientsfollowed up for suspicion of glaucoma. METHODS Participants completed the University of Illinois atChicago Fear of Falling Questionnaire. The extent of fear of falling was assessed using Rasch analysis.MAIN OUTCOME MEASURES Subject ability to perform tasks without fear of falling was expressed inlogits, with lower scores implying less ability and greater fear of falling. RESULTS Glaucoma subjects hadgreater VF loss than control subjects (median better-eye mean deviation [MD] of -8.0 decibels [dB] vs.+0.2 dB; P<0.001), but did not differ with regard to age, race, gender, employment status, the presenceof other adults in the home, body mass index (BMI), grip strength, cognitive ability, mood, or comorbidillness (P ≥ 0.1 for all). In multivariate models, glaucoma subjects reported greater fear of falling ascompared with controls (β = -1.20 logits; 95% confidence interval [CI], -1.87 to -0.53; P = 0.001), andfear of falling increased with greater VF loss severity (β = -0.52 logits per 5-dB decrement in the bettereye VF MD; 95% CI, -0.72 to -0.33; P<0.001). Other variables predicting greater fear of falling includedfemale gender (β = -0.55 logits; 95% CI, -1.03 to -0.06; P = 0.03), higher BMI (β = -0.07 logits per1-unit increase in BMI; 95% CI, -0.13 to -0.01; P = 0.02), living with another adult (β = -1.16 logits;95% CI, -0.34 to -1.99 logits; P = 0.006), and greater comorbid illness (β = -0.53 logits/1 additionalillness; 95% CI, -0.74 to -0.32; P<0.001). CONCLUSIONS Bilateral VF loss resulting from glaucoma isassociated with greater fear of falling, with an impact that exceeds numerous other risk factors. Given thephysical and psychological repercussions associated with fear of falling, significant quality-of-lifeimprovements may be achievable in patients with VF loss by screening for, and developing interventionsto minimize, fear of falling.", "metadata": {}}
+{"_id": "26672703", "title": "", "text": "Repeat instability: mechanisms of dynamic mutationsDisease-causing repeat instability is an importantand unique form of mutation that is linked to more than 40 neurological, neurodegenerative andneuromuscular disorders. DNA repeat expansion mutations are dynamic and ongoing within tissues andacross generations. The patterns of inherited and tissue-specific instability are determined by bothgene-specific cis-elements and trans-acting DNA metabolic proteins. Repeat instability probably involvesthe formation of unusual DNA structures during DNA replication, repair and recombination. Experimentaladvances towards explaining the mechanisms of repeat instability have broadened our understanding ofthis mutational process. They have revealed surprising ways in which metabolic pathways can drive orprotect from repeat instability.", "metadata": {}}
+{"_id": "26673492", "title": "", "text": "Demographic Risk Factors for Alcohol-Related Aggression In and Around Licensed Venues.AIMS Fewstudies have examined the role of gender and both area-level and individual socio-economic status (SES)as independent predictors of alcohol-related aggression (ARA) in and around licensed venues. METHODSThe aim of the present study was to investigate the relationship between gender, area-level SES andindividual SES (operationalised as occupational category) and ARA in and around licensed venues. Thesample comprised 697 men and 649 women aged 16-47, who completed a patron intercept survey aspart of a larger study assessing trends in harm and stakeholders' views surrounding local communitylevel interventions in dealing with alcohol-related problems in the night-time economy. RESULTS Binarylogistic regression analyses showed that age, gender, occupational category, area-level SES and level ofintoxication at time of interview were all significant predictors of involvement in ARA. Being male doubledthe odds of involvement in ARA, while age was a protective factor. Blue collar workers had more thandouble the odds of ARA involvement of professionals, while those living in the most socio-economicallydisadvantaged areas were over twice as likely to report experiencing ARA compared to those living in themost advantaged areas. However, assessment of the predictive model by gender revealed that effects ofage, occupational category and area-level SES were restricted to male participants, with greaterintoxication no longer predictive. CONCLUSIONS ARA among patrons was significantly more likely tooccur among men, those in blue collar occupations, and individuals living in low SES areas, suggestingboth individual and area-level disadvantage may play a role in ARA.", "metadata": {}}
+{"_id": "26688294", "title": "", "text": "Schizophrenia susceptibility pathway neuregulin 1–ErbB4 suppresses Src upregulation of NMDAreceptorsHypofunction of the N-methyl D-aspartate subtype of glutamate receptor (NMDAR) ishypothesized to be a mechanism underlying cognitive dysfunction in individuals with schizophrenia. Forthe schizophrenia-linked genes NRG1 and ERBB4, NMDAR hypofunction is thus considered a keydetrimental consequence of the excessive NRG1-ErbB4 signaling found in people with schizophrenia.However, we show here that neuregulin 1β–ErbB4 (NRG1β-ErbB4) signaling does not cause generalhypofunction of NMDARs. Rather, we find that, in the hippocampus and prefrontal cortex, NRG1β-ErbB4signaling suppresses the enhancement of synaptic NMDAR currents by the nonreceptor tyrosine kinaseSrc. NRG1β-ErbB4 signaling prevented induction of long-term potentiation at hippocampal Schaffercollateral–CA1 synapses and suppressed Src-dependent enhancement of NMDAR responses duringtheta-burst stimulation. Moreover, NRG1β-ErbB4 signaling prevented theta burst–inducedphosphorylation of GluN2B by inhibiting Src kinase activity. We propose that NRG1-ErbB4 signalingparticipates in cognitive dysfunction in schizophrenia by aberrantly suppressing Src-mediatedenhancement of synaptic NMDAR function.", "metadata": {}}
+{"_id": "26702468", "title": "", "text": "Intestinal bacteria and the regulation of immune cell homeostasis.The human intestine is colonized by anestimated 100 trillion bacteria. Some of these bacteria are essential for normal physiology, whereasothers have been implicated in the pathogenesis of multiple inflammatory diseases including IBD andasthma. This review examines the influence of signals from intestinal bacteria on the homeostasis of themammalian immune system in the context of health and disease. We review the bacterial composition ofthe mammalian intestine, known bacterial-derived immunoregulatory molecules, and the mammalianinnate immune receptors that recognize them. We discuss the influence of bacterial-derived signals onimmune cell function and the mechanisms by which these signals modulate the development andprogression of inflammatory disease. We conclude with an examination of successes and futurechallenges in using bacterial communities or their products in the prevention or treatment of humandisease.", "metadata": {}}
+{"_id": "26710772", "title": "", "text": "Sympathetic activation during early pregnancy in humans.Sympathetic activity has been reported toincrease in normotensive pregnant women, and to be even greater in women with gestationalhypertension and preeclampsia at term. Whether sympathetic overactivity develops early duringpregnancy, remaining high throughout gestation, or whether it only occurs at term providing thesubstrate for hypertensive disorders is unknown. We tested the hypothesis that sympathetic activationoccurs early during pregnancy in humans. Eleven healthy women (29 ± 3 (SD) years) without priorhypertensive pregnancies were tested during the mid-luteal phase (PRE) and early pregnancy (EARLY;6.2 ± 1.2 weeks of gestation). Muscle sympathetic nerve activity (MSNA) and haemodynamics weremeasured supine, at 30 deg and 60 deg upright tilt for 5 min each. Blood samples were drawn forcatecholamines, direct renin, and aldosterone. MSNA was significantly greater during EARLY than PRE(supine: 25 ± 8 vs. 14 ± 8 bursts min(-1), 60 deg tilt: 49 ± 14 vs. 40 ± 10 bursts min(-1); main effect, P< 0.05). Resting diastolic pressure trended lower (P = 0.09), heart rate was similar, total peripheralresistance decreased (2172 ± 364 vs. 2543 ± 352 dyne s cm(-5); P < 0.05), sympathetic vasculartransduction was blunted (0.10 ± 0.05 vs. 0.36 ± 0.47 units a.u.(-1) min(-1); P < 0.01), and both renin(supine: 27.9 ± 6.2 vs. 14.2 ± 8.7 pg ml(-1), P < 0.01) and aldosterone (supine: 16.7 ± 14.1 vs. 7.7 ±6.8 ng ml(-1), P = 0.05) were higher during EARLY than PRE. These results suggest that sympatheticactivation is a common characteristic of early pregnancy in humans despite reduced diastolic pressureand total peripheral resistance. These observations challenge conventional thinking about blood pressureregulation during pregnancy, showing marked sympathetic activation occurring within the first few weeksof conception, and may provide the substrate for pregnancy induced cardiovascular complications.", "metadata": {}}
+{"_id": "26720366", "title": "", "text": "Psychological adaptation in children with idiopathic short stature treated with growth hormone orplacebo.The influence of short stature on psychological adaptation in childhood and adolescence iscontroversial. GH is currently used to treat children with idiopathic short stature (ISS, also known asnon-GH-deficient short stature). This study represents the first double-blind, placebo-controlled trial ofthe effects of GH on the psychological adaptation of children and adolescents with ISS, treated with GHuntil adult height was attained. Sixty-eight children (53 males, 15 females), 9-16 yr old, with marked ISS(measured height or predicted adult height -2.5 sd or less) received either GH 0.074 mg/kg or placebo scthree times per week until height velocity decreased to less than 1.5 cm/yr. Parents completed the ChildBehavior Checklist (CBCL) and children the Self-Perception Profile (SPP) and Silhouette ApperceptionTechnique at baseline and annually thereafter. Baseline behavioral/emotional adjustment (CBCL) andself-concept (SPP) scores for children with ISS were within the normative range. The two study groupsexhibited similar behavioral and self-concept profiles (CBCL) during the first 2 yr of the study. However,CBCL behavior problems (internalizing, externalizing, and total problems) appeared to decline, in yr 3 and4, in the GH-treated group relative to the placebo-treated group. Group differences in CBCL competencydomains and the SPP were not observed at any point during the study. Short stature among children withISS enrolled in this long-term, placebo-controlled study was not associated with problems inpsychological adaptation or self-concept with the psychological instruments employed. GH treatment wasassociated with a trend toward improvement in problem behaviors, as measured by questionnaires(CBCL) completed by study participants' parents. It remains to be determined whether GH treatmentsignificantly impacts adaptation, psychosocial function, or quality of life in children with ISS.", "metadata": {}}
+{"_id": "26731863", "title": "", "text": "Distinct and essential roles of transcription factors IRF-3 and IRF-7 in response to viruses forIFN-alpha/beta gene induction.Induction of the interferon (IFN)-alpha/beta gene transcription invirus-infected cells is an event central to innate immunity. Mice lacking the transcription factor IRF-3 aremore vulnerable to virus infection. In embryonic fibroblasts, virus-induced IFN-alpha/beta geneexpression levels are reduced and the spectrum of the IFN-alpha mRNA subspecies altered. Furthermore,cells additionally defective in IRF-7 expression totally fail to induce these genes in response to infectionsby any of the virus types tested. In these cells, a normal profile of IFN-alpha/beta mRNA induction can beachieved by coexpressing both IRF-3 and IRF-7. These results demonstrate the essential and distinctroles of thetwo factors, which together ensure the transcriptional efficiency and diversity ofIFN-alpha/beta genes for the antiviral response.", "metadata": {}}
+{"_id": "26735018", "title": "", "text": "Interleukin-2- and interferon-gamma-secreting T cells in normal and diseased human intestinal mucosa.Asensitive reverse haemolytic plaque assay to detect lymphokine-secreting T cells, and Northern blotanalysis to detect expression of lymphokine messenger RNA (mRNA) were used to studyinterferon-gamma (IFN-gamma) and interleukin-2 (IL-2) production in the mucosa of children withCrohn's disease or ulcerative colitis (UC), and in histologically normal mucosa from patients withoutinflammatory bowel disease. In the mucosa of most patients with UC and control patients, IL-2- andIFN-gamma-secreting cells were absent or were present at only low levels. In contrast, in mucosa frompatients with Crohn's disease, lymphokine-secreting cells were readily detectable (3-18%). IFN-gammamRNA was detected by Northern blot analysis in 5/6 Crohn's tissues, but only in 1/5 UC samples andnone of nine samples of control mucosa. These studies reveal an ongoing cell-mediated immune responsein the mucosa in Crohn's disease.", "metadata": {}}
+{"_id": "26735905", "title": "", "text": "Metabolic reprogramming of stromal fibroblasts through p62-mTORC1 signaling promotes inflammationand tumorigenesis.The tumor microenvironment plays a critical role in cancer progression, but the precisemechanisms by which stromal cells influence the epithelium are poorly understood. Here we show thatp62 levels were reduced in the stroma of several tumors and that its loss in the tumor microenvironmentor stromal fibroblasts resulted in increased tumorigenesis of epithelial prostate cancer cells. Themechanism involves the regulation of cellular redox through an mTORC1/c-Myc pathway of stromalglucose and amino acid metabolism, resulting in increased stromal IL-6 production, which is required fortumor promotion in the epithelial compartment. Thus, p62 is an anti-inflammatory tumor suppressor thatacts through the modulation of metabolism in the tumor stroma.", "metadata": {}}
+{"_id": "26751583", "title": "", "text": "Drosophila RNAi screen reveals CD36 family member required for mycobacterial infection.Certainpathogens, such as Mycobacterium tuberculosis, survive within the hostile intracellular environment of amacrophage. To identify host factors required for mycobacterial entry and survival within macrophages,we performed a genomewide RNA interference screen in Drosophila macrophage-like cells, usingMycobacterium fortuitum. We identified factors required for general phagocytosis, as well as thoseneeded specifically for mycobacterial infection. One specific factor, Peste (Pes), is a CD36 family memberrequired for uptake of mycobacteria, but not Escherichia coli or Staphylococcus aureus. Moreover,mammalian class B scavenger receptors (SRs) conferred uptake of bacteria into nonphagocytic cells, withSR-BI and SR-BII uniquely mediating uptake of M. fortuitum, which suggests a conserved role for class BSRs in pattern recognition and innate immunity.", "metadata": {}}
+{"_id": "26798867", "title": "", "text": "Knowledge, attitudes, and practice on second primary cancer screening among cancer survivors: aqualitative study.OBJECTIVE The goal of this study was to examine the knowledge, attitude, and practiceon second cancer screening among cancer survivors. METHODS Three focus group interviews wereconducted with thirteen disease-free stomach, colorectal, breast and thyroid cancer survivors. Recurrentissues were identified and then placed into thematic categories. RESULTS None of the study participantshad heard SPC, and they could not differentiate SPC from 'recurrence' or 'metastasis.' Survivors believedthat they had been cured, and they were not aware of their increased risk of SPC. Although they had highawareness of cancer screening, they could not make a distinction between 'cancer screening' and 'routinesurveillance test' after cancer treatment. Survivors said that they would have had the screening for SPC ifthey had known about it. They preferred physicians as the most reliable source for screening information.CONCLUSION Cancer survivors had limited knowledge about SPC, and lack of information was the mainbarrier for SPC screening. PRACTICE IMPLICATIONS An educational intervention would help cancersurvivors to understand their risk of SPC and the needs of screening after the first cancer.", "metadata": {}}
+{"_id": "26848994", "title": "", "text": "LncRNA HANR Promotes Tumorigenesis and Increase of Chemoresistance in HepatocellularCarcinomaBackground/Aims: Hepatocellular carcinoma (HCC) is the fifth most common cancer in theworld and the third leading cause of cancer-related death. Critical roles for long non-coding RNAs(lncRNAs) have recently been demonstrated for a variety of cancers, including hepatocellular carcinoma.However, the effect and mechanism of lncRNAs in HCC tumorigenesis and chemoresistance have notbeen extensively characterized. Methods: In the current study, we have identified a HCC-expressedlncRNA termed as HANR (HCC associated long non-coding RNA). We identified HANR by microarrayanalysis and validated its up-regulated expression by quantitative PCR. RNA pull-down and pathwayanalyses were conducted to evaluate physical and functional interactions with HANR. In vivo experimentswere performed to assess tumorigenesis and increase of chemoresistance. In addition, the HANRexpression in HCC specimens was detected by FISH. Xenograft and orthotopic mice model wasconstructed to observe the effect of HANR on tumorigenesis and chemoresistance in vivo. Results: HANRwas demonstrated to be up-regulated in HCC patients and HCC cell lines. Increased HANR expression inHCC predicted short survival of patients. Knock-down of HANR markedly retarded cell proliferation,suppressed HCC xenograft/orthotopic tumor growth, induced apoptosis and enhanced chemosensitivity todoxorubicin, while over-expression of HANR showed the opposite effects. It was found that HANR bind toGSKIP for regulating the phosphorylation of GSK3β in HCC. Conclusion: Our results demonstrate thatHANR contributes to the development of HCC and is a promising therapeutic target for chemosensitizationof HCC cells to doxorubicin, which may represent a promising therapeutic target in the future.", "metadata": {}}
+{"_id": "26851674", "title": "", "text": "Dissection of signaling cascades through gp130 in vivo: reciprocal roles for STAT3- and SHP2-mediatedsignals in immune responses.We generated a series of knockin mouse lines, in which the cytokinereceptor gp130-dependent STAT3 and/or SHP2 signals were disrupted, by replacing the mouse gp130gene with human gp130 mutant cDNAs. The SHP2 signal-deficient mice (gp130F759/F759 were bornnormal but displayed splenomegaly and lymphadenopathy and an enhanced acute phase reaction. Incontrast, the STAT3 signal-deficient mice (gp130FXQ/FXXQ) died perinatally, like the gp130-deficientmice (gp130D/D). The gp130F759/F759 mice showed prolonged gp130-induced STAT3 activation,indicating a negative regulatory role for SHP2. Th1-type cytokine production and IgG2a and IgG2bproduction were increased in the gp130F759/F759 mice, while they were decreased in thegp130FXXQ/FXXQ immune system. These results indicate that the balance of positive and negativesignals generated through gp130 regulates the immune responses.", "metadata": {}}
+{"_id": "26873988", "title": "", "text": "Viral interleukin-10 expressed by human cytomegalovirus during the latent phase of infection modulateslatently infected myeloid cell differentiation.The human cytomegalovirus UL111A gene is expressedduring latent and productive infections, and it codes for homologs of interleukin-10 (IL-10). We examinedwhether viral IL-10 expressed during latency altered differentiation of latently infected myeloidprogenitors. In comparison to infection with parental virus or mock infection, latent infection with a virusin which the gene encoding viral IL-10 has been deleted upregulated cytokines associated with dendriticcell (DC) formation and increased the proportion of myeloid DCs. These data demonstrate that viral IL-10restricts the ability of latently infected myeloid progenitors to differentiate into DCs and identifies animmunomodulatory role for viral IL-10 which may limit the host's ability to clear latent virus.", "metadata": {}}
+{"_id": "26886351", "title": "", "text": "Bortezomib enhances dendritic cell (DC)-mediated induction of immunity to human myeloma viaexposure of cell surface heat shock protein 90 on dying tumor cells: therapeutic implications.Mostanticancer chemotherapies are immunosuppressive and induce nonimmunogenic tumor cell death.Bortezomib, a specific inhibitor of 26S proteasome, has shown clinical activity in several human tumors,including myeloma. Here we show that the uptake of human myeloma cells by dendritic cells (DCs) aftertumor cell death by bortezomib, but not gamma irradiation or steroids, leads to the induction ofantitumor immunity, including against primary tumor cells, without the need for any additional adjuvants.The delivery of activating signal from bortezomib-killed tumor cells to DCs depends on cell-cell contactbetween DCs and dying tumor cells and is mediated by bortezomib-induced exposure of heat shockprotein 90 (hsp90) on the surface of dying cells. The combination of bortezomib and geldanamycin (anhsp90 inhibitor) leads to greater apoptosis of tumor cells but abrogates their immunogenicity. These dataidentify drug-induced exposure of endogenous heat shock proteins on the surface of dying cells as amechanism of immunogenic death of human tumors. Specific targeting of bortezomib to tumors mayenhance their immunogenicity and the induction of antitumor immunity.", "metadata": {}}
+{"_id": "26887439", "title": "", "text": "Survivin depletion preferentially reduces the survival of activated K-Ras-transformed cells.To identifycancer-specific targets, we have conducted a synthetic lethal screen using a small interfering RNA(siRNA) library targeting approximately 4,000 individual genes for enhanced killing in the DLD-1 coloncarcinoma cell line that expresses an activated copy of the K-Ras oncogene. We found that siRNAstargeting baculoviral inhibitor of apoptosis repeat-containing 5 (survivin) significantly reduced thesurvival of activated K-Ras-transformed cells compared with its normal isogenic counterpart in which themutant K-Ras gene had been disrupted (DKS-8). In addition, survivin siRNA induced a transient G(2)-Marrest and marked polyploidy that was associated with increased caspase-3 activation in the activatedK-Ras cells. These results indicate that tumors expressing the activated K-Ras oncogene may beparticularly sensitive to inhibitors of the survivin protein.", "metadata": {}}
+{"_id": "26899920", "title": "", "text": "Small molecules enable cardiac reprogramming of mouse fibroblasts with a single factor, Oct4.It wasrecently shown that mouse fibroblasts could be reprogrammed into cells of a cardiac fate by forcedexpression of multiple transcription factors and microRNAs. For ultimate application of such areprogramming strategy for cell-based therapy or in vivo cardiac regeneration, reducing or eliminatingthe genetic manipulations by small molecules would be highly desirable. Here, we report the identificationof a defined small-molecule cocktail that enables the highly efficient conversion of mouse fibroblasts intocardiac cells with only one transcription factor, Oct4, without any evidence of entrance into thepluripotent state. Small-molecule-induced cardiomyocytes spontaneously contract and exhibit aventricular phenotype. Furthermore, these induced cardiomyocytes pass through a cardiac progenitorstage. This study lays the foundation for future pharmacological reprogramming approaches and providesa small-molecule condition for investigation of the mechanisms underlying the cardiac reprogrammingprocess.", "metadata": {}}
+{"_id": "26902591", "title": "", "text": "A switch from white to brown fat increases energy expenditure in cancer-associatedcachexia.Cancer-associated cachexia (CAC) is a wasting syndrome characterized by systemicinflammation, body weight loss, atrophy of white adipose tissue (WAT) and skeletal muscle. Limitedtherapeutic options are available and the underlying mechanisms are poorly defined. Here we show that aphenotypic switch from WAT to brown fat, a phenomenon termed WAT browning, takes place in the initialstages of CAC, before skeletal muscle atrophy. WAT browning is associated with increased expression ofuncoupling protein 1 (UCP1), which uncouples mitochondrial respiration toward thermogenesis instead ofATP synthesis, leading to increased lipid mobilization and energy expenditure in cachectic mice. Chronicinflammation and the cytokine interleukin-6 increase UCP1 expression in WAT, and treatments thatreduce inflammation or β-adrenergic blockade reduce WAT browning and ameliorate the severity ofcachexia. Importantly, UCP1 staining is observed in WAT from CAC patients. Thus, inhibition of WATbrowning represents a promising approach to ameliorate cachexia in cancer patients.", "metadata": {}}
+{"_id": "26907074", "title": "", "text": "Potential Mechanisms of Action of Lithium in Bipolar DisorderLithium has been used for over half acentury for the treatment of bipolar disorder as the archetypal mood stabilizer, and has a wealth ofempirical evidence supporting its efficacy in this role. Despite this, the specific mechanisms by whichlithium exerts its mood-stabilizing effects are not well understood. Given the inherently complex nature ofthe pathophysiology of bipolar disorder, this paper aims to capture what is known about the actions oflithium ranging from macroscopic changes in mood, cognition and brain structure, to its effects at themicroscopic level on neurotransmission and intracellular and molecular pathways. A comprehensiveliterature search of databases including MEDLINE, EMBASE and PsycINFO was conducted using relevantkeywords and the findings from the literature were then reviewed and synthesized. Numerous studiesreport that lithium is effective in the treatment of acute mania and for the long-term maintenance ofmood and prophylaxis; in comparison, evidence for its efficacy in depression is modest. However, lithiumpossesses unique anti-suicidal properties that set it apart from other agents. With respect to cognition,studies suggest that lithium may reduce cognitive decline in patients; however, these findings requirefurther investigation using both neuropsychological and functional neuroimaging probes. Interestingly,lithium appears to preserve or increase the volume of brain structures involved in emotional regulationsuch as the prefrontal cortex, hippocampus and amygdala, possibly reflecting its neuroprotective effects.At a neuronal level, lithium reduces excitatory (dopamine and glutamate) but increases inhibitory (GABA)neurotransmission; however, these broad effects are underpinned by complex neurotransmitter systemsthat strive to achieve homeostasis by way of compensatory changes. For example, at an intracellular andmolecular level, lithium targets second-messenger systems that further modulate neurotransmission. Forinstance, the effects of lithium on the adenyl cyclase and phospho-inositide pathways, as well as proteinkinase C, may serve to dampen excessive excitatory neurotransmission. In addition to these manyputative mechanisms, it has also been proposed that the neuroprotective effects of lithium are key to itstherapeutic actions. In this regard, lithium has been shown to reduce the oxidative stress that occurs withmultiple episodes of mania and depression. Further, it increases protective proteins such as brain-derivedneurotrophic factor and B-cell lymphoma 2, and reduces apoptotic processes through inhibition ofglycogen synthase kinase 3 and autophagy. Overall, it is clear that the processes which underpin thetherapeutic actions of lithium are sophisticated and most likely inter-related.", "metadata": {}}
+{"_id": "26952804", "title": "", "text": "The role of autophagy in cancer development and response to therapyAutophagy is a process in whichsubcellular membranes undergo dynamic morphological changes that lead to the degradation of cellularproteins and cytoplasmic organelles. This process is an important cellular response to stress orstarvation. Many studies have shed light on the importance of autophagy in cancer, but it is still unclearwhether autophagy suppresses tumorigenesis or provides cancer cells with a rescue mechanism underunfavourable conditions. What is the present state of our knowledge about the role of autophagy incancer development, and in response to therapy? And how can the autophagic process be manipulated toimprove anticancer therapeutics?", "metadata": {}}
+{"_id": "26973393", "title": "", "text": "The quest to overcome resistance to EGFR-targeted therapies in cancerAll patients with metastatic lung,colorectal, pancreatic or head and neck cancers who initially benefit from epidermal growth factorreceptor (EGFR)-targeted therapies eventually develop resistance. An increasing understanding of thenumber and complexity of resistance mechanisms highlights the Herculean challenge of killing tumorsthat are resistant to EGFR inhibitors. Our growing knowledge of resistance pathways provides anopportunity to develop new mechanism-based inhibitors and combination therapies to prevent orovercome therapeutic resistance in tumors. We present a comprehensive review of resistance pathwaysto EGFR-targeted therapies in lung, colorectal and head and neck cancers and discuss therapeuticstrategies that are designed to circumvent resistance.", "metadata": {}}
+{"_id": "26990001", "title": "", "text": "An organ culture model for the study of metanephric development.A murine whole organ metanephricculture system was designed to study the developmental aspects of mammalian nephrogenesis.Metanephros and ureteric bud were removed from CFI albino mouse embryos at 13.5 +/- 0.4 daysgestation, and grown in Dulbecco's modified Eagle's Minimal Essential Medium supplemented with 20 percent donor bovine serum at 37C in a mixed air--5 per cent CO2 environment. Under the experimentalconditions employed, the metanephric explants showed organotypic tubular and glomerular epithelialdevelopment. A well-developed proximal tubule with microvilli, and characteristic intracellular organellesand intercellular junctions developed by 72 hours of culture. By 120 hours of culture, uniquedevascularized glomeruli consisting of parietal and visceral epithelial layers formed. The glomerularvisceral epithelial cells formed foot processes and slit pore diaphragms, and produced islands ofbasement membrane. No endothelial or mesangial elements were present at any stage in organ culturedevelopment, indicating that advanced nephrogenesis can occur following initial epithelial-mesenchymalinduction despite the absence of vascularization. The whole organ culture model system isolates renalstructural development from the influences of perfusion and urine formation. The system thus affords theopportunity to study normal, as well as abnormal mammalian renal development under highly controlledexperimental conditions.", "metadata": {}}
+{"_id": "26993601", "title": "", "text": "Molecular layers underlying cytoskeletal remodelling during cortical developmentDuring neuraldevelopment, the cytoskeleton of newborn neurons undergoes extensive and dynamic remodelling tofacilitate the sequential steps of neurogenesis, cell migration and terminal differentiation. It is clear fromstudying the mechanisms that precipitate these functions that different configurations of the cytoskeletonprefigure the correct execution of each step and define cohorts of proteins the functions of which areindispensable for the control of neuronal migration but not terminal differentiation. These combinatorialprotein functions are also predetermined by regulated gene expression and the precise subcellularlocalisation of their protein products. Here, we expand on this view in the context of recent data on howthe cytoskeleton is regulated during the maturation of cortical neurons within the developing brain.", "metadata": {}}
+{"_id": "26996935", "title": "", "text": "Strong bias in the bacterial CRISPR elements that confer immunity to phage.Clustered regularlyinterspaced short palindromic repeats (CRISPR)-Cas systems provide adaptive immunity against phagevia spacer-encoded CRISPR RNAs that are complementary to invasive nucleic acids. Here, we challengeStreptococcus thermophilus with a bacteriophage, and used PCR-based metagenomics to monitorphage-derived spacers daily for 15 days in two experiments. Spacers that target the host chromosomeare infrequent and strongly selected against, suggesting autoimmunity is lethal. In experiments thatrecover over half a million spacers, we observe early dominance by a few spacer sub-populations andrapid oscillations in sub-population abundances. In two CRISPR systems and in replicate experiments, afew spacers account for the majority of spacer sequences. Nearly all phage locations targeted by theacquired spacers have a proto-spacer adjacent motif (PAM), indicating PAMs are involved in spaceracquisition. We detect a strong and reproducible bias in the phage genome locations from which spacersderive. This may reflect selection for specific spacers based on location and effectiveness.", "metadata": {}}
+{"_id": "27022864", "title": "", "text": "Chronic hypoxia induces modification of the N-methyl-D-aspartate receptor in rat brain.This studyexamined [3H]MK-801 binding to the N-methyl-D-aspartate (NMDA) receptor in membranes preparedfrom cerebral cortex, hippocampus and corpus striatum of 3 week old rats exposed to 10 weeks ofintermittent hypobaric hypoxia (4300 m; 450 Torr) and compared results with those of normoxiccontrols. The cortex, hippocampus and striatum of hypoxic animals had a 36, 35 and 31% reduction inbinding sites (Bmax) and a 29, 32 and 17% decrease (reflecting increased affinity) in the dissociationconstant (Kd) when compared to controls. In the cerebral cortex, both glutamate (100 microM) andglycine (10 microM) enhanced 3[H]MK-801 binding by two to 3-fold. Coagonist glutamate, however, hada higher EC50 (0.44 microM) in the hypoxic cortical membranes when compared to controls (0.28microM). No significant differences were found in the EC50 of glycine. The results show that the NMDAreceptor is altered in several brain regions of rats developing in a hypoxic environment.", "metadata": {}}
+{"_id": "27024392", "title": "", "text": "Cannabinoids in Clinical PracticeCannabis has a potential for clinical use often obscured by unreliable andpurely anecdotal reports. The most important natural cannabinoid is the psychoactivetetrahydrocannabinol (Δ9-THC); others include cannabidiol (CBD) and cannabigerol (CBG). Not all theobserved effects can be ascribed to THC, and the other constituents may also modulate its action; forexample CBD reduces anxiety induced by THC. A standardised extract of the herb may be therefore bemore beneficial in practice and clinical trial protocols have been drawn up to assess this. The mechanismof action is still not fully understood, although cannabinoid receptors have been cloned and naturalligands identified. Cannabis is frequently used by patients with multiple sclerosis (MS) for muscle spasmand pain, and in an experimental model of MS low doses of cannabinoids alleviated tremor. Most of thecontrolled studies have been carried out with THC rather than cannabis herb and so do not mimic theusual clincal situation. Small clinical studies have confirmed the usefulness of THC as an analgesic; CBDand CBG also have analgesic and antiinflammatory effects, indicating that there is scope for developingdrugs which do not have the psychoactive properties ofTHC. Patients taking the synthetic derivativenabilone for neurogenic pain actually preferred cannabis herb and reported that it relieved not only painbut the associated depression and anxiety. Cannabinoids are effective in chemotherapy-induced emesisand nabilone has been licensed for this use for several years. Currently, the synthetic cannabinoid HU211is undergoing trials as a protective agent after brain trauma. Anecdotal reports of cannabis use includecase studies in migraine and Tourette’s syndrome, and as a treatment for asthma and glaucoma. Apartfrom the smoking aspect, the safety profile of cannabis is fairly good. However, adverse reactions includepanic or anxiety attacks, which are worse in the elderly and in women, and less likely in children.Although psychosis has been cited as a consequence of cannabis use, an examination of psychiatrichospital admissions found no evidence of this, however, it may exacerbate existing symptoms. Therelatively slow elimination from the body of the cannabinoids has safety implications for cognitive tasks,especially driving and operating machinery; although driving impairment with cannabis is only moderate,there is a significant interaction with alcohol. Natural materials are highly variable and multiplecomponents need to be standardised to ensure reproducible effects. Pure natural and syntheticcompounds do not have these disadvantages but may not have the overall therapeutic effect of the herb.", "metadata": {}}
+{"_id": "27049238", "title": "", "text": "Large deformation of red blood cell ghosts in a simple shear flow.Red blood cells are known to changeshape in response to local flow conditions. Deformability affects red blood cell physiological function andthe hydrodynamic properties of blood. The immersed boundary method is used to simulatethree-dimensional membrane-fluid flow interactions for cells with the same internal and external fluidviscosities. The method has been validated for small deformations of an initially spherical capsule insimple shear flow for both neo-Hookean and the Evans-Skalak membrane models. Initially oblatespheroidal capsules are simulated and it is shown that the red blood cell membrane exhibits asymptoticbehavior as the ratio of the dilation modulus to the extensional modulus is increased and a goodapproximation of local area conservation is obtained. Tank treading behavior is observed and its periodcalculated.", "metadata": {}}
+{"_id": "27054878", "title": "", "text": "Preoperative C-reactive protein predicts long-term mortality and hospital length of stay after primary,nonemergent coronary artery bypass grafting.BACKGROUND Preoperative C-reactive protein (CRP) levelsmore than 10 mg/l have been shown to be associated with increased morbidity and mortality aftercardiac surgery. We examine the value of preoperative CRP levels less than 10 mg/l for predictinglong-term, all-cause mortality and hospital length of stay in surgical patients undergoing primary,nonemergent coronary artery bypass graft-only surgery. METHODS We examined the associationbetween preoperative CRP levels stratified into four categories (< 1, 1-3, 3-10, and > 10 mg/l), and 7-yrall-cause mortality and hospital length of stay in 914 prospectively enrolled primary, nonemergentcoronary artery bypass graft-only surgical patients using a proportional hazards regression model.RESULTS Eighty-seven patients (9.5%) died during a mean follow-up period of 4.8 +/- 1.5 yr. Afterproportional hazards adjustment, the 3-10 and > 10 mg/l preoperative CRP groups were associated withlong-term, all-cause mortality (hazards ratios [95% CI]: 2.50 [1.22-5.16], P = 0.01 and 2.66[1.21-5.80], P = 0.02, respectively) and extended hospital length of stay (1.32 [1.07-1.63], P < 0.001and 1.27 [1.02-1.62], P = 0.001, respectively). CONCLUSION We demonstrate that preoperative CRPlevels as low as 3 mg/l are associated with increased long-term mortality and extended hospital length ofstay in relatively lower-acuity patients undergoing primary, nonemergent coronary artery bypassgraft-only surgery. These important findings may allow for more objective risk stratification of patientswho present for uncomplicated surgical coronary revascularization.", "metadata": {}}
+{"_id": "27061085", "title": "", "text": "Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoformswitching during cell differentiation.High-throughput mRNA sequencing (RNA-Seq) promises simultaneoustranscript discovery and abundance estimation. However, this would require algorithms that are notrestricted by prior gene annotations and that account for alternative transcription and splicing. Here weintroduce such algorithms in an open-source software program called Cufflinks. To test Cufflinks, wesequenced and analyzed >430 million paired 75-bp RNA-Seq reads from a mouse myoblast cell line overa differentiation time series. We detected 13,692 known transcripts and 3,724 previously unannotatedones, 62% of which are supported by independent expression data or by homologous genes in otherspecies. Over the time series, 330 genes showed complete switches in the dominant transcription startsite (TSS) or splice isoform, and we observed more subtle shifts in 1,304 other genes. These resultssuggest that Cufflinks can illuminate the substantial regulatory flexibility and complexity in even thiswell-studied model of muscle development and that it can improve transcriptome-based genomeannotation.", "metadata": {}}
+{"_id": "27063470", "title": "", "text": "Sporadic Creutzfeldt-Jakob disease in the United Kingdom: analysis of epidemiological surveillance datafor 1970-96.OBJECTIVE To identify changes in the occurrence of Creutzfeldt-Jakob disease that might berelated to the epidemic of bovine spongiform encephalopathy. DESIGN Epidemiological surveillance of theUnited Kingdom population for Creutzfeldt-Jakob disease based on (a) referral of suspected cases byneurologists, neuropathologists, and neurophysiologists and (b) death certificates. SETTING England andWales during 1970-84, and whole of the United Kingdom during 1985-96. SUBJECTS All 662 patientsidentified as sporadic cases of Creutzfeldt-Jakob disease. MAIN OUTCOME MEASURES Age distribution ofpatients, age specific time trends of disease, occupational exposure to cattle, potential exposure tocausative agent of bovine spongiform encephalopathy. RESULTS During 1970-96 there was an increase inthe number of sporadic cases of Creutzfeldt-Jakob disease recorded yearly in England and Wales. Thegreatest increase was among people aged over 70. There was a statistically significant excess of casesamong dairy farm workers and their spouses and among people at increased risk of contact with livecattle infected with bovine spongiform encephalopathy. During 1994-6 there were six deaths fromsporadic Creutzfeldt-Jakob disease in the United Kingdom in patients aged under 30. CONCLUSIONS Theincrease in the incidence of sporadic Creutzfeldt-Jakob disease and the high incidence in dairy farmers inthe United Kingdom may be unrelated to bovine spongiform encephalopathy. The most striking change inthe pattern of Creutzfeldt-Jakob disease in the United Kingdom after the epidemic of bovine spongiformencephalopathy is provided by the incidence in a group of exceptionally young patients with a consistentand unusual neuropathological profile. The outcome of mouse transmission studies and the futureincidence of the disease in the United Kingdom and elsewhere, will be important in judging whether theagent causing bovine spongiform encephalopathy has infected humans.", "metadata": {}}
+{"_id": "27076725", "title": "", "text": "Documented head injury in early adulthood and risk of Alzheimer's disease and otherdementias.BACKGROUND The association between antecedent head injury and AD is inconsistent.OBJECTIVE To examine the association between early adult head injury, as documented by militaryhospital records, and dementia in late life; and to evaluate the interaction between head injury and APOEepsilon4 as risk factors for dementia. METHODS The study had a population-based prospective historicalcohort design. It included men who were World War II Navy and Marine veterans, and were hospitalizedduring their military service with a diagnosis of either a nonpenetrating head injury or another unrelatedcondition. In 1996 to 1997, military medical records were abstracted to document the occurrence anddetails of closed head injury. The entire sample was then evaluated for dementia and AD using amultistage procedure. There were 548 veterans with head injury and 1228 without head injury whocompleted all assigned stages of the study. The authors estimated risk of dementia, specifically AD, usingproportional hazards models. RESULTS Both moderate head injury (hazard ratio [HR] = 2.32; CI = 1.04to 5.17) and severe head injury (HR = 4.51; CI = 1.77 to 11.47) were associated with increased risk ofAD. Results were similar for dementia in general. The results for mild head injury were inconclusive.When the authors stratified by the number of APOE epsilon4 alleles, they observed a nonsignificant trendtoward a stronger association between AD and head injury in men with more epsilon4 alleles.CONCLUSIONS Moderate and severe head injuries in young men may be associated with increased risk ofAD and other dementias in late life. However, the authors cannot exclude the possibility that otherunmeasured factors may be influencing this association.", "metadata": {}}
+{"_id": "27077180", "title": "", "text": "Transient receptor potential channels as drug targets: from the science of basic research to the art ofmedicine.The large Trp gene family encodes transient receptor potential (TRP) proteins that form novelcation-selective ion channels. In mammals, 28 Trp channel genes have been identified. TRP proteinsexhibit diverse permeation and gating properties and are involved in a plethora of physiologic functionswith a strong impact on cellular sensing and signaling pathways. Indeed, mutations in human genesencoding TRP channels, the so-called \"TRP channelopathies,\" are responsible for a number of hereditarydiseases that affect the musculoskeletal, cardiovascular, genitourinary, and nervous systems. This reviewgives an overview of the functional properties of mammalian TRP channels, describes their roles inacquired and hereditary diseases, and discusses their potential as drug targets for therapeuticintervention.", "metadata": {}}
+{"_id": "27078065", "title": "", "text": "Identification of genes associated with the astrocyte-specific gene Gfap during astrocytedifferentiation.Chromosomes and genes are non-randomly arranged within the mammalian cell nucleus,and gene clustering is of great significance in transcriptional regulation. However, the relevance of geneclustering and their expression during the differentiation of neural precursor cells (NPCs) into astrocytesremains unclear. We performed a genome-wide enhanced circular chromosomal conformation capture(e4C) to screen for genes associated with the astrocyte-specific gene glial fibrillary acidic protein (Gfap)during astrocyte differentiation. We identified 18 genes that were specifically associated with Gfap andexpressed in NPC-derived astrocytes. Our results provide additional evidence for the functionalsignificance of gene clustering in transcriptional regulation during NPC differentiation.", "metadata": {}}
+{"_id": "27093166", "title": "", "text": "Ketamine reduces LPS-induced HMGB1 via activation of the Nrf2/HO-1 pathway and NF-κBsuppression.BACKGROUND Ketamine, as an anesthetic agent, has an anti-inflammatory effect. In thepresent study, we investigated whether ketamine inhibits release of high mobility group box 1 (HMGB1),a late-phase cytokine of sepsis, in lipopolysaccharide (LPS)-stimulated macrophages through hemeoxygenase-1 (HO-1) induction. METHODS Macrophages were preincubated with various concentrations ofketamine and then treated with LPS (1 μg/mL). The cell culture supernatants were collected to measureinflammatory mediators (HMGB1, nitric oxide, tumor necrosis factor-α, and interleukin 1β) byenzyme-linked immunosorbent assay. Moreover, HO-1 protein expression, the phosphorylation anddegradation of IκB-α, and the nuclear translocation of nuclear factor E2-related factor 2 and nuclearfactor κB (NF-κB) p65 were tested by Western blot analysis. In addition, to further identify the role ofHO-1 in this process, tin protoporphyrin (SnPP), an HO-1 inhibitor, was used. RESULTS Ketaminetreatment dose-dependently attenuated the increased levels of proinflammatory mediators (HMGB1,nitric oxide, tumor necrosis factor α, and interleukin 1β) and increased the HO-1 protein expression inLPS-activated macrophages. Furthermore, ketamine suppressed the phosphorylation and degradation ofIκB-α as well as the LPS-stimulated nuclear translocation of NF-κB p65 in macrophages. In addition, thepresent study also demonstrated that ketamine induced HO-1 expression through the nucleartranslocation of nuclear factor E2-related factor 2 in macrophages. The effects of ketamine onLPS-induced proinflammatory cytokines production were partially reversed by the HO inhibitor tinprotoporphyrin (SnPP). CONCLUSION Ketamine inhibits the release of HMGB1 in LPS-stimulatedmacrophages, and this effect is at least partly mediated by the activation of the Nrf2/HO-1 pathway andNF-κB suppression.", "metadata": {}}
+{"_id": "27099731", "title": "", "text": "Association Between Early Screening for Patent Ductus Arteriosus and In-Hospital Mortality AmongExtremely Preterm Infants.IMPORTANCE There is currently no consensus for the screening and treatmentof patent ductus arteriosus (PDA) in extremely preterm infants. Less pharmacological closure and moresupportive management have been observed without evidence to support these changes. OBJECTIVE Toevaluate the association between early screening echocardiography for PDA and in-hospital mortality.DESIGN, SETTING, AND PARTICIPANTS Comparison of screened and not screened preterm infantsenrolled in the EPIPAGE 2 national prospective population-based cohort study that included all preterminfants born at less than 29 weeks of gestation and hospitalized in 68 neonatal intensive care units inFrance from April through December 2011. Two main analyses were performed to adjust for potentialselection bias, one using propensity score matching and one using neonatal unit preference for earlyscreening echocardiography as an instrumental variable. EXPOSURES Early screening echocardiographybefore day 3 of life. MAIN OUTCOMES AND MEASURES The primary outcome was death between day 3and discharge. The secondary outcomes were major neonatal morbidities (pulmonary hemorrhage,severe bronchopulmonary dysplasia, severe cerebral lesions, and necrotizing enterocolitis). RESULTSAmong the 1513 preterm infants with data available to determine exposure, 847 were screened for PDAand 666 were not; 605 infants from each group could be paired. Exposed infants were treated for PDAmore frequently during their hospitalization than nonexposed infants (55.1% vs 43.1%; odds ratio [OR],1.62 [95% CI, 1.31 to 2.00]; absolute risk reduction [ARR] in events per 100 infants, -12.0 [95% CI,-17.3 to -6.7). Exposed infants had a lower hospital death rate (14.2% vs 18.5% ; OR, 0.73 [95% CI,0.54 to 0.98]; ARR, 4.3 [95% CI, 0.3 to 8.3]) and a lower rate of pulmonary hemorrhage (5.6% vs8.9%; OR, 0.60 [95% CI, 0.38 to 0.95]; ARR, 3.3 [95% CI, 0.4 to 6.3]). No differences in rates ofnecrotizing enterocolitis, severe bronchopulmonary dysplasia, or severe cerebral lesions were observed.In the overall cohort, instrumental variable analysis yielded an adjusted OR for in-hospital mortality of0.62 [95% CI, 0.37 to 1.04]. CONCLUSIONS AND RELEVANCE In this national population-based cohort ofextremely preterm infants, screening echocardiography before day 3 of life was associated with lowerin-hospital mortality and likelihood of pulmonary hemorrhage but not with differences in necrotizingenterocolitis, severe bronchopulmonary dysplasia, or severe cerebral lesions. However, results of theinstrumental variable analysis leave some ambiguity in the interpretation, and longer-term evaluation isneeded to provide clarity.", "metadata": {}}
+{"_id": "27123743", "title": "", "text": "Role of birthweight in the etiology of breast cancer.Breast cancer may originate in utero. We reviewed theavailable evidence on the association between birthweight and the risk of breast cancer. To date, 26research papers addressing this issue have been published. The majority of studies identified a positivelink between birthweight and premenopausal, but not postmenopausal, breast cancer. The relative riskestimate for breast cancer comparing women with high birthweight to women with low birthweightcombining all studies including both pre- and postmenopausal breast cancer was 1.23 (95% confidenceinterval 1.13-1.34). The mechanisms underlying this association likely include elevated levels of growthfactors that may increase the number of susceptible stem cells in the mammary gland or initiate tumorsthrough DNA mutations. Loss of imprinting (LOI) of growth hormone genes relevant for intrauterinegrowth, such as insulin-like growth factor 2 (IGF2), leads to abnormally high levels of these hormonesevidenced by high birthweight. LOI of IGF2 has also been found in mammary tumor tissue. The role ofenvironmental factors that stimulate such epigenetic regulation of gene expression remains to beelucidated.", "metadata": {}}
+{"_id": "27127885", "title": "", "text": "An activator of the cAMP/PKA/CREB pathway promotes osteogenesis from human mesenchymal stemcells.Mesenchymal stem cells (MSCs) are multipotent adult stem cells capable of differentiating along theosteoblast, adipocyte, and chondrocyte lineages. Regulation of MSCs differentiation may be a useful toolfor regenerative medicine and cell-based therapy. The discovery of small molecule that activates theosteogenic differentiation of MSCs could aid in the development of a new anabolic drug for osteoporosistreatment. We identified CW008, a derivative of pyrazole-pyridine, that stimulates osteoblastdifferentiation of human MSCs and increases bone formation in ovariectomized mice. CW008 promotesosteogenesis by activating cAMP/PKA/CREB signaling pathway and inhibiting leptin secretion. Theseresults suggest that CW008 is an agonist of cAMP/PKA/CREB pathway in osteogenic differentiation andthat application of CW008 may be useful for the treatment of bone-related diseases and for the study ofbone biology.", "metadata": {}}
+{"_id": "27129115", "title": "", "text": "Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus.BACKGROUNDEpidemiological and basic science evidence suggests that magnesium sulphate before birth may beneuroprotective for the fetus. OBJECTIVES To assess the effects of magnesium sulphate as aneuroprotective agent when given to women considered at risk of preterm birth. SEARCH STRATEGY Wesearched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 August 2008). SELECTIONCRITERIA Randomised controlled trials of antenatal magnesium sulphate therapy in women threateningor likely to give birth at less than 37 weeks' gestational age. For one subgroup analysis, studies werebroadly categorised by the primary intent of the study into \"neuroprotective intent\", or \"other intent(maternal neuroprotective - pre-eclampsia)\", or \"other intent (tocolytic)\". DATA COLLECTION ANDANALYSIS At least two authors assessed trial eligibility and quality, and extracted data. MAIN RESULTSFive trials (6145 babies) were eligible for this review. Antenatal magnesium sulphate therapy given towomen at risk of preterm birth substantially reduced the risk of cerebral palsy in their child (Relative Risk(RR) 0.68; 95% Confidence interval (CI) 0.54 to 0.87; five trials; 6145 infants). There was also asignificant reduction in the rate of substantial gross motor dysfunction (RR 0.61; 95% CI 0.44 to 0.85;four trials; 5980 infants). No statistically significant effect of antenatal magnesium sulphate therapy wasdetected on paediatric mortality (RR 1.04; 95% CI 0.92 to 1.17; five trials; 6145 infants), or on otherneurological impairments or disabilities in the first few years of life. Overall there were no significanteffects of antenatal magnesium therapy on combined rates of mortality with cerebral palsy, althoughthere were significant reductions for the neuroprotective groups RR 0.85; 95% CI 0.74 to 0.98; fourtrials; 4446 infants, but not for the other intent subgroups. There were higher rates of minor maternalside effects in the magnesium groups, but no significant effects on major maternal complications.AUTHORS' CONCLUSIONS The neuroprotective role for antenatal magnesium sulphate therapy given towomen at risk of preterm birth for the preterm fetus is now established. The number of women needed tobe treated to benefit one baby by avoiding cerebral palsy is 63 (95% confidence interval 43 to 87). Giventhe beneficial effects of magnesium sulphate on substantial gross motor function in early childhood,outcomes later in childhood should be evaluated to determine the presence or absence of later potentiallyimportant neurological effects, particularly on motor or cognitive function.", "metadata": {}}
+{"_id": "27134527", "title": "", "text": "The growing landscape of lysine acetylation links metabolism and cell signallingLysine acetylation is aconserved protein post-translational modification that links acetyl-coenzyme A metabolism and cellularsignalling. Recent advances in the identification and quantification of lysine acetylation by massspectrometry have increased our understanding of lysine acetylation, implicating it in many biologicalprocesses through the regulation of protein interactions, activity and localization. In addition, proteins arefrequently modified by other types of acylations, such as formylation, butyrylation, propionylation,succinylation, malonylation, myristoylation, glutarylation and crotonylation. The intricate link betweenlysine acylation and cellular metabolism has been clarified by the occurrence of several suchmetabolite-sensitive acylations and their selective removal by sirtuin deacylases. These emerging findingspoint to new functions for different lysine acylations and deacylating enzymes and also highlight themechanisms by which acetylation regulates various cellular processes.", "metadata": {}}
+{"_id": "27134931", "title": "", "text": "COMPASS, a histone H3 (Lysine 4) methyltransferase required for telomeric silencing of geneexpression.The trithorax (Trx) family of proteins is required for maintaining a specific pattern of geneexpression in some organisms. Recently we reported the isolation and characterization of COMPASS, amultiprotein complex that includes the Trx-related protein Set1 of the yeast Saccharomyces cerevisiae.Here we report that COMPASS catalyzes methylation of the fourth lysine of histone H3 in vitro. Set1 andseveral other components of COMPASS are also required for histone H3 methylation in vivo and fortranscriptional silencing of a gene located near a chromosome telomere.", "metadata": {}}
+{"_id": "27138601", "title": "", "text": "Free water elimination diffusion tractography: A comparison with conventional and fluid-attenuatedinversion recovery, diffusion tensor imaging acquisitions.PURPOSE White matter tractographyreconstructions using conventional diffusion tensor imaging (DTI) near cerebrospinal fluid (CSF) spacesare often adversely affected by CSF partial volume effects (PVEs). This study evaluates the ability of freewater elimination (FWE) DTI methods to minimize the PVE of CSF for deterministic tractographyapplications. MATERIALS AND METHODS Ten healthy individuals were scanned with \"traditional,\" FLAIR(fluid-attenuated inversion recovery), and FWE DTI scans. The fornix, corpus callosum, and cingulumbundles were reconstructed using deterministic tractography. The FWE DTI scan was performed twice toseparately match total acquisition time (long FWE) and number of measurements (encoding directions,short FWE) to the FLAIR and \"traditional\" DTI scans. PVE resolution was determined based onreconstructed tract volume. All reconstructions underwent blinded review for anatomical correctness,symmetry, and completeness. RESULTS Reconstructions of the fornix demonstrated that the FWE andFLAIR scans produce more complete, anatomically plausible reconstructions than \"traditional\" DTI.Additionally, the tract reconstructions using FWE-DTI were significantly larger than when FLAIR was usedwith DTI (P < 0.0005). FLAIR and the FWE methods led to signal-to-noise ratio (SNR) reductions of 33%and 11%, respectively, compared with conventional DTI. The long and short FWE acquisitions did notsignificantly (P ≥ 0.31) differ from one another for any of the reconstructed tracts. CONCLUSION TheFWE diffusion model overcomes CSF PVE without the time, SNR, and volumetric coverage penaltiesinherent to FLAIR DTI.", "metadata": {}}
+{"_id": "27150276", "title": "", "text": "A systematic review of randomized controlled trials of acupuncture in the treatment ofdepression.BACKGROUND Acupuncture has become a popular complementary and alternative treatmentapproach. This review examined the randomized controlled trials (RCTs) examining the effects ofacupuncture treatment of depression. METHODS RCTs of the treatment of depression with acupuncturewere located using MEDLINE, Allied and Complementary Medicine and the Cochrane Central Register ofControlled Trials. The methodology of RCTs was assessed using the Jadad criteria, and elements ofresearch design, i.e., randomization, blinding, assessment of attrition rates, were quantified forsystematic comparisons among studies. RESULTS Among the 9 RCTs examined, five were deemed to beof low quality based upon Jadad criteria. The odds ratios derived from comparing acupuncture withcontrol conditions within the RCTs suggests some evidence for the utility of acupuncture in depression.General trends suggest that acupuncture modalities were as effective as antidepressants employed fortreatment of depression in the limited studies available for comparison. However, placebo acupuncturetreatment was often no different from intended verum acupuncture. LIMITATIONS The RCTs extractedwere limited by small sample sizes, imprecise enrollment criteria, problems with randomization, blinding,brief duration of study and lack of longitudinal follow-up. CONCLUSIONS Despite the findings that theodds ratios of existing literature suggest a role for acupuncture in the treatment of depression, theevidence thus far is inconclusive. However, efforts are being made to standardize complementaryapproaches to treat depression, and further systematized research into their use is warranted.", "metadata": {}}
+{"_id": "27158570", "title": "", "text": "Genome-Wide Gene-Sodium Interaction Analyses on Blood Pressure: The Genetic Epidemiology Networkof Salt-Sensitivity Study.We performed genome-wide analyses to identify genomic loci that interact withsodium to influence blood pressure (BP) using single-marker-based (1 and 2 df joint tests) andgene-based tests among 1876 Chinese participants of the Genetic Epidemiology Network ofSalt-Sensitivity (GenSalt) study. Among GenSalt participants, the average of 3 urine samples was used toestimate sodium excretion. Nine BP measurements were taken using a random zero sphygmomanometer.A total of 2.05 million single-nucleotide polymorphisms were imputed using Affymetrix 6.0 genotype dataand the Chinese Han of Beijing and Japanese of Tokyo HapMap reference panel. Promising findings(P<1.00×10(-4)) from GenSalt were evaluated for replication among 775 Chinese participants of theMulti-Ethnic Study of Atherosclerosis (MESA). Single-nucleotide polymorphism and gene-based resultswere meta-analyzed across the GenSalt and MESA studies to determine genome-wide significance. The 1df tests identified interactions for UST rs13211840 on diastolic BP (P=3.13×10(-9)). The 2 df testsadditionally identified associations for CLGN rs2567241 (P=3.90×10(-12)) and LOC105369882rs11104632 (P=4.51×10(-8)) with systolic BP. The CLGN variant rs2567241 was also associated withdiastolic BP (P=3.11×10(-22)) and mean arterial pressure (P=2.86×10(-15)). Genome-wide gene-basedanalysis identified MKNK1 (P=6.70×10(-7)), C2orf80 (P<1.00×10(-12)), EPHA6 (P=2.88×10(-7)),SCOC-AS1 (P=4.35×10(-14)), SCOC (P=6.46×10(-11)), CLGN (P=3.68×10(-13)), MGAT4D(P=4.73×10(-11)), ARHGAP42 (P≤1.00×10(-12)), CASP4 (P=1.31×10(-8)), and LINC01478(P=6.75×10(-10)) that were associated with at least 1 BP phenotype. In summary, we identified 8 noveland 1 previously reported BP loci through the examination of single-nucleotide polymorphism andgene-based interactions with sodium.", "metadata": {}}
+{"_id": "27162821", "title": "", "text": "Percentile curves for hemoglobin and red cell volume in infancy and childhood.Percentile curves werecalculated for hemoglobin and mean corpuscular volume in children between 0.5 and 16 years of age.The curves were derived from several populations of non-indigent white children who lived near sea level.Subjects were excluded from the reference population if they had laboratory evidence of iron deficiency,thalassemia minor, and/or hemoglobinopathy. The final reference populations included 9,946 children forthe derivation of the hemoglobin curves and 2,314 for the MCV curves. The percentile curves should beparticularly applicable to the diagnosis and screening of iron deficiency and thalassemia minor.", "metadata": {}}
+{"_id": "27166444", "title": "", "text": "Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacologicaltreatment of insulin resistance in high-risk hispanic women.Type 2 diabetes frequently results fromprogressive failure of pancreatic beta-cell function in the presence of chronic insulin resistance. We testedwhether chronic amelioration of insulin resistance would preserve pancreatic beta-cell function and delayor prevent the onset of type 2 diabetes in high-risk Hispanic women. Women with previous gestationaldiabetes were randomized to placebo (n = 133) or the insulin-sensitizing drug troglitazone (400 mg/day;n = 133) administered in double-blind fashion. Fasting plasma glucose was measured every 3 months,and oral glucose tolerance tests (OGTTs) were performed annually to detect diabetes. Intravenousglucose tolerance tests (IVGTTs) were performed at baseline and 3 months later to identify earlymetabolic changes associated with any protection from diabetes. Women who did not develop diabetesduring the trial returned for OGTTs and IVGTTs 8 months after study medications were stopped. During amedian follow-up of 30 months on blinded medication, average annual diabetes incidence rates in the236 women who returned for at least one follow-up visit were 12.1 and 5.4% in women assigned toplacebo and troglitazone, respectively (P < 0.01). Protection from diabetes in the troglitazone group 1)was closely related to the degree of reduction in endogenous insulin requirements 3 months afterrandomization, 2) persisted 8 months after study medications were stopped, and 3) was associated withpreservation of beta-cell compensation for insulin resistance. Treatment with troglitazone delayed orprevented the onset of type 2 diabetes in high-risk Hispanic women. The protective effect was associatedwith the preservation of pancreatic beta-cell function and appeared to be mediated by a reduction in thesecretory demands placed on beta-cells by chronic insulin resistance.", "metadata": {}}
+{"_id": "27167110", "title": "", "text": "Androgen regulation of micro-RNAs in prostate cancer.BACKGROUND Androgens play a critical role in thegrowth of both androgen dependent and castration-resistant prostate cancer (CRPC). Only a fewmicro-RNAs (miRNAs) have been suggested to be androgen regulated. We aim to identify androgenregulated miRNAs. METHODS We utilized LNCaP derived model, we have established, and whichoverexpresses the androgen receptor (AR), the VCaP cell line, and 13 intact-castrated prostate cancer(PC) xenograft pairs, as well as clinical specimens of untreated (PC) and CRPC. The expression of miRNAswas analyzed by microarrays and quantitative RT-PCR (Q-RT-PCR). Transfection of pre-miR-141 andanti-miR-141 was also used. RESULTS Seventeen miRNAs were > 1.5-fold up- or downregulated upondihydrotestosterone (DHT) treatment in the cell lines, and 42 after castration in the AR-positivexenografts. Only four miRNAs (miR-10a, miR-141, miR-150*, and miR-1225-5p) showed similarandrogen regulation in both cell lines and xenografts. Of those, miR-141 was found to be expressed morein PC and CRPC compared to benign prostate hyperplasia. Additionally, the overexpression of miR-141enhanced growth of parental LNCaP cells while inhibition of miR-141 by anti-miR-141 suppressed thegrowth of the LNCaP subline overexpressing AR. CONCLUSIONS Only a few miRNAs were found to beandrogen-regulated in both cell lines and xenografts models. Of those, the expression of miR-141 wasupregulated in cancer. The ectopic overexpression of miR-141 increased growth of LNCaP cell suggestingit may contribute to the progression of PC.", "metadata": {}}
+{"_id": "27188320", "title": "", "text": "Relationship between drug treatment services, retention, and outcomes.OBJECTIVE This longitudinalstudy conducted path analyses to examine the relationships between treatment processes and outcomesamong patients in community-based drug treatment programs. METHODS A total of 1,939 patients from36 outpatient drug-free and residential treatment programs in 13 California counties were assessed atintake, discharge, three months after admission, and nine months after admission. Path analyses wereconducted to relate the quantity and quality of services that were received in the first three months oftreatment to treatment retention and outcomes at the nine-month follow-up. Patients were determined tohave a favorable outcome if for at least 30 days before the follow-up assessment they did not use drugs,were not involved in criminal activity, and lived in the community. The path analyses controlled forpatients' baseline characteristics. RESULTS Greater service intensity and satisfaction were positivelyrelated to either treatment completion or longer treatment retention, which in turn was related tofavorable treatment outcomes. Patients with greater problem severity received more services and weremore likely to be satisfied with treatment. These patterns were similar for patients regardless of whetherthey were treated in outpatient drug-free programs or residential programs. CONCLUSIONS The positiveassociation between process measures-that is, greater levels of service intensity, satisfaction, and eithertreatment completion or retention-and treatment outcome strongly suggests that improvements in thesekey elements of the treatment process will improve treatment outcomes.", "metadata": {}}
+{"_id": "27240667", "title": "", "text": "Breast cancer mortality trends in the United States according to estrogen receptor status and age atdiagnosis.PURPOSE Since 1990, overall breast cancer mortality rates in the United States decreased24%. This decline has been attributed to mammography screening and adjuvant systemic therapy.However, the efficacy of these modalities may depend on estrogen receptor (ER) expression and age. Wetherefore examined breast cancer mortality trends in the United States according to ER status and age.METHODS Using the Surveillance, Epidemiology, and End Results (SEER) program (1990-2003), wecalculated trends in incidence-based mortality (IBM), annual hazard rates for breast cancer deaths afterdiagnosis, and relative hazard rates for women with ER-positive and ER-negative tumors. Relative hazardrates were assessed with Cox proportional hazards models, adjusted for stage and grade, and stratifiedby age at diagnosis. RESULTS During the study period, IBM and annual hazard rates for breast cancerdeaths decreased among women with ER-positive and ER-negative tumors, although declines weregreater for those with ER-positive tumors. Among women younger than 70 years, relative hazard ratesdeclined 38% for those with ER-positive tumors versus 19% for those with ER-negative tumors. Amongwomen 70 years or older, relative hazard rates declined 14% for those with ER-positive tumors versus nosignificant decline for those with ER-negative tumors. CONCLUSION In the United States, breast cancermortality rates have declined among women with ER-positive and ER-negative tumors, with greaterdeclines among younger women and those with ER-positive tumors. Although mortality in all groupsremains unacceptably high, additional emphasis should be placed on improving outcomes of breastcancer patients older than 70 years and those of all ages with ER-negative tumors.", "metadata": {}}
+{"_id": "27240699", "title": "", "text": "An adenovirus mutant that replicates selectively in p53-deficient human tumor cells.The humanadenovirus E1B gene encodes a 55-kilodalton protein that inactivates the cellular tumor suppressorprotein p53. Here it is shown that a mutant adenovirus that does not express this viral protein canreplicate in and lyse p53-deficient human tumor cells but not cells with functional p53. Ectopic expressionof the 55-kilodalton EIB protein in the latter cells rendered them sensitive to infection with the mutantvirus. Injection of the mutant virus into p53-deficient human cervical carcinomas grown in nude micecaused a significant reduction in tumor size and caused complete regression of 60 percent of the tumors.These data raise the possibility that mutant adenoviruses can be used to treat certain human tumors.", "metadata": {}}
+{"_id": "27243019", "title": "", "text": "Immune reconstitution after cord blood transplantation: peculiarities, clinical implications andmanagement strategies.Umbilical cord blood (UCB) is now widely used as an alternative hematopoieticstem cell source for patients lacking closely matched related or unrelated adult donors. UCBtransplantation has traditionally been associated with delayed engraftment, poor immune reconstitutionand consequent increased risk of infection. More recent clinical studies, however, suggest thatconditioning regimens and in particular the omission of in vivo T-cell depletion may play a crucial role inpost-transplant T-cell expansion, facilitating a uniquely rapid immune recovery after UCB transplantation.The peculiar characteristics of UCB cells, the importance of thymic function and the role of conditioningregimens and graft-versus-host disease influencing immune reconstitution are described. The last part ofthe review reports available data on UCB, as well as third-party peripheral blood derived anti-viral celltherapy, which provides a novel approach to rescue UCB recipients with viral complications in thepost-transplant period.", "metadata": {}}
+{"_id": "27247460", "title": "", "text": "OVEREXPRESSION OF BOTH CLOCK AND BMAL1 INHIBITS ENTRY TO S PHASE IN HUMAN COLONCANCER CELLS.Many physiological, biochemical and behavioral processes operate under the circadianrhythm, which is generated by an internal time-keeping mechanism commonly referred to as thebiological clock, in almost all organisms from bacteria to mammals. The core circadian oscillator iscomposed of an autoregulatory transcription-translation feedback loop, in which CLOCK and BMAL1 arepositive regulators. A cell has two mechanisms, \"cell cycle\" and \"cell rhythm\", the relationship betweenwhich remains controversial. Therefore, the aim of this study was to explore the effect of Clock andBmal1 on cell cycle, especially on the G1 phase, using vectors with the tetracycline operator-repressorsystem. The present study revealed that simultaneous induction of Bmal1 and Clock had an influentialeffect on the cell cycle in SW480/T-REx/Clock/Bmal1 cells, in which both Clock and Bmal1 could beinduced by tetracycline. The observation that induction of both Clock and Bmal1 inhibited cell growth andthe significant increase of the G1 phase proportion of in SW480/T-REx/Clock/Bmal1 cells indicated thatentry from the G1 to S phase was inhibited by the induction of Clock and Bmal1. Furthermore,overexpression of Clock and Bmal1 prevented the cells from entering into the G2/M phase induced byPaclitaxel, and made the cells more resistant to the agent. In conclusion, we found that overexpression ofboth Clock and Bmal1 suppressed cell growth. In addition, the present study raised the possibility thatClock and Bmal1 may in part play a role in preventing the cells from entering G1 to S phase of cell cyclevia suppression of CyclinD1 expression, and thus acquiring resistance to Paclitaxel.", "metadata": {}}
+{"_id": "27260630", "title": "", "text": "Composition of gall bladder stones associated with octreotide: response to oral ursodeoxycholicacid.Octreotide, an effective treatment for acromegaly, induces gall bladder stones in 13-60% of patients.Because knowledge of stone composition is essential for studies of their pathogenesis, treatment, andprevention, this was investigated by direct and indirect methods in 14 octreotide treated acromegalicpatients with gall stones. Chemical analysis of gall stones retrieved at cholecystectomy from two patients,showed that they contained 71% and 87% cholesterol by weight. In the remaining 12 patients, localisedcomputed tomography of the gall bladder showed that eight had stones with maximum attenuationscores of < 100 Hounsfield units (values of < 100 HU predict cholesterol rich, dissolvable stones). Gallbladder bile was obtained by ultrasound guided, fine needle puncture from six patients. All six patientshad supersaturated bile (mean (SEM) cholesterol saturation index of 1.19 (0.08) (range 1.01-1.53)) andall had abnormally rapid cholesterol microcrystal nucleation times (< 4 days (range 1-4)), whilst in four,the bile contained cholesterol microcrystals immediately after sampling. Of the 12 patients considered fororal ursodeoxycholic acid (UDCA) treatment, two had a blocked cystic duct and were not started on UDCAwhile one was lost to follow up. After one year of treatment, five of the remaining nine patients showedeither partial (n = 3) or complete (n = 2) gall stone dissolution, suggesting that their stones werecholesterol rich. This corresponds, by actuarial (life table) analysis, to a combined gall stone dissolutionrate of 58.3 (15.9%). In conclusion, octreotide induced gall stones are generally small, multiple, andcholesterol rich although, in common with spontaneous gall stone disease, at presentation some patientswill have a blocked cystic duct and some gall stones containing calcium.", "metadata": {}}
+{"_id": "27264454", "title": "", "text": "Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results from a randomizedvehicle-controlled phase III study in Europe.BACKGROUND Imiquimod is an immune response modifierthat acts through toll-like receptor 7 to induce cytokine production and a subsequent innate and adaptivecell-mediated immune response. Clinical studies have demonstrated clinical and histological clearance ofsuperficial basal cell carcinoma (sBCC) after treatment with imiquimod 5% cream. OBJECTIVES Toevaluate the safety and clinical efficacy of imiquimod (Aldaratrade mark; 3M Pharmaceuticals, St Paul,MN, U.S.A.) 5% cream for the treatment of sBCC in a multicentre, randomized, parallel,vehicle-controlled, double-blind, phase III clinical study conducted at 26 centres in Europe. METHODSSubjects who had at least one histologically confirmed sBCC tumour were randomized to apply imiquimodor vehicle cream to the target tumour once daily, seven times per week (7 x/week) for 6 weeks. Thetarget tumour location was identified with an indelible ink mark before treatment initiation. The treatedtumour site was clinically assessed for treatment response at 12 weeks post-treatment and was thenexcised for histological evaluation. Efficacy assessments included the composite response rates(proportion of subjects with clinical and histological clearance) and response rates solely based onhistology (proportion of subjects with histological clearance). Safety assessments, which included adverseevents and scoring of local skin reactions (LSRs), were carried out throughout the study. RESULTS Intotal, 166 subjects were enrolled in this study. For the intent-to-treat dataset, there was a statisticallysignificant difference between imiquimod and vehicle groups for both composite clearance rates (clinicaland histological assessments) and histological clearance rates. Composite clearance was demonstrated in77% and 6% of subjects treated with imiquimod and vehicle cream, respectively. Histological clearancewas demonstrated in 80% and 6% of subjects treated with imiquimod and vehicle cream, respectively.The most frequently reported safety findings were investigator-assessed LSRs and spontaneous reportsby subjects of application site reactions, which occurred more frequently in the imiquimod group than inthe vehicle group. CONCLUSIONS Imiquimod 5% cream administered 7 x/week for 6 weeks is a safe andeffective treatment for sBCC when compared with vehicle cream.", "metadata": {}}
+{"_id": "27270151", "title": "", "text": "Changing the course of pancreatic cancer--Focus on recent translational advances.In the past decade,insightful preclinical research has led to important breakthroughs in our understanding of pancreaticcancer. Even though the vast majority of pancreatic cancers are KRAS mutated, not all pancreatic cancertumors are \"KRAS equal\"; there seems to be varying dependencies on the KRAS pathway. WhileKRAS-targeting therapies have been disappointing in the clinic, 'synthetic lethal' approaches hold promisein this setting. The pancreatic cancer stromal microenvironment appears to have contradictory roles.While there is evidence to suggest that stromal barrier prevents drug delivery, in other circumstances,stroma can play a protective role and its disruption enhances tumor dissemination. Clinical trials aimed atmanipulating the various stromal components are in progress. BRCA mutation-related pancreatic tumorsillustrate a unique subtype with enhanced susceptibility to DNA damaging agents and PARP-inhibition.DNA repair defects in cancer extend beyond germ line BRCA mutation and may extend the indications forDNA repair-targeting agents. Immune strategies are an area of active investigation in pancreatic cancer.Although the initial trials of single-agent checkpoint inhibitors have been negative, combinationalapproaches using immune-modifying agents and vaccines appear promising and goal is to identify an'immune-therapy responsive' profile in pancreatic cancer.", "metadata": {}}
+{"_id": "27274441", "title": "", "text": "Swc2 is a widely conserved H2AZ-binding module essential for ATP-dependent histone exchangeThehistone variant H2AZ is incorporated preferentially at specific locations in chromatin to modulatechromosome functions. In Saccharomyces cerevisiae, deposition of histone H2AZ is mediated by themultiprotein SWR1 complex, which catalyzes ATP-dependent exchange of nucleosomal histone H2A forH2AZ. Here, we define interactions between SWR1 components and H2AZ, revealing a link between theATPase domain of Swr1 and three subunits required for the binding of H2AZ. We discovered that Swc2binds directly to and is essential for transfer of H2AZ. Swc6 and Arp6 are necessary for the association ofSwc2 and for nucleosome binding, whereas other subunits, Swc5 and Yaf9, are required for H2AZtransfer but neither H2AZ nor nucleosome binding. Finally, the C-terminal α-helix of H2AZ is crucial for itsrecognition by SWR1. These findings provide insight on the initial events of histone exchange.", "metadata": {}}
+{"_id": "27279525", "title": "", "text": "Detection, characterization, and spontaneous differentiation in vitro of very small embryonic-like putativestem cells in adult mammalian ovary.The present study was undertaken to detect, characterize, andstudy differentiation potential of stem cells in adult rabbit, sheep, monkey, and menopausal humanovarian surface epithelium (OSE). Two distinct populations of putative stem cells (PSCs) of variable sizewere detected in scraped OSE, one being smaller and other similar in size to the surrounding red bloodcells in the scraped OSE. The smaller 1-3 μm very small embryonic-like PSCs were pluripotent in naturewith nuclear Oct-4 and cell surface SSEA-4, whereas the bigger 4-7 μm cells with cytoplasmic localizationof Oct-4 and minimal expression of SSEA-4 were possibly the tissue committed progenitor stem cells.Pluripotent gene transcripts of Oct-4, Oct-4A, Nanog, Sox-2, TERT, and Stat-3 in human and sheep OSEwere detected by reverse transcriptase-polymerase chain reaction. The PSCs underwent spontaneousdifferentiation into oocyte-like structures, parthenote-like structures, embryoid body-like structures, cellswith neuronal-like phenotype, and embryonic stem cell-like colonies, whereas the epithelial cellstransformed into mesenchymal phenotype by epithelial-mesenchymal transition in 3 weeks of OSEculture. Germ cell markers like c-Kit, DAZL, GDF-9, VASA, and ZP4 were immuno-localized in oocyte-likestructures. In conclusion, as opposed to the existing view of OSE being a bipotent source of oocytes andgranulosa cells, mammalian ovaries harbor distinct very small embryonic-like PSCs and tissue committedprogenitor stem cells population that have the potential to develop into oocyte-like structures in vitro,whereas mesenchymal fibroblasts appear to form supporting granulosa-like somatic cells. Research at thesingle-cell level, including complete gene expression profiling, is required to further confirm whetherpostnatal oogenesis is a conserved phenomenon in adult mammals.", "metadata": {}}
+{"_id": "27306942", "title": "", "text": "Rearrangement of CRLF2 is associated with mutation of JAK kinases, alteration of IKZF1, Hispanic/Latinoethnicity, and a poor outcome in pediatric B-progenitor acute lymphoblastic leukemia.Gene expressionprofiling of 207 uniformly treated children with high-risk B-progenitor acute lymphoblastic leukemiarevealed 29 of 207 cases (14%) with markedly elevated expression of CRLF2 (cytokine receptor-likefactor 2). Each of the 29 cases harbored a genomic rearrangement of CRLF2: 18 of 29 (62%) had atranslocation of the immunoglobulin heavy chain gene IGH@ on 14q32 to CRLF2 in the pseudoautosomalregion 1 of Xp22.3/Yp11.3, whereas 10 (34%) cases had a 320-kb interstitial deletion centromeric ofCRLF2, resulting in a P2RY8-CRLF2 fusion. One case had both IGH@-CRLF2 and P2RY8-CRLF2, andanother had a novel CRLF2 rearrangement. Only 2 of 29 cases were Down syndrome. CRLF2rearrangements were significantly associated with activating mutations of JAK1 or JAK2, deletion ormutation of IKZF1, and Hispanic/Latino ethnicity (Fisher exact test, P < .001 for each). Within thiscohort, patients with CRLF2 rearrangements had extremely poor treatment outcomes compared withthose without CRLF2 rearrangements (35.3% vs 71.3% relapse-free survival at 4 years; P < .001).Together, these observations suggest that activation of CRLF2 expression, mutation of JAK kinases, andalterations of IKZF1 cooperate to promote B-cell leukemogenesis and identify these pathways asimportant therapeutic targets in this disease.", "metadata": {}}
+{"_id": "27373088", "title": "", "text": "Substrate requirements for ErmC' methyltransferase activity.ErmC' is a methyltransferase that confersresistance to the macrolide-lincosamide-streptogramin B group of antibiotics by catalyzing themethylation of 23S rRNA at a specific adenine residue (A-2085 in Bacillus subtilis; A-2058 in Escherichiacoli). The gene for ErmC' was cloned and expressed to a high level in E. coli, and the protein was purifiedto virtual homogeneity. Studies of substrate requirements of ErmC' have shown that a 262-nucleotideRNA fragment within domain V of B. subtilis 23S rRNA can be utilized efficiently as a substrate formethylation at A-2085. Kinetic studies of the monomethylation reaction showed that the apparent Km ofthis 262-nucleotide RNA oligonucleotide was 26-fold greater than the value determined for full-size anddomain V 23S rRNA. In addition, the Vmax for this fragment also rose sevenfold. A model of RNA-ErmC'interaction involving multiple binding sites is proposed from the kinetic data presented.", "metadata": {}}
+{"_id": "27391365", "title": "", "text": "Validity of the World Health Organization Adult ADHD Self-Report Scale (ASRS) Screener in arepresentative sample of health plan members.The validity of the six-question World Health OrganizationAdult ADHD Self-Report Scale (ASRS) Screener was assessed in a sample of subscribers to a large healthplan in the US. A convenience subsample of 668 subscribers was administered the ASRS Screener twiceto assess test-retest reliability and then a third time in conjunction with a clinical interviewer for DSM-IVadult ADHD. The data were weighted to adjust for discrepancies between the sample and the populationon socio-demographics and past medical claims. Internal consistency reliability of the continuous ASRSScreener was in the range 0.63-0.72 and test-retest reliability (Pearson correlations) in the range0.58-0.77. A four-category version The ASRS Screener had strong concordance with clinician diagnoses,with an area under the receiver operating characteristic curve (AUC) of 0.90. The brevity and ability todiscriminate DSM-IV cases from non-cases make the six-question ASRS Screener attractive for use bothin community epidemiological surveys and in clinical outreach and case-finding initiatives.", "metadata": {}}
+{"_id": "27393799", "title": "", "text": "The body-mass index of twins who have been reared apart.To assess the relative importance of geneticand environmental effects on the body-mass index (weight in kilograms divided by the square of theheight in meters), we studied samples of identical and fraternal twins, reared apart or reared together.The samples consisted of 93 pairs of identical twins reared apart, 154 pairs of identical twins rearedtogether, 218 pairs of fraternal twins reared apart, and 208 pairs of fraternal twins reared together. Theintrapair correlation coefficients of the values for body-mass index of identical twins reared apart were0.70 for men and 0.66 for women. These are the most direct estimates of the relative importance ofgenetic influences (heritability) on the body-mass index, and they were only slightly lower than those fortwins reared together in this and earlier studies. Similar estimates were derived frommaximum-likelihood model-fitting analyses--0.74 for men and 0.69 for women. Nonadditive geneticvariance made a significant contribution to the estimates of heritability, particularly among men. Of thepotential environmental influences, only those unique to the individual and not those shared by familymembers were important, contributing about 30 percent of the variance. Sharing the same childhoodenvironment did not contribute to the similarity of the body-mass index of twins later in life. We concludethat genetic influences on body-mass index are substantial, whereas the childhood environment has littleor no influence. These findings corroborate and extend the results of earlier studies of twins andadoptees.", "metadata": {}}
+{"_id": "27396415", "title": "", "text": "A study of high cell density cultivation process of recombinant Helicobacter pylori multi-epitope vaccineengineering bacteria.OBJECTIVE To establish high cell density cultivation process of recombinantHelicobacter pylori multi-epitope vaccine engineering bacteria BIB. METHODS Based on the results ofshake flask fermentation, the process was magnified into volume of a 50 L fermenter to optimize andverify the factors affecting the yield of the target protein, such as the fermentation medium, workingseed inoculation amount, inducer concentration, induction starting time, induction duration, induceradding mode and feeding strategy. RESULTS After activated in modified TB medium at 37°C for 8 h, theBIB working seed was inoculated at 5% (v/v) and was induced for expression for another 11 h by thefinal concentration of 5 mmol/L lactose. In growth phase, glucose at rate of 80 ml/h was used as carbonsource, and in induction phase, glycerol at rate of 40 ml/h was used as carbon source; ammonia waterwas added dropwise to control pH at about 7.0, and revolution speed is adjusted to control the dissolvedoxygen at above 30%; ultimately the output of bacterial body was 70 g/L and protein expression amountwas about 32%. CONCLUSION After high cell density cultivation of the recombinant engineering bacteria,expression and yield of the target protein rBIB significantly increased.", "metadata": {}}
+{"_id": "27403802", "title": "", "text": "Phorbol esters and cytokines regulate the expression of the NEMO-related protein, a molecule involved ina NF-kappa B-independent pathway.The NF-kappaB signaling pathway plays a crucial role in the immune,inflammatory, and apoptotic responses. Recently, we identified the NF-kappaB Essential Modulator(NEMO) as an essential component of this pathway. NEMO is a structural and regulatory subunit of thehigh molecular kinase complex (IKK) responsible for the phosphorylation of NF-kappaB inhibitors. Database searching led to the isolation of a cDNA encoding a protein we called NRP (NEMO-related protein),which shows a strong homology to NEMO. Here we show that NRP is present in a novel high molecularweight complex, that contains none of the known members of the IKK complex. Consistently, we couldnot observe any effect of NRP on NF-kappaB signaling. Nonetheless, we could demonstrate thattreatment with phorbol esters induces NRP phosphorylation and decreases its half-life. Thisphosphorylation event could only be inhibited by K-252a and stauroporin. We also show that de novoexpression of NRP can be induced by interferon and tumor necrosis factor alpha and that these twostimuli have a synergistic effect on NRP expression. In addition, we observed that endogenous NRP isassociated with the Golgi apparatus. Analogous to NEMO, we find that NRP is associated in a complexwith two kinases, suggesting that NRP could play a similar role in another signaling pathway.", "metadata": {}}
+{"_id": "27408104", "title": "", "text": "Tailoring Nutritional Advice for Mexicans Based on Prevalence Profiles of Diet-Related Adaptive GenePolymorphismsDiet-related adaptive gene (DRAG) polymorphisms identified in specific populations areassociated with chronic disorders in carriers of the adaptive alleles due to changes in dietary and lifestylepatterns in recent times. Mexico's population is comprised of Amerindians (AM) and Mestizos who havevariable AM, European (EUR) and African genetic ancestry and an increased risk of nutrition-relatedchronic diseases. Nutritional advice based on the Mexican genome and the traditional food culture isneeded to develop preventive and therapeutic strategies. Therefore, we aimed to provide a prevalenceprofile of several DRAG polymorphisms in the Mexican population, including Central West (CW) Mexicosubpopulations. Geographic heat maps were built using ArcGIS10 (Esri, Redlands, CA, USA) software,based on the published data of the MTHFR C677T (rs1801133), ABCA1 Arg230Cys (rs9282541), APOET388C (rs429358)/C526T (rs7412), LCT C-13910T (rs4988235) polymorphisms and AMY1 copy numbervariation (CNV). Also, new data obtained by allelic discrimination-real-time polymerase chain reaction(RT-PCR) assays for the MTHFR, ABCA1, and APOE polymorphisms as well as the AMY1 CNV in the CWMexico subpopulations with different proportions of AM and EUR ancestry were included. In the CWregion, the highest frequency of the MTHFR 677T, ABCA1 230C and APOE ε4 adaptive alleles wasobserved in the AM groups, followed by Mestizos with intermediate AM ancestry. The LCT-13910T allelefrequency was highest in Mestizos-EUR but extremely low in AM, while the AMY1 diploid copy number was6.82 ± 3.3 copies. Overall, the heat maps showed a heterogeneous distribution of the DRAGpolymorphisms, in which the AM groups revealed the highest frequencies of the adaptive alleles followedby Mestizos. Given these genetic differences, genome-based nutritional advice should be tailored in aregionalized and individualized manner according to the available foods and Mexican traditional foodculture that may lead to a healthier dietary pattern.", "metadata": {}}
+{"_id": "27428509", "title": "", "text": "Prevention of Type 2 Diabetes Mellitus Through Inhibition of the Renin-Angiotensin SystemType 2diabetes mellitus is becoming a major health problem associated with excess morbidity and mortality. Asthe prevalence of type 2 diabetes is rapidly increasing, prevention of the disease should be considered asa key objective in the near future. Besides lifestyle changes, various pharmacological treatments haveproven their efficacy in placebo-controlled clinical trials, including antidiabetic drugs such as metformin,acarbose and troglitazone, or antiobesity agents such as orlistat. Arterial hypertension, a clinical entity inwhich insulin resistance is common, is strongly associated with type 2 diabetes and may precede thedisease by several years. While antihypertensive agents such as diuretics or β-adrenoceptor antagonistsmay worsen insulin resistance and impair glucose tolerance, newer antihypertensive agents exert neutralor even slightly positive metabolic effects. Numerous clinical trials have investigated the effects of ACEinhibitors or angiotensin II receptor antagonists (ARAs) on insulin sensitivity in hypertensive patients,with or without diabetes, with no consistent results. Almost half of the studies with ACE inhibitors inhypertensive nondiabetic individuals demonstrated a slight but significant increase in insulin sensitivity asassessed by insulin-stimulated glucose disposal during a euglycaemic hyperinsulinaemic clamp, while theother half failed to reveal any significant change. The effects of ARAs on insulin sensitivity are neutral inmost studies. Mechanisms of improvement of glucose tolerance and insulin sensitivity through theinhibition of the renin-angiotensin system (RAS) are complex. They may include improvement of bloodflow and microcirculation in skeletal muscles and, thereby, enhancement of insulin and glucose deliveryto the insulin-sensitive tissues, facilitating insulin signalling at the cellular level and improvement ofinsulin secretion by the β cells. Six recent large-scale clinical studies reported a remarkably consistentreduction in the incidence of type 2 diabetes in hypertensive patients treated with either ACE inhibitors orARAs for 3–6 years, compared with a thiazide diuretic, β-adrenoceptor antagonist, the calcium channelantagonist amlodipine or even placebo. The relative risk reduction averaged 14% (p = 0.034) in theCAPPP (Captopril Prevention Project) with captopril compared with a thiazide or β1-adrenoceptorantagonist, 34% (p < 0.001) in the HOPE (Heart Outcomes Prevention Evaluation) study with ramiprilcompared with placebo, 30% (p < 0.001) in the ALLHAT (Antihypertensive and Lipid-Lowering Treatmentto Prevent Heart Attack Trial) with lisinopril compared with chlortalidone, 25% (p < 0.001) in the LIFE(Losartan Intervention For Endpoint reduction in hypertension study) with losartan compared withatenolol, and 25% (p = 0.09) in the SCOPE (Study on Cognition and Prognosis in the Elderly) withcandesartan cilexetil compared with placebo, and 23% (p < 0.0001) in the VALUE (ValsartanAntihypertensive Long-term Use Evaluation) trial with valsartan compared with amlodipine. All thesestudies considered the development of diabetes as a secondary endpoint, except the HOPE trial where itwas a post hoc analysis. These encouraging observations led to the initiation of two large, prospective,placebo-controlled randomised clinical trials whose primary outcome is the prevention of type 2 diabetes:the DREAM (Diabetes REduction Approaches with ramipril and rosiglitazone Medications) trial with theACE inhibitor ramipril and the NAVIGATOR (Nateglinide And Valsartan in Impaired Glucose ToleranceOutcomes Research) trial with the ARA valsartan. Finally, ONTARGET (ONgoing Telmisartan Alone and incombination with Ramipril Global Endpoint Trial) will also investigate as a secondary endpoint whether itis possible to prevent the development of type 2 diabetes by blocking the RAS with either an ACEinhibitor or an ARA or a combination of both. Thus, the recent consistent observations of a 14–34%reduction of the development of diabetes in hypertensive patients receiving ACE inhibitors or ARAs areexciting. From a theoretical point of view, they emphasise that there are many aspects of thepathogenesis, prevention and treatment of type 2 diabetes that still need to be uncovered. From apractical point of view, they may offer a new strategy to reduce the ongoing epidemic and burden of type2 diabetes.", "metadata": {}}
+{"_id": "27437459", "title": "", "text": "Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in livercancerOncolytic viruses and active immunotherapeutics have complementary mechanisms of action(MOA) that are both self amplifying in tumors, yet the impact of dose on subject outcome is unclear.JX-594 (Pexa-Vec) is an oncolytic and immunotherapeutic vaccinia virus. To determine the optimalJX-594 dose in subjects with advanced hepatocellular carcinoma (HCC), we conducted a randomizedphase 2 dose-finding trial (n = 30). Radiologists infused low- or high-dose JX-594 into liver tumors (days1, 15 and 29); infusions resulted in acute detectable intravascular JX-594 genomes. Objectiveintrahepatic Modified Response Evaluation Criteria in Solid Tumors (mRECIST) (15%) and Choi (62%)response rates and intrahepatic disease control (50%) were equivalent in injected and distantnoninjected tumors at both doses. JX-594 replication and granulocyte-macrophage colony-stimulatingfactor (GM-CSF) expression preceded the induction of anticancer immunity. In contrast to tumorresponse rate and immune endpoints, subject survival duration was significantly related to dose (mediansurvival of 14.1 months compared to 6.7 months on the high and low dose, respectively; hazard ratio0.39; P = 0.020). JX-594 demonstrated oncolytic and immunotherapy MOA, tumor responses anddose-related survival in individuals with HCC.", "metadata": {}}
+{"_id": "27438378", "title": "", "text": "Misread protein creates membrane channels: an essential step in the bactericidal action ofaminoglycosides.Among the pleiotropic effects of aminoglycosides, their irreversible uptake and theirblockade of initiating ribosomes have appeared to explain their bactericidal action, while the contributionsof translational misreading and membrane damage and the mechanism of that damage have remaineduncertain. We now present evidence that incorporation of misread proteins into the membrane canaccount for the membrane damage. The bactericidal action thus appears to result from the followingsequence, in which each step is essential: slight initial entry of the antibiotic; interaction withchain-elongating ribosomes, resulting in misreading; incorporation of misread protein into the membrane,creating abnormal channels; increased (and irreversible) entry through these channels, and henceincreased misreading and formation of channels; and, finally, blockade of initiating ribosomes. Thismechanism can account for several previously unexplained observations: that streptomycin uptakerequires protein synthesis during, but not after, the lag before the membrane damage; thatstreptomycin-resistant cells, which fail to take up streptomycin, can do so after treatment by anotheraminoglycoside; and that puromycin at moderate concentrations accelerates streptomycin uptake, whilehigh concentrations (which release shorter chains) prevent it. In addition, puromycin, prematurelyreleasing polypeptides of normal sequence, also evidently creates channels, since it is reported topromote streptomycin uptake even in streptomycin-resistant cells. These findings imply that normalmembrane proteins must be selected not only for a hydrophobic anchoring surface, but also for a tight fitin the membrane.", "metadata": {}}
+{"_id": "27446873", "title": "", "text": "Rate of cervical cancer, severe intraepithelial neoplasia, and adenocarcinoma in situ in primary HPV DNAscreening with cytology triage: randomised study within organised screening programme.OBJECTIVE Toassess the performance and impact of primary human papillomavirus (HPV) DNA screening with cytologytriage compared with conventional cytology on cervical cancer and severe pre-cancerous lesions. DESIGNRandomised trial. SETTING Population based screening programme for cervical cancer in southern Finlandin 2003-5. PARTICIPANTS 58 076 women, aged 30-60, invited to the routine population based screeningprogramme for cervical cancer. INTERVENTIONS Primary HPV DNA test (hybrid capture II) with cytologytriage if the result was positive or conventional cytological screening (reference). MAIN OUTCOMEMEASURES Rate of cervical cancer, cervical intraepithelial neoplasia (CIN) grade III, and adenocarcinomain situ (as a composite outcome referred to as CIN III+) during 2003-7 through record linkage betweenfiles from the screening registry and the national cancer registry. RESULTS In the HPV and conventionalarms there were 95 600 and 95 700 woman years of follow-up and 76 and 53 cases of CIN III+,respectively (of which six and eight were cervical cancers). The relative rate of CIN III+ in the HPV armversus the conventional arm was 1.44 (95% confidence interval 1.01 to 2.05) among all women invitedfor screening and 1.77 (1.16 to 2.74) among those who attended. Among women with a normal ornegative test result, the relative rate of subsequent CIN III+ was 0.28 (0.04 to 1.17). The rate of cervicalcancer between arms was 0.75 (0.25 to 2.16) among women invited for screening and 1.98 (0.52 to9.38) among those who attended. CONCLUSIONS When incorporated into a well established organisedscreening programme, primary HPV screening with cytology triage was more sensitive than conventionalcytology in detecting CIN III+ lesions. The number of cases of cervical cancer was small, but consideringthe high probability of progression of CIN III the findings are of importance regarding cancer prevention.TRIAL REGISTRATION Current Controlled Trials ISRCTN23885553.", "metadata": {}}
+{"_id": "27449472", "title": "", "text": "Metabolic syndrome as a risk factor for diabetes.The metabolic syndrome was initially described as aninsulin-resistance syndrome characterized by the clustering of metabolic traits such as high triglycerides,low high-density lipoprotein cholesterol, high blood pressure, abdominal obesity and different degrees ofimpaired glucose regulation. Although different definitions have been developed by various consensusgroups, epidemiological studies demonstrate that they all associate the metabolic syndrome with asimilar cardiometabolic risk, which is high for diabetes (ranging between three- and 20-fold), dependingon the number of components and the inclusion of impaired fasting glucose, impaired glucose toleranceor both. The latter appear to indicate the failure of the beta cell to produce enough insulin to compensatefor the increased demand due to insulin resistance. There is a hyperbolic relationship between insulinproduction and insulin sensitivity, which can be calculated by the disposition index. When this is alteredthere is a higher risk of developing Type 2 diabetes. There have been no clinical trials in subjects selectedby the diagnosis of metabolic syndrome, but structured lifestyle changes have been tested in people withimpaired fasting glucose/impaired glucose tolerance and have been able to reduce incident Type 2diabetes by almost 50%, as long as a weight loss of at least 5% is achieved. Oral antidiabetic andanti-obesity drugs have also been successful to a lesser degree. Some fibrates have reduced or delayedincident diabetes. Extended-release niacin has a neutral effect and statins are controversial. ACEinhibitors and ARBs are the antihypertensive agents least associated with incident diabetes.", "metadata": {}}
+{"_id": "27453479", "title": "", "text": "The fallacy of the ecological fallacy: the potential misuse of a concept and the consequences.Ecologicalstudies have been evaluated in epidemiological contexts in terms of the \"ecological fallacy. \" Although theempirical evidence for a lack of comparability between correlations derived from ecological- andindividual-level analyses is compelling, the conceptual meaning of the ecological fallacy remainsproblematic. This paper argues that issues in cross-level inference can be usefully conceptualized asvalidity problems, problems not peculiar to ecological-level analyses. Such an approach increases therecognition of both potential inference problems in individual-level studies and the unique contributions ofecological variables. This, in turn, expands the terrain for the location of causes for disease andinterventions to improve the public's health.", "metadata": {}}
+{"_id": "27460509", "title": "", "text": "Blocking caspase-activated apoptosis improves contractility in failing myocardium.Cardiac myocyteapoptosis has been demonstrated in end-stage failing human hearts. The therapeutic utility of blockingapoptosis in congestive heart failure (CHF) has not been elucidated. This study investigated the role ofcaspase activation in cardiac contractility and sarcomere organization in the development of CHF. In arabbit model of heart failure obtained by rapid ventricular pacing, we demonstrate, using in vivotranscoronary adenovirus-mediated gene delivery of the potent caspase inhibitor p35, that caspaseactivation is associated with a reduction in contractile force of failing myocytes by destroying sarcomericstructure. In this animal model gene transfer of p35 prevented the rise in caspase 3 activity andDNA-histone formation. Genetically manipulated hearts expressing p35 had a significant improvement inleft ventricular pressure rise (+dp/dt), decreased end-diastolic chamber pressure (LVEDP), and thedevelopment of heart failure was delayed. To better understand this benefit, we examined the effects ofcaspase 3 on cardiomyocyte dysfunction in vitro. Microinjection of activated caspase 3 into the cytoplasmof intact myocytes induced sarcomeric disorganization and reduced contractility of the cells. These resultsdemonstrate a direct impact of caspases on cardiac function and may lead to novel therapeutic strategiesvia antiapoptotic regimens.", "metadata": {}}
+{"_id": "27466734", "title": "", "text": "Development and validation of QRISK3 risk prediction algorithms to estimate future risk of cardiovasculardisease: prospective cohort studyObjectives To develop and validate updated QRISK3 predictionalgorithms to estimate the 10 year risk of cardiovascular disease in women and men accounting forpotential new risk factors. Design Prospective open cohort study. Setting General practices in Englandproviding data for the QResearch database. Participants 1309 QResearch general practices in England:981 practices were used to develop the scores and a separate set of 328 practices were used to validatethe scores. 7.89 million patients aged 25-84 years were in the derivation cohort and 2.67 million patientsin the validation cohort. Patients were free of cardiovascular disease and not prescribed statins atbaseline. Methods Cox proportional hazards models in the derivation cohort to derive separate riskequations in men and women for evaluation at 10 years. Risk factors considered included those already inQRISK2 (age, ethnicity, deprivation, systolic blood pressure, body mass index, total cholesterol: highdensity lipoprotein cholesterol ratio, smoking, family history of coronary heart disease in a first degreerelative aged less than 60 years, type 1 diabetes, type 2 diabetes, treated hypertension, rheumatoidarthritis, atrial fibrillation, chronic kidney disease (stage 4 or 5)) and new risk factors (chronic kidneydisease (stage 3, 4, or 5), a measure of systolic blood pressure variability (standard deviation of repeatedmeasures), migraine, corticosteroids, systemic lupus erythematosus (SLE), atypical antipsychotics,severe mental illness, and HIV/AIDs). We also considered erectile dysfunction diagnosis or treatment inmen. Measures of calibration and discrimination were determined in the validation cohort for men andwomen separately and for individual subgroups by age group, ethnicity, and baseline disease status. Mainoutcome measures Incident cardiovascular disease recorded on any of the following three linked datasources: general practice, mortality, or hospital admission records. Results 363 565 incident cases ofcardiovascular disease were identified in the derivation cohort during follow-up arising from 50.8 millionperson years of observation. All new risk factors considered met the model inclusion criteria except forHIV/AIDS, which was not statistically significant. The models had good calibration and high levels ofexplained variation and discrimination. In women, the algorithm explained 59.6% of the variation in timeto diagnosis of cardiovascular disease (R2, with higher values indicating more variation), and the Dstatistic was 2.48 and Harrell's C statistic was 0.88 (both measures of discrimination, with higher valuesindicating better discrimination). The corresponding values for men were 54.8%, 2.26, and 0.86. Overallperformance of the updated QRISK3 algorithms was similar to the QRISK2 algorithms. ConclusionUpdated QRISK3 risk prediction models were developed and validated. The inclusion of additional clinicalvariables in QRISK3 (chronic kidney disease, a measure of systolic blood pressure variability (standarddeviation of repeated measures), migraine, corticosteroids, SLE, atypical antipsychotics, severe mentalillness, and erectile dysfunction) can help enable doctors to identify those at most risk of heart diseaseand stroke.", "metadata": {}}
+{"_id": "27527854", "title": "", "text": "The importance of engaging policy-makers at the outset to guide research on and introduction ofvaccines: the use of policy-maker surveys.Face-to-face surveys of policy-makers and other influentialleaders are a useful tool to identify, at an early stage, (a) major issues regarding the introduction of anew vaccine, (b) persons and groups in a country who play a major decision-making or influential role inthe introduction of vaccines, (c) potential obstacles to the introduction of vaccines, and (d) data-needs ofpolicy-makers to overcome these obstacles. By surveying the opinions and beliefs of those who will makeor influence decisions on whether to introduce a new vaccine, these studies can help ensure that researchactivities respond to the needs of policy-makers in countries endemic for the target diseases. Thesesurveys can also inform vaccine-introduction strategies by identifying financially and politically feasiblemeans of distributing, targeting, and financing the vaccines. This paper describes the methodology usedin conducting such surveys and discusses methodological issues. It also presents lessons learnt from twopolicy-maker surveys carried out in several Asian countries in regard to new-generation vaccines againstcholera, typhoid fever, and shigellosis; and future vaccines against dengue fever/dengue haemorrhagicfever.", "metadata": {}}
+{"_id": "27545868", "title": "", "text": "Histone acetyltransferase PCAF regulates inflammatory molecules in the development of renalinjury.Kidney diseases, including chronic kidney disease (CKD) and acute kidney injury (AKI), areassociated with inflammation. The mechanism that regulates inflammation in these renal injuries remainsunclear. Here, we demonstrated that p300/CBP-associated factor (PCAF), a histone acetyltransferase,was overexpressed in the kidneys of db/db mice and lipopolysaccharide (LPS)-injected mice. Moreover,elevated histone acetylation, such as H3K18ac, and up-regulation of some inflammatory genes, such asICAM-1, VCAM-1, and MCP-1, were found upon these renal injuries. Furthermore, increased H3K18ac wasrecruited to the promoters of ICAM-1, VCAM-1, and MCP-1 in the kidneys of LPS-injected mice. In vitrostudies demonstrated that PCAF knockdown in human renal proximal tubule epithelial cells (HK-2) led todownregulation of inflammatory molecules, including VCAM-1, ICAM-1, p50 subunit of NF-κB (p50), andMCP-1 mRNA and protein levels, together with significantly decreased H3K18ac level. Consistent withthese, overexpression of PCAF enhanced the expression of inflammatory molecules. Furthermore, PCAFdeficiency reduced palmitate-induced recruitment of H3K18ac on the promoters of ICAM-1 and MCP-1, aswell as inhibited palmitate-induced upregulation of these inflammatory molecules. In summary, thepresent work demonstrates that PCAF plays an essential role in the regulation of inflammatory moleculesthrough H3K18ac, which provides a potential therapeutic target for inflammation-related renal diseases.", "metadata": {}}
+{"_id": "27550580", "title": "", "text": "T1 mapping for myocardial extracellular volume measurement by CMR: bolus only versus primed infusiontechnique.OBJECTIVES The aim of this study was to determine the accuracy of the contrast \"bolus only\"T1 mapping cardiac magnetic resonance (CMR) technique for measuring myocardial extracellular volumefraction (ECV). BACKGROUND Myocardial ECV can be measured with T1 mapping before and aftercontrast agent if the contrast agent distribution between blood/myocardium is at equilibrium. Equilibriumdistribution can be achieved with a primed contrast infusion (equilibrium contrast-CMR [EQ-CMR]) ormight be approximated by the dynamic equilibration achieved by delayed post-bolus measurement. Thisbolus only approach is highly attractive, but currently limited data support its use. We compared thebolus only technique with 2 independent standards: collagen volume fraction (CVF) from myocardialbiopsy in aortic stenosis (AS); and the infusion technique in 5 representative conditions. METHODS Onehundred forty-seven subjects were studied: healthy volunteers (n = 50); hypertrophic cardiomyopathy (n= 25); severe AS (n = 22); amyloid (n = 20); and chronic myocardial infarction (n = 30). Bolus only (at15 min) and infusion ECV measurements were performed and compared. In 18 subjects with severe ASthe results were compared with histological CVF. RESULTS The ECV by both techniques correlated withhistological CVF (n = 18, r² = 0.69, p < 0.01 vs. r² = 0.71, p < 0.01, p = 0.42 for comparison). Acrosshealth and disease, there was strong correlation between the techniques (r² = 0.97). However, indiseases of high ECV (amyloid, hypertrophic cardiomyopathy late gadolinium enhancement, andinfarction), Bland-Altman analysis indicates the bolus only technique has a consistent and increasingoffset, giving a higher value for ECVs above 0.4 (mean difference ± limit of agreement for ECV <0.4 =-0.004 ± 0.037 vs. ECV >0.4 = 0.040 ± 0.075, p < 0.001). CONCLUSIONS Bolus only, T1mapping-derived ECV measurement is sufficient for ECV measurement across a range of cardiacdiseases, and this approach is histologically validated in AS. However, when ECV is >0.4, the bolus onlytechnique consistently measures ECV higher compared with infusion.", "metadata": {}}
+{"_id": "27555165", "title": "", "text": "Cytomegalovirus US2 destroys two components of the MHC class II pathway, preventing recognition byCD4+ T cellsHuman cytomegalovirus (HCMV) is a ubiquitous herpesvirus that causes life-threateningdisease in patients who are immunosuppressed for bone marrow or tissue transplantation or who haveAIDS (ref. 1). HCMV establishes lifelong latent infections and, after periodic reactivation from latency,uses a panel of immune evasion proteins to survive and replicate in the face of robust, fully primed hostimmunity. Monocyte/macrophages are important host cells for HCMV, serving as a latent reservoir and asa means of dissemination throughout the body. Macrophages and other HCMV-permissive cells, such asendothelial and glial cells, can express MHC class II proteins and present antigens to CD4+ Tlymphocytes. Here, we show that the HCMV protein US2 causes degradation of two essential proteins inthe MHC class II antigen presentation pathway: HLA-DR-α and DM-α. This was unexpected, as US2 hasbeen shown to cause degradation of MHC class I (refs. 5,6), which has only limited homology with class IIproteins. Expression of US2 in cells reduced or abolished their ability to present antigen to CD4+ Tlymphocytes. Thus, US2 may allow HCMV-infected macrophages to remain relatively 'invisible' to CD4+ Tcells, a property that would be important after virus reactivation.", "metadata": {}}
+{"_id": "27567994", "title": "", "text": "CD169-positive macrophages dominate antitumor immunity by crosspresenting dead cell-associatedantigens.The generation of tumor-directed cytotoxic T lymphocytes is considered crucial for the inductionof antitumor immunity. To activate these CD8(+) T cells, antigen-presenting cells (APCs) must initiallyacquire tumor cell-associated antigens. The major source of tumor antigens is dead tumor cells, but littleis known about how APCs in draining lymph nodes acquire and crosspresent these antigens. Here weshow that CD169(+) macrophages phagocytose dead tumor cells transported via lymphatic flow andsubsequently crosspresent tumor antigens to CD8(+) T cells. Subcutaneous immunization with irradiatedtumor cells protects mice from syngenic tumor. However, tumor antigen-specific CD8(+) T cell activationand subsequent antitumor immunity are severely impaired in mice depleted with CD169(+)macrophages. Neither migratory dendritic cells (DCs) nor lymph node-resident conventional DCs areessential for the crosspresentation of tumor antigens. Thus, we have identified CD169(+) macrophagesas lymph node-resident APCs dominating early activation of tumor antigen-specific CD8(+) T cells.", "metadata": {}}
+{"_id": "27569370", "title": "", "text": "Emerging mechanisms in morphogen-mediated axon guidance.Early in animal development, gradients ofsecreted morphogenic molecules, such as Sonic hedgehog (Shh), Wnt and TGFbeta/Bmp familymembers, regulate cell proliferation and determine the fate and phenotype of the target cells byactivating well-characterized signalling pathways, which ultimately control gene transcription. Shh, Wntand TGFbeta/Bmp signalling also play an important and evolutionary conserved role in neural circuitassembly. They regulate neuronal polarization, axon and dendrite development and synaptogenesis,processes that require rapid and local changes in cytoskeletal organization and plasma membranecomponents. A key question then is whether morphogen signalling at the growth cone uses similarmechanisms and intracellular pathway components to those described for morphogen-mediated cellspecification. This review discusses recent advances towards the understanding of this problem, showinghow Shh, Wnt and TGFbeta/Bmp have adapted their 'classical' signalling pathways or adopted alternativeand novel molecular mechanisms to influence different aspects of neuronal circuit formation.", "metadata": {}}
+{"_id": "27580223", "title": "", "text": "Lessons learnt from malaria epidemics in the Islamic Republic of Iran.The Islamic Republic of Iran is inthe pre-elimination phase of malaria control, but malaria epidemics are still a concern in the south of thecountry. This retrospective study presents the epidemiological characteristics and predisposing factors of60 of the malaria epidemics reported in Sistan va Baluchestan province during 2005-09. A zero-truncatednegative binomial model was used to investigate the relation between predictor variables and the totalnumber of malaria cases. Malaria epidemics occurred mainly in the southern part of the province, mostlybetween July and October, peaking in August. Most malaria epidemics were small-scale (68.3% were <100 cases) and short (51.7% lasted < 1 month). Plasmodium falciparum was present in 46.7% of theepidemics. An increase in the rainfall rate as well as population movements were the most significantpredisposing factors. The results may help inform an epidemic investigation and reporting system as thecountry approaches the malaria elimination phase.", "metadata": {}}
+{"_id": "27587267", "title": "", "text": "Autoradiography of chromosomal DNA fibers from Chinese hamster cells.Ignorance of the true length ofthe DNA molecules in the chromosomes of higher organisms has always been a major obstacle tounderstanding chromosome structure. Consequently, attempts have been made, usually with the aid ofelectron microscopy, to estimate the size of DNA in higher organisms. Solari (1) has reported the longestsuch DNA measured before now-a DNA fiber from a sea urchin sperm at least 93 μ, long.", "metadata": {}}
+{"_id": "27588420", "title": "", "text": "Epigenetic memory and preferential lineage-specific differentiation in induced pluripotent stem cellsderived from human pancreatic islet beta cells.Human induced pluripotent stem cells (HiPSCs) appear tobe highly similar to human embryonic stem cells (HESCs). Using two genetic lineage-tracing systems, wedemonstrate the generation of iPSC lines from human pancreatic islet beta cells. These reprogrammedcells acquired markers of pluripotent cells and differentiated into the three embryonic germ layers.However, the beta cell-derived iPSCs (BiPSCs) maintained open chromatin structure at key beta-cellgenes, together with a unique DNA methylation signature that distinguishes them from other PSCs.BiPSCs also demonstrated an increased ability to differentiate into insulin-producing cells both in vitroand in vivo, compared with ESCs and isogenic non-beta iPSCs. Our results suggest that the epigeneticmemory may predispose BiPSCs to differentiate more readily into insulin producing cells. These findingsdemonstrate that HiPSC phenotype may be influenced by their cells of origin, and suggest that theirskewed differentiation potential may be advantageous for cell replacement therapy.", "metadata": {}}
+{"_id": "27602752", "title": "", "text": "CCL2/monocyte chemoattractant protein-1 mediates enhanced transmigration of humanimmunodeficiency virus (HIV)-infected leukocytes across the blood-brain barrier: a potential mechanismof HIV-CNS invasion and NeuroAIDS.Encephalitis and dementia associated with acquiredimmunodeficiency syndrome (AIDS) are characterized by leukocyte infiltration into the CNS, microgliaactivation, aberrant chemokine expression, blood-brain barrier (BBB) disruption, and eventual loss ofneurons. Little is known about whether human immunodeficiency virus 1 (HIV-1) infection of leukocytesaffects their ability to transmigrate in response to chemokines and to alter BBB integrity. We nowdemonstrate that HIV infection of human leukocytes results in their increased transmigration across ourtissue culture model of the human BBB in response to the chemokine CCL2, as well as in disruption of theBBB, as evidenced by enhanced permeability, reduction of tight junction proteins, and expression ofmatrix metalloproteinases (MMP)-2 and MMP-9. HIV-infected cells added to our model did nottransmigrate in the absence of CCL2, nor did this condition alter BBB integrity. The chemokinesCXCL10/interferon-gamma-inducible protein of 10 kDa, CCL3/macrophage inflammatory protein-1alpha,or CCL5/RANTES (regulated on activation normal T-cell expressed and secreted) did not enhanceHIV-infected leukocyte transmigration or BBB permeability. The increased capacity of HIV-infectedleukocytes to transmigrate in response to CCL2 correlated with their increased expression of CCR2, thechemokine receptor for CCL2. These data suggest that CCL2, but not other chemokines, plays a key rolein infiltration of HIV-infected leukocytes into the CNS and the subsequent pathology characteristic ofNeuroAIDS.", "metadata": {}}
+{"_id": "27615329", "title": "", "text": "Prostaglandin E2 as an inhibitory modulator of fibrogenesis in human lung allografts.RATIONALE Donormesenchymal stromal/stem cell (MSC) expansion and fibrotic differentiation is associated withdevelopment of bronchiolitis obliterans syndrome (BOS) in human lung allografts. However, theregulators of fibrotic differentiation of these resident mesenchymal cells are not well understood.OBJECTIVES This study examines the role of endogenous and exogenous prostaglandin (PG)E2 as amodulator of fibrotic differentiation of human lung allograft-derived MSCs. METHODS Effect of PGE2 onproliferation, collagen secretion, and α-smooth muscle actin (α-SMA) expression was assessed inlung-resident MSCs (LR-MSCs) derived from patients with and without BOS. The response pathwayinvolved was elucidated by use of specific agonists and antagonists. MEASUREMENT AND MAIN RESULTSPGE2 treatment of LR-MSCs derived from normal lung allografts significantly inhibited their proliferation,collagen secretion, and α-SMA expression. On the basis of pharmacologic and small-interfering RNAapproaches, a PGE2/E prostanoid (EP)2/adenylate cyclase pathway was implicated in these suppressiveeffects. Stimulation of endogenous PGE2 secretion by IL-1β was associated with amelioration of theirmyofibroblast differentiation in vitro, whereas its inhibition by indomethacin augmented α-SMAexpression. LR-MSCs from patients with BOS secreted significantly less PGE2 than non-BOS LR-MSCs.Furthermore, BOS LR-MSCs were found to be defective in their ability to induce cyclooxygenase-2, andtherefore unable to up-regulate PGE2 synthesis in response to IL-1β. BOS LR-MSCs also demonstratedresistance to the inhibitory actions of PGE2 in association with a reduction in the EP2/EP1 ratio.CONCLUSIONS These data identify the PGE2 axis as an important autocrine-paracrine brake on fibroticdifferentiation of LR-MSCs, a failure of which is associated with BOS.", "metadata": {}}
+{"_id": "27635177", "title": "", "text": "Association of DNA polymerase mu (pol mu) with Ku and ligase IV: role for pol mu in end-joiningdouble-strand break repair.Mammalian DNA polymerase mu (pol mu) is related to terminaldeoxynucleotidyl transferase, but its biological role is not yet clear. We show here that after exposure ofcells to ionizing radiation (IR), levels of pol mu protein increase. pol mu also forms discrete nuclear fociafter IR, and these foci are largely coincident with IR-induced foci of gammaH2AX, a previouslycharacterized marker of sites of DNA double-strand breaks. pol mu is thus part of the cellular response toDNA double-strand breaks. pol mu also associates in cell extracts with the nonhomologous end-joiningrepair factor Ku and requires both Ku and another end-joining factor, XRCC4-ligase IV, to form a stablecomplex on DNA in vitro. pol mu in turn facilitates both stable recruitment of XRCC4-ligase IV toKu-bound DNA and ligase IV-dependent end joining. In contrast, the related mammalian DNA polymerasebeta does not form a complex with Ku and XRCC4-ligase IV and is less effective than pol mu in facilitatingjoining mediated by these factors. Our data thus support an important role for pol mu in the end-joiningpathway for repair of double-strand breaks.", "metadata": {}}
+{"_id": "27647593", "title": "", "text": "Stromal-epithelial metabolic coupling in cancer: integrating autophagy and metabolism in the tumormicroenvironment.Cancer cells do not exist as pure homogeneous populations in vivo. Instead they areembedded in \"cancer cell nests\" that are surrounded by stromal cells, especially cancer associatedfibroblasts. Thus, it is not unreasonable to suspect that stromal fibroblasts could influence themetabolism of adjacent cancer cells, and visa versa. In accordance with this idea, we have recentlyproposed that the Warburg effect in cancer cells may be due to culturing cancer cells by themselves, outof their normal stromal context or tumor microenvironment. In fact, when cancer cells are co-culturedwith fibroblasts, then cancer cells increase their mitochondrial mass, while fibroblasts lose theirmitochondria. An in depth analysis of this phenomenon reveals that aggressive cancer cells are\"parasites\" that use oxidative stress as a \"weapon\" to extract nutrients from surrounding stromal cells.Oxidative stress in fibroblasts induces the autophagic destruction of mitochondria, by mitophagy. Then,stromal cells are forced to undergo aerobic glycolysis, and produce energy-rich nutrients (such as lactateand ketones) to \"feed\" cancer cells. This mechanism would allow cancer cells to seed anywhere, withoutblood vessels as a food source, as they could simply induce oxidative stress wherever they go, explaininghow cancer cells survive during metastasis. We suggest that stromal catabolism, via autophagy andmitophagy, fuels the anabolic growth of tumor cells, promoting tumor progression and metastasis. Wehave previously termed this new paradigm \"The Autophagic Tumor Stroma Model of Cancer Metabolism\",or the \"Reverse Warburg Effect\". We also discuss how glutamine addiction (glutaminolysis) in cancer cellsfits well with this new model, by promoting oxidative mitochondrial metabolism in aggressive cancercells.", "metadata": {}}
+{"_id": "27665523", "title": "", "text": "Oxidative stress in renal dysfunction: mechanisms, clinical sequelae and therapeutic optionsOxidativestress has been increasingly linked to the high incidence of cardiovascular events in patients with chronickidney disease (CKD), especially as traditional cardiovascular risk factors seem to not be able to accountfor the huge cardiovascular morbidity and mortality in this population group. Oxidative stress is increasedin patients with renal impairment as a result of increased oxidant activity and reduced antioxidantcapacity, and this is increased in a graded manner with increasing renal dysfunction. Inflammation, whichis also present in CKD, further amplifies the oxidant generation process. The two clinical sequelae ofoxidative stress are endothelial dysfunction and left ventricular hypertrophy, which have adversecardiovascular consequences. With our new understanding of oxidative stress, it is now important toassess treatment options that reduce it in the hope that they reverse endothelial dysfunction and leftventricular hypertrophy and the clinical sequelae of these abnormalities.", "metadata": {}}
+{"_id": "27686445", "title": "", "text": "Effect of age, sex, and sites on the cellularity of the adipose tissue in mice and rats rendered obese by ahigh-fat diet.Cell size and number of parametrial fat pads were determined in Swiss mice made obese bymeans of a high-fat diet (40% lard w/w) given ad lib. This diet and a control were introduced to twogroups of mothers during gestation and lactation, and sucklings were given the same diets as theirmothers at weaning and throughout life.2-wk old mice suckled by mothers fed a high-fat diet have fatterparametrial pads. This difference is due solely to an increase in fat cell size. After weaning, until the 18thwk, the two groups differed with a striking fat cell enlargement seen in the obese group. Later on,whereas cell numbers did not change in the control group, a constant and uninterrupted increase innumber is shown in those of obese mice until the 52nd wk. Hyperplasia was observed only in adults.When the high-fat diet was introduced to adult rats it also triggered an increase in fat cell number. Threesites of fat pads were compared in both sexes at 32 wk of age. All sites increased in weight in the high-fatfed group. This was due to: hyperplasia in perirenal site, hypertrophy in epididymal and subcutaneoussites, and hyperplasia plus hypertrophy in the parametrial one. So, in each sex, adipose sites in the obesemice reacted to the diet in a site-specific way. It was concluded that the level of fat in a diet is involved inboth formation and maturation of new fat cells and in the regulation of fat cell lipid content. The twoprocesses may be separated or may act together according to the adipose tissue site.", "metadata": {}}
+{"_id": "27693891", "title": "", "text": "Transcriptional integration of mitochondrial biogenesis.Gene regulatory factors encoded by the nucleargenome are essential for mitochondrial biogenesis and function. Some of these factors act exclusivelywithin the mitochondria to regulate the control of mitochondrial transcription, translation, and otherfunctions. Others govern the expression of nuclear genes required for mitochondrial metabolism andorganelle biogenesis. The peroxisome proliferator-activated receptor γ coactivator-1 (PGC-1) family oftranscriptional coactivators play a major role in transducing and integrating physiological signalsgoverning metabolism, differentiation, and cell growth to the transcriptional machinery controllingmitochondrial functional capacity. Thus, the PGC-1 coactivators serve as a central component of thetranscriptional regulatory circuitry that coordinately controls the energy-generating functions ofmitochondria in accordance with the metabolic demands imposed by changing physiological conditions,senescence, and disease.", "metadata": {}}
+{"_id": "27709445", "title": "", "text": "RFID system evaluation against radiated transient noiseIn this paper a radiofrequency identificationsystem according to standard ISO/IEC 14443 type-B is evaluated in  presence of transient noise. Thisreal time communication system working at 13.56 MHz is interfered in a controlled environment bydifferent transient bursts varying their level, frequency and duration. The transient burst interference isapplied in an AC main wire close to the system and the effect over the digital communication system isevaluated using two different methods. The first one is observing directly an RFID equipment in presenceof transient signals, and the second one is capturing the  interference in time domain an evaluating itseffect by means of simulation. The RFID system is affected by these transient noises  causing differenttypes of errors. It is shown that it is essential to measure and evaluate in time domain the transientphenomena to ensure that the RFID system do not have susceptibility problems.", "metadata": {}}
+{"_id": "27711043", "title": "", "text": "Musculoskeletal pain in Europe: its impact and a comparison of population and medical perceptions oftreatment in eight European countries.OBJECTIVES To describe the impact of musculoskeletal pain (MP);to compare management of MP by the population and by primary care physicians; and to identifymisconceptions about treatment. METHODS 5803 people with MP and 1483 primary care physicians,randomly selected, in eight European countries were interviewed by telephone. A structuredquestionnaire was used to ask about usual management of MP and perceived benefits and risks oftreatment. Current health status (SF-12) was also assessed. RESULTS From primary care physicians'perceptions, MP appears to be well managed. All presenting patients are offered some form of treatment,90% or more doctors are trying to improve patients' quality of life, and most are aware and concernedabout the risks of treatment with NSAIDs. From a population perspective, up to 27% of people with paindo not seek medical help and of those who do, several wait months/years before seeing a doctor. 55% orfewer patients who have seen a doctor are currently receiving prescription treatment for their pain.Communication between doctors and patients is poor; few patients are given information about theircondition; and many have misconceptions about treatment. CONCLUSIONS Management of MP is similaracross eight European countries, but there is discordance between physician and patient perspectives ofcare. Some people with pain have never sought medical help despite being in constant/daily pain. Thosewho do seek help receive little written information or explanation and many have misperceptions aboutthe benefits and risks of treatment that limit their ability to actively participate in decisions about theircare.", "metadata": {}}
+{"_id": "27712433", "title": "", "text": "[Palliative care in Germany].The delivery of palliative care in Germany is still characterized by awide-spread undersupply both for inpatients and outpatients. Nevertheless over the last 15 yearsprogress has also been made in Germany, which is pleasing and which has directed professional andpublic attention increasingly to the situation of the incurably ill and dying. In the course of thisdevelopment the first structures for specialized palliative care have been established. In particular thesituation for inpatients in hospitals and hospices is pleasing, even if a satisfaction for total coverage is notyet reached. More seriously however is the demand for the outpatients. Financial means, which aresteered so far only rudimentarily for palliative care, must be made sufficiently available, in order to beable to meet the demand with the help of appropriate structural offers. It is important to realize theneeds of the incurably ill and dying and of their relatives and friends. Our society has to call attention tothis subject and it should be placed on the healthpolitical agenda as a topic of the highest priority level.The current developments in the federation and in the federal states are encouraging and allowing hopethat the delivery of palliative care for all who need it (and not only the ill) will improve further in thecoming years.", "metadata": {}}
+{"_id": "27731651", "title": "", "text": "A view to a kill: the bacterial type VI secretion system.The bacterial type VI secretion system (T6SS) isan organelle that is structurally and mechanistically analogous to an intracellular membrane-attachedcontractile phage tail. Recent studies determined that a rapid conformational change in the structure of asheath protein complex propels T6SS spike and tube components along with antibacterial andantieukaryotic effectors out of predatory T6SS(+) cells and into prey cells. The contracted organelle isthen recycled in an ATP-dependent process. T6SS is regulated at transcriptional and posttranslationallevels, the latter involving detection of membrane perturbation in some species. In addition to directlytargeting eukaryotic cells, the T6SS can also target other bacteria coinfecting a mammalian host,highlighting the importance of the T6SS not only for bacterial survival in environmental ecosystems, butalso in the context of infection and disease. This review highlights these and other advances in ourunderstanding of the structure, mechanical function, assembly, and regulation of the T6SS.", "metadata": {}}
+{"_id": "27768226", "title": "", "text": "Open Access Increases Citation RatePLoS Biology publishes today a research article by GuntherEysenbach that is not about biology. It is about citations. It provides robust evidence that open-accessarticles (OA articles) are more immediately recognized and cited than non-OA articles. As such, it addsobjective support to the belief we have always held that open-access publication speeds up scientificdialog between researchers and, consequently, should be extended to the whole scientific literature asquickly as possible. It is therefore fitting that we publish such a paper. We have long argued that papersfreely available in a journal will be more often read and cited than those behind a subscription barrier.However, solid evidence to support or refute such a claim has been surprisingly hard to find. Since mostopen-access journals are new, comparisons of the effects of open access with establishedsubscription-based journals are easily confounded by age and reputation. In the current study,Eysenbach compared citations compiled by Thomson Scientific (formerly Thomson ISI) to individualarticles published between June 2004 and December 2004 in the same journal—namely, Proceedings ofthe National Academy of Sciences (PNAS), which announced its open-access option for authors on June 8of that year, with an associated publication charge of US$1,000. Non-OA articles in PNAS are subject to asix-month “toll-access” delay before the article becomes publicly available. The results of this naturalexperiment are clear: in the 4 to 16 months following publication, OA articles gained a significant citationadvantage over non-OA articles during the same period. They are twice as likely to be cited 4 to 10months after publication and almost three times as likely between 10 and 16 months. Given that PNASdelays open access for only six months, the disparity between OA and non-OA articles in journals wherethe delay is longer or where articles remain “toll-access” is likely to be even greater. Eysenbach alsolooked at the impact of self-archiving non-OA articles. One route to open access, it is argued, is forauthors to archive their published articles on their own Web sites or in institutional repositories, althoughthis does not include an explicit business model to cover the cost of peer-review and publishing. Theanalysis revealed that self-archived articles are also cited less often than OA articles from the samejournal. Yes, you're right; we do have a strong and vested interest in publishing results that so obviouslyendorse our existence. Moreover, the author of the article is also an editor of an open-access journal. Butsometimes a potential conflict of interest can actually help to ensure rigor. In this case, we have an acuteinterest in ensuring that the article meets the same, if not higher, standards as any other research articlewe publish. Not only must the conclusions provide a significant advance for the field, but the study mustbe technically sound, with appropriate evidence to support those conclusions. As with all our researcharticles, we consulted throughout the evaluation process with an academic editor with appropriateexpertise—in this case, Carol Tenopir, professor of information sciences at the University of Tennessee(Knoxville, Tennessee, United States). The article was reviewed by two experts in bibliometric analysesand information science, and an experienced research biologist with expertise in statistics. They allenthusiastically supported publication, although one understandably questioned the suitability of PLoSBiology as the publication venue. We have no intention of making PLoS Biology a regular home forbibliometric studies (even when about open access). What makes this study worth publishing in PLoSBiology is not only the relative strength of evidence supporting the claim but also the extent to whichmany (especially other publishers) have anticipated such an analysis. As far as we are aware, no otherstudy has compared OA and non-OA articles from the same journal and controlled for so many potentiallyconfounding factors. Eysenbach's multivariate analysis took into account the number of days sincepublication, number of authors, article type, country of the corresponding author, funding type, subjectarea, submission track ( PNAS has three different ways that authors can submit a paper), and theprevious citation record of the first and last authors. He even administered a supplementaryquestionnaire to assess whether authors choosing the OA option in PNAS chose to do so for only theirmost important research (they didn't). As Ian Rowlands from the Centre for Publishing at UniversityCollege London—and one of the reviewers who agreed to be identified in this article—said at the start ofhis review:          “Many (most) of the papers and presentations I have read/seen on this topic have", "metadata": {}}
+{"_id": "27772649", "title": "", "text": "Serum immunoglobulin A from patients with celiac disease inhibits human T84 intestinal crypt epithelialcell differentiation.BACKGROUND & AIMS Celiac disease is characterized by disturbed jejunal crypt-villusaxis biology with immunoglobulin (Ig) A deposits underlining the epithelium. The aim of this study was totest whether celiac disease serum IgA (reticulin/endomysial autoantibodies) interferes with themesenchymal-epithelial cell cross-talk. METHODS Differentiation of T84 epithelial cells was induced withIMR-90 fibroblasts or transforming growth factor beta in three-dimensional collagen gel cultures. Theeffects of purified celiac IgA and monoclonal tissue transglutaminase antibodies (CUB7402) were studiedby adding the antibodies to the cocultures. RESULTS Active celiac disease IgA, reactive for tissuetransglutaminase, significantly inhibited T84 epithelial cell differentiation (P < 0.001) and increasedepithelial cell proliferation (P = 0.024). Similar effects were obtained with antibodies against tissuetransglutaminase. CONCLUSIONS Celiac disease-associated IgA class antibodies disturb transforminggrowth factor beta-mediated fibroblast-epithelial cell cross-talk in this in vitro crypt-villus axis model.This primary finding indicates that celiac disease-specific autoantibodies may also contribute to theformation of the gluten-triggered jejunal mucosal lesion in celiac disease.", "metadata": {}}
+{"_id": "27789588", "title": "", "text": "Pathogenesis of diseases associated with antineutrophil cytoplasm autoantibodies.Little is known aboutthe etiologies of diseases associated with circulating antineutrophil cytoplasm autoantibodies (ANCA),such as primary vasculitides and inflammatory bowel diseases. However, the understanding of immunemechanisms supposedly involved in the pathogenesis of these diseases is still growing. In the presentreview, we first focus on the mechanisms triggering the development of ANCA, including the potentialrole of microbial superantigens and the possible defect(s) in the progression of apoptosis or in theremoval of apoptotic cells. We next concentrate on the contribution of ANCA to the clinical symptoms andon the pathogenic role of ANCA, including the accessibility of ANCA antigens as targets for circulatingantibodies and the mode of action of ANCA. Mechanisms of neutrophil activation by ANCA include theengagement of Fcgamma receptors, the possible mechanisms of neutrophil-mediated tissue damage, andthe neutrophil-endothelial interaction.", "metadata": {}}
+{"_id": "27815697", "title": "", "text": "The common marmoset as a novel animal model system for biomedical and neuroscience researchapplications.The common marmoset (Callithrix jacchus), a small New World primate, has been attractingmuch attention in the research field of biomedical science and neuroscience, based on its (i)cross-reactivity with human cytokines or hormones, (ii) comparative ease in handling due to its smallsize, (iii) high reproductive efficiency, (iv) establishment of basic research tools, and (v) advantages of itsunique behavioral and cognitive characters. Various neurological disease models have been developed inthe common marmoset, including Parkinson's disease, Huntington's disease, Alzheimer's disease, stroke,multiple sclerosis and spinal cord injury. We recently developed transgenic common marmoset withgermline transmission, which is expected to provide a new animal model for the study of human diseases.In this review, we summarize the recent progress of biomedical research and neuroscience usingcommon marmoset as an excellent model system.", "metadata": {}}
+{"_id": "27822315", "title": "", "text": "Liver receptor homolog-1 regulates the transcription of steroidogenic enzymes and induces thedifferentiation of mesenchymal stem cells into steroidogenic cells.Steroidogenic factor-1 (SF-1, alsoknown as Ad4BP) has been demonstrated to be a primary transcriptional regulator ofsteroidogenic-related genes. However, mRNA for liver receptor homolog-1 (LRH-1), which together withSF-1, belongs to the NR5A nuclear receptor family, is expressed at much higher levels than SF-1 mRNA inthe human gonad. In our previous studies, we demonstrated that SF-1 induced the differentiation of bonemarrow-derived mesenchymal stem cells (MSCs) into steroidogenic cells such as Leydig or adrenocorticalcells. The introduction of LRH-1 into human MSCs (hMSCs) with the aid of cAMP also induced theexpression of steroidogenic enzymes, including CYP17, and their differentiation into steroidhormone-producing cells. Promoter analysis, EMSA, and chromatin immunoprecipitation assay usingLRH-1-transduced hMSCs indicated that three LRH-1 binding sites were responsible for CYP17transactivation. Immunohistochemical studies showed that LRH-1 protein was expressed in human Leydigcells. The CYP17 promoter region was highly methylated in hMSCs, whereas it was demethylated by theintroduction of LRH-1 and cAMP treatment. These results indicate that LRH-1 could represent another keyregulator of the steroidogenic lineage in MSCs and play a vital role in steroid hormone production inhuman Leydig cells.", "metadata": {}}
+{"_id": "27840664", "title": "", "text": "Checkpoint responses to replication fork barriers.The fidelity of DNA replication is of paramountimportance to the maintenance of genome integrity. When an active replication fork is perturbed,multiple cellular pathways are recruited to stabilize the replication apparatus and to help to bypass orcorrect the causative problem. However, if the problem is not corrected, the fork may collapse, exposingfree DNA ends to potentially inappropriate processing. In prokaryotes, replication fork collapse promotesthe activity of recombination proteins to restore a replication fork. Recent work has demonstrated thatrecombination is also intimately linked to replication in eukaryotic cells, and that recombination proteinsare recruited to collapsed, but not stalled, replication forks. In this review we discuss the different typesof potential replication fork barriers (RFB) and how these distinct RFBs can result in different DNAstructures at the stalled replication fork. The DNA structure checkpoints which act within S phase respondto different RFBs in different ways and we thus discuss the processes that are controlled by the DNAreplication checkpoints, paying particular attention to the function of the intra-S phase checkpoint thatstabilises the stalled fork.", "metadata": {}}
+{"_id": "27841037", "title": "", "text": "Ecology, economics and political will: the vicissitudes of malaria strategies in Asia.The documentedhistory of malaria in parts of Asia goes back more than 2,000 years, during which the disease has been amajor player on the socioeconomic stage in many nation states as they waxed and waned in power andprosperity. On a much shorter time scale, the last half century has seen in microcosm a history of largefluctuations in endemicity and impact of malaria across the spectrum of rice fields and rain forests,mountains and plains that reflect the vast ecological diversity inhabited by this majority aggregation ofmankind. That period has seen some of the most dramatic changes in social and economic structure, inpopulation size, density and mobility, and in political structure in history: all have played a part in thechanging face of malaria in this extensive region of the world. While the majority of global malaria casescurrently reside in Africa, greater numbers inhabited Asia earlier this century before malaria programssavored significant success, and now Asia harbors a global threat in the form of the epicenter ofmultidrug resistant Plasmodium falciparum which is gradually encompassing the tropical world. The latterreflects directly the vicissitudes of economic change over recent decades, particularly the mobility ofpopulations in search of commerce, trade and personal fortunes, or caught in the misfortunes of physicalconflicts. The period from the 1950s to the 1990s has witnessed near \"eradication\" followed byresurgence of malaria in Sri Lanka, control and resurgence in India, the influence of war and postwarinstability on drug resistance in Cambodia, increase in severe and cerebral malaria in Myanmar duringprolonged political turmoil, the essential disappearance of the disease from all but forested border areasof Thailand where it remains for the moment intractable, the basic elimination of vivax malaria frommany provinces of central China. Both positive and negative experiences have lessons to teach in thedebate between eradication and control as alternative strategies. China has for years held high the goalof \"basic elimination\", eradication by another name, in sensible semi-defiance of WHO dictates. TheChinese experience makes it clear that, given community organization, exhaustive attention to casedetection, management and focus elimination, plus the political will at all levels of society, it is possibleboth to eliminate malaria from large areas of an expansive nation and to implement surveillancenecessary to maintain something approaching eradication status in those areas. But China has notsucceeded in the international border regions of the tropical south where unfettered populationmovement confounds the program. Thailand, Malaysia and to an extent Vietnam have also reachedessential elimination in their rice field plains by vigorous vertical programs but fall short at their forestedborders. Economics is central to the history of the rise and fall of nations, and to the history of disease inthe people who constitute nations. The current love affair with free market economics as the main drivingforce for advance of national wealth puts severe limitations on the essential involvement of communitiesin malaria management. The task of malaria control or elimination needs to be clearly related to the basicmacroeconomic process that preoccupies governments, not cloistered away in the health sectorHistorically malaria has had a severe, measurable, negative impact on the productivity of nations.Economic models need rehoning with political aplomb and integrating with technical and demographicstrategies. Recent decades in Chinese malaria history carry some lessons that may be relevant in thiscontext.", "metadata": {}}
+{"_id": "27866735", "title": "", "text": "Global and regional risk of disabling sequelae from bacterial meningitis: a systematic review andmeta-analysis.Few data sources are available to assess the global and regional risk of sequelae frombacterial meningitis. We aimed to estimate the risks of major and minor sequelae caused by bacterialmeningitis, estimate the distribution of the different types of sequelae, and compare risk by region andincome. We systematically reviewed published papers from 1980 to 2008. Standard global burden ofdisease categories (cognitive deficit, bilateral hearing loss, motor deficit, seizures, visual impairment,hydrocephalus) were labelled as major sequelae. Less severe, minor sequelae (behavioural problems,learning difficulties, unilateral hearing loss, hypotonia, diplopia), and multiple impairments were alsoincluded. 132 papers were selected for inclusion. The median (IQR) risk of at least one major or minorsequela after hospital discharge was 19.9% (12.3-35.3%). The risk of at least one major sequela was12.8% (7.2-21.1%) and of at least one minor sequela was 8.6% (4.4-15.3%). The median (IQR) risk ofat least one major sequela was 24.7% (16.2-35.3%) in pneumococcal meningitis; 9.5% (7.1-15.3%) inHaemophilus influenzae type b (Hib), and 7.2% (4.3-11.2%) in meningococcal meningitis. The mostcommon major sequela was hearing loss (33.9%), and 19.7% had multiple impairments. In therandom-effects meta-analysis, all-cause risk of a major sequela was twice as high in the African (pooledrisk estimate 25.1% [95% CI 18.9-32.0%]) and southeast Asian regions (21.6% [95% CI 13.1-31.5%])as in the European region (9.4% [95% CI 7.0-12.3%]; overall I(2)=89.5%, p<0.0001). Risks oflong-term disabling sequelae were highest in low-income countries, where the burden of bacterialmeningitis is greatest. Most reported sequelae could have been averted by vaccination with Hib,pneumococcal, and meningococcal vaccines.", "metadata": {}}
+{"_id": "27873158", "title": "", "text": "Efficacy of human papillomavirus testing for the detection of invasive cervical cancers and cervicalintraepithelial neoplasia: a randomised controlled trial.BACKGROUND Human papillomavirus (HPV)testing is known to be more sensitive, but less specific than cytology for detecting cervical intraepithelialneoplasia (CIN). We assessed the efficacy of cervical-cancer screening policies that are based on HPVtesting. METHODS Between March, 2004, and December, 2004, in two separate recruitment phases,women aged 25-60 years were randomly assigned to conventional cytology or to HPV testing incombination with liquid-based cytology (first phase) or alone (second phase). Randomisation was done bycomputer in two screening centres and by sequential opening of numbered sealed envelopes in theremaining seven centres. During phase one, women who were HPV-positive and aged 35-60 years werereferred to colposcopy, whereas women aged 25-34 years were referred to colposcopy only if cytologywas also abnormal or HPV testing was persistently positive. During phase two, women in the HPV groupwere referred for colposcopy if the HPV test was positive. Two rounds of screening occurred in eachphase, and all women had cytology testing only at the second round. The primary endpoint was thedetection of grade 2 and 3 CIN, and of invasive cervical cancers during the first and second screeningrounds. Analysis was done by intention to screen. This trial is registered, number ISRCTN81678807.FINDINGS In total for both phases, 47,001 women were randomly assigned to the cytology group and47,369 to HPV testing. 33,851 women from the cytology group and 32,998 from the HPV-testing grouphad a second round of screening. We also retrieved the histological diagnoses from screening doneelsewhere. The detection of invasive cervical cancers was similar for the two groups in the first round ofscreening (nine in the cytology group vs seven in the HPV group, p=0.62); no cases were detected in theHPV group during round two, compared with nine in the cytology group (p=0.004). Overall, in the tworounds of screening, 18 invasive cancers were detected in the cytology group versus seven in the HPVgroup (p=0.028). Among women aged 35-60 years, at round one the relative detection (HPV vs cytology)was 2.00 (95% CI 1.44-2.77) for CIN2, 2.08 (1.47-2.95) for CIN3, and 2.03 (1.60-2.57) for CIN2 and 3together. At round two the relative detection was 0.54 (0.23-1.28) for CIN2, 0.48 (0.21-1.11) for CIN3,and 0.51 (0.28-0.93) for CIN2 and 3 together. Among women aged 25-34 years, there was significantheterogeneity between phases in the relative detection of CIN3. At round one the relative detection was0.93 (0.52-1.64) in phase one and 3.91 (2.02-7.57) in phase two. At round two the relative detectionwas 1.34 (0.46-3.84) in phase one and 0.20 (0.04-0.93) in phase two. Pooling both phases, the detectionratio of CIN2 for women aged 25-34 years was 4.09 (2.24-7.48) at round one and 0.64 (0.23-1.27) atround two. INTERPRETATION HPV-based screening is more effective than cytology in preventing invasivecervical cancer, by detecting persistent high-grade lesions earlier and providing a longer low-risk period.However, in younger women, HPV screening leads to over-diagnosis of regressive CIN2. FUNDINGEuropean Union, Italian Ministry of Health, Regional Health Administrations of Piemonte, Tuscany, Venetoand Emilia-Romagna, and Public Health Agency of Lazio.", "metadata": {}}
+{"_id": "27889071", "title": "", "text": "Microcytosis, iron deficiency and thalassaemia in a multi-ethnic community: a pilot study.The highprevalence of microcytosis (defined here as mean cell haemoglobin<27 pg) with no other abnormality is aprincipal cause of confusion in screening for haemoglobin disorders. Here we report the results of a smallpilot study aiming to resolve this confusion by routinely proceeding to plasma ferritin and HPLC assay,using the original sequestrene blood sample, when microcytosis is detected. Participants comprised arandom sample of 1,302 people referred for a full blood count by their General Practitioner (GP) to thelaboratory of a North London district general hospital serving a multi-ethnic inner-city population.Ethnicity was established by questionnaire. In North Europeans, microcytosis was present in 3% of males(half were iron-deficient) and 11% of females (most were iron-deficient). Among ethnic minorities,microcytosis was present in 35% of males (one tenth were iron-deficient), and 45% of females (less thanhalf were iron-deficient): an exclusion diagnosis of \"probable alpha thalassaemia\" could be made in theremainder. We conclude that when microcytosis is present, routine further analysis of the originalsequestrene sample by plasma ferritin assay and haemoglobinopathy screening could lead to a moreefficient and cost-effective laboratory service for primary care and maternity services.", "metadata": {}}
+{"_id": "27900414", "title": "", "text": "Crystal structure of the human AAA+ protein RuvBL1.RuvBL1 is an evolutionarily highly conservedeukaryotic protein belonging to the AAA(+)-family of ATPases (ATPase associated with diverse cellularactivities). It plays important roles in essential signaling pathways such as the c-Myc and Wnt pathwaysin chromatin remodeling, transcriptional and developmental regulation, and DNA repair and apoptosis.Herein we present the three-dimensional structure of the selenomethionine variant of human RuvBL1refined using diffraction data to 2.2A of resolution. The crystal structure of the hexamer is formed ofADP-bound RuvBL1 monomers. The monomers contain three domains, of which the first and the third areinvolved in ATP binding and hydrolysis. Although it has been shown that ATPase activity of RuvBL1 isneeded for several in vivo functions, we could only detect a marginal activity with the purified protein.Structural homology and DNA binding studies demonstrate that the second domain, which is uniqueamong AAA(+) proteins and not present in the bacterial homolog RuvB, is a novel DNA/RNA-bindingdomain. We were able to demonstrate that RuvBL1 interacted with single-stranded DNA/RNA anddouble-stranded DNA. The structure of the RuvBL1.ADP complex, combined with our biochemical results,suggest that although RuvBL1 has all the structural characteristics of a molecular motor, even of anATP-driven helicase, one or more as yet undetermined cofactors are needed for its enzymatic activity.", "metadata": {}}
+{"_id": "27907205", "title": "", "text": "Characteristics of a monoclonal antibody (RM124) against acute myelocytic leukemia cells.A monoclonalantibody was raised against cells from an experimental rat myelocytic leukemia (BNML). The majorcharacteristics of the rat leukemia model resemble those of human acute myelocytic leukemia. Themonoclonal antibody (MCA) RM124 was characterized with respect to its labeling pattern of BNMLleukemia cells, normal rat bone marrow cells, and the hemopoietic stem cell (HSC), by flow cytometricmethods and complement-dependent cytotoxicity assays. Flow cytometry revealed a much higherlabeling of the leukemic cells by the MCA-RM124 compared with normal bone marrow cells, includingCFU-S and CFU-C. Only a subpopulation of the normal granulocytes showed cross reactivity, however, ata lower labeling density. On using the cytotoxicity assays, it was evident that there was a selective killingof leukemic cells as compared with the activity towards the normal hemopoietic stem cells (CFU-S).", "metadata": {}}
+{"_id": "27910499", "title": "", "text": "Quantitative assessment of T-cell repertoire recovery after hematopoietic stem celltransplantationDelayed T cell recovery and restricted T cell receptor (TCR) diversity after allogeneichematopoietic stem cell transplantation (allo-HSCT) are associated with increased risks of infection andcancer relapse. Technical challenges have limited faithful measurement of TCR diversity after allo-HSCT.Here we combined 5' rapid amplification of complementary DNA ends PCR with deep sequencing toquantify TCR diversity in 28 recipients of allo-HSCT using a single oligonucleotide pair. Analysis ofduplicate blood samples confirmed that we accurately determined the frequency of individual TCRs. After6 months, cord blood-graft recipients approximated the TCR diversity of healthy individuals, whereasrecipients of T cell-depleted peripheral-blood stem cell grafts had 28-fold and 14-fold lower CD4(+) andCD8(+) T cell diversities, respectively. After 12 months, these deficiencies had improved for the CD4(+)but not the CD8(+) T cell compartment. Overall, this method provides unprecedented views of T cellrepertoire recovery after allo-HSCT and may identify patients at high risk of infection or relapse.", "metadata": {}}
+{"_id": "27944135", "title": "", "text": "Silver sulfadiazine for the treatment of partial-thickness burns and venous stasis ulcers.BACKGROUNDFor decades silver-containing antibiotics such as silver sulfadiazine (SSD) have been applied as standardtopical therapy for patients with partial-thickness burns and venous stasis ulcers. This evidence-basedreview intends to answer the following research question: in ambulatory patients with partial-thicknessburns or stasis dermatitis ulcers, does the use of topical SSD compared with nonantibiotic dressingsimprove mortality, wound healing, re-epithelialization, or infection rates? METHODS MEDLINE, EMBASE,Cochrane Library, and other databases were searched. We considered trials that enrolled patients of anyage with partial-thickness burns or venous stasis ulcers and randomized them to either topical SSD orplacebo, saline-soaked gauze, paraffin gauze, sterile dry dressing, or nonantibiotic moist dressing.Outcomes included mortality, wound healing, speed of re-epithelialization, and infection rates. RESULTSFor burns, our search revealed 400 potential articles. No human studies met the inclusion criteria. Only 7animal studies (1 mouse, 4 rat, and 2 pig) were relevant to the proposed question. These animal studiesprovided conflicting results. Whereas some support the use of SSD for treatment of partial-thicknessburns, others question its effectiveness. For stasis dermatitis ulcer, the search identified 50 articles forreview, of which 20 abstracts were reviewed, and one article met the inclusion criteria. This study did notshow any significant improvement in the rate of complete healing in SSD group compared with placeboeither at 4 weeks (relative risk 6.2, 95% confidence interval 0.8-48) or at 1 year (relative risk 5.2, 95%confidence interval 0.6-41.6) of follow-up. CONCLUSION There is insufficient evidence to either supportor refute the routine use of SSD for ambulatory patients with either partial-thickness burns or stasisdermatitis ulcers to decrease mortality, prevent infection, or augment wound healing in human beings.", "metadata": {}}
+{"_id": "27949347", "title": "", "text": "Putting p53 in ContextTP53 is the most frequently mutated gene in human cancer. Functionally, p53 isactivated by a host of stress stimuli and, in turn, governs an exquisitely complex anti-proliferativetranscriptional program that touches upon a bewildering array of biological responses. Despite the manyunveiled facets of the p53 network, a clear appreciation of how and in what contexts p53 exerts itsdiverse effects remains unclear. How can we interpret p53's disparate activities and the consequences ofits dysfunction to understand how cell type, mutation profile, and epigenetic cell state dictate outcomes,and how might we restore its tumor-suppressive activities in cancer?", "metadata": {}}
+{"_id": "27995781", "title": "", "text": "Modeling the evolution of culture-adapted human embryonic stem cells.The long-term culture of humanembryonic stem (ES) cells is inevitably subject to evolution, since any mutant that arises with a growthadvantage will be selectively amplified. However, the evolutionary influences of population size, mutationrate, and selection pressure are frequently overlooked. We have constructed a Monte Carlo simulationmodel to predict how changes in these factors can influence the appearance and spread of mutant EScells, and verified its applicability by comparison with in vitro data. This simulation provides an estimatefor the expected rate of generation of culture-adapted ES cells under different assumptions for the keyparameters. In particular, it highlights the effect of population size, suggesting that the maintenance ofcells in small populations reduces the likelihood that abnormal cultures will develop.", "metadata": {}}
+{"_id": "28006126", "title": "", "text": "CD28 delivers a unique signal leading to the selective recruitment of RelA and p52 NF-kappaB subunits onIL-8 and Bcl-xL gene promoters.CD28 is one of the most important costimulatory receptors necessary forfull T lymphocyte activation. The CD28 receptor can enhance T cell antigen receptor (TCR) signals, as wellas deliver independent signals. Indeed, CD28 engagement by B7 can generate TCR-independent signalsleading to IkappaB kinase and NF-kappaB activation. Here we demonstrate that the TCR-independentCD28 signal leads to the selective transcription of survival (Bcl-xL) and inflammatory (IL-8 and B cellactivation factor, but not proliferative (IL-2), genes, in a NF-kappaB-dependent manner. CD28-stimulatedT cells actively secrete IL-8, and Bcl-xL up-regulation protects T cells from radiation-induced apoptosis.The transcription of CD28-induced genes is mediated by the specific recruitment of RelA and p52NF-kappaB subunits to target promoters. In contrast, p50 and c-Rel, which preferentially bind NF-kappaBsites on the IL-2 gene promoter after anti-CD3 stimulation, are not involved. Thus, we identify CD28 as akey regulator of genes important for both survival and inflammation.", "metadata": {}}
+{"_id": "28015516", "title": "", "text": "Netting neutrophils are major inducers of type I IFN production in pediatric systemic lupuserythematosus.Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized bya breakdown of tolerance to nuclear antigens and the development of immune complexes. Genomicapproaches have shown that human SLE leukocytes homogeneously express type I interferon(IFN)-induced and neutrophil-related transcripts. Increased production and/or bioavailability of IFN-α andassociated alterations in dendritic cell (DC) homeostasis have been linked to lupus pathogenesis.Although neutrophils have long been shown to be associated with lupus, their potential role in diseasepathogenesis remains elusive. Here, we show that mature SLE neutrophils are primed in vivo by type IIFN and die upon exposure to SLE-derived anti-ribonucleoprotein antibodies, releasing neutrophilextracellular traps (NETs). SLE NETs contain DNA as well as large amounts of LL37 and HMGB1,neutrophil proteins that facilitate the uptake and recognition of mammalian DNA by plasmacytoid DCs(pDCs). Indeed, SLE NETs activate pDCs to produce high levels of IFN-α in a DNA- and TLR9 (Toll-likereceptor 9)-dependent manner. Our results reveal an unsuspected role for neutrophils in SLEpathogenesis and identify a novel link between nucleic acid-recognizing antibodies and type I IFNproduction in this disease.", "metadata": {}}
+{"_id": "28017005", "title": "", "text": "Assessment for selection for the health care professions and specialty training: consensus statement andrecommendations from the Ottawa 2010 Conference.Assessment for selection in medicine and the healthprofessions should follow the same quality assurance processes as in-course assessment. The literatureon selection is limited and is not strongly theoretical or conceptual. For written testing, there is evidenceof the predictive validity of Medical College Admission Test (MCAT) for medical school and licensingexamination performance. There is also evidence for the predictive validity of grade point average,particularly in combination with MCAT for graduate entry but little evidence about the predictive validityof school leaver scores. Interviews have not been shown to be robust selection measures. Studies ofmultiple mini-interviews have indicated good predictive validity and reliability. Of other measures used inselection, only the growing interest in personality testing appears to warrant future work. Wideningaccess to medical and health professional programmes is an increasing priority and relates to the socialaccountability mandate of medical and health professional schools. While traditional selection measuresdo discriminate against various population groups, there is little evidence on the effect of non-traditionalmeasures in widening access. Preparation and outreach programmes show most promise. In summary,the areas of consensus for assessment for selection are small in number. Recommendations for futureaction focus on the adoption of principles of good assessment and curriculum alignment, use ofmulti-method programmatic approaches, development of interdisciplinary frameworks and utilisation ofsophisticated measurement models. The social accountability mandate of medical and health professionalschools demands that social inclusion, workforce issues and widening of access are embedded in theprinciples of good assessment for selection.", "metadata": {}}
+{"_id": "28025754", "title": "", "text": "THE GLYOXAL BIS(2-HYDROXYANIL) METHOD MODIFIED FOR LOCALIZING INSOLUBLE CALCIUMSALTS.TO enable staining of insoluble calcium salts with glyoxal bis(2-hydroxyanil) (GBHA), the originalsolution containing 2 ml of 0.4% GBHA in absolute ethanol, and 0.3 ml of aqueous 5% NaOH, and limitedto staining only soluble calcium salts, was modified as follows: 1, 2 ml of 0.4% GBHA in absolute ethanolin 0.6 ml of 10% aqueous NaOH; 11, 0.1 gm GBHA in 2 ml of 3.4% NaOH in 75% ethanol. To preventdiffusion and loss of calcium, the tissues were processed by the freeze-substitution or freeze-dry methodand sections stained without removing the paraffin. Modification I is effective only when 1 or 2 dropsplaced on the section are evaporated gradually to dryness, concentrating the GBHA and NaOH on theinsoluble calcium salts. Modification II is effective when dried or poured on the the section and allowed tostain for 5 min. The stained slides are immersed for 15 min in 90% ethanol saturated with KCN andNa2CO3 for specificity to calcium; rinsed and counterstained in 95% ethanol containing 0.1% each offast...", "metadata": {}}
+{"_id": "28069701", "title": "", "text": "Detecting selective sweeps: a new approach based on hidden markov models.Detecting and localizingselective sweeps on the basis of SNP data has recently received considerable attention. Here weintroduce the use of hidden Markov models (HMMs) for the detection of selective sweeps in DNAsequences. Like previously published methods, our HMMs use the site frequency spectrum, and thespatial pattern of diversity along the sequence, to identify selection. In contrast to earlier approaches, ourHMMs explicitly model the correlation structure between linked sites. The detection power of ourmethods, and their accuracy for estimating the selected site location, is similar to that of competingmethods for constant size populations. In the case of population bottlenecks, however, our methodsfrequently showed fewer false positives.", "metadata": {}}
+{"_id": "28071965", "title": "", "text": "A Balance between Secreted Inhibitors and Edge Sensing Controls Gastruloid Self-Organization.Theearliest aspects of human embryogenesis remain mysterious. To model patterning events in the humanembryo, we used colonies of human embryonic stem cells (hESCs) grown on micropatterned substrateand differentiated with BMP4. These gastruloids recapitulate the embryonic arrangement of themammalian germ layers and provide an assay to assess the structural and signaling mechanismspatterning the human gastrula. Structurally, high-density hESCs localize their receptors to transforminggrowth factor β at their lateral side in the center of the colony while maintaining apical localization ofreceptors at the edge. This relocalization insulates cells at the center from apically applied ligands whilemaintaining response to basally presented ones. In addition, BMP4 directly induces the expression of itsown inhibitor, NOGGIN, generating a reaction-diffusion mechanism that underlies patterning. We developa quantitative model that integrates edge sensing and inhibitors to predict human fate positioning ingastruloids and, potentially, the human embryo.", "metadata": {}}
+{"_id": "28086354", "title": "", "text": "Tenectin is a novel alphaPS2betaPS integrin ligand required for wing morphogenesis and male genitallooping in Drosophila.Morphogenesis of the adult structures of holometabolous insects is regulated byecdysteroids and juvenile hormones and involves cell-cell interactions mediated in part by the cell surfaceintegrin receptors and their extracellular matrix (ECM) ligands. These adhesion molecules and theirregulation by hormones are not well characterized. We describe the gene structure of a newly describedECM molecule, tenectin, and demonstrate that it is a hormonally regulated ECM protein required forproper morphogenesis of the adult wing and male genitalia. Tenectin's function as a new ligand of thePS2 integrins is demonstrated by both genetic interactions in the fly and by cell spreading and celladhesion assays in cultured cells. Its interaction with the PS2 integrins is dependent on RGD andRGD-like motifs. Tenectin's function in looping morphogenesis in the development of the male genitalialed to experiments that demonstrate a role for PS integrins in the execution of left-right asymmetry.", "metadata": {}}
+{"_id": "28107602", "title": "", "text": "Schedule-dependent interaction between anticancer treatmentsThe oncogene MDMX is overexpressed inmany cancers, leading to suppression of the tumor suppressor p53. Inhibitors of the oncogene productMDMX therefore might help reactivate p53 and enhance the efficacy of DNA-damaging drugs. However,we currently lack a quantitative understanding of how MDMX inhibition affects the p53 signaling pathwayand cell sensitivity to DNA damage. Live cell imaging showed that MDMX depletion triggered two distinctphases of p53 accumulation in single cells: an initial postmitotic pulse, followed by low-amplitudeoscillations. The response to DNA damage was sharply different in these two phases; in the first phase,MDMX depletion was synergistic with DNA damage in causing cell death, whereas in the second phase,depletion of MDMX inhibited cell death. Thus a quantitative understanding of signal dynamics and cellularstates is important for designing an optimal schedule of dual-drug administration.", "metadata": {}}
+{"_id": "28138927", "title": "", "text": "Potent, Selective, and Orally Bioavailable Inhibitors of VPS34 Provide Chemical Tools to ModulateAutophagy in Vivo.Autophagy is a dynamic process that regulates lysosomal-dependent degradation ofcellular components. Until recently the study of autophagy has been hampered by the lack of reliablepharmacological tools, but selective inhibitors are now available to modulate the PI 3-kinase VPS34,which is required for autophagy. Here we describe the discovery of potent and selective VPS34 inhibitors,their pharmacokinetic (PK) properties, and ability to inhibit autophagy in cellular and mouse models.", "metadata": {}}
+{"_id": "28149602", "title": "", "text": "The role of neutrophils in the pathogenesis of systemic lupus erythematosus.PURPOSE OF REVIEW Recentdiscoveries implicate neutrophils as important regulators of innate and adaptive immunity and in thedevelopment of organ damage in systemic autoimmune diseases, including systemic lupus erythematosus(SLE). RECENT FINDINGS Various putative SLE biomarkers are neutrophil-related, including neutrophilgranular proteins and histones undergoing post-translational modifications during neutrophil extracellulartrap (NET) formation. In the bone marrow, lupus neutrophils can drive B and T cell abnormalities, at leastin part, by their enhanced production of type-I interferons, tumor necrosis factor-alpha (TNFα) and theB-cell stimulating factors B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL). Lupusneutrophils and, in particular, lupus low-density granulocytes (a distinct pathogenic subset) displayepigenetic modifications and genomic alterations that may be relevant to their deleterious roles in SLE.Proteins and enzymes externalized by lupus NETs can affect vascular health by inducing endothelialapoptosis and oxidizing lipoproteins. Hampering NET formation through peptidylarginine deiminaseinhibitors abrogates lupus phenotype and atherosclerosis in murine studies. SUMMARY Recent discoveriessupport the notion that neutrophils, low-density granulocytes and aberrant NET formation and clearanceplay important roles in lupus pathogenesis. Future studies should focus on how to selectively target theseimmunostimulatory pathways in this disease.", "metadata": {}}
+{"_id": "28164534", "title": "", "text": "Enhancement of proteasome function by PA28α overexpression protects against oxidative stress.Theprincipal function of the proteasome is targeted degradation of intracellular proteins. Proteasomedysfunction has been observed in experimental cardiomyopathies and implicated in human congestiveheart failure. Measures to enhance proteasome proteolytic function are currently lacking but would bebeneficial in testing the pathogenic role of proteasome dysfunction and could have significant therapeuticpotential. The association of proteasome activator 28 (PA28) with the 20S proteasome may play a role inantigen processing. It is unclear, however, whether the PA28 plays any important role outside of antigenpresentation, although up-regulation of PA28 has been observed in certain types of cardiomyopathy.Here, we show that PA28α overexpression (PA28αOE) stabilized PA28β, increased 11S proteasomes, andenhanced the degradation of a previously validated proteasome surrogate substrate (GFPu) in culturedneonatal rat cardiomyocytes. PA28αOE significantly attenuated H(2)O(2)-induced increases in the proteincarbonyls and markedly suppressed apoptosis in cultured cardiomyocytes under basal conditions or whenstressed by H(2)O(2). We conclude that PA28αOE is sufficient to up-regulate 11S proteasomes, enhanceproteasome-mediated removal of misfolded and oxidized proteins, and protect against oxidative stress incardiomyocytes, providing a highly sought means to increase proteasomal degradation of abnormalcellular proteins.", "metadata": {}}
+{"_id": "28193026", "title": "", "text": "A unified concept of species and its consequences for the future of taxonomyContemporary speciesconcepts are diverse. Nonetheless, all share the fundamental idea that species are segments of lineagesat the population level of biological organization. They differ in the secondary properties (e.g., intrinsicreproductive isolation, monophyly, diagnosability) that are treated as necessary for considering lineagesto be species. A unified species concept can be achieved by interpreting the common fundamental idea ofbeing a separately evolving lineage segment as the only necessary property of species and viewing thevarious secondary properties either as lines of evidence relevant to assessing lineage separation or asproperties that define different subcategories of the species category (e.g., reproductively isolatedspecies, monophyletic species, diagnosable species). This unified species concept has a number ofconsequences for taxonomy, including the need to acknowledge that undifferentiated and undiagnosablelineages are species, that species can fuse, that species can be nested within other species, that thespecies category is not a taxonomic rank, and that new taxonomic practices and conventions are neededto accommodate these conclusions. Although acceptance of a unified species concept has some radicalconsequences for taxonomy, it also reflects a change in the general conceptualization of the speciescategory that has been underway for more than a half-century — a shift from viewing the speciescategory as one member of the hierarchy of taxonomic ranks to viewing it as a natural kind whosemembers are the units at one of the levels of biological organization. This change is related to a moregeneral shift in the primary concern of the discipline of systematics (including taxonomy), from theutilitarian activity of classifying organisms to the scientific activity of testing hypotheses about lineageboundaries and phylogenetic relationships. The unified species concept is a natural outcome of thisconceptual shift and represents the more complete acceptance of the idea that species are one of thefundamental units of biology. As such, the unified species concept is central to the future of taxonomy.", "metadata": {}}
+{"_id": "28195565", "title": "", "text": "Regulation of the small GTP-binding protein Rho by cell adhesion and the cytoskeleton.Soluble factorsfrom serum such as lysophosphatidic acid (LPA) are thought to activate the small GTP-binding proteinRho based on their ability to induce actin stress fibers and focal adhesions in a Rho-dependent manner.Cell adhesion to extracellular matrices (ECM) has also been proposed to activate Rho, but this point hasbeen controversial due to the difficulty of distinguishing changes in Rho activity from the structuralcontributions of ECM to the formation of focal adhesions. To address these questions, we established anassay for GTP-bound cellular Rho. Plating Swiss 3T3 cells on fibronectin-coated dishes elicited a transientinhibition of Rho, followed by a phase of Rho activation. The activation phase was greatly enhanced byserum. In serum-starved adherent cells, LPA induced transient Rho activation, whereas in suspendedcells Rho activation was sustained. Furthermore, suspended cells showed higher Rho activity thanadherent cells in the presence of serum. These data indicate the existence of an adhesion-dependentnegative-feedback loop. We also observed that both cytochalasin D and colchicine trigger Rho activationdespite their opposite effects on stress fibers and focal adhesions. Our results show that ECM,cytoskeletal structures and soluble factors all contribute to regulation of Rho activity.", "metadata": {}}
+{"_id": "28206748", "title": "", "text": "Core binding factors are necessary for natural killer cell development and cooperate with Notch signalingduring T-cell specification.CBFbeta is the non-DNA binding subunit of the core binding factors (CBFs).Mice with reduced CBFbeta levels display profound, early defects in T-cell but not B-cell development.Here we show that CBFbeta is also required at very early stages of natural killer (NK)-cell development.We also demonstrate that T-cell development aborts during specification, as the expression of Gata3 andTcf7, which encode key regulators of T lineage specification, is substantially reduced, as are functionalthymic progenitors. Constitutively active Notch or IL-7 signaling cannot restore T-cell expansion ordifferentiation of CBFbeta insufficient cells, nor can overexpression of Runx1 or CBFbeta overcome a lackof Notch signaling. Therefore, the ability of the prethymic cell to respond appropriately to Notch isdependent on CBFbeta, and both signals converge to activate the T-cell developmental program.", "metadata": {}}
+{"_id": "28207326", "title": "", "text": "VEGF and podocytes in diabetic nephropathy.Vascular endothelial growth factor-A (VEGF-A) is a proteinsecreted by podocytes that is necessary for survival of endothelial cells, podocytes, and mesangial cells.VEGF-A regulates slit-diaphragm signaling and podocyte shape via VEGF-receptor 2-nephrin-nck-actininteractions. Chronic hyperglycemia-induced excess podocyte VEGF-A and low endothelial nitric oxidedrive the development and the progression of diabetic nephropathy. The abnormal cross-talk betweenVEGF-A and nitric oxide pathways is fueled by the diabetic milieu, resulting in increased oxidative stress.Recent findings on these pathogenic molecular mechanisms provide new potential targets for therapy fordiabetic renal disease.", "metadata": {}}
+{"_id": "28230867", "title": "", "text": "Detection and distribution patterns of telomerase activity in insects.Telomeres of most insects consist ofpentanucleotide (TTAGG)n repeats, although the repeats are absent in Diptera and some other insectspecies, where the telomere regions are perhaps maintained without telomerase. To understand variousand unusual telomere formation in insects, we have studied the characteristic features of a putativeinsect telomerase that has not been previously described. Using a modified telomeric repeat amplificationprotocol (TRAP), we first detected the telomerase activity in crickets, cockroaches and two Lepidopteraninsects. The telomerase from crickets and cockroaches required dATP, dGTP and dTTP but not dCTP as asubstrate and sequence analyses of the products of TRAP revealed that the (TTAGG)n repeats aresynthesized by telomerase. The cockroach telomerase was detected both in somatic (fat body, muscleand neural tissues) and germ line (testis) cells, suggesting that expression of this enzyme is notregulated in a tissue-specific manner at an adult stage. While we detected high levels of telomeraseactivity in crickets and cockroaches, we could not detect activity in all tissues and cell cultures of thesilkworm, Bombyx mori and in two Drosophila and one Sarcophaga cell lines. This supports the theorythat Dipteran insects maintain their telomeres without telomerase.", "metadata": {}}
+{"_id": "28243325", "title": "", "text": "Conversion of the lac repressor into an allosterically regulated transcriptional activator for mammaliancells.A novel mammalian regulatory system was created by using the Escherichia coli lac repressor. Thelac repressor was converted into a mammalian transcriptional activator by modifying the lac repressorcoding region to include a nuclear localization signal from the simian virus 40 (SV40) large tumor antigenand the transcription activation domain from the herpes simplex virus type 1 virion protein 16. The lacactivator protein (LAP) fusions were potent activators of several promoters containing lac operatorsequences positioned either upstream or downstream of the transcription unit. A single lac operatorallowed for transactivation, whereas multiple operators acted synergistically when separated by a smalldistance. Promoters containing 14 or 21 operator sequences were induced at least 1,000-fold in responseto LAP, reaching levels of activity 20 to 30 times greater than that of the SV40 early promoter in HeLacells. Activation was strongly inhibited by isopropyl-beta-D-thiogalactoside (IPTG), indicating that LAPretained the functions needed for allosteric regulation. LAP was bifunctional, also acting as a repressor ofexpression of an SV40 promoter containing an operator immediately downstream of the TATA box.Finally, genetic selection schemes were developed such that LAP-expressing cell lines can be generated athigh frequency from either established or primary cells in culture.", "metadata": {}}
+{"_id": "28247027", "title": "", "text": "Antigen availability determines CD8\u0000 T cell-dendritic cell interaction kinetics and memory fatedecisions.T cells are activated by antigen (Ag)-bearing dendritic cells (DCs) in lymph nodes in threephases. The duration of the initial phase of transient, serial DC-T cell interactions is inversely correlatedwith Ag dose. The second phase, characterized by stable DC-T cell contacts, is believed to be necessaryfor full-fledged T cell activation. Here we have shown that this is not the case. CD8\u0000 T cells interactingwith DCs presenting low-dose, short-lived Ag did not transition to phase 2, whereas higher Ag doseyielded phase 2 transition. Both antigenic constellations promoted T cell proliferation and effectordifferentiation but yielded different transcriptome signatures at 12 hr and 24 hr. T cells that experiencedphase 2 developed long-lived memory, whereas conditions without stable contacts yielded immunologicalamnesia. Thus, T cells make fate decisions within hours after Ag exposure, resulting in long-term memoryor abortive effector responses, correlating with T cell-DCs interaction kinetics.", "metadata": {}}
+{"_id": "28249680", "title": "", "text": "BAX/BAK-independent mitoptosis during cell death induced by proteasome inhibition?Proteasomeinhibitors induce rapid death of cancer cells. We show that in epithelial cancer cells, such death isassociated with dramatic and simultaneous up-regulation of several BH3-only proteins, including BIK,BIM, MCL-1S, NOXA, and PUMA, as well as p53. Elevated levels of these proteins seem to be the result ofdirect inhibition of their proteasomal degradation, induction of transcription, and active translation.Subsequent cell death is independent of BAX, and probably BAK, and proceeds through the intrinsicmitochondrial apoptosis pathway. We identify the cascade of molecular events responsible for cell deathinduced by a prototypical proteasome inhibitor, MG132, starting with rapid accumulation of BH3-onlyproteins in the mitochondria, proceeding through mitochondrial membrane permeabilization andsubsequent loss of DeltaPsi(m), and leading to irreversible changes of mitochondrial ultrastructure,degradation of mitochondrial network, and detrimental impairment of crucial mitochondrial functions. Ourresults also establish a rationale for the broader use of proteasome inhibitors to kill apoptosis-resistanttumor cells that lack functional BAX/BAK proteins.", "metadata": {}}
+{"_id": "28264919", "title": "", "text": "Site of action of a ribosomal RNA methylase responsible for resistance to erythromycin and otherantibiotics.The enzyme which confers resistance to erythromycin in the producing organism Streptomyceserythraeus dimethylates a single adenine residue in Bacillus stearothermophilus 23 S rRNA. Thiscorresponds to residue Ade 2058 in Escherichia coli 23 S RNA. The methylase responsible for resistanceto macrolides, lincomycin, and streptogramin B-related antibiotics in Staphylococcus aureus also acts atthis site.", "metadata": {}}
+{"_id": "28271439", "title": "", "text": "53BP1 nuclear bodies form around DNA lesions generated by mitotic transmission of chromosomes underreplication stressCompletion of genome duplication is challenged by structural and topological barriersthat impede progression of replication forks. Although this can seriously undermine genome integrity, thefate of DNA with unresolved replication intermediates is not known. Here, we show that mild replicationstress increases the frequency of chromosomal lesions that are transmitted to daughter cells. ThroughoutG1, these lesions are sequestered in nuclear compartments marked by p53-binding protein 1 (53BP1)and other chromatin-associated genome caretakers. We show that the number of such 53BP1 nuclearbodies increases after genetic ablation of BLM, a DNA helicase associated with dissolution of entangledDNA. Conversely, 53BP1 nuclear bodies are partially suppressed by knocking down SMC2, a condensinsubunit required for mechanical stability of mitotic chromosomes. Finally, we provide evidence that53BP1 nuclear bodies shield chromosomal fragile sites sequestered in these compartments againsterosion. Together, these data indicate that restoration of DNA or chromatin integrity at loci prone toreplication problems requires mitotic transmission to the next cell generations.", "metadata": {}}
+{"_id": "28334217", "title": "", "text": "Targeted inhibition of tumor-specific glutaminase diminishes cell-autonomous tumorigenesis.Glutaminase(GLS), which converts glutamine to glutamate, plays a key role in cancer cell metabolism, growth, andproliferation. GLS is being explored as a cancer therapeutic target, but whether GLS inhibitors affectcancer cell-autonomous growth or the host microenvironment or have off-target effects is unknown.Here, we report that loss of one copy of Gls blunted tumor progression in an immune-competentMYC-mediated mouse model of hepatocellular carcinoma. Compared with results in untreated animalswith MYC-induced hepatocellular carcinoma, administration of the GLS-specific inhibitorbis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES) prolonged survival without anyapparent toxicities. BPTES also inhibited growth of a MYC-dependent human B cell lymphoma cell line(P493) by blocking DNA replication, leading to cell death and fragmentation. In mice harboring P493tumor xenografts, BPTES treatment inhibited tumor cell growth; however, P493 xenografts expressing aBPTES-resistant GLS mutant (GLS-K325A) or overexpressing GLS were not affected by BPTES treatment.Moreover, a customized Vivo-Morpholino that targets human GLS mRNA markedly inhibited P493xenograft growth without affecting mouse Gls expression. Conversely, a Vivo-Morpholino directed atmouse Gls had no antitumor activity in vivo. Collectively, our studies demonstrate that GLS is required fortumorigenesis and support small molecule and genetic inhibition of GLS as potential approaches fortargeting the tumor cell-autonomous dependence on GLS for cancer therapy.", "metadata": {}}
+{"_id": "28338268", "title": "", "text": "Dominant optic atrophy, deafness, ptosis, ophthalmoplegia, dystaxia, and myopathy. A newsyndrome.Twenty-three members of a 96-member family exhibited an autosomal dominant disorderwhich has not previously been described. This disorder involves progressive optic atrophy, abnormalelectroretinography without retinal pigment changes, and progressive sensorineural hearing loss usuallyevident in the first or second decade of life. In midlife, ptosis, ophthalmoplegia, dystaxia, and anonspecific myopathy occur.", "metadata": {}}
+{"_id": "28369117", "title": "", "text": "Dynein is required for polarized dendritic transport and uniform microtubule orientation in axonsAxonsand dendrites differ in both microtubule organization and in the organelles and proteins they contain.Here we show that the microtubule motor dynein has a crucial role in polarized transport and incontrolling the orientation of axonal microtubules in Drosophila melanogaster dendritic arborization (da)neurons. Changes in organelle distribution within the dendritic arbors of dynein mutant neurons correlatewith a proximal shift in dendritic branch position. Dynein is also necessary for the dendrite-specificlocalization of Golgi outposts and the ion channel Pickpocket. Axonal microtubules are normally orienteduniformly plus-end-distal; however, without dynein, axons contain both plus- and minus-end distalmicrotubules. These data suggest that dynein is required for the distinguishing properties of the axon anddendrites: without dynein, dendritic organelles and proteins enter the axon and the axonal microtubulesare no longer uniform in polarity.", "metadata": {}}
+{"_id": "28386343", "title": "", "text": "Small molecule screening in human induced pluripotent stem cell-derived terminal cell types.A need forbetter clinical outcomes has heightened interest in the use of physiologically relevant human cells in thedrug discovery process. Patient-specific human induced pluripotent stem cells may offer a relevant,robust, scalable, and cost-effective model of human disease physiology. Small molecule high throughputscreening in human induced pluripotent stem cell-derived cells with the intent of identifying noveltherapeutic compounds is starting to influence the drug discovery process; however, the use of thesecells presents many high throughput screening development challenges. This technology has the potentialto transform the way drug discovery is performed.", "metadata": {}}
+{"_id": "28390999", "title": "", "text": "Gene expression during gonadogenesis in the chicken embryo.Genes implicated in vertebrate sexdetermination and differentiation were studied in embryonic chicken gonads using reverse transcriptionand the polymerase chain reaction (RT-PCR). Expression profiles were obtained during gonadal sexdifferentiation for AMH, SOX9, SOX3, the Wilm's Tumour gene, WT1, and the orphan nuclear receptorgenes, SF1 and DAX1. Some of these genes showed sexually dimorphic expression profiles duringgonadal development, whereas others were expressed at similar levels in both sexes. The gene encodingAnti-Müllerian hormone (AMH) was expressed in both sexes prior to and during sexual differentiation ofthe gonads, with levels of expression consistently higher in males than in females. SOX9 expression wasmale-specific, and was up-regulated after the detection of AMH transcripts. SOX3 expression wasobserved prior to clear SOX9 expression and was up-regulated in both sexes at the onset of gonadal sexdifferentiation (but declined later in development). The WT1 gene was highly expressed in both sexes,whereas SF1 expression was clearly higher in developing ovaries compared to testes. DAX1 transcriptswere observed in both sexes at all stages examined, but expression appeared somewhat higher indeveloping ovaries. These expression profiles are analysed in terms of current theories of vertebrate sexdetermination.", "metadata": {}}
+{"_id": "28392393", "title": "", "text": "Organ-resident, nonlymphoid cells suppress proliferation of autoimmune T-helper lymphocytes.Localpresentation of autoantigen by organ-resident cells inappropriately expressing Ia determinants has beenimplicated in organ-specific autoimmunity. Experimental autoimmune uveoretinitis, induced in rats byimmunization with retinal soluble antigen, is used as a model of organ-specific autoimmunity. In an invitro system derived from this model, uveitogenic rat T-helper lymphocytes specific to the retinal solubleantigen, or control T-helper lymphocytes reactive to the purified protein derivative of tuberculin, werecocultured with Ia-expressing syngeneic retinal glial cells (Müller cells) in the presence of specific antigen.Antigen presentation was not apparent under ordinary culture conditions, and the Müller cells profoundlysuppressed the proliferative response of primed T-helper lymphocytes to antigen presented onconventional antigen-presenting cells, as well as their subsequent interleukin-2 (IL-2)-dependentexpansion. Suppression of proliferation was accompanied by inhibition of IL-2 production in response toantigen, as well as by reduction in high-affinity IL-2 receptor expression, and proceeded via acontact-dependent mechanism. These results suggest a role for locally acting suppression mechanisms inimmune regulation and maintenance of tissue homeostasis.", "metadata": {}}
+{"_id": "28419824", "title": "", "text": "Drug induced refractory headache--clinical features and management.Two hundred patients who weretaking daily symptomatic or immediate relief medications, often in excessive quantities, yet sufferingfrom daily or near daily severe headaches were studied. One hundred and sixteen (58%) of them werealso taking concomitant prophylactic medications and they were ineffective. Low tyramine, low caffeinedietary instructions and biofeedback training were given to all patients. The effect of continuingsymptomatic medications, discontinuing symptomatic medications, and adding or changing prophylacticmedications were studied in the various treatment groups. It is concluded that; 1.) Daily use ofsymptomatic or immediate relief medications result in chronic daily headache. 2.) Discontinuing dailysymptomatic medications itself result in improvement of headache. 3.) Concomitant use of symptomaticmedications nullifies the effect of prophylactic medications. 4.) Discontinuing daily symptomaticmedications enhances the beneficial effect of prophylactic medications.", "metadata": {}}
+{"_id": "28436879", "title": "", "text": "Neuromodulation of neurons and synapses.Neuromodulation underlies the flexibility of neural circuitoperation and behavior. Individual neuromodulators can have divergent actions in a neuron by targetingmultiple physiological mechanisms. Conversely, multiple neuromodulators may have convergent actionsthrough overlapping targets. The divergent and convergent neuromodulator actions can beunambiguously synergistic or antagonistic, but neuromodulation often entails balanced adjustment ofnonlinear membrane and synaptic properties by targeting ion channel and synaptic dynamics rather thanjust excitability or synaptic strength. In addition, neuromodulators can exert effects at multipletimescales, from short-term adjustments of neuron and synapse function to persistent long-termregulation. This short review summarizes some highlights of the diverse actions of neuromodulators onion channel and synaptic properties.", "metadata": {}}
+{"_id": "28441310", "title": "", "text": "Mutation frequency and specificity with age in liver, bladder and brain of lacI transgenic mice.Mutationfrequency and specificity were determined as a function of age in nuclear DNA from liver, bladder, andbrain of Big Blue lacI transgenic mice aged 1.5-25 months. Mutations accumulated with age in liver andaccumulated more rapidly in bladder. In the brain a small initial increase in mutation frequency wasobserved in young animals; however, no further increase was observed in adult mice. To investigate theorigin of mutations, the mutational spectra for each tissue and age were determined. DNA sequenceanalysis of mutant lacI transgenes revealed no significant changes in mutational specificity in any tissueat any age. The spectra of mutations found in aging animals were identical to those in younger animals,suggesting that they originated from a common set of DNA lesions manifested during DNA replication.The data also indicated that there were no significant age-related mutational changes due to oxidativedamage, or errors resulting from either changes in the fidelity of DNA polymerase or the efficiency of DNArepair. Hence, no evidence was found to support hypotheses that predict that oxidative damage oraccumulation of errors in nuclear DNA contributes significantly to the aging process, at least in thesethree somatic tissues.", "metadata": {}}
+{"_id": "28468276", "title": "", "text": "Breaching the basement membrane: who, when and how?The basement membrane (BM), a specializednetwork of extracellular matrix macromolecules, surrounds epithelial, endothelial, muscle, fat and nervecells. During development, immune surveillance and disease states ranging from cancer to fibrosis, hostcells penetrate the BM by engaging tissue-invasive programs, the identity of which remain largelyundefined. Although it is commonly assumed that all cells employ similar mechanisms to cross BMbarriers, accumulating evidence indicates that cells might selectively mobilize protease-dependent or-independent invasion programs. New data indicate that protease-dependent transmigration is largelyreliant on a group of membrane-anchored metalloenzymes, termed the membrane-type matrixmetalloproteinases, which irreversibly remodel BM structure. By contrast, mechanisms that enableprotease-independent transmigration remain undefined and potentially involve the reversible disassemblyof the BM network. Further characterization of the molecular mechanisms underlying BM transmigrationshould provide important insights into pathophysiologic tissue remodeling events and also enable thedevelopment of novel therapeutics.", "metadata": {}}
+{"_id": "28517384", "title": "", "text": "Soluble MD-2 is an acute-phase protein and an opsonin for Gram-negative bacteria.Myeloid differentiationfactor-2 (MD-2) is a lipopolysaccharide (LPS)-binding protein usually coexpressed with and binding toToll-like receptor 4 (TLR4), conferring LPS responsiveness of immune cells. MD-2 is also found as asoluble protein. Soluble MD-2 (sMD-2) levels are markedly elevated in plasma from patients with severeinfections, and in other fluids from inflamed tissues. We show that sMD-2 is a type II acute-phaseprotein. Soluble MD-2 mRNA and protein levels are up-regulated in mouse liver after the induction of anacute-phase response. It is secreted by human hepatocytic cells and up-regulated by interleukin-6.Soluble MD-2 binds to Gram-negative but not Gram-positive bacteria, and sMD-2 secreted by hepatocyticcells is an essential cofactor for the activation of TLR4-expressing cells by Gram-negative bacteria.Soluble MD-2 opsonization of Gram-negative bacteria accelerates and enhances phagocytosis, principallyby polymorphonuclear neutrophils. In summary, our results demonstrate that sMD-2 is a newlyrecognized type II acute-phase reactant, an opsonin for Gram-negative bacteria, and a cofactor essentialfor the activation of TLR4-expressing cells. This suggests that sMD-2 plays a key role in the host innateimmune response to Gram-negative infections.", "metadata": {}}
+{"_id": "28530299", "title": "", "text": "Division-coupled astrocytic differentiation and age-related depletion of neural stem cells in the adulthippocampus.Production of new neurons in the adult hippocampus decreases with age; this decline mayunderlie age-related cognitive impairment. Here we show that continuous depletion of the neural stemcell pool, as a consequence of their division, may contribute to the age-related decrease in hippocampalneurogenesis. Our results indicate that adult hippocampal stem cells, upon exiting their quiescent state,rapidly undergo a series of asymmetric divisions to produce dividing progeny destined to become neuronsand subsequently convert into mature astrocytes. Thus, the decrease in the number of neural stem cellsis a division-coupled process and is directly related to their production of new neurons. We present ascheme of the neurogenesis cascade in the adult hippocampus that includes a proposed \"disposable stemcell\" model and accounts for the disappearance of hippocampal neural stem cells, the appearance of newastrocytes, and the age-related decline in the production of new neurons.", "metadata": {}}
+{"_id": "28542402", "title": "", "text": "P19 embryonal carcinoma cells.P19 cells are a line of pluripotent embryonal carcinoma able to growcontinuously in serum-supplemented media. The differentiation of these cells can be controlled bynontoxic drugs. Retinoic acid effectively induces the development of neurons, astroglia and microglia--celltypes normally derived from the neuroectoderm. Aggregates of P19 cells exposed to dimethyl sulfoxidedifferentiate into endodermal and mesodermal derivatives including cardiac and skeletal muscle. P19 cellscan be effectively transfected with DNA encoding recombinant genes and stable lines expressing thesegenes can be readily isolated. These manipulations make P19 cells suitable material for investigating themolecular mechanisms governing developmental decision made by differentiating pluripotent cells.", "metadata": {}}
+{"_id": "28562710", "title": "", "text": "Iguanas and Salmonella marina infection in children: a reflection of the increasing incidence ofreptile-associated salmonellosis in the United States.OBJECTIVE To investigate clinical aspects and riskfactors for Salmonella serotype Marina infection in the United States. METHODS We identified all isolatesof S Marina reported in 1994 to the National Salmonella Surveillance System. Patients were interviewedabout demographic information, clinical course, diet, travel history, and contact with reptiles beforeillness. RESULTS Twenty-six (81%) of 32 patients were infants (<1 year of age) and 24 (75%) weremale. This differs from other Salmonella isolates reported to the Centers for Disease Control andPrevention in 1994, of which 14% were from infants and 49% from male patients. Eleven patients (34%)were hospitalized for a median of 3.5 days (range: 2 to 21 days), and 1 died. Of 28 patients (88%) withreported iguana exposure, only 4 (14%) touched the reptile, and only 12 respondents (43%) realizedthat it might have been the source of infection. Seven (32%) of 22 families who owned an iguana at thetime of illness continued to own an iguana when contacted a median of 28 weeks later. Persons whothought that the iguana was the source of infection were more likely to have given away or sold the petthan those who did not. Four isolates (13%) were from blood. Bacteremia was associated with takingantibiotics during the 30 days before S Marina infection (odds ratio: 24; 95% confidence interval:1.2-1309). CONCLUSION S Marina infection is a potentially serious illness associated with iguanaexposure, and it reflects the larger problem of reptile-associated salmonellosis. Many parents do notknow that owning an iguana puts their children at risk for Salmonella infection. Pediatricians,veterinarians, and pet store owners should inform their patients and customers of the potential risks ofowning reptiles and provide appropriate preventive education.", "metadata": {}}
+{"_id": "28592273", "title": "", "text": "Siblings with opposite chromosome constitutions, dup(2q)/del(7q) and del(2q)/dup(7q).Chromosome7q36 microdeletion syndrome is a rare genomic disorder characterized by underdevelopment of the brain,microcephaly, anomalies of the sex organs, and language problems. Developmental delay, intellectualdisability, autistic spectrum disorders, BDMR syndrome, and unusual facial morphology are the keyfeatures of the chromosome 2q37 microdeletion syndrome. A genetic screening for two brothers withglobal developmental delay using high-resolution chromosomal analysis and subtelomeric multiplexligation-dependent probe amplification revealed subtelomeric rearrangements on the same sites of2q37.2 and 7q35, with reversed deletion and duplication. Both of them showed dysmorphic facialfeatures, severe disability of physical and intellectual development, and abnormal genitalia withdifferential abnormalities in their phenotypes. The family did not have abnormal genetic phenotypes.According to the genetic analysis of their parents, adjacent-1 segregation from their mother's wassuggested as a mechanism of their gene mutation. By comparing the phenotypes of our patients withprevious reports on similar patients, we tried to obtain the information of related genes and theirchromosomal locations.", "metadata": {}}
+{"_id": "28598374", "title": "", "text": "Methods for quantifying follicular numbers within the mouse ovary.Accurate estimation of the number ofovarian follicles at various stages of development is an important indicator of the process offolliculogenesis in relation to the endocrine signals and paracrine/autocrine mechanisms that control thegrowth and maturation of the oocytes and their supporting follicular cells. There are 10-fold or greaterdifferences in follicular numbers per ovary at similar ages and/or strains reported in earlier studies usingvarious methods, leading to difficulties with interpretation of ovarian function in control vs experimentalconditions. This study describes unbiased, assumption-free stereological methods for quantification ofearly and growing follicular numbers in the mouse ovary. A fractionator approach was used to sample adefined fraction of histological sections of adult wild-type ovaries. Primordial and primary follicles werecounted independently with the optical and physical disector methods. The fractionator/disector methods,which are independent of follicular size or shape, gave estimations of 1930 +/- 286 (S.E.M.) and 2227+/- 101 primordial follicles, and 137 +/- 25 and 265 +/- 32 primary follicles per ovary at 70 and 100days of age respectively. From exact counts on serial sections, secondary and later follicular numbers at100 days of age were estimated at 135 per ovary. Remnants of zona pellucidae (a marker of previousfollicular atresia) were estimated using a fractionator/physical disector approach and were approximately500 per ovary. The application of the quantitative methods described will facilitate an improvedunderstanding of follicular dynamics and the factors that mediate their growth and maturation and allowfor a better comparison between different studies.", "metadata": {}}
+{"_id": "28614776", "title": "", "text": "Identification of functional cooperative mutations of SETD2 in human acute leukemiaAcute leukemiacharacterized by chromosomal rearrangements requires additional molecular disruptions to develop intofull-blown malignancy, yet the cooperative mechanisms remain elusive. Using whole-genome sequencingof a pair of monozygotic twins discordant for MLL (also called KMT2A) gene–rearranged leukemia, weidentified a transforming MLL-NRIP3 fusion gene and biallelic mutations in SETD2 (encoding a histoneH3K36 methyltransferase). Moreover, loss-of-function point mutations in SETD2 were recurrent (6.2%) in241 patients with acute leukemia and were associated with multiple major chromosomal aberrations. Weobserved a global loss of H3K36 trimethylation (H3K36me3) in leukemic blasts with mutations in SETD2.In the presence of a genetic lesion, downregulation of SETD2 contributed to both initiation andprogression during leukemia development by promoting the self-renewal potential of leukemia stem cells.Therefore, our study provides compelling evidence for SETD2 as a new tumor suppressor. Disruption ofthe SETD2-H3K36me3 pathway is a distinct epigenetic mechanism for leukemia development.", "metadata": {}}
+{"_id": "28617573", "title": "", "text": "Evidence regarding human papillomavirus testing in secondary prevention of cervical cancer.More thanever, clinicians need regularly updated reviews given the continuously increasing amount of newinformation regarding innovative cervical cancer prevention methods. A summary is given from recentmeta-analyses and systematic reviews on 3 possible clinical applications of human papillomavirus (HPV)testing: triage of women with equivocal or low-grade cytologic abnormalities; prediction of thetherapeutic outcome after treatment of cervical intraepithelial neoplasia (CIN) lesions, and last not butnot least, primary screening for cervical cancer and pre-cancer. Consistent evidence is availableindicating that HPV-triage with the Hybrid Capture(®) 2 assay (Qiagen Gaithersburg, Inc., MD, USA[previously Digene Corp.] (HC2) is more accurate (higher sensitivity, similar specificity) than repeatcytology to triage women with equivocal Pap smear results. Several other tests show at least similaraccuracy but mRNA testing with the APTIMA(®) (Gen-Probe Inc., San Diego, CA, USA) test is similarlysensitive but more specific compared to HC2. In triage of low-grade squamous intraepithelial lesions(LSIL), HC2 is more sensitive but its specificity is substantially lower compared to repeat cytology. TheAPTIMA(®) test is more specific than HC2 without showing a loss in sensitivity. Identification of DNA ofHPV types 16 and/or 18, or RNA from the five most carcinogenic HPV types allow selecting women athighest risk for CIN3+ but the sensitivity and negative predictive value of these markers are lower thanfull-range high-risk HPV (hrHPV) testing. After conservative treatment of cervical pre-cancer, HPV testingpicks up more quickly, with higher sensitivity and not lower specificity, residual or recurrent high-gradeCIN than follow-up cytology. Primary screening for hrHPV generally detects more CIN2, CIN3 or cancercompared to cytology at cut-off atypical squamous cells of undetermined significance (ASC-US) or LSIL,but is less specific. Combined HPV and cytology screening provides a further small gain in sensitivity atthe expense of a considerable loss in specificity if positive by either test is referred to colposcopy, incomparison with HPV testing only. Randomised trials and follow-up of cohort studies consistentlydemonstrate a significantly lower cumulative incidence of CIN3+ and even of cancer, in women aged 30years or older, who were at enrollment hrHPV DNA negative compared to those who were cytologicallynegative. The difference in cumulative risk of CIN3+ or cancer for double negative (cytology & HPV)versus only HPV-negative women is small. HC2, GP5+/6+ PCR (polymerase chain reaction), cobas(®)4800 PCR (Roche Molecular Systems Inc., Alameda, CA, USA) and Real Time PCR (Abbott Molecular, DesPlaines, IL, USA) can be considered as clinically validated for use in primary screening. The loss inspecificity associated with primary HPV-based screening can be compensated by appropriate algorithmsinvolving reflex cytology and/or HPV genotyping for HPV16 or 18. There exists a substantial evidencebase to support that HPV testing is advantageous both in triage of women with equivocal abnormalcytology, in surveillance after treatment of CIN lesions and in primary screening of women aged 30 yearsor older. However, the possible advantages offered by HPV-based screening require a well organisedprogram with good compliance with screening and triage policies. This article forms part of a specialsupplement entitled \"Comprehensive Control of HPV Infections and Related Diseases\" Vaccine Volume 30,Supplement 5, 2012.", "metadata": {}}
+{"_id": "28633594", "title": "", "text": "International standards for fetal growth based on serial ultrasound measurements: the Fetal GrowthLongitudinal Study of the INTERGROWTH-21st Project.BACKGROUND In 2006, WHO producedinternational growth standards for infants and children up to age 5 years on the basis ofrecommendations from a WHO expert committee. Using the same methods and conceptual approach, theFetal Growth Longitudinal Study (FGLS), part of the INTERGROWTH-21(st) Project, aimed to developinternational growth and size standards for fetuses. METHODS The multicentre, population-based FGLSassessed fetal growth in geographically defined urban populations in eight countries, in which most of thehealth and nutritional needs of mothers were met and adequate antenatal care was provided. We usedultrasound to take fetal anthropometric measurements prospectively from 14 weeks and 0 days ofgestation until birth in a cohort of women with adequate health and nutritional status who were at lowrisk of intrauterine growth restriction. All women had a reliable estimate of gestational age confirmed byultrasound measurement of fetal crown-rump length in the first trimester. The five primary ultrasoundmeasures of fetal growth--head circumference, biparietal diameter, occipitofrontal diameter, abdominalcircumference, and femur length--were obtained every 5 weeks (within 1 week either side) from 14weeks to 42 weeks of gestation. The best fitting curves for the five measures were selected usingsecond-degree fractional polynomials and further modelled in a multilevel framework to account for thelongitudinal design of the study. FINDINGS We screened 13,108 women commencing antenatal care atless than 14 weeks and 0 days of gestation, of whom 4607 (35%) were eligible. 4321 (94%) eligiblewomen had pregnancies without major complications and delivered live singletons without congenitalmalformations (the analysis population). We documented very low maternal and perinatal mortality andmorbidity, confirming that the participants were at low risk of adverse outcomes. For each of the five fetalgrowth measures, the mean differences between the observed and smoothed centiles for the 3rd, 50th,and 97th centiles, respectively, were small: 2·25 mm (SD 3·0), 0·02 mm (3·0), and -2·69 mm (3·2) forhead circumference; 0·83 mm (0·9), -0·05 mm (0·8), and -0·84 mm (1·0) for biparietal diameter; 0·63mm (1·2), 0·04 mm (1·1), and -1·05 mm (1·3) for occipitofrontal diameter; 2·99 mm (3·1), 0·25 mm(3·2), and -4·22 mm (3·7) for abdominal circumference; and 0·62 mm (0·8), 0·03 mm (0·8), and -0·65mm (0·8) for femur length. We calculated the 3rd, 5th 10th, 50th, 90th, 95th and 97th centile curvesaccording to gestational age for these ultrasound measures, representing the international standards forfetal growth. INTERPRETATION We recommend these international fetal growth standards for the clinicalinterpretation of routinely taken ultrasound measurements and for comparisons across populations.FUNDING Bill & Melinda Gates Foundation.", "metadata": {}}
+{"_id": "28644298", "title": "", "text": "Role of NF-kappa B in cell survival and transcription of latent membrane protein 1-expressing orEpstein-Barr virus latency III-infected cells.Epstein-Barr virus (EBV) latency III infection converts Blymphocytes into lymphoblastoid cell lines (LCLs) by expressing EBV nuclear and membrane proteins,EBNAs, and latent membrane proteins (LMPs), which regulate transcription through Notch and tumornecrosis factor receptor pathways. The role of NF-kappa B in LMP1 and overall EBV latency IIItranscriptional effects was investigated by treating LCLs with BAY11-7082 (BAY11). BAY11 rapidly andirreversibly inhibited NF-kappa B, decreased mitochondrial membrane potential, induced apoptosis, andaltered LCL gene expression. BAY11 effects were similar to those of an NF-kappa B inhibitor, Delta N-Ikappa B alpha, in effecting decreased JNK1 expression and in microarray analyses. More than 80% ofarray elements that decreased with Delta N-I kappa B alpha expression decreased with BAY11 treatment.Newly identified NF-kappa B-induced, LMP1-induced, and EBV-induced genes included pleckstrin, Jun-B,c-FLIP, CIP4, and I kappa B epsilon. Of 776 significantly changed array elements, 134 were fourfoldupregulated in EBV latency III, and 74 were fourfold upregulated with LMP1 expression alone, whereasonly 28 were more than fourfold downregulated by EBV latency III. EBV latency III-regulated geneproducts mediate cell migration (EBI2, CCR7, RGS1, RANTES, MIP1 alpha, MIP1 beta, CXCR5, andRGS13), antigen presentation (major histocompatibility complex proteins and JAW1), mitogen-activatedprotein kinase pathway (DUSP5 and p62Dok), and interferon (IFN) signaling (IFN-gamma R alpha, IRF-4,and STAT1). Comparison of EBV latency III LCL gene expression to immunoglobulin M (IgM)-stimulated Bcells, germinal-center B cells, and germinal-center-derived lymphomas clustered LCLs withIgM-stimulated B cells separately from germinal-center cells or germinal-center lymphoma cells.Expression of IRF-2, AIM1, ASK1, SNF2L2, and components of IFN signaling pathways furtherdistinguished EBV latency III-infected B cells from IgM-stimulated or germinal-center B cells.", "metadata": {}}
+{"_id": "28647122", "title": "", "text": "Endotoxin tolerance: new mechanisms, molecules and clinical significance.Prior exposure of innateimmune cells like monocytes/macrophages to minute amounts of endotoxin cause them to becomerefractory to subsequent endotoxin challenge, a phenomenon called \"endotoxin tolerance\". Clinically, thisstate is associated with monocytes/macrophages in sepsis patients where they contribute to\"immunosuppression\" and mortality. The molecular mechanisms underlying endotoxin tolerance remainelusive. The recent appreciation of inflammation as a self-regulating process, the relative contribution ofMyD88 versus TRIF signaling pathways in inducing activation or tolerance, plasticity of NF-kappaBfunction and the role of chromatin modification and microRNAs in LPS-induced gene reprogrammingurges a re-evaluation of endotoxin tolerance. This review integrates these new findings into an up-to-dateaccount of endotoxin tolerance, its molecular basis and clinical implications in different pathologies.", "metadata": {}}
+{"_id": "28651643", "title": "", "text": "Pancreatic tumor cells with mutant K-ras suppress ERK activity by MEK-dependent induction of MAPkinase phosphatase-2.Activating mutations within the K-ras gene occur in a high percentage of humanpancreatic carcinomas. We reported previously that the presence of oncogenic, activated K-ras in humanpancreatic carcinoma cell lines did not result in constitutive activation of the extracellular signal-regulatedkinases (ERK1 and ERK2). In the present study, we further characterized the ERK signaling pathway inpancreatic tumor cell lines in order to determine whether the ERK pathway is subject to a compensatorydownregulation. We found that the attenuation of serum-induced ERK activation was not due to a delay inthe kinetics of ERK phosphorylation. Treatment with the tyrosine phosphatase inhibitor orthovanadateincreased the level of ERK phosphorylation, implicating a vanadate-sensitive tyrosine phosphatase in thenegative regulation of ERK. Furthermore, expression of a dual specificity phosphatase capable ofinactivating ERK known as mitogen-activated protein (MAP) kinase phosphatase-2 (MKP-2) was elevatedin most of the pancreatic tumor cell lines and correlated with the presence of active MAP kinase kinase(MEK). Taken together, these results suggest that pancreatic tumor cells expressing oncogenic K-rascompensate, in part, by upregulating the expression of MKP-2 to repress the ERK signaling pathway.", "metadata": {}}
+{"_id": "28697248", "title": "", "text": "E2F3 is a mediator of DNA damage-induced apoptosis.The E2F transcription factors have emerged ascritical apoptotic effectors. Herein we report that the E2F family member E2F3a can be induced by DNAdamage through transcriptional and posttranslational mechanisms. We demonstrate that theposttranslational induction of human E2F3a is dependent on the checkpoint kinases. Moreover, we showthat human E2F3a is a substrate for the checkpoint kinases (chk kinases) and that mutation of the chkphosphorylation site eliminates the DNA damage inducibility of the protein. Furthermore, we demonstratethat E2F1 and E2F2 are transcriptionally induced by DNA damage in an E2f3-dependent manner. Finally,using both in vitro and in vivo approaches, we establish that E2f3 is required for DNA damage-inducedapoptosis. Thus, our data reveal the novel ability of E2f3 to function as a master regulator of the DNAdamage response.", "metadata": {}}
+{"_id": "28704738", "title": "", "text": "miR-294/miR-302 promotes proliferation, suppresses G1-S restriction point, and inhibits ESCdifferentiation through separable mechanisms.The miR-294 and miR-302 microRNAs promote theabbreviated G1 phase of the embryonic stem cell (ESC) cell cycle and suppress differentiation induced bylet-7. Here, we evaluated the role of the retinoblastoma (Rb) family proteins in these settings. Undernormal growth conditions, miR-294 promoted the rapid G1-S transition independent of the Rb family. Incontrast, miR-294 suppressed the further accumulation of cells in G1 in response to nutrient deprivationand cell-cell contact in an Rb-dependent fashion. We uncovered five additional miRNAs (miR-26a,miR-99b, miR-193, miR-199a-5p, and miR-218) that silenced ESC self-renewal in the absence of othermiRNAs, all of which were antagonized by miR-294 and miR-302. Four of the six differentiation-inducingmiRNAs induced an Rb-dependent G1 accumulation. However, all six still silenced self-renewal in theabsence of the Rb proteins. These results show that the miR-294/miR-302 family acts throughRb-dependent and -independent pathways to regulate the G1 restriction point and the silencing ofself-renewal, respectively.", "metadata": {}}
+{"_id": "28707489", "title": "", "text": "Bacteriophage latent-period evolution as a response to resource availability.Bacteriophages (phages)modify microbial communities by lysing hosts, transferring genetic material, and effecting lysogenicconversion. To understand how natural communities are affected it is important to develop predictivemodels. Here we consider how variation between models--in eclipse period, latent period, adsorptionconstant, burst size, the handling of differences in host quantity and host quality, and in modelingstrategy--can affect predictions. First we compare two published models of phage growth, which differprimarily in terms of how they model the kinetics of phage adsorption; one is a computer simulation andthe other is an explicit calculation. At higher host quantities (approximately 10(8) cells/ml), both modelsclosely predict experimentally determined phage population growth rates. At lower host quantities (10(7)cells/ml), the computer simulation continues to closely predict phage growth rates, but the explicit modeldoes not. Next we concentrate on predictions of latent-period optima. A latent-period optimum is thelatent period that maximizes the population growth of a specific phage growing in the presence of aspecific quantity and quality of host cells. Both models predict similar latent-period optima at higher hostdensities (e.g., 17 min at 10(8) cells/ml). At lower host densities, however, the computer simulationpredicts latent-period optima that are much shorter than those suggested by explicit calculations (e.g.,90 versus 1,250 min at 10(5) cells/ml). Finally, we consider the impact of host quality on phagelatent-period evolution. By taking care to differentiate latent-period phenotypic plasticity fromlatent-period evolution, we argue that the impact of host quality on phage latent-period evolution may berelatively small.", "metadata": {}}
+{"_id": "28712203", "title": "", "text": "Neutrophil elastase-mediated lung disease.Elastases of both the neutrophil and macrophage have beenimplicated in lung disease initiation and progression. Although it is unlikely that these proteases evolvedfor the purpose of injuring lung tissue, the elastin-rich connective tissue framework of the lungs appearsto be particularly susceptible to the action of elastolytic proteases. Assuming that neutrophil elastasemost likely plays a role in the migration of neutrophils toward a site of inflammation and degradation ofproteins from invading organisms or other products of the inflammatory response, it is the role ofinhibitors of this protease to protect normal tissues from its effects. In alpha-1 antitrypsin deficiency wefind an experiment of nature that disrupts this protease-anti-protease balance, resulting in an increasedrisk of destructive lung disease.", "metadata": {}}
+{"_id": "28724565", "title": "", "text": "Role of TRPML and two-pore channels in endolysosomal cation homeostasis.The transient receptorpotential (TRP) channels TRPML1, TRPML2, and TRPML3 (also called mucolipins 1-3 or MCOLN1-3) arenonselective cation channels. Mutations in the Trpml1 gene cause mucolipidosis type IV in humans withclinical features including psychomotor retardation, corneal clouding, and retinal degeneration, whereasmutations in the Trpml3 gene cause deafness, circling behavior, and coat color dilution in mice. Nodisease-causing mutations are reported for the Trpml2 gene. Like TRPML channels, which are expressedin the endolysosomal pathway, two-pore channels (TPCs), namely TPC1, TPC2, and TPC3, are found inintracellular organelles, in particular in endosomes and lysosomes. Both TRPML channels and TPCs mayfunction as calcium/cation release channels in endosomes, lysosomes, and lysosome-related organelleswith TRPMLs being activated by phosphatidylinositol 3,5-bisphosphate and regulated by pH and TPCsbeing activated by nicotinic acid adenine dinucleotide phosphate in a calcium- and pH-dependent manner.They may also be involved in endolysosomal transport and fusion processes, e.g., as intracellular calciumsources. Currently, however, the exact physiological roles of TRPML channels and TPCs remain quiteelusive, and whether TRPML channels are purely endolysosomal ion channels or whether they may alsobe functionally active at the plasma membrane in vivo remains to be determined.", "metadata": {}}
+{"_id": "28738741", "title": "", "text": "Adult T-cell leukemia/lymphoma in London: clinical experience of 21 cases.Adult T-cellleukemia/lymphoma (ATLL) is uncommon in the United Kingdom and has so far been restricted to peopleof Afro-Caribbean extraction. Between 1981 and 1995, 21 cases presented to 2 inner London teachinghospitals where 17% of the population are of Afro-Caribbean origin. Clinical presentations were similar tothose of the disease in HTLV-I-endemic areas. Major responses (CR + PR) were obtained in 10/16assessable patients (63%) treated with combination chemotherapy. However, median survival was only5.5 months. Disease progression and opportunistic infection were the major causes of treatment failureand death. Three patients (14%) relapsed in the central nervous system (CNS). Our cases confirm theprofound immunosuppression in ATLL. The poor prognosis of acute and lymphoma types of ATLL highlightthe need for new approaches to treatment such as zidovudine and alpha-interferon, incorporatingprophylaxis against CNS disease and opportunistic infections.", "metadata": {}}
+{"_id": "28783084", "title": "", "text": "Regeneration, tissue injury and the immune response.The involvement of the immune system in theresponse to tissue injury has raised the possibility that it might influence tissue, organ or appendageregeneration following injury. One hypothesis that has been discussed is that inflammatory aspects maypreclude the occurrence of regeneration, but there is also evidence for more positive roles of immunecomponents. The vertebrate eye is an immunoprivileged site where inflammatory aspects are inhibited byseveral immunomodulatory mechanisms. In various newt species the ocular tissues such as the lens areregenerative and it has recently been shown that the response to local injury of the lens involvesactivation of antigen-presenting cells which traffic to the spleen and return to displace and engulf thelens, thereby inducing regeneration from the dorsal iris. The activation of thrombin from prothrombin inthe dorsal iris is one aspect of the injury response that is important in the initiation of regeneration. Thepossible relationships between the immune response and the regenerative response are considered withrespect to phylogenetic variation of regeneration in general, and lens regeneration in particular.", "metadata": {}}
+{"_id": "28806780", "title": "", "text": "Poverty, Hunger, Education, and Residential Status Impact Survival in HIVDespite combinationantiretroviral therapy (ART), HIV infected people have higher mortality than non-infected. Lowersocioeconomic status (SES) predicts higher mortality in many chronic illnesses but data in people withHIV is limited. We evaluated 878 HIV infected individuals followed from 1995 to 2005. Cox proportionalhazards for all-cause mortality were estimated for SES measures and other factors. Mixed effectsanalyses examined how SES impacts factors predicting death. The 200 who died were older, had lowerCD4 counts, and higher viral loads (VL). Age, transmission category, education, albumin, CD4 counts, VL,hunger, and poverty predicted death in univariate analyses; age, CD4 counts, albumin, VL, and povertyin the multivariable model. Mixed models showed associations between (1) CD4 counts with educationand hunger; (2) albumin with education, homelessness, and poverty; and (3) VL with education andhunger. SES contributes to mortality in HIV infected persons directly and indirectly, and should be atarget of health policy in this population.", "metadata": {}}
+{"_id": "28809022", "title": "", "text": "The INO80 ATP-dependent chromatin remodeling complex is a nucleosome spacing factor.Themobilization of nucleosomes by the ATP-dependent remodeler INO80 is quite different from anotherremodeler (SWI/SNF) that is also involved in gene activation. Unlike that recently shown for SWI/SNF,INO80 is unable to disassemble nucleosomes when remodeling short nucleosomal arrays. Instead, INO80more closely resembles, although with notable exceptions, the nucleosome spacing activity of ISW2 andISW1a, which are generally involved in transcription repression. INO80 required a minimum of 33 to 43bp of extranucleosomal DNA for mobilizing nucleosomes, with 70 bp being optimal. INO80 prefers tomove mononucleosomes to the center of DNA, like ISW2 and ISW1a, but does so with higher precision.Unlike ISW2/1a, INO80 does not require the H4 tail for nucleosome mobilization; instead, the H2Ahistone tail negatively regulates nucleosome movement by INO80. INO80 moved arrays of two or threenucleosomes with 50 or 79 bp of linker DNA closer together, with a final length of \u000030 bp of linker DNAor a repeat length of \u0000177 bp. A minimum length of >30 bp of linker DNA was required for nucleosomemovement and spacing by INO80 in arrays.", "metadata": {}}
+{"_id": "28821565", "title": "", "text": "Concentrations of tenofovir and emtricitabine in saliva: implications for preexposure prophylaxis of oralHIV acquisition.To prevent acquisition of HIV through oral sex, drugs used for preexposure prophylaxis(Prep) need to diffuse in saliva. We measured tenofovir (TFV) and emtricitabine (FTC) concentrationssimultaneously in the plasma and saliva of 41 HIV-infected patients under stable antiretroviral treatment.Mean ratios of saliva/plasma concentration were 3% (±4%) and 86.9% (±124%) for TFV and FTC,respectively. Tenofovir disoproxil fumarate (TDF) should be used in combination with FTC to prevent oralacquisition of HIV.", "metadata": {}}
+{"_id": "28845338", "title": "", "text": "Increased lean body mass as an early indicator of olanzapine-induced weight gain in healthy men.One ofthe primary limitations of many psychiatric medications is weight gain, the mechanism of which remainsto be fully elucidated. We conducted a 2-week double-blind placebo-controlled study on weight gain witholanzapine, which is frequently but unpredictably associated with this side effect, to address the possiblemechanisms of weight gain independent of changes in the psychiatric condition for which it is prescribed.Healthy male volunteers were randomly assigned to olanzapine (5 mg/day for 7 days, then 10 mg/day for7 days) or a matching placebo. Of the 24 participants, 19 completed the study (olanzapine, n=13;placebo, n=6). Body weight, glucose, triglyceride, total cholesterol, lipid, leptin, insulin, and aldosteronelevels, resting metabolic rate, body composition, physical activity, and 24-h dietary intake were assessed.A significant increase in weight as well as triglyceride, insulin, and leptin levels were found in theolanzapine group as a whole. In participants receiving olanzapine who actually gained weight (n=8), leanbut not fat mass increased, as did insulin, fasting glucose, total cholesterol, low-density lipoprotein, andnon-high-density lipoprotein levels, whereas aldosterone levels decreased. There were no significantmetabolic or endocrine changes in participants receiving placebo or in those receiving olanzapine who didnot gain weight. Early metabolic changes appear to be independent of accumulation of fat.", "metadata": {}}
+{"_id": "28894097", "title": "", "text": "QTc interval length and QT dispersion as predictors of mortality in patients with non-insulin-dependentdiabetes.Patients with non-insulin-dependent diabetes (NIDDM) are at independent risk of cardiovasculardeath. The reason is only partially understood. The aim of our study was therefore to evaluate the impactof corrected QT interval length (QTc) and QT dispersion (QT-disp) on mortality in a cohort of 324Caucasian NIDDM patients. A resting 12-lead ECG was recorded at baseline. Maximum (QT-max) andminimum QT (QT-min) intervals were measured, and QT-max was corrected for heart rate (QTc-max).QT-disp was defined as the difference between QT-max and QT-min. QTc-max was 454 (376-671)ms(1/2) (median (range)) and QT-disp 61 (0-240) ms. Prolonged QTc interval (PQTc), defined asQTc-max > 440 ms(1/2), was present in 67% of the patients and prolonged QT-disp (PQT-disp), definedas QT-disp > 50 ms, was present in 51%. During the 9-year follow-up period, 100 patients died (52 fromcardiovascular diseases). Thirty-seven percent of the patients with PQTc died compared with 17% withnormal QTc interval (p<0.001). The Cox proportional hazard model, including putative risk factors atbaseline, revealed the following independent predictors of all cause mortality; QTc-max (p<0.05), age(p<0.0001), albuminuria (p<0.01), retinopathy (p<0.01), HbA1c (p<0.05), insulin treatment (p<0.01),total cholesterol (p<0.01), serum creatinine (p<0.05) and presence of cardiac heart disease based onMinnesota coded ECG (p<0.001). Whereas QT-disp was not a predictor, QTc-max interval was anindependent predictor of cardiovascular mortality. Our study showed a high prevalence of QTc andQT-disp abnormalities and indicated that QTc-max but not QT-disp is an independent predictor of allcause and cardiovascular mortality in NIDDM patients.", "metadata": {}}
+{"_id": "28904104", "title": "", "text": "Repriming of DNA synthesis at stalled replication forks by human PrimPolDNA replication forks thatcollapse during the process of genomic duplication lead to double-strand breaks and constitute a threat togenomic stability. The risk of fork collapse is higher in the presence of replication inhibitors or after UVirradiation, which introduces specific modifications in the structure of DNA. In these cases, forkprogression may be facilitated by error-prone translesion synthesis (TLS) DNA polymerases.Alternatively, the replisome may skip the damaged DNA, leaving an unreplicated gap to be repaired afterreplication. This mechanism strictly requires a priming event downstream of the lesion. Here we showthat PrimPol, a new human primase and TLS polymerase, uses its primase activity to mediateuninterrupted fork progression after UV irradiation and to reinitiate DNA synthesis after dNTP depletion.As an enzyme involved in tolerance to DNA damage, PrimPol might become a target for cancer therapy.", "metadata": {}}
+{"_id": "28910120", "title": "", "text": "Recombinant human tumor necrosis factor administered as a five-day continuous infusion in cancerpatients: phase I toxicity and effects on lipid metabolism.Recombinant human tumor necrosis factor(rH-TNF) is a cytotoxic monokine with pleiotropic effects. A phase I trial of rH-TNF was initiated using afive-day continuous intravenous (IV) infusion repeated every 28 days. Thirty-eight courses of therapywere administered to 19 patients. The starting dose was 5 X 10(4) U/m2/d, with escalations to 1.0 X10(5), 2.0 X 10(5), 2.4 X 10(5), and 3.0 X 10(5) U/m2/d. Systemic side effects, including fever, chills,hypotension, fatigue, anorexia, and headaches, were mild and self-limiting. At the maximum tolerateddose of 3.0 X 10(5) U/m2/d, dose-limiting hematologic toxicity was manifested by transientthrombocytopenia and leukopenia. Elevated bilirubin levels were also seen at the higher dose levels.Lipoprotein analysis demonstrated that the five-day treatment with rH-TNF was associated withdecreases in high-density lipoproteins, as well as increases in triglycerides and very-low-densitylipoproteins. Pharmacokinetic studies using an enzyme-linked immunosorbent assay (ELISA) testindicated plasma rH-TNF levels less than 0.2 U/mL. The recommended phase II dose of rH-TNFadministered as a five-day continuous infusion is 2.4 X 10(5) U/m2/d.", "metadata": {}}
+{"_id": "28928964", "title": "", "text": "Tissue-specific expression and regulation of sexually dimorphic genes in mice.We report a comprehensiveanalysis of gene expression differences between sexes in multiple somatic tissues of 334 mice derivedfrom an intercross between inbred mouse strains C57BL/6J and C3H/HeJ. The analysis of a large numberof individuals provided the power to detect relatively small differences in expression between sexes, andthe use of an intercross allowed analysis of the genetic control of sexually dimorphic gene expression.Microarray analysis of 23,574 transcripts revealed that the extent of sexual dimorphism in geneexpression was much greater than previously recognized. Thus, thousands of genes showed sexualdimorphism in liver, adipose, and muscle, and hundreds of genes were sexually dimorphic in brain. Thesegenes exhibited highly tissue-specific patterns of expression and were enriched for distinct pathwaysrepresented in the Gene Ontology database. They also showed evidence of chromosomal enrichment, notonly on the sex chromosomes, but also on several autosomes. Genetic analyses provided evidence of theglobal regulation of subsets of the sexually dimorphic genes, as the transcript levels of a large number ofthese genes were controlled by several expression quantitative trait loci (eQTL) hotspots that exhibitedtissue-specific control. Moreover, many tissue-specific transcription factor binding sites were found to beenriched in the sexually dimorphic genes.", "metadata": {}}
+{"_id": "28931537", "title": "", "text": "The role of prevention in oncology practice: results from a 2004 survey of American Society of ClinicalOncology members.PURPOSE In 2004, the American Society of Clinical Oncology (ASCO) CancerPrevention Committee surveyed the members to describe involvement in clinical prevention activities.METHODS A previously administered survey, with updated items on genetics, chemoprevention, andsurvivorship, was mailed to a stratified random sample of 2,000 domestic members and a conveniencesample of 3,144 international members. RESULTS A total of 49.7% of domestic members contacted andsurvey eligible responded (n = 851). Nonresponders were younger (50.5 v 51.7 years; P < .01); 465international members responded. Overall, 35% had received formal instruction in cancer prevention andcontrol, and most respondents expected increased use of prevention, screening/early detection, and riskreduction/genetic counseling in their practices in the next 5 years. Most reported caring for cancersurvivors, including providing general medical care. They also either directly provide or refer patients forcancer prevention and control services (eg, cancer screening, tobacco and nutrition counseling, riskreduction, and chemoprevention). Multivariable modeling found fewer perceived barriers to inclusion ofcancer prevention activities in clinical practice among those practicing in an academic setting, seeing ahigher proportion of patients without a cancer diagnosis, having formal training in prevention and control,expecting an increase in prevention activities in the next 5 years, and providing community advice onprevention. CONCLUSION Barriers to the inclusion of cancer prevention and control activities in oncologyclinical practice exist. Nevertheless, a substantial proportion of both domestic and international ASCOmembers report an interest in cancer prevention and control activities, with a desire for more specificeducational programs in this emerging area of oncology practice.", "metadata": {}}
+{"_id": "28937856", "title": "", "text": "Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase.The Sir2 deacetylasemodulates organismal life-span in various species. However, the molecular mechanisms by which Sir2increases longevity are largely unknown. We show that in mammalian cells, the Sir2 homolog SIRT1appears to control the cellular response to stress by regulating the FOXO family of Forkhead transcriptionfactors, a family of proteins that function as sensors of the insulin signaling pathway and as regulators oforganismal longevity. SIRT1 and the FOXO transcription factor FOXO3 formed a complex in cells inresponse to oxidative stress, and SIRT1 deacetylated FOXO3 in vitro and within cells. SIRT1 had a dualeffect on FOXO3 function: SIRT1 increased FOXO3's ability to induce cell cycle arrest and resistance tooxidative stress but inhibited FOXO3's ability to induce cell death. Thus, one way in which members of theSir2 family of proteins may increase organismal longevity is by tipping FOXO-dependent responses awayfrom apoptosis and toward stress resistance.", "metadata": {}}
+{"_id": "29015485", "title": "", "text": "TLR-Mediated Innate Production of IFN-γ by CD8+ T Cells Is Independent of Glycolysis.CD8(+) T cells canrespond to unrelated infections in an Ag-independent manner. This rapid innate-like immune responseallows Ag-experienced T cells to alert other immune cell types to pathogenic intruders. In this study, weshow that murine CD8(+) T cells can sense TLR2 and TLR7 ligands, resulting in rapid production of IFN-γbut not of TNF-α and IL-2. Importantly, Ag-experienced T cells activated by TLR ligands produce sufficientIFN-γ to augment the activation of macrophages. In contrast to Ag-specific reactivation, TLR-dependentproduction of IFN-γ by CD8(+) T cells relies exclusively on newly synthesized transcripts without inducingmRNA stability. Furthermore, transcription of IFN-γ upon TLR triggering depends on the activation ofPI3K and serine-threonine kinase Akt, and protein synthesis relies on the activation of the mechanistictarget of rapamycin. We next investigated which energy source drives the TLR-induced production ofIFN-γ. Although Ag-specific cytokine production requires a glycolytic switch for optimal cytokine release,glucose availability does not alter the rate of IFN-γ production upon TLR-mediated activation. Rather,mitochondrial respiration provides sufficient energy for TLR-induced IFN-γ production. To our knowledge,this is the first report describing that TLR-mediated bystander activation elicits a helper phenotype ofCD8(+) T cells. It induces a short boost of IFN-γ production that leads to a significant but limitedactivation of Ag-experienced CD8(+) T cells. This activation suffices to prime macrophages but keeps Tcell responses limited to unrelated infections.", "metadata": {}}
+{"_id": "29022271", "title": "", "text": "Recommendations for the presurgical psychosocial evaluation of bariatric surgery patients.Psychosocialfactors have significant potential to affect long-term outcomes of bariatric surgery, including emotionaladjustment, adherence to the recommended postoperative lifestyle regimen, weight loss outcomes, andco-morbidity improvement and or resolution. Thus, it is recommended that bariatric behavioral healthclinicians with specialized knowledge and experience be involved in the evaluation and care of patientsboth before and after surgery. The evaluating clinician plays a number of important roles in themultidisciplinary treatment of the bariatric patient. Central among these is the role of identifying factorsthat may pose challenges to optimal surgical outcome and providing recommendations to the patient andbariatric team on how to address these issues. This document outlines recommendations for thepsychosocial evaluation of bariatric surgery patients, appropriate qualifications of those conducting theseevaluations, communication of evaluation results and suggested treatment plan, and the extension ofbehavioral healthcare of the bariatric patient to the entire span of the surgical and postsurgical process.", "metadata": {}}
+{"_id": "29023309", "title": "", "text": "Simian immunodeficiency virus–induced mucosal interleukin-17 deficiency promotes Salmonelladissemination from the gutSalmonella typhimurium causes a localized enteric infection inimmunocompetent individuals, whereas HIV-infected individuals develop a life-threatening bacteremia.Here we show that simian immunodeficiency virus (SIV) infection results in depletion of T helper type 17(TH17) cells in the ileal mucosa of rhesus macaques, thereby impairing mucosal barrier functions to S.typhimurium dissemination. In SIV-negative macaques, the gene expression profile induced by S.typhimurium in ligated ileal loops was dominated by TH17 responses, including the expression ofinterleukin-17 (IL-17) and IL-22. TH17 cells were markedly depleted in SIV-infected rhesus macaques,resulting in blunted TH17 responses to S. typhimurium infection and increased bacterial dissemination.IL-17 receptor–deficient mice showed increased systemic dissemination of S. typhimurium from the gut,suggesting that IL-17 deficiency causes defects in mucosal barrier function. We conclude that SIVinfection impairs the IL-17 axis, an arm of the mucosal immune response preventing systemic microbialdissemination from the gastrointestinal tract.", "metadata": {}}
+{"_id": "29025270", "title": "", "text": "An adoption study of human obesity.We examined the contributions of genetic factors and the familyenvironment to human fatness in a sample of 540 adult Danish adoptees who were selected from apopulation of 3580 and divided into four weight classes: thin, median weight, overweight, and obese.There was a strong relation between the weight class of the adoptees and the body-mass index of theirbiologic parents - for the mothers, P less than 0.0001; for the fathers, P less than 0.02. There was norelation between the weight class of the adoptees and the body-mass index of their adoptive parents.Cumulative distributions of the body-mass index of parents showed similar results; there was a strongrelation between the body-mass index of biologic parents and adoptee weight class and no relationbetween the index of adoptive parents and adoptee weight class. Furthermore, the relation betweenbiologic parents and adoptees was not confined to the obesity weight class, but was present across thewhole range of body fatness - from very thin to very fat. We conclude that genetic influences have animportant role in determining human fatness in adults, whereas the family environment alone has noapparent effect.", "metadata": {}}
+{"_id": "29073751", "title": "", "text": "Redox-dependent downregulation of Rho by RacRac and Rho GTPases function as critical regulators ofactin cytoskeleton remodelling during cell spreading and migration. Here we demonstrate thatRac-mediated reactive oxygen species (ROS) production results in the downregulation of Rho activity.The redox-dependent decrease in Rho activity is required for Rac-induced formation of membrane rufflesand integrin-mediated cell spreading. The pathway linking generation of ROS to downregulation of Rhoinvolves inhibition of the low-molecular-weight protein tyrosine phosphatase (LMW-PTP) and then anincrease in the tyrosine phosphorylation and activation of its target, p190Rho-GAP. Our findings define anovel mechanism for the coupling of changes in cellular redox state to the control of actin cytoskeletonrearrangements by Rho GTPases.", "metadata": {}}
+{"_id": "29090823", "title": "", "text": "The epidemiology of trachoma in Eastern Equatoria and Upper Nile States, southern Sudan.OBJECTIVELimited surveys and anecdotal data indicate that trachoma is endemic in the states of Eastern Equatoriaand Upper Nile in southern Sudan. However, its magnitude and geographical distribution are largelyunknown. We conducted surveys to ascertain the prevalence and geographical distribution of trachoma,and to identify targets for control interventions. METHODS Population-based cross-sectional surveys wereconducted in nine sites in southern Sudan between September 2001 and June 2004. Two-stage randomcluster sampling with probability proportional to size was used to select the sample. Trachoma gradingwas done using the WHO simplified grading system. FINDINGS A total of 17 016 persons were examined,a response rate of 86.1% of the enumerated population. Prevalence of signs of active trachoma inchildren aged 1-9 years was: TF=53.7% (95% confidence interval (CI)=52.1-55.3); TI=42.7% (95%CI=41.2-44.2); TF and/or TI=64.1% (95% CI=62.5-65.5). Prevalence of trichiasis (TT) in children agedless than 15 years was 1.2% (95% CI=0.9-1.4), while TT prevalence in persons aged 15 years and abovewas 9.2% (95% CI=8.6-9.9). Women were more likely to have trichiasis compared to men (odds ratio(OR)=1.57; 95% CI=1.34-1.84). Tentative extrapolation to the states of Eastern Equatoria and UpperNile estimates that there is a backlog of 178,250 (lower and upper bounds=156,027-205,995) personsrequiring surgery and the entire population, estimated to be over 3.9 million, is in need of the SAFEstrategy to control blinding trachoma. CONCLUSION Trachoma is a public health problem in all nine of thestudy sites surveyed. The unusually high prevalence of active trachoma and TT in children points to theseverity of the problem. There is urgent need to implement trachoma control interventions in trachomaendemic regions of southern Sudan.", "metadata": {}}
+{"_id": "29098525", "title": "", "text": "A single residue determines the cooperative binding property of a primosomal DNA replication protein,PriB, to single-stranded DNA.PriB is a primosomal protein required for re-initiation of replication inbacteria. We characterized and compared the DNA-binding properties of PriB from Salmonella entericaserovar Typhimurium LT2 (StPriB) and Escherichia coli (EcPriB). Only one residue of EcPriB, V6, wasdifferent in StPriB (replaced by A6). Previous structural information revealed that this residue is locatedon the putative dimer-dimer interface of PriB and is not involved in single-stranded DNA (ssDNA) binding.The cooperative binding mechanism of StPriB to DNA is, however, very different from that of EcPriB.Unlike EcPriB, which forms a single complex with ssDNAs of various lengths, StPriB forms two or moredistinct complexes. Based on these results, as well as information on structure, binding modes forforming a stable complex of PriB with ssDNA of 25 nucleotides (nt), (EcPriB)25, and (StPriB)25 areproposed.", "metadata": {}}
+{"_id": "29107180", "title": "", "text": "Genomic organization and chromosomal location of the human dsRNA adenosine deaminase gene: theenzyme for glutamate-activated ion channel RNA editing.The structure of the human gene encoding thedouble-stranded RNA (dsRNA) adenosine deaminase (DRADA) was characterized. This nuclear localizedenzyme is involved in the RNA editing required for the expression of certain subtypes of glutamate-gatedion channel subunits. The DRADA gene span 30 kb pairs and harbors 15 exons. The transcription of theDRADA gene driven by the putative promoter region, which contains no typical TATA or CCAAT box-likesequences, is initiated at multiple sites, 164 to 216 nucleotides upstream of the translation initiationcodon. The three dsRNA binding motifs (DRBM), 70 amino acid residues long, are each encoded by twoexons plus an intervening sequence that interrupts the motif at the identical amino acid position. Thisfinding is consistent with the notion that the dsRNA binding domains may be composed of two separatefunctional subdomains. Fluorescent in situ hybridization localized the DRADA gene on the long armchromosome 1, region q21. The gene structure and sequence information reported in this study willfacilitate the investigation of involvement of DRADA in hereditary diseases that may be the result ofmalfunction of glutamate-gated ion channels.", "metadata": {}}
+{"_id": "29107210", "title": "", "text": "\"We charge them; otherwise we cannot run the hospital\" front line workers, clients and health financingpolicy implementation gaps in Ghana.OBJECTIVES This paper examines policy implementation gaps ofuser fees plus exemptions and health insurance in providing financial access to primary clinical care forchildren under five in Ghana. METHODS Methods included analysis of routine data, focus groupdiscussions, in-depth interviews, and administration of a structured questionnaire. RESULTS Providersmodified exemptions policy implementation arrangements, sometimes giving partial or no exemptions.Clients who knew or suspected exemption entitlements failed to request them because of fear of negativereactions from providers. Providers attributed their modification of implementation arrangements andnegative reactions to the threat posed to the financial viability of their institutions by reimbursementuncertainty and delays. At the time of the study insurance coverage was low and frontline workers werenot noticeably modifying implementation arrangements. However, the underlying goal conflicts, resourcescarcity, conditions of work and relationships between frontline workers and clients that fueled theexemptions policy implementation gaps were unchanged. The potential for the health insurance policy tostumble over implementation gaps as happened with the exemptions policy therefore remained.CONCLUSIONS Policies that do not take into account the incentives for frontline worker adherence andalign them better with policy objectives may experience implementation gaps.", "metadata": {}}
+{"_id": "29124963", "title": "", "text": "EML4-ALK translocation predicts better outcome in lung adenocarcinoma patients with wild-typeEGFR.INTRODUCTION The echinoderm microtubule-associated protein like 4-anaplastic lymphoma kinase(EML4-ALK) fusion represents a novel target in a subset of non-small cell lung cancer, especiallyadenocarcinoma. EML4-ALK fusion is mutually exclusive with epidermal growth factor receptor (EGFR)mutations. To understand the impact of EML4-ALK on the prognosis of non-small cell lung cancer, weexamined EML4-ALK fusion in lung adenocarcinoma from patients with wild-type EGFR and analyzed theirclinical treatment outcomes. METHODS Lung adenocarcinoma patients with malignant pleural effusionshaving wild-type EGFR and measurable target lesions were enrolled for EML4-ALK analysis by reversetranscription-polymerase chain reaction and direct sequencing. Demographic data, EML4-ALK status, andsurvival data were analyzed. We also performed fluorescence in situ hybridization on some availabletumor samples to validate the PCR result. In addition, K-ras mutation was analyzed for patients withoutEML4-ALK fusion genes. RESULTS A total of 116 patients with wild-type EGFR sequencing results hadcomplete clinical data for analysis. No patients received ALK inhibitor therapy. There were 39 patients(34%) with the EML4-ALK fusion gene. The concordance rate between reverse transcription-polymerasechain reaction and fluorescence in situ hybridization was 85%. The K-ras mutation rate for patientswithout EML4-ALK fusion gene was 6.5%. By multivariate analysis, patients who had better performancestatus (p < 0.001) and EML4-ALK translocation (p = 0.017) had longer overall survival. Comparingpatients with tumors harboring variant 1 with those harboring nonvariant 1 EML4-ALK fusion genes, therewere no significant differences in clinical factors and survival outcome. CONCLUSION For lungadenocarcinoma patients with wild-type EGFR, EML4-ALK translocation is associated with longer overallsurvival.", "metadata": {}}
+{"_id": "29125354", "title": "", "text": "Transcriptional Repression of Gata3 Is Essential for Early B Cell CommitmentThe mechanisms underlyingthe silencing of alternative fate potentials in very early B cell precursors remain unclear. Using gain- andloss-of-function approaches together with a synthetic Zinc-finger polypeptide (6ZFP) engineered toprevent transcription factor binding to a defined cis element, we show that the transcription factor EBF1promotes B cell lineage commitment by directly repressing expression of the T-cell-lineage-requisiteGata3 gene. Ebf1-deficient lymphoid progenitors exhibited increased T cell lineage potential and elevatedGata3 transcript expression, whereas enforced EBF1 expression inhibited T cell differentiation and causedrapid loss of Gata3 mRNA. Notably, 6ZFP-mediated perturbation of EBF1 binding to a Gata3 regulatoryregion restored Gata3 expression, abrogated EBF1-driven suppression of T cell differentiation, andprevented B cell differentiation via a GATA3-dependent mechanism. Furthermore, EBF1 binding to Gata3regulatory sites induced repressive histone modifications across this region. These data identify atranscriptional circuit critical for B cell lineage commitment.", "metadata": {}}
+{"_id": "29134911", "title": "", "text": "Isolation and partial characterization of an unusual human immunodeficiency retrovirus from two personsof west-central African origin.An unusual human retrovirus was isolated from two patients with persistentgeneralized lymphadenopathy who originate from West-Central Africa and are currently residing inBelgium. Although the virus shared a number of the same biological and morphological properties ashuman immunodeficiency retrovirus type 1 (HIV-1) and HIV-2, significant antigenic differences could bedemonstrated. Several of the viral proteins also differed in molecular weight from the correspondingHIV-1 and HIV-2 proteins. Partial chemical cleavage of the most highly conserved viral proteins resultedin patterns which differed from those of HIV-1 and HIV-2. Furthermore, nucleic acid hybridizationexperiments were capable of discriminating between the virus types. Sequence analysis of the viral U3region revealed a unique enhancer organization not found in other immunodeficiency viruses. The dataindicated that the new isolate is more closely related to HIV-1 than to HIV-2 but clearly differs in anumber of important respects.", "metadata": {}}
+{"_id": "29148743", "title": "", "text": "Role of circulating nitrite and S-nitrosohemoglobin in the regulation of regional blood flow in humans.Todetermine the relative contributions of endothelial-derived nitric oxide (NO) vs. intravascular nitrogenoxide species in the regulation of human blood flow, we simultaneously measured forearm blood flow andarterial and venous levels of plasma nitrite, LMW-SNOs and HMW-SNOs, and red cell S-nitrosohemoglobin(SNO-Hb). Measurements were made at rest and during regional inhibition of NO synthesis, followed byforearm exercise. Surprisingly, we found significant circulating arterial-venous plasma nitrite gradients,providing a novel delivery source for intravascular NO. Further supporting the notion that circulatingnitrite is bioactive, the consumption of nitrite increased significantly with exercise during the inhibition ofregional endothelial synthesis of NO. The role of circulating S-nitrosothiols and SNO-Hb in the regulationof basal vascular tone is less certain. We found that low-molecular-weight S-nitrosothiols wereundetectable and S-nitroso-albumin levels were two logs lower than previously reported. In fact,S-nitroso-albumin primarily formed in the venous circulation, even during NO synthase inhibition.Whereas SNO-Hb was measurable in the human circulation (brachial artery levels of 170 nM in wholeblood), arterial-venous gradients were not significant, and delivery of NO from SNO-Hb was minimal. Inconclusion, we present data that suggest (i) circulating nitrite is bioactive and provides a deliverygradient of intravascular NO, (ii) S-nitroso-albumin does not deliver NO from the lungs to the tissue butforms in the peripheral circulation, and (iii) SNO-Hb and S-nitrosothiols play a minimal role in theregulation of basal vascular tone, even during exercise stress.", "metadata": {}}
+{"_id": "29183629", "title": "", "text": "Extra centrosomes and/or chromosomes prolong mitosis in human cellsUsing laser microsurgery and cellfusion we have explored how additional centrosomes and/or chromosomes influence the duration ofmitosis in human cells. We found that doubling the chromosome number added approximately 10 min toa 20 min division, whereas doubling the number of centrosomes added approximately 30 min more. Extracentrosomes and/or chromosomes prolong mitosis by delaying satisfaction of the spindle assemblycheckpoint. Thus mitosis can be prolonged by non-genetic means and extra chromosomes andcentrosomes probably contribute to the elevated mitotic index seen in many tumours.", "metadata": {}}
+{"_id": "29185044", "title": "", "text": "Familial recurrence-pattern analysis of nonsyndromic isolated cleft palate--a Danish Registry study.Thefinding of an association between genetic variation at the transforming growth-factor alpha (TGFA) locusand nonsyndromic isolated cleft palate (CP) represents a potentially important breakthrough in ourunderstanding of this condition. The present study was undertaken to assess the feasibility of detectinglinkage to putative CP-susceptibility loci, such as TGFA. To this end, the familial recurrence pattern for CPwas evaluated to determine the most likely mode of inheritance for this condition. The study tookadvantage of the high ascertainment and uniform registration of CP in Denmark. In addition, the studyutilized estimates of familial recurrence that were obtained by register linkage and, hence, were notsubject to either recall bias or the potentially biasing influence of nonresponders. The recurrence risks forfirst-, second-, and third-degree relatives of 1,364 nonsyndromic CP probands were estimated to be2.74% (72/2,628), 0.28% (3/1,068), and 0.00% (0/360), respectively. These estimates are close topublished estimates based on questionnaire and interview data. The population prevalence fornonsyndromic CP was, however, found to be considerable higher than usually reported (0.058%[1,456/2,523,023]). Analyses of these and previously published data, using the method presented byRisch, indicated that major-locus or additive multilocus inheritance of CP is unlikely. The familialrecurrence pattern was, however, consistent with CP being determined by several interacting loci. Undersuch a model, a single locus accounting for more than a sixfold increase in the risk to first-degreerelatives of CP probands is unlikely, whereas a single locus accounting for a threefold increase provided agood fit to the data. Such a locus could be detected in a realistic sample of affected sib pairs.", "metadata": {}}
+{"_id": "29190724", "title": "", "text": "Gene methylation in gastric cancer.Gastric cancer is one of the most common malignancies and remainsthe second leading cause of cancer-related death worldwide. Over 70% of new cases and deaths occur indeveloping countries. In the early years of the molecular biology revolution, cancer research mainlyfocuses on genetic alterations, including gastric cancer. Epigenetic mechanisms are essential for normaldevelopment and maintenance of tissue-specific gene expression patterns in mammals. Disruption ofepigenetic processes can lead to altered gene function and malignant cellular transformation. Recentadvancements in the rapidly evolving field of cancer epigenetics have shown extensive reprogramming ofevery component of the epigenetic machinery in cancer, including DNA methylation, histonemodifications, nucleosome positioning, noncoding RNAs, and microRNAs. Aberrant DNA methylation inthe promoter regions of gene, which leads to inactivation of tumor suppressor and other cancer-relatedgenes in cancer cells, is the most well-defined epigenetic hallmark in gastric cancer. The advantages ofgene methylation as a target for detection and diagnosis of cancer in biopsy specimens and non-invasivebody fluids such as serum and gastric washes have led to many studies of application in gastric cancer.This review focuses on the most common and important phenomenon of epigenetics, DNA methylation, ingastric cancer and illustrates the impact epigenetics has had on this field.", "metadata": {}}
+{"_id": "29214508", "title": "", "text": "Klebsiella aerogenes urease gene cluster: sequence of ureD and demonstration that four accessory genes(ureD, ureE, ureF, and ureG) are involved in nickel metallocenter biosynthesis.The region locatedimmediately upstream from the Klebsiella aerogenes urease structural genes was sequenced and shownto possess an open reading frame capable of encoding a 29.8-kDa peptide. Deletions were generated inthis gene, denoted ureD, and in each of the genes (ureE, ureF, and ureG) located immediatelydownstream of the three structural genes. Transformation of the mutated plasmids into Escherichia coliresulted in high levels of urease expression, but the enzyme was inactive (deletions in ureD, ureF, orureG) or only partially active (deletions in ureE). Ureases were purified from the recombinant cells andshown to be identical to control enzyme when analyzed by gel filtration chromatography and sodiumdodecyl sulfate-polyacrylamide gel electrophoresis; however, in every case the activity levels correlatedto nickel contents as analyzed by atomic absorption analysis. UreD, UreE, UreF, and UreG peptides weretentatively identified by gel electrophoretic comparison of mutant and control cell extracts, by in vivoexpression of separately cloned genes, or by in vitro transcription-translation analyses; the assignmentswere confirmed for UreE and UreG by amino-terminal sequencing. The latter peptides (apparent M(r)s,23,900 and 28,500) were present at high levels comparable to those of the urease subunits, whereas theamounts of UreF (apparent M(r), 27,000) and UreD (apparent M(r), 29,300) were greatly reduced,perhaps because of the lack of good ribosome binding sites in the regions upstream of these open readingframes. These results demonstrate that all four accessory genes are necessary for the functionalincorporation of the urease metallocenter.", "metadata": {}}
+{"_id": "29224825", "title": "", "text": "Hepatic polyploidy and liver growth control.The onset of cellular polyploidy is recognized in alldifferentiated mammalian tissues. Polyploidy has been noted frequently in the normal liver, as well as inpathophysiological states of the liver. As insights into the significance of polyploidy accumulate gradually,it is becoming clear that cells belonging to high ploidy classes exhibit advancement toward terminaldifferentiation and cellular senescence with greater probabilities of apoptosis. Involvement of specificgenetic abnormalities, such as impaired DNA repair, may lead to hepatocellular polyploidy. Workingmodels indicate that extensive polyploidy could lead to organ failure, as well as to oncogenesis withactivation of precancerous cell clones.", "metadata": {}}
+{"_id": "29231620", "title": "", "text": "Disturbances in the positioning, proliferation and apoptosis of neural progenitors contribute to subcorticalband heterotopia formation.Cortical malformations are commonly associated with intractable epilepsy andother developmental disorders. Our studies utilize the tish rat, a spontaneously occurring genetic modelof subcortical band heterotopia (SBH) associated with epilepsy, to evaluate the developmental eventsunderlying SBH formation in the neocortex. Our results demonstrate that Pax6(+) and Tbr2(+)progenitors are mislocalized in tish(+/-) and tish(-/-)- neocortex throughout neurogenesis. In addition,mislocalized tish(-/-) progenitors possess a longer cell cycle than wild type or normally-positionedtish(-/-) progenitors, owing to a lengthened G(2)+M+G(1) time. This mislocalization is not associatedwith adherens junction breakdown or loss of radial glial polarity in the ventricular zone (VZ), as assessedby immunohistochemistry against phalloidin (to identify F-actin), aPKC-λ and Par3. However, vimentinimmunohistochemistry indicates that the radial glial scaffold is disrupted in the region of the tish(-/-)heterotopia. Moreover, lineage tracing experiments using in utero electroporation in tish(-/-) neocortexdemonstrate that mislocalized progenitors do not retain contact with the ventricular surface and thatventricular/subventricular zone (SVZ) progenitors produce neurons that migrate into both the heterotopiaand cortical plate (CP). Taken together, these findings define a series of developmental errorscontributing to SBH formation that differs fundamentally from a primary error in neuronal migration.", "metadata": {}}
+{"_id": "29253460", "title": "", "text": "Sex-related differences in the presentation, treatment and outcomes among patients with acute coronarysyndromes: the Global Registry of Acute Coronary Events.OBJECTIVE To assess whether sex differencesexist in the angiographic severity, management and outcomes of acute coronary syndromes (ACS).METHODS The study comprised 7638 women and 19 117 men with ACS who underwent coronaryangiography and were included in GRACE (Global Registry of Acute Coronary Events) from 1999-2006.Normal vessels/mild disease was defined as <50% stenosis in all epicardial vessels; advanced diseasewas defined as >or=one vessel with >or=50% stenosis. RESULTS Women were older than men and hadhigher rates of cardiovascular risk factors. Men and women presented equally with chest pain; however,jaw pain and nausea were more frequent among women. Women were more likely to have normal/milddisease (12% vs 6%, p<0.001) and less likely to have left-main and three-vessel disease (27% vs 32%,p<0.001) or undergo percutaneous coronary intervention (65% vs 68%, p<0.001). Women and menwith normal and mild disease were treated less aggressively than those with advanced disease. Womenwith advanced disease had a higher risk of death (4% vs 3%, p<0.01). After adjustment for age andextent of disease, women were more likely to have adverse outcomes (death, myocardial infarction,stroke and rehospitalisation) at six months compared to men (odds ratio 1.24, 95% confidence interval1.14 to 1.34); however, sex differences in mortality were no longer statistically significant.CONCLUSIONS Women with ACS were more likely to have cardiovascular disease risk factors and atypicalsymptoms such as nausea compared with men, but were more likely to have normal/mild angiographiccoronary artery disease. Further study regarding sex differences related to disease severity is warranted.", "metadata": {}}
+{"_id": "29288582", "title": "", "text": "GITR, a member of the TNF receptor superfamily, is costimulatory to mouse T lymphocytesubpopulations.GITR (glucocorticoid-induced TNFR family related gene) is a member of the TNFRsuperfamily (TNFRSF) that is expressed in different cell types, including T lymphocytes. Because of a highhomology in its cytoplasmic region with other known costimulatory members of the TNFRSF, weinvestigated whether GITR played a costimulatory role in T lymphocyte subpopulations. Our results showthat the proliferation response of CD8+ and CD4+ peripheral T cell subpopulations was potentiated whena GITR costimulus was added to an anti-CD3 stimulus. Furthermore, expression of the mainactivation-induced receptor (IL-2Ralpha) and production of IL-2 and IFN-gamma were increased morewith a GITR costimulus than with anti-CD3 alone. GITR stimulation also enhanced anti-CD3-induced ERKphosphorylation, suggesting that GITR is involved in MAPK-pathway activation. Interestingly,CD4+CD25+ regulatory T cell (Treg cell) proliferation was triggered by the GITR costimulus; Treg cellproliferation was paralleled by the loss of the anergic phenotype and suppressor activity. Nevertheless,unstimulated GITR(-/-) CD4+CD25+ and GITR(+/+) CD4+CD25+ cells were equally able to exertsuppressor activity on CD4+CD25- responder cells. These results indicate a novel function for GITR ascostimulatory molecule of T cell subsets.", "metadata": {}}
+{"_id": "29321530", "title": "", "text": "PI3K and cancer: lessons, challenges and opportunitiesThe central role of phosphoinositide 3-kinase(PI3K) activation in tumour cell biology has prompted a sizeable effort to target PI3K and/or downstreamkinases such as AKT and mammalian target of rapamycin (mTOR) in cancer. However, emerging clinicaldata show limited single-agent activity of inhibitors targeting PI3K, AKT or mTOR at tolerated doses. Oneexception is the response to PI3Kδ inhibitors in chronic lymphocytic leukaemia, where a combination ofcell-intrinsic and -extrinsic activities drive efficacy. Here, we review key challenges and opportunities forthe clinical development of inhibitors targeting the PI3K–AKT–mTOR pathway. Through a greater focus onpatient selection, increased understanding of immune modulation and strategic application of rationalcombinations, it should be possible to realize the potential of this promising class of targeted anticanceragents.", "metadata": {}}
+{"_id": "29334259", "title": "", "text": "Sequence-based species delimitation for the DNA taxonomy of undescribed insects.Cataloging the verylarge number of undescribed species of insects could be greatly accelerated by automated DNA basedapproaches, but procedures for large-scale species discovery from sequence data are currently lacking.Here, we use mitochondrial DNA variation to delimit species in a poorly known beetle radiation in thegenus Rivacindela from arid Australia. Among 468 individuals sampled from 65 sites and multiplemorphologically distinguishable types, sequence variation in three mtDNA genes (cytochrome oxidasesubunit 1, cytochrome b, 16S ribosomal RNA) was strongly partitioned between 46 or 47 putative speciesidentified with quantitative methods of species recognition based on fixed unique (\"diagnostic\")characters. The boundaries between groups were also recognizable from a striking increase in branchingrate in clock-constrained calibrated trees. Models of stochastic lineage growth (Yule models) werecombined with coalescence theory to develop a new likelihood method that determines the point oftransition from species-level (speciation and extinction) to population-level (coalescence) evolutionaryprocesses. Fitting the location of the switches from speciation to coalescent nodes on the ultrametric treeof Rivacindela produced a transition in branching rate occurring at 0.43 Mya, leading to an estimate of 48putative species (confidence interval for the threshold ranging from 47 to 51 clusters within 2 logL units).Entities delimited in this way exhibited biological properties of traditionally defined species, showingcoherence of geographic ranges, broad congruence with morphologically recognized species, and levels ofsequence divergence typical for closely related species of insects. The finding of discontinuousevolutionary groupings that are readily apparent in patterns of sequence variation permits largelyautomated species delineation from DNA surveys of local communities as a scaffold for taxonomy in thispoorly known insect group.", "metadata": {}}
+{"_id": "29347970", "title": "", "text": "CCR6 regulates the migration of inflammatory and regulatory T cells.Th17 and regulatory T (Treg) cellsplay opposite roles in autoimmune diseases. However, the mechanisms underlying their proper migrationto inflammatory tissues are unclear. In this study, we report that these two T cell subsets both expressCCR6. CCR6 expression in Th17 cells is regulated by TGF-beta and requires two nuclear receptors,RORalpha and RORgamma. Th17 cells also express the CCR6 ligand CCL20, which is inducedsynergistically by TGF-beta and IL-6, which requires STAT3, RORgamma and IL-21. Th17 cells, byproducing CCL20, promote migration of Th17 and Treg cells in vitro in a CCR6-dependent manner. Lackof CCR6 in Th17 cells reduces the severity of experimental autoimmune encephalomyelitis and Th17 andTreg recruitment into inflammatory tissues. Similarly, CCR6 on Treg cells is also important for theirrecruitment into inflammatory tissues. Our data indicate an important role of CCR6 in Treg and Th17 cellmigration.", "metadata": {}}
+{"_id": "29362104", "title": "", "text": "Inhibition of receptor-mediated calcium influx in T cells by unsaturated non-esterified fatty acids.Theeffect of omega-3, omega-6 and omega-9 unsaturated fatty acids (UFAs) on receptor-mediated Ca2+entry was investigated in a T-cell line (JURKAT) by using anti-CD3 antibodies (OKT3) to induceintracellular Ca2+ [( Ca2+]i) increase and Ca2+ influx. All the UFAs, as well as Ni2+ ions and12-O-tetradecanoylphorbol 13-acetate, decreased the OKT3-induced sustained [Ca2+]i increase to basallevels. Although non-esterified fatty acids activate protein kinase C (PKC) [McPhail, Clayton & Snyderman(1984) Science 224, 622-624; Murakami, Chan & Routtenberg (1986) J. Biol. Chem. 261, 15424-15429],studies using H-7 and analysis of the PKC-dependent phosphorylation of 19 and 80 kDa markersubstrates ruled out the involvement of PKC in UFA-induced inhibition of Ca2+ entry. Flow-cytometryanalysis showed that UFAs do not interfere with antibody-receptor binding. BSA (0.2%, w/v) reversed theeffect of UFAs after these fatty acids have decreased the OKT3-induced [Ca2+]i increase to basal levels.The relevance of these findings and possible mechanisms for inhibition by UFAs of receptor-mediatedCa2+ influx were discussed.", "metadata": {}}
+{"_id": "29366489", "title": "", "text": "Deleted in liver cancer-1 (DLC-1): a tumor suppressor not just for liver.Deleted in liver cancer 1 (DLC-1),as its name implied, was originally isolated as a potential tumor suppressor gene often deleted inhepatocellular carcinoma. Further studies have indicated that down-expression of DLC-1 either bygenomic deletion or DNA methylation is associated with a variety of cancer types including lung, breast,prostate, kidney, colon, uterus, ovary, and stomach. Re-expression of DLC-1 in cancer cells regulates thestructure of actin cytoskeleton and focal adhesions and significantly inhibits cell growth, supporting itsrole as a tumor suppressor. This tumor suppressive function relies on DLC-1's RhoGTPase activatingprotein (RhoGAP) activity and steroidogenic acute regulatory (StAR)-related lipid transfer (START)domain, as well as its focal adhesion localization, which is recruited by the Src Homology 2 (SH2)domains of tensins in a phosphotyrosine-independent fashion. Therefore, the expression and subcellularlocalization of DLC-1 could be a useful molecular marker for cancer prognosis, whereas DLC-1 and itsdownstream signaling molecules might be therapeutic targets for the treatment of cancer.", "metadata": {}}
+{"_id": "29367554", "title": "", "text": "Interaction of Helicobacter pylori with gastric epithelial cells is mediated by the p53 proteinfamily.BACKGROUND & AIMS Although the p53 tumor suppressor has been extensively studied, manycritical questions remain unanswered about the biological functions of p53 homologs, p73 and p63.Accumulating evidence suggests that both p73 and p63 play important roles in regulation of apoptosis,cell differentiation, and therapeutic drug sensitivity. METHODS Gastric epithelial cells were coculturedwith Helicobacter pylori, and the roles of p63 and p73 proteins were assessed by luciferase reporter,real-time polymerase chain reaction, immunoblotting, and cell survival assays. Short hairpin RNA anddominant-negative mutants were used to inhibit activity of p73 and p63 isoforms. Human and murinegastric tissues were analyzed by immunohistochemistry with p73 and p63 antibodies and modifiedSteiner's silver method. RESULTS Interaction of H pylori with gastric epithelial cells leads to robustup-regulation of p73 protein in vitro and in vivo in human gastritis specimens and H pylori-infected mice.The p73 increase resulted in up-regulation of pro-apoptotic genes, NOXA, PUMA, and FAS receptor ingastric epithelial cells. Down-regulation of p73 activity suppressed cell death and Fas receptor induced byH pylori. Bacterial virulence factors within the cag pathogenicity island, c-Abl tyrosine kinase, andinteraction with p63 isoforms control the activity of p73. CONCLUSION Our findings implicate p73 in Hpylori-induced apoptosis and more generally suggest that the p53 family may play a role in the epithelialcell response to H pylori infection.", "metadata": {}}
+{"_id": "29381091", "title": "", "text": "Brown and white adipose tissues: intrinsic differences in gene expression and response to cold exposurein miceBrown adipocytes dissipate energy, whereas white adipocytes are an energy storage site. Weexplored the plasticity of different white adipose tissue depots in acquiring a brown phenotype by coldexposure. By comparing cold-induced genes in white fat to those enriched in brown compared with whitefat, at thermoneutrality we defined a \"brite\" transcription signature. We identified the genes, pathways,and promoter regulatory motifs associated with \"browning,\" as these represent novel targets forunderstanding this process. For example, neuregulin 4 was more highly expressed in brown adiposetissue and upregulated in white fat upon cold exposure, and cell studies showed that it is a neuriteoutgrowth-promoting adipokine, indicative of a role in increasing adipose tissue innervation in responseto cold. A cell culture system that allows us to reproduce the differential properties of the discrete adiposedepots was developed to study depot-specific differences at an in vitro level. The key transcriptionalevents underpinning white adipose tissue to brown transition are important, as they represent anattractive proposition to overcome the detrimental effects associated with metabolic disorders, includingobesity and type 2 diabetes.", "metadata": {}}
+{"_id": "29387024", "title": "", "text": "Continuous glucose monitoring in pregnant women with type 1 diabetes (CONCEPTT): a multicentreinternational randomised controlled trialBACKGROUND Pregnant women with type 1 diabetes are ahigh-risk population who are recommended to strive for optimal glucose control, but neonatal outcomesattributed to maternal hyperglycaemia remain suboptimal. Our aim was to examine the effectiveness ofcontinuous glucose monitoring (CGM) on maternal glucose control and obstetric and neonatal healthoutcomes. METHODS In this multicentre, open-label, randomised controlled trial, we recruited womenaged 18-40 years with type 1 diabetes for a minimum of 12 months who were receiving intensive insulintherapy. Participants were pregnant (≤13 weeks and 6 days' gestation) or planning pregnancy from 31hospitals in Canada, England, Scotland, Spain, Italy, Ireland, and the USA. We ran two trials in parallelfor pregnant participants and for participants planning pregnancy. In both trials, participants wererandomly assigned to either CGM in addition to capillary glucose monitoring or capillary glucosemonitoring alone. Randomisation was stratified by insulin delivery (pump or injections) and baselineglycated haemoglobin (HbA1c). The primary outcome was change in HbA1c from randomisation to 34weeks' gestation in pregnant women and to 24 weeks or conception in women planning pregnancy, andwas assessed in all randomised participants with baseline assessments. Secondary outcomes includedobstetric and neonatal health outcomes, assessed with all available data without imputation. This trial isregistered with ClinicalTrials.gov, number NCT01788527. FINDINGS Between March 25, 2013, and March22, 2016, we randomly assigned 325 women (215 pregnant, 110 planning pregnancy) to capillaryglucose monitoring with CGM (108 pregnant and 53 planning pregnancy) or without (107 pregnant and57 planning pregnancy). We found a small difference in HbA1c in pregnant women using CGM (meandifference -0·19%; 95% CI -0·34 to -0·03; p=0·0207). Pregnant CGM users spent more time in target(68% vs 61%; p=0·0034) and less time hyperglycaemic (27% vs 32%; p=0·0279) than did pregnantcontrol participants, with comparable severe hypoglycaemia episodes (18 CGM and 21 control) and timespent hypoglycaemic (3% vs 4%; p=0·10). Neonatal health outcomes were significantly improved, withlower incidence of large for gestational age (odds ratio 0·51, 95% CI 0·28 to 0·90; p=0·0210), fewerneonatal intensive care admissions lasting more than 24 h (0·48; 0·26 to 0·86; p=0·0157), fewerincidences of neonatal hypoglycaemia (0·45; 0·22 to 0·89; p=0·0250), and 1-day shorter length ofhospital stay (p=0·0091). We found no apparent benefit of CGM in women planning pregnancy. Adverseevents occurred in 51 (48%) of CGM participants and 43 (40%) of control participants in the pregnancytrial, and in 12 (27%) of CGM participants and 21 (37%) of control participants in the planning pregnancytrial. Serious adverse events occurred in 13 (6%) participants in the pregnancy trial (eight [7%] CGM,five [5%] control) and in three (3%) participants in the planning pregnancy trial (two [4%] CGM and one[2%] control). The most common adverse events were skin reactions occurring in 49 (48%) of 103 CGMparticipants and eight (8%) of 104 control participants during pregnancy and in 23 (44%) of 52 CGMparticipants and five (9%) of 57 control participants in the planning pregnancy trial. The most commonserious adverse events were gastrointestinal (nausea and vomiting in four participants during pregnancyand three participants planning pregnancy). INTERPRETATION Use of CGM during pregnancy in patientswith type 1 diabetes is associated with improved neonatal outcomes, which are likely to be attributed toreduced exposure to maternal hyperglycaemia. CGM should be offered to all pregnant women with type 1diabetes using intensive insulin therapy. This study is the first to indicate potential for improvements innon-glycaemic health outcomes from CGM use. FUNDING Juvenile Diabetes Research Foundation,Canadian Clinical Trials Network, and National Institute for Health Research.", "metadata": {}}
+{"_id": "29399239", "title": "", "text": "Neutrophil extracellular traps: Is immunity the second function of chromatin?Neutrophil extracellulartraps (NETs) are made of processed chromatin bound to granular and selected cytoplasmic proteins. NETsare released by white blood cells called neutrophils, maybe as a last resort, to control microbialinfections. This release of chromatin is the result of a unique form of cell death, dubbed \"NETosis. \" Herewe review our understanding of how NETs are made, their function in infections and as danger signals,and their emerging importance in autoimmunity and coagulation.", "metadata": {}}
+{"_id": "29422484", "title": "", "text": "Phosphorylation of p35 and p39 by Cdk5 determines the subcellular location of the holokinase in aphosphorylation-site-specific manner.Cdk5 is a member of the cyclin-dependent kinase (Cdk) family,which is activated by neuronal activators p35 or p39. Cdk5 regulates a variety of neuronal activitiesincluding migration, synaptic activity and neuronal death. p35 and p39 impart cytoplasmic membraneassociation of p35-Cdk5 and p39-Cdk5, respectively, through their myristoylation, but it is not clearlyunderstood how the cellular localization is related to different functions. We investigated the role of Cdk5activity in the subcellular localization of p35-Cdk5 and p39-Cdk5. Cdk5 activity affected the localization ofp35-Cdk5 and p39-Cdk5 through phosphorylation of p35 or p39. Using unphosphorylated orphosphomimetic mutants of p35 and p39, we found that phosphorylation at Ser8, common to p35 andp39, by Cdk5 regulated the cytoplasmic localization and perinuclear accumulation of unphosphorylatedS8A mutants, and whole cytoplasmic distribution of phosphomimetic S8E mutants. Cdk5 activity wasnecessary to retain Cdk5-activator complexes in the cytoplasm. Nevertheless, small but distinct amountsof p35 and p39 were detected in the nucleus. In particular, nuclear p35 and p39 were increased when theCdk5 activity was inhibited. p39 had a greater propensity to accumulate in the nucleus than p35, andphosphorylation at Thr84, specific to p39, regulated the potential nuclear localization activity of the Lyscluster in p39. These results suggest that the subcellular localization of the Cdk5-activator complexes isdetermined by its kinase activity, and also implicate a role for p39-Cdk5 in the nucleus.", "metadata": {}}
+{"_id": "29423324", "title": "", "text": "Interleukin-12 and -23 Control Plasticity of CD127(+) Group 1 and Group 3 Innate Lymphoid Cells in theIntestinal Lamina Propria.Human group 1 ILCs consist of at least three phenotypically distinct subsets,including NK cells, CD127(+) ILC1, and intraepithelial CD103(+) ILC1. In inflamed intestinal tissues fromCrohn's disease patients, numbers of CD127(+) ILC1 increased at the cost of ILC3. Here we found thatdifferentiation of ILC3 to CD127(+) ILC1 is reversible in vitro and in vivo. CD127(+) ILC1 differentiated toILC3 in the presence of interleukin-2 (IL-2), IL-23, and IL-1β dependent on the transcription factorRORγt, and this process was enhanced in the presence of retinoic acid. Furthermore, we observed inresection specimen from Crohn's disease patients a higher proportion of CD14(+) dendritic cells (DC),which in vitro promoted polarization from ILC3 to CD127(+) ILC1. In contrast, CD14(-) DCs promoteddifferentiation from CD127(+) ILC1 toward ILC3. These observations suggest that environmental cuesdetermine the composition, function, and phenotype of CD127(+) ILC1 and ILC3 in the gut.", "metadata": {}}
+{"_id": "29429111", "title": "", "text": "Transcriptional regulation of neuronal genes and its effect on neural functions: expression and function offorkhead transcription factors in neurons.Forkhead box transcription factor, class O (FOXO) is amammalian homologue of DAF-16, which is known to regulate the lifespan of Caenorhabditis elegans andincludes subfamilies of forkhead transcription factors such as AFX, FKHRL1, and FKHR. FKHR isphosphorylated on three sites (Thr-24, Ser-256, and Ser-319) in a phosphatidylinositol 3-kinase(PI3K)/Akt-dependent manner, thereby inhibiting death signals. We here documented dephosphorylationof FKHR following transient forebrain ischemia with its concomitant translocation into the nucleus inneurons in gerbil and mouse brains. The activation of FKHR preceded delayed neuronal death in thevulnerable hippocampal regions following ischemic brain injury. The FKHR activation was accompanied byan increase in DNA binding activity for FKHR-responsive element on the Fas ligand promoter. We alsodefined FKHR-induced downstream targets such as Fas ligand and Bim in brain ischemia. Therefore, wepropose a new strategy to rescue neurons from delayed neuronal death by promoting the survivalsignaling. Sodium orthovanadate, a protein tyrosine phosphatase inhibitor, up-regulated Akt activity inthe brain and in turn rescue neurons from delayed neuronal death by inhibiting FKHR-dependent or-independent death signals in neurons.", "metadata": {}}
+{"_id": "29459383", "title": "", "text": "ERAAP synergizes with MHC class I molecules to make the final cut in the antigenic peptide precursors inthe endoplasmic reticulum.The major histocompatibility complex class I molecules display peptides(pMHC I) on the cell surface for immune surveillance by CD8(+) T cells. These peptides are generated byproteolysis of intracellular polypeptides by the proteasome in the cytoplasm and then in the endoplasmicreticulum (ER) by the ER aminopeptidase associated with antigen processing (ERAAP). To define theunknown mechanism of ERAAP function in vivo, we analyzed naturally processed peptides in cells with orwithout appropriate MHC I and ERAAP. In the absence of MHC I, ERAAP degraded the antigenicprecursors in the ER. However, MHC I molecules could bind proteolytic intermediates and were essentialfor generation of the final peptide by ERAAP. Thus, ERAAP synergizes with MHC I to generate the finalpMHC I repertoire.", "metadata": {}}
+{"_id": "29460384", "title": "", "text": "Estimates of animal and plant protein intake in US adults: results from the Third National Health andNutrition Examination Survey, 1988-1991.OBJECTIVE To describe the sources of protein intake in asample of the US adult population and among subgroups defined by race-ethnicity, age, and gender.DESIGN The Third National Health and Nutrition Examination Survey, 1988-1991, is a stratified randomsample of the total civilian noninstitutionalized population, drawn from the 50 United States and theDistrict of Columbia. For all foods consumed by the participants, based on a 24-hour dietary recall,protein sources and the contribution of each protein type to the total protein intake were determined.SUBJECTS Adult participants in the third National Health and Nutrition Examination Survey (n = 7,924).STATISTICAL ANALYSES Weighted total, age-specific, and age-adjusted mean protein intakes werecalculated using SAS and WesVarPC. Statistical differences were determined by 2-tailed t tests. RESULTSThe main protein source in the American diet is animal protein (69%). Meat, fish, and poultry proteincombined contributed the most to animal protein (42%), followed by dairy protein (20%). Grains (18%)contributed the most to plant protein consumption. Women consumed a lower percentage of beef (14%)and pork (7%) protein than did men (18% and 9%, respectively). Women also consumed a higherpercentage of poultry (13%), dairy (22%), and fruit and vegetable (11%) protein than did men (11%,19%, and 9%, respectively). Blacks reported eating a higher percentage of poultry (18%) and pork(11%) protein and a lower percent of dairy protein (14%) than did whites (12%, 7%, and 22%,respectively) and Mexican-Americans (11%, 8%, and 17%, respectively). Mexican-Americans consumeda higher percentage of legume (7%) and egg (7%) protein than did whites (4% and 4%, respectively)and blacks (4% and 5%, respectively). Whites consumed a higher percentage of grain protein (19%)than did blacks (16%) and Mexican-Americans (15%). CONCLUSIONS These results show that, althoughthe percentage of total energy from protein may be similar among race-ethnicities and between men andwomen, their sources of protein are different. These differences should be taken into account whenproviding nutrition education for specific populations.", "metadata": {}}
+{"_id": "29467201", "title": "", "text": "CYP18A1, a key enzyme of Drosophila steroid hormone inactivation, is essential formetamorphosis.Ecdysteroids are steroid hormones, which coordinate major developmental transitions ininsects. Both the rises and falls in circulating levels of active hormones are important for coordinatingmolting and metamorphosis, making both ecdysteroid biosynthesis and inactivation of physiologicalrelevance. We demonstrate that Drosophila melanogaster Cyp18a1 encodes a cytochrome P450 enzyme(CYP) with 26-hydroxylase activity, a prominent step in ecdysteroid catabolism. A clear ortholog ofCyp18a1 exists in most insects and crustaceans. When Cyp18a1 is transfected in Drosophila S2 cells,extensive conversion of 20-hydroxyecdysone (20E) into 20-hydroxyecdysonoic acid is observed. This is amulti-step process, which involves the formation of 20,26-dihydroxyecdysone as an intermediate. InDrosophila larvae, Cyp18a1 is expressed in many target tissues of 20E. We examined the consequencesof Cyp18a1 inactivation on Drosophila development. Null alleles generated by excision of a P element andRNAi knockdown of Cyp18a1 both result in pupal lethality, possibly as a consequence of impairedecdysteroid degradation. Our data suggest that the inactivation of 20E is essential for properdevelopment and that CYP18A1 is a key enzyme in this process.", "metadata": {}}
+{"_id": "29473081", "title": "", "text": "The sialyltransferase ST3GAL6 influences homing and survival in multiple myeloma.Glycosylation is astepwise procedure of covalent attachment of oligosaccharide chains to proteins or lipids, and alterationsin this process, especially increased sialylation, have been associated with malignant transformation andmetastasis. The role of altered sialylation in multiple myeloma (MM) cell trafficking has not beenpreviously investigated. In the present study we identified high expression of β-galactosideα-2,3-sialyltransferase, ST3GAL6, in MM cell lines and patients. This gene plays a key role in selectinligand synthesis in humans through the generation of functional sialyl Lewis X. In MRC IX patients, highexpression of this gene is associated with inferior overall survival. In this study we demonstrate thatknockdown of ST3GAL6 results in a significant reduction in levels of α-2,3-linked sialic acid on the surfaceof MM cells with an associated significant reduction in adhesion to MM bone marrow stromal cells andfibronectin along with reduced transendothelial migration in vitro. In support of our in vitro findings, wedemonstrate significantly reduced homing and engraftment of ST3GAL6 knockdown MM cells to the bonemarrow niche in vivo, along with decreased tumor burden and prolonged survival. This study points tothe importance of altered glycosylation, particularly sialylation, in MM cell adhesion and migration.", "metadata": {}}
+{"_id": "29495185", "title": "", "text": "New developments in the epidemiology of cancer prognosis: traditional and molecular predictors oftreatment response and survival.There have been numerous epidemiologic investigations to determinefactors that may affect cancer risk. There is also a rich tradition of evaluating potential somatic changesin the cancer itself to predict recurrence and/or mortality after diagnosis. However, there has beenrelatively little", "metadata": {}}
+{"_id": "29504413", "title": "", "text": "Behavioral effects of estrogen receptor gene disruption in male mice.Gonadal steroid hormones regulatesexually dimorphic development of brain functions and behaviors. Their nuclear receptors offer theopportunity to relate molecular events in neurons to simple instinctive mammalian behaviors. We havedetermined the role of estrogen receptor (ER) activation by endogenous estrogen in the development ofmale-typical behaviors by the use of transgenic estrogen-receptor-deficient (ERKO) mice. Surprisingly, inspite of the fact that they are infertile, ERKO mice showed normal motivation to mount females but theyachieved less intromissions and virtually no ejaculations. Aggressive behaviors were dramatically reducedand male-typical offensive attacks were rarely displayed by ERKO males. Moreover, ER gene disruptiondemasculinized open-field behaviors. In the brain, despite the evident loss of functional ER protein, theandrogen-dependent system appears to be normally present in ERKO mice. Together, these findingsindicate that ER gene expression during development plays a major role in the organization ofmale-typical aggressive and emotional behaviors in addition to simple sexual behaviors.", "metadata": {}}
+{"_id": "29509926", "title": "", "text": "High-Density Lipoproteins Exert Pro-inflammatory Effects on Macrophages via Passive CholesterolDepletion and PKC-NF-κB/STAT1-IRF1 Signaling.Membrane cholesterol modulates a variety of cellsignaling pathways and functions. While cholesterol depletion by high-density lipoproteins (HDLs) haspotent anti-inflammatory effects in various cell types, its effects on inflammatory responses inmacrophages remain elusive. Here we show overt pro-inflammatory effects of HDL-mediated passivecholesterol depletion and lipid raft disruption in murine and human primary macrophages in vitro. Thesepro-inflammatory effects were confirmed in vivo in peritoneal macrophages from apoA-I transgenic mice,which have elevated HDL levels. In line with these findings, the innate immune responses required forclearance of P. aeruginosa bacterial infection in lung were compromised in mice with low HDL levels.Expression analysis, ChIP-PCR, and combinatorial pharmacological and genetic intervention studiesunveiled that both native and reconstituted HDL enhance Toll-like-receptor-induced signaling byactivating a PKC-NF-κB/STAT1-IRF1 axis, leading to increased inflammatory cytokine expression. HDL'spro-inflammatory activity supports proper functioning of macrophage immune responses.", "metadata": {}}
+{"_id": "29518440", "title": "", "text": "Hypoxia of the renal medulla--its implications for disease.In land mammals, a major task of the kidney isto reabsorb water to allow survival in a dry environment. Water conservation is enhanced by the renalmedulla, which concentrates the urine to a level up to four times the osmolality of plasma. To producethis unique gradient of osmolality, the medulla has a countercurrent system of vessels and tubules thatdictates active reabsorption of sodium in a milieu poor in oxygen (Figure 1).1 In this review, we describehow hypoxia of the medulla may relate to susceptibility to acute and chronic renal injury. The RenalMedullary Concentrating Mechanism as . . .", "metadata": {}}
+{"_id": "29526125", "title": "", "text": "Troponin concentrations for stratification of patients with acute coronary syndromes in relation totherapeutic efficacy of tirofiban. PRISM Study Investigators. Platelet Receptor Inhibition in IschemicSyndrome Management.BACKGROUND A major challenge for physicians is to identify patients with acutecoronary syndromes who may benefit from treatment with glycoprotein-IIb/IIIa-receptor antagonists. Weinvestigated whether troponin concentrations can be used to stratify patients for benefit from treatmentwith tirofiban. METHODS We enrolled 2222 patients of the Platelet Receptor Inhibition in IschemicSyndrome Management study with coronary artery disease and who had had chest pain in the previous24 h. All patients received aspirin and were randomly assigned treatment with tirofiban or heparin. Wetook baseline measurements of troponin I and troponin T. We recorded death, myocardial infarction, orrecurrent ischaemia after 48 h infusion treatment and at 7 days and 30 days. FINDINGS 629 (28.3%)patients had troponin I concentrations higher than the diagnostic threshold of 1.0 microg/L and 644(29.0%) troponin T concentrations higher than 0.1 microg/L. 30-day event rates (death, myocardialinfarction) were 13.0% for troponin-I-positive patients compared with 4.9% for troponin-I-negativepatients (p<0.0001), and 13.7% compared wth 3.5% for troponin T (p<0.001). At 30 days, introponin-I-positive patients, tirofiban had lowered the risk of death (adjusted hazard ratio 0.25 [95% CI0.09-0.68], p=0.004) and myocardial infarction (0.37 [0.16-0.84], p=0.01). This benefit was seen inmedically managed patients (0.30 [0.10-0.84], p=0.004) and those undergoing revascularisation (0.37[0.15-0.93] p=0.02) after 48 h infusion treatment. By contrast, no treatment effect was seen fortroponin-I-negative patients. Similar benefits were seen for troponin-T-positive patients.INTERPRETATION Troponin I and troponin T reliably identified high-risk patients with acute coronarysyndromes, managed medically and by revascularisation, who would benefit from tirofiban.", "metadata": {}}
+{"_id": "29557235", "title": "", "text": "Evolution and function of ubiquitin-like protein-conjugation systemsUbiquitin functions by covalentlymodifying other proteins. In the past few years, a surprising number of other proteins have beenidentified that, despite often being only slightly similar to ubiquitin, can also be attached to proteins.Newly discovered parallels between the activation of ubiquitin and the biosynthesis of certain enzymecofactors now hint at the possible evolutionary origins of the ubiquitin system.", "metadata": {}}
+{"_id": "29564505", "title": "", "text": "Inflammatory biomarkers and exacerbations in chronic obstructive pulmonary disease.IMPORTANCEExacerbations of respiratory symptoms in chronic obstructive pulmonary disease (COPD) have profoundand long-lasting adverse effects on patients. OBJECTIVE To test the hypothesis that elevated levels ofinflammatory biomarkers in individuals with stable COPD are associated with an increased risk of havingexacerbations. DESIGN, SETTING, AND PARTICIPANTS Prospective cohort study examining 61,650participants with spirometry measurements from the Copenhagen City Heart Study (2001-2003) and theCopenhagen General Population Study (2003-2008). Of these, 6574 had COPD, defined as a ratiobetween forced expiratory volume in 1 second (FEV1) and forced vital capacity below 0.7. MAINOUTCOMES AND MEASURES Baseline levels of C-reactive protein (CRP) and fibrinogen and leukocytecount were measured in participants at a time when they were not experiencing symptoms ofexacerbations. Exacerbations were recorded and defined as short-course treatment with oralcorticosteroids alone or in combination with an antibiotic or as a hospital admission due to COPD. Levelsof CRP and fibrinogen and leukocyte count were defined as high or low according to cut points of 3 mg/L,14 μmol/L, and 9 ×10(9)/L, respectively. RESULTS During follow-up, 3083 exacerbations were recorded(mean, 0.5/participant). In the first year of follow-up, multivariable-adjusted odds ratios for havingfrequent exacerbations were 1.2 (95% CI, 0.7-2.2; 17 events/1000 person-years) for individuals with 1high biomarker, 1.7 (95% CI, 0.9-3.2; 32 events/1000 person-years) for individuals with 2 highbiomarkers, and 3.7 (95% CI, 1.9-7.4; 81 events/1000 person-years) for individuals with 3 highbiomarkers compared with individuals who had no elevated biomarkers (9 events/1000 person-years;trend: P = 2 × 10(-5)). Corresponding hazard ratios using maximum follow-up time were 1.4 (95% CI,1.1-1.8), 1.6 (95% CI, 1.3-2.2), and 2.5 (95% CI, 1.8-3.4), respectively (trend: P = 1 × 10(-8)). Theaddition of inflammatory biomarkers to a basic model including age, sex, FEV1 percent predicted,smoking, use of any inhaled medication, body mass index, history of previous exacerbations, and timesince most recent prior exacerbation improved the C statistics from 0.71 to 0.73 (comparison: P = 9 ×10(-5)). Relative risks were consistent in those with milder COPD, in those with no history of frequentexacerbations, and in the 2 studies separately. The highest 5-year absolute risks of having frequentexacerbations in those with 3 high biomarkers (vs no high biomarkers) were 62% (vs 24%) for thosewith Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades C-D (n = 558), 98% (vs 64%)in those with a history of frequent exacerbations (n = 127), and 52% (vs 15%) for those with GOLDgrades 3-4 (n = 465). CONCLUSIONS AND RELEVANCE Simultaneously elevated levels of CRP andfibrinogen and leukocyte count in individuals with COPD were associated with increased risk of havingexacerbations, even in those with milder COPD and in those without previous exacerbations. Furtherinvestigation is needed to determine the clinical value of these biomarkers for risk stratification.", "metadata": {}}
+{"_id": "29634262", "title": "", "text": "Gene supplementation therapy for recessive forms of inherited retinal dystrophiesOver the last decade,gene supplementation therapy for inherited retinal degeneration has come of age. Early proof-of-conceptstudies in animal models of disease showed modest, but genuine improvements in retinal function and/orsurvival. Further development of the vectors used for gene transfer to the retina has led to bettertreatment efficacy in a wide variety of animal models, leading in 2008 to the initiation of three clinicaltrials for Leber congenital amaurosis caused by retinal pigment epithelium 65 deficiency. The results fromthese trials suggest that the treatment of inherited retinal dystrophy by gene therapy can be safe andeffective. Here, we examine the progress of gene supplementation therapy in the retina, and discuss thepotential for using gene therapy to treat different forms of inherited retinal degeneration.", "metadata": {}}
+{"_id": "29638116", "title": "", "text": "Complex Tissue and Disease Modeling using hiPSCs.Defined genetic models based on human pluripotentstem cells have opened new avenues for understanding disease mechanisms and drug screening. Many ofthese models assume cell-autonomous mechanisms of disease but it is possible that disease phenotypesor drug responses will only be evident if all cellular and extracellular components of a tissue are presentand functionally mature. To derive optimal benefit from such models, complex multicellular structureswith vascular components that mimic tissue niches will thus likely be necessary. Here we consideremerging research creating human tissue mimics and provide some recommendations for moving thefield forward.", "metadata": {}}
+{"_id": "29641682", "title": "", "text": "Reprogramming somatic cells towards pluripotency by cellular fusion.Pluripotent cells arise within theinner cell mass (ICM) of mammals and have the potential to generate all cell types of the adult organismthrough a process of commitment and ordered differentiation. Despite many decades of investigation, themechanisms that guide and stabilise cell fate choice as well as those that can be engineered to promoteits reversal, remain only partially resolved. Reprogramming of somatic cells towards a pluripotent-likestate can be achieved by several different experimental routes including nuclear transfer, the supply of adefined cocktail of transcription factors, or by fusing somatic cells with a pluripotent stem cell partner.These approaches have been used to demonstrate the remarkable intrinsic epigenetic plasticity of manyterminally differentiated cell types, as well as to define the factors that are required for pluripotentconversion. In this review we summarise some recent advances using cell fusion-based studies to betterunderstand the basis of pluripotency and the epigenetic mechanisms that promote cell typeinter-conversion.", "metadata": {}}
+{"_id": "29657303", "title": "", "text": "Anorectic drugs and pulmonary hypertension from the bedside to the bench.Anorectic drugs have beenused for more than 30 years as an aid in weight reduction for obese persons. The use of aminorex, anamphetamine analog that increases norepinephrine levels in the central nervous system, led to anepidemic of primary pulmonary hypertension (PPH) in Europe in the late 1960s and early 1970s. The useof fenfluramine and later dexfenfluramine [drugs that inhibit 5-hydroxytryptamine (5-HT) release andreuptake and increases 5-HT and thus 5-HT secretion in the brain] was associated with a second epidemicof PPH. All of these drugs have been voluntarily withdrawn from the market. The pathogenesis of PPH inpatients treated with these agents is uncertain, but recent evidence suggests that potassium channelabnormalities and vasoactive and proliferative properties of 5-HT may play a role. There is increasingexperimental evidence suggesting that aminorex, fenfluramine and dexfenfluramine inhibit4-aminopyridine-sensitive currents in potassium channels resulting in vasoconstriction in pulmonaryresistance vessels and perhaps smooth muscle cell proliferation. 5-HT causes pulmonary arteryvasoconstriction and smooth muscle cell proliferation. Its levels are known to be high in those withfenfluramine-induced PPH. However, a firm cause-and-effect relationship has not yet been established.One potentially beneficial effect of the epidemics of anorectic-related PPH is that it may have providedimportant insights into the causes of PPH unrelated to anorectic agents.", "metadata": {}}
+{"_id": "29689140", "title": "", "text": "B-catenin deficiency, but not Myc deletion, suppresses the immediate phenotypes of APC loss in theliver.Dysregulated Wnt signaling is seen in approximately 30% of hepatocellular carcinomas; thus, findingpathways downstream of the activation of Wnt signaling is key. Here, using cre-lox technology, wedeleted the Apc gene in the adult mouse liver and observed a rapid increase in nuclear beta-catenin andc-Myc, which is associated with an induction of proliferation that led to hepatomegaly within 4 days ofgene deletion. To investigate the downstream pathways responsible for these phenotypes, we analyzedthe impact of inactivating APC in the context of deficiency of the potentially key effectors beta-cateninand c-Myc. beta-catenin loss rescues both the proliferation and hepatomegaly phenotypes after APC loss.However, c-Myc deletion, which rescues the phenotypes of APC loss in the intestine, had no effect on thephenotypes of APC loss in the liver. The consequences of the deregulation of the Wnt pathway within theliver are therefore strikingly different from those observed within the intestine, with the vast majority ofWnt targets being beta-catenin-dependent but c-Myc-independent in the liver.", "metadata": {}}
+{"_id": "29691654", "title": "", "text": "Uncoupling Mitochondrial Respiration for Diabesity.Until recently, the mechanism of adaptivethermogenesis was ascribed to the expression of uncoupling protein 1 (UCP1) in brown and beigeadipocytes. UCP1 is known to catalyze a proton leak of the inner mitochondrial membrane, resulting inuncoupled oxidative metabolism with no production of adenosine triphosphate and increased energyexpenditure. Thus increasing brown and beige adipose tissue with augmented UCP1 expression is a viabletarget for obesity-related disorders. Recent work demonstrates an UCP1-independent pathway touncouple mitochondrial respiration. A secreted enzyme, PM20D1, enriched in UCP1+ adipocytes, exhibitscatalytic and hydrolytic activity to reversibly form N-acyl amino acids. N-acyl amino acids act asendogenous uncouplers of mitochondrial respiration at physiological concentrations. Administration ofPM20D1 or its products, N-acyl amino acids, to diet-induced obese mice improves glucose tolerance byincreasing energy expenditure. In short-term studies, treated animals exhibit no toxicity whileexperiencing 10% weight loss primarily of adipose tissue. Further study of this metabolic pathway mayidentify novel therapies for diabesity, the disease state associated with diabetes and obesity.", "metadata": {}}
+{"_id": "29723642", "title": "", "text": "A functional polymorphism in the prodynorphin gene promotor is associated with temporal lobeepilepsy.The prodynorphin gene (PDYN) encoding the anticonvulsant peptide dynorphin is a strongcandidate for a seizure suppressor gene and thus a possible modulator of susceptibility to temporal lobeepilepsy. We performed a case control association study in 155 patients with nonlesional temporal lobeepilepsy and 202 controls and found that PDYN promotor low-expression L-alleles confer an increased riskfor temporal lobe epilepsy in patients with a family history for seizures. Irrespective of the familialbackground, L-homozygotes display a higher risk for secondarily generalized seizures and statusepilepticus.", "metadata": {}}
+{"_id": "29735200", "title": "", "text": "Cardiovascular and renal benefits of dry bean and soybean intake.Dry beans and soybeans arenutrient-dense, fiber-rich, and are high-quality sources of protein. Protective and therapeutic effects ofboth dry bean and soybean intake have been documented. Studies show that dry bean intake has thepotential to decrease serum cholesterol concentrations, improve many aspects of the diabetic state, andprovide metabolic benefits that aid in weight control. Soybeans are a unique source of the isoflavonesgenistein and diadzein, which have numerous biological functions. Soybeans and soyfoods potentiallyhave multifaceted health-promoting effects, including cholesterol reduction, improved vascular health,preserved bone mineral density, and reduction of menopausal symptoms. Soy appears to have salutaryeffects on renal function, although these effects are not well understood. Whereas populations consuminghigh intakes of soy have lower prevalences of certain cancers, definitive experimental data are insufficientto clarify a protective role of soy. The availability of legume products and resources is increasing,incorporating dry beans and soyfoods into the diet can be practical and enjoyable. With the shift toward amore plant-based diet, dry beans and soy will be potent tools in the treatment and prevention of chronicdisease.", "metadata": {}}
+{"_id": "29745822", "title": "", "text": "Nonuniform probability of glutamate release at a hippocampal synapse.A change in the probability ofneurotransmitter release (Pr) is an important mechanism underlying synaptic plasticity. Although Pr isoften assumed to be the same for all terminals at a single synapse, this assumption is difficult to reconcilewith the nonuniform size and structure of synaptic terminals in the central nervous system. Releaseprobability was measured at excitatory synapses on cultured hippocampal neurons by analysis of theprogressive block of N-methyl-D-aspartate receptor-mediated synaptic currents by the irreversible openchannel blocker MK-801. Release probability was nonuniform (range of 0.09 to 0.54) for terminals arisingfrom a single axon, the majority of which had a low Pr. However, terminals with high Pr are more likely tobe affected by the activity-dependent modulation that occurs in long-term potentiation.", "metadata": {}}
+{"_id": "29785642", "title": "", "text": "An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-typezinc-finger domainsAutoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is theonly described systemic autoimmune disease with established monogenic background, and the firstautoimmune disorder localized outside the major histocompatibility complex (MHC) region. The primarybiochemical defect in APECED is unknown. We have isolated a novel gene, AIRE, encoding for a putativenuclear protein featuring two PHD-type zinc-finger motifs, suggesting its involvement in transcriptionalregulation. Five mutations in AIRE are reported in individuals with this disorder. This is the first report ofa single-gene defect causing a systemic human autoimmune disease, providing a tool for exploring themolecular basis of autoimmunity.", "metadata": {}}
+{"_id": "29788648", "title": "", "text": "NuA4 lysine acetyltransferase Esa1 is targeted to coding regions and stimulates transcription elongationwith Gcn5.NuA4, the major H4 lysine acetyltransferase (KAT) complex in Saccharomyces cerevisiae, isrecruited to promoters and stimulates transcription initiation. NuA4 subunits contain domains that bindmethylated histones, suggesting that histone methylation should target NuA4 to coding sequences duringtranscription elongation. We show that NuA4 is cotranscriptionally recruited, dependent on its physicalassociation with elongating polymerase II (Pol II) phosphorylated on the C-terminal domain bycyclin-dependent kinase 7/Kin28, but independently of subunits (Eaf1 and Tra1) required for NuA4recruitment to promoters. Whereas histone methylation by Set1 and Set2 is dispensable for NuA4'sinteraction with Pol II and targeting to some coding regions, it stimulates NuA4-histone interaction andH4 acetylation in vivo. The NuA4 KAT, Esa1, mediates increased H4 acetylation and enhanced RSCoccupancy and histone eviction in coding sequences and stimulates the rate of transcription elongation.Esa1 cooperates with the H3 KAT in SAGA, Gcn5, to enhance these functions. Our findings delineate apathway for acetylation-mediated nucleosome remodeling and eviction in coding sequences thatstimulates transcription elongation by Pol II in vivo.", "metadata": {}}
+{"_id": "29806339", "title": "", "text": "Targeting mitotic exit leads to tumor regression in vivo: Modulation by Cdk1, Mastl, and the PP2A/B55α,δphosphatase.Targeting mitotic exit has been recently proposed as a relevant therapeutic approachagainst cancer. By using genetically engineered mice, we show that the APC/C cofactor Cdc20 is essentialfor anaphase onset in vivo in embryonic or adult cells, including progenitor/stem cells. Ablation of Cdc20results in efficient regression of aggressive tumors, whereas current mitotic drugs display limited effects.Yet, Cdc20 null cells can exit from mitosis upon inactivation of Cdk1 and the kinase Mastl (Greatwall).This mitotic exit depends on the activity of PP2A phosphatase complexes containing B55α or B55δregulatory subunits. These data illustrate the relevance of critical players of mitotic exit in mammals andtheir implications in the balance between cell death and mitotic exit in tumor cells.", "metadata": {}}
+{"_id": "29807737", "title": "", "text": "DrugBank 5.0: a major update to the DrugBank database for 2018DrugBank (www.drugbank.ca) is aweb-enabled database containing comprehensive molecular information about drugs, their mechanisms,their interactions and their targets. First described in 2006, DrugBank has continued to evolve over thepast 12 years in response to marked improvements to web standards and changing needs for drugresearch and development. This year's update, DrugBank 5.0, represents the most significant upgrade tothe database in more than 10 years. In many cases, existing data content has grown by 100% or moreover the last update. For instance, the total number of investigational drugs in the database has grown byalmost 300%, the number of drug-drug interactions has grown by nearly 600% and the number ofSNP-associated drug effects has grown more than 3000%. Significant improvements have been made tothe quantity, quality and consistency of drug indications, drug binding data as well as drug-drug anddrug-food interactions. A great deal of brand new data have also been added to DrugBank 5.0. Thisincludes information on the influence of hundreds of drugs on metabolite levels (pharmacometabolomics),gene expression levels (pharmacotranscriptomics) and protein expression levels (pharmacoprotoemics).New data have also been added on the status of hundreds of new drug clinical trials and existing drugrepurposing trials. Many other important improvements in the content, interface and performance of theDrugBank website have been made and these should greatly enhance its ease of use, utility and potentialapplications in many areas of pharmacological research, pharmaceutical science and drug education.", "metadata": {}}
+{"_id": "29828242", "title": "", "text": "Analyzing mechanisms of alternative pre-mRNA splicing using in vitro splicing assays.The development ofin vitro assays to analyze pre-mRNA splicing resulted in the discovery of many fundamental featurescharacterizing splicing signals and the machinery that completes this process. Because in vitro assays canbe manipulated by various biochemical approaches, the versatility of investigating alternative pre-mRNAsplicing in the test tube appears endless. Importantly, modifications in reaction conditions can lead to theaccumulation, isolation, and characterization of reaction intermediates, a prerequisite for gainingmechanistic insights into how the spliceosome carries out intron removal, and how regulatory elementsassist the general splicing machinery in defining splice sites and alternative exons. These considerableexperimental advantages have made the in vitro splicing system a standard assay, even though thisapproach is independent from RNA transcription and other RNA processing events, and in some respectsdeviates from the natural process of mRNA biogenesis. Here, we describe the tools and techniquesnecessary to carry out in vitro splicing assays. Analyses of various experimental designs are presented tohighlight the approaches taken to gain insights into the mechanisms by which splice site recognition andactivation are communicated with the general splicing machinery. Methods to measure the kinetics ofsplicing, to observe the formation of the pre-spliceosomal complexes, and to manipulate and modify thein vitro system to resolve the regulatory influences in alternative splicing are presented.", "metadata": {}}
+{"_id": "29845974", "title": "", "text": "New Roles for Pharmacists in Community Mental Health Care: A Narrative ReviewMedicines are a majortreatment modality for many mental illnesses, and with the growing burden of mental disordersworldwide pharmacists are ideally positioned to play a greater role in supporting people with a mentalillness. This narrative review aims to describe the evidence for pharmacist-delivered services in mentalhealth care and address the barriers and facilitators to increasing the uptake of pharmacist services aspart of the broader mental health care team. This narrative review is divided into three main sections: (1)the role of the pharmacist in mental health care in multidisciplinary teams and in supporting earlydetection of mental illness; (2) the pharmacists' role in supporting quality use of medicines in medicationreview, strategies to improve medication adherence and antipsychotic polypharmacy, and shared decisionmaking; and (3) barriers and facilitators to the implementation of mental health pharmacy services with afocus on organizational culture and mental health stigma. In the first section, the review presents newroles for pharmacists within multidisciplinary teams, such as in case conferencing or collaborative drugtherapy management; and new roles that would benefit from increased pharmacist involvement, such asthe early detection of mental health conditions, development of care plans and follow up of people withmental health problems. The second section describes the impact of medication review services and otherpharmacist-led interventions designed to reduce inappropriate use of psychotropic medicines andimprove medication adherence. Other new potential roles discussed include the management ofantipsychotic polypharmacy and involvement in patient-centered care. Finally, barriers related topharmacists' attitudes, stigma and skills in the care of patients with mental health problems and barriersaffecting pharmacist-physician collaboration are described, along with strategies to reduce mental healthstigma.", "metadata": {}}
+{"_id": "29851836", "title": "", "text": "UV light-induced DNA synthesis arrest in HeLa cells is associated with changes in phosphorylation ofhuman single-stranded DNA-binding protein.We show that DNA replication activity in extracts of humanHeLa cells decreases following UV irradiation. Alterations in replication activity in vitro parallel theUV-induced block in cell cycle progression of these cells in culture. UV irradiation also induces specificchanges in the pattern of phosphorylation of the 34 kDa subunit of a DNA replication protein, humansingle-stranded DNA-binding protein (hSSB). The appearance of a hyperphosphorylated form of hSSBcorrelates with reduced in vitro DNA replication activity in extracts of UV-irradiated cells. Replicationactivity can be restored to these extracts in vitro by addition of purified hSSB. These results suggest thatUV-induced DNA synthesis arrest may be mediated in part through phosphorylation-related alterations inthe activity of hSSB, an essential component of the DNA replication apparatus.", "metadata": {}}
+{"_id": "29863668", "title": "", "text": "P446L-importin-beta inhibits nuclear envelope assembly by sequestering nuclear envelope assemblyfactors to the microtubules.The P446L mutant Drosophila importin-beta (P446L-imp-beta) has beenreported to prohibit--in dominant negative fashion--nuclear envelope (NE) assembly. Along elucidatingthe mode of action of P446L-imp-beta we studied in vitro NE assembly on Sepharose beads. WhileDrosophila embryo extracts support NE assembly over Sepharose beads coated with Ran, NE assemblydoes not take place in extracts supplied with exogenous P446L-imp-beta. A NE also forms overimportin-beta-coated beads. Surprisingly, when immobilized to Sepharose beads P446L-imp-beta asefficiently recruits NE vesicles as normal importin-beta. The discrepancy in behavior of cytoplasmic andbead-bound P446L-imp-beta appears to be related to icreased--as compared to normalimportin-beta--microtubule (MT) binding ability of P446L-imp-beta. While wild-type importin-beta is ableto bind MTs and the binding decreases upon RanGTP interaction, P446L-imp-beta cannot be removedfrom the MTs by RanGTP. P446L-imp-beta, like normal importin-beta, binds some types of thenucleoporins that have been known to be required for NE assembly at the end of mitosis. It appears thatthe inhibitory effect of P446L-imp-beta on NE assembly is caused by sequestering some of thenucleoporins required for NE assembly to the MTs.", "metadata": {}}
+{"_id": "29877890", "title": "", "text": "Histone chaperones and nucleosome assembly.Recent structures of the nucleosome core particle revealdetails of histone-histone and histone-DNA interactions. These structures have now set the stage forunderstanding chromatin assembly and dynamics during replication and transcription. Histonechaperones and chromatin remodeling complexes are important in both of these processes. Thenucleosome and its protein core, the histone octamer, have twofold symmetry, which histone chaperonesmay use to bind core histones. Recent studies suggest that the nucleoplasmin pentamer may mediatehistone storage, sperm chromatin decondensation and nucleosome assembly, by dimerizing to form adecamer. In this model, histone binding on the lateral surface of the chaperone involves stereospecificinteractions and a shared twofold axis.", "metadata": {}}
+{"_id": "29947146", "title": "", "text": "Intestinal methane production in obese individuals is associated with a higher body massindex.BACKGROUND Obesity is an epidemic that affects 1 in 3 individuals in the United States, and recentevidence suggests that enteric microbiota may play a significant role in the development of obesity. Thisstudy evaluated the association between methanogenic archaea and obesity in human subjects.METHODS Subjects with a body mass index (BMI) of 30 kg/m² or higher were prospectively recruitedfrom the weight loss program of a tertiary care medical center. Subjects who met the study's inclusioncriteria were asked to complete a questionnaire that included a series of visual analogue scores for bowelsymptom severities. Subjects then provided a single end-expiratory breath sample to quantitate methanelevels. Bivariate and multivariate analyses were used to determine associations with BMI. RESULTS Atotal of 58 patients qualified for enrollment. Twenty percent of patients (n = 12) had breath test resultsthat were positive for methane (>3 parts per million [ppm]), with a mean breath methane concentrationof 12.2±3.1 ppm. BMI was significantly higher in methane-positive subjects (45.2±2.3 kg/m²) than inmethane-negative subjects (38.5±0.8 kg/m²; P=.001). Methane-positive subjects also had a greaterseverity of constipation than methane-negative subjects (21.3±6.4 vs 9.5±2.4; P=.043). Multipleregression analysis illustrated a significant association between BMI and methane, constipation, andantidepressant use. However, methane remained an independent predictor of elevated BMI whencontrolling for antidepressant use (P<.001) and when controlling for both constipation and antidepressantuse (6.55 kg/m² greater BMI; P=.003). CONCLUSION This is the first human study to demonstrate that ahigher concentration of methane detected by breath testing is a predictor of significantly greater obesityin overweight subjects.", "metadata": {}}
+{"_id": "29955650", "title": "", "text": "Study of infectious intestinal disease in England: rates in the community, presenting to general practice,and reported to national surveillance. The Infectious Intestinal Disease Study Executive.OBJECTIVE Toestablish the incidence and aetiology of infectious intestinal disease in the community and presenting togeneral practitioners. Comparison with incidence and aetiology of cases reaching national laboratorybased surveillance. DESIGN Population based community cohort incidence study, general practice basedincidence studies, and case linkage to national laboratory surveillance. SETTING 70 general practicesthroughout England. PARTICIPANTS 459 975 patients served by the practices. Community surveillance of9776 randomly selected patients. MAIN OUTCOME MEASURES Incidence of infectious intestinal disease incommunity and reported to general practice. RESULTS 781 cases were identified in the communitycohort, giving an incidence of 19.4/100 person years (95% confidence interval 18.1 to 20.8). 8770 casespresented to general practice (3.3/100 person years (2.94 to 3.75)). One case was reported to nationalsurveillance for every 1.4 laboratory identifications, 6.2 stools sent for laboratory investigation, 23 casespresenting to general practice, and 136 community cases. The ratio of cases in the community to casesreaching national surveillance was lower for bacterial pathogens (salmonella 3.2:1, campylobacter 7.6:1)than for viruses (rotavirus 35:1, small round structured viruses 1562:1). There were many cases forwhich no organism was identified. CONCLUSIONS Infectious intestinal disease occurs in 1 in 5 peopleeach year, of whom 1 in 6 presents to a general practitioner. The proportion of cases not recorded bynational laboratory surveillance is large and varies widely by microorganism. Ways of supplementing thenational laboratory surveillance system for infectious intestinal diseases should be considered.", "metadata": {}}
+{"_id": "29981186", "title": "", "text": "Venous thrombosis in cancer patients: insights from the FRONTLINE survey.BACKGROUND Venousthromboembolism (VTE) is a common complication in cancer patients and a significant cause of morbidityand mortality. However, little information is available on oncologists' perceptions of the risk of VTE and itsmanagement. The Fundamental Research in Oncology and Thrombosis (FRONTLINE) study is the firstcomprehensive global survey of thrombosis and cancer. The study was designed to collect data on theperceived risk and patterns of practice with regard to VTE in cancer patients undergoing surgical andmedical management of their malignancy and to provide information on international and regionalpractice patterns, allowing for the design of research studies to answer the concerns of practicingclinicians. METHODS Literature reviews were performed to provide a current evidence base against whichto compare the findings, and a survey was developed under the guidance of an advisory board. Apaper-based reply-paid questionnaire was distributed globally between July and November 2001 toclinicians involved in cancer care and was made available on a dedicated website. FINDINGS A total of3,891 completed responses were available for analysis. Brain and pancreatic tumors were considered tocarry a high risk for VTE, and 80% of respondents considered the use of central venous lines to beassociated with a high risk of VTE. Marked differences were seen in the use of thromboprophylaxis forsurgical and medical cancer patients, with over 50% of surgeons reporting that they initiatedthromboprophylaxis routinely, while most medical oncologists reported using thromboprophylaxis in lessthan 5% of medical patients. Low molecular weight heparin (LMWH) was the most popular method ofthromboprophylaxis employed in both surgical and medical patients and was more favored by Europeanthan U.S. clinicians. Some 20% of respondents reported using aspirin for prophylaxis, despite there beingno reliable evidence for this agent as effective in prevention in this population. For the treatment of VTE,LMWH was again the most common initial treatment, although, for the long-term, oral anticoagulationtherapy was widely adopted. Many patients were treated for VTE on an outpatient basis, and secondaryprevention of VTE was typically continued for 3 to 6 months after an episode of deep vein thrombosis orfor longer in the case of pulmonary embolism. INTERPRETATION The results of the FRONTLINE surveydemonstrate a need for guidelines to direct clinical practice in line with evidence-based data concerningcancer and VTE. Oncologists need to be educated regarding the true risks of VTE associated with certaincancers and on strategies for prevention and treatment to reduce the morbidity and mortality associatedwith VTE in all cancer patients. The study has also helped identify areas for future research.", "metadata": {}}
+{"_id": "30034334", "title": "", "text": "A dual function of the CRISPR-Cas system in bacterial antivirus immunity and DNA repair.ClusteredRegularly Interspaced Short Palindromic Repeats (CRISPRs) and the associated proteins (Cas) comprise asystem of adaptive immunity against viruses and plasmids in prokaryotes. Cas1 is a CRISPR-associatedprotein that is common to all CRISPR-containing prokaryotes but its function remains obscure. Here weshow that the purified Cas1 protein of Escherichia coli (YgbT) exhibits nuclease activity againstsingle-stranded and branched DNAs including Holliday junctions, replication forks and 5'-flaps. The crystalstructure of YgbT and site-directed mutagenesis have revealed the potential active site. Genome-widescreens show that YgbT physically and genetically interacts with key components of DNA repair systems,including recB, recC and ruvB. Consistent with these findings, the ygbT deletion strain showed increasedsensitivity to DNA damage and impaired chromosomal segregation. Similar phenotypes were observed instrains with deletion of CRISPR clusters, suggesting that the function of YgbT in repair involvesinteraction with the CRISPRs. These results show that YgbT belongs to a novel, structurally distinct familyof nucleases acting on branched DNAs and suggest that, in addition to antiviral immunity, at least somecomponents of the CRISPR-Cas system have a function in DNA repair.", "metadata": {}}
+{"_id": "30041340", "title": "", "text": "Antibodies from patients with rheumatoid arthritis target citrullinated histone 4 contained in neutrophilsextracellular traps.BACKGROUND Histone deimination regulates gene function and contributes toantimicrobial response, allowing the formation of neutrophil extracellular traps (NETs). Deiminatedproteins are target of anti-citrullinated peptides antibodies (ACPA) in rheumatoid arthritis (RA).OBJECTIVE The objective of this paper is to test the hypothesis that RA sera react with deiminatedhistones contained in NETs. METHODS Neutrophils from peripheral blood were stimulated with A23187and acid treated; NETosis was induced by phorbol myristate acetate, and NET proteins were isolated.Sera were tested by immunoblot on acid extracted proteins from neutrophils and from NETs, and byELISA on deiminated histone H4 or H4-derived peptides. Bands reactive with RA sera were excised fromgels, digested with trypsin and subjected to matrix-assisted laser desorption/ionisation time of flight(MALDI-TOF) analysis, before and after derivatisation to detect citrullinated peptides. RESULTS RA serareacted with a deiminated antigen of 11 KDa from activated neutrophils, recognised also by anti-H4 andantideiminated H4 antibodies. A similar reactivity was observed with NET proteins. The antigen fromneutrophils or NETs was identified as citrullinated H4 by MALDI-TOF analysis. By ELISA, RA sera bound invitro citrullinated H4. Citrullinated H4 14-34 and 31-50 peptides detected antibodies in 67% and 63% ofRA sera and in less than 5% of controls; antibody titre was correlated with anti-CCP2. CONCLUSIONSCitrullinated H4 from activated neutrophils and NETs is a target of antibodies in RA, and syntheticcitrullinated H4-derived peptides are a new substrate for ACPA detection. As NETosis can generateantigens for ACPA, these data suggest a novel connection between innate and adaptive immunity in RA.", "metadata": {}}
+{"_id": "30041895", "title": "", "text": "Mechanosensitive ion channel Piezo2 is important for enterochromaffin cell response to mechanicalforcesKEY POINTS The gastrointestinal epithelial enterochromaffin (EC) cell synthesizes the vast majorityof the body's serotonin. As a specialized mechanosensor, the EC cell releases this serotonin in responseto mechanical forces. However, the molecular mechanism of EC cell mechanotransduction is unknown. Inthe present study, we show, for the first time, that the mechanosensitive ion channel Piezo2 is specificallyexpressed by the human and mouse EC cells. Activation of Piezo2 by mechanical forces results in acharacteristic ionic current, the release of serotonin and stimulation of gastrointestinal secretion. Piezo2inhibition by drugs or molecular knockdown decreases mechanosensitive currents, serotonin release anddownstream physiological effects. The results of the present study suggest that the mechanosensitive ionchannel Piezo2 is specifically expressed by the EC cells of the human and mouse small bowel and that it isimportant for EC cell mechanotransduction. ABSTRACT The enterochromaffin (EC) cell in thegastrointestinal (GI) epithelium is the source of nearly all systemic serotonin (5-hydroxytryptamine;5-HT), which is an important neurotransmitter and endocrine, autocrine and paracrine hormone. The ECcell is a specialized mechanosensor, and it is well known that it releases 5-HT in response to mechanicalforces. However, the EC cell mechanotransduction mechanism is unknown. The present study aimed todetermine whether Piezo2 is involved in EC cell mechanosensation. Piezo2 mRNA was expressed inhuman jejunum and mouse mucosa from all segments of the small bowel. Piezo2 immunoreactivitylocalized specifically within EC cells of human and mouse small bowel epithelium. The EC cell modelreleased 5-HT in response to stretch, and had Piezo2 mRNA and protein, as well as amechanically-sensitive inward non-selective cation current characteristic of Piezo2. Both inward currentsand 5-HT release were inhibited by Piezo2 small interfering RNA and antagonists (Gd3+ and D-GsMTx4).Jejunum mucosal pressure increased 5-HT release and short-circuit current via submucosal 5-HT3 and5-HT4 receptors. Pressure-induced secretion was inhibited by the mechanosensitive ion channelantagonists gadolinium, ruthenium red and D-GsMTx4. We conclude that the EC cells in the human andmouse small bowel GI epithelium selectively express the mechanosensitive ion channel Piezo2, and alsothat activation of Piezo2 by force leads to inward currents, 5-HT release and an increase in mucosalsecretion. Therefore, Piezo2 is critical to EC cell mechanosensitivity and downstream physiological effects.", "metadata": {}}
+{"_id": "30058568", "title": "", "text": "Improved prognosis of thoracic aortic aneurysms: a population-based study.CONTEXT Managing thoracicaortic aneurysms identified incidentally by increased use of computed tomography, echocardiography,and magnetic resonance imaging is problematic, especially in the elderly. OBJECTIVE To ascertainwhether the previously reported poor prognosis for individuals with thoracic aortic aneurysms haschanged with better medical therapies and improved surgical techniques that can now be applied toaneurysm management. DESIGN Population-based cohort study. SETTING AND PATIENTS All 133patients with the diagnosis of degenerative thoracic aortic aneurysms among Olmsted County, Minnesota,residents between 1980 and 1994 compared with a previously reported cohort of similar patientsbetween 1951 and 1980. MAIN OUTCOME MEASURES The primary clinical end points were incidence,cumulative rupture risk, rupture risk as a function of aneurysm size, and survival. RESULTS In contrast toabdominal aortic aneurysms, for which men are affected predominately, 51% of thoracic aorticaneurysms were identified in women who were considerably older at recognition than men (mean age,75.9 vs 62.8 years, respectively; P= .01). The overall incidence rate of 10.4 per 100000 person-years(95% confidence interval [CI], 8.6-12.2) between 1980 and 1994 was more than 3-fold higher than therate from 1951 to 1980. The cumulative risk of rupture was 20% after 5 years. Seventy-nine percent ofruptures occurred in women (P= .01). The 5-year risk of rupture as a function of aneurysm size atrecognition was 0% for aneurysms less than 4 cm in diameter, 16% (95% CI, 4%-28%) for those 4 to5.9 cm, and 31% (95% CI, 5%-56%) for aneurysms 6 cm or more. Overall 5-year survival improved to56% (95% CI, 48%-66%) between 1980 and 1994 compared with only 19% between 1951 and 1980(P<.01). CONCLUSIONS In this population, elderly women represent an increasing portion of all patientswith clinically recognized thoracic aortic aneurysms and constitute the majority of patients whoseaneurysm eventually ruptures. Overall survival for thoracic aortic aneurysms has improved significantly inthe past 15 years.", "metadata": {}}
+{"_id": "30101891", "title": "", "text": "Intravenous valproate is well tolerated in unstable patients with status epilepticus.The authors reviewedhospital records of 13 patients with status epilepticus and hypotension who received IV valproatetherapy. Most patients were elderly (74.4 +/- 12.5 [SD] years) and received a loading dose of valproateof 25.1 +/- 5.0 mg/kg (range 14.7 to 32.7), at a rate of 36.6 +/- 25.1 mg/min (range 6.3 to 100). Therewere no significant changes in blood pressure, pulse, or use of vasopressors. The data suggest thatvalproate loading is well tolerated, even in patients with cardiovascular instability.", "metadata": {}}
+{"_id": "30122260", "title": "", "text": "Interplays between ATM/Tel1 and ATR/Mec1 in sensing and signaling DNA double-strand breaks.DNAdouble-strand breaks (DSBs) are highly hazardous for genome integrity because they have the potentialto cause mutations, chromosomal rearrangements and genomic instability. The cellular response to DSBsis orchestrated by signal transduction pathways, known as DNA damage checkpoints, which areconserved from yeasts to humans. These pathways can sense DNA damage and transduce thisinformation to specific cellular targets, which in turn regulate cell cycle transitions and DNA repair. Themammalian protein kinases ATM and ATR, as well as their budding yeast corresponding orthologs Tel1and Mec1, act as master regulators of the checkpoint response to DSBs. Here, we review the early stepsof DSB processing and the role of DNA-end structures in activating ATM/Tel1 and ATR/Mec1 in an orderlyand reciprocal manner.", "metadata": {}}
+{"_id": "30152134", "title": "", "text": "The ‘definitive’ (and ‘primitive’) guide to zebrafish hematopoiesisProgressive advances using zebrafish asa model organism have provided hematologists with an additional genetic system to study blood cellformation and hematological malignancies. Despite extensive evolutionary divergence between bony fish(teleosts) and mammals, the molecular pathways governing hematopoiesis have been highly conserved.As a result, most (if not all) of the critical hematopoietic transcription factor genes identified in mammalshave orthologues in zebrafish. As in other vertebrates, all of the teleost blood lineages are believed tooriginate from a pool of pluripotent, self-renewing hematopoietic stem cells. Here, we provide a detailedreview of the timing, anatomical location, and transcriptional regulation of zebrafish ‘primitive’ and‘definitive’ hematopoiesis as well as discuss a model of T-cell leukemia and recent advances in blood celltransplantation. Given that many of the regulatory genes that control embryonic hematopoiesis havebeen implicated in oncogenic pathways in adults, an understanding of blood cell ontogeny is likely toprovide insights into the pathophysiology of human leukemias.", "metadata": {}}
+{"_id": "30184745", "title": "", "text": "Steroid receptor interactions with heat shock protein and immunophilin chaperones.We have provided ahistorical perspective on a body of steroid receptor research dealing with the structure and physiologicalsignificance of the untransformed 9S receptor that has often confused both novice and expertinvestigators. The frequent controversies and equivocations of earlier studies were due to the fact thatthe native, hormone-free state of these receptors is a large multiprotein complex that resisted descriptionfor many years because of its unstable and dynamic nature. The untransformed 9S state of the steroidand dioxin receptors has provided a unique system for studying the function of the ubiquitous, abundant,and conserved heat shock protein, hsp90. The hormonal control of receptor association with hsp90provided a method of manipulating the receptor heterocomplex in a manner that was physiologicallymeaningful. For several steroid receptors, binding to hsp90 was required for the receptor to be in a nativehormone-binding state, and for all of the receptors, hormone binding promoted dissociation of thereceptor from hsp90 and conversion of the receptor to the DNA-binding state. Although the complexesbetween tyrosine kinases and hsp90 were discovered earlier, the hormonal regulation or steroid receptorassociation with hsp90 permitted much more rapid and facile study of hsp90 function. The observationsthat hsp90 binds to the receptors through their HBDs and that these domains can be fused to structurallydifferent proteins bringing their function under hormonal control provided a powerful linkage between thehormonal regulation of receptor binding to hsp90 and the initial step in steroid hormone action. Becausethe 9S receptor hsp90 heterocomplexes could be physically stabilized by molybdate, their proteincomposition could be readily studied, and it became clear that these complexes are multiproteinstructures containing a number of unique proteins, such as FKBP51, FKBP52, CyP-40, and p23, that werediscovered because of their presence in these structures. Further analysis showed that hsp90 itself existsin a variety of native multiprotein heterocomplexes independent of steroid receptors and other 'substrate'proteins. Cell-free systems can now be used to study the formation of receptor heterocomplexes. As weoutlined in the scheme of Fig. 1, the multicomponent receptor-hsp90 heterocomplex assembly system isbeing reconstituted, and the importance of individual proteins, such as hsp70, p60, and p23, in theassembly process is becoming recognized. It should be noted that our understanding of the mechanismand purpose of steroid receptor heterocomplex assembly is still at an early stage. We can now speculateon the roles of receptor-associated proteins in receptor action, both as individuals and as a group, buttheir actual functions are still vague or unknown. We can make realistic models about the chaperoningand trafficking of steroid receptors, but we don't yet know how these processes occur, we don't knowwhere chaperoning occurs in the cell (e.g. Is it limited to the cytoplasm? Is it a diffuse process or doeschaperoning occur in association with structural elements?), and, with the exception of the requirementfor hormone binding, we don't know the extent to which the hsp90-based chaperone system impacts onsteroid hormone action. It is not yet clear how far the discovery of this hsp90 heterocomplex assemblysystem will be extended to the development of a general understanding of protein processing in the cell.Because this assembly system is apparently present in all eukaryotic cells, it probably performs anessential function for many proteins. The bacterial homolog of hsp90 is not an essential protein, buthsp90 is essential in eukaryotes, and recent studies indicate that the development of the cell nucleusfrom prokaryotic progenitors was accompanied by the duplication of genes for hsp90 and hsp70 (698).(ABSTRACT TRUNCATED)", "metadata": {}}
+{"_id": "30208015", "title": "", "text": "Molecular Characterization of Oxysterol Binding to the Epstein-Barr Virus-induced Gene 2(GPR183)*Oxysterols are oxygenated cholesterol derivates that are emerging as a physiologicallyimportant group of molecules. Although they regulate a range of cellular processes, only fewoxysterol-binding effector proteins have been identified, and the knowledge of their binding mode islimited. Recently, the family of G protein-coupled seven transmembrane-spanning receptors (7TMreceptors) was added to this group. Specifically, the Epstein-Barr virus-induced gene 2 (EBI2 or GPR183)was shown to be activated by several oxysterols, most potently by 7α,25-dihydroxycholesterol(7α,25-OHC). Nothing is known about the binding mode, however. Using mutational analysis, we identifyhere four key residues for 7α,25-OHC binding: Arg-87 in TM-II (position II:20/2.60), Tyr-112 andTyr-116 (positions III:09/3.33 and III:13/3.37) in TM-III, and Tyr-260 in TM-VI (position VI:16/6.51).Substituting these residues with Ala and/or Phe results in a severe decrease in agonist binding andreceptor activation. Docking simulations suggest that Tyr-116 interacts with the 3β-OH group in theagonist, Tyr-260 with the 7α-OH group, and Arg-87, either directly or indirectly, with the 25-OH group,although nearby residues likely also contribute. In addition, Tyr-112 is involved in 7α,25-OHC binding butvia hydrophobic interactions. Finally, we show that II:20/2.60 constitutes an important residue for ligandbinding in receptors carrying a positively charged residue at this position. This group is dominated bylipid- and nucleotide-activated receptors, here exemplified by the CysLTs, P2Y12, and P2Y14. Inconclusion, we present the first molecular characterization of oxysterol binding to a 7TM receptor andidentify position II:20/2.60 as a generally important residue for ligand binding in certain 7TM receptors.", "metadata": {}}
+{"_id": "30221601", "title": "", "text": "Up-regulation of neuronal calcium sensor-1 (NCS-1) in the prefrontal cortex of schizophrenic and bipolarpatients.The delineation of dopamine dysfunction in the mentally ill has been a long-standing quest ofbiological psychiatry. The present study focuses on a recently recognized group of dopaminereceptor-interacting proteins as possible novel sites of dysfunction in schizophrenic and bipolar patients.We demonstrate that the dorsolateral prefrontal cortex in schizophrenia and bipolar cases from theStanley Foundation Neuropathology Consortium display significantly elevated levels of the D2 dopaminereceptor desensitization regulatory protein, neuronal calcium sensor-1. These levels of neuronal calciumsensor-1 were not influenced by age, gender, hemisphere, cause of death, postmortem period, alcoholconsumption, or antipsychotic and mood stabilizing medications. The present study supports thehypothesis that schizophrenia and bipolar disorder may be associated with abnormalities in dopaminereceptor-interacting proteins.", "metadata": {}}
+{"_id": "30224907", "title": "", "text": "c-Abl: activation and nuclear targetsThe c-Abl tyrosine kinase and its transforming variants have beenimplicated in tumorigenesis and in many important cellular processes. c-Abl is localized in the nucleusand the cytoplasm, where it plays distinct roles. The effects of c-Abl are mediated by multipleprotein-protein and protein-DNA interactions and its tyrosine kinase domain. At the biochemical level, themechanism of c-Abl kinase activation and the identification of its target proteins and cellular machinerieshave in part been solved. However, the phenotypic outcomes of these molecular events remained in largeelusive. c-Abl has been shown to regulate the cell cycle and to induce under certain conditions cell growtharrest and apoptosis. In this respect the interaction of c-Abl with p53 and p73 has attracted particularattention. Recent findings have implicated c-Abl in an ionizing irradiation signaling pathway that elicitsapoptosis. In this pathway p73 is an important immediate downstream effector. Here I review the currentknowledge about these nuclear processes in which c-Abl is engaged and discuss some of their possibleimplications on cell physiology.", "metadata": {}}
+{"_id": "30226988", "title": "", "text": "Cancer survival increases in Europe, but international differences remain wide.The EUROCARE projectanalysed cancer survival data from 45 population-based cancer registries in 17 European countries,revealing wide international differences in cancer survival. We calculated 5-year relative survival for1836287 patients diagnosed with one of 13 cancers during the period 1978-1989. The data, from 20cancer registries in 13 countries, were grouped into four regions: Finland, Sweden, Iceland (NorthernEurope); Denmark, England and Scotland (UK and Denmark); France, The Netherlands, Germany, Italyand Switzerland (Western Europe); Estonia and Poland (Eastern Europe), and broken down into fourperiods (1978-1980, 1981-1983, 1984-1986, 1987-1989). For each cancer, mean European and regionalsurvival was estimated as the weighted mean of 5-year relative survival in each country. Survivalincreased with time for all tumours, particularly for cancers of testis (12% increase, i.e. from 79.9 to91.9%), breast, large bowel, skin melanoma (approximately 9-10%), and lymphomas (approximately7%). For most solid tumours, survival was highest in Northern Europe and lowest in Eastern Europe, andalso low in the UK and Denmark. Regional variation was less marked for the lymphomas. Survivalimproved more in Western than Northern Europe, and the differences between these regions fell forbowel cancer (from 8.0% for those diagnosed in 1978-1980 to 2% for those diagnosed in 1987-1989),breast cancer (from 7.4% to 3.9%), skin melanoma (from 13.4% to 11.0%) and Hodgkin's disease (from7.2 to 0.6%). For potentially curable malignancies such as Hodgkin's disease, large bowel, breast andtesticular cancers, there were substantial increases in survival, suggesting an earlier diagnosis and moreeffective treatment. The persisting regional differences suggest there are corresponding differences in theavailability of diagnostic and therapeutic facilities, and in the effectiveness of healthcare systems.", "metadata": {}}
+{"_id": "30261663", "title": "", "text": "A nuclear translation-like factor eIF4AIII is recruited to the mRNA during splicing and functions innonsense-mediated decay.In eukaryotes, a surveillance mechanism known as nonsense-mediated decay(NMD) degrades the mRNA when a premature-termination codon (PTC) is present. NMD requirestranslation to read the frame of the mRNA and detect the PTC. During pre-mRNA splicing, the exon-exonjunction complex (EJC) is recruited to a region 20-24 nt upstream of the exon junction on the maturemRNA. The presence of a PTC upstream from the EJC elicits NMD. Eukaryotic initiation factor 4A (eIF4A)III is a nuclear protein that interacts physically or functionally with translation initiation factors eIF4G andeIF4B, respectively, and shares strikingly high identity with the initiation factors eIF4AI/II. Here we showthat siRNA against eIF4AIII, but not against eIF4AI/II, inhibits NMD. Moreover, eIF4AIII, but not eIF4AI,is specifically recruited to the EJC during splicing. The observations that eIF4AIII is loaded onto the mRNAduring splicing in the nucleus, has properties related to a translation initiation factor, and functions inNMD raises the possibility that eIF4AIII substitutes for eIF4AI/II during NMD.", "metadata": {}}
+{"_id": "30292811", "title": "", "text": "Swaddling: a systematic review.Swaddling was an almost universal child-care practice before the 18thcentury. It is still tradition in certain parts of the Middle East and is gaining popularity in the UnitedKingdom, the United States, and The Netherlands to curb excessive crying. We have systematicallyreviewed all articles on swaddling to evaluate its possible benefits and disadvantages. In general,swaddled infants arouse less and sleep longer. Preterm infants have shown improved neuromusculardevelopment, less physiologic distress, better motor organization, and more self-regulatory ability whenthey are swaddled. When compared with massage, excessively crying infants cried less when swaddled,and swaddling can soothe pain in infants. It is supportive in cases of neonatal abstinence syndrome andinfants with neonatal cerebral lesions. It can be helpful in regulating temperature but can also causehyperthermia when misapplied. Another possible adverse effect is an increased risk of the development ofhip dysplasia, which is related to swaddling with the legs in extension and adduction. Although swaddlingpromotes the favorable supine position, the combination of swaddling with prone position increases therisk of sudden infant death syndrome, which makes it necessary to warn parents to stop swaddling ifinfants attempt to turn. There is some evidence that there is a higher risk of respiratory infections relatedto the tightness of swaddling. Furthermore, swaddling does not influence rickets onset or boneproperties. Swaddling immediately after birth can cause delayed postnatal weight gain under certainconditions, but does not seem to influence breastfeeding parameters.", "metadata": {}}
+{"_id": "30297355", "title": "", "text": "Expression of the Norrie disease gene (Ndp) in developing and adult mouse eye, ear, and brain.TheNorrie disease gene (Ndp) codes for a secreted protein, Norrin, that activates canonical Wnt signaling bybinding to its receptor, Frizzled-4. This signaling system is required for normal vascular development inthe retina and for vascular survival in the cochlea. In mammals, the pattern of Ndp expression beyondthe retina is poorly defined due to the low abundance of Norrin mRNA and protein. Here, we characterizeNdp expression during mouse development by studying a knock-in mouse that carries the codingsequence of human placental alkaline phosphatase (AP) inserted at the Ndp locus (Ndp(AP)). In the CNS,Ndp(AP) expression is apparent by E10.5 and is dynamic and complex. The anatomically delimitedregions of Ndp(AP) expression observed prenatally in the CNS are replaced postnatally by widespreadexpression in astrocytes in the forebrain and midbrain, Bergman glia in the cerebellum, and Müller glia inthe retina. In the developing and adult cochlea, Ndp(AP) expression is closely associated with two denselyvascularized regions, the stria vascularis and a capillary plexus between the organ of Corti and the spiralganglion. These observations suggest the possibility that Norrin may have developmental and/orhomeostatic functions beyond the retina and cochlea.", "metadata": {}}
+{"_id": "30303335", "title": "", "text": "Control of NFAT Isoform Activation and NFAT-Dependent Gene Expression through Two Coincident andSpatially Segregated Intracellular Ca2+ SignalsExcitation-transcription coupling, linking stimulation at thecell surface to changes in nuclear gene expression, is conserved throughout eukaryotes. How closelyrelated coexpressed transcription factors are differentially activated remains unclear. Here, we show thattwo Ca2+-dependent transcription factor isoforms, NFAT1 and NFAT4, require distinct sub-cellular InsP3and Ca2+ signals for physiologically sustained activation. NFAT1 is stimulated by sub-plasmalemmalCa2+ microdomains, whereas NFAT4 additionally requires Ca2+ mobilization from the inner nuclearenvelope by nuclear InsP3 receptors. NFAT1 is rephosphorylated (deactivated) more slowly than NFAT4 inboth cytoplasm and nucleus, enabling a more prolonged activation phase. Oscillations in cytoplasmicCa2+, long considered the physiological form of Ca2+ signaling, play no role in activating either NFATprotein. Instead, effective sustained physiological activation of NFAT4 is tightly linked to oscillations innuclear Ca2+. Our results show how gene expression can be controlled by coincident yet geographicallydistinct Ca2+ signals, generated by a freely diffusible InsP3 message.", "metadata": {}}
+{"_id": "30351165", "title": "", "text": "Brain region-specific up-regulation of mouse apolipoprotein E by pharmacological estrogentreatments.Cerebral apolipoprotein E (apoE) has been implicated in neuronal protection and repair. Dueto the variable levels and types of estrogen receptors within different brain regions, the effect of estrogenon apoE and the mechanism of this effect may vary within different regions. Ovariectomized femaleC57BL/6 mice were treated with pharmacological levels of 17 beta-estradiol or placebo for 5 days,resulting in supraphysiological plasma levels of estradiol in the treated mice. ApoE and glial fibrillaryacidic protein (GFAP) levels were measured in the cortex, hippocampus and diencephalon. 17beta-Estradiol up-regulated apoE but not GFAP in the cortex and diencephalon, whereas in thehippocampus, GFAP and apoE were equally up-regulated. Treatment of estrogen receptor (ER) alphaknockout mice with 17 beta-estradiol or treatment of C57BL/6 mice with 17 alpha-estradiol, a poorestrogen receptor agonist, specifically induced apoE in the cortex, but not in the diencephalon. Theseresults indicate that 17 beta-estradiol effects on apoE are either directly or indirectly mediated by ERalpha in the diencephalon, while the effects in the cortex may be mediated by a non-classical mechanismor by ER beta. Measurement of mRNA levels in estrogen versus placebo-treated wild-type mice indicatedthat the effect of 17 beta-estradiol on apoE was not associated with changes in apoE mRNA levels.", "metadata": {}}
+{"_id": "30353437", "title": "", "text": "ATM and ataxia telangiectasia.Ataxia telangiectasia (AT) has long intrigued the biomedical researchcommunity owing to the spectrum of defects that are characteristic of the disease, includingneurodegeneration, immune dysfunction, radiosensitivity and cancer predisposition. Following theidentification of mutations in ATM (ataxia telangiectasia, mutated) as the underlying cause of the disease,biochemical analysis of this protein kinase has shown that it is a crucial nexus for the cellular response toDNA double-stranded breaks. Many ATM kinase substrates are important players in the cellular responsesthat prevent cancer. Accordingly, AT is a disease that results from defects in the response to specifictypes of DNA damage. Thus, although it is a rare neurodegenerative disease, understanding the biologyof AT will lead to a greater understanding of the fundamental processes that underpin cancer andneurodegeneration.", "metadata": {}}
+{"_id": "30369606", "title": "", "text": "A novel immortalized human endometrial stromal cell line with normal progestational response.Obtainingprimary human endometrial stromal cells (HESCs) for in vitro studies is limited by the scarcity ofadequate human material and the inability to passage these cells in culture for long periods.Immortalization of these cells would greatly facilitate studies; however, the process of immortalizationoften results in abnormal karyotypes and aberrant functional characteristics. To meet this need, we haveintroduced telomerase into cultured HESCs to prevent the normal shortening of telomeres observed inadult somatic cells during mitosis. We have now developed and analyzed a newly immortalized HESC linethat contains no clonal chromosomal structural or numerical abnormalities. In addition, when comparedwith the primary unpassaged parent cells, the new cell line displayed similar biochemical endpoints aftertreatment with ovarian steroids. Classical decidualization response to estradiol plus medroxyprogesteroneacetate were seen in both morphologically, and progestin was seen to induce or regulate the expressionof IGF binding protein-1, fibronectin, prolactin, tissue factor, plasminogen activator inhibitor-1, andFas/Fas ligand. In summary, an immortalized HESC line has been developed that is karyotypically,morphologically, and phenotypically similar to the primary parent cells, and it is a powerful and consistentresource for in vitro work.", "metadata": {}}
+{"_id": "30379039", "title": "", "text": "Comparison of the intrinsic kinase activity and substrate specificity of c-Abl and Bcr-Abl.We studied theintrinsic tyrosine kinase activity and substrate specificity of c-Abl and Bcr-Abl protein tyrosine kinases(PTKs) using the peptide substrates discovered from a synthetic combinatorial peptide library. Our dataindicate that the phosphorylation of these peptides by Bcr-Abl was consistently stronger than that byc-Abl. Bcr-Abl also showed substrate preference towards those peptides with one or more positivecharges.", "metadata": {}}
+{"_id": "30398773", "title": "", "text": "Strong association between respiratory viral infection early after hematopoietic stem cell transplantationand the development of life-threatening acute and chronic alloimmune lung syndromes.Alloimmune lungsyndromes (allo-LS), including idiopathic pneumonia syndrome, bronchiolitis obliterans syndrome, andbronchiolitis obliterans organizing pneumonia, are severe complications after hematopoietic stem celltransplantation (HSCT). In our cohort of 110 pediatric patients, 30 had allo-LS (27.3%), 18 withidiopathic pneumonia syndrome and 12 with bronchiolitis obliterans syndrome. Multivariate analysisshowed that respiratory viral infection early after HSCT is an important predictor for the development ofallo-LS (P <.0001). This was true for all viruses tested. In multivariate analysis, allo-LS was the onlypredictor for higher mortality (P = .04). Paradoxically, prolonged administration of immunosuppressiveagents because of acute graft-versus-host disease had a protective effect on the development of allo-LS(P = .004). We hypothesize that early infection of the respiratory tract with a common cold virus makesthe lungs a target for alloimmunity.", "metadata": {}}
+{"_id": "30437264", "title": "", "text": "Hepatitis C virus blocks interferon effector function by inducing protein kinase R phosphorylation.HepatitisC virus (HCV) is a single-stranded RNA virus encoding a single polyprotein whose translation is driven byan internal ribosome entry site (IRES). HCV infection strongly induces antiviral interferon-stimulated gene(ISG) expression in the liver, yet it persists, suggesting that HCV can block ISG effector function. We nowshow that HCV infection triggers phosphorylation and activation of the RNA-dependent protein kinasePKR, which inhibits eukaryotic translation initiation factor eIF2 alpha and attenuates ISG proteinexpression despite normal ISG mRNA induction. ISG protein induction is restored and the antiviral effectsof interferon are enhanced when PKR expression is suppressed in interferon-treated infected cells.Whereas host protein translation, including antiviral ISGs, is suppressed by activated PKR, HCVIRES-dependent translation is not. These results suggest that the ability of HCV to activate PKR may,paradoxically, be advantageous for the virus during an IFN response by preferentially suppressing thetranslation of ISGs.", "metadata": {}}
+{"_id": "30464859", "title": "", "text": "The influence of denervation on grafted hindlimb regeneration of larval Xenopus laevis.The aim of thepresent research is to ascertain whether in larval Xenopus laevis nerve-independence for theregeneration of early stage limbs and nerve-dependence of late stage limbs observed in a previous work(Filoni and Paglialunga, '90) is related to extrinsic (systemic) factors or to intrinsic changes taking placein the limb cells themselves during development. In this paper the regenerative capacity of early and latestage hindlimbs under the same extrinsic conditions, insofar as both are grafted onto the denervatedhindlimbs of host larvae at the same developmental stage, is studied. All the grafted limbs are amputatedafter the host larvae have reached stage 57-58 (according to Nieuwkoop and Faber, '56). In experimentI, the grafted limb is amputated at stage 52, at the thigh level; in experiment II, the grafted limb isamputated at stage 54-55, at the tarsalia level; in experiment III the grafted limb is amputated at stage57, at the tarsalia level. In all three experiments, together with the grafted limb, also the host limb isamputated at the tarsalia level. The results show that while grafted limbs amputated at stages 52 and54-55 regenerate in the absence of nerves, grafted limbs amputated at stage 57 cannot. The failure oflate stage grafted limbs to regenerate cannot be explained in terms of an immune-type inhibiting reactionsince it has been observed also in denervated autografted limbs and in the host limbs. Since all thegrafted limbs are in the same environmental conditions, the results show that in larval Xenopus laevisnerve-independence for regeneration of early stage limbs and nerve-dependence of late stage limbs arenot related to factors extrinsic to the limb but to intrinsic changes taking place in the limb cellsthemselves during development.", "metadata": {}}
+{"_id": "30468386", "title": "", "text": "Adult c-Kit(+) progenitor cells are necessary for maintenance and regeneration of olfactory neurons.Theolfactory epithelium houses chemosensory neurons, which transmit odor information from the nose to thebrain. In adult mammals, the olfactory epithelium is a uniquely robust neuroproliferative zone, with theability to replenish its neuronal and non-neuronal populations due to the presence of germinal basal cells.The stem and progenitor cells of these germinal layers, and their regulatory mechanisms, remainincompletely defined. Here we show that progenitor cells expressing c-Kit, a receptor tyrosine kinasemarking stem cells in a variety of embryonic tissues, are required for maintenance of the adultneuroepithelium. Mouse genetic fate-mapping analyses show that embryonically, a c-Kit(+) populationcontributes to olfactory neurogenesis. In adults under conditions of normal turnover, there is relativelysparse c-Kit(+) progenitor cell (ckPC) activity. However, after experimentally induced neuroepithelialinjury, ckPCs are activated such that they reconstitute the neuronal population. There are also occasionalnon-neuronal cells found to arise from ckPCs. Moreover, the selective depletion of the ckPC population,utilizing temporally controlled targeted diphtheria toxin A expression, results in failure of neurogenesisafter experimental injury. Analysis of this model indicates that most ckPCs reside among the globosebasal cell populations and act downstream of horizontal basal cells, which can serve as stem cells.Identification of the requirement for olfactory c-Kit-expressing progenitors in olfactory maintenanceprovides new insight into the mechanisms involved in adult olfactory neurogenesis. Additionally, wedefine an important and previously unrecognized site of adult c-Kit activity.", "metadata": {}}
+{"_id": "30471052", "title": "", "text": "Neurogenin3: a master regulator of pancreatic islet differentiation and regeneration.The basichelix-loop-helix transcription factor neurogenin-3 (Ngn3, Neurog3) is critical for the development of theendocrine cells of the islets. Either disrupted or forced expression of Ngn3 early in mouse pancreasdevelopment abrogates the formation of islets. The successive waves of Ngn3 expression that occurduring the primary and secondary transitions of endocrine cell development temporally determine thefour distinct endocrine cell lineages, α, β, PP, and δ cells that express glucagon, insulin, pancreaticpolypeptide, and somatostatin, respectively. During islet regeneration after injury of the adult mousepancreas, such as by duct ligation or streptozotocin, Ngn3 is activated in duct-associated stem/progenitorcells that transform into alpha and/or beta cells (Xu et al, Collombat et al). The important role of Ngn3 asa master regulator of endocrine pancreas development directs attention to finding therapeutic approachesto enhance Ngn3 expression in diabetes as a means to increase beta cell mass and functions.", "metadata": {}}
+{"_id": "30492966", "title": "", "text": "Detection of Mycoplasmas in Patients with Amyotrophic Lateral SclerosisAmyotrophic Lateral Sclerosis(ALS) is a progressive degenerative  disease of the motor neurons and the cause is unknown. Diversefactors such as  genetic defects, nutritional deficiencies, head trauma, environmental toxin,  autoimmuneresponses and viral and bacterial infections are involved. Mycoplasmas  have been implicated as causalagents of different illnesses in human. The  purpose of this study was to investigate the presence ofmycoplasmas in  the bloodstream of patients with ALS. Patients with ALS and healthy individuals  wereincluded in the study. A blood sample was taken in tubes with or without  anticoagulant. Mycoplasmaswere detected by culture or direct PCR, and the  presence of antibodies IgM and IgG against LAMPs ofthese microorganisms by  Western blot. Cultures for aerobic facultative bacteria were also done. Bloodsamples  from 13 patients and 44 healthy individuals were screened. All blood cultures  fornon-fermentative mycoplasmas and aerobic facultative bacteria were  negative. Cultures for fermentativemycoplasmas were considered positive after  identification of mycoplasmal DNA by PCR. Mycoplasma sp.was detected by culture or  direct PCR in 6/13 (46%) patients and in 4/44 (9%) of healthy individuals. M.fermentans was detected by PCR using  specific primers in six patients and in two healthy individuals.IgM against  LAMPs of M. fermentans were detected  in 6/13 (46%) blood samples from patients and in13/44 (30%) from healthy  individuals, while. IgG was detected in 4/13 (31%) patients and in 3/44(7%)  healthy individuals. The results of this study show that mycoplasmas cause a  systemic infectionand could play a role in the origin or progression of the  ALS.", "metadata": {}}
+{"_id": "30500829", "title": "", "text": "Correlation and variable importance in random forestsThis paper is about variable selection with therandom forests algorithm in presence of correlated predictors. In high-dimensional regression orclassification frameworks, variable selection is a difficult task, that becomes even more challenging in thepresence of highly correlated predictors. Firstly we provide a theoretical study of the permutationimportance measure for an additive regression model. This allows us to describe how the correlationbetween predictors impacts the permutation importance. Our results motivate the use of the RecursiveFeature Elimination (RFE) algorithm for variable selection in this context. This algorithm recursivelyeliminates the variables using permutation importance measure as a ranking criterion. Next varioussimulation experiments illustrate the efficiency of the RFE algorithm for selecting a small number ofvariables together with a good prediction error. Finally, this selection algorithm is tested on the LandsatSatellite data from the UCI Machine Learning Repository.", "metadata": {}}
+{"_id": "30507607", "title": "", "text": "An Oct4-Centered Protein Interaction Network in Embryonic Stem CellsTranscription factors, such asOct4, are critical for establishing and maintaining pluripotent cell identity. Whereas the genomic locationsof several pluripotency transcription factors have been reported, the spectrum of their interactionpartners is underexplored. Here, we use an improved affinity protocol to purify Oct4-interacting proteinsfrom mouse embryonic stem cells (ESCs). Subsequent purification of Oct4 partners Sall4, Tcfcp2l1, Dax1,and Esrrb resulted in an Oct4 interactome of 166 proteins, including transcription factors andchromatin-modifying complexes with documented roles in self-renewal, but also many factors notpreviously associated with the ESC network. We find that Esrrb associated with the basal transcriptionmachinery and also detect interactions between transcription factors and components of the TGF-beta,Notch, and Wnt signaling pathways. Acute depletion of Oct4 reduced binding of Tcfcp2l1, Dax1, and Esrrbto several target genes. In conclusion, our purification protocol allowed us to bring greater definition tothe circuitry controlling pluripotent cell identity.", "metadata": {}}
+{"_id": "30534237", "title": "", "text": "GABA(B) receptor 1 polymorphism (G1465A) is associated with temporal lobe epilepsy.BACKGROUNDDysfunction of gamma-aminobutyric acid (GABA) (B) receptors has been implicated in the pathogenesisof temporal lobe epilepsy (TLE). OBJECTIVE To evaluate the genetic contribution of cloned humanGABA(B) receptors to TLE. METHODS The authors genotyped 141 patients (78 women and 63 men; meanage = 49.1 +/- 18.0 years) with nonlesional TLE and 372 age- and sex-matched normal individuals forthe known polymorphism G1465A in the human GABA(B) receptor 1 [GABA(B[1])] gene. RESULTS Therewas a highly significant overrepresentation of the G1465A heterozygote in patients with TLE comparedwith controls. The A/G genotype was found in 17% of the 141 patients with TLE and in only 0.5% of the372 controls (p < 0.0001). The authors also found that patients carrying the A allele had a significantlyhigher risk (p = 0.003, OR = 6.47, 95% CI = 2.02 to 20.76) of developing drug-resistant TLE.Furthermore, the age at onset of seizures tended to be lower in patients with A/G genotype, but thedifference was not significant. CONCLUSIONS The results of this study indicate that the GABA(B[1])polymorphism (G1465A) confers a highly increased susceptibility to TLE. Moreover, it seems to influencethe severity of this common epileptic disorder.", "metadata": {}}
+{"_id": "30543439", "title": "", "text": "Crystal structure, biochemical and cellular activities demonstrate separate functions of MTH1 andMTH2Deregulated redox metabolism in cancer leads to oxidative damage to cellular components includingdeoxyribonucleoside triphosphates (dNTPs). Targeting dNTP pool sanitizing enzymes, such as MTH1, is ahighly promising anticancer strategy. The MTH2 protein, known as NUDT15, is described as the secondhuman homologue of bacterial MutT with 8-oxo-dGTPase activity. We present the first NUDT15 crystalstructure and demonstrate that NUDT15 prefers other nucleotide substrates over 8-oxo-dGTP. Keystructural features are identified that explain different substrate preferences for NUDT15 and MTH1. Wefind that depletion of NUDT15 has no effect on incorporation of 8-oxo-dGTP into DNA and does not impactcancer cell survival in cell lines tested. NUDT17 and NUDT18 were also profiled and found to have far lessactivity than MTH1 against oxidized nucleotides. We show that NUDT15 is not a biologically relevant8-oxo-dGTPase, and that MTH1 is the most prominent sanitizer of the cellular dNTP pool known to date.", "metadata": {}}
+{"_id": "30553457", "title": "", "text": "De novo expression of Trpm4 initiates secondary hemorrhage in spinal cord injuryThe role of transientreceptor potential M4 (Trpm4), an unusual member of the Trp family of ion channels, is poorlyunderstood. Using rodent models of spinal cord injury, we studied involvement of Trpm4 in theprogressive expansion of secondary hemorrhage associated with capillary fragmentation, the mostdestructive mechanism of secondary injury in the central nervous system. Trpm4 mRNA and protein wereabundantly upregulated in capillaries preceding their fragmentation and formation of petechialhemorrhages. Trpm4 expression in vitro rendered COS-7 cells highly susceptible to oncotic swelling andoncotic death following ATP depletion. After spinal cord injury, in vivo gene suppression in rats treatedwith Trpm4 antisense or in Trpm4−/− mice preserved capillary structural integrity, eliminated secondaryhemorrhage, yielded a threefold to fivefold reduction in lesion volume and produced a substantialimprovement in neurological function. To our knowledge, this is the first example of a Trp channel thatmust undergo de novo expression for manifestation of central nervous system pathology.", "metadata": {}}
+{"_id": "30580263", "title": "", "text": "Differential expression of bcl-2 in intestinal epithelia. Correlation with attenuation of apoptosis in coloniccrypts and the incidence of colonic neoplasia.The cell-positional incidence of both spontaneous anddamage-induced apoptosis of epithelial cells was assessed in longitudinal sections of the crypts of smallintestine and colon of BDF1 mice. This was compared, using immunohistochemistry, with the pattern ofexpression of bcl-2, a suppressor of apoptosis. In the small intestine, apoptosis was maximal around cellposition 4 from the base of the crypt; this closely corresponds to the position considered to contain thestem cells. In the colon, however, apoptosis was not confined to the area considered to harbour the stemcells (position 1 and 2). Instead, apoptosis was attenuated and distributed along the length of the crypt.Some cells at the base of murine colonic crypts expressed bcl-2 protein, whereas bcl-2 was absent in thecrypts of the small intestine. Most pertinently, bcl-2 was absent from small intestinal crypt cells atpositions 4-5 (the stem cell region). The importance of the expression of bcl-2 to the attenuation ofapoptosis in stem cells was confirmed by analysis of the levels of both spontaneous and inducedapoptosis in homozygously bcl-2 null C57BL/6 mice: in colonic crypts the level of spontaneous apoptosisrose significantly, and selectively at the base of the crypt, in comparison with crypts from wild-typeanimals. In contrast, there was no rise in spontaneous apoptosis in the small intestinal crypts from thebcl-2 null animals. Analysis of sections of human colon and small intestine also showed that expression ofbcl-2 was confined to the base of the colonic crypt. The attenuation of apoptosis by bcl-2 in the region ofthe stem cells of the colonic crypts may dispose these to neoplastic transformation. Indeed, analysis ofhuman carcinomas revealed expression of bcl-2, which in some samples was reciprocal with theexpression of p53.", "metadata": {}}
+{"_id": "30639847", "title": "", "text": "Aortic stiffness, blood pressure progression, and incident hypertension.CONTEXT Vascular stiffnessincreases with advancing age and is a major risk factor for age-related morbidity and mortality. Vascularstiffness and blood pressure pulsatility are related; however, temporal relationships between vascularstiffening and blood pressure elevation have not been fully delineated. OBJECTIVE To examine temporalrelationships among vascular stiffness, central hemodynamics, microvascular function, and bloodpressure progression. DESIGN, SETTING, AND PARTICIPANTS Longitudinal community-based cohortstudy conducted in Framingham, Massachusetts. The present investigation is based on the 2 latestexamination cycles (cycle 7: 1998-2001; cycle 8: 2005-2008 [last visit: January 25, 2008]) of theFramingham Offspring study (recruited: 1971-1975). Temporal relationships among blood pressure and 3measures of vascular stiffness and pressure pulsatility derived from arterial tonometry (carotid-femoralpulse wave velocity [CFPWV], forward wave amplitude [FWA], and augmentation index) were examinedover a 7-year period in 1759 participants (mean [SD] age: 60 [9] years; 974 women). MAIN OUTCOMEMEASURES The primary outcomes were blood pressure and incident hypertension during examinationcycle 8. The secondary outcomes were CFPWV, FWA, and augmentation index during examination cycle8. RESULTS In a multivariable-adjusted regression model, higher FWA (β, 1.3 [95% CI, 0.5-2.1] mm Hgper 1 SD; P = .002) and higher CFPWV (β, 1.5 [95% CI, 0.5-2.6] mm Hg per 1 SD; P = .006) duringexamination cycle 7 were jointly associated with systolic blood pressure during examination cycle 8.Similarly, in a model that included systolic and diastolic blood pressure and additional risk factors duringexamination cycle 7, higher FWA (odds ratio [OR], 1.6 [95% CI, 1.3-2.0] per 1 SD; P < .001),augmentation index (OR, 1.7 [95% CI, 1.4-2.0] per 1 SD; P < .001), and CFPWV (OR, 1.3 [95% CI,1.0-1.6] per 1 SD; P = .04) were associated with incident hypertension during examination cycle 8 (338cases [32%] in 1048 participants without hypertension during examination cycle 7). Conversely, bloodpressure during examination cycle 7 was not associated with CFPWV during examination cycle 8. Higherresting brachial artery flow (OR, 1.23 [95% CI, 1.04-1.46]) and lower flow-mediated dilation (OR, 0.80[95% CI, 0.67-0.96]) during examination cycle 7 were associated with incident hypertension (in modelsthat included blood pressure and tonometry measures collected during examination cycle 7).CONCLUSION In this cohort, higher aortic stiffness, FWA, and augmentation index were associated withhigher risk of incident hypertension; however, initial blood pressure was not independently associatedwith risk of progressive aortic stiffening.", "metadata": {}}
+{"_id": "30655442", "title": "", "text": "The EMBL nucleotide sequence database.The EMBL Nucleotide Sequence Database(http://www.ebi.ac.uk/embl. html ) constitutes Europe's primary nucleotide sequence resource. DNA andRNA sequences are directly submitted from researchers and genome sequencing groups and collectedfrom the scientific literature and patent applications (Fig. 1). In collaboration with DDBJ and GenBank thedatabase is produced, maintained and distributed at the European Bioinformatics Institute. Databasereleases are produced quarterly and are distributed on CD-ROM. EBI's network services allow access tothe most up-to-date data collection via Internet and World Wide Web interface, providing databasesearching and sequence similarity facilities plus access to a large number of additional databases.", "metadata": {}}
+{"_id": "30658796", "title": "", "text": "Anaphase catastrophe is a target for cancer therapy.Neoplastic cells are genetically unstable. Strategiesthat target pathways affecting genome instability can be exploited to disrupt tumor cell growth,potentially with limited consequences to normal cells. Chromosomal instability (CIN) is one type ofgenome instability characterized by mitotic defects that increase the rate of chromosomemis-segregation. CIN is frequently caused by extra centrosomes that transiently disrupt normal bipolarspindle geometry needed for accurate chromosome segregation. Tumor cells survive with extracentrosomes because of biochemical pathways that cluster centrosomes and promote chromosomesegregation on bipolar spindles. Recent work shows that targeted inhibition of these pathways preventscentrosome clustering and forces chromosomes to segregate to multiple daughter cells, an eventtriggering apoptosis that we refer to as anaphase catastrophe. Anaphase catastrophe specifically killstumor cells with more than 2 centrosomes. This death program can occur after genetic or pharmacologicinhibition of cyclin dependent kinase 2 (Cdk2) and is augmented by combined treatment with amicrotubule inhibitor. This proapoptotic effect occurs despite the presence of ras mutations in cancercells. Anaphase catastrophe is a previously unrecognized mechanism that can be pharmacologicallyinduced for apoptotic death of cancer cells and is, therefore, appealing to engage for cancer therapy andprevention.", "metadata": {}}
+{"_id": "30675656", "title": "", "text": "Dishevelled Activates JNK and Discriminates between JNK Pathways in Planar Polarity and winglessSignalingFrizzled family proteins have been described as receptors of Wnt signaling molecules. InDrosophila, the two known Frizzled proteins are associated with distinct developmental processes.Genesis of epithelial planar polarity requires Frizzled, whereas Dfz2 affects morphogenesis bywingless-mediated signaling. Dishevelled is required in both signaling pathways. Here, we use geneticand overexpression assays to show that Dishevelled activates JNK cascades. Rescue analysis revealsdifferent protein domain requirements in Dishevelled for the two pathways; the C-terminal DEP domain isessential to rescue planar polarity defects and induce JNK signaling. Furthermore, the planarpolarity-specific dsh1 allele is mutated in the DEP domain. Our results indicate that different Wnt/Fzsignals activate distinct intracellular pathways, and Dishevelled discriminates among them by distinctdomain interactions.", "metadata": {}}
+{"_id": "30714190", "title": "", "text": "Genome-wide lineage-specific transcriptional networks underscore Ikaros-dependent lymphoid priming inhematopoietic stem cells.The mechanisms regulating lineage potential during early hematopoiesis wereinvestigated. First, a cascade of lineage-affiliated gene expression signatures, primed in hematopoieticstem cells (HSCs) and differentially propagated in lineage-restricted progenitors, was identified.Lymphoid transcripts were primed as early as the HSC, together with myeloid and erythroid transcripts.Although this multilineage priming was resolved upon subsequent lineage restrictions, an unexpectedcosegregation of lymphoid and myeloid gene expression and potential past a nominal myeloid restrictionpoint was identified. Finally, we demonstrated that whereas the zinc finger DNA-binding factor Ikaros wasrequired for induction of lymphoid lineage priming in the HSC, it was also necessary for repression ofgenetic programs compatible with self-renewal and multipotency downstream of the HSC. Takentogether, our studies provide new insight into the priming and restriction of lineage potentials duringearly hematopoiesis and identify Ikaros as a key bivalent regulator of this process.", "metadata": {}}
+{"_id": "30720103", "title": "", "text": "Vitamin D status: measurement, interpretation, and clinical application.Vitamin D, the sunshine vitamin,is now recognized not only for its importance in promoting bone health in children and adults but also forother health benefits, including reducing the risk of chronic diseases such as autoimmune diseases,common cancer, and cardiovascular disease. Vitamin D made in the skin or ingested in the diet isbiologically inert and requires 2 successive hydroxylations first in the liver on carbon 25 to form25-hydroxyvitamin D [25(OH)D], and then in the kidney for a hydroxylation on carbon 1 to form thebiologically active form of vitamin D, 1,25-dihydroxyvitamin D [1,25(OH)(2)D]. With the identification of25(OH)D and 1,25(OH)(2)D, methods were developed to measure these metabolites in the circulation.Serum 25(OH)D is the barometer for vitamin D status. Serum 1,25(OH)(2)D provides no informationabout vitamin D status and is often normal or even increased as the result of secondaryhyperparathyroidism associated with vitamin D deficiency. Most experts agree that 25(OH)D of <20ng/mL is considered to be vitamin D deficiency, whereas a 25(OH)D of 21-29 ng/mL is considered to beinsufficient. The goal should be to maintain both children and adults at a level >30 ng/mL to take fulladvantage of all the health benefits that vitamin D provides.", "metadata": {}}
+{"_id": "30741007", "title": "", "text": "Lessons from the past: managing insecticide resistance in malaria control and eradicationprogrammes.The distribution of insecticide-treated bednets to help combat the burden of malaria insub-Saharan Africa has accelerated in the past 5 years. Additionally, many countries are also considering,or have already begun, indoor residual spraying campaigns. These are positive developments, sincevector control has repeatedly proven to be an effective means of reducing malaria transmission.However, the sustainability of these insecticide-based interventions relies on the continuing susceptibilityof the anopheles vectors to the limited number of available insecticides. Continual monitoring for earlysigns of insecticide resistance and the adoption of carefully considered resistance management strategiesare therefore required. Regrettably, this essential monitoring component is frequently given a low priorityin the push to meet ambitious coverage targets. We outline the key requirements for establishing aninsecticide resistance surveillance system and urge all those involved in malaria vector control, eitherdirectly or as facilitators, to ensure that these measures are incorporated into control programmes.Failure to act now will inevitably lead to a future breakdown in disease control and jeopardise hopes oferadicating this major public-health problem.", "metadata": {}}
+{"_id": "30774694", "title": "", "text": "T helper 2 cytokines inhibit autophagic control of intracellular Mycobacterium tuberculosis.Autophagy is arecently recognized immune effector mechanism against intracellular pathogens. The role of autophagy ininnate immunity has been well established, but the extent of its regulation by the adaptive immuneresponse is less well understood. The T helper 1 (Th1) cell cytokine IFN-gamma induces autophagy inmacrophages to eliminate Mycobacterium tuberculosis. Here, we report that Th2 cytokines affectautophagy in macrophages and their ability to control intracellular M. tuberculosis. IL-4 and IL-13abrogated autophagy and autophagy-mediated killing of intracellular mycobacteria in murine and humanmacrophages. Inhibition of starvation-induced autophagy by IL-4 and IL-13 was dependent on Aktsignaling, whereas the inhibition of IFN-gamma-induced autophagy was Akt independent and signaltransducer and activator of transcription 6 (STAT6) dependent. These findings establish a mechanismthrough which Th1-Th2 polarization differentially affects the immune control of intracellular pathogens.", "metadata": {}}
+{"_id": "30786800", "title": "", "text": "Lipid-based nutrient supplement increases the birth size of infants of primiparous women inGhana.BACKGROUND The International Lipid-Based Nutrient Supplements Project developed asmall-quantity (20 g/d) lipid-based nutrient supplement (LNS) for pregnant and lactating women.OBJECTIVE We evaluated the effects of prenatal LNS supplementation on fetal growth. DESIGN In acommunity-based, partially double-blind, individually randomized controlled trial, 1320 women ≤20 wkpregnant received 60 mg Fe/400 μg folic acid (IFA), or 1-2 Recommended Dietary Allowances of 18micronutrients, including 20 mg Fe (MMN), or LNS with the same micronutrients as the MMN group, plus4 minerals and macronutrients contributing 118 kcal (LNS) daily until delivery. Fetal growth wascompared across groups by using intention-to-treat analysis. The primary outcome was birth length.RESULTS This analysis included 1057 women (IFA = 349, MMN = 354, LNS = 354). Groups did not differsignificantly in mean birth length, length-for-age z score (LAZ), head circumference, or percentage lowbirth length but differed in mean birth weight (P = 0.044), weight-for-age z score (WAZ; P = 0.046), andBMI-for-age z score (BMIZ; P = 0.040), with a trend toward differences in low birth weight (P = 0.069).In pairwise comparisons, the LNS group had greater mean birth weight (+85 g; P = 0.040), WAZ (+0.19;P = 0.045), and BMIZ (+0.21; P = 0.035) and a lower risk of low birth weight (RR: 0.61, 95% CI: 0.39,0.96; P = 0.032) than did the IFA group. The other group differences were not significant. The effect ofintervention was modified by mother's parity, age, height, baseline hemoglobin, household foodinsecurity, and child sex, with parity being the most consistent modifier. Among primiparous women (IFA= 131; MMN = 110; LNS = 128), the LNS group had greater mean birth length (+0.91 cm; P = 0.001),LAZ (+0.47; P = 0.001), weight (+237 g; P < 0.001), WAZ (+0.56; P < 0.001), BMIZ (+0.52; P <0.001), head circumference (0.50 cm; P = 0.017), and head circumference-for-age z score (+0.40; P =0.022) than did the IFA group; similar differences were found when comparing the LNS and MMN groupsamong primiparous women, and no group differences were found among multiparous women.CONCLUSION Prenatal LNS supplementation can improve fetal growth among vulnerable women inGhana, particularly primiparous women. This trial was registered at clinicaltrials.gov as NCT00970866.", "metadata": {}}
+{"_id": "30805636", "title": "", "text": "Peroxisome proliferator-activated receptor ligand bezafibrate for prevention of type 2 diabetes mellitus inpatients with coronary artery disease.BACKGROUND Recent studies have shown that type 2 diabetes ispreventable by both lifestyle interventions and medications that influence primary glucose metabolism.Whether pharmacological interventions that influence primary lipid metabolism can also delaydevelopment of type 2 diabetes is unknown. The goal of this study was to evaluate the effect of theperoxisome proliferator-activated receptor ligand bezafibrate on the progression of impaired fastingglucose phase to type 2 diabetes in patients with coronary artery disease over a 6.2-year follow-upperiod. METHODS AND RESULTS The study sample comprised 303 nondiabetic patients 42 to 74 years ofage with a fasting blood glucose level of 110 to 125 mg/dL (6.1 to 6.9 mmol/L). The patients receivedeither 400 mg bezafibrate retard (156 patients) or placebo (147 patients) once a day. No patients wereusing statins, and use of ACE inhibitors, which also reduce diabetes incidence, was relatively low. Duringfollow-up, development of new-onset diabetes was recorded in 146 patients: in 80 (54.4%) from theplacebo group and 66 (42.3%) from the bezafibrate group (P=0.04). The mean time until onset of newdiabetes was significantly delayed in patients on bezafibrate compared with patients on placebo:4.6+/-2.3 versus 3.8+/-2.6 years (P=0.004). Multivariate analysis identified bezafibrate treatment as anindependent predictor of reduced risk of new diabetes development (hazard ratio, 0.70; 95% CI, 0.49 to0.99). Other significant variables associated with future overt type 2 diabetes in patients with impairedfasting glucose were total cholesterol level (hazard ratio, 1.22; 95% CI 1.0 to 1.51) and body mass index(hazard ratio, 1.10; 95% CI, 1.05 to 1.16). CONCLUSIONS Bezafibrate reduces the incidence and delaysthe onset of type 2 diabetes in patients with impaired fasting glucose. Whether the combination ofbezafibrate with other recommended drugs for secondary prevention (statins and ACE inhibitors) wouldbe as efficacious as suggested by our results remains to be determined.", "metadata": {}}
+{"_id": "30813140", "title": "", "text": "Familial occurrence of chronic tension-type headache.Chronic tension-type headache (CTTH) assessed byproband report was evaluated in a family study of CTTH. A clinical interview of first-degree relatives by aphysician was used as index of validity. Familial occurrence of CTTH in first-degree relatives was alsoinvestigated. Patterns of familial aggregation of CTTH were assessed by calculating the populationrelative risk. A neurological resident carried out all the interviews of probands and their first-degreerelatives. The operational diagnostic criteria of the International Headache Society were used. The 122probands had 377 first-degree relatives. Sensitivity, specificity, predictive values, and chance-correctedagreement rate for the diagnosis CTTH were 68%, 86%, 53% (PVpos), 92% (PVneg), and 0.48,respectively. The low sensitivity of CTTH assessed by proband report indicates that a clinical interview bya physician is necessary in family studies of CTTH. Clinically interviewed parents, siblings, and childrenhad a 2.1 to 3.9-fold significantly increased risk of CTTH compared with the general population. Thegender of the probands did not influence the risk of CTTH among first-degree relatives. The significantlyincreased familial risk of CTTH and no increased risk of CTTH in spouses suggest that a genetic factor isinvolved in CTTH.", "metadata": {}}
+{"_id": "30835854", "title": "", "text": "Complex formation of SMAP/KAP3, a KIF3A/B ATPase motor-associated protein, with a humanchromosome-associated polypeptide.We have recently isolated SMAP (Smg GDS-associated protein; SmgGDS: small G protein GDP dissociation stimulator) as a novel Smg GDS-associated protein, which hasArmadillo repeats and is phosphorylated by Src tyrosine kinase. SMAP is a human counterpart of mouseKAP3 (kinesin superfamily-associated protein) that is associated with mouse KIF3A/B (a kinesinsuperfamily protein), which functions as a microtubule-based ATPase motor for organelle transport. Weisolated here a SMAP-interacting protein from a human brain cDNA library, identified it to be a humanhomolog of Xenopus XCAP-E (Xenopus chromosome-associated polypeptide), a subunit of condensinsthat regulate the assembly and structural maintenance of mitotic chromosomes, and named it HCAP(Human chromosome-associated polypeptide). Tissue and subcellular distribution analyses indicated thatHCAP was ubiquitously expressed and highly concentrated in the nuclear fraction, where SMAP and KIF3Bwere also present. SMAP was extracted as a ternary complex with HCAP and KIF3B from the nuclearfraction in the presence of Mg-ATP. The results suggest that SMAP/KAP3 serves as a linker between HCAPand KIF3A/B in the nucleus, and that SMAP/KAP3 plays a role in the interaction of chromosomes with anATPase motor protein.", "metadata": {}}
+{"_id": "30844602", "title": "", "text": "Surveillance for foodborne-disease outbreaks--United States, 1993-1997.PROBLEM/CONDITION Since1973, CDC has maintained a collaborative surveillance program for collection and periodic reporting ofdata on the occurrence and causes of foodborne-disease outbreaks (FBDOs) in the United States.REPORTING PERIOD COVERED This summary reviews data from January 1993 through December 1997.DESCRIPTION OF SYSTEM The Foodborne-Disease Outbreak Surveillance System reviews dataconcerning FBDOs, defined as the occurrence of two or more cases of a similar illness resulting from theingestion of a common food. State and local public health departments have primary responsibility foridentifying and investigating FBDOs. State, local, and territorial health departments use a standard formto report these outbreaks to CDC. RESULTS During 1993-1997, a total of 2,751 outbreaks of foodbornedisease were reported (489 in 1993, 653 in 1994, 628 in 1995, 477 in 1996, and 504 in 1997). Theseoutbreaks caused a reported 86,058 persons to become ill. Among outbreaks for which the etiology wasdetermined, bacterial pathogens caused the largest percentage of outbreaks (75%) and the largestpercentage of cases (86%). Salmonella serotype Enteritidis accounted for the largest number ofoutbreaks, cases, and deaths; most of these outbreaks were attributed to eating eggs. Chemical agentscaused 17% of outbreaks and 1% of cases; viruses, 6% of outbreaks and 8% of cases; and parasites,2% of outbreaks and 5% of cases. INTERPRETATION The annual number of FBDOs reported to CDC didnot change substantially during this period or from previous years. During this reporting period, S.Enteritidis continued to be a major cause of illness and death. In addition, multistate outbreaks caused bycontaminated produce and outbreaks caused by Escherichia coli O157:H7 remained prominent. ACTIONSTAKEN Current methods to detect FBDOs are improving, and several changes to improve the ease andtimeliness of reporting FBDO data are occurring (e.g., a revised form to simplify FBDO reporting by statehealth departments and electronic reporting methods). State and local health departments continue toinvestigate and report FBDOs as part of efforts to better understand and define the epidemiology offoodborne disease in the United States. At the regional and national levels, surveillance data provide anindication of the etiologic agents, vehicles of transmission, and contributing factors associated withFBDOs and help direct public health actions to reduce illness and death caused by FBDOs.", "metadata": {}}
+{"_id": "30861948", "title": "", "text": "Nuclear-cytoplasmic shuttling of C-ABL tyrosine kinase.The ubiquitously expressed nonreceptor tyrosinekinase c-Abl contains three nuclear localization signals, however, it is found in both the nucleus and thecytoplasm of proliferating fibroblasts. A rapid and transient loss of c-Abl from the nucleus is observedupon the initial adhesion of fibroblasts onto a fibronectin matrix, suggesting the possibility of nuclearexport [Lewis, J., Baskaran, R. , Taagepera, S., Schwartz, M. & Wang, J. (1996) Proc. Natl. Acad. Sci.USA 93, 15174-15179]. Here we show that the C terminus of c-Abl does indeed contain a functionalnuclear export signal (NES) with the characteristic leucine-rich motif. The c-Abl NES can functionallycomplement an NES-defective HIV Rev protein (RevDelta3NI) and can mediate the nuclear export ofglutathione-S-transferase. The c-Abl NES function is sensitive to the nuclear export inhibitor leptomycinB. Mutation of a single leucine (L1064A) in the c-Abl NES abrogates export function. The NES-mutatedc-Abl, termed c-Abl NES(-), is localized exclusively to the nucleus. Treatment of cells with leptomycin Balso leads to the nuclear accumulation of wild-type c-Abl protein. The c-Abl NES(-) is not lost from thenucleus when detached fibroblasts are replated onto fibronectin matrix. Taken together, these resultsdemonstrate that c-Abl shuttles continuously between the nucleus and the cytoplasm and that the rate ofnuclear import and export can be modulated by the adherence status of fibroblastic cells.", "metadata": {}}
+{"_id": "30884033", "title": "", "text": "Regulation of embryonic stem cell pluripotency by heat shock protein 90.Deciphering the molecular basisof stem cell pluripotency is fundamental to the understanding of stem cell biology, early embryonicdevelopment, and to the clinical application of regenerative medicine. We report here that the molecularchaperone heat shock protein 90 (Hsp90) is essential for mouse embryonic stem cell (ESC) pluripotencythrough regulating multiple pluripotency factors, including Oct4, Nanog, and signal transducer andactivator of transcription 3. Inhibition of Hsp90 by either 17-N-Allylamino-17-demethoxygeldanamycin ormiRNA led to ESC differentiation. Overexpression of Hsp90β partially rescued the phenotype; inparticular, the levels of Oct4 and Nanog were restored. Notably, Hsp90 associated with Oct4 and Nanogin the same cellular complex and protected them from degradation by the ubiquitin proteasome pathway,suggesting that Oct4 and Nanog are potential novel Hsp90 client proteins. In addition, Hsp90 inhibitionreduced the mRNA level of Oct4, but not that of Nanog, indicating that Hsp90 participates in Oct4 mRNAprocessing or maturation. Hsp90 inhibition also increased expression of some protein markers formesodermal lineages, implying that Hsp90 suppresses mesodermal differentiation from ESCs. Thesefindings support a new role for Hsp90 in maintaining ESC pluripotency by sustaining the level of multiplepluripotency factors, particularly Oct4 and Nanog.", "metadata": {}}
+{"_id": "30908508", "title": "", "text": "CD4+CD25+Foxp3+Regulatory T Cells Protect Endothelial Function Impaired by Oxidized Low DensityLipoprotein via the KLF-2 Transcription FactorObjective: To investigate the regulation of CD4+CD25+Regulatory T cells (Tregs) on pro-inflammatory adhesion molecules, Krüppel-Like Factor-2 (KLF-2) and itsdownstream transcriptional targets in human umbilical vein endothelial cells (HUVECs) impaired byox-LDL and the mechanisms of it. Methods and results: HUVECs were cultured in the continuous presenceof ox-LDL(0 mg/L,25 mg/L,50 mg/L,100 mg/L) for 4, 6, 12 and 24 hours to allow identification ofearly-and late-induced genes, respectively, whereas non-stimulated controls were taken at 0 hours. Theexpression of pro-inflammatory adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1),intracellular adhesion molecule-1 (ICAM-1), E-selectin, KLF-2 and its target genes eNOS, PAI-1 weredetermined by real time RT-PCR and/or western-blot analysis. Expression of pro-inflammatory adhesionmolecules, KLF-2, eNOS and PAI-1 in HUVEC cultured alone or with anti-CD3 mAbs activated Tregs,followed by addition of ox-LDL (50 mg/L) for 6 hours, are compared to expression levels in controlcultures. Ox-LDL treated HUVECs increased pro-inflammatory adhesion molecules expression, as well asincreased PAI-1 but decreased eNOS expression accompanied with significant downregulating of KLF-2 ata dose and time dependent manner. Furthermore, ox-LDL increased pro-inflammatory adhesionmolecules but inhibited KLF2 expression was reversed by addition of Tregs. Small interfering RNAreduced endogenous KLF-2 expression and partly reversed the suppressive effect of Tregs on HUVECsactivation, which strongly implicate KLF-2 as a transcriptional regulator of the Tregs-mediated effects inendothelial cells. Mechanism studies reveal that Treg-mediated KLF2 expression in HUVECs impaired byox-LDL requires cell contact as well as soluble factors. Conclusions: Tregs could protect endothelialfunction that is largely dependent on KLF2 and its downstream transcriptional targets regulation involvingcell-to-cell contact and soluble factors.", "metadata": {}}
+{"_id": "30915421", "title": "", "text": "Metformin Normalizes Type 2 Diabetes-Induced Decrease in Cell Proliferation and NeuroblastDifferentiation in the Rat Dentate GyrusIn this study, we observed the effects of metformin, one of themost widely prescribed drugs for the treatment of type 2 diabetes, on cell proliferation and neuroblastdifferentiation in the subgranular zone of the hippocampal dentate gyrus (SZDG) in Zucker diabetic fatty(ZDF) rats, which are a model for type 2 diabetes. For this, metformin was administered orally once a dayto 14-week-old ZDF rats for 2 weeks and the animals were sacrificed at 16 weeks of age. During thisperiod, blood glucose levels were higher in the vehicle-treated ZDF rats than in the Zucker lean control(ZLC) rats. Metformin treatment significantly decreased the blood glucose levels from 15.5 weeks of age.In the SZDG, Ki67 (a marker for cell proliferation)- and doublecortin (DCX, a marker for differentiatedneuroblasts)-immunoreactive cells were much lower in the vehicle-treated ZDF rats than in the ZLC rats.In the metformin-treated ZDF group, Ki67- and DCX-immunoreactive cells were significantly increased inthe SZDG compared to those in the vehicle-treated ZDF group. These results suggest that diabetessignificantly reduces cell proliferation and neuroblast differentiation in the SZDG and that metformintreatment normalizes the reduction of cell proliferation and neuroblast differentiation in the SZDG indiabetic rats.", "metadata": {}}
+{"_id": "30919024", "title": "", "text": "Molecular mechanisms underlying tumor dormancy.Evidence suggests that dormant, microscopic tumorsare not only common, but are highly prevalent in otherwise healthy individuals. Due to their small sizeand non-invasive nature, these dormant tumors remain asymptomatic and, in most cases, undetected.With advances in diagnostic imaging and molecular biology, it is now becoming clear that such neoplasmscan remain in an asymptomatic, dormant stage for considerable periods of time without expanding insize. Although a number of processes may play a role in thwarting the expansion of microscopic tumors,one critical mechanism behind tumor dormancy is the ability of the tumor population to induceangiogenesis. Although cancer can arise through multiple pathways, it is assumed that essentially mosttumors begin as microscopic, non-angiogenic neoplasms which cannot expand in size until vasculature isestablished. It is now becoming clear that cancer does not progress through a continuous exponentialgrowth and mass expansion. Clinical cancer is usually manifested only in late, unavoidably symptomaticstages of the disease when tumors are sufficiently large to be readily detected. While dormancy inprimary tumors is best defined as the time between the carcinogenic transformation event and the onsetof inexorable progressive growth, it can also occur as minimal residual or occult disease from treatedtumors or as micro-metastases. The existence of dormant tumors has important implications for the earlydetection and treatment of cancer. Elucidating the regulatory machinery of these processes will beinstrumental in identifying novel early cancer biomarkers and could provide a rationale for thedevelopment of dormancy-promoting tumor therapies. Despite the high prevalence of microscopic,dormant tumors in humans and the significant clinical implications of their early detection, this area incancer research has, to date, been under-investigated. In this mini review observations, models andexperimental approaches to study tumor dormancy are summarized. Additionally, analogies anddistinctions between the concepts of \"tumor dormancy\" and that of the \"cellular dormancy\" of tumorcells, as well as between the \"exit from tumor dormancy\" and the \"onset of the angiogenic switch\" arediscussed.", "metadata": {}}
+{"_id": "30933307", "title": "", "text": "The myeloid transcription factor GATA-2 regulates the viral UL144 gene during human cytomegaloviruslatency in an isolate-specific manner.It is generally accepted that, following primary infection, humancytomegalovirus (HCMV) establishes lifelong latency in CD34(+) progenitor cells and other derivativecells of the myeloid lineage. In this study, we show that the viral UL144 gene is expressed during latentinfection in two cell types of the myeloid lineage, CD34(+) and CD14(+) monocytes, and that the UL144protein is functional in latently infected monocytes. However, this latency-associated expression of UL144occurs only in certain isolates of HCMV and depends on the presence of functional GATA-2 transcriptionfactor binding sites in the UL144 promoter, in contrast to the viral latency-associated gene LUNA, whichwe also show is regulated by GATA-2 but expressed uniformly during latent infection independent of thevirus isolate. Taken together, these data suggest that the HCMV latency-associated transcriptome may bevirus isolate specific and dependent on the repertoire of transcription factor binding sites in the promotersof latency-associated genes.", "metadata": {}}
+{"_id": "30981192", "title": "", "text": "How to control residual cardiovascular risk despite statin treatment: focusing onHDL-cholesterol.Lowering low-density lipoprotein-cholesterol (LDL-C) is the primary target in themanagement of dyslipidemia in patients at high risk of cardiovascular disease. However, patients whohave achieved LDL-C levels below the currently recommended targets may still experience cardiovascularevents. This may result, in part, from elevated triglyceride (TG) levels and low levels of high-densitylipoprotein-cholesterol (HDL-C). Low HDL-C and high TG levels are common and are recognized asindependent risk factors for cardiovascular morbidity and mortality. Furthermore, atherogenicdyslipidemia, characterized by low levels of HDL-C, high TG, and small, dense LDL particles, is a typicalphenotype of dyslipidemia in subjects with insulin resistance and metabolic syndrome. Therefore, toreduce further the risk of coronary heart disease (CHD), raising HDL-C and lowering TG may be thesecondary therapeutic target for patients who achieve LDL-C levels below the currently recommendedtargets but are still at risk of CHD. However, whether increasing HDL-C levels alone reduces CHD has notyet been confirmed in large randomized clinical trials, and whether functional HDL is more important thanHDL-C in reducing CHD remains controversial. Large CHD endpoint trials that include many patients withdiabetes are underway to compare combination treatments with statin and niacin, fibrates, or cholesterylester transfer protein inhibitors with statin alone treatments. In this review, we discuss the rationale andimportance of increasing HDL-C levels with and without lowering TG levels in the treatment andprevention of cardiovascular events.", "metadata": {}}
+{"_id": "30983338", "title": "", "text": "The prevalence of congenital malformations is still higher in pregnant women with pregestational diabetesdespite near-normal HbA1c: a literature review.AIMS/HYPOTHESIS We assessed the association betweencongenital malformations and maternal hyperglycemia in pregnant women with pregestational (type 1 ortype 2) diabetes and investigated if the rate of congenital malformations was similar in women withnear-normal glycemic control compared to the background population. We also assessed the associationbetween congenital malformations and maternal hyperglycemia in pregnant women with pregestationaldiabetes with special focus on women with near-normal HbA1c in early pregnancy. MATERIALS ANDMETHODS This is a literature review based on an electronic literature search of the databases PubMed,Cochrane, Embase and Web of Science conducted in July 2017 using the search terms diabetes,pregnancy, HbA1c or glycemic control and congenital anomaly or congenital anomaly. We includedoriginal papers in English published after 1997 with data on congenital malformations and HbA1c in atleast 250 women with pregestational diabetes. RESULTS Nine papers with in total 6225 women with type1 diabetes and 2334 women with type 2 diabetes were included. The prevalence of congenitalmalformations was 6.4% in women with type 1 diabetes and 4.3% in women with type 2 diabetes and forthe combined group of women with pregestational diabetes, the relative risk compared to the backgroundpopulation was 3.2. In women with HbA1c < 53 mmol/mol (7.0%) in early pregnancy or HbA1c 53-64mmol/mol (7.0-8.0%) the prevalence of congenital malformations was 4.3 and 3.7%, respectively, with arelative risk of 2.2 and 1.9, respectively. CONCLUSIONS In pregnant women with pregestational diabetesthe prevalence of congenital abnormalities was threefold higher in women with pregestational diabetescompared to the background population. However, HbA1c below 53 mmol/mol (7.0%) in early pregnancywas also associated with a two times increased risk of congenital malformations compared to thebackground population.", "metadata": {}}
+{"_id": "31001322", "title": "", "text": "Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB.Weshow that NF-kappaB and transcriptional targets are activated in liver by obesity and high-fat diet (HFD).We have matched this state of chronic, subacute 'inflammation' by low-level activation of NF-kappaB inthe liver of transgenic mice, designated LIKK, by selectively expressing constitutively active IKK-b inhepatocytes. These mice exhibit a type 2 diabetes phenotype, characterized by hyperglycemia, profoundhepatic insulin resistance, and moderate systemic insulin resistance, including effects in muscle. Thehepatic production of proinflammatory cytokines, including IL-6, IL-1beta and TNF-alpha, was increasedin LIKK mice to a similar extent as induced by HFD in in wild-type mice. Parallel increases were observedin cytokine signaling in liver and mucscle of LIKK mice. Insulin resistance was improved by systemicneutralization of IL-6 or salicylate inhibition of IKK-beta. Hepatic expression of the IkappaBalphasuperrepressor (LISR) reversed the phenotype of both LIKK mice and wild-type mice fed an HFD. Thesefindings indicate that lipid accumulation in the liver leads to subacute hepatic 'inflammation' throughNF-kappaB activation and downstream cytokine production. This causes insulin resistance both locally inliver and systemically.", "metadata": {}}
+{"_id": "31019903", "title": "", "text": "Homelessness and health.Homelessness affects tens of thousands of canadians and has important healthimplications. Homeless people are at increased risk of dying prematurely and suffer from a wide range ofhealth problems, including seizures, chronic obstructive pulmonary disease, musculoskeletal disorders,tuberculosis, and skin and foot problems. Homeless people also face significant barriers that impair theiraccess to health care. More research is needed to identify better ways to deliver care to this population.", "metadata": {}}
+{"_id": "31070360", "title": "", "text": "Serum metabolomics in animal models and human disease.PURPOSE OF REVIEW The aim of this study isto highlight some recent uses of serum metabolomics in human and animal studies. The main themes arethe importance of understanding the underlying variation in human metabolism and the use of serummetabolomics in disease profiling. RECENT FINDINGS Several studies have attempted to use serummetabolomics to develop noninvasive biomarkers of disease and/or track the consequences of nutritionaland genetic interventions. Many advances have been made with common changes being identified inageing, the menopause and cancer but several problems of interpretation have emerged from thesestudies. These include the small sample sizes in most human studies and the differences between humanand rodent metabolomes. However, a metabolic screen of over 1000 'healthy' humans (the Humsermetproject) has highlighted many variables that may be used to refine the interpretation and design ofprevious and future human studies alike, in addition to data mining. SUMMARY Some common serummetabolome alterations have been identified but many inconsistencies remain. The construction of ahuman serum metabolome database should be informative in the design of future human and animalmodel studies.", "metadata": {}}
+{"_id": "31107919", "title": "", "text": "Differential Requirement of the Extracellular Domain in Activation of Class B G Protein-coupledReceptors.G protein-coupled receptors (GPCRs) from the secretin-like (class B) family are key players inhormonal homeostasis and are important drug targets for the treatment of metabolic disorders andneuronal diseases. They consist of a large N-terminal extracellular domain (ECD) and a transmembranedomain (TMD) with the GPCR signature of seven transmembrane helices. Class B GPCRs are activated bypeptide hormones with their C termini bound to the receptor ECD and their N termini bound to the TMD.It is thought that the ECD functions as an affinity trap to bind and localize the hormone to the receptor.This in turn would allow the hormone N terminus to insert into the TMD and induce conformationalchanges of the TMD to activate downstream signaling. In contrast to this prevailing model, wedemonstrate that human class B GPCRs vary widely in their requirement of the ECD for activation. In onegroup, represented by corticotrophin-releasing factor receptor 1 (CRF1R), parathyroid hormone receptor(PTH1R), and pituitary adenylate cyclase activating polypeptide type 1 receptor (PAC1R), the ECDrequirement for high affinity hormone binding can be bypassed by induced proximity and mass actioneffects, whereas in the other group, represented by glucagon receptor (GCGR) and glucagon-likepeptide-1 receptor (GLP-1R), the ECD is required for signaling even when the hormone is covalentlylinked to the TMD. Furthermore, the activation of GLP-1R by small molecules that interact with theintracellular side of the receptor is dependent on the presence of its ECD, suggesting a direct role of theECD in GLP-1R activation.", "metadata": {}}
+{"_id": "31141365", "title": "", "text": "Genome-wide maps of histone modifications unwind in vivo chromatin states of the hair folliclelineage.Using mouse skin, where bountiful reservoirs of synchronized hair follicle stem cells (HF-SCs) fuelcycles of regeneration, we explore how adult SCs remodel chromatin in response to activating cues. Byprofiling global mRNA and chromatin changes in quiescent and activated HF-SCs and their committed,transit-amplifying (TA) progeny, we show that polycomb-group (PcG)-mediated H3K27-trimethylationfeatures prominently in HF-lineage progression by mechanisms distinct from embryonic-SCs. In HF-SCs,PcG represses nonskin lineages and HF differentiation. In TA progeny, nonskin regulators remainPcG-repressed, HF-SC regulators acquire H3K27me3-marks, and HF-lineage regulators lose them.Interestingly, genes poised in embryonic stem cells, active in HF-SCs, and PcG-repressed in TA progenyencode not only key transcription factors, but also signaling regulators. We document their importance inbalancing HF-SC quiescence, underscoring the power of chromatin mapping in dissecting SC behavior.Our findings explain how HF-SCs cycle through quiescent and activated states without losing stemnessand define roles for PcG-mediated repression in governing a fate switch irreversibly.", "metadata": {}}
+{"_id": "31148090", "title": "", "text": "Two classes of endogenous small RNAs in Tetrahymena thermophila.Endogenous small RNAs function inRNA interference (RNAi) pathways to guide RNA cleavage, translational repression, or methylation of DNAor chromatin. In Tetrahymena thermophila, developmentally regulated DNA elimination is governed by anRNAi mechanism involving approximately 27-30-nucleotide (nt) RNAs. Here we characterize the sequencefeatures of the approximately 27-30-nt RNAs and a approximately 23-24-nt RNA class representing asecond RNAi pathway. The approximately 23-24-nt RNAs accumulate strain-specifically manner and mapto the genome in clusters that are antisense to predicted genes. These findings reveal the existence ofdistinct endogenous RNAi pathways in the unicellular T. thermophila, a complexity previouslydemonstrated only in multicellular organisms.", "metadata": {}}
+{"_id": "31154082", "title": "", "text": "The binding of maize DHN1 to lipid vesicles. Gain of structure and lipid specificity.Dehydrins (DHNs; lateembryogenesis abundant D-11) are a family of plant proteins induced in response to abiotic stresses suchas drought, low temperature, and salinity or during the late stages of embryogenesis. Spectral andthermal properties of these proteins in purified form suggest that they are \"intrinsically unstructured. \"However, DHNs contain at least one copy of a consensus 15-amino acid sequence, the \"K segment,\"which resembles a class A2 amphipathic alpha-helical, lipid-binding domain found in other proteins suchas apolipoproteins and alpha-synuclein. The presence of the K segment raises the question of whetherDHNs bind lipids, bilayers, or phospholipid vesicles. Here, we show that maize (Zea mays) DHN DHN1 canbind to lipid vesicles that contain acidic phospholipids. We also observe that DHN1 binds more favorablyto vesicles of smaller diameter than to larger vesicles, and that the association of DHN1 with vesiclesresults in an apparent increase of alpha-helicity of the protein. Therefore, DHNs, and presumablysomewhat similar plant stress proteins in the late embryogenesis abundant and cold-regulated classesmay undergo function-related conformational changes at the water/membrane interface, perhaps relatedto the stabilization of vesicles or other endomembrane structures under stress conditions.", "metadata": {}}
+{"_id": "31166180", "title": "", "text": "Requirement of heterochromatin for cohesion at centromeres.Centromeres are heterochromatic in manyorganisms, but the mitotic function of this silent chromatin remains unknown. During cell division, newlyreplicated sister chromatids must cohere until anaphase when Scc1/Rad21-mediated cohesion isdestroyed. In metazoans, chromosome arm cohesins dissociate during prophase, leaving centromeres asthe only linkage before anaphase. It is not known what distinguishes centromere cohesion from armcohesion. Fission yeast Swi6 (a Heterochromatin protein 1 counterpart) is a component of silentheterochromatin. Here we show that this heterochromatin is specifically required for cohesion betweensister centromeres. Swi6 is required for association of Rad21-cohesin with centromeres but not alongchromosome arms and, thus, acts to distinguish centromere from arm cohesion. Therefore, one functionof centromeric heterochromatin is to attract cohesin, thereby ensuring sister centromere cohesion andproper chromosome segregation.", "metadata": {}}
+{"_id": "31200375", "title": "", "text": "Gene expression in human skeletal muscle: alternative normalization method and effect of repeatedbiopsiesThe reverse transcriptase-polymerase chain reaction (RT-PCR) method has lately become widelyused to determine transcription and mRNA content in rodent and human muscle samples. However, thecommon use of endogenous controls for correcting for variance in cDNA between samples is not optimal.Specifically, we investigated (1) a new normalization method based on determining the cDNA content bythe flourophores PicoGreen and OliGreen, (2) effect of repeated muscle biopsies on mRNA geneexpression, and (3) the spatial heterogeneity in mRNA expression across the muscle. Standard curvesusing oligo standards revealed a high degree of sensitivity and linearity (2.5–45 ng; R 2>0.99) withOliGreen reagent, as was the case for OliGreen analyses with standard curves constructed from serialdilutions of representative RT samples (R 2 >0.99 for a ten times dilution range of a representativereversed transcribed (RT) sample). Likewise, PicoGreen reagent detected the RNA:DNA hybrid content inRT samples with great sensitivity. Standard curves constructed from both double-stranded lambda DNA(1–10 ng) and from serial dilutions of representative RT samples consistently resulted in linearity with R 2>0.99. The present determination of cDNA content in reversed transcribed human skeletal muscle RNAsamples by both PicoGreen and OliGreen analyses suggests that these fluorophores provide a potentialalternative normalization procedure for human gene expression studies. In addition, the present studyshows that multiple muscle biopsies obtained from the same muscle do not influence the mRNA responseinduced by an acute exercise bout for any of the genes examined.", "metadata": {}}
+{"_id": "31208367", "title": "", "text": "The Impact of Location of Progressive Visual Field Loss on Longitudinal Changes in Quality of Life ofPatients with Glaucoma.PURPOSE To evaluate the association between rates of progressive loss indifferent regions of the visual field and longitudinal changes in quality of life (QoL). DESIGN Prospective,observational cohort study. PARTICIPANTS The study included 236 patients with glaucomatous visualfield loss followed for an average of 4.3±1.5 years. METHODS All subjects had the 25-item National EyeInstitute Visual Functioning Questionnaire (NEI VFQ-25) performed annually and standard automatedperimetry (SAP) at 6-month intervals. Subjects were included if they had a minimum of 2 NEI VFQ-25and 5 SAP tests during follow-up. Evaluation of rates of visual field change was performed using 4different regions (central inferior, central superior, peripheral inferior, and peripheral superior) of theintegrated binocular visual field. The association between change in NEI VFQ-25 Rasch-calibrated scoresand change in different regions of the visual field was investigated with a joint multivariable longitudinallinear mixed model. MAIN OUTCOME MEASURES The relationship between change in QoL scores andchange of mean sensitivity in different regions of the visual field. RESULTS There was a significantcorrelation between change in the NEI VFQ-25 Rasch scores during follow-up and change in differentregions of the visual field. Each 1 decibel (dB)/year change in binocular mean sensitivity of the centralinferior area was associated with a decline of 2.6 units/year in the NEI VFQ-25 scores (R(2) = 35%; P <0.001). Corresponding associations with change in QoL scores for the peripheral inferior, central superior,and peripheral superior areas of the visual field had R(2) values of 30%, 24%, and 19%, respectively.The association for the central inferior visual field area was statistically significantly stronger than thoseof the central superior area (P = 0.011) and peripheral superior area (P = 0.001), but not the peripheralinferior area (P = 0.171). Greater declines in NEI VFQ-25 scores were also seen in patients who hadworse visual field sensitivity at baseline. CONCLUSIONS Progressive decline in sensitivity in the centralinferior area of the visual field had the strongest association with longitudinal decline in QoL of patientswith glaucoma.", "metadata": {}}
+{"_id": "31229233", "title": "", "text": "Use of thiazolidinediones and the risk of bladder cancer among people with type 2 diabetes: ameta-analysis.BACKGROUND Patients with type 2 diabetes have a 40% increased risk of bladder cancer.Thiazolidinediones, especially pioglitazone, may increase the risk. We conducted a systematic review andmeta-analysis to evaluate the risk of bladder cancer among adults with type 2 diabetes takingthiazolidinediones. METHODS We searched key biomedical databases (including MEDLINE, Embase andScopus) and sources of grey literature from inception through March 2012 for published and unpublishedstudies, without language restrictions. We included randomized controlled trials (RCTs), cohort studiesand case-control studies that reported incident bladder cancer among people with type 2 diabetes whoever (v. never) were exposed to pioglitazone (main outcome), rosiglitazone or any thiazolidinedione.RESULTS Of the 1787 studies identified, we selected 4 RCTs, 5 cohort studies and 1 case-control study.The total number of patients was 2,657,365, of whom 3643 had newly diagnosed bladder cancer, for anoverall incidence of 53.1 per 100,000 person-years. The one RCT that reported on pioglitazone use foundno significant association with bladder cancer (risk ratio [RR] 2.36, 95% confidence interval [CI]0.91-6.13). The cohort studies of thiazolidinediones (pooled RR 1.15, 95% CI 1.04-1.26; I(2) = 0%) andof pioglitazone specifically (pooled RR 1.22, 95% CI 1.07-1.39; I(2) = 0%) showed significantassociations with bladder cancer. No significant association with bladder cancer was observed in the twoRCTs that evaluated rosiglitazone use (pooled RR 0.87, 95% CI 0.34-2.23; I(2) = 0%). INTERPRETATIONThe limited evidence available supports the hypothesis that thiazolidinediones, particularly pioglitazone,are associated with an increased risk of bladder cancer among adults with type 2 diabetes.", "metadata": {}}
+{"_id": "31272411", "title": "", "text": "Immune signaling by RIG-I-like receptors.The RIG-I-like receptors (RLRs) RIG-I, MDA5, and LGP2 play amajor role in pathogen sensing of RNA virus infection to initiate and modulate antiviral immunity. TheRLRs detect viral RNA ligands or processed self RNA in the cytoplasm to trigger innate immunity andinflammation and to impart gene expression that serves to control infection. Importantly, RLRs cooperatein signaling crosstalk networks with Toll-like receptors and other factors to impart innate immunity and tomodulate the adaptive immune response. RLR regulation occurs at a variety of levels ranging fromautoregulation to ligand and cofactor interactions and posttranslational modifications. Abberant RLRsignaling or dysregulation of RLR expression is now implicated in the development of autoimmunediseases. Understanding the processes of RLR signaling and response will provide insights to guideRLR-targeted therapeutics for antiviral and immune-modifying applications.", "metadata": {}}
+{"_id": "31293581", "title": "", "text": "Ionizing radiation-induced long-term expression of senescence markers in mice is independent of p53 andimmune status.Exposure to IR has been shown to induce the formation of senescence markers, aphenotype that coincides with lifelong delayed repair and regeneration of irradiated tissues. Wehypothesized that IR-induced senescence markers could persist long-term in vivo, possibly contributingto the permanent reduction in tissue functionality. Here, we show that mouse tissues exposed to asublethal dose of IR display persistent (up to 45 weeks, the maximum time analyzed) DNA damage fociand increased p16(INK4a) expression, two hallmarks of cellular senescence and aging. BrdU-labelingexperiments revealed that IR-induced damaged cells are preferentially eliminated, at least partially, in atissue-dependent manner. Unexpectedly, the accumulation of damaged cells was found to occurindependent from the DNA damage response modulator p53, and from an intact immune system, as theirlevels were similar in wild-type and Rag2(-/-) gammaC(-/-) mice, the latter being deficient in T, B, andNK cells. Together, our results provide compelling evidence that exposure to IR induces long-termexpression of senescence markers in vivo, an effect that may contribute to the reduced tissuefunctionality observed in cancer survivors.", "metadata": {}}
+{"_id": "31304956", "title": "", "text": "Cranial neural crest and the building of the vertebrate headHead development in vertebrates involves acomplex series of molecular and morphogenetic events that generate a coordinated pattern of cartilages,bones and nerves, and result in species-specific craniofacial morphologies. A specialized cell type ofneural origin, the neural crest, is central to this process, as it provides the main source of craniofacialmesenchyme. The degree of patterning information that is intrinsic to the neural crest has been recentlydebated, and new advances have underscored the influence of environmental signalling on thetranscriptional readout that coordinates craniofacial morphogenesis in space and time.", "metadata": {}}
+{"_id": "31311495", "title": "", "text": "Tamoxifen resistance in MCF7 cells promotes EMT-like behaviour and involves modulation of beta-cateninphosphorylation.We have previously demonstrated that, following acquisition of endocrine resistance,breast cancer cells display an altered growth rate together with increased aggressive behaviour in vitro.Since dysfunctional cell-cell adhesive interactions can promote an aggressive phenotype, we investigatedthe integrity of this protein complex in our breast cancer model of tamoxifen resistance. In culture,tamoxifen-resistant MCF7 (TamR) cells grew as loosely packed colonies with loss of cell-cell junctions anddemonstrated altered morphology characteristic of cells undergoing epithelial-to-mesenchymal transition(EMT). Neutralising E-cadherin function promoted the invasion and inhibited the aggregation ofendocrine-sensitive MCF7 cells, whilst having little effect on the behaviour of TamR cells. Additionally,TamR cells had increased levels of tyrosine-phosphorylated beta-catenin, whilstserine/threonine-phosphorylated beta-catenin was decreased. These cells also displayed loss ofassociation between beta-catenin and E-cadherin, increased cytoplasmic and nuclear beta-catenin andelevated transcription of beta-catenin target genes known to be involved in tumour progression and EMT.Inhibition of EGFR kinase activity in TamR cells reduced beta-catenin tyrosine phosphorylation, increasedbeta-catenin-E-cadherin association and promoted cell-cell adhesion. In such treated cells, theassociation of beta-catenin with Lef-1 and the transcription of c-myc, cyclin-D1, CD44 and COX-2 werealso reduced. These results suggest that homotypic adhesion in tamoxifen-resistant breast cancer cells isdysfunctional due to EGFR-driven modulation of the phosphorylation status of beta-catenin and maycontribute to an enhanced aggressive phenotype and transition towards a mesenchymal phenotype invitro.", "metadata": {}}
+{"_id": "31313782", "title": "", "text": "Expression profiles of Toll-like receptors in non-small cell lung cancer and idiopathic pulmonaryfibrosis.Patients with idiopathic pulmonary fibrosis (IPF) have a higher incidence             of lung cancer.The role of Toll-like receptors (TLRs), a key component of the             innate immunity, in interstitial lungdiseases (ILDs) and lung cancer pathogenesis             is not clarified. TLR2, TLR3, TLR4, TLR7, TLR8 andTLR9 mRNA expression was quantitatively             measured by real-time reverse transcriptasepolymerase chain reaction (RT-PCR)             in bronchoalveolar lavage fluid (BALF) of 16 IPF patients, 16non-small cell lung             cancer (NSCLC) patients and 9 control subjects. TLR2, TLR3, TLR4 and TLR9protein             expression was assessed on BALF T-lymphocytes using flow cytometry. TLR3mRNA             expression was significantly higher in NSCLC compared to IPF (p=0.023) andcontrols             (p=0.001). TLR7 mRNA expression levels were significantly higher in bothNSCLC             and IPF groups compared to controls (p=0.029, p=0.009). TLR9 expression atthe             mRNA level was significantly higher in both NSCLC and IPF groups compared tocontrols             (p=0.01, p=0.001). Finally, TLR2 mRNA expression was significantly higher inIPF             patients compared to controls (p=0.042). Flow cytometry revealed decreasedTLR3             and TLR9 expression in IPF patients compared to the NSCLC group (p=0.02,p=0.014)             and decreased TLR9 expression in IPF compared with the controls (p=0.04).TLR2             protein expression was significantly higher in IPF patients compared toNSCLC             (p=0.04). Increased expression of endosomal TLRs in NSCLC patients andelevated             expression of TLR2 in pulmonary fibrosis are the main results of this study.These             results do not provide support for a common TLR pathway hypothesis betweenNSCLC             and IPF.", "metadata": {}}
+{"_id": "31324978", "title": "", "text": "A protein farnesyltransferase inhibitor ameliorates disease in a mouse model of progeria.Progerias arerare genetic diseases characterized by premature aging. Several progeroid disorders are caused bymutations that lead to the accumulation of a lipid-modified (farnesylated) form of prelamin A, a proteinthat contributes to the structural scaffolding for the cell nucleus. In progeria, the accumulation offarnesyl-prelamin A disrupts this scaffolding, leading to misshapen nuclei. Previous studies have shownthat farnesyltransferase inhibitors (FTIs) reverse this cellular abnormality. We tested the efficacy of anFTI (ABT-100) in Zmpste24-deficient mice, a mouse model of progeria. The FTI-treated mice exhibitedimproved body weight, grip strength, bone integrity, and percent survival at 20 weeks of age. Theseresults suggest that FTIs may have beneficial effects in humans with progeria.", "metadata": {}}
+{"_id": "31347396", "title": "", "text": "A rare mutation in UNC5C predisposes to late-onset Alzheimer's disease and increases neuronal celldeathWe have identified a rare coding mutation, T835M (rs137875858), in the UNC5C netrin receptorgene that segregated with disease in an autosomal dominant pattern in two families enriched forlate-onset Alzheimer's disease and that was associated with disease across four large case-controlcohorts (odds ratio = 2.15, Pmeta = 0.0095). T835M alters a conserved residue in the hinge region ofUNC5C, and in vitro studies demonstrate that this mutation leads to increased cell death in humanHEK293T cells and in rodent neurons. Furthermore, neurons expressing T835M UNC5C are moresusceptible to cell death from multiple neurotoxic stimuli, including β-amyloid (Aβ), glutamate andstaurosporine. On the basis of these data and the enriched hippocampal expression of UNC5C in the adultnervous system, we propose that one possible mechanism in which T835M UNC5C contributes to the riskof Alzheimer's disease is by increasing susceptibility to neuronal cell death, particularly in vulnerableregions of the Alzheimer's disease brain.", "metadata": {}}
+{"_id": "31363207", "title": "", "text": "Treatment of active tuberculosis in HIV-coinfected patients: a systematic review andmeta-analysis.BACKGROUND Patients with human immunodeficiency virus (HIV) infection andtuberculosis have an increased risk of death, treatment failure, and relapse. METHODS A systematicreview and meta-analysis of randomized, controlled trials and cohort studies was conducted to evaluatethe impact of duration and dosing schedule of rifamycin and use of antiretroviral therapy in the treatmentof active tuberculosis in HIV-positive patients. In included studies, the initial tuberculosis diagnosis,failure, and/or relapse were microbiologically confirmed, and patients received standardized rifampin- orrifabutin-containing regimens. Pooled cumulative incidence of treatment failure, death during treatment,and relapse were calculated using random-effects models. Multivariable meta-regression was performedusing negative binomial regression. RESULTS After screening 5158 citations, 6 randomized trials and 21cohort studies were included. Relapse was more common with regimens using 2 months rifamycin(adjusted risk ratio, 3.6; 95% confidence interval, 1.1-11.7) than with regimens using rifamycin for atleast 8 months. Compared with daily therapy in the initial phase (n=3352 patients from 35 study arms),thrice-weekly therapy (n=211 patients from 5 study arms) was associated with higher rates of failure(adjusted risk ratio, 4.0; 95% confidence interval, 1.5-10.4) and relapse [adjusted risk ratio, 4.8; 95%confidence interval, 1.8-12.8). There were trends toward higher relapse rates if rifamycins were used foronly 6 months, compared with > or =8 months, or if antiretroviral therapy was not used. CONCLUSIONSThis review raises serious concerns regarding current recommendations for treatment of HIV-tuberculosiscoinfection. The data suggest that at least 8 months duration of rifamycin therapy, initial daily dosing,and concurrent antiretroviral therapy might be associated with better outcomes, but adequately poweredrandomized trials are urgently needed to confirm this.", "metadata": {}}
+{"_id": "31387717", "title": "", "text": "Crystal structure and association behaviour of the GluR2 amino-terminal domain.Fast excitatoryneurotransmission is mediated largely by ionotropic glutamate receptors (iGluRs), tetrameric,ligand-gated ion channel proteins comprised of three subfamilies, AMPA, kainate and NMDA receptors,with each subfamily sharing a common, modular-domain architecture. For all receptor subfamilies, activechannels are exclusively formed by assemblages of subunits within the same subfamily, a molecularprocess principally encoded by the amino-terminal domain (ATD). However, the molecular basis by whichthe ATD guides subfamily-specific receptor assembly is not known. Here we show that AMPA receptorGluR1- and GluR2-ATDs form tightly associated dimers and, by the analysis of crystal structures of theGluR2-ATD, propose mechanisms by which the ATD guides subfamily-specific receptor assembly.", "metadata": {}}
+{"_id": "31407112", "title": "", "text": "Deficiency in l-serine deaminase results in abnormal growth and cell division of Escherichia coli K-12.Theloss of the ability to deaminate l-serine severely impairs growth and cell division in Escherichia coli K-12.A strain from which the three genes (sdaA, sdaB, tdcG) coding for this organism's three l-serinedeaminases had been deleted grows well in glucose minimal medium but, on subculture into minimalmedium with glucose and casamino acids, it makes very large, abnormally shaped cells, many of whichlyse. When inoculated into Luria-Bertani (LB) broth with or without glucose, it makes very long filaments.Provision of S-adenosylmethionine restores cell division in LB broth with glucose, and repairs much of thedifficulty in growth in medium with casamino acids. We suggest that replication of E. coli is regulated bymethylation, that an unusually high intracellular l-serine concentration, in the presence of other aminoacids, starves the cell for S-adenosylmethionine and that it is the absence of S-adenosylmethionineand/or of C1-tetrahydrofolate derivatives that prevents normal cell division.", "metadata": {}}
+{"_id": "31439189", "title": "", "text": "Stem cell characteristics in prostate cancer cell lines.BACKGROUND Recent studies indicate the presenceof a small, stem-like cell population in several human cancers that is crucial for the tumour(re)population. OBJECTIVE Six established prostate cancer (PCa) cell lines-DU145, DuCaP, LAPC-4,22Rv1, LNCaP, and PC-3-were examined for their stem cell properties in vitro. DESIGN, SETTINGS, ANDPARTICIPANTS The colony-forming efficiency and self-renewal ability of morphologically distinguishableholoclones and paraclones were tested with low-density plating and serial passaging. Expression of theputative stem cell marker CD133 and breast cancer resistance protein (BCRP) was examined with flowcytometry, and immunohistochemical stainings were made for CD133, alpha2-integrin, nestin, BCRP,cytokeratin 5 (CK5), and cytokeratin 18 (CK18). RESULTS AND LIMITATIONS Five out of six cell linesformed clear holo-, mero-, and paraclones. Unlike paraclones, we can maintain DU145 holoclones inculture for several passages, which is indicative of self-renewal ability. Using fluorescence-activated cellsorting (FACS) analysis only in DU145 cells, a small fraction (0.01%) of CD133(+) cells was detected.CD133(+) cells; however, like DU145 BCRP(+) (0.15%) cells, they were not more clonogenic, and theydid not show more holoclone formation than the marker-negative cells or unselected cells.Immunohistochemistry revealed alpha2-integrin and BCRP as potential stem cell markers and CK5 withthe combination of CK18 to distinguish transient amplifying cells. CONCLUSIONS These results indicatethe possible presence of stem-like cells in several established PCa cell lines. CD133 selection does notenrich for stem-like cells in PCa cell lines.", "metadata": {}}
+{"_id": "31460499", "title": "", "text": "Resistance to antimicrobials in humans and animals.Overusing antibiotics is not the only cause andreducing use is not the only solution   W arning signs of antimicrobial resistance, chinks in theantimicrobial armour, began to appear in the middle of the last century, and by the 1990s various reportshad signalled the dangers of excessive or inappropriate use of antibiotics in clinical medicine and of theuse of antibiotics in animal feed as growth promoters.1–3 Overuse of antimicrobials emerged as the mainculprit, and reducing their use was seen as the answer. But it may not be that simple. The idea thatreducing antibiotic use would redress the problem formed part of a positive response on the part of theUnited Kingdom government to the House of Lords report,1 including a public information campaign,surveillance of resistance along the food chain, targets with respect to hospital acquired infections, andsetting up of an overarching advisory body on all aspects of antibiotic use. However, the concept ofoveruse has proved too simplistic, for, although the evidence of overprescribing as the …", "metadata": {}}
+{"_id": "31495049", "title": "", "text": "Unmet needs and depressive symptoms among low--income older adults.Previous studies have foundthat declining health, decreased social interaction, and inadequate financial resources were significantrisk factors for late-life depression, and social support from families and friends and religiosity weresignificant protective factors. In this study, we examined if low-income older adults' perceived unmetneed for home- and community-based services for many aging-associated problems would beindependently associated with their depressive symptoms, controlling for these known risk and protectivefactors. We interviewed a total of 213 community-residing older adults to assess their depressivesymptoms, using the Geriatric Depression Scale (GDS), and unmet needs in the areas of personalassistance, instrumental and environmental support, emotional support, and other facilitative/enablingservices. We found that the number of unmet needs was significantly positively associated with theseolder adults' depressive symptoms, although it explained only a small proportion of the variance of theGDS scores. Future research and practice implications are discussed.", "metadata": {}}
+{"_id": "31514338", "title": "", "text": "A key role for Ctf4 in coupling the MCM2-7 helicase to DNA polymerase alpha within the eukaryoticreplisome.The eukaryotic replisome is a crucial determinant of genome stability, but its structure is stillpoorly understood. We found previously that many regulatory proteins assemble around the MCM2-7helicase at yeast replication forks to form the replisome progression complex (RPC), which might linkMCM2-7 to other replisome components. Here, we show that the RPC associates with DNA polymerasealpha that primes each Okazaki fragment during lagging strand synthesis. Our data indicate that acomplex of the GINS and Ctf4 components of the RPC is crucial to couple MCM2-7 to DNA polymerasealpha. Others have found recently that the Mrc1 subunit of RPCs binds DNA polymerase epsilon, whichsynthesises the leading strand at DNA replication forks. We show that cells lacking both Ctf4 and Mrc1experience chronic activation of the DNA damage checkpoint during chromosome replication and do notcomplete the cell cycle. These findings indicate that coupling MCM2-7 to replicative polymerases is animportant feature of the regulation of chromosome replication in eukaryotes, and highlight a key role forCtf4 in this process.", "metadata": {}}
+{"_id": "31543713", "title": "", "text": "Data analysis methods for detection of differential protein expression in two-dimensional gelelectrophoresis.The recent development of microarray technology has led statisticians andbioinformaticians to develop new statistical methodologies for comparing different biological samples. Theobjective is to identify a small number of differentially expressed genes from among thousands. Inquantitative proteomics, analysis of protein expression using two-dimensional gel electrophoresis showssome similarities with transcriptomic studies. Thus, the goal of this study was to evaluate different dataanalysis methodologies widely used in array analysis using different proteomic data sets of hundreds ofproteins. Even with few replications, the significance analysis of microarrays method appeared to be morepowerful than the Student's t test in truly declaring differentially expressed proteins. This procedure willavoid wasting time due to false positives and losing information with false negatives.", "metadata": {}}
+{"_id": "31554917", "title": "", "text": "A clinical approach to circadian rhythm sleep disorders.Circadian rhythm sleep disorders are characterizedby complaints of insomnia and excessive sleepiness that are primarily due to alterations in the internalcircadian timing system or a misalignment between the timing of sleep and the 24-h social and physicalenvironment. In addition to physiological and environmental factors, maladaptive behaviors often play animportant role in the development of many of the circadian rhythm sleep disorders. This review will focuson the clinical approach to the diagnosis and management of the various circadian rhythm sleepdisorders, including delayed sleep phase disorder, advanced sleep phase disorder, non-entrained type,irregular sleep-wake rhythm, shift work sleep disorder and jet lag disorder. Diagnostic tools such as sleepdiaries and wrist activity monitoring are often useful in confirming the diagnosis. Because behavioral andenvironmental factors often are involved in the development of these conditions, a multimodal approachis usually necessary. Interventions include sleep hygiene education, timed exposure to bright light as wellas avoidance of bright light at the wrong time of the day and pharmacologic approaches, such asmelatonin. However, it should be noted that the use of melatonin is not an FDA-approved indication forthe treatment of circadian rhythm sleep disorders.", "metadata": {}}
+{"_id": "31560225", "title": "", "text": "SIVrcm infection of macaques.In a prior report, we described the isolation and characterization ofSIVrcm, a distinct primate lentivirus found in a household pet Red-Capped Mangabey (RCM) in Gabon.SIVrcm is divergent from HIV-1 and HIV-2/SIV families of primate lentiviruses. In this report, additionalin vitro replication studies and the results of SIVrcm infection in macaques are presented. SIVrcm causeslittle cytopathic effedct in Molt 4 Clone 8 cells and in rhesus and human PBMCs. In vivo, SIVrcm isnon-pathogenic after 200 days in rhesus macaques and after one year in cynomolgous macaques, butdoes cause a chronic infection in both macaques.", "metadata": {}}
+{"_id": "31562330", "title": "", "text": "Integrating nutrition security with treatment of people living with HIV: lessons from Kenya.BACKGROUNDThe increased caloric requirements of HIV-positive individuals, undesirable side effects of treatment thatmay be worsened by malnutrition (but alleviated by nutritional support), and associated declines inadherence and possible increased drug resistance are all justifications for developing better interventionsto strengthen the nutrition security of individuals receiving antiretroviral treatment. OBJECTIVE Tohighlight key benefits and challenges relating to interventions aimed at strengthening the nutritionsecurity of people living with HIV who are receiving antiretroviral treatment. METHODS Qualitativeresearch was undertaken on a short-term nutrition intervention linked to the provision of freeantiretroviral treatment for people living with HIV in western Kenya in late 2005 and early 2006.RESULTS Patients enrolled in the food program while on treatment regimens self-reported greateradherence to their medication, fewer side effects, and a greater ability to satisfy increased appetite. Mostclients self-reported weight gain, recovery of physical strength, and the resumption of labor activitieswhile enrolled in dual (food supplementation and treatment) programs. Such improvements were seen tocatalyze increased support from family and community. CONCLUSIONS These findings provide furtherempirical support to calls for a more holistic and comprehensive response to the coexistence of AIDSepidemics with chronic nutrition insecurity. Future work is needed to clarify ways of bridging the gapbetween short-term nutritional support to individuals and longer-term livelihood security programmingfor communities affected by AIDS. Such interdisciplinary research will need to be matched byintersectoral action on the part of the agriculture and health sectors in such environments.", "metadata": {}}
+{"_id": "31564409", "title": "", "text": "Acylated and desacyl ghrelin stimulate lipid accumulation in human visceral adipocytesObjectives:Theorexigenic hormone ghrelin circulates mainly in two forms, acylated and desacyl ghrelin. We evaluatedthe impact of obesity and obesity-associated type 2 diabetes (T2D) on ghrelin forms and the potentialrole of acylated and desacyl ghrelin in the control of adipogenesis in humans. Methods:Plasmaconcentrations of the different ghrelin forms were measured in 80 subjects. The expression of the ghrelinreceptor (growth hormone secretagogue receptor, GHS-R) was analyzed in omental adipose tissue usingwestern blot and immunohistochemistry, and the effect of acylated ghrelin and desacyl ghrelin (0.1–1000pmol l−1) on adipogenesis was determined in vitro in omental adipocytes. Results:Circulatingconcentrations of acylated ghrelin were increased, whereas desacyl ghrelin levels were decreased, inobesity and obesity-associated T2D. Body mass index, waist circumference, insulin and HOMA(homeostasis model assessment) index were positively correlated with acylated ghrelin levels. Obeseindividuals showed a lower protein expression of GHS-R in omental adipose tissue. In differentiatingomental adipocytes, incubation with both acylated and desacyl ghrelin significantly increased PPARγ(peroxisome proliferator-activated receptor γ) and SREBP1 (sterol-regulatory element binding protein-1)mRNA levels, as well as several fat storage-related proteins, including acetyl-CoA carboxylase, fatty acidsynthase, lipoprotein lipase and perilipin. Consequently, both the ghrelin forms stimulatedintracytoplasmatic lipid accumulation. Conclusions:Both acylated and desacyl ghrelin stimulate lipidaccumulation in human visceral adipocytes. Given the lipogenic effect of acylated ghrelin on visceraladipocytes, the herein-reported elevation of its circulating concentrations in obese individuals may play arole in excessive fat accumulation in obesity.", "metadata": {}}
+{"_id": "31591262", "title": "", "text": "Significant correlation between LKB1 and LGR5 gene expression and the association with poorrecurrence-free survival in rectal cancer after preoperative chemoradiotherapyThe aim of the presentstudy was to investigate whether the gene expression levels of LKB1 and LGR5 correlated with clinicaloutcome in patients with locally advanced rectal cancer treated with preoperative chemoradiotherapy(CRT). Residual cancer cells were obtained from 52 patients with locally advanced rectal cancer treatedwith preoperative CRT. Total RNA was then isolated from formalin-fixed, paraffin-embedded specimensusing microdissection. The expression levels of LKB1 and LGR5 genes were measured using real-timereverse-transcription polymerase chain reaction and by immunohistochemistry. In addition, in vitrostudies were performed using colon cancer cell lines to study the serial changes of LKB1, LGR5 andPRKAA1 (AMPK) gene expression levels after irradiation. Our data demonstrate that specimens obtainedfrom patients with poor pathological response and tumor recurrence had significantly higher geneexpression levels of LKB1 and LGR5 than those without them (P < 0.05), and there was a significantpositive correlation between LKB1 and LGR5 gene expression after CRT (Spearman’s ρ: 0.429, P =0.0023). The patients with high expression levels of both LKB1 and LGR5 had a significantly lowerrecurrence-free survival compared with the other group (P = 0.0055, 95 % confidence interval:1.39–11.08). Lastly, in vitro studies demonstrated a similar pattern of serial gene expression amongLKB1, LGR5 and PRKAA1 after irradiation. Our results suggest that LKB1 and LGR5 expression may beimplicated in resistance to CRT, therefore contributing to tumor relapse in patients with locally advancedrectal cancer treated with preoperative CRT.", "metadata": {}}
+{"_id": "31612088", "title": "", "text": "Evaluating the impact of pharmacists in mental health: a systematic review.Efforts to improve theoutcomes of patients with mental illness often have involved incorporating the skills of a variety of healthcare professionals into collaborative care models. For over 30 years, clinical pharmacists have contributedto these care models in capacities ranging from educator to consultant to provider. This systematicreview evaluates the quantity and quality of medical literature examining the impact of pharmacists inmental health from 1972-2003. Although we identified approximately 35 publications describing the rolesof clinical pharmacists in this regard, only 16 were of sufficient scientific rigor to permit evaluation andcomparison. The 16 studies were divided equally between inpatient and outpatient settings and wereconducted in a variety of health care organizations (e.g., Veterans Administration, health maintenanceorganizations, community mental health clinics, and nursing homes). Nine of the studies examined therole of pharmacists in providing treatment recommendations and patient education, five featuredpharmacists as providers (with prescriptive authority), and the remaining two described the impactpharmacists have in delivering education to the psychiatric staff. Six of the 16 studies were prospective,but only three of these incorporated a randomization procedure for patients or facilities. Collectively, theresults of the 16 studies were positive, demonstrating improvements in outcomes, prescribing practices,patient satisfaction, and resource use. Unfortunately, most of the investigations were small, andsignificant limitations in study design limited further comparison. Given the long history and anecdotalsuccess of pharmacists in mental health care settings, additional multicenter cost-effectiveness trials arewarranted to further support the role of the psychiatric pharmacist.", "metadata": {}}
+{"_id": "31616203", "title": "", "text": "Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breastcancer.PURPOSE Brain metastases develop in one third of patients with advanced HER2+ breast cancer.Effective therapy for patients with central nervous system (CNS) progression after cranial radiation isextremely limited and represents a major clinical challenge. Lapatinib, an epidermal growth factorreceptor/HER2 inhibitor, was associated with regressions of CNS lesions in a small phase 2 trial. Thecurrent study was done to further evaluate the CNS activity of lapatinib. The study was later amended toallow patients who progressed on lapatinib the option of receiving lapatinib plus capecitabine.EXPERIMENTAL DESIGN Eligible patients had HER2+ breast cancer, progressive brain metastases, priortrastuzumab, and cranial radiotherapy. The primary end point was CNS objective response, defined as>or=50% volumetric reduction of CNS lesion(s) in the absence of increasing steroid use, progressiveneurologic signs and symptoms, or progressive extra-CNS disease. RESULTS Two-hundred and forty-twopatients entered the study. CNS objective responses to lapatinib were observed in 6% of patients. In anexploratory analysis, 21% of patients experienced a >or=20% volumetric reduction in their CNS lesions.An association was observed between volumetric reduction and improvement in progression-free survivaland neurologic signs and symptoms. Of the 50 evaluable patients who entered the lapatinib pluscapecitabine extension, 20% experienced a CNS objective response and 40% experienced a >or=20%volumetric reduction in their CNS lesions. CONCLUSIONS This study confirms the modest CNS antitumoractivity of lapatinib. Additional responses were observed with the combination of lapatinib andcapecitabine. Further studies of lapatinib-based regimens for CNS metastases from HER2+ breast cancerare warranted.", "metadata": {}}
+{"_id": "31624828", "title": "", "text": "Control of signaling-mediated clearance of apoptotic cells by the tumor suppressor p53The inefficientclearance of dying cells can lead to abnormal immune responses, such as unresolved inflammation andautoimmune conditions. We show that tumor suppressor p53 controls signaling-mediated phagocytosis ofapoptotic cells through its target, Death Domain1α (DD1α), which suggests that p53 promotes both theproapoptotic pathway and postapoptotic events. DD1α appears to function as an engulfment ligand orreceptor that engages in homophilic intermolecular interaction at intercellular junctions of apoptotic cellsand macrophages, unlike other typical scavenger receptors that recognize phosphatidylserine on thesurface of dead cells. DD1α-deficient mice showed in vivo defects in clearing dying cells, which led tomultiple organ damage indicative of immune dysfunction. p53-induced expression of DD1α thus preventspersistence of cell corpses and ensures efficient generation of precise immune responses.", "metadata": {}}
+{"_id": "31634628", "title": "", "text": "Circulating tumor DNA as a non-invasive substitute to metastasis biopsy for tumor genotyping andpersonalized medicine in a prospective trial across all tumor types.Cell-free tumor DNA (ctDNA) has thepotential to enable non-invasive diagnostic tests for personalized medicine in providing similar molecularinformation as that derived from invasive tumor biopsies. The histology-independent phase II SHIVA trialmatches patients with targeted therapeutics based on previous screening of multiple somatic mutationsusing metastatic biopsies. To evaluate the utility of ctDNA in this trial, as an ancillary study we performedde novo detection of somatic mutations using plasma DNA compared to metastasis biopsies in 34 patientscovering 18 different tumor types, scanning 46 genes and more than 6800 COSMIC mutations with amultiplexed next-generation sequencing panel. In 27 patients, 28 of 29 mutations identified in metastasisbiopsies (97%) were detected in matched ctDNA. Among these 27 patients, one additional mutation wasfound in ctDNA only. In the seven other patients, mutation detection from metastasis biopsy failed due toinadequate biopsy material, but was successful in all plasma DNA samples providing three more potentialactionable mutations. These results suggest that ctDNA analysis is a potential alternative and/orreplacement to analyses using costly, harmful and lengthy tissue biopsies of metastasis, irrespective ofcancer type and metastatic site, for multiplexed mutation detection in selecting personalized therapiesbased on the patient's tumor genetic content.", "metadata": {}}
+{"_id": "31682248", "title": "", "text": "TGF-beta suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling.Alterations ofTGF-beta signaling have been described in colorectal cancer, although the molecular consequences arelargely unknown. By using transgenic mice overexpressing TGF-beta or a dominant-negativeTGF-betaRII, we demonstrate that TGF-beta signaling in tumor infiltrating T lymphocytes controls thegrowth of dysplastic epithelial cells in experimental colorectal cancer, as determined by histology and anovel system for high-resolution chromoendoscopy. At the molecular level, TGF-beta signaling in T cellsregulated STAT-3 activation in tumor cells via IL-6. IL-6 signaling required tumor cell-derived solubleIL-6R rather than membrane bound IL-6R and suppression of such TGF-beta-dependent IL-6trans-signaling prevented tumor progression in vivo. Taken together, our data provide novel insights intoTGF-beta signaling in colorectal cancer and suggest novel therapeutic approaches for colorectal cancerbased on inhibition of TGF-beta-dependent IL-6 trans-signaling.", "metadata": {}}
+{"_id": "31715818", "title": "", "text": "New opportunities: the use of nanotechnologies to manipulate and track stem cells.Nanotechnologies areemerging platforms that could be useful in measuring, understanding, and manipulating stem cells.Examples include magnetic nanoparticles and quantum dots for stem cell labeling and in vivo tracking;nanoparticles, carbon nanotubes, and polyplexes for the intracellular delivery of genes/oligonucleotidesand protein/peptides; and engineered nanometer-scale scaffolds for stem cell differentiation andtransplantation. This review examines the use of nanotechnologies for stem cell tracking, differentiation,and transplantation. We further discuss their utility and the potential concerns regarding theircytotoxicity.", "metadata": {}}
+{"_id": "31761981", "title": "", "text": "The emergence of order in the Drosophila pupal retina.During pupation, long-range order is imposed onthe autonomously developing ommatidia which compose the Drosophila eye. To accomplish this, eightadditional cell types arise: the primary, secondary, and tertiary pigment cells, and the four cells that formthe bristle. These cells form an interweaving lattice between ommatidia. The lattice is refined whenexcess cells are removed to bring neighboring ommatidia into register. Recent evidence suggests that inlarval development, local contacts direct cell fate. The same appears to be true during pupaldevelopment: the contacts a cell makes predict the cell type it will become. Cells which contact theanterior or posterior cone cells in an ommatidium invariably become primary pigment cells. Cells whichcontact primary pigment cells from different ommatidia become secondary and tertiary pigment cells.Bristle development is in several ways distinct from ommatidial development. The four cells of eachbristle group appear to be immediate descendents of a single founder cell. During their earlydifferentiation, they do not make stereotyped contacts with surrounding ommatidial cells, but do makeparticular contacts within the bristle group. And unlike the surrounding ommatidia, differentiation of thebristles radiates from the center of the eye to the edges. As cells are removed during two stages ofprogrammed cell death, the bristles are brought into their final position. When all cells in the lattice haveachieved their final position, a second stage of retinal development begins as structures specific to eachcell type are produced. This paper follows these various stages of pupal development, and suggests howlocal cell-cell contacts may produce the cells needed for a functional retina.", "metadata": {}}
+{"_id": "31803596", "title": "", "text": "Gene expression analysis by cDNA microarray in oral squamous cell carcinoma.BACKGROUND Oralsquamous cell carcinoma (OSCC) is common type of human cancer, but little is known about themolecular mechanisms deciding on this malignancy. Comprehensive gene expression profiling is essentialfor understanding OSCC. METHODS cDNA microarray was used to analyze expression patterns of 16 617genes in nine OSCC patients. RESULTS Forty-seven genes with altered expression among all cases wereextracted. The ontology of these 47 genes was classified into 10 categories. To validate the microarraydata, the expression of genes, including TGFBI, FADD and DUSP1 was analyzed by reversetranscriptase-polymerase chain reaction (RT-PCR). By hierarchical clustering analysis, the nine caseswere divided into two clusters. CONCLUSIONS The 47 genes are suggested as having a functionalsignificance in oral squamous cell carcinogenesis. It is also suggested that the gene expression patternsby hierarchical clustering analysis can represent degrees of differentiation. The postoperative recoverywas uneventful and patients free from tumor after surgery. In the future, on the occasion when the timecomes that the number of cases accumulated for microarray increases and each case is observed moreover a long-term, these data of 5-year survival rate will be added. Thereby, it will become possible torepresent the malignancy of OSCC by these gene expression patterns.", "metadata": {}}
+{"_id": "31834381", "title": "", "text": "Risk factors associated with symptoms of gastroesophageal reflux.BACKGROUND Although patients withgastroesophageal reflux are often instructed to change their lifestyle, population-based data on the riskfactors for reflux in the United States are lacking. METHODS We performed a cross-sectional study in anage- and gender-stratified random sample of the population of Olmsted County, Minnesota. Residentsaged 25 to 74 years were mailed a valid self-report questionnaire that measured reflux symptoms andpotential risk factors. Logistic regression was used to estimate the odds ratios (OR) with 95% confidenceintervals (CI) for reflux symptoms (heartburn or acid regurgitation) associated with potential risk factors.RESULTS Overall, 1,524 (72%) of 2,118 eligible subjects responded. A body mass index >30 kg/m2 (OR= 2.8; CI, 1.7 to 4.5), reporting an immediate family member with heartburn or disease of theesophagus or stomach (OR = 2.6; CI, 1.8 to 3.7), a past history of smoking (OR = 1.6; CI, 1.1 to 2.3),consuming more than seven drinks per week (OR = 1.9; Cl, 1.1 to 3.3), and a higher psychosomaticsymptom checklist score (OR per 5 units = 1.4; CI, 1.3 to 1.6) were independently associated withfrequent (at least weekly) reflux symptoms. CONCLUSION Obesity is a strong risk factor forgastroesophageal reflux, although the value of weight reduction remains to be proven. That family historywas also a risk factor suggests that there may be a genetic component to the disorder.", "metadata": {}}
+{"_id": "31844040", "title": "", "text": "A mathematical investigation of the effects of inhibitor therapy on three putative phosphorylationcascades governing the two-component system of the agr operon.Two-component systems (TCSs) arewidely employed by bacteria to sense specific external signals and conduct an appropriate response via aphosphorylation cascade within the cell. The TCS of the agr operon in the bacterium Staphylococcusaureus forms part of a regulatory process termed quorum sensing, a cell-to-cell communicationmechanism used to assess population density. Since S. aureus manipulates this \"knowledge\" in order toco-ordinate production of its armoury of exotoxin virulence factors required to promote infection, it isimportant to understand fully how this process works. We present three models of the agr operon, eachincorporating a different phosphorylation cascade for the TCS since the precise nature of the cascade isnot fully understood. Using numerical and asymptotic techniques we examine the effects of inhibitortherapy, a novel approach to controlling bacterial infection through the attenuation of virulence, on eachof these three cascades. We present results which, if evaluated against appropriate experimental data,provide insights into the potential effectiveness of such therapy. Moreover, the TCS models presentedhere are of broad relevance given that TCSs are widely conserved throughout the bacterial kingdom.", "metadata": {}}
+{"_id": "31851367", "title": "", "text": "Coregulators in nuclear estrogen receptor action: from concept to therapeutic targeting.Estrogens are keyregulators of growth, differentiation, and the physiological functions of a wide range of target tissues,including the male and female reproductive tracts, breast, and skeletal, nervous, cardiovascular,digestive and immune systems. The majority of these biological activities of estrogens are mediatedthrough two genetically distinct receptors, ERalpha and ERbeta, which function as hormone-inducibletranscription factors. Over the past decade, it has become increasingly clear that the recruitment ofcoregulatory proteins to ERs is required for ER-mediated transcriptional and biological activities. These\"coactivator\" complexes enable the ERs to respond appropriately: 1) to hormones or pharmacologicalligands, 2) interpret extra- and intra-cellular signals, 3) catalyze the process of chromatin condensationand 4) to communicate with the general transcription apparatus at target gene promoters. In addition toactivating proteins, the existence of corepressors, proteins that function as negative regulators of ERactivity in either physiological or pharmacological contexts, provides an additional level of complexity inER action. This review also describes current efforts aimed at developing pharmaceutical agents thattarget ER-cofactor interactions as therapeutics for estrogen-associated pathologies.", "metadata": {}}
+{"_id": "31882215", "title": "", "text": "Autophagy and mTORC1 regulate the stochastic phase of somatic cell reprogrammingWe describe robustinduction of autophagy during the reprogramming of mouse fibroblasts to induced pluripotent stem cellsby four reprogramming factors (Sox2, Oct4, Klf4 and c-Myc), henceforth 4F. This process occursindependently of p53 activation, and is mediated by the synergistic downregulation of mechanistic targetof rapamycin complex 1 (mTORC1) and the induction of autophagy-related genes. The 4F coordinatelyrepress mTORC1, but bifurcate in their regulation of autophagy-related genes, with Klf4 and c-Mycinducing them but Sox2 and Oct4 inhibiting them. On one hand, inhibition of mTORC1 facilitatesreprogramming by promoting cell reshaping (mitochondrial remodelling and cell size reduction). On theother hand, mTORC1 paradoxically impairs reprogramming by triggering autophagy. Autophagy does notparticipate in cell reshaping in reprogramming but instead degrades p62, whose accumulation inautophagy-deficient cells facilitates reprogramming. Our results thus reveal a complex signalling networkinvolving mTORC1 inhibition and autophagy induction in the early phase of reprogramming, whosedelicate balance ultimately determines reprogramming efficiency.", "metadata": {}}
+{"_id": "31884697", "title": "", "text": "Lithium Therapy Improves Neurological Function and Hippocampal Dendritic Arborization in aSpinocerebellar Ataxia Type 1 Mouse ModelBackground  Spinocerebellar ataxia type 1 (SCA1) is adominantly inherited neurodegenerative disorder characterized by progressive motor and cognitivedysfunction. Caused by an expanded polyglutamine tract in ataxin 1 (ATXN1), SCA1 pathogenesisinvolves a multifactorial process that likely begins with misfolding of ATXN1, which has functionalconsequences on its interactions, leading to transcriptional dysregulation. Because lithium has beenshown to exert neuroprotective effects in a variety of conditions, possibly by affecting gene expression,we tested the efficacy of lithium treatment in a knock-in mouse model of SCA1 (Sca1154Q/2Q mice) thatreplicates many features of the human disease. Methods and Findings  Sca1154Q/2Q mice and theirwild-type littermates were fed either regular chow or chow that contained 0.2% lithium carbonate.Dietary lithium carbonate supplementation resulted in improvement of motor coordination, learning, andmemory in Sca1154Q/2Q mice. Importantly, motor improvement was seen when treatment was initiatedboth presymptomatically and after symptom onset. Neuropathologically, lithium treatment attenuated thereduction of dendritic branching in mutant hippocampal pyramidal neurons. We also report that lithiumtreatment restored the levels of isoprenylcysteine carboxyl methyltransferase (Icmt; alternatively,Pccmt), down-regulation of which is an early marker of mutant ATXN1 toxicity. Conclusions  The effect oflithium on a marker altered early in the course of SCA1 pathogenesis, coupled with its positive effect onmultiple behavioral measures and hippocampal neuropathology in an authentic disease model, make it anexcellent candidate treatment for human SCA1 patients.", "metadata": {}}
+{"_id": "31889025", "title": "", "text": "The progression from hypertension to congestive heart failure.OBJECTIVES - To study the relative andpopulation-attributable risks of hypertension for the development of congestive heart failure (CHF), toassess the time course of progression from hypertension to CHF, and to identify risk factors thatcontribute to the development of overt heart failure in hypertensive subjects. DESIGN - Inception cohortstudy. SETTING - General community. PARTICIPANTS - Original Framingham Heart Study andFramingham Offspring Study participants aged 40 to 89 years and free of CHF. To reflect morecontemporary experience, the starting point of this study was January 1, 1970. EXPOSURE MEASURES -Hypertension (blood pressure of at least 140 mm Hg systolic or 90 mm Hg diastolic or current use ofmedications for treatment of high blood pressure) and other potential CHF risk factors were assessed atperiodic clinic examinations. OUTCOME MEASURE - The development of CHF. RESULTS - A total of 5143eligible subjects contributed 72422 person-years of observation. During up to 20.1 years of follow-up(mean, 14.1 years), there were 392 new cases of heart failure; in 91% (357/392), hypertensionantedated the development of heart failure. Adjusting for age and heart failure risk factors in proportionalhazards regression models, the hazard for developing heart failure in hypertensive compared withnormotensive subjects was about 2-fold in men and 3-fold in women. Multivariable analyses revealed thathypertension had a high population-attributable risk for CHF, accounting for 39% of cases in men and59% in women. Among hypertensive subjects, myocardial infarction, diabetes, left ventricularhypertrophy, and valvular heart disease were predictive of increased risk for CHF in both sexes. Survivalfollowing the onset of hypertensive CHF was bleak; only 24% of men and 31% of women survived 5years. CONCLUSIONS - Hypertension was the most common risk factor for CHF, and it contributed a largeproportion of heart failure cases in this population-based sample. Preventive strategies directed towardearlier and more aggressive blood pressure control are likely to offer the greatest promise for reducingthe incidence of CHF and its associated mortality.", "metadata": {}}
+{"_id": "31890716", "title": "", "text": "Association of plasma resistin with glomerular filtration rate and albuminuria in hypertensiveadults.Resistin, a recently discovered proinflammatory cytokine, has been variably associated with insulinresistance, inflammation, and renal dysfunction. We investigated the association of plasma resistin withestimated glomerular filtration rate and albuminuria in 1575 hypertensive adults without known coronaryheart disease or stroke (857 blacks and 718 non-Hispanic whites). Resistin was measured by a solidphase sandwich immunoassay, estimated glomerular filtration rate was estimated from serum creatinine,and albuminuria was expressed as urine albumin:creatinine ratio. After adjustment for coronary heartdisease risk factors (age, sex, body mass index, smoking history, systolic blood pressure, diabetes, andtotal and high-density lipoprotein cholesterol) and use of renin-angiotensin blockers and statins, higherplasma resistin levels were associated with lower estimated glomerular filtration rate in both ethnicgroups (each P<0.0001); the association remained significant after further adjustment for a marker ofinsulin resistance (homeostasis model assessment for insulin resistance) and a marker of inflammation(plasma C-reactive protein) and was seen in subjects with and without diabetes (each P<0.0001) in bothethnic groups. Higher plasma resistin levels were associated with a higher urine albumin:creatinine ratioin black subjects with diabetes (P<0.0001) and non-Hispanic white subjects with diabetes (P=0.032),independent of coronary heart disease risk factors, hypertension medication use, and statin use; theassociation remained significant after additional adjustment for homeostasis model assessment for insulinresistance and C-reactive protein. In adults with hypertension, higher circulating resistin levels wereassociated with a lower estimated glomerular filtration rate and with increased urine albumin:creatinineratio in the presence of concomitant diabetes. This association was independent of coronary heart diseaserisk factors and markers of insulin resistance and inflammation.", "metadata": {}}
+{"_id": "31902059", "title": "", "text": "Large-scale candidate gene scan reveals the role of chemoreceptor genes in host plant specialization andspeciation in the pea aphid.Understanding the drivers of speciation is critical to interpreting patterns ofbiodiversity. The identification of the genetic changes underlying adaptation and reproductive isolation isnecessary to link barriers to gene flow to the causal origins of divergence. Here, we present a novelapproach to the genetics of speciation, which should complement the commonly used approaches ofquantitative trait locus mapping and genome-wide scans for selection. We present a large-scale candidategene approach by means of sequence capture, applied to identifying the genetic changes underlyingreproductive isolation in the pea aphid, a model system for the study of ecological speciation. Targetedresequencing enabled us to scale up the candidate gene approach, specifically testing for the role ofchemosensory gene families in host plant specialization. Screening for the signature of divergence underselection at 172 candidate and noncandidate loci, we revealed a handful of loci that show high levels ofdifferentiation among host races, which almost all correspond to odorant and gustatory receptor genes.This study offers the first indication that some chemoreceptor genes, often tightly linked together in thegenome, could play a key role in local adaptation and reproductive isolation in the pea aphid andpotentially other phytophagous insects. Our approach opens a new route toward the functional genomicsof ecological speciation.", "metadata": {}}
+{"_id": "31902335", "title": "", "text": "The cancer stem cell hypothesis: a guide to potential molecular targets.Common cancer theories holdthat tumor is an uncontrolled somatic cell proliferation caused by the progressive addition of randommutations in critical genes that control cell growth. Nevertheless, various contradictions related to themutation theory have been reported previously. These events may be elucidated by the persistence ofresidual tumor cells, called Cancer Stem Cells (CSCs) responsible for tumorigenesis, tumor maintenance,tumor spread, and tumor relapse. Herein, we summarize the current understanding of CSCs, with a focuson the possibility to identify specific markers of CSCs, and discuss the clinical application of targetingCSCs for cancer treatment.", "metadata": {}}
+{"_id": "31933981", "title": "", "text": "Serum amyloid A: An acute-phase protein involved in tumour pathogenesisThe synthesis of acute-phaseprotein serum amyloid A (SAA) is largely regulated by inflammation- associated cytokines and a highconcentration of circulating SAA may represent an ideal marker for acute and chronic inflammatorydiseases. However, SAA is also synthesized in extrahepatic tissues, e.g. human carcinoma metastasesand cancer cell lines. An increasing body of in vitro data supports the concept of involvement of SAA incarcinogenesis and neoplastic diseases. Accumulating evidence suggests that SAA might be included in agroup of biomarkers to detect a pattern of physiological events that reflect the growth of malignancy andhost response. This review is meant to provide a broad overview of the many ways that SAA couldcontribute to tumour development, and accelerate tumour progression and metastasis, and to gain abetter understanding of this acute-phase reactant as a possible link between chronic inflammation andneoplasia.", "metadata": {}}
+{"_id": "31942055", "title": "", "text": "Body size and outcomes on peritoneal dialysis in the United States.BACKGROUND Being overweight isoften cited as a relative contraindication to peritoneal dialysis. Our primary objective was to determinewhether actual mortality rates support this opinion. METHODS Retrospective cohort study of UnitedStates Medicare patients initiating dialysis between 1995 and 2000 (N = 418,021; 11% peritonealdialysis). RESULTS Seven percent were underweight [body mass index (BMI) < 18.5 kg/m2], 27% wereoverweight (BMI 25.0 to 29.9 kg/m2), and 23% were obese (BMI> 29.9 kg/m2) at dialysis initiation.Compared to those with normal BMI, the adjusted odds of initiating peritoneal dialysis were 0.70 (P <0.05) in underweight, 1.12 (P < 0.05) in overweight, and 0.87 (P < 0.05) in obese subjects. Amongperitoneal dialysis patients, adjusted mortality hazard ratios in the first, second, and third year were 1.45(P < 0.05), 1.28 (P < 0.05), and 1.17 for the underweight, respectively; 0.84 (P < 0.05), 0.89 (P <0.05), and 0.98 for the overweight, respectively; and 0.89 (P < 0.05), 0.99, and 1.00 for the obese,respectively. Apart from higher third-year mortality in the obese, associations were similar aftercensoring at a switch to hemodialysis. For transplantation, the corresponding results were 0.76 (P <0.05), 0.90 (P < 0.05), and 0.88 for the underweight, respectively; 0.95, 1.06, and 0.93 for theoverweight, respectively; and 0.62 (P < 0.05), 0.68, and 0.71 for the obese, respectively. For switchingto hemodialysis, hazards ratios were 0.92, 0.97, and 0.80 for the underweight, respectively; 1.07, 1.11(P < 0.05), and 1.03 for the overweight, respectively; and 1.28 (P < 0.05), 1.29 (P < 0.05), and 1.36 (P< 0.05) for the obese, respectively. CONCLUSION Although less likely to initiate peritoneal dialysis,overweight and obese peritoneal dialysis patients have longer survival than those with lower BMI, notadequately explained by lower transplantation and technique survival rates.", "metadata": {}}
+{"_id": "31962403", "title": "", "text": "The anaphase promoting complex/cyclosome: a machine designed to destroyThe anaphase promotingcomplex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryoticcell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions,and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex. Recentdiscoveries have revealed an unexpected multitude of mechanisms that control APC/C activity, and haveprovided a first insight into how this unusual ubiquitin ligase recognizes its substrates.", "metadata": {}}
+{"_id": "32001951", "title": "", "text": "Regulation of the expression of alkaline phosphatase in a human breast-cancer cell line.Treatment of thecultured human breast-cancer cells BC-M1 with dexamethasone induced a placental-type alkalinephosphatase (ALP). Both the ALP activity and the mRNA level in the cells were increased. The induction ofALP activity by dexamethasone was time- and dose-dependent. The accumulation of ALP mRNA wasinhibited by both actinomycin D and cycloheximide, indicating that its induction is a complex event andmay involve other regulatory proteins. Retinoic acid showed opposing effects with dexamethasone on theexpression of alkaline phosphatase. Retinoic acid (RA) and phorbol 12-myristate 13-acetate alsosubstantially reduced the dexamethasone-induced expression of ALP. Studies on thermostability andsensitivity to various amino acid inhibitors indicated that the BC-M1 ALP is most similar to the placentalform. Northern hybridization analysis also revealed that ALP mRNA transcripts in BC-M1 and termplacenta are similar in size and are distinct from that of the placental-like mRNA transcript inchoriocarcinoma cells. Analysis of the degradation of BC-M1 ALP mRNA showed a similar half-life of 27 hin the untreated and in dexamethasone- or RA-treated cells. These findings demonstrated that theinduction of ALP in BC-M1 cells by dexamethasone is mainly due to the increase in the transcription of theALP gene.", "metadata": {}}
+{"_id": "32012666", "title": "", "text": "Declining tuberculosis notification trend associated with strengthened TB and expanded HIV care inSwaziland.This retrospective observational review documents the efforts of the Swaziland NationalTuberculosis (TB) Control Programme between 2004 and 2014. The objective is to describe the disparitybetween actual declines in case notification and increases in estimated incidence. The review of policiesand practices shows the most influential factors associated with the decrease in TB case notification to bean increase in access to antiretroviral therapy for co-infected TB patients, the general success of TB andhuman immunodeficiency virus service integration in the country and improvements in implementation ofall components of directly observed treatment, active case finding, and rapid diagnosis using newtechnologies.", "metadata": {}}
+{"_id": "32023005", "title": "", "text": "Advances in techniques of testing mycobacterial drug sensitivity, and the use of sensitivity tests intuberculosis control programmes.In a paper arising out of an informal international consultation ofspecialists in the bacteriology of tuberculosis held in 1961, an attempt was made to formulate criteria,and specify technical procedures, for reliable tests of sensitivity (the absolute-concentration method, theresistance-ratio method and the proportion method) to the 3 main antituberculosis drugs (isoniazid,streptomycin and p-aminosalicylic acid). Seven years later, a further consultation was held to review thelatest developments in the field and to suggest how sensitivity tests might be put to practical use intuberculosis control programmes. The participants reached agreement on how to define drug sensitivityand resistance, and stressed the importance of using a discrimination approach to the calibration ofsensitivity tests. Their views are contained in the present paper, which also includes descriptions of thesensitivity tests used by the Medical Research Council of Great Britain for first- and second-line drugs(minimal inhibitory concentration and resistance-ratio methods), the two main variants of the proportionmethod developed by the Institut Pasteur, Paris, and a method for calibrating sensitivity tests.", "metadata": {}}
+{"_id": "32084655", "title": "", "text": "Time from finding abnormality on mass-screening to final diagnosis of lung cancer.Mass-screening forlung cancer is rather a unique system in Japan. This study illustrates time from finding abnormality onmass-screening to final diagnosis of lung cancer. Among the 517 patients with lung cancer who wereadmitted to our hospital over a 10-year period up to December 2001, 83 (16.1%) were detected bymass-screening. We reviewed medical records of the 83 patients and determined the intervals from themass-screening to the pathological diagnosis with clinical staging. Time from the mass-screening to thedate of hospital visit was <2 months in 62 (74.7%) cases. Five (6.0%) patients visited hospital more than6 months after the mass-screening. With respect to the interval, there was no statistical difference ingender (p=0.0680) and age (p=0.1532). Among 60 patients who were referred from outside, onaverage, patients visited our hospital 0.5 month after they first sought medical attention at nearby clinic,and at our hospital 0.5 month was required to make a pathological diagnosis of lung cancer with TNMstaging. There was a statistical difference in survival between the patients who were diagnosed <4months and the patients who were diagnosed >4 months from the screening (p=0.0487). The interval inmost cases was acceptable. However, further improvements are still needed to minimize the delay and tomaximize the benefits of early cancer detection.", "metadata": {}}
+{"_id": "32101982", "title": "", "text": "Krüppel-like factor 2 (KLF2) regulates B-cell reactivity, subset differentiation, and trafficking moleculeexpression.The transcription factor Krüppel-like factor 2 (KLF2) is critical for normal trafficking of Tlymphocytes, but its role in B cells is unclear. We report that B cell-specific KLF2 deficiency leads todecreased expression of the trafficking molecules CD62L and β7-integrin, yet expression of sphingosine-1phosphate receptor 1 (which is a critical target of KLF2 in T cells) was, unexpectedly, minimally altered.Unexpectedly, Klf2 deletion led to a drastic reduction in the B1 B-cell pool and a substantial increase intransitional and marginal zone B-cell numbers. In addition, we observed that KLF2-deficient B cellsshowed increased apoptosis and impaired proliferation after B-cell receptor cross-linking. Geneexpression analysis indicated that KLF2-deficient follicular B cells display numerous characteristics sharedby normal marginal zone B cells, including reduced expression of several signaling molecules that maycontribute to defective activation of these cells. Hence, our data indicate that KLF2 plays a critical role indictating normal subset differentiation and functional reactivity of mature B cells.", "metadata": {}}
+{"_id": "32159283", "title": "", "text": "Antibiotics and risk of subsequent first-time acute myocardial infarction.CONTEXT Increasing evidencesupports the hypothesis of a causal association between certain bacterial infections and increased risk ofdeveloping acute myocardial infarction. If such a causal association exists, subjects who used antibioticsactive against the bacteria, regardless of indication, might be at lower risk of developing acute myocardialinfarction than nonusers. OBJECTIVE To determine whether previous use of antibiotics decreases the riskof developing a first-time acute myocardial infarction. DESIGN Population-based case-control analysis.SETTING The United Kingdom-based General Practice Research Database comprising 350 generalpractices. PATIENTS A total of 3315 case patients aged 75 years or younger with a diagnosis of first-timeacute myocardial infarction between 1992 and 1997 and 13139 controls without myocardial infarctionmatched to cases for age, sex, general practice attended, and calendar time. MAIN OUTCOME MEASURESUse of antibiotics among those who did or did not have a first-time acute myocardial infarction. RESULTSCases were significantly less likely to have used tetracycline antibiotics (adjusted odds ratio [OR], 0.70;95% confidence interval [CI], 0.55-0.90) or quinolones (adjusted OR, 0.45; 95% CI, 0.21-0.95). Noeffect was found for previous use of macrolides (primarily erythromycin), sulfonamides, penicillins, orcephalosporins. CONCLUSIONS The findings from this large case-control analysis provide further, albeitindirect, evidence for an association between bacterial infections with organisms susceptible totetracycline or quinolone antibiotics and the risk of acute myocardial infarction. These results ofpreliminary nature should stimulate more research to further explore the role of infections in the etiologyof acute myocardial infarction.", "metadata": {}}
+{"_id": "32170702", "title": "", "text": "Thrombopoietin/MPL signaling regulates hematopoietic stem cell quiescence and interaction with theosteoblastic niche.Maintenance of hematopoietic stem cells (HSCs) depends on interaction with theirniche. Here we show that the long-term (LT)-HSCs expressing the thrombopoietin (THPO) receptor, MPL,are a quiescent population in adult bone marrow (BM) and are closely associated with THPO-producingosteoblastic cells. THPO/MPL signaling upregulated beta1-integrin and cyclin-dependent kinase inhibitorsin HSCs. Furthermore, inhibition and stimulation of THPO/MPL pathway by treatments with anti-MPLneutralizing antibody, AMM2, and with THPO showed reciprocal regulation of quiescence of LT-HSC. AMM2treatment reduced the number of quiescent LT-HSCs and allowed exogenous HSC engraftment withoutirradiation. By contrast, exogenous THPO transiently increased quiescent HSC population andsubsequently induced HSC proliferation in vivo. Altogether, these observations suggest that THPO/MPLsignaling plays a critical role of LT-HSC regulation in the osteoblastic niche.", "metadata": {}}
+{"_id": "32177659", "title": "", "text": "Interlaboratory reproducibility and proficiency testing within the human papillomavirus cervical cancerscreening program in Catalonia, Spain.In Catalonia, a screening protocol for cervical cancer, includinghuman papillomavirus (HPV) DNA testing using the Digene Hybrid Capture 2 (HC2) assay, wasimplemented in 2006. In order to monitor interlaboratory reproducibility, a proficiency testing (PT) surveyof the HPV samples was launched in 2008. The aim of this study was to explore the repeatability of theHC2 assay's performance. Participating laboratories provided 20 samples annually, 5 randomly chosensamples from each of the following relative light unit (RLU) intervals: <0.5, 0.5 to 0.99, 1 to 9.99, and≥10. Kappa statistics were used to determine the agreement levels between the original and the PTreadings. The nature and origin of the discrepant results were calculated by bootstrapping. A total of 946specimens were retested. The kappa values were 0.91 for positive/negative categorical classification and0.79 for the four RLU intervals studied. Sample retesting yielded systematically lower RLU values thanthe original test (P<0.005), independently of the time elapsed between the two determinations (median,53 days), possibly due to freeze-thaw cycles. The probability for a sample to show clinically discrepantresults upon retesting was a function of the RLU value; samples with RLU values in the 0.5 to 5 intervalshowed 10.80% probability to yield discrepant results (95% confidence interval [CI], 7.86 to 14.33)compared to 0.85% probability for samples outside this interval (95% CI, 0.17 to 1.69). Globally, theHC2 assay shows high interlaboratory concordance. We have identified differential confidence thresholdsand suggested the guidelines for interlaboratory PT in the future, as analytical quality assessment of HPVDNA detection remains a central component of the screening program for cervical cancer prevention.", "metadata": {}}
+{"_id": "32181055", "title": "", "text": "The role of regulatory variation in complex traits and diseaseWe are in a phase of unprecedentedprogress in identifying genetic loci that cause variation in traits ranging from growth and fitness in simpleorganisms to disease in humans. However, a mechanistic understanding of how these loci influence traitsis lacking for the majority of loci. Studies of the genetics of gene expression have emerged as a key toolfor linking DNA sequence variation to phenotypes. Here, we review recent insights into the molecularnature of regulatory variants and describe their influence on the transcriptome and the proteome. Wediscuss conceptual advances from studies in model organisms and present examples of complete chainsof causality that link individual polymorphisms to changes in gene expression, which in turn result inphysiological changes and, ultimately, disease risk.", "metadata": {}}
+{"_id": "32194449", "title": "", "text": "Adhesion disengagement uncouples intrinsic and extrinsic forces to drive cytokinesis in epithelialtissues.Cytokinesis entails cell invagination by a contractile actomyosin ring. In epithelia,E-cadherin-mediated adhesion connects the cortices of contacting cells; thus, it is unclear howinvagination occurs, how the new junction forms, and how tissue integrity is preserved. Investigations inDrosophila embryos first show that apicobasal cleavage is polarized: invagination is faster from the basalthan from the apical side. Ring contraction but not its polarized constriction is controlled by septinfilaments and Anillin. Polarized cleavage is due instead to mechanical anchorage of the ring to E-cadherincomplexes. Formation of the new junction requires local adhesion disengagement in the cleavage furrow,followed by new E-cadherin complex formation at the new interface. E-cadherin disengagement dependson the tension exerted by the cytokinetic ring and by neighboring cells. We uncover intrinsic and extrinsicforces necessary for cytokinesis and present a framework for understanding how tissue cohesion ispreserved during epithelial division.", "metadata": {}}
+{"_id": "32250572", "title": "", "text": "The epithelial inward rectifier channel Kir7.1 displays unusual K+ permeation properties.Rat and humancDNAs were isolated that both encoded a 360 amino acid polypeptide with a tertiary structure typical ofinwardly rectifying K+ channel (Kir) subunits. The new proteins, termed Kir7.1, were <37% identical toother Kir subunits and showed various unique residues at conserved sites, particularly near the poreregion. High levels of Kir7.1 transcripts were detected in rat brain, lung, kidney, and testis. In situhybridization of rat brain sections demonstrated that Kir7.1 mRNA was absent from neurons and glia butstrongly expressed in the secretory epithelial cells of the choroid plexus (as confirmed by in situpatch-clamp measurements). In cRNA-injected Xenopus oocytes Kir7.1 generated macroscopic Kircurrents that showed a very shallow dependence on external K+ ([K+]e), which is in marked contrast toall other Kir channels. At a holding potential of -100 mV, the inward current through Kir7.1 averaged -3.8+/- 1.04 microA with 2 mM [K+]e and -4.82 +/- 1.87 microA with 96 mM [K+]e. Kir7.1 has a methionineat position 125 in the pore region where other Kir channels have an arginine. When this residue wasreplaced by the conserved arginine in mutant Kir7.1 channels, the pronounced dependence of K+permeability on [K+]e, characteristic for other Kir channels, was restored and the Ba2+ sensitivity wasincreased by a factor of approximately 25 (Ki = 27 microM). These findings support the important role ofthis site in the regulation of K+ permeability in Kir channels by extracellular cations.", "metadata": {}}
+{"_id": "32263707", "title": "", "text": "Oral fingolimod (FTY720) for relapsing multiple sclerosis.BACKGROUND Fingolimod (FTY720) is a new oralimmunomodulating agent under evaluation for the treatment of relapsing multiple sclerosis. METHODSWe randomly assigned 281 patients to receive oral fingolimod, at a dose of 1.25 mg or 5.0 mg, or aplacebo once daily, and we followed these patients for 6 months with magnetic resonance imaging (MRI)and clinical evaluations (core study, months 0 to 6). The primary end point was the total number ofgadolinium-enhanced lesions recorded on T(1)-weighted MRI at monthly intervals for 6 months. In anextension study in which the investigators and patients remained unaware of the dose assignments(months 7 to 12), patients who received placebo underwent randomization again to one of the fingolimoddoses. RESULTS A total of 255 patients completed the core study. The median total number ofgadolinium-enhanced lesions on MRI was lower with 1.25 mg of fingolimod (1 lesion, P<0.001) and 5.0mg of fingolimod (3 lesions, P=0.006) than with placebo (5 lesions). The annualized relapse rate was0.77 in the placebo group, as compared with 0.35 in the group given 1.25 mg of fingolimod (P=0.009)and 0.36 in the group given 5.0 mg of fingolimod (P=0.01). For the 227 patients who completed theextension study, the number of gadolinium-enhanced lesions and relapse rates remained low in thegroups that received continuous fingolimod, and both measures decreased in patients who switched fromplacebo to fingolimod. Adverse events included nasopharyngitis, dyspnea, headache, diarrhea, andnausea. Clinically asymptomatic elevations of alanine aminotransferase levels were more frequent withfingolimod (10 to 12%, vs. 1% in the placebo group). One case of the posterior reversibleencephalopathy syndrome occurred in the 5.0-mg group. Fingolimod was also associated with an initialreduction in the heart rate and a modest decrease in the forced expiratory volume in 1 second.CONCLUSIONS In this proof-of-concept study, fingolimod reduced the number of lesions detected on MRIand clinical disease activity in patients with multiple sclerosis. Evaluation in larger, longer-term studies iswarranted. (Clinicaltrials.gov numbers, NCT00333138 [core study] and NCT00235430 [ClinicalTrials.gov][extension].).", "metadata": {}}
+{"_id": "32275758", "title": "", "text": "Nonoverlapping functions of DNA polymerases mu, lambda, and terminal deoxynucleotidyltransferaseduring immunoglobulin V(D)J recombination in vivo.DNA polymerases mu (pol mu), lambda (pol lambda),and terminal deoxynucleotidyltransferase (TdT) are enzymes of the pol X family that share homology insequence and functional domain organization. We showed previously that pol mu participates in lightchain but surprisingly not heavy chain gene rearrangement. We show here that immunoglobulin heavychain junctions from pol lambda-deficient animals have shorter length with normal N-additions, thusindicating that pol lambda is recruited during heavy chain rearrangement at a step that precedes theaction of TdT. In contrast to previous in vitro studies, analysis of animals with combined inactivation ofthese enzymes revealed no overlapping or compensatory activities for V(D)J recombination between polmu, pol lambda, and TdT. This complex usage of polymerases with distinct catalytic specificities maycorrespond to the specific function that the third hypervariable region assumes for each immunoglobulinchain, with pol lambda maintaining a large heavy chain junctional heterogeneity and pol mu ensuring arestricted light chain junctional variability.", "metadata": {}}
+{"_id": "32322418", "title": "", "text": "Moderate regular exercise increases basal production of nitric oxide in elderly women.Vascular endothelialcells produce nitric oxide (NO), which is a potent vasodilator substance and is thought to haveantiatherosclerotic properties. Therefore, it has also been proposed that NO may be useful to regulatevascular tonus and prevent progression of atherosclerosis. On the other hand, NO activity reduces withaging. We previously reported that the plasma nitrite/nitrate (NOx: the stable end product of NO)concentration was significantly increased by intense aerobic exercise training in healthy young humans.We hypothesized that lifestyle modification (e.g., even mild regular exercise training) can increase NOproduction in previously sedentary older humans. We measured the plasma NOx concentration beforeand after a mild aerobic exercise training regimen (cycling on a leg ergometer at 80% ventilatorythreshold for 30 min, 5 days/week) for 3 months in elderly women. In addition, we assessed the plasmaconcentration of cyclic guanosine monophosphate (cGMP), a second messenger of NO, in the samesamples. The individual ventilatory threshold increased significantly after the 3-month exercise training.The blood pressure at rest significantly decreased after exercise training. These results suggest that the3-month exercise training in the older women produced favorable physiological effects. The plasmaconcentration of NOx significantly increased by the exercise training, and the plasma concentration ofcGMP also increased by the exercise training. The present study suggests that even a mild regularaerobic-endurance exercise increases NO production in previously sedentary older humans, which mayhave beneficial effects (i.e., antihypertensive and antiatherosclerotic effects by endogenous NO) on thecardiovascular system.", "metadata": {}}
+{"_id": "32324430", "title": "", "text": "Competition between target sites of regulators shapes post-transcriptional generegulationPost-transcriptional gene regulation (PTGR) of mRNA turnover, localization and translation ismediated by microRNAs (miRNAs) and RNA-binding proteins (RBPs). These regulators exert their effectsby binding to specific sequences within their target mRNAs. Increasing evidence suggests thatcompetition for binding is a fundamental principle of PTGR. Not only can miRNAs be sequestered andneutralized by the targets with which they interact through a process termed 'sponging', but competitionbetween binding sites on different RNAs may also lead to regulatory crosstalk between transcripts. Here,we quantitatively model competition effects under physiological conditions and review the role ofendogenous sponges for PTGR in light of the key features that emerge.", "metadata": {}}
+{"_id": "32328114", "title": "", "text": "Primary prevention of ischemic stroke: A statement for healthcare professionals from the Stroke Councilof the American Heart Association.Stroke ranks as the third leading cause of death in the United States.It is now estimated that there are more than 700 000 incident strokes annually and 4.4 million strokesurvivors.1 2 The economic burden of stroke was estimated by the American Heart Association to be $51billion (direct and indirect costs) in 1999.3 Despite the advent of treatment of selected patients withacute ischemic stroke with tissue plasminogen activator and the promise of other experimental therapies,the best approach to reducing the burden of stroke remains prevention.4 5 High-risk or stroke-proneindividuals can be identified and targeted for specific interventions.6 This is important becauseepidemiological data suggest a substantial leveling off of prior declines in stroke-related mortality and apossible increase in stroke incidence.7 8   The Stroke Council of the American Heart Association formedan ad hoc writing group to provide a clear and concise overview of the evidence regarding variousestablished and potential stroke risk factors. The writing group was chosen based on expertise in specificsubject areas, and it used literature review, reference to previously published guidelines, and expertopinion to summarize existing evidence and formulate recommendations (Table 1\u0000). View thistable:   Table 1. Levels of Evidence and Grading of Recommendations    As given in Tables 2 through4\u0000\u0000\u0000, risk factors or risk markers for a first stroke were classified according to potential formodification (nonmodifiable, modifiable, or potentially modifiable) and strength of evidence (welldocumented, less well documented).5 The tables give the estimated prevalence, population attributablerisk, relative risk, and risk reduction with treatment for each factor when known. Population attributablerisk reflects the proportion of ischemic strokes in the population that can be attributed to a particular riskfactor and is given by the formula 100×[prevalence(relative risk−1)/prevalence(relative risk−1)+1]). …", "metadata": {}}
+{"_id": "32353339", "title": "", "text": "Chimeric live, attenuated vaccine against Japanese encephalitis (ChimeriVax-JE): phase 2 clinical trialsfor safety and immunogenicity, effect of vaccine dose and schedule, and memory response to challengewith inactivated Japanese encephalitis antigen.ChimeriVax-JE is a live, attenuated vaccine againstJapanese encephalitis, using yellow fever (YF) 17D vaccine as a vector. In a double-blind phase 2 trial, 99adults received vaccine, placebo, or YF 17D vaccine (YF-VAX). ChimeriVax-JE was well tolerated, with nodifferences in adverse events between treatment groups. Viremias resulting from administration ofChimeriVax-JE and YF-VAX were of short duration and low titer; 82 (94%) of 87 subjects administeredgraded doses (1.8-5.8 log(10)) of ChimeriVax-JE developed neutralizing antibodies. A second dose,administered 30 days later, had no booster effect. Previous inoculation with YF did not interfere withChimeriVax-JE, but there was a suggestion (not statistically significant) that ChimeriVax-JE interferedwith YF-VAX administered 30 days later. A separate study explored immunological memory both insubjects who had received ChimeriVax-JE 9 months before and in ChimeriVax-JE-naive subjectschallenged with inactivated mouse-brain vaccine (JE-VAX). Anamnestic responses were observed inpreimmune individuals. ChimeriVax-JE appears to be a safe vaccine that provides protective levels ofneutralizing antibody after a single dose.", "metadata": {}}
+{"_id": "32357890", "title": "", "text": "Global prevalence of anxiety disorders: a systematic review and meta-regression.BACKGROUND Theliterature describing the global prevalence of anxiety disorders is highly variable. A systematic review andmeta-regression were undertaken to estimate the prevalence of anxiety disorders and to identify factorsthat may influence these estimates. The findings will inform the new Global Burden of Disease study.Method A systematic review identified prevalence studies of anxiety disorders published between 1980and 2009. Electronic databases, reference lists, review articles and monographs were searched andexperts then contacted to identify missing studies. Substantive and methodological factors associatedwith inter-study variability were identified through meta-regression analyses and the global prevalence ofanxiety disorders was calculated adjusting for study methodology. RESULTS The prevalence of anxietydisorders was obtained from 87 studies across 44 countries. Estimates of current prevalence rangedbetween 0.9% and 28.3% and past-year prevalence between 2.4% and 29.8%. Substantive factorsincluding gender, age, culture, conflict and economic status, and urbanicity accounted for the greatestproportion of variability. Methodological factors in the final multivariate model (prevalence period,number of disorders and diagnostic instrument) explained an additional 13% of variance betweenstudies. The global current prevalence of anxiety disorders adjusted for methodological differences was7.3% (4.8-10.9%) and ranged from 5.3% (3.5-8.1%) in African cultures to 10.4% (7.0-15.5%) inEuro/Anglo cultures. CONCLUSIONS Anxiety disorders are common and the substantive andmethodological factors identified here explain much of the variability in prevalence estimates. Specificattention should be paid to cultural differences in responses to survey instruments for anxiety disorders.", "metadata": {}}
+{"_id": "32372280", "title": "", "text": "Expression of optineurin, a glaucoma-linked gene, is influenced by elevated intraocularpressure.Optineurin (optic neuropathy inducing protein; OPTN) was recently linked to 16.7% of familieswith primary open-angle glaucoma. The function of OPTN in the eye is not known, but is present in thetrabecular meshwork, which is responsible for maintenance of intraocular pressure (IOP). To gain insightinto the role of OPTN in the development of glaucoma we studied its expression in response to factorsknown to be associated with the disease: elevated IOP, tumor necrosis factor-alpha (TNFalpha), anddexamethasone (DEX). We performed the treatments in human organ cultures under conditionsmimicking physiological pressure. We find OPTN significantly upregulated after 2, 4, and 7 days ofsustained elevated IOP. OPTN expression is also induced 2.3-fold by TNFalpha and 2.6-fold by prolongedDEX treatment. These results demonstrate that OPTN is part of the transcriptome responding toglaucomatous insults and support the protective role of this protein in the trabecular meshwork.", "metadata": {}}
+{"_id": "32390525", "title": "", "text": "Prevention of malaria in long-term travelers.CONTEXT Long-term travelers, defined here as thosetraveling for periods of 6 months or longer, face particular challenges regarding malaria prevention.Current guidelines for malaria prevention primarily address prevention of Plasmodium falciparuminfections in short-term travelers. OBJECTIVES To examine the risk of malaria in long-term travelers,recent developments in personal protective measures, and the safety and tolerability of malariachemoprophylaxis during long-term use and to consider prevention strategies including continuouschemoprophylaxis, stand-by emergency self-treatment, seasonal prophylaxis, and strategies to preventprimary infection and relapses from P vivax malaria. EVIDENCE ACQUISITION Comprehensive search ofscientific publications including MEDLINE via both OVID and PubMED for relevant studies and articles witha cutoff date of July 2006, using the search terms long-term travel and malaria prevention, long-termmalaria chemoprophylaxis, and insect repellent and malaria. Additional references were obtained fromsearching the bibliographies of the selected articles, from dissertations, and from the proceedings ofrelevant conferences on travel medicine. There were no language restrictions. EVIDENCE SYNTHESISLong-term travelers have a higher risk of malaria than short-term travelers. Long-term travelersunderuse personal protective measures and adhere poorly to continuous chemoprophylaxis regimens. Anumber of strategies are used during long-term stays: discontinuation of chemoprophylaxis after theinitial period, sequential regimens with different medications for chemoprophylaxis, stand-by emergencyself-treatment, and seasonal chemoprophylaxis targeting high-incidence periods or locations. Allstrategies have advantages and drawbacks. Counterfeit drugs sold in countries endemic for malaria poseserious concern for long-term travelers who purchase their medications overseas. Vivax malaria causessignificant illness in travelers, but relapses of vivax malaria are not prevented with the current first-linechemoprophylaxis regimens. Consensus guidelines are needed for prevention of malaria in long-termtravelers. CONCLUSIONS Prevention of malaria in long-term travelers is a complex issue and requiresexpert advice from travel medicine specialists. Recommendations for prevention of malaria in long-termtravelers must be individualized.", "metadata": {}}
+{"_id": "32408470", "title": "", "text": "Activation of AMPKα2 in adipocytes is essential for nicotine-induced insulin resistance in vivoCigarettesmoking promotes body weight reduction in humans while paradoxically also promoting insulin resistance(IR) and hyperinsulinemia. However, the mechanisms behind these effects are unclear. Here we showthat nicotine, a major constituent of cigarette smoke, selectively activates AMP-activated protein kinaseα2 (AMPKα2) in adipocytes, which in turn phosphorylates MAP kinase phosphatase-1 (MKP1) at serine334, initiating its proteasome-dependent degradation. The nicotine-dependent reduction of MKP1 inducesthe aberrant activation of both p38 mitogen-activated protein kinase and c-Jun N-terminal kinase, leadingto increased phosphorylation of insulin receptor substrate 1 (IRS1) at serine 307. Phosphorylation of IRS1leads to its degradation, protein kinase B inhibition, and the loss of insulin-mediated inhibition of lipolysis.Consequently, nicotine increases lipolysis, which results in body weight reduction, but this increase alsoelevates the levels of circulating free fatty acids and thus causes IR in insulin-sensitive tissues. Theseresults establish AMPKα2 as an essential mediator of nicotine-induced whole-body IR in spite ofreductions in adiposity.", "metadata": {}}
+{"_id": "32421068", "title": "", "text": "Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved byEuropean Medicines Agency: retrospective cohort study of drug approvals 2009-13Objective Todetermine the availability of data on overall survival and quality of life benefits of cancer drugs approvedin Europe. Design Retrospective cohort study. Setting Publicly accessible regulatory and scientific reportson cancer approvals by the European Medicines Agency (EMA) from 2009 to 2013.Main outcomemeasures Pivotal and postmarketing trials of cancer drugs according to their design features(randomisation, crossover, blinding), comparators, and endpoints. Availability and magnitude of benefiton overall survival or quality of life determined at time of approval and after market entry. ValidatedEuropean Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) used to assessthe clinical value of the reported gains in published studies of cancer drugs. Results From 2009 to 2013,the EMA approved the use of 48 cancer drugs for 68 indications. Of these, eight indications (12%) wereapproved on the basis of a single arm study. At the time of market approval, there was significantprolongation of survival in 24 of the 68 (35%). The magnitude of the benefit on overall survival rangedfrom 1.0 to 5.8 months (median 2.7 months). At the time of market approval, there was an improvementin quality of life in seven of 68 indications (10%). Out of 44 indications for which there was no evidenceof a survival gain at the time of market authorisation, in the subsequent postmarketing period there wasevidence for extension of life in three (7%) and reported benefit on quality of life in five (11%). Of the 68cancer indications with EMA approval, and with a median of 5.4 years' follow-up (minimum 3.3 years,maximum 8.1 years), only 35 (51%) had shown a significant improvement in survival or quality of life,while 33 (49%) remained uncertain. Of 23 indications associated with a survival benefit that could bescored with the ESMO-MCBS tool, the benefit was judged to be clinically meaningful in less than half(11/23, 48%).Conclusions This systematic evaluation of oncology approvals by the EMA in 2009-13shows that most drugs entered the market without evidence of benefit on survival or quality of life. At aminimum of 3.3 years after market entry, there was still no conclusive evidence that these drugs eitherextended or improved life for most cancer indications. When there were survival gains over existingtreatment options or placebo, they were often marginal.", "metadata": {}}
+{"_id": "32423829", "title": "", "text": "A cluster randomized, controlled trial of breast and cervix cancer screening in Mumbai, India:methodology and interim results after three rounds of screening.Cervix and Breast cancers are the mostcommon cancers among women worldwide and extract a large toll in developing countries. In May 1998,supported by a grant from the NCI (US), the Tata Memorial Hospital, Mumbai, India, started acluster-randomized, controlled, screening-trial for cervix and breast cancer using trained primary healthworkers to provide health-education, visual-inspection of cervix (with 4% acetic acid-VIA) and clinicalbreast examination (CBE) in the screening arm, and only health education in the control arm. Fourrounds of screening at 2-year intervals will be followed by 8 years of monitoring for incidence andmortality from cervix and breast cancers. The methodology and interim results after three rounds ofscreening are presented here. Good randomization was achieved between the screening (n = 75360) andcontrol arms (n = 76178). In the screening arm we see: High screening participation rates; Low attrition;Good compliance to diagnostic confirmation; Significant downstaging; Excellent treatment completionrate; Improving case fatality ratios. The ever-screened and never-screened participants in the screeningarm show significant differences with reference to the variables religion, language, age, education,occupation, income and health-seeking behavior for gynecological and breast-related complaints. Duringthe same period, in the control arm we see excellent participation rate for health education; Low attritionand a good number of symptomatic referrals for both cervix and breast.", "metadata": {}}
+{"_id": "32450297", "title": "", "text": "Evidence for energy-dependent accumulation of paraquat into rat lungTHE herbicide paraquat(N,N′-dimethyl 4,4′-bipyridilium) can produce widespread oedema and fibrosis in the human lung afteraccidental ingestion1–3. In those cases where death occurs after several weeks, there are no apparentpulmonary changes during the first few days following ingestion. Animal experiments in a variety ofspecies have shown the lung to be the major target organ4–6. After administration of paraquat toanimals, the lung has a high initial concentration and retains paraquat7–9. This retention appears to berelated to the development of lung damage7 (L. L. Smith and M. S. Rose, unpublished work). Themechanism of retention of paraquat by the lung is at present not understood.", "metadata": {}}
+{"_id": "32454714", "title": "", "text": "Role of gut commensal microflora in the development of experimental autoimmuneencephalomyelitis.Mucosal tolerance has been considered a potentially important pathway for thetreatment of autoimmune disease, including human multiple sclerosis and experimental conditions suchas experimental autoimmune encephalomyelitis (EAE). There is limited information on the capacity ofcommensal gut bacteria to induce and maintain peripheral immune tolerance. Inbred SJL and C57BL/6mice were treated orally with a broad spectrum of antibiotics to reduce gut microflora. Reduction of gutcommensal bacteria impaired the development of EAE. Intraperitoneal antibiotic-treated mice showed nosignificant decline in the gut microflora and developed EAE similar to untreated mice, suggesting thatreduction in disease activity was related to alterations in the gut bacterial population. Protection wasassociated with a reduction of proinflammatory cytokines and increases in IL-10 and IL-13. Adoptivetransfer of low numbers of IL-10-producing CD25(+)CD4(+) T cells (>75% FoxP3(+)) purified fromcervical lymph nodes of commensal bacteria reduced mice and in vivo neutralization of CD25(+) cellssuggested the role of regulatory T cells maintaining peripheral immune homeostasis. Our datademonstrate that antibiotic modification of gut commensal bacteria can modulate peripheral immunetolerance that can protect against EAE. This approach may offer a new therapeutic paradigm in thetreatment of multiple sclerosis and perhaps other autoimmune conditions.", "metadata": {}}
+{"_id": "32462603", "title": "", "text": "Epidemiology of surgically managed pelvic organ prolapse and urinary incontinence.OBJECTIVE Todetermine the incidence of surgically managed pelvic organ prolapse and urinary incontinence in apopulation-based cohort, and to describe their clinical characteristics. METHODS Our retrospective cohortstudy included all patients undergoing surgical treatment for prolapse and incontinence during 1995; allwere members of Kaiser Permanente Northwest, which included 149,554 women age 20 or older. Astandardized data-collection form was used to review all inpatient and outpatient charts of the 395women identified. Variables examined included age, ethnicity, height, weight, vaginal parity, smokinghistory, medical history, and surgical history, including the preoperative evaluation, procedureperformed, and details of all prior procedures. Analysis included calculation of age-specific andcumulative incidences and determination of the number of primary operations compared with repeatoperations performed for prolapse or incontinence. RESULTS The age-specific incidence increased withadvancing age. The lifetime risk of undergoing a single operation for prolapse or incontinence by age 80was 11.1%. Most patients were older, postmenopausal, parous, and overweight. Nearly half were currentor former smokers and one-fifth had chronic lung disease. Reoperation was common (29.2% of cases),and the time intervals between repeat procedures decreased with each successive repair. CONCLUSIONPelvic floor dysfunction is a major health issue for older women, as shown by the 11.1% lifetime risk ofundergoing a single operation for pelvic organ prolapse and urinary incontinence, as well as the largeproportion of reoperations. Our results warrant further epidemiologic research in order to determine theetiology, natural history, and long-term treatment outcomes of these conditions.", "metadata": {}}
+{"_id": "32463364", "title": "", "text": "Antihypertensive classes, cognitive decline and incidence of dementia: a networkmeta-analysis.OBJECTIVES Prevention of cognitive decline and dementia with blood pressure loweringtreatments has shown inconsistent results. We compared the effects of different classes ofantihypertensive drugs on the incidence of dementia, and on cognitive function. METHODS We conducteda systematic review and included 19 randomized trials (18 515 individuals) and 11 studies (831 674individuals) analysing the effects of antihypertensive treatment on cognition and on the incidence ofdementia, respectively, in hypertensive patients without prior cerebrovascular disorders. Networkmeta-analysis was used for the comparison of antihypertensive classes. RESULTS Antihypertensivetreatment, regardless of the drug class, had benefits on overall cognition [effect size 0.05, 95%confidence interval (CI) 0.02-0.07] and all cognitive functions except language. Antihypertensivetreatment reduced the risk of all-cause dementia by 9%, with reference to the control group (hazard ratio0.91, 95% CI 0.89-0.94), when randomized trials and observationnal studies were combined (n = 15).Result was not significant with randomized trials alone (n = 4). Angiotensin II receptor blockers (ARBs)had larger benefits than placebo on overall cognition (adjusted effect size 0.60 ± 0.18, P = 0.02). ARBswere more effective than β-blockers (0.67 ± 0.18, P = 0.01), diuretics (0.54 ± 0.19, P = 0.04) andangiotensin-converting enzyme inhibitors (0.47 ± 0.17, P = 0.04) in rank. The mean change in bloodpressure did not differ significantly between the different antihypertensive drug classes. CONCLUSIONOur results support the notion that antihypertensive treatment has beneficial effects on cognitive declineand prevention of dementia, and indicate that these effects may differ between drug classes with ARBspossibly being the most effective.", "metadata": {}}
+{"_id": "32481310", "title": "", "text": "Abnormal hemoglobins in a quarter million people.Hemolysates of erythrocytes from more than a quartermillion people in Alabama were electrophoresed on cellulose acetate, pH 8.4, and those samplesexhibiting an abnormality were also electrophoresed in citrate agar, pH 6.0. The globin chains of mutantsother than Hb S and C were electrophoresed in urea-mercaptoethanol buffers at both pH 8.9 and pH 6.0,and 60 of them were also analyzed structurally. Of about 6000 samples from whites, only three containedabnormal hemoglobins--Hb D Los Angeles, Hb J Baltimore, and one unidentified. Of 249,000 samplesfrom blacks, about 29,000 contained electrophoretically detectable abnormalities, most of themassociated with Hb S or C, present in a frequency of about 9% and 3%, respectively. About 1000 samplesresolved into patterns of potential clinical significance. Twenty other mutant hemoglobins were detected,in various genetic combinations in 164 kindreds; four of these-Hb Alabama, Montgomery, Titusville, andMobile--were previously unknown. The methods used are rapid, economical, and well suited for largescale surveys. They provide highly specific characterizations of many mutant hemoglobins, and nodiscrepancies were found between the presumptive identifications based on these characterizations andthe definitive identifications obtained from structural analyses.", "metadata": {}}
+{"_id": "32532238", "title": "", "text": "Cellular adaptation to mechanical stress: role of integrins, Rho, cytoskeletal tension andmechanosensitive ion channels.To understand how cells sense and adapt to mechanical stress, we appliedtensional forces to magnetic microbeads bound to cell-surface integrin receptors and measured changesin bead displacement with sub-micrometer resolution using optical microscopy. Cells exhibited four typesof mechanical responses: (1) an immediate viscoelastic response; (2) early adaptive behaviorcharacterized by pulse-to-pulse attenuation in response to oscillatory forces; (3) later adaptive cellstiffening with sustained (>15 second) static stresses; and (4) a large-scale repositioning response withprolonged (>1 minute) stress. Importantly, these adaptation responses differed biochemically. Theimmediate and early responses were affected by chemically dissipating cytoskeletal prestress (isometrictension), whereas the later adaptive response was not. The repositioning response was prevented byinhibiting tension through interference with Rho signaling, similar to the case of the immediate and earlyresponses, but it was also prevented by blocking mechanosensitive ion channels or by inhibiting Srctyrosine kinases. All adaptive responses were suppressed by cooling cells to 4 degrees C to slowbiochemical remodeling. Thus, cells use multiple mechanisms to sense and respond to static and dynamicchanges in the level of mechanical stress applied to integrins.", "metadata": {}}
+{"_id": "32533299", "title": "", "text": "Cutting edge: Candida albicans hyphae formation triggers activation of the Nlrp3 inflammasome.Theproinflammatory cytokine IL-1beta plays an important role in antifungal immunity; however, themechanisms by which fungal pathogens trigger IL-1beta secretion are unclear. In this study we show thatinfection with Candida albicans is sensed by the Nlrp3 inflammasome, resulting in the subsequent releaseof IL-1beta. The ability of C. albicans to switch from a unicellular yeast form into a filamentous form isessential for activation of the Nlrp3 inflammasome, as C. albicans mutants incapable of forming hyphaewere defective in their ability to induce macrophage IL- 1beta secretion. Nlrp3-deficient mice alsodemonstrated increased susceptibility to infection with C. albicans, which is consistent with a key role forNlrp3 in innate immune responses to the pathogen C. albicans.", "metadata": {}}
+{"_id": "32534305", "title": "", "text": "Type 2 diabetes and subsequent incidence of breast cancer in the Nurses' Health Study.OBJECTIVEHyperinsulinemia may promote mammary carcinogenesis. Insulin resistance has been linked to anincreased risk of breast cancer and is also characteristic of type 2 diabetes. We prospectively evaluatedthe association between type 2 diabetes and invasive breast cancer incidence in the Nurses' HealthStudy. RESEARCH DESIGN AND METHODS A total of 116,488 female nurses who were 30-55 years oldand free of cancer in 1976 were followed through 1996 for the occurrence of type 2 diabetes and through1998 for incident invasive breast cancer, verified by medical records and pathology reports. RESULTSDuring 2.3 million person-years of follow-up, we identified 6,220 women with type 2 diabetes and 5,189incident cases of invasive breast cancer. Women with type 2 diabetes had a modestly elevated incidenceof breast cancer (hazard ratio [HR] = 1.17; 95% CI 1.01-1.35) compared with women without diabetes,independent of age, obesity, family history of breast cancer, history of benign breast disease,reproductive factors, physical activity, and alcohol consumption. This association was apparent amongpostmenopausal women (1.16; 0.98-1.62) but not premenopausal women (0.83; 0.48-1.42). Theassociation was predominant among women with estrogen receptor-positive breast cancer (1.22;1.01-1.47). CONCLUSIONS Women with type 2 diabetes may have a slightly increased risk of breastcancer.", "metadata": {}}
+{"_id": "32556431", "title": "", "text": "Virus-encoded microRNAs.MicroRNAs (miRNAs) are the subject of enormous interest. They are smallnon-coding RNAs that play a regulatory role in numerous and diverse cellular processes such as immunefunction, apoptosis and tumorigenesis. Several virus families have been shown to encode miRNAs, and anappreciation for their roles in the viral infectious cycle continues to grow. Despite the identification ofnumerous (>225) viral miRNAs, an in depth functional understanding of most virus-encoded miRNAs islacking. Here we focus on a few viral miRNAs with well-defined functions. We use these examples toextrapolate general themes of viral miRNA activities including autoregulation of viral gene expression,avoidance of host defenses, and a likely important role in maintaining latent and persistent infections. Wehypothesize that although the molecular mechanisms and machinery are similar, the majority of viralmiRNAs may utilize a target strategy that differs from host miRNAs. That is, many viral miRNAs may haveevolved to regulate viral-encoded transcripts or networks of host genes that are unique to viral miRNAs.Included in this latter category is a likely abundant class of viral miRNAs that may regulate only one or afew principal host genes. Key steps forward for the field are discussed, including the need for additionalfunctional studies that utilize surgical viral miRNA mutants combined with relevant models of infection.", "metadata": {}}
+{"_id": "32587939", "title": "", "text": "Wolfram syndrome 1 and adenylyl cyclase 8 interact at the plasma membrane to regulate insulinproduction and secretionEndoplasmic reticulum (ER) stress causes pancreatic β-cell dysfunction andcontributes to β-cell loss and the progression of type 2 diabetes. Wolfram syndrome 1 (WFS1) has beenshown to be an important regulator of the ER stress signalling pathway; however, its role in β-cellfunction remains unclear. Here we provide evidence that WFS1 is essential for glucose- and glucagon-likepeptide 1 (GLP-1)-stimulated cyclic AMP production and regulation of insulin biosynthesis and secretion.Stimulation with glucose causes WFS1 translocation from the ER to the plasma membrane, where it formsa complex with adenylyl cyclase 8 (AC8), an essential cAMP-generating enzyme in the β-cell thatintegrates glucose and GLP-1 signalling. ER stress and mutant WFS1 inhibit complex formation andactivation of AC8, reducing cAMP synthesis and insulin secretion. These findings reveal that anER-stress-related protein has a distinct role outside the ER regulating both insulin biosynthesis andsecretion. The reduction of WFS1 protein on the plasma membrane during ER stress is a contributingfactor for β-cell dysfunction and progression of type 2 diabetes.", "metadata": {}}
+{"_id": "32598644", "title": "", "text": "Two Rice GRAS Family Genes Responsive to N-Acetylchitooligosaccharide Elicitor are Induced byPhytoactive Gibberellins: Evidence for Cross-Talk Between Elicitor and Gibberellin Signaling in Rice CellsInthis study, we present data showing that two members of the GRAS family of genes from rice, CIGR1 andCIGR2(chitin-inducible gibberellin-responsive), inducible by the potent elicitorN-acetylchitooligosaccharide (GN), are rapidly induced by exogenous gibberellins. The pattern of mRNAaccumulation was dependent on the dose and biological activity of the gibberellins, suggesting that theinduction of the genes by gibberellin is mediated by a biological receptor capable of specific recognitionand signal transduction upon perception of the phytoactive compounds. Further pharmacological analysisrevealed that the CIGR1 and CIGR2 mRNA accumulation by treatment with gibberellin is dependent uponprotein phosphorylation/dephosphorylation events. In rice calli derived from slender rice 1, a constitutivegibberellin-responsive mutant, or d1, a mutant deficient in the α-subunit of the heterotrimeric G-protein,CIGR1 and CIGR2 were induced by a GN elicitor, yet not by gibberellin. Neither gibberellin nor GN showedrelated activities in defense or development, respectively. These results strongly suggested that thesignal transduction cascade from gibberellin is independent of that from GN, and further implied thatCIGR1 and CIGR2 have dual, distinct roles in defense and development.", "metadata": {}}
+{"_id": "32611468", "title": "", "text": "Ghrelin's second life: from appetite stimulator to glucose regulator.Ghrelin, a 28 amino acid peptidehormone produced by the stomach, was the first orexigenic hormone to be discovered from theperiphery. The octanoyl modification at Ser³, mediated by ghrelin O-acyltransferase (GOAT), is essentialfor ghrelin's biological activity. Ghrelin stimulates food intake through binding to its receptor (GRLN-R) onneurons in the arcuate nucleus of the hypothalamus. Ghrelin is widely expressed throughout the body;accordingly, it is implicated in several other physiological functions, which include growth hormonerelease, gastric emptying, and body weight regulation. Ghrelin and GRLN-R expression are also found inthe pancreas, suggesting a local physiological role. Accordingly, several recent studies now point towardsan important role for ghrelin and its receptor in the regulation of blood glucose homeostasis, which is themain focus of this review. Several mechanisms of this regulation by ghrelin have been proposed, and onepossibility is through the regulation of insulin secretion. Despite some controversy, most studies suggestthat ghrelin exerts an inhibitory effect on insulin secretion, resulting in increased circulating glucoselevels. Ghrelin may thus be a diabetogenic factor. Obesity-related type 2 diabetes has become anincreasingly important health problem, almost reaching epidemic proportions in the world; therefore,antagonists of the ghrelin-GOAT signaling pathway, which will tackle both energy- and glucosehomeostasis, may be considered as promising new therapies for this disease.", "metadata": {}}
+{"_id": "32638085", "title": "", "text": "Histone acetylation and deacetylation in yeastHistone acetylation and deacetylation in the yeastSaccharomyces cerevisiae occur by targeting acetyltransferase and deacetylase enzymes to genepromoters and, in an untargeted and global manner, by affecting most nucleosomes. Recently, new rolesfor histone acetylation have been uncovered, not only in transcription but also in DNA replication, repairand heterochromatin formation. Interestingly, specific acetylatable lysines can function as binding sitesfor regulatory factors. Moreover, histone deacetylation is not only repressive but can be required for geneactivity.", "metadata": {}}
+{"_id": "32665136", "title": "", "text": "Neuroinflammation in spinal cord injury: therapeutic targets for neuroprotection andregeneration.Traumatic spinal cord injury triggers a complex local inflammatory reaction capable ofenhancing repair and exacerbating pathology. The composition and effector potential of the post-injurycellular and molecular immune cascade changes as a function of time and distance from the lesion.Production along this time-space continuum of cytokines, proteases, and growth factors establishesdynamic environments that lead to the death, damage, repair or growth of affected neurons and glia.Microenvironmental cues, therefore, generated by the cells therein, may determine these distinct fates ofrepair versus pathology. To harness repair, it is necessary to manipulate the assembly and phenotype ofcells that comprise the neuroinflammatory response to injury. Here, the potential of theneuroinflammatory response to cause outcomes such as pain, regeneration, and functional recovery isreviewed.", "metadata": {}}
+{"_id": "32671519", "title": "", "text": "Evaluation of systemic amyloidosis by scintigraphy with 123I-labeled serum amyloid Pcomponent.BACKGROUND In systemic amyloidosis the distribution and progression of disease have beendifficult to monitor, because they can be demonstrated only by biopsy. Serum amyloid P component(SAP) is a normal circulating plasma protein that is deposited on amyloid fibrils because of its specificbinding affinity for them. We investigated whether labeled SAP could be used to locate amyloid deposits.METHODS Purified human SAP labeled with iodine-123 was given intravenously to 50 patients withbiopsy-proved systemic amyloidosis--25 with the AL (primary) type and 25 with the AA (secondary)type--and to 26 control patients with disease and 10 healthy subjects. Whole-body images and regionalviews were obtained after 24 hours and read in a blinded fashion. RESULTS In the patients withamyloidosis the 123I-SAP was localized rapidly and specifically in amyloid deposits. The scintigraphicimages obtained were characteristic and appeared to identify the extent of amyloid deposition in all 50patients. There was no uptake of the 123I-SAP by the control patients and the healthy subjects. In allpatients with AA amyloidosis the spleen was affected, whereas the scans showed uptake in the heart,skin, carpal region, and bone marrow only in patients with the AL type. Positive images were seen in sixpatients in whom biopsies had been negative or unsuccessful; in all six, amyloid was subsequently foundon biopsy or at autopsy. Progressive amyloid deposition was observed in 9 of 11 patients studied serially.CONCLUSIONS Scintigraphy after the injection of 123I-SAP can be used for diagnosing, locating, andmonitoring the extent of systemic amyloidosis.", "metadata": {}}
+{"_id": "32697244", "title": "", "text": "The Neurovascular Unit Coming of Age: A Journey through Neurovascular Coupling in Health andDiseaseThe concept of the neurovascular unit (NVU), formalized at the 2001 Stroke Progress ReviewGroup meeting of the National Institute of Neurological Disorders and Stroke, emphasizes the intimaterelationship between the brain and its vessels. Since then, the NVU has attracted the interest of theneuroscience community, resulting in considerable advances in the field. Here the current state ofknowledge of the NVU will be assessed, focusing on one of its most vital roles: the coupling betweenneural activity and blood flow. The evidence supports a conceptual shift in the mechanisms ofneurovascular coupling, from a unidimensional process involving neuronal-astrocytic signaling to localblood vessels to a multidimensional one in which mediators released from multiple cells engage distinctsignaling pathways and effector systems across the entire cerebrovascular network in a highlyorchestrated manner. The recently appreciated NVU dysfunction in neurodegenerative diseases, althoughstill poorly understood, supports emerging concepts that maintaining neurovascular health promotesbrain health.", "metadata": {}}
+{"_id": "32712381", "title": "", "text": "Effects of MAL61 and MAL62 overexpression on maltose fermentation of baker's yeast in lean dough.Thepredominant fermentable sugar in lean dough is maltose. To improve the leavening ability of baker'syeast in lean dough, maltose metabolism should be improved. Maltase (alpha-glucosidase, encoded byMAL62) and maltose permease (encoded by MAL61) are the major factors involved in maltosemetabolism. The major rate-limiting factor in maltose metabolism and leavening ability of baker's yeastremains unclear. In this work, MAL61 and/or MAL62 overexpression strains were constructed toinvestigate the decisive factor for maltose metabolism of industrial baker's yeast in lean dough. Ourresults show that elevated maltose permease activity by MAL61 overexpression yielded less improvementin maltose fermentation compared to elevated maltase activity by MAL62 overexpression. Significantincrease in maltase activity by MAL62 overexpression could result in a 44% increase in leavening abilityof industrial baker's yeast in lean dough and a 39% increase in maltose metabolism in a mediumcontaining glucose and maltose. Thus, maltase was the rate-limiting factor in maltose fermentation ofindustrial baker's yeast in lean dough. This study lays a foundation for breeding of industrial baker's yeastfor quick dough leavening.", "metadata": {}}
+{"_id": "32720933", "title": "", "text": "Human papillomavirus genotype 31 does not express detectable microRNA levels during latent orproductive virus replication.It has recently become clear that several pathogenic DNA viruses expressvirally encoded microRNAs in infected cells. In particular, numerous microRNAs have been identified in arange of human and animal herpesviruses, and individual microRNAs have also been identified inmembers of the polyoma- and adenovirus families. Although their functions remain largely unknown, itseems likely that these viral microRNAs play an important role in viral replication in vivo. Here we presentan analysis of the microRNAs expressed in human cells during the latent and productive phases of thehuman papillomavirus genotype 31 (HPV31) replication cycle. Although over 500 cellular microRNAs werecloned and identified, not a single HPV31-specific microRNA was obtained. We therefore concluded thatHPV31, and possibly human papillomaviruses in general, does not express viral microRNAs.", "metadata": {}}
+{"_id": "32721137", "title": "", "text": "Integrated genomic profiling of endometrial carcinoma associates aggressive tumors with indicators ofPI3 kinase activation.Although 75% of endometrial cancers are treated at an early stage, 15% to 20% ofthese recur. We performed an integrated analysis of genome-wide expression and copy-number data forprimary endometrial carcinomas with extensive clinical and histopathological data to detect featurespredictive of recurrent disease. Unsupervised analysis of the expression data distinguished 2 majorclusters with strikingly different phenotypes, including significant differences in disease-free survival. Toidentify possible mechanisms for these differences, we performed a global genomic survey ofamplifications, deletions, and loss of heterozygosity, which identified 11 significantly amplified and 13significantly deleted regions. Amplifications of 3q26.32 harboring the oncogene PIK3CA were associatedwith poor prognosis and segregated with the aggressive transcriptional cluster. Moreover, samples withPIK3CA amplification carried signatures associated with in vitro activation of PI3 kinase (PI3K), asignature that was shared by aggressive tumors without PIK3CA amplification. Tumors with loss of PTENexpression or PIK3CA overexpression that did not have PIK3CA amplification also shared the PI3Kactivation signature, high protein expression of the PI3K pathway member STMN1, and an aggressivephenotype in test and validation datasets. However, mutations of PTEN or PIK3CA were not associatedwith the same expression profile or aggressive phenotype. STMN1 expression had independent prognosticvalue. The results affirm the utility of systematic characterization of the cancer genome in clinicallyannotated specimens and suggest the particular importance of the PI3K pathway in patients who haveaggressive endometrial cancer.", "metadata": {}}
+{"_id": "32742683", "title": "", "text": "Alteration of the Antitumor Immune Response by Cancer-Associated FibroblastsAmong cells present inthe tumor microenvironment, activated fibroblasts termed cancer-associated fibroblasts (CAFs), play acritical role in the complex process of tumor-stroma interaction. CAFs, one of the prominent stromal cellpopulations in most types of human carcinomas, have been involved in tumor growth, angiogenesis,cancer stemness, extracellular matrix remodeling, tissue invasion, metastasis, and evenchemoresistance. During the past decade, these activated tumor-associated fibroblasts have also beeninvolved in the modulation of the anti-tumor immune response on various levels. In this review, wedescribe our current understanding of how CAFs accomplish this task as well as their potential therapeuticimplications.", "metadata": {}}
+{"_id": "32743723", "title": "", "text": "Confusion and memory loss from capsular genu infarction: a thalamocortical disconnection syndrome?Weexamined six patients with an abrupt change in behavior after infarction involving the inferior genu of theinternal capsule. The acute syndrome featured fluctuating alertness, inattention, memory loss, apathy,abulia, and psychomotor retardation, suggesting frontal lobe dysfunction. Contralateral hemiparesis anddysarthria were generally mild, except when the infarct extended into the posterior limb.Neuropsychological testing in five patients with left-sided infarcts revealed severe verbal memory loss.Additional cognitive deficits consistent with dementia occurred in four patients. A right-sided infarctcaused transient impairment in visuospatial memory. Functional brain imaging in three patients showed afocal reduction in hemispheric perfusion most prominent in the ipsilateral inferior and medial frontalcortex. We infer that the capsular genu infarct interrupted the inferior and anterior thalamic peduncles,resulting in functional deactivation of the ipsilateral frontal cortex. These observations suggest that onemechanism for cognitive deterioration from a lacunar infarct is thalamocortical disconnection ofwhite-matter tracts, in some instances leading to \"strategic-infarct dementia. \"", "metadata": {}}
+{"_id": "32766786", "title": "", "text": "Neoadjuvant androgen ablation before radical prostatectomy in cT2bNxMo prostate cancer: 5-yearresults.PURPOSE In the initial report of the Lupron Depot Neoadjuvant Prostate Cancer Study Grouppatients who received 3 months of androgen deprivation had a significant decrease in the positive marginrate. We monitored these patients for 5 years and to our knowledge present the longest followup of anyneoadjuvant trial. MATERIALS AND METHODS A multi-institutional prospective randomized trial wasperformed between February 1992 and April 1994 involving patients with stage cT2b prostate cancer,including 138 who received 3 months of leuprolide plus flutamide before radical prostatectomy and 144who underwent radical prostatectomy only. Patients were followed every 6 months with serum prostatespecific antigen (PSA) testing for 5 years. Biochemical recurrence was defined as PSA greater than 0.4ng./ml. RESULTS At 5 years there was no difference in the biochemical recurrence rate. PSA was lessthan 0.4 ng./ml. in 64.8% of the patients in the neoadjuvant androgen ablation plus prostatectomy and67.6% in the prostatectomy only group (p = 0.663). CONCLUSIONS Although 3 months of androgendeprivation before radical prostatectomy resulted in an apparently significant decrease in positive surgicalmargins, a 5-year followup does not indicate any difference in the recurrence rate. Until studiesdocument improvement in biochemical or clinical recurrence with longer periods of treatment, inductionandrogen deprivation before radical prostatectomy is not indicated.", "metadata": {}}
+{"_id": "32770503", "title": "", "text": "Full-length transcriptome assembly from RNA-Seq data without a reference genome.Massively parallelsequencing of cDNA has enabled deep and efficient probing of transcriptomes. Current approaches fortranscript reconstruction from such data often rely on aligning reads to a reference genome, and are thusunsuitable for samples with a partial or missing reference genome. Here we present the Trinity methodfor de novo assembly of full-length transcripts and evaluate it on samples from fission yeast, mouse andwhitefly, whose reference genome is not yet available. By efficiently constructing and analyzing sets of deBruijn graphs, Trinity fully reconstructs a large fraction of transcripts, including alternatively splicedisoforms and transcripts from recently duplicated genes. Compared with other de novo transcriptomeassemblers, Trinity recovers more full-length transcripts across a broad range of expression levels, with asensitivity similar to methods that rely on genome alignments. Our approach provides a unified solutionfor transcriptome reconstruction in any sample, especially in the absence of a reference genome.", "metadata": {}}
+{"_id": "32776084", "title": "", "text": "Growth restricted in vitro culture conditions alter the imprinted gene expression patterns of mouseembryonic stem cells.Embryonic stem (ES) cell-derived clones and chimeras are often associated withgrowth abnormalities during fetal development, leading to the production of over/under-weight offspringthat show elevated neonatal mortality and morbidity. Due to the role played by imprinted genes incontrolling fetal growth, much of the blame is pointed at improper epigenetic reprogramming of cells usedin the procedures. We have analyzed the expression pattern of two growth regulatory imprinted genes,namely insulin like growth factor II (Igf2) and H19, in mouse ES cells cultured under growth restrictedconditions and after in vitro aging. Culture of cells with serum-depleted media (starvation) and at highcell density (confluence) increased the expression of both imprinted genes and led to aberrantmethylation profiles of differentially methylated regions in key regulatory sites of Igf2 and H19. Thesefindings confirm that growth constrained cultures of ES cells are associated with alterations tomethylation of the regulatory domains and the expression patterns of imprinted genes, suggesting apossible role of epigenetic factors in the loss of developmental potential.", "metadata": {}}
+{"_id": "32777637", "title": "", "text": "When is antipsychotic polypharmacy supported by research evidence? Implications for QI.BACKGROUNDConcurrent use of multiple standing antipsychotics (antipsychotic polypharmacy) is increasingly commonamong both inpatients and outpatients. Although this has often been cited as a potential quality-of-careproblem, reviews of research evidence on antipsychotic polypharmacy have not distinguished betweenappropriate versus inappropriate use. METHODS A MEDLINE search from 1966 to December 2007 wascompleted to identify studies comparing changes in symptoms, functioning, and/or side effects betweenpatients treated with multiple antipsychotics and patients treated with a single antipsychotic. The studieswere reviewed in two groups on the basis of whether prescribing was concordant with guidelinerecommendations for multiple-antipsychotic use. RESULTS A review of the literature, including threerandomized controlled trials, found no support for the use of antipsychotic polypharmacy in patientswithout an established history of treatment resistance to multiple trials of monotherapy. In patients witha history of treatment resistance to multiple monotherapy trials, limited data support antipsychoticpolypharmacy, but positive outcomes were primarily found in studies of clozapine augmented with asecond-generation antipsychotic. DISCUSSION Research evidence is consistent with the goal of avoidingantipsychotic polypharmacy in patients who lack guideline-recommended indications for its use. The JointCommission is implementing a core measure set for Hospital-Based Inpatient Psychiatric Services. Two ofthe measures address antipsychotic polypharmacy. The first measure assesses the overall rate. Thesecond measure determines whether clinically appropriate justification has been documented supportingthe use of more than one antipsychotic medication.", "metadata": {}}
+{"_id": "32787042", "title": "", "text": "The Liverpool uveal melanoma liver metastases pathway: outcome following liver resection.AIM Todetermine the outcome of patients that underwent liver resection for metastases from uveal melanoma.METHODS Over a 9-year period, patients referred with uveal melanoma metastases were included.Following treatment of primary uveal melanoma, high-risk patients were offered to be enrolled into a6-monthly non-contrast liver magnetic resonance imaging (MRI) surveillance. Following detection of livermetastases, patients were staged with a contrast-enhanced (Primovist(®)) liver MRI, computertomography (CT) of the thorax and staging laparoscopy. RESULTS 155 patients were referred with uvealmelanoma liver metastases, of which 17 (11.0%) patients had liver resection and one patient was treatedwith percutaneous radio-frequency ablation. The majority of patients undergoing liver resection weretreated with multiple metastectomies (n = 8) and three patients had major liver resections. The overallmedian survival for patients treated with surgery/ablation was 27 (14-90) months, and this wassignificantly better compared to patients treated palliatively [median = 8(1-30) months, P < 0.001].Following surgery, 11 patients had recurrent disease [median = 13(6-36) months]. Patients who hadundergone a major liver resection had a significantly poorer disease-free survival (P = 0.037).CONCLUSIONS Patients who can undergo surgical resection for metastatic uveal melanoma have a morefavorable survival compared to those who do not.", "metadata": {}}
+{"_id": "32797183", "title": "", "text": "Smooth muscle lineage diversity in the chick embryo. Two types of aortic smooth muscle cell differ ingrowth and receptor-mediated transcriptional responses to transforming growth factor-beta.Lineageanalysis studies in the avian embryo have identified two types of smooth muscle cells (SMCs) in thetunica media of large elastic arteries; one that originates within the cardiac neural crest and is ectodermin origin (Ect) and another that arises from local mesenchyme of mesodermal origin (Mes). To determineif differences in primary embryonic lineage can give rise to SMCs with stable differences in growth anddifferentiation properties, we isolated Ect and Mes SMCs from the Day 14 chick embryo aorta. We reportthat despite different primary embryonic origins, Ect and Mes SMCs express nearly identical levels ofseven SMC differentiation markers in vitro, consistent with their common smooth muscle developmentalfates in vivo. By contrast, Ect SMCs displayed a greater capacity for growth in serum-free medium thanMes SMCs, but only under conditions permitting short-range cell-cell interactions. Most of the peptidegrowth factors tested that might account for serum-independent growth (PDGF-AA, PDGF-BB, basic FGF,EGF, or activin) stimulated DNA synthesis to similar extents in Ect and Mes SMCs. However, we founddramatic, lineage-dependent differences in SMC responses to transforming growth factor-beta(TGF-beta). Exposure to TGF-beta 1 (0.4 to 400 pmole/liter) consistently increased DNA synthesis in EctSMCs, whereas in paired cultures of Mes SMCs, TGF-beta 1 was growth inhibitory. In SMC culturestransfected with p3TP-lux, a luciferase reporter controlled by the TGF-beta 1-response elements of thehuman PAI-1 promoter, TGF-beta 1 (120 pM) produced 12 +/- 2-fold increases in luciferase activity in EctSMCs and only 3 +/- 1.5-fold increases in Mes SMCs. Analysis of TGF-beta receptor phenotypes byNorthern blot, radioligand binding, and crosslinking assays showed that Ect and Mes SMCs expressedsimilar levels of types I, II, and III TGF-beta receptors. However, using a polyclonal antibody specific forthe chick type II TGF-beta receptor subunit, we demonstrate that Mes SMCs produce a fully glycosylatedform of this protein while Ect SMCs elaborate only an unglycosylated type II TGF-beta receptor. Theseresults show that Ect and Mes SMCs exhibit lineage-dependent differences in growth andreceptor-mediated transcriptional responses to at least one important class of SMC morphogens andgrowth modifiers, e.g., the TGF-betas. Our findings suggest that different SMC populations within acommon vessel wall may respond in lineage-dependent ways to signals that direct formation of the tunicamedia in the embryo and to factors involved in the progression of vascular disease later in life.", "metadata": {}}
+{"_id": "32827351", "title": "", "text": "THE USE OF LEAD CITRATE AT HIGH pH AS AN ELECTRON-OPAQUE STAIN IN ELECTRONMICROSCOPYAqueous solutions of lead salts (1, 2) and saturated solutions of lead hydroxide (1) havebeen used as stains to enhance the electron-scattering properties of components of biological materialsexamined in the electron microscope. Saturated solutions of lead hydroxide (1), while staining moreintensely than either lead acetate or monobasic lead acetate (l , 2), form insoluble lead carbonate uponexposure to air. The avoidance of such precipitates which contaminate surfaces of sections duringstaining has been the stimulus for the development of elaborate procedures for exclusion of air or carbondioxide (3, 4). Several modifications of Watson's lead hydroxide stain (1) have recently appeared (5-7).All utilize relatively high pH (approximately 12) and one contains small amounts of tartrate (6), arelatively weak complexing agent (8), in addition to lead. These modified lead stains are less liable tocontaminate the surface of the section with precipitated stain products. The stain reported here differsfrom previous alkaline lead stains in that the chelating agent, citrate, is in sufficient excess to sequesterall lead present. Lead citrate, soluble in high concentrations in basic solutions, is a chelate compound withan apparent association constant (log Ka) between ligand and lead ion of 6.5 (9). Tissue binding sites,presumably organophosphates, and other anionic species present in biological components followingfixation, dehydration, and plastic embedding apparently have a greater affinity for this cation than leadcitrate inasmuch as cellular and extracellular structures in the section sequester lead from the stainingsolution. Alkaline lead citrate solutions are less likely to contaminate sections, as no precipitates formwhen droplets of fresh staining solution are exposed to air for periods of up to 30 minutes. The resultantstaining of the sections is of high intensity in sections of Aralditeor Epon-embedded material. Cytoplasmicmembranes, ribosomes, glycogen, and nuclear material are stained (Figs. 1 to 3). STAIN SOLUTION:Lead citrate is prepared by", "metadata": {}}
+{"_id": "32850528", "title": "", "text": "Amylase, Lipase, and Acute Pancreatitis in People With Type 2 Diabetes Treated With Liraglutide: ResultsFrom the LEADER Randomized Trial.OBJECTIVE To evaluate serum amylase and lipase levels and the rateof acute pancreatitis in patients with type 2 diabetes and high cardiovascular risk randomized toliraglutide or placebo and observed for 3.5-5.0 years. RESEARCH DESIGN AND METHODS A total of 9,340patients with type 2 diabetes were randomized to either liraglutide or placebo (median observation time3.84 years). Fasting serum lipase and amylase were monitored. Acute pancreatitis was adjudicated in ablinded manner. RESULTS Compared with the placebo group, liraglutide-treated patients had increases inserum lipase and amylase of 28.0% and 7.0%, respectively. Levels were increased at 6 months and thenremained stable. During the study, 18 (0.4% [1.1 events/1,000 patient-years of observation] [PYO])liraglutide-treated and 23 (0.5% [1.7 events/1,000 PYO]) placebo patients had acute pancreatitisconfirmed by adjudication. Most acute pancreatitis cases occurred ≥12 months after randomization.Liraglutide-treated patients with prior history of pancreatitis (n = 147) were not more likely to developacute pancreatitis than similar patients in the placebo group (n = 120). Elevations of amylase and lipaselevels did not predict future risk of acute pancreatitis (positive predictive value <1.0%) in patientstreated with liraglutide. CONCLUSIONS In a population with type 2 diabetes at high cardiovascular risk,there were numerically fewer events of acute pancreatitis among liraglutide-treated patients (regardlessof previous history of pancreatitis) compared with the placebo group. Liraglutide was associated withincreases in serum lipase and amylase, which were not predictive of an event of subsequent acutepancreatitis.", "metadata": {}}
+{"_id": "32852283", "title": "", "text": "Zoledronic acid is unable to induce apoptosis, but slows tumor growth and prolongs survival fornon-small-cell lung cancers.BACKGROUND Although zoledronic acid (ZOL), a third-generationnitrogen-containing bisphosphonate, has been identified as an attractive therapeutic agent against breastcancer, prostate cancer, multiple myeloma as well as small-cell lung cancer (SCLC), as best as we areaware, the anti-tumor effect of ZOL upon non-small-cell lung cancer (NSCLC) remains to be effectivelyinvestigated. This study examined the effects of ZOL upon the line-1 tumor cell, using a murine lungadenocarcinoma cell line similar to the behavior of human lung adenocarcinoma. METHODS Weinvestigated the anti-tumor effects of ZOL (3-100 microM) on line-1 tumor cells in vitro, including cellularproliferation, by means of an MTT assay, cell-cycle analysis by flow cytometry and by assessing the levelof apoptosis by annexin V/propidium iodide (PI) and 4'-6-diamidino-2-phenylindole (DAPI) staining.Further, we evaluated the growth and survival of line-1 tumor cells following ZOL treatment (1microg/kg/week) using an animal model. We also examined the in vivo cell-cycle pattern usinglacZ-expressing line-1 cells (line-1/lacZ). RESULTS ZOL significantly slowed the line-1 tumor growth in adose-dependent manner in vitro. The treated line-1 tumor cells typically arrested at the S/G2/M-phase ofthe cell-cycle following ZOL exposure, but no apoptotic cells could be detected by either annexin V/PI orDAPI staining. When the ZOL was washed out, the drug-inhibited cells continued to proliferate again andthe cell-cycle prolongation elicited earlier by the drug, then disappeared. Within 72-96 h following drugremoval, the cell-cycle of the treated cells revealed a similar distribution to that of the untreated controls.In vivo studies demonstrated that ZOL significantly slowed the line-1 tumor growth. Indeed, mice livedsignificantly longer when they had been ZOL-treated than was the case for untreated mice (p<0.05).Using line-1/lacZ cells, the in vivo cell-cycle distribution of line-1 tumor cells subsequent to ZOL exposurerevealed S/G2/M-phase arrest that was identical to the in vitro culture. CONCLUSIONS ZOL maintains thepotential to reduce tumor burden and prolong survival for murine pulmonary adenocarcinoma. The flowcytometrical analysis of cell-cycle demonstrated that ZOL induces no apoptosis but is able to arrest line-1tumor cells at the S/G2/M-phase. Although the clinical relevance of these results warrants verification forhuman lung cancer patients, ZOL combined with chemotherapy and/or radiotherapy appears to be a newtherapeutic strategy for the effective treatment of NSCLC.", "metadata": {}}
+{"_id": "32906513", "title": "", "text": "A central role for central tolerance.Recent elucidation of the role of central tolerance in preventingorgan-specific autoimmunity has changed our concepts of self/nonself discrimination. This paradigmaticshift is largely attributable to the discovery of promiscuous expression of tissue-restricted self-antigens(TRAs) by medullary thymic epithelial cells (mTECs). TRA expression in mTECs mirrors virtually all tissuesof the body, irrespective of developmental or spatio-temporal expression patterns. This reviewsummarizes current knowledge on the cellular and molecular regulation of TRA expression in mTECs,outlines relevant mechanisms of antigen presentation and modes of tolerance induction, and discussesimplications for the pathogenesis of autoimmune diseases and other biological processes such as fertility,pregnancy, puberty, and tumor defense.", "metadata": {}}
+{"_id": "32909242", "title": "", "text": "Contribution of traditional healers to a rural tuberculosis control programme in Hlabisa, SouthAfrica.SETTING The rural health district of Hlabisa, KwaZulu-Natal, South Africa.   OBJECTIVES To assessthe acceptability and effectiveness of traditional healers as supervisors of tuberculosis (TB) treatment inan existing directly observed treatment, short-course (DOTS) programme. DESIGN An observationalstudy comparing treatment outcomes among new TB patients in the three intervention sub-districtsoffered the additional option of traditional healers for directly observed treatment (DOT) supervision withthose in the remainder of the district offered the standard range of options for DOT supervision (healthfacility, community health worker and lay persons). A comparison was also made of treatment outcomesbetween different options for DOT supervision. RESULTS A total of 3461 TB patients were registered inHlabisa District from April 1999 to December 2000, of whom 2823 were discharged from hospital to theambulatory DOT programme. Treatment outcomes were known for 1816 patients in Hlabisa District (275patients in the intervention area and 1541 patients in the control area). There was no significantdifference (P < 0.5) in treatment outcome in the intervention and control areas (77% vs. 75%). Among275 patients with known outcomes in the intervention area, 48 patients were supervised by traditionalhealers and 227 patients supervised by people other than traditional healers. Treatment completion wasnot significantly higher among patients supervised by traditional healers than among patients supervisedby other categories of DOT supervisor (88% vs. 75%, P = 0.3841). Interviews with 41 of 51 traditionalhealer patients who had completed treatment revealed high levels of satisfaction with the care received.CONCLUSIONS Traditional healers make an effective contribution to TB programme performance in thispilot scheme in Hlabisa district. Further evaluation will be necessary as this approach is scaled up.", "metadata": {}}
+{"_id": "32922179", "title": "", "text": "Alzheimer's disease: the two-hit hypothesis.There are many lines of evidence showing that oxidativestress and aberrant mitogenic changes have important roles in the pathogenesis of Alzheimer's disease(AD). However, although both oxidative stress and cell cycle-related abnormalities are early events,occurring before any cytopathology, the relation between these two events, and their role inpathophysiology was, until recently, unclear. However, on the basis of studies of mitogenic and oxidativestress signalling pathways in AD, we proposed a \"two-hit hypothesis\" which states that although eitheroxidative stress or abnormalities in mitotic signalling can independently serve as initiators, bothprocesses are necessary to propagate disease pathogenesis. In this paper, we summarise evidence foroxidative stress and abnormal mitotic alterations in AD and explain the two-hit hypothesis by describinghow both mechanisms are necessary and invariant features of disease.", "metadata": {}}
+{"_id": "32927401", "title": "", "text": "Toll-like receptor 7 mediates pruritusToll-like receptors are typically expressed in immune cells toregulate innate immunity. We found that functional Toll-like receptor 7 (TLR7) was expressed in C-fiberprimary sensory neurons and was important for inducing itch (pruritus), but was not necessary foreliciting mechanical, thermal, inflammatory and neuropathic pain in mice. Our results indicate that TLR7mediates itching and is a potential therapeutic target for anti-itch treatment in skin disease conditions.", "metadata": {}}
+{"_id": "32927475", "title": "", "text": "Antigen presentation by major histocompatibility complex class I-B molecules.Class I-b genes constitutethe majority of MHC class I loci. These monomorphic or oligomorphic molecules have been described inmany organisms; they are best characterized in the mouse, which contains a substantial number ofpotentially intact genes. Two main characteristics differentiate class I-b from class I-a molecules: limitedpolymorphism and lower cell surface expression. These distinguishing features suggest possiblegeneralizations regarding the evolution and function of this class. Additionally, class I-b proteins tend tohave shorter cytoplasmic domains or in some cases may be secreted or may substitute a lipid anchor forthe transmembrane domain. Some are also expressed in a limited distribution of cells or tissues. At leastsix mouse MHC class I-b molecules have been shown to present antigens to alpha beta or gamma delta Tcells. Recent advances have provided insight into the physiological function of H-2M3a and have definedthe natural peptide-binding motif of Qa-2. In addition, significant progress has been made toward betterunderstanding of other class I-b molecules, including Qa-1, TL, HLA-E, HLA-G, and the MHC-unlinkedclass I molecule CD1. We begin this review, however, by arguing that the dichotomous categorization ofMHC genes as class I-a and I-b is conceptually misleading, despite its historical basis and practicalusefulness. With these reservations in mind, we then discuss antigen presentation by MHC class I-bmolecules with particular attention to their structure, polymorphism, requirements for peptide antigenbinding and tissue expression.", "metadata": {}}
+{"_id": "32955023", "title": "", "text": "Pdgfrβ+ Mural Preadipocytes Contribute to Adipocyte Hyperplasia Induced by High-Fat-Diet Feeding andProlonged Cold Exposure in Adult Mice.The expansion of white adipose tissue (WAT) in obesity involvesde novo differentiation of new adipocytes; however, the cellular origin of these cells remains unclear.Here, we utilize Zfp423(GFP) reporter mice to characterize adipose mural (Pdgfrβ(+)) cells with varyinglevels of the preadipocyte commitment factor Zfp423. We find that adipose tissue contains distinct muralpopulations, with levels of Zfp423 distinguishing adipogenic from inflammatory-like mural cells. Using our\"MuralChaser\" lineage tracking system, we uncover adipose perivascular cells as developmentalprecursors of adipocytes formed in obesity, with adipogenesis and precursor abundance regulated in adepot-dependent manner. Interestingly, Pdgfrβ(+) cells do not significantly contribute to the initialcold-induced recruitment of beige adipocytes in WAT; it is only after prolonged cold exposure that thesecells differentiate into beige adipocytes. These results provide genetic evidence for a mural cell origin ofwhite adipocytes in obesity and suggest that beige adipogenesis may originate from multiple sources.", "metadata": {}}
+{"_id": "32969964", "title": "", "text": "Effect of clinical guidelines on medical practice: a systematic review of rigorous evaluations.Althoughinterest in clinical guidelines has never been greater, uncertainty persists about whether they areeffective. The debate has been hampered by the lack of a rigorous overview. We have identified 59published evaluations of clinical guidelines that met defined criteria for scientific rigour; 24 investigatedguidelines for specific clinical conditions, 27 studied preventive care, and 8 looked at guidelines forprescribing or for support services. All but 4 of these studies detected significant improvements in theprocess of care after the introduction of guidelines and all but 2 of the 11 studies that assessed theoutcome of care reported significant improvements. We conclude that explicit guidelines do improveclinical practice, when introduced in the context of rigorous evaluations. However, the size of theimprovements in performance varied considerably.", "metadata": {}}
+{"_id": "32975424", "title": "", "text": "Threonine as a carbon source for Escherichia coli.Threonine can be used aerobically as the sole source ofcarbon and energy by mutants of Escherichia coli K-12. The pathway used involves the conversion ofthreonine via threonine dehydrogenase to aminoketobutyric acid, which is further metabolized byaminoketobutyric acid ligase, forming acetyl coenzyme A and glycine. A strain devoid of serinetranshydroxymethylase uses this pathway and excretes glycine as a waste product. Aminoketobutyricacid ligase activity was demonstrated after passage of crude extracts through Sephadex G100.", "metadata": {}}
+{"_id": "32985041", "title": "", "text": "Protein S-nitrosylation: a physiological signal for neuronal nitric oxideNitric oxide (NO) has been linked tonumerous physiological and pathophysiological events that are not readily explained by the wellestablished effects of NO on soluble guanylyl cyclase. Exogenous NO S-nitrosylates cysteine residues inproteins, but whether this is an important function of endogenous NO is unclear. Here, using a newproteomic approach, we identify a population of proteins that are endogenously S-nitrosylated, anddemonstrate the loss of this modification in mice harbouring a genomic deletion of neuronal NO synthase(nNOS). Targets of NO include metabolic, structural and signalling proteins that may be effectors forneuronally generated NO. These findings establish protein S-nitrosylation as a physiological signallingmechanism for nNOS.", "metadata": {}}
+{"_id": "33030946", "title": "", "text": "Hypoxia\u0000Sensitive COMMD1 Integrates Signaling and Cellular Metabolism in Human Macrophages andSuppresses OsteoclastogenesisSummary Hypoxia augments inflammatory responses andosteoclastogenesis by incompletely understood mechanisms. We identified COMMD1 as a cell\u0000intrinsicnegative regulator of osteoclastogenesis that is suppressed by hypoxia. In human macrophages,COMMD1 restrained induction of NF\u0000&kgr;B signaling and a transcription factor E2F1\u0000dependentmetabolic pathway by the cytokine RANKL. Downregulation of COMMD1 protein expression by hypoxiaaugmented RANKL\u0000induced expression of inflammatory and E2F1 target genes and downstreamosteoclastogenesis. E2F1 targets included glycolysis and metabolic genes including CKB that enabled cellsto meet metabolic demands in challenging environments, as well as inflammatory cytokine\u0000driven targetgenes. Expression quantitative trait locus analysis linked increased COMMD1 expression with decreasedbone erosion in rheumatoid arthritis. Myeloid deletion of Commd1 resulted in increasedosteoclastogenesis in arthritis and inflammatory osteolysis models. These results identify COMMD1 andan E2F\u0000metabolic pathway as key regulators of osteoclastogenic responses under pathologicalinflammatory conditions and provide a mechanism by which hypoxia augments inflammation and bonedestruction. Graphical Abstract Figure. No Caption available. HighlightsCOMMD1 is a negative regulator ofosteoclast differentiationCOMMD1 suppresses bone loss in RA and inflammatory arthritis and osteolysismodelsCOMMD1 negatively regulates E2F1\u0000dependent metabolic pathways in macrophagesHypoxiasuppresses COMMD1 expression to augment osteoclastogenesis &NA; Pathways that promoteosteoclastogenesis are well characterized but less is known about negative regulators that suppresspathological bone loss. Murata et al. identify COMMD1 as an inhibitor of osteoclastogenesis that restrainsNF\u0000&kgr;B\u0000 and E2F1\u0000CKB\u0000mediated metabolic pathways in macrophages.", "metadata": {}}
+{"_id": "33036897", "title": "", "text": "Production of tyrosol by Candida albicans biofilms and its role in quorum sensing and biofilmdevelopment.Tyrosol and farnesol are quorum-sensing molecules produced by Candida albicans whichaccelerate and block, respectively, the morphological transition from yeasts to hyphae. In this study, wehave investigated the secretion of tyrosol by C. albicans and explored its likely role in biofilmdevelopment. Both planktonic (suspended) cells and biofilms of four C. albicans strains, including threemutants with defined defects in the Efg 1 and Cph 1 morphogenetic signaling pathways, synthesizedextracellular tyrosol during growth at 37 degrees C. There was a correlation between tyrosol productionand biomass for both cell types. However, biofilm cells secreted at least 50% more tyrosol than didplanktonic cells when tyrosol production was related to cell dry weight. The addition of exogenousfarnesol to a wild-type strain inhibited biofilm formation by up to 33% after 48 h. Exogenous tyrosolappeared to have no effect, but scanning electron microscopy revealed that tyrosol stimulated hyphaproduction during the early stages (1 to 6 h) of biofilm development. Experiments involving thesimultaneous addition of tyrosol and farnesol at different concentrations suggested that the action offarnesol was dominant, and 48-h biofilms formed in the presence of both compounds consisted almostentirely of yeast cells. When biofilm supernatants were tested for their abilities to inhibit or enhance germtube formation by planktonic cells, the results indicated that tyrosol activity exceeds that of farnesol after14 h, but not after 24 h, and that farnesol activity increases significantly during the later stages (48 to 72h) of biofilm development. Overall, our results support the conclusion that tyrosol acts as aquorum-sensing molecule for biofilms as well as for planktonic cells and that its action is most significantduring the early and intermediate stages of biofilm formation.", "metadata": {}}
+{"_id": "33063763", "title": "", "text": "Regulated nucleo/cytoplasmic exchange of HOG1 MAPK requires the importin beta homologs NMD5 andXPO1.MAP kinase signaling modules serve to transduce extracellular signals to the nucleus of eukaryoticcells, but little is known about how signals cross the nuclear envelope. Exposure of yeast cells toincreases in extracellular osmolarity activates the HOG1 MAP kinase cascade, which is composed of threetiers of protein kinases, namely the SSK2, SSK22 and STE11 MAPKKKs, the PBS2 MAPKK, and the HOG1MAPK. Using green fluorescent protein (GFP) fusions of these kinases, we found that HOG1, PBS2 andSTE11 localize to the cytoplasm of unstressed cells. Following osmotic stress, HOG1, but neither PBS2 norSTE11, translocates into the nucleus. HOG1 translocation occurs very rapidly, is transient, and correlateswith the phosphorylation and activation of the MAP kinase by its MAPKK. HOG1 phosphorylation isnecessary and sufficient for nuclear translocation, because a catalytically inactive kinase whenphosphorylated is translocated to the nucleus as efficiently as the wild-type. Nuclear import of the MAPKunder stress conditions requires the activity of the small GTP binding protein Ran-GSP1, but not theNLS-binding importin alpha/beta heterodimer. Rather, HOG1 import requires the activity of a gene,NMD5, that encodes a novel importin beta homolog. Similarly, export of dephosphorylated HOG1 fromthe nucleus requires the activity of the NES receptor XPO1/CRM1. Our findings define the requirementsfor the regulated nuclear transport of a stress-activated MAP kinase.", "metadata": {}}
+{"_id": "33068577", "title": "", "text": "FBW7 regulates endothelial functions by targeting KLF2 for ubiquitination and degradationF-box and WDrepeat domain-containing 7 (FBW7), the substrate-binding subunit of E3 ubiquitin ligase SCFFBW7 (acomplex of SKP1, cullin-1 and FBW7), plays important roles in various physiological and pathologicalprocesses. Although FBW7 is required for vascular development, its function in the endothelium remainsto be investigated. In this study, we show that FBW7 is an important regulator of endothelial functions,including angiogenesis, leukocyte adhesion and the endothelial barrier integrity. Using RNA interference,we found that the depletion of FBW7 markedly impairs angiogenesis in vitro and in vivo. We identified thezinc finger transcription factor Krüppel-like factor 2 (KLF2) as a physiological target of FBW7 inendothelial cells. Knockdown of FBW7 expression resulted in the accumulation of endogenous KLF2protein in endothelial cells. FBW7-mediated KLF2 destruction was shown to depend on thephosphorylation of KLF2 via glycogen synthase kinase-3 (GSK3) at two conserved phosphodegrons.Mutating these phosphodegron motifs abolished the FBW7-mediated degradation and ubiquitination ofKLF2. The siRNA-mediated knockdown of FBW7 showed that KLF2 is an essential target of FBW7 in theregulation of endothelial functions. Moreover, FBW7-mediated KLF2 degradation was shown to be criticalfor angiogenesis in teratomas and in zebrafish development. Taken together, our study suggests a rolefor FBW7 in the processes of endothelial cell migration, angiogenesis, inflammation and barrier integrity,and provides novel insights into the regulation of KLF2 stability in vivo.", "metadata": {}}
+{"_id": "33076846", "title": "", "text": "Role of RhoA-specific guanine exchange factors in regulation of endomitosis inmegakaryocytes.Polyploidization can precede the development of aneuploidy in cancer. Polyploidization inmegakaryocytes (Mks), in contrast, is a highly controlled developmental process critical for efficientplatelet production via unknown mechanisms. Using primary cells, we demonstrate that the guanineexchange factors GEF-H1 and ECT2, which are often overexpressed in cancer and are essential for RhoAactivation during cytokinesis, must be downregulated for Mk polyploidization. The first (2N-4N)endomitotic cycle requires GEF-H1 downregulation, whereas subsequent cycles (>4N) require ECT2downregulation. Exogenous expression of both GEF-H1 and ECT2 prevents endomitosis, resulting inproliferation of 2N Mks. Furthermore, we have shown that the mechanism by which polyploidization isprevented in Mks lacking Mkl1, which is mutated in megakaryocytic leukemia, is via elevated GEF-H1expression; shRNA-mediated GEF-H1 knockdown alone rescues this ploidy defect. These mechanisticinsights enhance our understanding of normal versus malignant megakaryocytopoiesis, as well asaberrant mitosis in aneuploid cancers.", "metadata": {}}
+{"_id": "33118292", "title": "", "text": "Optimal therapy for reduction of lipoprotein(a).WHAT IS KNOWN AND OBJECTIVE There is a growingbody of experimental and clinical evidence for the atherogenic and pro-thrombotic potential ofLipoprotein(a) [Lp(a)], as well as for its causative role in coronary heart disease and stroke. We commenton novel strategies for reducing Lp(a) levels. COMMENT Irrespective of the underlying biologicalmechanisms explaining the athero-thrombotic potential of this lipoprotein, most work has focused on theidentification of suitable therapies for hyperlipoproteinemia(a). These include apheresis techniques,nicotinic acid and statins. None of these strategies have been shown to be definitely effective orconvenient for the patient and new strategies are being attempted. Promising results are emerging withtherapeutic interventions targeting the 'inflammatory pathways' by inhibition of Interleukin-6 (IL-6)signalling with natural compounds (e.g., Ginko biloba) or the IL-6 receptor antibody Tocilizumab. Thesemay both lower Lp(a) and cardiovascular risk of the patients. Besides inhibiting platelet function,antiplatelet therapy with aspirin may also decrease the plasma concentration of Lp(a) and modulate itsinfluence on platelets. WHAT IS NEW AND CONCLUSION We highlight the inadequacy of currentapproaches for lowering Lp(a) and draw attention to novel insights that may lead to better treatment.", "metadata": {}}
+{"_id": "33127778", "title": "", "text": "Early gastric cancer and dysplasia.Since the concept of early gastric cancer was first described in Japan in1962, its treatment has evolved from curative surgical resection to endoscopic resection, initially withpolypectomy to more recently with endoscopic submucosal dissection. As worldwide experience withthese endoscopic techniques evolve and gain acceptance, studies have confirmed its comparableeffectiveness with historical surgical outcomes in carefully selected patients. The criteria for endoscopicresection have expanded to offer more patients improved quality of life, avoiding the morbidity andmortality associated with surgery. This article summarizes the evolutional role of endoscopic and surgicaltherapy in early gastric cancer.", "metadata": {}}
+{"_id": "33135135", "title": "", "text": "The impact of homelessness on children.This article reviews and critiques community-based research onthe effects of homelessness on children. Homeless children confront serious threats to their ability tosucceed and their future well-being. Of particular concern are health problems, hunger, poor nutrition,developmental delays, anxiety, depression, behavioral problems, and educational underachievement.Factors that may mediate the observed outcomes include inadequate shelter conditions, instability inresidences and shelters, inadequate services, and barriers to accessing services that are available. Publicpolicy initiatives are needed to meet the needs of homeless children.", "metadata": {}}
+{"_id": "33169058", "title": "", "text": "Strategies of microbial cheater control.The potential benefits of cooperation in microorganisms can beundermined by genetic conflict within social groups, which can take the form of 'cheating'. Forcooperation to succeed as an evolutionary strategy, the negative effects of such conflict must somehowbe either prevented or mitigated. To generate an interpretive framework for future research in microbialbehavioural ecology, here we outline a wide range of hypothetical mechanisms by which cheaters mightbe constrained.", "metadata": {}}
+{"_id": "33203108", "title": "", "text": "Golden Hours in Severe Paraquat Poisoning-The Role of Early Haemoperfusion Therapy.INTRODUCTIONParaquat is a commonly ingested poison especially in Southern India. There is no antidote for paraquatpoison and consumption is often fatal. The usual cause of death is either acute lung injury or multi-organfailure. AIM To evaluate the role of early haemoperfusion as a therapy in paraquat poisoned patients.MATERIALS AND METHODS This study was a retrospective analysis of patients admitted to a TertiaryMedical College Hospital between January 2012 and December 2015 with history of paraquatconsumption, comparing outcomes in those who received only gastric lavage and symptomatic treatmentwith those who received haemoperfusion as a therapy. The role of early haemoperfusion (≤ 6 hours) vslate haemoperfusion (> 6 hours) in paraquat poisoned patients was also compared. The data of thesepatients was extracted and analysed with respect to age, sex, mode of treatment, the outcome inpatients who received early and late haemoperfusion. RESULTS A total of 101 patients were studied outof which 62 died. Deaths were more in those patients who received only gastric lavage with symptomatictreatment as therapy compared to those who received haemoperfusion i.e., 92.1% vs 42.9%respectively. We also found that, the survival rate was better in patients who received earlyhaemoperfusion. CONCLUSION Early haemoperfusion was helpful in the management of severe paraquatpoisoning and improved the survival rate in these patients.", "metadata": {}}
+{"_id": "33257464", "title": "", "text": "Changes in the prevalence of cerebral palsy for children born very prematurely within a population-basedprogram over 30 years.CONTEXT Although cerebral palsy (CP) among extremely premature infants hasbeen reported as a major morbidity outcome, there are difficulties comparing published CP rates frommany sites over various birth years. OBJECTIVE To assess the changes in population-based, gestationalage-specific prevalence rates of CP among extremely premature infants over 30 years. DESIGNProspective population-based longitudinal outcome study. SETTING AND PARTICIPANTS In NorthernAlberta, 2318 infants 20 to 27 weeks' gestational age with birth weights of 500 to 1249 g were livebornfrom 1974 through 2003. By 2 years of age, 1437 (62%) had died, 23 (1%) were lost to follow-up, and858 (37%) had received multidisciplinary neurodevelopmental assessment. MAIN OUTCOME MEASUREPopulation-based prevalence rates of CP were determined. Logistic regression with linear spline was usedto assess changes in CP prevalence over time. RESULTS At age 2 years, 122 (14.2%) of 858 survivorshad CP. This diagnosis was confirmed for each child by age 3 years or older. Among those whosegestational age was 20 to 25 weeks, population-based survival increased from 4% to 31% (P<.001),while CP prevalence per 1000 live births increased monotonically from 0 to 110 until the years 1992-1994(P<.001) and decreased thereafter to 22 in the years 2001-2003 (P<.001). Among those whosegestational age was 26 to 27 weeks, population-based survival increased from 23% to between 75% and80% (P<.001), while CP prevalence per 1000 live births increased monotonically from 15 to 155 until theyears 1992-1994 (P<.001) and then decreased to 16 in the years 2001-2003 (P<.001). For all survivorsborn in the years 2001-2003, CP prevalence was 19 per 1000 live births. CONCLUSION Population-basedCP prevalence rates for children whose gestational age was 20 to 27 weeks and whose birth weightranged from 500 to 1249 g show steady reductions in the last decade with stable or reducing mortality,reversing trends prior to 1992-1994.", "metadata": {}}
+{"_id": "33339202", "title": "", "text": "Desferrioxamine treatment of porphyria cutanea tarda in a patient with HIV and chronic renalfailure.Porphyria cutanea tarda (PCT) can occur in HIV patients. Current evidence suggests that HIVinfection may interfere with the hepatic cytochrome oxidase system, leading to porphyrin metabolismimpairment. Moreover, chronic hemodialysis in renal failure may be a risk factor for PCT. In addition tothe contributory factors for PCT associated to HIV infection, it is possible that porphyrin accumulationsecondary to renal failure may play a role in the expression of this disease. We report a case of PCT in anHIV-1 infected patient under blood dialysis, refractory to antimalarials and controlled withdesferrioxamine.", "metadata": {}}
+{"_id": "33387953", "title": "", "text": "Mutations in G protein beta subunits promote transformation and kinase inhibitor resistanceActivatingmutations in genes encoding G protein α (Gα) subunits occur in 4-5% of all human cancers, butoncogenic alterations in Gβ subunits have not been defined. Here we demonstrate that recurrentmutations in the Gβ proteins GNB1 and GNB2 confer cytokine-independent growth and activate canonicalG protein signaling. Multiple mutations in GNB1 affect the protein interface that binds Gα subunits as wellas downstream effectors and disrupt Gα interactions with the Gβγ dimer. Different mutations in Gβproteins clustered partly on the basis of lineage; for example, all 11 GNB1 K57 mutations were in myeloidneoplasms, and seven of eight GNB1 I80 mutations were in B cell neoplasms. Expression ofpatient-derived GNB1 variants in Cdkn2a-deficient mouse bone marrow followed by transplantationresulted in either myeloid or B cell malignancies. In vivo treatment with the dual PI3K-mTOR inhibitorBEZ235 suppressed GNB1-induced signaling and markedly increased survival. In several human tumors,mutations in the gene encoding GNB1 co-occurred with oncogenic kinase alterations, including theBCR-ABL fusion protein, the V617F substitution in JAK2 and the V600K substitution in BRAF.Coexpression of patient-derived GNB1 variants with these mutant kinases resulted in inhibitor resistancein each context. Thus, GNB1 and GNB2 alterations confer transformed and resistance phenotypes acrossa range of human tumors and may be targetable with inhibitors of G protein signaling.", "metadata": {}}
+{"_id": "33390472", "title": "", "text": "Isolation of major pancreatic cell types and long-term culture-initiating cells using novel human surfacemarkers.We have developed a novel panel of cell-surface markers for the isolation and study of all majorcell types of the human pancreas. Hybridomas were selected after subtractive immunization of Balb/Cmice with intact or dissociated human islets and assessed for cell-type specificity and cell-surfacereactivity by immunohistochemistry and flow cytometry. Antibodies were identified by specific binding ofsurface antigens on islet (panendocrine or alpha-specific) and nonislet pancreatic cell subsets (exocrineand duct). These antibodies were used individually or in combination to isolate populations of alpha, beta,exocrine, or duct cells from primary human pancreas by FACS and to characterize the detailed cellcomposition of human islet preparations. They were also employed to show that human islet expansioncultures originated from nonendocrine cells and that insulin expression levels could be increased to up to1% of normal islet cells by subpopulation sorting and overexpression of the transcription factors Pdx-1and ngn3, an improvement over previous results with this culture system. These methods permit theanalysis and isolation of functionally distinct pancreatic cell populations with potential for cell therapy.", "metadata": {}}
+{"_id": "33397197", "title": "", "text": "Re-engineered CD40 receptor enables potent pharmacological activation of dendritic-cell cancer vaccinesin vivoModest clinical outcomes of dendritic-cell (DC) vaccine trials call for the refinement of DC vaccinedesign. Although many potential antigens have been identified, development of methods to enhanceantigen presentation by DCs has lagged. We have engineered a potent, drug-inducible CD40 (iCD40)receptor that permits temporally controlled, lymphoid-localized, DC-specific activation. iCD40 iscomprised of a membrane-localized cytoplasmic domain of CD40 fused to drug-binding domains. Thisallows it to respond to a lipid-permeable, high-affinity dimerizer drug while circumventingectodomain-dependent negative-feedback mechanisms. These modifications permit prolonged activationof iCD40-expressing DCs in vivo, resulting in more potent CD8+ T-cell effector responses, including theeradication of previously established solid tumors, relative to activation of DCs ex vivo (P < 0.01), typicalof most clinical DC protocols. In addition, iCD40-mediated DC activation exceeded that achieved bystimulating the full-length, endogenous CD40 receptor both in vitro and in vivo. Because iCD40 isinsulated from the extracellular environment and can be activated within the context of an immunologicalsynapse, iCD40-expressing DCs have a prolonged lifespan and should lead to more potent vaccines,perhaps even in immune-compromised patients.", "metadata": {}}
+{"_id": "33409100", "title": "", "text": "Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney diseaseand end-stage renal disease: a randomized controlled trial.CONTEXT High plasma homocysteine levelsare a risk factor for mortality and vascular disease in observational studies of patients with chronic kidneydisease. Folic acid and B vitamins decrease homocysteine levels in this population but whether they lowermortality is unknown. OBJECTIVE To determine whether high doses of folic acid and B vitaminsadministered daily reduce mortality in patients with chronic kidney disease. DESIGN, SETTING, ANDPARTICIPANTS Double-blind randomized controlled trial (2001-2006) in 36 US Department of VeteransAffairs medical centers. Median follow-up was 3.2 years for 2056 participants aged 21 years or older withadvanced chronic kidney disease (estimated creatinine clearance < or =30 mL/min) (n = 1305) orend-stage renal disease (n = 751) and high homocysteine levels (> or = 15 micromol/L). INTERVENTIONParticipants received a daily capsule containing 40 mg of folic acid, 100 mg of pyridoxine hydrochloride(vitamin B6), and 2 mg of cyanocobalamin (vitamin B12) or a placebo. MAIN OUTCOME MEASURES Theprimary outcome was all-cause mortality. Secondary outcomes included myocardial infarction (MI),stroke, amputation of all or part of a lower extremity, a composite of these 3 plus all-cause mortality,time to initiation of dialysis, and time to thrombosis of arteriovenous access in hemodialysis patients.RESULTS Mean baseline homocysteine level was 24.0 micromol/L in the vitamin group and 24.2micromol/L in the placebo group. It was lowered 6.3 micromol/L (25.8%; P < .001) in the vitamin groupand 0.4 micromol/L (1.7%; P = .14) in the placebo group at 3 months, but there was no significant effecton mortality (448 vitamin group deaths vs 436 placebo group deaths) (hazard ratio [HR], 1.04; 95% CI,0.91-1.18). No significant effects were demonstrated for secondary outcomes or adverse events: therewere 129 MIs in the vitamin group vs 150 for placebo (HR, 0.86; 95% CI, 0.67-1.08), 37 strokes in thevitamin group vs 41 for placebo (HR, 0.90; 95% CI, 0.58-1.40), and 60 amputations in the vitamin groupvs 53 for placebo (HR, 1.14; 95% CI, 0.79-1.64). In addition, the composite of MI, stroke, andamputations plus mortality (P = .85), time to dialysis (P = .38), and time to thrombosis in hemodialysispatients (P = .97) did not differ between the vitamin and placebo groups. CONCLUSION Treatment withhigh doses of folic acid and B vitamins did not improve survival or reduce the incidence of vasculardisease in patients with advanced chronic kidney disease or end-stage renal disease. TRIALREGISTRATION clinicaltrials.gov Identifier: NCT00032435.", "metadata": {}}
+{"_id": "33417012", "title": "", "text": "Treated individuals who progress to action or maintenance for one behavior are more likely to makesimilar progress on another behavior: coaction results of a pooled data analysis of three trials.OBJECTIVEThis study compared, in treatment and control groups, the phenomena of coaction, which is theprobability that taking effective action on one behavior is related to taking effective action on a secondbehavior. METHODS Pooled data from three randomized trials of Transtheoretical Model (TTM) tailoredinterventions (n=9461), completed in the U.S. in 1999, were analyzed to assess coaction in threebehavior pairs (diet and sun protection, diet and smoking, and sun protection and smoking). Odds ratios(ORs) compared the likelihood of taking action on a second behavior compared to taking action on onlyone behavior. RESULTS Across behavior pairs, at 12 and 24 months, the ORs for the treatment groupwere greater on an absolute basis than for the control group, with two being significant. The combinedORs at 12 and 24 months, respectively, were 1.63 and 1.85 for treatment and 1.20 and 1.10 for control.CONCLUSIONS The results of this study with addictive, energy balance and appearance-related behaviorswere consistent with results found in three studies applying TTM tailoring to energy balance behaviors.Across studies, there was more coaction within the treatment group. Future research should identifypredictors of coaction in more multiple behavior change interventions.", "metadata": {}}
+{"_id": "33458992", "title": "", "text": "Trabecular bone score as an indicator for skeletal deterioration in diabetes.CONTEXT Trabecular bonescore (TBS) is a novel texture index that evaluates the pixel gray-level variations in lumbar spinedual-energy X-ray absorptiometry images and is related to bone microarchitecture independent of bonemineral density (BMD). OBJECTIVE We investigated lumbar spine TBS as an indicator for skeletaldeterioration in diabetes. DESIGN AND SETTING Cross-sectional data were collected from subjectsparticipating in an ongoing prospective, community-based, cohort study from 2009 to 2010.PARTICIPANTS We included 1229 men and 1529 postmenopausal women older than 50 years in theAnsung cohort. OUTCOME MEASURES Biochemical parameters, lumbar spine TBS, and BMD fromdual-energy X-ray absorptiometry images were measured. RESULTS Lumbar spine TBS was lower in menwith diabetes than in nondiabetic men (1.287 ± 0.005 vs 1.316 ± 0.003, P < .001), whereas lumbarspine BMD was higher in men with diabetes (1.135 ± 0.010 vs 1.088 ± 0.006 g/cm(2)). Lumbar spineTBS was lower in women with diabetes than in nondiabetic women only in an unadjusted model (1.333 ±0.004 vs 1.353 ± 0.003). However, women younger than 65 years (n = 707) with diabetes had a lowerTBS than those without diabetes, even after adjusted for covariates (P < .001). Diabetes was notassociated with BMD at femur sites in both genders. TBS was negatively correlated with glycatedhemoglobin, fasting plasma glucose, fasting insulin, and homeostasis model assessment for insulinresistance but not with homeostasis model assessment for β-cell function in both genders. CONCLUSIONSThe inverse association between lumbar spine TBS and insulin resistance may make it an indicator fordetermining skeletal deterioration in diabetic patients who have high BMD.", "metadata": {}}
+{"_id": "33499189", "title": "", "text": "Full activation of the T cell receptor requires both clustering and conformational changes at CD3.T cellreceptor (TCR-CD3) triggering involves both receptor clustering and conformational changes at thecytoplasmic tails of the CD3 subunits. The mechanism by which TCRalphabeta ligand binding confersconformational changes to CD3 is unknown. By using well-defined ligands, we showed that induction ofthe conformational change requires both multivalent engagement and the mobility restriction of theTCR-CD3 imposed by the plasma membrane. The conformational change is elicited by cooperativerearrangements of two TCR-CD3 complexes and does not require accompanying changes in the structureof the TCRalphabeta ectodomains. This conformational change at CD3 reverts upon ligand dissociationand is required for T cell activation. Thus, our permissive geometry model provides a molecularmechanism that rationalizes how the information of ligand binding to TCRalphabeta is transmitted to theCD3 subunits and to the intracellular signaling machinery.", "metadata": {}}
+{"_id": "33507866", "title": "", "text": "Class III PI3K Vps34 plays an essential role in autophagy and in heart and liver function.A criticalregulator of autophagy is the Class III PI3K Vps34 (also called PIK3C3). Although Vps34 is known to playan essential role in autophagy in yeast, its role in mammals remains elusive. To elucidate thephysiological function of Vps34 and to determine its precise role in autophagy, we have generatedVps34(f/f) mice, in which expression of Cre recombinase results in a deletion of exon 4 of Vps34 and aframe shift causing a deletion of 755 of the 887 amino acids of Vps34. Acute ablation of Vps34 in MEFsupon adenoviral Cre infection results in a diminishment of localized generation of phosphatidylinositol3-phosphate and blockade of both endocytic and autophagic degradation. Starvation-inducedautophagosome formation is blocked in both Vps34-null MEFs and liver. Liver-specificAlbumin-Cre;Vps34(f/f) mice developed hepatomegaly and hepatic steatosis, and impaired proteinturnover. Ablation of Vps34 in the heart of muscle creatine kinase-Cre;Vps34(f/f) mice led tocardiomegaly and decreased contractility. In addition, while amino acid-stimulated mTOR activation wassuppressed in the absence of Vps34, the steady-state level of mTOR signaling was not affected inVps34-null MEFs, liver, or cardiomyocytes. Taken together, our results indicate that Vps34 plays anessential role in regulating functional autophagy and is indispensable for normal liver and heart function.", "metadata": {}}
+{"_id": "33533307", "title": "", "text": "Sex-based differences in the effect of digoxin for the treatment of heart failure.BACKGROUND TheDigitalis Investigation Group trial reported that treatment with digoxin did not decrease overall mortalityamong patients with heart failure and depressed left ventricular systolic function, although it did reducehospitalizations slightly. Even though the epidemiologic features, causes, and prognosis of heart failurevary between men and women, sex-based differences in the effect of digoxin were not evaluated.METHODS We conducted a post hoc subgroup analysis to assess whether there were sex-baseddifferences in the effect of digoxin therapy among the 6800 patients in the Digitalis Investigation Groupstudy. The presence of an interaction between sex and digoxin therapy with respect to the primary endpoint of death from any cause was evaluated with the use of Mantel-Haenszel tests of heterogeneity anda multivariable Cox proportional-hazards model, adjusted for demographic and clinical variables.RESULTS There was an absolute difference of 5.8 percent (95 percent confidence interval, 0.5 to 11.1)between men and women in the effect of digoxin on the rate of death from any cause (P=0.034 for theinteraction). Specifically, women who were randomly assigned to digoxin had a higher rate of death thanwomen who were randomly assigned to placebo (33.1 percent vs. 28.9 percent; absolute difference, 4.2percent, 95 percent confidence interval, -0.5 to 8.8). In contrast, the rate of death was similar amongmen randomly assigned to digoxin and men randomly assigned to placebo (35.2 percent vs. 36.9percent; absolute difference, -1.6 percent; 95 percent confidence interval, -4.2 to 1.0). In themultivariable analysis, digoxin was associated with a significantly higher risk of death among women(adjusted hazard ratio for the comparison with placebo, 1.23; 95 percent confidence interval, 1.02 to1.47), but it had no significant effect among men (adjusted hazard ratio, 0.93; 95 percent confidenceinterval, 0.85 to 1.02; P=0.014 for the interaction). CONCLUSIONS The effect of digoxin therapy differsbetween men and women. Digoxin therapy is associated with an increased risk of death from any causeamong women, but not men, with heart failure and depressed left ventricular systolic function.", "metadata": {}}
+{"_id": "33535222", "title": "", "text": "Recipient-type specific CD4+CD25+ regulatory T cells favor immune reconstitution and controlgraft-versus-host disease while maintaining graft-versus-leukemia.CD4+CD25+ regulatory T cells(Treg's) play a pivotal role in preventing organ-specific autoimmune diseases and in inducing tolerance toallogeneic organ transplants. We and others recently demonstrated that high numbers of Treg's can alsomodulate graft-versus-host disease (GVHD) if administered in conjunction with allogeneic hematopoieticstem cell transplantation in mice. In a clinical setting, it would be impossible to obtain enough freshlypurified Treg's from a single donor to have a therapeutic effect. Thus, we performed regulatory T cellexpansion ex vivo by stimulation with allogeneic APCs, which has the additional effect of producingalloantigen-specific regulatory T cells. Here we show that regulatory T cells specific for recipient-typealloantigens control GVHD while favoring immune reconstitution. Irrelevant regulatory T cells onlymediate a partial protection from GVHD. Preferential survival of specific regulatory T cells, but not ofirrelevant regulatory T cells, was observed in grafted animals. Additionally, the use of specific regulatoryT cells was compatible with some form of graft-versus-tumor activity. These data suggest thatrecipient-type specific Treg's could be preferentially used in the control of GVHD in future clinical trials.", "metadata": {}}
+{"_id": "33535447", "title": "", "text": "Expression of the gene encoding the chemorepellent semaphorin III is induced in the fibroblastcomponent of neural scar tissue formed following injuries of adult but not neonatal CNS.This studyevaluates the expression of the chemorepellent semaphorin III (D)/collapsin-1 (sema III) followinglesions to the rat CNS. Scar tissue, formed after penetrating injuries to the lateral olfactory tract (LOT),cortex, perforant pathway, and spinal cord, contained numerous spindle-shaped cells expressing highlevels of sema III mRNA. The properties of these cells were investigated in detail in the lesioned LOT.Most sema III mRNA-positive cells were located in the core of the scar and expressed proteinscharacteristic for fibroblast-like cells. Neuropilin-1, a sema III receptor, was expressed in injured neuronswith projections to the lesion site, in a subpopulation of scar-associated cells and in blood vessels aroundthe scar. In contrast to lesions made in the mature CNS, LOT transection in neonates did not induce semaIII mRNA expression within cells in the lesion and was followed by vigorous axonal regeneration. Theconcomitant expression of sema III and its receptor neuropilin-1 in the scar suggests that semaIII/neuropilin-1-mediated mechanisms are involved in CNS scar formation. The expression of thesecreted chemorepellent sema III following CNS injury provides the first evidence that chemorepulsivesemaphorins may contribute to the inhibitory effects exerted by scars on the outgrowth of injured CNSneurites. The vigorous regrowth of injured axons in the absence of sema III following early neonatallesions is consistent with this notion. The inactivation of sema III in scar tissue by either antibodyperturbation or by genetic or pharmacological intervention could be a powerful means to promotelong-distance regeneration in the adult CNS.", "metadata": {}}
+{"_id": "33554389", "title": "", "text": "The relationship of the level of cyclic amp to differentiation in primary cultures of chick musclecells.Abstract The effect of increased levels of cAMP upon the differentiation of primary cultures of chickmyo blasts has been investigated. 0.1 mM But 2 cAMP or 1 mM 3-isobutyl-1-methylxanthine was addedto the cultures 24 h after plating and maintained throughout the 70 h period of culture examined. Bothreagents were found to markedly delay the time of fusion of the myoblasts but had no observable effectupon the increase in activity of creatine phosphokinase. Morphological examination of the cells revealedno difference in the relative numbers of myoblasts and fibroblasts between the control, But 2 cAMP and3-isobutyl-1-methylxanthine cultures, but the latter reagent appeared to cause some inhibition of cellproliferation.", "metadata": {}}
+{"_id": "33569870", "title": "", "text": "Intact endothelial autophagy is required to maintain vascular lipid homeostasis.The physiological role ofautophagic flux within the vascular endothelial layer remains poorly understood. Here, we show that inprimary endothelial cells, oxidized and native LDL stimulates autophagosome formation. Moreover, byboth confocal and electron microscopy, excess native or modified LDL appears to be engulfed withinautophagic structures. Transient knockdown of the essential autophagy gene ATG7 resulted in higherlevels of intracellular (125) I-LDL and oxidized LDL (OxLDL) accumulation, suggesting that in endothelialcells, autophagy may represent an important mechanism to regulate excess, exogenous lipids. Thephysiological importance of these observations was assessed using mice containing a conditional deletionof ATG7 within the endothelium. Following acute intravenous infusion of fluorescently labeled OxLDL,mice lacking endothelial expression of ATG7 demonstrated prolonged retention of OxLDL within theretinal pigment epithelium (RPE) and choroidal endothelium of the eye. In a chronic model of lipid excess,we analyzed atherosclerotic burden in ApoE(-/-) mice with or without endothelial autophagic flux. Theabsence of endothelial autophagy markedly increased atherosclerotic burden. Thus, in both an acute andchronic in vivo model, endothelial autophagy appears critically important in limiting lipid accumulationwithin the vessel wall. As such, strategies that stimulate autophagy, or prevent the age-dependentdecline in autophagic flux, might be particularly beneficial in treating atherosclerotic vascular disease.", "metadata": {}}
+{"_id": "33634749", "title": "", "text": "Induction of circadian gene expression in human subcutaneous adipose-derived stem cells.OBJECTIVEGenes encoding the circadian transcriptional apparatus exhibit robust oscillatory expression in murineadipose tissues. This study tests the hypothesis that human subcutaneous adipose-derived stem cells(ASCs) provide an in vitro model in which to monitor the activity of the core circadian transcriptionalapparatus. RESEARCH METHODS AND PROCEDURES Primary cultures of undifferentiated oradipocyte-differentiated ASCs were treated with dexamethasone, rosiglitazone, or 30% fetal bovineserum. The response of undifferentiated ASCs to dexamethasone was further evaluated in the presenceof lithium chloride. Lithium inhibits glycogen synthase kinase 3, a key component of the circadianapparatus. Total RNA was harvested at 4-hour intervals over 48 hours and examined by real-time reversetranscription polymerase chain reaction (RT-PCR). RESULTS Adipocyte-differentiated cells respondedmore rapidly to treatments than their donor-matched undifferentiated controls; however, the period ofthe circadian gene oscillation was longer in the adipocyte-differentiated cells. Dexamethasone generatedcircadian gene expression patterns with mean periods of 25.4 and 26.7 hours in undifferentiated andadipocyte-differentiated ASCs, respectively. Both rosiglitazone and serum shock generated a significantlylonger period in adipocyte-differentiated ASCs relative to undifferentiated ASCs. The Bmal1 profile wasphase-shifted by approximately 8 to 12 hours relative to Per1, Per3, and Cry2, consistent with theirexpression in vivo. Lithium chloride inhibited adipogenesis and significantly lengthened the period of Per3and Rev-erbalpha gene expression profiles by >5 hours in dexamethasone-activated undifferentiatedASCs. DISCUSSION These results support the initial hypothesis and validate ASCs as an in vitro model forthe analysis of circadian biology in human adipose tissue.", "metadata": {}}
+{"_id": "33638477", "title": "", "text": "BCL9 promotes tumor progression by conferring enhanced proliferative, metastatic, and angiogenicproperties to cancer cells.Several components of the Wnt signaling cascade have been shown to functioneither as tumor suppressor proteins or as oncogenes in multiple human cancers, underscoring therelevance of this pathway in oncogenesis and the need for further investigation of Wnt signalingcomponents as potential targets for cancer therapy. Here, using expression profiling analysis as well as invitro and in vivo functional studies, we show that the Wnt pathway component BCL9 is a novel oncogenethat is aberrantly expressed in human multiple myeloma as well as colon carcinoma. We show that BCL9enhances beta-catenin-mediated transcriptional activity regardless of the mutational status of the Wntsignaling components and increases cell proliferation, migration, invasion, and the metastatic potential oftumor cells by promoting loss of epithelial and gain of mesenchymal-like phenotype. Most importantly,BCL9 knockdown significantly increased the survival of xenograft mouse models of cancer by reducingtumor load, metastasis, and host angiogenesis through down-regulation of c-Myc, cyclin D1, CD44, andvascular endothelial growth factor expression by tumor cells. Together, these findings suggest thatderegulation of BCL9 is an important contributing factor to tumor progression. The pleiotropic roles ofBCL9 reported in this study underscore its value as a drug target for therapeutic intervention in severalmalignancies associated with aberrant Wnt signaling.", "metadata": {}}
+{"_id": "33667484", "title": "", "text": "Programmed cell death pathways in cancer: a review of apoptosis, autophagy and programmednecrosis.Programmed cell death (PCD), referring to apoptosis, autophagy and programmed necrosis, isproposed to be death of a cell in any pathological format, when mediated by an intracellular program.These three forms of PCD may jointly decide the fate of cells of malignant neoplasms; apoptosis andprogrammed necrosis invariably contribute to cell death, whereas autophagy can play either pro-survivalor pro-death roles. Recent bulk of accumulating evidence has contributed to a wealth of knowledgefacilitating better understanding of cancer initiation and progression with the three distinctive types of celldeath. To be able to decipher PCD signalling pathways may aid development of new targeted anti-cancertherapeutic strategies. Thus in this review, we present a brief outline of apoptosis, autophagy andprogrammed necrosis pathways and apoptosis-related microRNA regulation, in cancer. Taken together,understanding PCD and the complex interplay between apoptosis, autophagy and programmed necrosismay ultimately allow scientists and clinicians to harness the three types of PCD for discovery of furthernovel drug targets, in the future cancer treatment.", "metadata": {}}
+{"_id": "33669399", "title": "", "text": "Loss of gametophytic self-incompatibility with evolution of inbreeding depression.Gametophyticself-incompatibility (SI) in plants is a widespread mechanism preventing self-fertilization and the ensuinginbreeding depression, but it often evolves to self-compatibility. We analyze genetic mechanisms for thebreakdown of gametophytic SI, incorporating a dynamic model for the evolution of inbreeding depressionallowing for partial purging of nearly recessive lethal mutations by selfing, and accounting for pollenlimitation and sheltered load linked to the S-locus. We consider two mechanisms for the breakdown ofgametophytic SI: a nonfunctional S-allele and an unlinked modifier locus that inactivates the S-locus. Weshow that, under a wide range of conditions, self-compatible alleles can invade a self-incompatiblepopulation. Conditions for invasion are always less stringent for a nonfunctional S-allele than for amodifier locus. The spread of self-compatible genotypes is favored by extremely high or low selfing rates,a small number of S-alleles, and pollen limitation. Observed parameter values suggest that themaintenance of gametophytic SI is caused by a combination of high inbreeding depression inself-incompatible populations coupled with intermediate selfing rates of the self-compatible genotypesand sheltered load linked to the S-locus.", "metadata": {}}
+{"_id": "33677323", "title": "", "text": "The oncogenic microRNA miR-22 targets the TET2 tumor suppressor to promote hematopoietic stem cellself-renewal and transformation.MicroRNAs are frequently deregulated in cancer. Here we show thatmiR-22 is upregulated in myelodysplastic syndrome (MDS) and leukemia and its aberrant expressioncorrelates with poor survival. To explore its role in hematopoietic stem cell function and malignancy, wegenerated transgenic mice conditionally expressing miR-22 in the hematopoietic compartment. Thesemice displayed reduced levels of global 5-hydroxymethylcytosine (5-hmC) and increased hematopoieticstem cell self-renewal accompanied by defective differentiation. Conversely, miR-22 inhibition blockedproliferation in both mouse and human leukemic cells. Over time, miR-22 transgenic mice developed MDSand hematological malignancies. We also identify TET2 as a key target of miR-22 in this context. Ectopicexpression of TET2 suppressed the miR-22-induced phenotypes. Downregulation of TET2 protein alsocorrelated with poor clinical outcomes and miR-22 overexpression in MDS patients. Our results thereforeidentify miR-22 as a potent proto-oncogene and suggest that aberrations in the miR-22/TET2 regulatorynetwork are common in hematopoietic malignancies.", "metadata": {}}
+{"_id": "33684572", "title": "", "text": "Transmission of atherosclerosis susceptibility with gut microbial transplantation.Recent studies indicateboth clinical and mechanistic links between atherosclerotic heart disease and intestinal microbialmetabolism of certain dietary nutrients producing trimethylamine N-oxide (TMAO). Here we test thehypothesis that gut microbial transplantation can transmit choline diet-induced TMAO production andatherosclerosis susceptibility. First, a strong association was noted between atherosclerotic plaque andplasma TMAO levels in a mouse diversity panel (n = 22 strains, r = 0.38; p = 0.0001). Anatherosclerosis-prone and high TMAO-producing strain, C57BL/6J, and an atherosclerosis-resistant andlow TMAO-producing strain, NZW/LacJ, were selected as donors for cecal microbial transplantation intoapolipoprotein e null mice in which resident intestinal microbes were first suppressed with antibiotics.Trimethylamine (TMA) and TMAO levels were initially higher in recipients on choline diet that receivedcecal microbes from C57BL/6J inbred mice; however, durability of choline diet-dependent differences inTMA/TMAO levels was not maintained to the end of the study. Mice receiving C57BL/6J cecal microbesdemonstrated choline diet-dependent enhancement in atherosclerotic plaque burden as compared withrecipients of NZW/LacJ microbes. Microbial DNA analyses in feces and cecum revealed transplantation ofdonor microbial community features into recipients with differences in taxa proportions between donorstrains that were transmissible to recipients and that tended to show coincident proportions with TMAOlevels. Proportions of specific taxa were also identified that correlated with plasma TMAO levels in donorsand recipients and with atherosclerotic lesion area in recipients. Atherosclerosis susceptibility may betransmitted via transplantation of gut microbiota. Gut microbes may thus represent a novel therapeutictarget for modulating atherosclerosis susceptibility.", "metadata": {}}
+{"_id": "33720691", "title": "", "text": "The complete primary structure of the spermadhesin AWN, a zona pellucida-binding protein isolated fromboar spermatozoa.AWN is a boar protein which originates in secretions of the male accessory glands andwhich becomes sperm surface-associated upon ejaculation. It is one of the components thought tomediate sperm adhesion to the egg's zona pellucida through a carbohydrate-recognition mechanism.AWN may, thus, participate in the initial events of fertilization in the pig. In this report we describe itscomplete primary structure by combination of protein-chemical and mass spectrometric methods. AWNexists as two isoforms, AWN-1 and AWN-2, which differ in that AWN-2 is N-terminally acetylated. Theamino acid sequence of AWN contains 133 amino acid residues and two disulphide bridges betweennearest-neighbour cysteine residues. Analysis of the amino acid sequence of the AWN proteins showedsignificant similarity only to AQN-1 and AQN-3, two other boar spermadhesins.", "metadata": {}}
+{"_id": "33723822", "title": "", "text": "What influences government adoption of vaccines in developing countries? A policy process analysis.Thispaper proposes a framework for examining the process by which government consideration and adoptionof new vaccines takes place, with specific reference to developing country settings. The cases of earlyHepatitis B vaccine adoption in Taiwan and Thailand are used to explore the relevance of explanatoryfactors identified in the literature as well as the need to go beyond a variable-centric focus by highlightingthe role of policy context and process in determining the pace and extent of adoption. The cases suggestthe feasibility and importance of modeling 'causal diversity'-the complex set of necessary and sufficientconditions leading to particular decisional outcomes-in a broad range of country contexts. A betterunderstanding of the lenses through which government decision-makers filter information, and of thearenas in which critical decisions are shaped and taken, may assist both analysts (in predictinginstitutionalization of new vaccines) and advocates (in crafting targeted strategies to accelerate theirdiffusion).", "metadata": {}}
+{"_id": "33733520", "title": "", "text": "Benzodiazepines and injurious falls in community dwelling elders.BACKGROUND Benzodiazepines arefrequently used medications in the elderly, in whom they are associated with an increased risk of falling,with sometimes dire consequences. OBJECTIVE To estimate the impact of benzodiazepine-associatedinjurious falls in a population of elderly persons. METHOD A nested case-control study was conductedusing data collected during 10 years of follow-up of the French PAQUID (Personnes Agées QUID)community-based cohort. The main outcome measure was the occurrence of an injurious fall, which wasdefined as a fall resulting in hospitalization, fracture, head trauma or death. Controls (3 : 1) werefrequency-matched to cases. Benzodiazepine exposure was the use of benzodiazepines over the previous2 weeks reported at the follow-up visit preceding the fall. RESULTS Benzodiazepine use was significantlyassociated with the occurrence of injurious falls, with a significant interaction with age. The adjusted oddsratio for injurious falls in subjects exposed to benzodiazepines was 2.2 (95% CI 1.4, 3.4) in subjects aged> or = 80 years and 1.3 (95% CI 0.9, 1.9) in subjects aged <80 years. The population attributable riskfor injurious falls in subjects exposed to benzodiazepines was 28.1% (95% CI 16.7, 43.2) for subjectsaged > or =80 years. The incidence of injurious falls in subjects aged > or = 80 years exposed tobenzodiazepines in the PAQUID cohort was 2.8/100 person-years. Over 9% of these falls were fatal.According to these results and to recent population estimates, benzodiazepine use could be heldresponsible for almost 20 000 injurious falls in subjects aged > or = 80 years every year in France, andfor nearly 1800 deaths. CONCLUSION Given the considerable morbidity and mortality associated withbenzodiazepine use and the fact that existing good practice guidelines on benzodiazepines have not beeneffective in preventing their misuse (possibly because they have not been applied), new methods forlimiting use of benzodiazepines in the elderly need to be found.", "metadata": {}}
+{"_id": "33740844", "title": "", "text": "Effect of women's nutrition before and during early pregnancy on maternal and infant outcomes: asystematic review.Current understanding of biologic processes indicates that women's nutritional statusbefore and during early pregnancy may play an important role in determining early developmentalprocesses and ensuring successful pregnancy outcomes. We conducted a systematic review of theevidence for the impact of maternal nutrition before and during early pregnancy (<12 weeks gestation)on maternal, neonatal and child health outcomes and included 45 articles (nine intervention trials and 32observational studies) that were identified through PubMed and EMBASE database searches andexamining review articles. Intervention trials and observational studies show that periconceptional (<12weeks gestation) folic acid supplementation significantly reduced the risk of neural tube defects.Observational studies suggest that preconceptional and periconceptional intake of vitamin and mineralsupplements is associated with a reduced risk of delivering offspring who are low birthweight and/orsmall-for-gestational age (SGA) and preterm deliveries (PTD). Some studies report that indicators ofmaternal prepregnancy size, low stature, underweight and overweight are associated with increased risksof PTD and SGA. The available data indicate the importance of women's nutrition prior to and during thefirst trimester of pregnancy, but there is a need for well-designed prospective studies and controlled trialsin developing country settings that examine relationships with low birthweight, SGA, PTD, stillbirth andmaternal and neonatal mortality. The knowledge gaps that need to be addressed include the evaluation ofpericonceptional interventions such as food supplements, multivitamin-mineral supplements and/orspecific micronutrients (iron, zinc, iodine, vitamin B-6 and B-12) as well as the relationship betweenmeasures of prepregnancy body size and composition and maternal, neonatal and child health outcomes.", "metadata": {}}
+{"_id": "33792330", "title": "", "text": "Kinesin-2 controls development and patterning of the vertebrate skeleton by Hedgehog- andGli3-dependent mechanisms.Hedgehog signaling plays an essential role in patterning of the vertebrateskeleton. Here we demonstrate that conditional inactivation of the Kif3a subunit of the kinesin-2intraflagellar transport motor in mesenchymal skeletal progenitor cells results in severe patterningdefects in the craniofacial area, the formation of split sternum and the development of polydactyly. Thesedeformities are reminiscent of those previously described in mice with deregulated hedgehog signaling.We show that in Kif3a-deficient mesenchymal tissues both the repressor function of Gli3 transcriptionfactor and the activation of the Shh transcriptional targets Ptch and Gli1 are compromised. Quantitativeanalysis of gene expression demonstrates that the Gli1 transcript level is dramatically reduced, whereasGli3 expression is not significantly affected by kinesin-2 depletion. However, the motor appears to berequired for the efficient cleavage of the full-length Gli3 transcription factor into a repressor form.", "metadata": {}}
+{"_id": "33796570", "title": "", "text": "Ablation of NF1 function in neurons induces abnormal development of cerebral cortex and reactive gliosisin the brain.Neurofibromatosis type 1 (NF1) is a prevalent genetic disorder that affects growth propertiesof neural-crest-derived cell populations. In addition, approximately one-half of NF1 patients exhibitlearning disabilities. To characterize NF1 function both in vitro and in vivo, we circumvent the embryoniclethality of NF1 null mouse embryos by generating a conditional mutation in the NF1 gene using Cre/loxPtechnology. Introduction of a Synapsin I promoter driven Cre transgenic mouse strain into the conditionalNF1 background has ablated NF1 function in most differentiated neuronal populations. These mice haveabnormal development of the cerebral cortex, which suggests that NF1 has an indispensable role in thisaspect of CNS development. Furthermore, although they are tumor free, these mice display extensiveastrogliosis in the absence of conspicuous neurodegeneration or microgliosis. These results indicate thatNF1-deficient neurons are capable of inducing reactive astrogliosis via a non-cell autonomousmechanism.", "metadata": {}}
+{"_id": "33835579", "title": "", "text": "Pathology of postprimary tuberculosis in humans and mice: contradiction of long-held beliefs.Tuberculosisremains one of the world's leading infectious causes of death. Approximately 80% of all disease is due topostprimary (secondary) tuberculosis in the lung. Unfortunately, tissues of developing lesions are seldomavailable and there are no recognized models of postprimary tuberculosis. In the preantibiotic era whentissues were more abundant, several investigators described early postprimary tuberculosis as a lipidpneumonia quite different from the caseating granulomas commonly described today. We usedhistopathologic, immunohistochemical and acid fast stains to examine tissues from several people withuntreated primary and postprimary tuberculosis and compared the findings with those of mice withreactivation tuberculosis. The results confirmed that developing postprimary tuberculosis begins as a lipidpneumonia accompanied by bronchial obstruction in which infection is restricted to foamy alveolarmacrophages. Cavities result from a combination of caseation of tuberculous pneumonia andmicrovascular occlusion characteristic of delayed type hypersensitivity (DTH). Reactivation tuberculosis inthe mouse begins as a similar tuberculous lipid pneumonia with bronchial obstruction and evidence forparticipation of DTH. Developing necrosis in both species is associated with localization of organismswithin lipid droplets. These results suggest that reactivation tuberculosis in mice is a valuable model ofdeveloping human postprimary tuberculosis.", "metadata": {}}
+{"_id": "33872649", "title": "", "text": "Secondary aerosolization of viable Bacillus anthracis spores in a contaminated US Senate Office.CONTEXTBioterrorist attacks involving letters and mail-handling systems in Washington, DC, resulted in Bacillusanthracis (anthrax) spore contamination in the Hart Senate Office Building and other facilities in the USCapitol's vicinity. OBJECTIVE To provide information about the nature and extent of indoor secondaryaerosolization of B anthracis spores. DESIGN Stationary and personal air samples, surface dust, and swabsamples were collected under semiquiescent (minimal activities) and then simulated active officeconditions to estimate secondary aerosolization of B anthracis spores. Nominal size characteristics,airborne concentrations, and surface contamination of B anthracis particles (colony-forming units) wereevaluated. RESULTS Viable B anthracis spores reaerosolized under semiquiescent conditions, with amarked increase in reaerosolization during simulated active office conditions. Increases were observed forB anthracis collected on open sheep blood agar plates (P<.001) and personal air monitors (P =.01)during active office conditions. More than 80% of the B anthracis particles collected on stationarymonitors were within an alveolar respirable size range of 0.95 to 3.5 micro m.   CONCLUSIONS Bacillusanthracis spores used in a recent terrorist incident reaerosolized under common office activities. Thesefindings have important implications for appropriate respiratory protection, remediation, and reoccupancyof contaminated office environments.", "metadata": {}}
+{"_id": "33884866", "title": "", "text": "Fingolimod provides long-term protection in rodent models of cerebral ischemia.OBJECTIVE Thesphingosine-1-phosphate (S1P) receptor agonist fingolimod (FTY720), that has shown efficacy inadvanced multiple sclerosis clinical trials, decreases reperfusion injury in heart, liver, and kidney. Wetherefore tested the therapeutic effects of fingolimod in several rodent models of focal cerebral ischemia.To assess the translational significance of these findings, we asked whether fingolimod improvedlong-term behavioral outcomes, whether delayed treatment was still effective, and whetherneuroprotection can be obtained in a second species. METHODS We used rodent models of middlecerebral artery occlusion and cell-culture models of neurotoxicity and inflammation to examine thetherapeutic potential and mechanisms of neuroprotection by fingolimod. RESULTS In a transient mousemodel, fingolimod reduced infarct size, neurological deficit, edema, and the number of dying cells in thecore and periinfarct area. Neuroprotection was accompanied by decreased inflammation, asfingolimod-treated mice had fewer activated neutrophils, microglia/macrophages, and intercellularadhesion molecule-1 (ICAM-1)-positive blood vessels. Fingolimod-treated mice showed a smaller infarctand performed better in behavioral tests up to 15 days after ischemia. Reduced infarct was observed in apermanent model even when mice were treated 4 hours after ischemic onset. Fingolimod also decreasedinfarct size in a rat model of focal ischemia. Fingolimod did not protect primary neurons againstglutamate excitotoxicity or hydrogen peroxide, but decreased ICAM-1 expression in brain endothelial cellsstimulated by tumor necrosis factor alpha. INTERPRETATION These findings suggest thatanti-inflammatory mechanisms, and possibly vasculoprotection, rather than direct effects on neurons,underlie the beneficial effects of fingolimod after stroke. S1P receptors are a highly promising target instroke treatment.", "metadata": {}}
+{"_id": "33904473", "title": "", "text": "Induced regeneration—the progress and promise of direct reprogramming for heart repairRegeneration ofcardiac tissue has the potential to transform cardiovascular medicine. Recent advances in stem cellbiology and direct reprogramming, or transdifferentiation, have produced powerful new tools to advancethis goal. In this Review we examine key developments in the generation of new cardiomyocytes in vitroas well as the exciting progress that has been made toward in vivo reprogramming of cardiac tissue. Wealso address controversies and hurdles that challenge the field.", "metadata": {}}
+{"_id": "33904789", "title": "", "text": "\"Sandwich\"-type immunoassay of carcinoembryonic antigen in patients receiving murine monoclonalantibodies for diagnosis and therapy.Measurements of carcinoembryonic antigen (CEA) in blood increaseddramatically in some patients who were receiving injections of monoclonal antibody. CEA titers weremeasured with a monoclonal antibody-based double-determinant enzyme immunoassay in whichuntreated plasma specimens were diluted with an equal volume of buffer containing mouse serum.Increasing CEA titers were accompanied by the appearance and coincident increase in titers of humanantibody against mouse Ig (HAMA). Adsorption of these sera with solid-phase anti-human IgG or ProteinA restored antigen titers to pretreatment values; evidently the serum factor eliciting false-positive CEAtiters was most probably HAMA. Neither addition of undiluted mouse serum to the assay mixture norpretreatment by heating plasma specimens to 70 degrees C effectively abolished HAMA interference. Bycontrast, protein precipitation with polyethylene glycol (130 g/L) or heating plasma samples to 90degrees C eliminated false-positive titers caused by HAMA, but did not reduce authentic CEA titers.", "metadata": {}}
+{"_id": "33911859", "title": "", "text": "Mutant dynactin in motor neuron diseaseImpaired axonal transport in motor neurons has been proposedas a mechanism for neuronal degeneration in motor neuron disease. Here we show linkage of a lowermotor neuron disease to a region of 4 Mb at chromosome 2p13. Mutation analysis of a gene in thisinterval that encodes the largest subunit of the axonal transport protein dynactin showed a singlebase-pair change resulting in an amino-acid substitution that is predicted to distort the folding ofdynactin's microtubule-binding domain. Binding assays show decreased binding of the mutant protein tomicrotubules. Our results show that dysfunction of dynactin-mediated transport can lead to human motorneuron disease.", "metadata": {}}
+{"_id": "33912020", "title": "", "text": "Thioredoxin mediates oxidation-dependent phosphorylation of CRMP2 and growth conecollapse.Semaphorin3A (Sema3A) is a repulsive guidance molecule for axons, which acts by inducinggrowth cone collapse through phosphorylation of CRMP2 (collapsin response mediator protein 2). Here,we show a role for CRMP2 oxidation and thioredoxin (TRX) in the regulation of CRMP2 phosphorylationand growth cone collapse. Sema3A stimulation generated hydrogen peroxide (H2O2) through MICAL(molecule interacting with CasL) and oxidized CRMP2, enabling it to form a disulfide-linked homodimerthrough cysteine-504. Oxidized CRMP2 then formed a transient disulfide-linked complex with TRX, whichstimulated CRMP2 phosphorylation by glycogen synthase kinase-3, leading to growth cone collapse. Wealso reconstituted oxidation-dependent phosphorylation of CRMP2 in vitro, using a limited set of purifiedproteins. Our results not only clarify the importance of H2O2 and CRMP2 oxidation in Sema3A-inducedgrowth cone collapse but also indicate an unappreciated role for TRX in linking CRMP2 oxidation tophosphorylation.", "metadata": {}}
+{"_id": "33912748", "title": "", "text": "Pathologic indicators of degradation and inflammation in human osteoarthritic cartilage are abrogated byexposure to n-3 fatty acids.OBJECTIVE To determine if n-3 polyunsaturated fatty acid (PUFA)supplementation (versus treatment with n-6 polyunsaturated or other fatty acid supplements) affects themetabolism of osteoarthritic (OA) cartilage. METHODS The metabolic profile of human OA cartilage wasdetermined at the time of harvest and after 24-hour exposure to n-3 PUFAs or other classes of fattyacids, followed by explant culture for 4 days in the presence or absence of interleukin-1 (IL-1).Parameters measured were glycosaminoglycan release, aggrecanase and matrix metalloproteinase (MMP)activity, and the levels of expression of messenger RNA (mRNA) for mediators of inflammation,aggrecanases, MMPs, and their natural tissue inhibitors (tissue inhibitors of metalloproteinases [TIMPs]).RESULTS Supplementation with n-3 PUFA (but not other fatty acids) reduced, in a dose-dependentmanner, the endogenous and IL-1-induced release of proteoglycan metabolites from articular cartilageexplants and specifically abolished endogenous aggrecanase and collagenase proteolytic activity.Similarly, expression of mRNA for ADAMTS-4, MMP-13, and MMP-3 (but not TIMP-1, -2, or -3) was alsospecifically abolished with n-3 PUFA supplementation. In addition, n-3 PUFA supplementation abolishedthe expression of mRNA for mediators of inflammation (cyclooxygenase 2, 5-lipoxygenase,5-lipoxygenase-activating protein, tumor necrosis factor alpha, IL-1alpha, and IL-1beta) without affectingthe expression of message for several other proteins involved in normal tissue homeostasis.CONCLUSION These studies show that the pathologic indicators manifested in human OA cartilage can besignificantly altered by exposure of the cartilage to n-3 PUFA, but not to other classes of fatty acids.", "metadata": {}}
+{"_id": "33918970", "title": "", "text": "Interactive effects of oligofructose and obesity predisposition on gut hormones and microbiota indiet-induced obese rats.OBJECTIVE Oligofructose (OFS) is a prebiotic that reduces energy intake and fatmass via changes in gut satiety hormones and microbiota. The effects of OFS may vary depending onpredisposition to obesity. The aim of this study was to examine the effect of OFS in diet-induced obese(DIO) and diet-resistant (DR) rats. METHODS Adult, male DIO, and DR rats were randomized to:high-fat/high-sucrose (HFS) diet or HFS diet + 10% OFS for 6 weeks. Body composition, food intake, gutmicrobiota, plasma gut hormones, and cannabinoid CB(1) receptor expression in the nodose ganglia weremeasured. RESULTS OFS reduced body weight, energy intake, and fat mass in both phenotypes (P <0.05). Select gut microbiota differed in DIO versus DR rats (P < 0.05), the differences being eliminatedby OFS. OFS did not modify plasma ghrelin or CB(1) expression in nodose ganglia, but plasma levels ofGIP were reduced and PYY were elevated (P < 0.05) by OFS. CONCLUSIONS OFS was able to reducebody weight and adiposity in both prone and resistant obese phenotypes. OFS-induced changes in gutmicrobiota profiles in DIO and DR rats, along with changes in gut hormone levels, likely contribute to thesustained lower body weights.", "metadata": {}}
+{"_id": "33920995", "title": "", "text": "RKIKK motif in the intracellular domain is critical for spatial and dynamic organization of ICAM-1:functional implication for the leukocyte adhesion and transmigration.No direct evidence has beenreported whether the spatial organization of ICAM-1 on the cell surface is linked to its physiologicalfunction in terms of leukocyte adhesion and transendothelial migration (TEM). Here we observed thatICAM-1 by itself directly regulates the de novo elongation of microvilli and is thereby clustered on themicrovilli. However, truncation of the intracellular domain resulted in uniform cell surface distribution ofICAM-1. Mutation analysis revealed that the C-terminal 21 amino acids are dispensable, whereas asegment of 5 amino acids ((507)RKIKK(511)) in the NH-terminal third of intracellular domain, is requiredfor the proper localization and dynamic distribution of ICAM-1 and the association of ICAM-1 with F-actin,ezrin, and moesin. Importantly, deletion of the (507)RKIKK(511) significantly delayed theLFA-1-dependent membrane projection and decreased leukocyte adhesion and subsequent TEM.Endothelial cells treated with cell-permeant penetratin-ICAM-1 peptides comprising ICAM-1 RKIKKsequences inhibited leukocyte TEM. Collectively, these findings demonstrate that (507)RKIKK(511) is anessential motif for the microvillus ICAM-1 presentation and further suggest a novel regulatory role forICAM-1 topography in leukocyte TEM.", "metadata": {}}
+{"_id": "33934971", "title": "", "text": "Immunology of the tick-host interaction and the control of ticks and tick-borne diseases.The firstexperimental vaccination against ticks was carried out 60 years ago. Since then, progress has been slow,although the recent commercial release of a recombinant vaccine against Boophilus microplus issignificant. The nature of naturally acquired protective immunity against ticks is poorly understood,particularly in the important, domesticated ruminant hosts. Characterization of the antigens of naturallyacquired immunity remains limited, although more has been achieved with 'concealed' antigens. Crucialquestions remain about the true impact of tick-induced immunosuppression and the effect of immunity onthe transmission of tick-borne diseases, despite some fascinating and important recent results, asdiscussed here by Peter Willadsen and Frans Jongejan.", "metadata": {}}
+{"_id": "33955641", "title": "", "text": "Rapid method for the isolation of lipoproteins from human serum by precipitation withpolyanions.Procedures are described for the isolation of lipoproteins from human serum by precipitationwith polyanions and divalent cations. A mixture of low and very low density lipoproteins can be preparedwithout ultracentrifugation by precipitation with heparin and either MnCl(2) alone or MgCl(2) plussucrose. In both cases the precipitation is reversible, selective, and complete. The highly concentratedisolated lipoproteins are free of other plasma proteins as judged by immunological and electrophoreticmethods. The low density and very low density lipoproteins can then be separated from each other byultracentrifugation. The advantage of the method is that large amounts of lipoproteins can be preparedwith only a single preparative ultracentrifugation. Polyanions other than heparin may also be used; whenthe precipitation of the low and very low density lipoproteins is achieved with dextran sulfate andMnCl(2), or sodium phosphotungstate and MgCl(2), the high density lipoproteins can subsequently beprecipitated by increasing the concentrations of the reagents. These lipoproteins, containing smallamounts of protein contaminants, are further purified by ultracentrifugation at d 1.22. With a singlepreparative ultracentrifugation, immunologically pure high density lipoproteins can be isolated from largevolumes of serum.", "metadata": {}}
+{"_id": "33960383", "title": "", "text": "The role of oral antidiabetic agents: why and when to use an early-phase insulin secretion agent in TypeII diabetes mellitusAbstract Evidence obtained in the 1990's strongly supports the notion that glycaemiccontrol is important not only in Type I (insulin-dependent), but also in Type II (non-insulin-dependent)diabetes mellitus. Although measurement of HbA1c is the standard for assessing the effect of glucosecontrol in the occurrence and prevention of diabetic sequelae, more recent evidence indicates that otherglucose parameters are also important. Postchallenge and postprandial hyperglycaemic peaks seem to beprospective determinants of vascular damage in early Type II diabetes. Currently, there is no overallaccepted standard approach for the pharmacological management of Type II diabetes. The UnitedKingdom Prospective Diabetes Study has shown that reaching a near-normal glycaemic target is criticallyimportant and the pharmacotherapy of this progressive disease is difficult. Loss of endogenous insulinsecretion has been substantiated to cause the progression of Type II diabetes in the United KingdomProspective Diabetes Study. Early insulinization, however, was not advantageous over other forms oftherapy. The advent of polypharmacy in recent years has greatly strengthened the treatment of thisdisease. This synergy has been extended of late with the development of early-phase insulin secretionagents. Two such agents, nateglinide and repaglinide, can be used to reduce mealtime glucose excursionsand HbA1c as monotherapy, and in combination with metformin; their antidiabetic potential is similar tothe combination treatment with glibenclamide and metformin. Additional substantiation of their long-termeffect on improving life expectancy and reducing diabetic complications in Type II diabetic patients is nowrequired.", "metadata": {}}
+{"_id": "33986200", "title": "", "text": "Layered hydrogels accelerate iPSC-derived neuronal maturation and reveal migration defects caused byMeCP2 dysfunction.Probing a wide range of cellular phenotypes in neurodevelopmental disorders usingpatient-derived neural progenitor cells (NPCs) can be facilitated by 3D assays, as 2D systems cannotentirely recapitulate the arrangement of cells in the brain. Here, we developed a previously unidentified3D migration and differentiation assay in layered hydrogels to examine how these processes are affectedin neurodevelopmental disorders, such as Rett syndrome. Our soft 3D system mimics the brainenvironment and accelerates maturation of neurons from human induced pluripotent stem cell(iPSC)-derived NPCs, yielding electrophysiologically active neurons within just 3 wk. Using this platform,we revealed a genotype-specific effect of methyl-CpG-binding protein-2 (MeCP2) dysfunction oniPSC-derived neuronal migration and maturation (reduced neurite outgrowth and fewer synapses) in 3Dlayered hydrogels. Thus, this 3D system expands the range of neural phenotypes that can be studied invitro to include those influenced by physical and mechanical stimuli or requiring specific arrangements ofmultiple cell types.", "metadata": {}}
+{"_id": "33986507", "title": "", "text": "Inducible gene expression: diverse regulatory mechanismsThe rapid activation of gene expression inresponse to stimuli occurs largely through the regulation of RNA polymerase II-dependent transcription.In this Review, we discuss events that occur during the transcription cycle in eukaryotes that areimportant for the rapid and specific activation of gene expression in response to external stimuli. Inaddition to regulated recruitment of the transcription machinery to the promoter, it has now been shownthat control steps can include chromatin remodelling and the release of paused polymerase. Recent worksuggests that some components of signal transduction cascades also play an integral part in activatingtranscription at target genes.", "metadata": {}}
+{"_id": "33989422", "title": "", "text": "On the origins of ultra-fine anaphase bridges.Comment on: Chan KL, Palmai-Pallag T, Ying S, Hickson ID.Replication stress induces sister-chromatid bridging at fragile site loci in mitosis. Nat Cell Biol 2009;11:753-60.", "metadata": {}}
+{"_id": "34016944", "title": "", "text": "Resistance to gefitinib in PTEN-null HER-overexpressing tumor cells can be overcome through restorationof PTEN function or pharmacologic modulation of constitutive phosphatidylinositol 3'-kinase/Akt pathwaysignaling.PURPOSE Tyrosine kinase (TK) inhibitors are emerging as a promising new approach to thetreatment of HER overexpressing tumors, however optimal use of these agents awaits further definitionof the downstream signaling pathways that mediate their effects. We reported previously that both EGFR-and Her2-overexpressing tumors are sensitive to the new EGFR-selective TK inhibitor gefitinib (ZD1839,\"Iressa\"), and sensitivity to this agent correlated with its ability to down-regulate Akt. However,EGFR-overexpressing MDA-468 cells, which lack PTEN function, are resistant to ZD1839, and ZD1839 isunable to down-regulate Akt activity in these cells. EXPERIMENTAL DESIGN To study the role of PTENfunction, we generated MDA468 cells with tet-inducible PTEN expression. RESULTS We show here thatthe resistance of MDA-468 cells to ZD1839 is attributable to EGFR-independent constitutive Akt activationcaused by loss of PTEN function in these cells. Reconstitution of PTEN function through tet-inducibleexpression restores ZD1839 sensitivity to these cells and reestablishes EGFR-stimulated Akt signaling.Although restoration of PTEN function to tumors is difficult to implement clinically, much of the effects ofPTEN loss are attributable to overactive PI3K/Akt pathway signaling, and this overactivity can bemodulated by pharmacologic approaches. We show here that pharmacologic down-regulation ofconstitutive PI3K/Akt pathway signaling using the PI3K inhibitor LY294002 similarly restoresEGFR-stimulated Akt signaling and sensitizes MDA-468 cells to ZD1839. CONCLUSIONS Sensitivity toZD1839 requires intact growth factor receptor-stimulated Akt signaling activity. PTEN loss leads touncoupling of this signaling pathway and results in ZD1839 resistance, which can be reversed withreintroduction of PTEN or pharmacologic down-regulation of constitutive PI3K/Akt pathway activity. Thesedata have important predictive and therapeutic clinical implications.", "metadata": {}}
+{"_id": "34016987", "title": "", "text": "Transcriptome analysis reveals human cytomegalovirus reprograms monocyte differentiation toward anM1 macrophage.Monocytes are primary targets for human CMV (HCMV) infection and are proposed to beresponsible for hematogenous dissemination of the virus. Monocytes acquire different functional traitsduring polarization to the classical proinflammatory M1 macrophage or the alternative antiinflammatoryM2 macrophage. We hypothesized that HCMV induced a proinflammatory M1 macrophage followinginfection to promote viral dissemination because, biologically, a proinflammatory state provides the toolsto drive infected monocytes from the blood into the tissue. To test this hypothesis of monocyteconversion from a normal quiescent phenotype to an inflammatory phenotype, we used AffymetrixMicroarray to acquire a transcriptional profile of infected monocytes at a time point our data emphasizedis a key temporal regulatory point following infection. We found that HCMV significantly up-regulated 583(5.2%) of the total genes and down-regulated 621 (5.5%) of the total genes>or=1.5-fold at 4 hpostinfection. Further ontology analysis revealed that genes implicated in classical M1 macrophageactivation were stimulated by HCMV infection. We found that 65% of genes strictly associated with M1polarization were up-regulated, while only 4% of genes solely associated with M2 polarization wereup-regulated. Analysis of the monocyte chemokinome at the transcriptional level showed that 44% of M1and 33% of M2 macrophage chemokines were up-regulated. Proteomic analysis using chemokine Abarrays confirmed the secretion of these chemotactic proteins from HCMV-infected monocytes. Overall, theresults identify that the HCMV-infected monocyte transcriptome displayed a unique M1/M2 polarizationsignature that was skewed toward the classical M1 activation phenotype.", "metadata": {}}
+{"_id": "34025053", "title": "", "text": "Antithymocyte globulin treatment for patients with recent-onset type 1 diabetes: 12-month results of arandomised, placebo-controlled, phase 2 trial.BACKGROUND Type 1 diabetes results from T-cell-mediateddestruction of β cells. Findings from preclinical studies and pilot clinical trials suggest that antithymocyteglobulin (ATG) might be effective for reducing this autoimmune response. We assessed the safety andefficacy of rabbit ATG in preserving islet function in participants with recent-onset type 1 diabetes, andreport here our 12-month results. METHODS For this phase 2, randomised, placebo-controlled, clinicaltrial, we enrolled patients with recent-onset type 1 diabetes, aged 12-35 years, and with a peakC-peptide of 0.4 nM or greater on mixed meal tolerance test from 11 sites in the USA. We used acomputer generated randomisation sequence to randomly assign patients (2:1, with permuted-blocks ofsize three or six and stratified by study site) to receive either 6.5 mg/kg ATG or placebo over a course offour days. All participants were masked and initially managed by an unmasked drug management team,which managed all aspects of the study until month 3. Thereafter, to maintain masking for diabetesmanagement throughout the remainder of the study, participants received diabetes management from anindependent, masked study physician and nurse educator. The primary endpoint was thebaseline-adjusted change in 2-h area under the curve C-peptide response to mixed meal tolerance testfrom baseline to 12 months. Analyses were by intention to treat. This is a planned interim analysis of anon-going trial that will run for 24 months of follow-up. This study is registered with ClinicalTrials.gov,number NCT00515099. FINDINGS Between Sept 10, 2007, and June 1, 2011, we screened 154individuals, randomly allocating 38 to ATG and 20 to placebo. We recorded no between-group differencein the primary endpoint: participants in the ATG group had a mean change in C-peptide area under thecurve of -0.195 pmol/mL (95% CI -0.292 to -0.098) and those in the placebo group had a mean changeof -0.239 pmol/mL (-0.361 to -0.118) in the placebo group (p=0.591). All except one participant in theATG group had both cytokine release syndrome and serum sickness, which was associated with atransient rise in interleukin-6 and acute-phase proteins. Acute T cell depletion occurred in the ATG group,with slow reconstitution over 12 months. However, effector memory T cells were not depleted, and theratio of regulatory to effector memory T cells declined in the first 6 months and stabilised thereafter.ATG-treated patients had 159 grade 3-4 adverse events, many associated with T-cell depletion,compared with 13 in the placebo group, but we detected no between-group difference in incidence ofinfectious diseases. INTERPRETATION Our findings suggest that a brief course of ATG does not result inpreservation of β-cell function 12 months later in patients with new-onset type 1 diabetes. GeneralisedT-cell depletion in the absence of specific depletion of effector memory T cells and preservation ofregulatory T cells seems to be an ineffective treatment for type 1 diabetes.", "metadata": {}}
+{"_id": "34034749", "title": "", "text": "The nucleosome family: dynamic and growing.Ever since the discovery of the nucleosome in 1974,scientists have stumbled upon discrete particles in which DNA is wrapped around histone complexes ofdifferent stoichiometries: octasomes, hexasomes, tetrasomes, \"split\" half-nucleosomes, and, recently,bona fide hemisomes. Do all these particles exist in vivo? Under what conditions? What is theirphysiological significance in the complex DNA transactions in the eukaryotic nucleus? What are theirdynamics? This review summarizes research spanning more than three decades and provides a newmeaning to the term \"nucleosome. \" The nucleosome can no longer be viewed as a single static entity:rather, it is a family of particles differing in their structural and dynamic properties, leading to differentfunctionalities.", "metadata": {}}
+{"_id": "34054472", "title": "", "text": "Association between serum corin levels and risk of acute myocardial infarction.BACKGROUNDAccumulating evidence has indicated that corin plays critical roles in regulating salt-water balance, bloodpressure and cardiac function by activating natriuretic peptides. The present case-control study wasdesigned to evaluate the association of serum soluble corin with acute myocardial infarction (AMI).METHODS We enrolled 856 consecutive AMI patients and 856 control subjects and explored the possiblerelation between serum corin levels and AMI risk using logistic regression model. RESULTS Patients withAMI had higher BMI, were less physically active, and were more likely to have histories of hypertension,diabetes, hyperlipidemia and smoking compared with the controls. Serum levels of corin were remarkablyreduced in AMI patients (825±263pg/ml) compared with those in healthy controls (1246±425pg/ml).Odds ratios of ST elevation (STEMI) and non-ST elevation myocardial infarction (NSTEMI) weresignificantly decreased with the increasing levels of serum corin in both men and women (P for trend,<0.001) after adjustment for body mass index, hypertension, diabetes, hyperlipidemia, smoking, andphysical activity. CONCLUSIONS Our study demonstrates that serum levels of corin are significantlydecreased in AMI patients, and it is inversely associated with the incidences of STEMI and NSTEMI in bothmen and women.", "metadata": {}}
+{"_id": "34066665", "title": "", "text": "Crosstalk between the estrogen receptor and the HER tyrosine kinase receptor family: molecularmechanism and clinical implications for endocrine therapy resistance.Breast cancer evolution and tumorprogression are governed by the complex interactions between steroid receptor [estrogen receptor (ER)and progesterone receptor] and growth factor receptor signaling. In recent years, the field of cancertherapy has witnessed the emergence of multiple strategies targeting these specific cancer pathways andkey molecules (ER and growth factor receptors) to arrest tumor growth and achieve tumor eradication;treatment success, however, has varied and both de novo (up front) and acquired resistance have provena challenge. Recent studies of ER biology have revealed new insights into ER action in breast cancer andhave highlighted the role of an intimate crosstalk between the ER and HER family signaling pathways as afundamental contributor to the development of resistance to endocrine therapies against the ER pathway.The aim of this review article is to summarize the current knowledge on mechanisms of resistance ofbreast cancer cells to endocrine therapies due to the crosstalk between the ER and the HER growth factorreceptor signaling pathways and to explore new available therapeutic strategies that could prolongduration of response and circumvent endocrine resistant tumor growth.", "metadata": {}}
+{"_id": "34071621", "title": "", "text": "Nuclear PTEN functions as an essential regulator of SRF-dependent transcription to control smoothmuscle differentiationVascular disease progression is associated with marked changes in vascular smoothmuscle cell (SMC) phenotype and function. SMC contractile gene expression and, thus differentiation, isunder direct transcriptional control by the transcription factor, serum response factor (SRF); however, themechanisms dynamically regulating SMC phenotype are not fully defined. Here we report that the lipidand protein phosphatase, PTEN, has a novel role in the nucleus by functioning as an indispensibleregulator with SRF to maintain the differentiated SM phenotype. PTEN interacts with the N-terminaldomain of SRF and PTEN-SRF interaction promotes SRF binding to essential promoter elements inSM-specific genes. Factors inducing phenotypic switching promote loss of nuclear PTEN throughnucleo-cytoplasmic translocation resulting in reduced myogenically active SRF, but enhanced SRF activityon target genes involved in proliferation. Overall decreased expression of PTEN was observed in intimalSMCs of human atherosclerotic lesions underlying the potential clinical importance of these findings.", "metadata": {}}
+{"_id": "34074902", "title": "", "text": "SEROSURVEY FOR FELINE LEUKEMIA VIRUS AND LENTIVIRUSES IN CAPTIVE SMALL NEOTROPIC FELIDSIN SÃO PAULO STATE, BRAZILAbstract Feline leukemia virus (FeLV), Gammaretrovirus, and felineimmunodeficiency virus, a Lentivirus, are members of the family Retroviridae, and may establishpersistent infections in the domestic cat (Felis catus). Cytoproliferative and cytosuppressive disordersmay result from infection with these viruses. Morbidity and mortality rates are high in domestic catsworldwide. Infection of endangered neotropic small felids with these viruses could be devastating. Toinvestigate the prevalence of FeLV and feline lentiviruses in neotropic small felids kept in captivity in SãoPaulo state, Brazil, serum samples from 104 animals belonging to the species Leopardus pardalis,Leopardus tigrinus, Leopardus wiedii, Herpailurus yaguarondi, and Oncifelis geoffroyi were tested forFeLV and feline lentiviruses by commercially available immunoassays. All results were negative,suggesting that retrovirus infection is not an important clinical problem in these populations. Becausedomestic cats in São Paulo city are naturally infected with these pathogens, and feral cats are commonlyfound in zoologic facilities in Brazil, preventive measures should be taken to avoid transmission ofretroviruses to naive populations of wild and captive neotropic felids in Brazil.", "metadata": {}}
+{"_id": "34101101", "title": "", "text": "Comparing the metabolism of quercetin in rats, mice and gerbilsSeveral species of rodents are used toinvestigate the metabolism of quercetin in vivo. However, it is unclear whether they are a proper animalmodel. Thus, we compared the metabolism of quercetin in Wistar rats (rats), Balb/c mice (mice) andMongolian gerbils (gerbils). We determined the levels of quercetin metabolites, quercetin-3-glucuronide(Q3G), quercetin-3′-sulfate (Q3′S) and methyl-quercetin isorhamnetin (IH), in the plasma, lungs andlivers of three species of animals by high-performance liquid chromatography after acute and/or chronicquercetin administration. The metabolic enzyme activities in the intestinal mucosal membrane and liverwere also investigated. First, we found that after acute quercetin administration, the Q3′S level was thehighest in gerbils. However, after long-term supplementation (20 weeks), Q3G was the dominantmetabolite in the plasma, lungs and livers followed by IH and Q3′S in all animals, although the gerbils stillhad a higher Q3′S conversion ratio. The average concentrations of total quercetin concentration in theplasma of gerbils were the highest in both short- and long-term studies. The activities of uridine5′-diphosphate-glucuronosyltransferase, phenolsulfotransferase and catechol-O-methyltransferase wereinduced by quercetin in a dose- and tissue-dependent manner in all animals. Taken together, in general,after long-term supplementation the metabolism of quercetin is similar in all animals and is comparableto that of humans. However, the accumulation of quercetin and Q3′S conversion ratio in gerbils arehigher than those in the other animals.", "metadata": {}}
+{"_id": "34103335", "title": "", "text": "Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cellsA long-standinghypothesis on tumorigenesis is that cell division failure, generating genetically unstable tetraploid cells,facilitates the development of aneuploid malignancies. Here we test this idea by transiently blockingcytokinesis in p53-null (p53-/-) mouse mammary epithelial cells (MMECs), enabling the isolation ofdiploid and tetraploid cultures. The tetraploid cells had an increase in the frequency ofwhole-chromosome mis-segregation and chromosomal rearrangements. Only the tetraploid cells weretransformed in vitro after exposure to a carcinogen. Furthermore, in the absence of carcinogen, only thetetraploid cells gave rise to malignant mammary epithelial cancers when transplanted subcutaneouslyinto nude mice. These tumours all contained numerous non-reciprocal translocations and an 8–30-foldamplification of a chromosomal region containing a cluster of matrix metalloproteinase (MMP) genes.MMP overexpression is linked to mammary tumours in humans and animal models. Thus, tetraploidyenhances the frequency of chromosomal alterations and promotes tumour development in p53-/- MMECs.", "metadata": {}}
+{"_id": "34105878", "title": "", "text": "Claspin, a Chk1-regulatory protein, monitors DNA replication on chromatin independently of RPA, ATR,and Rad17.Claspin is required for the ATR-dependent activation of Chk1 in Xenopus egg extractscontaining incompletely replicated DNA. We show here that Claspin associates with chromatin in aregulated manner during S phase. Binding of Claspin to chromatin depends on the pre-replicationcomplex (pre-RC) and Cdc45 but not on replication protein A (RPA). These dependencies suggest thatbinding of Claspin occurs around the time of initial DNA unwinding at replication origins. By contrast, bothATR and Rad17 require RPA for association with DNA. Claspin, ATR, and Rad17 all bind to chromatinindependently. These findings suggest that Claspin plays a role in monitoring DNA replication during Sphase. Claspin, ATR, and Rad17 may collaborate in checkpoint regulation by detecting different aspects ofa DNA replication fork.", "metadata": {}}
+{"_id": "34121231", "title": "", "text": "Cold-related respiratory symptoms in the general population.INTRODUCTION Cold-related respiratorysymptoms are common among northern populations, especially among people suffering from respiratorydiseases. However, the prevalence of such symptoms in the general population and the thresholdtemperatures at which the symptoms start to emerge are poorly known. OBJECTIVES The present studydetermined the prevalence and threshold temperatures of self-reported respiratory symptoms related tocold, separately for healthy people and those with respiratory disease. MATERIALS AND METHODS Sixthousand five hundred ninety-one men and women aged 25 years-74 years from the national FINRISKstudy were queried about cold-related respiratory symptoms. The results were expressed asage-adjusted prevalence figures and coefficients from multivariate regressions. RESULTS Cold-relatedrespiratory symptoms were more often reported by people with asthma (men 69%/women 78%) and bysubjects with chronic bronchitis (65%/76%) than the healthy subjects (18%/21%). A binomial regressionshowed an increase of symptom prevalence by age and excesses of 4%, 50% and 21% units because offemale sex, asthma and chronic bronchitis, respectively. The reported threshold temperature forcold-related symptoms was -14 degrees C for males and -15 degrees C for females, and it showed someincrease by age (0 degrees C-5 degrees C), asthma (2 degrees C) and chronic bronchitis (3 degrees C).The threshold temperature for mucus production was exceptional as it decreased by age (2 degrees C-5degrees C) and asthma (2 degrees C). The effects of smoking and education were marginal.CONCLUSION Cold-related respiratory symptoms are common in patients with chronic respiratorydiseases, but they start to emerge at relatively low temperatures. In a cold climate, the cold-relatedsymptoms may have an impact on the health-related quality of life.", "metadata": {}}
+{"_id": "34139429", "title": "", "text": "Carvedilol for children and adolescents with heart failure: a randomized controlled trial.CONTEXTAlthough beta-blockers improve symptoms and survival in adults with heart failure, little is known aboutthese medications in children and adolescents. OBJECTIVE To prospectively evaluate the effects ofcarvedilol in children and adolescents with symptomatic systemic ventricular systolic dysfunction.DESIGN, SETTING, AND PARTICIPANTS A multicenter, randomized, double-blind, placebo-controlledstudy of 161 children and adolescents with symptomatic systolic heart failure from 26 US centers. Inaddition to treatment with conventional heart failure medications, patients were assigned to receiveplacebo or carvedilol. Enrollment began in June 2000 and the last dose was given in May 2005 (eachpatient received medication for 8 months). INTERVENTIONS Patients were randomized in a 1:1:1 ratio totwice-daily dosing with placebo, low-dose carvedilol (0.2 mg/kg per dose if weight <62.5 kg or 12.5 mgper dose if weight > or =62.5 kg), or high-dose carvedilol (0.4 mg/kg per dose if weight <62.5 kg or 25mg per dose if weight > or =62.5 kg) and were stratified according to whether each patient's systemicventricle was a left ventricle or not. MAIN OUTCOME MEASURES The primary outcome was a compositemeasure of heart failure outcomes in patients receiving carvedilol (low- and high-dose combined) vsplacebo. Secondary efficacy variables included individual components of this composite,echocardiographic measures, and plasma b-type natriuretic peptide levels. RESULTS There was nostatistically significant difference between groups for the composite end point based on the percentage ofpatients who improved, worsened, or were unchanged. Among 54 patients assigned to placebo, 30improved (56%), 16 worsened (30%), and 8 were unchanged (15%); among 103 patients assigned tocarvedilol, 58 improved (56%), 25 worsened (24%), and 20 were unchanged (19%). The rates ofworsening were lower than expected. The odds ratio for worsened outcome for patients in the combinedcarvedilol group vs the placebo group was 0.79 (95% CI, 0.36-1.59; P = .47). A prespecified subgroupanalysis noted significant interaction between treatment and ventricular morphology (P = .02), indicatinga possible differential effect of treatment between patients with a systemic left ventricle (beneficial trend)and those whose systemic ventricle was not a left ventricle (nonbeneficial trend). CONCLUSIONS Thesepreliminary results suggest that carvedilol does not significantly improve clinical heart failure outcomes inchildren and adolescents with symptomatic systolic heart failure. However, given the lower than expectedevent rates, the trial may have been underpowered. There may be a differential effect of carvedilol inchildren and adolescents based on ventricular morphology. TRIAL REGISTRATION clinicaltrials.govIdentifier: NCT00052026.", "metadata": {}}
+{"_id": "34189936", "title": "", "text": "The circadian clock gene BMAL1 is a novel therapeutic target for malignant pleuralmesothelioma.Malignant pleural mesothelioma (MPM) is a highly aggressive neoplasm arising from themesothelial cells lining the parietal pleura and it exhibits poor prognosis. Although there has beensignificant progress in MPM treatment, development of more efficient therapeutic approaches is needed.BMAL1 is a core component of the circadian clock machinery and its constitutive overexpression in MPMhas been reported. Here, we demonstrate that BMAL1 may serve as a molecular target for MPM. Themajority of MPM cell lines and a subset of MPM clinical specimens expressed higher levels of BMAL1compared to a nontumorigenic mesothelial cell line (MeT-5A) and normal parietal pleural specimens,respectively. A serum shock induced a rhythmical BMAL1 expression change in MeT-5A but not inACC-MESO-1, suggesting that the circadian rhythm pathway is deregulated in MPM cells. BMAL1knockdown suppressed proliferation and anchorage-dependent and independent clonal growth in twoMPM cell lines (ACC-MESO-1 and H290) but not in MeT-5A. Notably, BMAL1 depletion resulted in cellcycle disruption with a substantial increase in apoptotic and polyploidy cell population in association withdownregulation of Wee1, cyclin B and p21(WAF1/CIP1) and upregulation of cyclin E expression. BMAL1knockdown induced mitotic catastrophe as denoted by disruption of cell cycle regulators and induction ofdrastic morphological changes including micronucleation and multiple nuclei in ACC-MESO-1 cells thatexpressed the highest level of BMAL1. Taken together, these findings indicate that BMAL1 has a criticalrole in MPM and could serve as an attractive therapeutic target for MPM.", "metadata": {}}
+{"_id": "34198365", "title": "", "text": "Mechanism and Regulation of DNA-Protein Crosslink Repair by the DNA-Dependent MetalloproteaseSPRTNCovalent DNA-protein crosslinks (DPCs) are toxic DNA lesions that interfere with essentialchromatin transactions, such as replication and transcription. Little was known about DPC-specific repairmechanisms until the recent identification of a DPC-processing protease in yeast. The existence of a DPCprotease in higher eukaryotes is inferred from data in Xenopus laevis egg extracts, but its identityremains elusive. Here we identify the metalloprotease SPRTN as the DPC protease acting in metazoans.Loss of SPRTN results in failure to repair DPCs and hypersensitivity to DPC-inducing agents. SPRTNaccomplishes DPC processing through a unique DNA-induced protease activity, which is controlled byseveral sophisticated regulatory mechanisms. Cellular, biochemical, and structural studies define a DNAswitch triggering its protease activity, a ubiquitin switch controlling SPRTN chromatin accessibility, andregulatory autocatalytic cleavage. Our data also provide a molecular explanation on how SPRTNdeficiency causes the premature aging and cancer predisposition disorder Ruijs-Aalfs syndrome.", "metadata": {}}
+{"_id": "34198460", "title": "", "text": "'Zero is not good for me': implications of infertility in Ghana.BACKGROUND Given the high value placedon children in sub-Saharan Africa, previous research suggests that infertility increases the risk ofpsychological distress and marital conflict, encourages risky sexual behavior and deprives infertileindividuals and couples of an important source of economic and social capital. This paper explores theimplications of infertility for women in Ghana, West Africa. METHODS Semi-structured interview datacollected from 107 women (aged 21-48 years, mean 33 years) seeking treatment in gynecological andobstetric clinics in Accra, Ghana, are analyzed. Based on iterative open coding of the interviews, the focusof the analysis is on mental health, marital instability, social interaction and gendered experiences.RESULTS Infertile women report facing severe social stigma, marital strain and a range of mental healthdifficulties. Many women feel that they shoulder a disproportionate share of the blame for infertility and,by extension, face greater social consequences than male partners for difficulties conceiving. Women whodo not self-identify as infertile corroborate these findings, asserting that the social consequences ofinfertility are severe, particularly for women. CONCLUSIONS Infertility in Ghana has importantconsequences for social interactions, marital stability and mental health. These consequences are notperceived to be shared equally by Ghanaian men.", "metadata": {}}
+{"_id": "34208005", "title": "", "text": "Ethical dilemmas in a randomized trial of asthma treatment: can Bayesian statistical analysis explain theresults?OBJECTIVES The original objective was to determine whether the use of bilevel positive airwaypressure (BiPAP) ventilation would reduce the need for endotracheal intubation, the length of hospitalstay, and hospital charges in patients with status asthmaticus. The development of physician treatmentbias made patient enrollment difficult. The article subsequently describes the use of Bayesian statistics toexplain study results when this bias occurs. METHODS This study was a prospective, randomizedcontrolled clinical trial conducted over a 34.5-month period at an urban university hospital with anemergency department census of 94,000 annual visits. Patients remaining in status asthmaticus afterinitial standard treatment with inhaled beta-agonists and steroids were randomized to receive BiPAPventilation plus standard treatment versus standard treatment alone (non-BiPAP), with intubation foreither group as needed. Patients with concurrent cardiac or other pulmonary diseases were excluded. Theprimary outcome measures were endotracheal intubation rate and length of hospital stay. Secondaryoutcome measures included vital signs (respiratory rate, pulse rate, blood pressure), changes inexpiratory peak flow, changes in pulse oximetry values, and hospital charges. Data were analyzed usingFisher's exact test, Mann-Whitney tests, and Bayesian statistics. For patients enrolled in the study morethan once, data analysis was performed on the first enrollment only. RESULTS Nineteen patients wereenrolled in the BiPAP group and 16 patients in the non-BiPAP group. Patients were frequently enrolledmore than once and the data from the subsequent enrollments were excluded from the analysis. Amarked decrease in enrollment, due to physician treatment bias, led to a premature termination of thestudy. Demographics showed that the groups were similar in age, sex, initial peak flow rate, and arterialblood gas measurements. There was a 7.3% increase (95% CI = -22 to +45) in the intubation rate in thenon-BiPAP group (n = 2) compared with that for the BiPAP group (n = 1). No significant difference wasseen in length of hospital stay or hospital charges, although there was a favorable trend toward the BiPAPgroup. Complications encountered in the BiPAP group included one patient with discomfort associatedwith the nasal BiPAP mask. Bayesian analysis demonstrated that in order for the collected data to beconvincing at the 95% confidence level, the prior conviction among treating physicians that BiPAP was asuccessful treatment modality would have had to be 98.9%. CONCLUSIONS In this study, BiPAPappeared to have no deleterious effects in patients with status asthmaticus, with a trend towarddecreased endotracheal intubation rate, decreased length of hospital stay, and decreased hospitalcharges. Although further study with more patients is needed to determine the clinical and statisticalsignificance of this intervention, ethical concerns regarding withholding BiPAP treatment from the patientsin the control group forced a premature termination of the study in the authors' institution.", "metadata": {}}
+{"_id": "34227917", "title": "", "text": "Mental health in prison populations. A review--with special emphasis on a study of Danish prisoners onremand.OBJECTIVE To review the literature on mental health and psychiatric morbidity in prisonpopulations and relate findings to a Danish study on remand prisoners. METHOD The literature isreviewed and subdivided in the following section: validity of psychometrics in prison populations,prevalence of psychiatric disorders prior to imprisonment, incidence of psychiatric disorders duringimprisonment, psychopathy related to psychiatric comorbidity, dependence syndromes with specialemphasis on different administrations of heroin use (smoke vs. injection). The results are compared witha longitudinal Danish study on remand prisoners in either solitary confinement (SC) or non-SC. RESULTSMany factors must be taken into consideration when dealing with prisoners and mental health, e.g.international differences, the prison setting, demographics and methodological issues. The prisonpopulations in general are increasing worldwide. Psychometrics may perform differently in prisonpopulations compared with general populations with the General Health Questionnaire-28 having a lowvalidity in remand prisoners. Psychiatric morbidity including schizophrenia is higher and perhapsincreasing in prison populations compared with general populations with dependence syndromes beingthe most frequent disorders. The early phase of imprisonment is a vulnerable period with a moderatelyhigh incidence of adjustment disorders and twice the incidence in SC compared with non-SC. Prevalenceof psychopathy is lower in European than North American prisons. Medium to high scores of psychopathyis related to higher psychiatric comorbidity. Opioid dependence is the most frequent drug disorder withsubjects using injection representing a more dysfunctional group than subjects using smokeadministration. Many mentally ill prisoners remain undetected and undertreated. CONCLUSION There is agrowing population of mentally ill prisoners being insufficiently detected and treated.", "metadata": {}}
+{"_id": "34228604", "title": "", "text": "Why females live longer than males: control of longevity by sex hormones.Females live longer than malesin many species, including humans. We have traced a possible explanation for this phenomenon to thebeneficial action of estrogens, which bind to estrogen receptors and increase the expression oflongevity-associated genes, including those encoding the antioxidant enzymes superoxide dismutase andglutathione peroxidase. As a result, mitochondria from females produce fewer reactive oxygen speciesthan those from males. Administering estrogens has serious drawbacks, however--they are feminizing(and thus cannot be administered to males) and may increase the incidence of serious diseases such asuterine cancer in postmenopausal women. Phytoestrogens, which are present in soy or wine, may havesome of the favorable effects of estrogens without their undesirable effects. Study of gender differencesin longevity may help us to understand the basic processes of aging and to devise practical strategies toincrease the longevity of both females and males.", "metadata": {}}
+{"_id": "34254203", "title": "", "text": "The pre-B-cell receptor: selector of fitting immunoglobulin heavy chains for the B-cell repertoireIn thisOpinion article, I address the role of the pre-B-cell receptor (pre-BCR) in the development ofantigen-specific B cells in terms of immunoglobulin heavy chain (IgH) variable-region repertoire selection,precursor B-cell differentiation and proliferation, and IgH allelic exclusion. Comparisons with the role ofthe pre-T-cell receptor (pre-TCR) in T-cell development raise provocative questions. Why do B- and T-celllineages both use a surrogate chain — the surrogate light chain and the pre-TCR α-chain, respectively —as a step to develop their repertoires of antigen-recognizing cells? What are the functions of the pre-BCRand pre-TCR in lymphocyte differentiation and antigen-receptor allelic exclusion? This article, togetherwith the accompanying article by Harald von Boehmer, hopes to answer some of these questions.", "metadata": {}}
+{"_id": "34258065", "title": "", "text": "Helicobacter species methods and protocols. Introduction.Helicobacter infection is a chronic persistentcondition which is responsible for the majority of cases of gastric and duodenal ulcers, and gastric cancer.The study of the bacteria, the interaction of the bacteria with the host, and the host immune responsehas greatly benefited from standardization of culture techniques and animal models. The followingchapters will describe the clinical aspects of infection and touch on the important techniques for optimalinvestigation of this infection.", "metadata": {}}
+{"_id": "34268160", "title": "", "text": "Effectiveness of statin-eluting stent on early inflammatory response and neointimal thickness in a porcinecoronary model.BACKGROUND Drug-eluting stent (DES) implantation is routine during coronaryrevascularization because DES significantly reduce rates of restenosis and target lesion revascularizationcompared with bare metal stent (BMS). However, available DES have limitations, such as late thrombosisbecause of delayed healing with poorer endothelialization and persistent local inflammation. Statins caninhibit cell proliferation, inflammation, and restore endothelial function. The present study evaluated theability of stent-based cerivastatin delivery to reduce stent-induced inflammatory responses and adverseeffects on endothelial function, and to inhibit neointimal hyperplasia in a porcine coronary model.METHODS AND RESULTS Pigs were randomized into groups in which the coronary arteries (9 pigs, 18coronaries in each group) had either a cerivastatin-eluting stent (CES) or a BMS. All animals survivedwithout any adverse effects. Inflammatory cell infiltration evaluated using scanning electron microscopyon day 3 after stenting was significantly decreased in the treated vessels (inflammation score:1.15+/-0.12 vs 2.43+/-0.34, p<0.0001). At day 28, endothelial function with intracoronary infusion ofbradykinin was preserved in both the CES and BMS groups. Volumetric intravascular ultrasound imagesrevealed decreased intimal volume in the CES group (28.3+/-5.4 vs 75.9+/-4.2 mm3, p<0.0001).Histomorphometric analysis showed reduced neointimal area (1.74+/-0.45 vs 3.83+/-0.51 mm2,p<0.0001) in the CES group despite similar injury scores (1.77+/-0.30 vs 1.77+/-0.22, p=0.97).CONCLUSION In porcine coronary arteries CES significantly decreased neointimal hyperplasia with adecreased early inflammatory response and without endothelial dysfunction.", "metadata": {}}
+{"_id": "34287602", "title": "", "text": "Genetic variation in West Nile virus from naturally infected mosquitoes and birds suggests quasispeciesstructure and strong purifying selection.Intrahost genetic diversity was analysed in naturally infectedmosquitoes and birds to determine whether West Nile virus (WNV) exists in nature as a quasispecies andto quantify selective pressures within and between hosts. WNV was sampled from ten infected birds andten infected mosquito pools collected on Long Island, NY, USA, during the peak of the 2003 WNVtransmission season. A 1938 nt fragment comprising the 3' 1159 nt of the WNV envelope (E) codingregion and the 5' 779 nt of the non-structural protein 1 (NS1) coding region was amplified and cloned and20 clones per specimen were sequenced. Results from this analysis demonstrate that WNV infections arederived from a genetically diverse population of genomes in nature. The mean nucleotide diversity was0.016 % within individual specimens and the mean percentage of clones that differed from the consensussequence was 19.5 %. WNV sequences in mosquitoes were significantly more genetically diverse thanWNV in birds. No host-dependent bias for particular types of mutations was observed and estimates ofgenetic diversity did not differ significantly between E and NS1 coding sequences. Non-consensus clonesobtained from two avian specimens had highly similar genetic signatures, providing preliminary evidencethat WNV genetic diversity may be maintained throughout the enzootic transmission cycle, rather thanarising independently during each infection. Evidence of purifying selection was obtained from both intra-and interhost WNV populations. Combined, these data support the observation that WNV populations maybe structured as a quasispecies and document strong purifying natural selection in WNV populations.", "metadata": {}}
+{"_id": "34316341", "title": "", "text": "Overlapping patterns of IGF2 and H19 expression during human development: biallelic IGF2 expressioncorrelates with a lack of H19 expression.The spatial patterns of IGF2 and H19 gene expression arestrikingly similar during parts of human embryonic/fetal and early postnatal development. Notableexceptions were found with the ciliary anlage of the embryonic retina and the choroidplexus/leptomeninges, where transcripts from the IGF2 but not the H19 locus could be detected.Moreover, in contrast to the other tissue samples examined, the choroid plexus/leptomeninges expressedboth parental IGF2 alleles. Whilst RNase protection analysis revealed a weak activity of the P1 promoterin the choroid plexus/leptomeninges, the P2, P3 and P4 promoters were all active wherever IGF2 wasexpressed. We discuss these observations with respect to a hypothesized coordinated control of thereciprocally imprinted and closely linked IGF2 and H19 loci.", "metadata": {}}
+{"_id": "34328964", "title": "", "text": "Intimal smooth muscle cell proliferation after balloon catheter injury. The role of basic fibroblast growthfactor.The localization and synthesis of basic fibroblast growth factor (bFGF) in the rat carotid artery wereinvestigated at times of chronic smooth muscle cell proliferation. Immunocytochemical staining showedthe presence of bFGF in the uninjured arterial wall, and after balloon injury, this cellular staining wasdecreased. Western and northern blot analyses likewise showed that the amount of bFGF protein andmRNA decreased after injury. A neutralizing antibody to bFGF was administered 4 and 5 days after injuryand was found to have no effect on intimal smooth muscle cell proliferation. These data suggest that anincrease in the expression of bFGF is not necessary for chronic smooth muscle cell proliferation observedafter balloon catheter injury and that bFGF is not the major mitogen responsible for intimal smoothmuscle cell proliferation.", "metadata": {}}
+{"_id": "34338075", "title": "", "text": "Prevention of central venous catheter-associated thrombosis: a meta-analysis.PURPOSE Anticoagulantprophylaxis in patients with central venous catheters is controversial. We performed a meta-analysis ofrandomized controlled trials of anticoagulant prophylaxis in patients with central venous catheters.METHODS MEDLINE and EMBASE were searched up to May 2006, supplemented by manual searches ofconference proceedings and bibliographies. RESULTS Fifteen trials were included. Unfractionated heparininfusion, oral fixed low-dose vitamin K antagonist, and subcutaneous low-molecular-weight heparin wereevaluated. For all catheter-associated deep vein thrombosis (symptomatic and asymptomatic combined),the summary relative risks ranged from 0.31 to 0.73 (all achieved statistical significance). Forsymptomatic deep vein thrombosis, the summary relative risks ranged from 0.28 to 0.72, but did notachieve statistical significance for any individual regimen. CONCLUSION Anticoagulant prophylaxis iseffective for preventing all catheter-associated deep vein thrombosis in patients with central venouscatheters. The effectiveness for preventing symptomatic venous thromboembolism, including pulmonaryembolism, remains uncertain.", "metadata": {}}
+{"_id": "34369306", "title": "", "text": "Long-term efficacy of nicotine replacement therapy for smoking cessation in adolescents: a randomizedcontrolled trial.BACKGROUND A double-blind RCT on the short-term efficacy of nicotine patchescompared to placebo patches among Dutch adolescents was conducted. The findings demonstrated thatnicotine patches are efficacious for smoking cessation at end-of-treatment; however, only in highlycompliant participants. We tested whether the effects of NRT also held in 6- (T7) and 12-month (T8)follow-up assessments. METHODS Adolescents aged 12-18 years, who smoked at least seven cigarettes aday and who were motivated to quit smoking were recruited at school yards and randomly assigned toeither a nicotine patch (n=182) or a placebo patch (n=180) condition according to a computer generatedlist. Participants (N=257, age: 16.7 ± 1.13 years) attended an information meeting followed by a 6- or9-week treatment. Smoking cessation, compliance, and potential covariates were measured by means ofonline questionnaires. Smoking cessation at T8 was biochemically validated by saliva cotinine. RESULTSAt T7, 8.1% and 5.7% of participants were abstinent in the nicotine and placebo patch groups,respectively. At T8, abstinence was 4.4% and 6.6%, respectively. Intention-to-treat analyses showed nosignificant effects of NRT on abstinence rates at T7 (OR=1.54, 95% CI=0.57, 4.16) and validatedabstinence rates at T8 (OR=0.64, 95% CI=0.21, 1.93) neither after considering compliance nor afteradjusting for covariates. CONCLUSIONS NRT fails in helping adolescents quit smoking at 6- and 12-monthfollow-ups. This finding suggests that a more intensive approach is needed to assist youngsters in theirquit attempts.", "metadata": {}}
+{"_id": "34378726", "title": "", "text": "Interferon gamma in autoimmunity: A complicated player on a complex stage.Early views of autoimmunedisease cast IFNγ as a prototypic pro-inflammatory factor. It is now clear that IFNγ is capable of bothpro- and anti-inflammatory activities with the functional outcome dependent on the physiological andpathological setting examined. Here, the major immune modulatory activities of IFNγ are reviewed andcurrent evidence for the impact of IFNγ on pathology and regulation of several autoimmune diseases anddisease models is summarized.", "metadata": {}}
+{"_id": "34386619", "title": "", "text": "The first gene of the Bacillus subtilis clpC operon, ctsR, encodes a negative regulator of its own operonand other class III heat shock genes.The Bacillus subtilis clpC operon is regulated by two stress inductionpathways relying on either sigmaB or a class III stress induction mechanism acting at a sigmaA-likepromoter. When the clpC operon was placed under the control of theisopropyl-beta-D-thiogalactopyranoside (IPTG)-inducible Pspac promoter, dramatic repression of thenatural clpC promoters fused to a lacZ reporter gene was noticed after IPTG induction. This resultstrongly indicated negative regulation of the clpC operon by one of its gene products. Indeed, thenegative regulator could be identified which is encoded by the first gene of the clpC operon, ctsR,containing a predicted helix-turn-helix DNA-binding motif. Deletion of ctsR abolished the negativeregulation and resulted in high expression of both the clpC operon and the clpP gene under nonstressedconditions. Nevertheless, a further increase in clpC and clpP mRNA levels was observed after heat shock,even in the absence of sigmaB, suggesting a second induction mechanism at the vegetative promoter.Two-dimensional gel analysis and mRNA studies showed that the expression of other class III stressgenes was at least partially influenced by the ctsR deletion. Studies with different clpC promoterfragments either fused to the reporter gene bgaB or used in gel mobility shift experiments with thepurified CtsR protein revealed a possible target region where the repressor seemed to bind in vivo and invitro. Our data demonstrate that the CtsR protein acts as a global repressor of the clpC operon, as well asother class III heat shock genes, by preventing unstressed transcription from either the sigmaB- orsigmaA-dependent promoter and might be inactivated or dissociate under inducing stress conditions.", "metadata": {}}
+{"_id": "34436231", "title": "", "text": "Role for c-myc in activation-induced apoptotic cell death in T cell hybridomas.Immature T cells and someT cell hybridomas undergo apoptotic cell death when activated through the T cell receptor complex, aphenomenon that is probably related to antigen induced negative selection of developing T cells. Thisactivation-induced apoptosis depends on active protein and RNA synthesis in the dying cells, althoughnone of the genes required for this process have previously been identified. Antisense oligonucleotidescorresponding to c-myc block the constitutive expression of c-Myc protein in T cell hybridomas andinterfere with all aspects of activation-induced apoptosis without affecting lymphokine production in thesecells. These data indicate that c-myc expression is a necessary component of activation-inducedapoptosis.", "metadata": {}}
+{"_id": "34439544", "title": "", "text": "Examining BCL-2 family function with large unilamellar vesicles.The BCL-2 (B cell CLL/Lymphoma) familyis comprised of approximately twenty proteins that collaborate to either maintain cell survival or initiateapoptosis(1). Following cellular stress (e.g., DNA damage), the pro-apoptotic BCL-2 family effectors BAK(BCL-2 antagonistic killer 1) and/or BAX (BCL-2 associated X protein) become activated and compromisethe integrity of the outer mitochondrial membrane (OMM), though the process referred to asmitochondrial outer membrane permeabilization (MOMP)(1). After MOMP occurs, pro-apoptotic proteins(e.g., cytochrome c) gain access to the cytoplasm, promote caspase activation, and apoptosis rapidlyensues(2). In order for BAK/BAX to induce MOMP, they require transient interactions with members ofanother pro-apoptotic subset of the BCL-2 family, the BCL-2 homology domain 3 (BH3)-only proteins,such as BID (BH3-interacting domain agonist)(3-6). Anti-apoptotic BCL-2 family proteins (e.g., BCL-2related gene, long isoform, BCL-xL; myeloid cell leukemia 1, MCL-1) regulate cellular survival by tightlycontrolling the interactions between BAK/BAX and the BH3-only proteins capable of directly inducingBAK/BAX activation(7,8). In addition, anti-apoptotic BCL-2 protein availability is also dictated bysensitizer/de-repressor BH3-only proteins, such as BAD (BCL-2 antagonist of cell death) or PUMA (p53upregulated modulator of apoptosis), which bind and inhibit anti-apoptotic members(7,9). As most of theanti-apoptotic BCL-2 repertoire is localized to the OMM, the cellular decision to maintain survival orinduce MOMP is dictated by multiple BCL-2 family interactions at this membrane. Large unilamellarvesicles (LUVs) are a biochemical model to explore relationships between BCL-2 family interactions andmembrane permeabilization(10). LUVs are comprised of defined lipids that are assembled in ratiosidentified in lipid composition studies from solvent extracted Xenopus mitochondria (46.5%phosphatidylcholine, 28.5% phosphatidylethanoloamine, 9% phosphatidylinositol, 9%phosphatidylserine, and 7% cardiolipin)(10). This is a convenient model system to directly explore BCL-2family function because the protein and lipid components are completely defined and tractable, which isnot always the case with primary mitochondria. While cardiolipin is not usually this high throughout theOMM, this model does faithfully mimic the OMM to promote BCL-2 family function. Furthermore, a morerecent modification of the above protocol allows for kinetic analyses of protein interactions and real-timemeasurements of membrane permeabilization, which is based on LUVs containing a polyanionic dye(ANTS: 8-aminonaphthalene-1,3,6-trisulfonic acid) and cationic quencher (DPX: p-xylene-bis-pyridiniumbromide)(11). As the LUVs permeabilize, ANTS and DPX diffuse apart, and a gain in fluorescence isdetected. Here, commonly used recombinant BCL-2 family protein combinations and controls using theLUVs containing ANTS/DPX are described.", "metadata": {}}
+{"_id": "34445160", "title": "", "text": "The Hippo pathway effector YAP controls mouse hepatic stellate cell activation.BACKGROUND & AIMSHepatic stellate cell activation is a wound-healing response to liver injury. However, continued activationof stellate cells during chronic liver damage causes excessive matrix deposition and the formation ofpathological scar tissue leading to fibrosis and ultimately cirrhosis. The importance of sustained stellatecell activation for this pathological process is well recognized, and several signalling pathways that canpromote stellate cell activation have been identified, such as the TGFβ-, PDGF-, and LPS-dependentpathways. However, the mechanisms that trigger and drive the early steps in activation are not wellunderstood. METHODS AND RESULTS We identified the Hippo pathway and its effector YAP as a keypathway that controls stellate cell activation. YAP is a transcriptional co-activator and we found that itdrives the earliest changes in gene expression during stellate cell activation. Activation of stellate cells invivo by CCl4 administration to mice or activation in vitro caused rapid activation of YAP as revealed by itsnuclear translocation and by the induction of YAP target genes. YAP was also activated in stellate cells ofhuman fibrotic livers as evidenced by its nuclear localization. Importantly, knockdown of YAP expressionor pharmacological inhibition of YAP prevented hepatic stellate cell activation in vitro and pharmacologicalinhibition of YAP impeded fibrogenesis in mice. CONCLUSIONS YAP activation is a critical driver of hepaticstellate cell activation and inhibition of YAP presents a novel approach for the treatment of liver fibrosis.", "metadata": {}}
+{"_id": "34469966", "title": "", "text": "Human Monocytes Engage an Alternative Inflammasome Pathway.Interleukin-1β (IL-1β) is a cytokinewhose bioactivity is controlled by activation of the inflammasome. However, in response tolipopolysaccharide, human monocytes secrete IL-1β independently of classical inflammasome stimuli.Here, we report that this constituted a species-specific response that is not observed in the murinesystem. Indeed, in human monocytes, lipopolysaccharide triggered an \"alternative inflammasome\" thatrelied on NLRP3-ASC-caspase-1 signaling, yet was devoid of any classical inflammasome characteristicsincluding pyroptosome formation, pyroptosis induction, and K(+) efflux dependency. Genetic dissection ofthe underlying signaling pathway in a monocyte transdifferentiation system revealed that alternativeinflammasome activation was propagated by TLR4-TRIF-RIPK1-FADD-CASP8 signaling upstream ofNLRP3. Importantly, involvement of this signaling cascade was limited to alternative inflammasomeactivation and did not extend to classical NLRP3 activation. Because alternative inflammasome activationembraces both sensitivity and promiscuity of TLR4, we propose a pivotal role for this signaling cascade inTLR4-driven, IL-1β-mediated immune responses and immunopathology in humans.", "metadata": {}}
+{"_id": "34481589", "title": "", "text": "The use of biosimilars in immune-mediated disease: A joint Italian Society of Rheumatology (SIR), ItalianSociety of Dermatology (SIDeMaST), and Italian Group of Inflammatory Bowel Disease (IG-IBD) positionpaper.Biological agents are widely used in rheumatology, dermatology and inflammatory bowel disease.Evidence about their efficacy and safety has been strengthened for all those therapeutic indications overthe last decade. Biosimilar agents are monoclonal antibodies similar to previously approved biologics. Inthe European Union, they have been approved for all the indications in the management ofimmune-mediated inflammatory diseases (IMIDs), although data only in rheumatoid arthritis andankylosing spondylitis are currently available. Direct evidence on efficacy, safety, and immunogenicity ofbiosimilars is mandatory in psoriasis, psoriatic arthritis, and inflammatory bowel disease, as well as inchildren. Based on the current evidence in the literature, we present the joint official position of theItalian Societies of Rheumatology, Dermatology and Inflammatory Bowel Disease on the use ofbiosimilars in IMIDs.", "metadata": {}}
+{"_id": "34498093", "title": "", "text": "The coordination of cyclic microtubule association/dissociation and tail swing of cytoplasmic dynein.Thedynein motor domain is composed of a tail, head, and stalk and is thought to generate a force tomicrotubules by swinging the tail against the head during its ATPase cycle. For this \"power stroke,\"dynein has to coordinate the tail swing with microtubule association/dissociation at the tip of the stalk.Although a detailed picture of the former process is emerging, the latter process remains to beelucidated. By using the single-headed recombinant motor domain of Dictyostelium cytoplasmic dynein,we address the questions of how the interaction of the motor domain with a microtubule is modulated byATPase steps, how the two mechanical cycles (the microtubule association/dissociation and tail swing)are coordinated, and which ATPase site among the multiple sites in the motor domain regulates thecoordination. Based on steady-state and pre-steady-state measurements, we demonstrate that the twomechanical cycles proceed synchronously at most of the intermediate states in the ATPase cycle: themotor domain in the poststroke state binds strongly to the microtubule with a K(d) of approximately 0.2microM, whereas most of the motor domains in the prestroke state bind weakly to the microtubule with aK(d) of >10 microM. However, our results suggest that the timings of the microtubule affinity change andtail swing are staggered at the recovery stroke step in which the tail swings from the poststroke to theprestroke position. The ATPase site in the AAA1 module of the motor domain was found to be responsiblefor the coordination of these two mechanical processes.", "metadata": {}}
+{"_id": "34498325", "title": "", "text": "A conserved modified wobble nucleoside (mcm5s2U) in lysyl-tRNA is required for viability inyeast.Transfer RNAs specific for Gln, Lys, and Glu from all organisms (except Mycoplasma) and organelleshave a 2-thiouridine derivative (xm(5)s(2)U) as wobble nucleoside. These tRNAs read the A- andG-ending codons in the split codon boxes His/Gln, Asn/Lys, and Asp/Glu. In eukaryotic cytoplasmic tRNAsthe conserved constituent (xm(5)-) in position 5 of uridine is 5-methoxycarbonylmethyl (mcm(5)). Aprotein (Tuc1p) from yeast resembling the bacterial protein TtcA, which is required for the synthesis of2-thiocytidine in position 32 of the tRNA, was shown instead to be required for the synthesis of2-thiouridine in the wobble position (position 34). Apparently, an ancient member of the TtcA family hasevolved to thiolate U34 in tRNAs of organisms from the domains Eukarya and Archaea. Deletion of theTUC1 gene together with a deletion of the ELP3 gene, which results in the lack of the mcm(5) side chain,removes all modifications from the wobble uridine derivatives of the cytoplasmic tRNAs specific for Gln,Lys, and Glu, and is lethal to the cell. Since excess of the unmodified form of these three tRNAs rescuedthe double mutant elp3 tuc1, the primary function of mcm(5)s(2)U34 seems to be to improve theefficiency to read the cognate codons rather than to prevent mis-sense errors. Surprisingly,overexpression of the mcm(5)s(2)U-lacking tRNA(Lys) alone was sufficient to restore viability of thedouble mutant.", "metadata": {}}
+{"_id": "34537906", "title": "", "text": "The molecular requirements for cytokinesis.After anaphase onset, animal cells build an actomyosincontractile ring that constricts the plasma membrane to generate two daughter cells connected by acytoplasmic bridge. The bridge is ultimately severed to complete cytokinesis. Myriad techniques havebeen used to identify proteins that participate in cytokinesis in vertebrates, insects, and nematodes. Aconserved core of about 20 proteins are individually involved with cytokinesis in most animal cells. Thesecomponents are found in the contractile ring, on the central spindle, within the RhoA pathway, and onvesicles that expand the membrane and sever the bridge. Cytokinesis involves additional proteins, butthey, or their requirement in cytokinesis, are not conserved among animal cells.", "metadata": {}}
+{"_id": "34544514", "title": "", "text": "Ibuprofen for the treatment of patent ductus arteriosus in preterm or low birth weight (or both)infants.BACKGROUND Indomethacin is used as standard therapy to close a patent ductus arteriosus(PDA) but is associated with reduced blood flow to several organs. Ibuprofen, another cyclo-oxygenaseinhibitor, may be as effective as indomethacin with fewer adverse effects. OBJECTIVES To determine theeffectiveness and safety of ibuprofen compared with indomethacin, other cyclo-oxygenase inhibitor,placebo or no intervention for closing a patent ductus arteriosus in preterm, low birth weight, or pretermand low birth weight infants. SEARCH METHODS We searched The Cochrane Library, MEDLINE, EMBASE,Clincialtrials.gov, Controlled-trials.com, and www.abstracts2view.com/pas in May 2014. SELECTIONCRITERIA Randomised or quasi-randomised controlled trials of ibuprofen for the treatment of a PDA innewborn infants. DATA COLLECTION AND ANALYSIS Data collection and analysis conformed to themethods of the Cochrane Neonatal Review Group. MAIN RESULTS We included 33 studies enrolling 2190infants. Two studies compared intravenous (iv) ibuprofen versus placebo (270 infants). In one study (134infants) ibuprofen reduced the incidence of failure to close a PDA (risk ratio (RR) 0.71, 95% confidenceinterval (CI) 0.51 to 0.99; risk difference (RD) -0.18, 95% CI -0.35 to -0.01; number needed to treat foran additional beneficial outcome (NNTB) 6, 95% CI 3 to 100). In one study (136 infants), ibuprofenreduced the composite outcome of infant mortality, infants who dropped out, or infants who requiredrescue treatment (RR 0.58, 95% CI 0.38 to 0.89; RD -0.22, 95% CI -0.38 to -0.06; NNTB 5, 95% CI 3 to17). One study (64 infants) compared oral ibuprofen with placebo and noted a significant reduction infailure to close a PDA (RR 0.26, 95% CI 0.11 to 0.62; RD -0.44, 95% CI -0.65 to -0.23; NNTB 2, 95% CI2 to 4).Twenty-one studies (1102 infants) reported failure rates for PDA closure with ibuprofen (oral oriv) compared with indomethacin (oral or iv). There was no significant difference between the groups(typical RR 1.00, 95% CI 0.84 to 1.20; I(2) = 0%; typical RD 0.00, 95% CI -0.05 to 0.05; I(2) = 0%).The risk of developing necrotising enterocolitis (NEC) was reduced for ibuprofen (16 studies, 948 infants;typical RR 0.64, 95% CI 0.45 to 0.93; typical RD -0.05, 95% CI -0.08 to -0.01; NNTB 20, 95% CI 13 to100; I(2) = 0% for both RR and RD). The duration of ventilatory support was reduced with ibuprofen(oral or iv) compared with iv or oral indomethacin (six studies, 471 infants; mean difference (MD) -2.4days, 95% CI -3.7 to -1.0; I(2) = 19%).Eight studies (272 infants) reported on failure rates for PDAclosure in a subgroup of the above studies comparing oral ibuprofen with indomethacin (oral or iv). Therewas no significant difference between the groups (typical RR 0.96, 95% CI 0.73 to 1.27; typical RD -0.01,95% CI -0.12 to 0.09). The risk of NEC was reduced with oral ibuprofen compared with indomethacin(oral or iv) (seven studies, 249 infants; typical RR 0.41, 95% CI 0.23 to 0.73; typical RD -0.13, 95% CI-0.22 to -0.05; NNTB 8, 95% CI 5 to 20; I(2) = 0% for both RR and RD). There was a decreased risk offailure to close a PDA with oral ibuprofen compared with iv ibuprofen (four studies, 304 infants; typicalRR 0.41, 95% CI 0.27 to 0.64; typical RD -0.21, 95% CI -0.31 to -0.12; NNTB 5, 95% CI 3 to 8).Transient renal insufficiency was less common in infants who received ibuprofen compared withindomethacin. High dose versus standard dose of iv ibuprofen, early versus expectant administration of ivibuprofen, echocardiographically guided iv ibuprofen treatment vs. standard iv ibuprofen treatment andcontinuous infusion of ibuprofen vs. intermittent boluses of ibuprofen and long-term follow-up werestudied in too few trials to draw any conclusions. AUTHORS' CONCLUSIONS Ibuprofen is as effective asindomethacin in closing a PDA and currently appears to be the drug of choice. Ibuprofen reduces the riskof NEC and transient renal insufficiency. Oro-gastric administration of ibuprofen appears as effective as ivadministration. To make further recommendations, studies are needed to assess the effectiveness ofhigh-dose versus standard-dose ibuprofen, early versus expectant administration of ibuprofen,echocardiographically guided versus standard iv ibuprofen, and continuous infusion versus intermittentboluses of ibuprofen. Studies are lacking evaluating the effect of ibuprofen on longer-term outcomes ininfants with PDA.", "metadata": {}}
+{"_id": "34559336", "title": "", "text": "A gradient of template dependence defines distinct biological roles for family X polymerases innonhomologous end joining.Three Pol X family members have been linked to nonhomologous end joining(NHEJ) in mammals. Template-independent TdT promotes diversity during NHEJ-dependent repair ofV(D)J recombination intermediates, but the roles of the template-dependent polymerases mu and lambdain NHEJ remain unclear. We show here that pol mu and pol lambda are similarly recruited by NHEJ factorsto fill gaps when ends have partially complementary overhangs, suggesting equivalent roles promotingaccuracy in NHEJ. However, only pol mu promotes accuracy during immunoglobulin kappa recombination.This distinctive in vivo role correlates with the TdT-like ability of pol mu, but not pol lambda, to act whenprimer termini lack complementary bases in the template strand. However, unlike TdT, synthesis by polmu in this context is primarily instructed by a template from another DNA molecule. This apparentgradient of template dependence is largely attributable to a small structural element that is present butdifferent in all three polymerases.", "metadata": {}}
+{"_id": "34582256", "title": "", "text": "Involvement of sympathetic nervous system and brown fat in endotoxin-induced fever in rats.The objectof this study was to assess the role of brown adipose tissue (BAT) and the sympathetic nervous system inthe rise in heat production associated with endotoxin-induced fever. Oxygen consumption (VO2) wasfound to be significantly increased (28%) over a 4-h period after two doses of endotoxin (Escherichia colilipopolysaccharide, 0.3 mg/100 g body wt) given 24 h apart. Injection of a mixed beta-adrenoceptorantagonist (propranolol) reduced VO2 by 14% in endotoxin-treated rats, whereas the selective beta 1-(atenolol) or beta 2- (ICI 118551) antagonists suppressed VO2 by 10%. These drugs did not affect VO2in control animals. BAT thermogenic activity assessed from measurements of in vitro mitochondrialguanosine 5'-diphosphate (GDP) binding was elevated by 54% in interscapular BAT and by 171% in otherBAT depots. Surgical denervation of one lobe of the interscapular depot prevented these responses.Endotoxin failed to stimulate GDP binding in rats fed protein-deficient diets. This may have been becauseBAT thermogenic activity was already elevated in control rats fed these diets or because endotoxincaused a marked suppression of food intake in the protein-deficient animals. The results indicate thatsympathetic activation of BAT is involved in the thermogenic responses to endotoxin and that these canbe modified by dietary manipulation.", "metadata": {}}
+{"_id": "34603465", "title": "", "text": "Metabolic, Epigenetic, and Transgenerational Effects of Gut Bacterial Choline Consumption.Choline is anessential nutrient and methyl donor required for epigenetic regulation. Here, we assessed the impact ofgut microbial choline metabolism on bacterial fitness and host biology by engineering a microbialcommunity that lacks a single choline-utilizing enzyme. Our results indicate that choline-utilizing bacteriacompete with the host for this nutrient, significantly impacting plasma and hepatic levels of methyl-donormetabolites and recapitulating biochemical signatures of choline deficiency. Mice harboring high levels ofcholine-consuming bacteria showed increased susceptibility to metabolic disease in the context of ahigh-fat diet. Furthermore, bacterially induced reduction of methyl-donor availability influenced globalDNA methylation patterns in both adult mice and their offspring and engendered behavioral alterations.Our results reveal an underappreciated effect of bacterial choline metabolism on host metabolism,epigenetics, and behavior. This work suggests that interpersonal differences in microbial metabolismshould be considered when determining optimal nutrient intake requirements.", "metadata": {}}
+{"_id": "34604584", "title": "", "text": "Genome-wide analysis reveals SR protein cooperation and competition in regulated splicing.SR proteinsare well-characterized RNA binding proteins that promote exon inclusion by binding to exonic splicingenhancers (ESEs). However, it has been unclear whether regulatory rules deduced on model genes applygenerally to activities of SR proteins in the cell. Here, we report global analyses of two prototypical SRproteins, SRSF1 (SF2/ASF) and SRSF2 (SC35), using splicing-sensitive arrays and CLIP-seq on mouseembryo fibroblasts (MEFs). Unexpectedly, we find that these SR proteins promote both inclusion andskipping of exons in vivo, but their binding patterns do not explain such opposite responses. Furtheranalyses reveal that loss of one SR protein is accompanied by coordinated loss or compensatory gain inthe interaction of other SR proteins at the affected exons. Therefore, specific effects on regulated splicingby one SR protein actually depend on a complex set of relationships with multiple other SR proteins inmammalian genomes.", "metadata": {}}
+{"_id": "34615397", "title": "", "text": "Human tuberculous granulomas induce peripheral lymphoid follicle-like structures to orchestrate localhost defence in the lung.The human tuberculous granuloma provides the morphological basis for localimmune processes central to the outcome of tuberculosis. Because of the scarcity of information inhuman patients, the aim of the present study was to gain insights into the functional and structuralproperties of infiltrated tissue. To this end, the mycobacterial load in lesions and dissemination todifferent tissue locations were investigated, as well as distribution, biological functions, and interactionsof host immune cells. Analysis of early granuloma formation in formerly healthy lung tissue revealed aspatio-temporal sequence of cellular infiltration to sites of mycobacterial infection. A general structure ofthe developing granuloma was identified, comprising an inner cell layer with few CD8(+) cellssurrounding the necrotic centre and an outer area of lymphocyte infiltration harbouringmycobacteria-containing antigen-presenting cells as well as CD4(+), CD8(+), and B cells in activefollicle-like centres resembling secondary lymphoid organs. It is concluded that the follicular structures inthe peripheral rim of granulomas serve as a morphological substrate for the orchestration of the enduringhost response in pulmonary tuberculosis.", "metadata": {}}
+{"_id": "34630025", "title": "", "text": "Eosinophil pathogenicity mechanisms and therapeutics in neuromyelitis optica.Eosinophils are abundantin inflammatory demyelinating lesions in neuromyelitis optica (NMO). We used cell culture, ex vivo spinalcord slices, and in vivo mouse models of NMO to investigate the role of eosinophils in NMO pathogenesisand the therapeutic potential of eosinophil inhibitors. Eosinophils cultured from mouse bone marrowproduced antibody-dependent cell-mediated cytotoxicity (ADCC) in cell cultures expressing aquaporin-4in the presence of NMO autoantibody (NMO-IgG). In the presence of complement, eosinophils greatlyincreased cell killing by a complement-dependent cell-mediated cytotoxicity (CDCC) mechanism. NMOpathology was produced in NMO-IgG-treated spinal cord slice cultures by inclusion of eosinophils or theirgranule toxins. The second-generation antihistamines cetirizine and ketotifen, which haveeosinophil-stabilizing actions, greatly reduced NMO-IgG/eosinophil-dependent cytotoxicity and NMOpathology. In live mice, demyelinating NMO lesions produced by continuous intracerebral injection ofNMO-IgG and complement showed marked eosinophil infiltration. Lesion severity was increased intransgenic hypereosinophilic mice. Lesion severity was reduced in mice made hypoeosinophilic byanti-IL-5 antibody or by gene deletion, and in normal mice receiving cetirizine orally. Our resultsimplicate the involvement of eosinophils in NMO pathogenesis by ADCC and CDCC mechanisms andsuggest the therapeutic utility of approved eosinophil-stabilizing drugs.", "metadata": {}}
+{"_id": "34733465", "title": "", "text": "Association of cystic fibrosis with abnormalities in fatty acid metabolism.BACKGROUND Patients withcystic fibrosis have altered levels of plasma fatty acids. We previously demonstrated that arachidonic acidlevels are increased and docosahexaenoic acid levels are decreased in affected tissues from cysticfibrosis-knockout mice. In this study we determined whether humans with mutations in the cystic fibrosistransmembrane conductance regulator (CFTR) gene have a similar fatty acid defect in tissues expressingCFTR. METHODS Fatty acids from nasal- and rectal-biopsy specimens, nasal epithelial scrapings, andplasma were analyzed from 38 subjects with cystic fibrosis and compared with results in 13 obligateheterozygotes, 24 healthy controls, 11 subjects with inflammatory bowel disease, 9 subjects with upperrespiratory tract infection, and 16 subjects with asthma. RESULTS The ratio of arachidonic todocosahexaenoic acid was increased in mucosal and submucosal nasal-biopsy specimens (P<0.001) andrectal-biopsy specimens (P=0.009) from subjects with cystic fibrosis and pancreatic sufficiency andsubjects with cystic fibrosis and pancreatic insufficiency, as compared with values in healthy controlsubjects. In nasal tissue, this change reflected an increase in arachidonic acid levels and a decrease indocosahexaenoic acid levels. In cells from nasal mucosa, the ratio of arachidonic to docosahexaenoic acidwas increased in subjects with cystic fibrosis (P<0.001), as compared with healthy controls, with valuesin obligate heterozygotes intermediate between these two groups (P<0.001). The ratio was not increasedin subjects with inflammatory bowel disease. Subjects with asthma and those with upper respiratory tractinfection had values intermediate between those in subjects with cystic fibrosis and those in healthycontrol subjects. CONCLUSIONS These data indicate that alterations in fatty acids similar to those incystic fibrosis-knockout mice are present in CFTR-expressing tissue from subjects with cystic fibrosis.", "metadata": {}}
+{"_id": "34735369", "title": "", "text": "Actin dynamics and cell-cell adhesion in epithelia.Recent advances in the field of intercellular adhesionhighlight the importance of adherens junction association with the underlying actin cytoskeleton. In skinepithelial cells a dynamic feature of adherens junction formation involves filopodia, which physicallyproject into the membrane of adjacent cells, catalyzing the clustering of adherens junction proteincomplexes at their tips. In turn, actin polymerization is stimulated at the cytoplasmic interface of thesecomplexes. Although the mechanism remains unclear, the VASP/Mena family of proteins seems to beinvolved in organizing actin polymerization at these sites. In vivo, adherens junction formation appears torely upon filopodia in processes where epithelial sheets must be physically moved closer to form stableintercellular connections, for example, in ventral closure in embryonic development or wound healing inthe postnatal animal.", "metadata": {}}
+{"_id": "34747208", "title": "", "text": "Lamin A-dependent nuclear defects in human aging.Mutations in the nuclear structural protein lamin Acause the premature aging syndrome Hutchinson-Gilford progeria (HGPS). Whether lamin A plays anyrole in normal aging is unknown. We show that the same molecular mechanism responsible for HGPS isactive in healthy cells. Cell nuclei from old individuals acquire defects similar to those of HGPS patientcells, including changes in histone modifications and increased DNA damage. Age-related nuclear defectsare caused by sporadic use, in healthy individuals, of the same cryptic splice site in lamin A whoseconstitutive activation causes HGPS. Inhibition of this splice site reverses the nuclear defects associatedwith aging. These observations implicate lamin A in physiological aging.", "metadata": {}}
+{"_id": "34753204", "title": "", "text": "Zmpste24 deficiency in mice causes spontaneous bone fractures, muscle weakness, and a prelamin Aprocessing defect.Zmpste24 is an integral membrane metalloproteinase of the endoplasmic reticulum.Biochemical studies of tissues from Zmpste24-deficient mice (Zmpste24(-/-)) have indicated a role forZmpste24 in the processing of CAAX-type prenylated proteins. Here, we report the pathologicconsequences of Zmpste24 deficiency in mice. Zmpste24(-/-) mice gain weight slowly, appearmalnourished, and exhibit progressive hair loss. The most striking pathologic phenotype is multiplespontaneous bone fractures-akin to those occurring in mouse models of osteogenesis imperfecta. Corticaland trabecular bone volumes are significantly reduced in Zmpste24(-/-) mice. Zmpste24(-/-) mice alsomanifested muscle weakness in the lower and upper extremities, resembling mice lacking thefarnesylated CAAX protein prelamin A. Prelamin A processing was defective both in fibroblasts lackingZmpste24 and in fibroblasts lacking the CAAX carboxyl methyltransferase Icmt but was normal infibroblasts lacking the CAAX endoprotease Rce1. Muscle weakness in Zmpste24(-/-) mice can bereasonably ascribed to defective processing of prelamin A, but the brittle bone phenotype suggests abroader role for Zmpste24 in mammalian biology.", "metadata": {}}
+{"_id": "34760396", "title": "", "text": "Human and other faeces as breeding media of the trachoma vector Musca sorbens.The fly Musca sorbensWiedemann (Diptera: Muscidae) apparently transmits Chlamydia trachomatis, causing human trachoma.The literature indicates that M. sorbens breeds predominantly in isolated human faeces on the soilsurface, but not in covered pit latrines. We sought to identify breeding media of M. sorbens in a ruralGambian village endemic for trachoma. Test breeding media were presented for oviposition on soil-filledbuckets and monitored for adult emergence. Musca sorbens emerged from human (6/9 trials), calf (3/9),cow (3/9), dog (2/9) and goat (1/9) faeces, but not from horse faeces, composting kitchen scraps or asoil control (0/9 of each). After adjusting for mass of medium, the greatest number of flies emerged fromhuman faeces (1426 flies/kg). Median time for emergence was 9 (inter quartile range = 8-9.75) dayspost-oviposition. Of all flies emerging from faeces 81% were M. sorbens. Male and female flies emergingfrom human faeces were significantly larger than those from other media, suggesting that they would bemore fecund and live longer than smaller flies from other sources. Female flies caught from children'seyes were of a similar size to those from human faeces, but significantly larger than those from othermedia. We consider that human faeces are the best larval medium for M. sorbens, although somebreeding also occurs in animal faeces. Removal of human faeces from the environment, through theprovision of basic sanitation, is likely to greatly reduce fly density, eye contact and hence trachomatransmission, but if faeces of other animals are present M. sorbens will persist.", "metadata": {}}
+{"_id": "34818263", "title": "", "text": "Current Health and Environmental Status of the Maasai People in Sub-Saharan AfricaAs time passes, theAIDS pandemic continues to spike, affecting an estimated 38.6 million people worldwide. In response, asatellite health clinic is being d esigned by two Cal Poly students to serve the Maasai people living in theKajiado district in Southern Kenya. The Maasai have traditionally lived as pastoralists, surviving off oftheir cattle with which they share their water, increasing the risk for contamination. However, as thepopulation of Kenya increases, the land the Maasai have traditionally used for grazing is shrink ing. Forthis reason, some have turned to farming to maintain their liveli hood. These factors have contributed tothe desertification and deforestation of their region. As the lifestyle of the Maasai evolves, they rely moreon maize than meat and dairy products for their nutrients. All of these changes have contributed to theevolution of the Maasai culture. We will address these changes in order to better understand the Maasai,as well as highlight pos sible further aid needed to support their survival.", "metadata": {}}
+{"_id": "34846352", "title": "", "text": "Identification and characterization of a widely expressed form of adenylyl cyclase.A novel mammalianadenylyl cyclase was identified by reverse transcription-polymerase chain reaction amplification usingdegenerate primers based on a conserved region of previously described adenylyl cyclases (Premont, R.T. (1994) Methods Enzymol. 238, 116-127). The full-length cDNA sequence obtained from mouse brainpredicts a 1353-amino acid protein possessing a 12-membrane span topology, and containing tworegions of high similarity with the catalytic domains of adenylyl cyclases. Comparison of this noveladenylyl cyclase with the eight previously described mammalian enzymes indicates that this type 9adenylyl cyclase sequence is the most divergent, defining a sixth distinct subclass of mammalian adenylylcyclases. The AC9 gene has been localized to human chromosome band 16p13.3-13.2. The 8.5-kb mRNAencoding the type 9 adenylyl cyclase is widely distributed, being readily detected in all tissues tested, andis found at very high levels in skeletal muscle and brain. AC9 mRNA is found throughout rat brain but isparticularly abundant in hippocampus, cerebellum, and neocortex. An antiserum directed against thecarboxyl terminus of the type 9 adenylyl cyclase detects native and expressed recombinant AC9 proteinin tissue and cell membranes. Levels of the AC9 protein are highest in mouse brain membranes.Characterization of expressed recombinant AC9 reveals that the protein is a functional adenylyl cyclasethat is stimulated by Mg2+, forskolin, and mutationally activated Gsalpha. AC9 activity is not affected byCa2+/calmodulin or by G protein betagamma-subunits. Thus AC9 represents a functional Gprotein-regulated adenylyl cyclase found in brain and in most somatic tissues.", "metadata": {}}
+{"_id": "34854444", "title": "", "text": "Expression of Golli mRNA during development in primary immune lymphoid organs of the ratThegene-of-the-oligodendrocyte lineage (Golli)-MBP transcription unit contains three Golli-specific exonstogether with eight exons of the \"classical\" myelin basic protein (MBP) gene, yielding alternatively splicedproteins which share amino acid sequence with MBP. Unlike MBP, a late antigen expressed only in thenervous system, Golli gene products are expressed pre- and post-natally at many sites. In this study, wedetermined the sequence of Golli in rat by RT-PCR and 5' RACE and showed that Golli sequences areexpressed in primary lymphoid organs as early as e16.5, which could explain the anergic rat T cellresponse we previously observed in Golli-induced meningitis.", "metadata": {}}
+{"_id": "34873974", "title": "", "text": "Diagnostic accuracy of single baseline measurement of Elecsys Troponin T high-sensitive assay fordiagnosis of acute myocardial infarction in emergency department: systematic review andmeta-analysisOBJECTIVE To obtain summary estimates of the accuracy of a single baseline measurementof the Elecsys Troponin T high-sensitive assay (Roche Diagnostics) for the diagnosis of acute myocardialinfarction in patients presenting to the emergency department. DESIGN Systematic review andmeta-analysis of diagnostic test accuracy studies. DATA SOURCES Medline, Embase, and other relevantelectronic databases were searched for papers published between January 2006 and December 2013.STUDY SELECTION Studies were included if they evaluated the diagnostic accuracy of a single baselinemeasurement of Elecsys Troponin T high-sensitive assay for the diagnosis of acute myocardial infarctionin patients presenting to the emergency department with suspected acute coronary syndrome. STUDYAPPRAISAL AND DATA SYNTHESIS The first author screened all titles and abstracts identified through thesearches and selected all potentially relevant papers. The screening of the full texts, the data extraction,and the methodological quality assessment, using the adapted QUADAS-2 tool, were conductedindependently by two reviewers with disagreements being resolved through discussion or arbitration. Ifappropriate, meta-analysis was conducted using the hierarchical bivariate model. RESULTS Twenty threestudies reported the performance of the evaluated assay at presentation. The results for 14 ng/L and 3-5ng/L cut-off values were pooled separately. At 14 ng/L (20 papers), the summary sensitivity was 89.5%(95% confidence interval 86.3% to 92.1%) and the summary specificity was 77.1% (68.7% to 83.7%).At 3-5 ng/L (six papers), the summary sensitivity was 97.4% (94.9% to 98.7%) and the summaryspecificity was 42.4% (31.2% to 54.5%). This means that if 21 of 100 consecutive patients have thetarget condition (21%, the median prevalence across the studies), 2 (95% confidence interval 2 to 3) of21 patients with acute myocardial infarction will be missed (false negatives) if 14 ng/L is used as a cut-offvalue and 18 (13 to 25) of 79 patients without acute myocardial infarction will test positive (falsepositives). If the 3-5 ng/L cut-off value is used, <1 (0 to 1) patient with acute myocardial infarction willbe missed and 46 (36 to 54) patients without acute myocardial infarction will test positive.CONCLUSIONS The results indicate that a single baseline measurement of the Elecsys Troponin Thigh-sensitive assay could be used to rule out acute myocardial infarction if lower cut-off values such as 3ng/L or 5 ng/L are used. However, this method should be part of a comprehensive triage strategy andmay not be appropriate for patients who present less than three hours after symptom onset. Care mustalso be exercised because of the higher imprecision of the evaluated assay and the greater effect oflot-to-lot reagent variation at low troponin concentrations. SYSTEMATIC REVIEW REGISTRATIONPROSPERO registration number CRD42013003926.", "metadata": {}}
+{"_id": "34876410", "title": "", "text": "Pericyte differentiation.Pericytes are defined in vivo by their location: They are embedded within thebasement membrane of microvessels. They form an integral part of the microvascular wall and arebelieved to participate in angiogenesis, although their precise role is not clear. Pericytes derived from theretinal microvasculature have been cultured and identified by a series of phenotypic characteristics thatclearly distinguishes them from other stromal cells such as smooth muscle cells. Pericytes in vitro formmulticellular nodules rich in extracellular matrix. This matrix becomes mineralized in the presence ofgrowth medium containing serum, without exogenous beta-glycerophosphate. These results indicate thatpericytes represent primitive mesenchymal cells able to differentiate into an osteogenic phenotype.Pericyte differentiation also is defined by alterations in their response to transforming growth factor beta1 and changes in the synthesis and/or deposition of various extracellular matrix proteins such as laminin,Type IV collagen, tenascin, Type X collagen osteonectin, and thrombospondin-1. Angiogenesis isassociated commonly with mineralization. These data suggest that pericytes may contribute tomineralization in vivo.", "metadata": {}}
+{"_id": "34905328", "title": "", "text": "Membrane association of the CD3ε signaling domain is required for optimal T cell development andfunction.The TCR:CD3 complex transduces signals that are critical for optimal T cell development andadaptive immunity. In resting T cells, the CD3ε cytoplasmic tail associates with the plasma membrane viaa proximal basic-rich stretch (BRS). In this study, we show that mice lacking a functional CD3ε-BRSexhibited substantial reductions in thymic cellularity and limited CD4- CD8- double-negative (DN) 3 toDN4 thymocyte transition, because of enhanced DN4 TCR signaling resulting in increased cell death andTCR downregulation in all subsequent populations. Furthermore, positive, but not negative, T cellselection was affected in mice lacking a functional CD3ε-BRS, which led to limited peripheral T cellfunction and substantially reduced responsiveness to influenza infection. Collectively, these resultsindicate that membrane association of the CD3ε signaling domain is required for optimal thymocytedevelopment and peripheral T cell function.", "metadata": {}}
+{"_id": "34935825", "title": "", "text": "A new era in ovulation induction.OBJECTIVE To evaluate the efficacy of aromatase inhibitors in ovulationinduction, superovulation, and IVF. DESIGN A literature search was conducted with the key words\"aromatase inhibitor,\" \"letrozole,\" \"anastrazole,\" \"ovulation induction,\" \"ovulation,\" and \"superovulation\"in MEDLINE, EMBASE, and the Cochrane Database of systematic reviews. RESULT(S) Ovulation inductionwith letrozole is associated with an ovulation rate of 70%-84% and a pregnancy rate of 20%-27% percycle. In one study, ovulation and pregnancy rates with letrozole seemed to be higher than those ofanastrazole. In superovulation, letrozole is associated with few developing follicles and thickendometrium. The use of letrozole for superovulation is associated with a pregnancy rate higher thanwith the use of clomiphene citrate (CC) (16.7% vs. 5.6%). The addition of letrozole to FSH treatmentleads to a decreased FSH requirement. The pregnancy rate for treatment with letrozole and FSH wassimilar to that for FSH alone. CONCLUSION(S) Aromatase inhibitors are as effective as or superior to CCin ovulation induction and in superovulation. Unlike CC, they do not carry an antiestrogenic effect on theendometrium. Given the advantages of aromatase inhibitors, they can be used to replace CC asovulation-inducing drugs. Their role in IVF remains to be determined.", "metadata": {}}
+{"_id": "34982259", "title": "", "text": "Of lineage and legacy: the development of mammalian hematopoietic stem cellsThe hematopoieticsystem is one of the first complex tissues to develop in the mammalian conceptus. Of particular interestin the field of developmental hematopoiesis is the origin of adult bone marrow hematopoietic stem cells.Tracing their origin is complicated because blood is a mobile tissue and because hematopoietic cellsemerge from many embryonic sites. The origin of the adult mammalian blood system remains a topic oflively discussion and intense research. Interest is also focused on developmental signals that induce theadult hematopoietic stem cell program, as these may prove useful for generating and expanding theseclinically important cell populations ex vivo. This review presents a historical overview of and the mostrecent data on the developmental origins of hematopoiesis.", "metadata": {}}
+{"_id": "35004872", "title": "", "text": "Long crocidolite asbestos fibers cause polyploidy by sterically blocking cytokinesis.Asbestos has beendescribed as a physical carcinogen in that its carcinogenic effects appear to be related primarily to fiberdimensions. It has been hypothesized that long asbestos fibers may interfere with chromosomedistribution during cell division, causing genomic changes that lead to cell transformation and neoplasticprogression. Using high-resolution time-lapse light microscopy and serial-section electron microscopy, wehave followed individual crocidolite asbestos fibers through the later stages of cell division in LLC-MK2epithelial cells, and have detailed for the first time their effect on cytokinesis. We found that long fibers(15-55 microgram), trapped by the cleavage furrow, sterically blocked cytokinesis, sometimes resultingin the formation of a binucleated cell. The ends of blocking fibers were usually found within invaginationsof the newly formed nuclei. Nuclear envelope-fiber attachment was evident when a chromatin strand ranwith the fiber into the intercellular bridge. Such strands may break, causing chromosome structuralrearrangements. Our data are the first to show that individual crocidolite fibers can cause genomicchanges by sterically blocking cytokinesis and that fiber length and affinity for the nuclear envelope areimportant factors. Such genomic changes may be among the initial events leading to asbestos-inducedcancers.", "metadata": {}}
+{"_id": "35008773", "title": "", "text": "Neural induction and early patterning in vertebrates.In vertebrates, the development of the nervoussystem is triggered by signals from a powerful 'organizing' region of the early embryo during gastrulation.This phenomenon--neural induction--was originally discovered and given conceptual definition byexperimental embryologists working with amphibian embryos. Work on the molecular circuitry underlyingneural induction, also in the same model system, demonstrated that elimination of ongoing transforminggrowth factor-β (TGFβ) signaling in the ectoderm is the hallmark of anterior neural-fate acquisition. Thisobservation is the basis of the 'default' model of neural induction. Endogenous neural inducers aresecreted proteins that act to inhibit TGFβ ligands in the dorsal ectoderm. In the ventral ectoderm, wherethe signaling ligands escape the inhibitors, a non-neural fate is induced. Inhibition of the TGFβ pathwayhas now been demonstrated to be sufficient to directly induce neural fate in mammalian embryos as wellas pluripotent mouse and human embryonic stem cells. Hence the molecular process that delineatesneural from non-neural ectoderm is conserved across a broad range of organisms in the evolutionarytree. The availability of embryonic stem cells from mouse, primates, and humans will facilitate furtherunderstanding of the role of signaling pathways and their downstream mediators in neural induction invertebrate embryos.", "metadata": {}}
+{"_id": "35022568", "title": "", "text": "What's in the 'treatment gap'? Ethnographic perspectives on addiction and global mental health fromChina, Russia, and the United States.Recent years have seen the emergence of a 'global mental health'agenda, focused on providing evidence-based interventions for mental illnesses in low- andmiddle-income countries. Anthropologists and cultural psychiatrists have engaged in vigorous debatesabout the appropriateness of this agenda. In this article, we reflect on these debates, drawing onethnographic fieldwork on the management of substance use disorders in China, Russia, and the UnitedStates. We argue that the logic of 'treatment gaps,' which guides much research and intervention underthe rubric of global mental health, partially obscures the complex assemblages of institutions,therapeutics, knowledges, and actors framing and managing addiction (as well as other mental healthissues) in any particular setting.", "metadata": {}}
+{"_id": "35062452", "title": "", "text": "Generation of mice deficient in both KLF3/BKLF and KLF8 reveals a genetic interaction and a role forthese factors in embryonic globin gene silencing.Krüppel-like factors 3 and 8 (KLF3 and KLF8) are highlyrelated transcriptional regulators that bind to similar sequences of DNA. We have previously shown thatin erythroid cells there is a regulatory hierarchy within the KLF family, whereby KLF1 drives theexpression of both the Klf3 and Klf8 genes and KLF3 in turn represses Klf8 expression. While theerythroid roles of KLF1 and KLF3 have been explored, the contribution of KLF8 to this regulatory networkhas been unknown. To investigate this, we have generated a mouse model with disrupted KLF8expression. While these mice are viable, albeit with a reduced life span, mice lacking both KLF3 and KLF8die at around embryonic day 14.5 (E14.5), indicative of a genetic interaction between these two factors.In the fetal liver, Klf3 Klf8 double mutant embryos exhibit greater dysregulation of gene expression thaneither of the two single mutants. In particular, we observe derepression of embryonic, but not adult,globin expression. Taken together, these results suggest that KLF3 and KLF8 have overlapping roles invivo and participate in the silencing of embryonic globin expression during development.", "metadata": {}}
+{"_id": "35079452", "title": "", "text": "Mycobacterium tuberculosis phagosome maturation arrest: selective targeting of PI3P-dependentmembrane trafficking.The ability of Mycobacterium tuberculosis to enter host macrophages, and reside ina phagosome, which does not mature into a phagolysosome, is central to the spread of tuberculosis andthe associated pandemic involving billions of people worldwide. Tuberculosis can be viewed as a diseasewith a significant intracellular trafficking and organellar biogenesis component. Current understanding ofthe block in M. tuberculosis phagosome maturation also sheds light on fundamental aspects ofphagolysosome biogenesis. The maturation block involves interference with the recruitment and functionof rabs, rab effectors (phosphatidylinositol 3-kinases and tethering molecules such as EEA1), SNAREs(Syntaxin 6 and cellubrevin) and Ca2+/calmodulin signaling. M. tuberculosis analogs of mammalianphosphatidylinositols interfere with these systems and associated processes.", "metadata": {}}
+{"_id": "35085326", "title": "", "text": "SvpA, a novel surface virulence-associated protein required for intracellular survival of Listeriamonocytogenes.A previously unknown protein, designated SvpA (surface virulence-associated protein)and implicated in the virulence of the intracellular pathogen Listeria monocytogenes, was identified. This64 kDa protein, encoded by svpA, is both secreted in culture supernatants and surface-exposed, asshown by immunogold labelling of whole bacteria with an anti-SvpA antibody. Analysis of the peptidesequence revealed that SvpA contains a leader peptide, a predicted C-terminal transmembrane regionand a positively charged tail resembling that of the surface protein ActA, suggesting that SvpA mightpartially reassociate with the bacterial surface by its C-terminal membrane anchor. An allelic mutant wasconstructed by disrupting svpA in the wild-type strain LO28. The virulence of this mutant was stronglyattenuated in the mouse, with a 2 log decrease in the LD50 and restricted bacterial growth in organs ascompared to the wild-type strain. This reduced virulence was not related either to a loss of adherence orto a lower expression of known virulence factors, which remained unaffected in the svpA mutant. It wascaused by a restriction of intracellular growth of mutant bacteria. By following the intracellular behaviourof bacteria within bone-marrow-derived macrophages by confocal and electron microscopy studies, it wasfound that most svpA mutant bacteria remained confined within phagosomes, in contrast to wild-typebacteria which rapidly escaped to the cytoplasm. The regulation of svpA was independent of PrfA, thetranscriptional activator of virulence genes in L. monocytogenes. In fact, SvpA was down-regulated byMecA, ClpC and ClpP, which are highly homologous to proteins of Bacillus subtilis forming a regulatorycomplex controlling the competence state of this saprophyte. The results indicate that: (i) SvpA is a novelfactor involved in the virulence of L. monocytogenes, promoting bacterial escape from phagosomes ofmacrophages; (ii) SvpA is, at least partially, associated with the surface of bacteria; and (iii) SvpA isPrfA-independent and controlled by a MecA-dependent regulatory network.", "metadata": {}}
+{"_id": "35087728", "title": "", "text": "Measuring adherence to highly active antiretroviral therapy: implications for research and practice.Highlyactive antiretroviral therapy (HAART) has radically changed the course of HIV disease, producingsubstantial reductions in both HIV-related morbidity and mortality. However, the complexity of the typicaldaily HAART regimen is substantial, and high levels of adherence are essential for complete andlong-term viral suppression and the avoidance of drug resistance. The complexity of HAART has made theassessment of medication adherence of paramount importance. Even though various methods are in use,each measures only a subset of adherence behaviors, and each measure has limited predictive validity.Given the individual and public health concerns associated with adherence to HAART, there is a need forthe continued development and validation of measures of medication adherence.", "metadata": {}}
+{"_id": "35100235", "title": "", "text": "Survival rates of tropical and temperate passerines: a Trinidadian perspective.Mark-recapture datacollected using mist nets over a 10-yr period in Trinidad were used to estimate adult survival rates for 17species of forest passerines. Trinidadian survival rates (mean 65%, range 45%-85%) were significantlyhigher than published estimates for European (mean survival 52%, range 32%-71%) and North American(mean survival 53%, range 29%-63%) passerines of similar body size (equivalent to 45% higher meanlife expectancy in Trinidad). These findings were confirmed after controlling for phylogeny using a methodof independent contrasts. Transient and/or young birds were an important feature of the Trinidad data,and studies that fail to allow for the presence of such birds risk underestimating adult survival. This studylends support to the hypothesis that avian survival rates are higher in the humid tropics, although themagnitude of the difference may be smaller than previously suggested.", "metadata": {}}
+{"_id": "35149431", "title": "", "text": "P0 glycoprotein peptides 56–71 and 180–199 dose-dependently induce acute and chronic experimentalautoimmune neuritis in Lewis rats associated with epitope spreadingTwo synthetic peripheral nervemyelin P0 protein peptides, an immunodominant (amino acids 180-199) and a cryptic (amino acids56-71) one, induced an acute or chronic course of experimental autoimmune neuritis (EAN) in Lewis rats,when given at low dose (50-100 microg/rat) or high dose (250 microg/rat), respectively. Correspondingto the different clinical course, pathological changes and immune responses were found: (1) Onset ofclinical signs of P0 peptide 56-71 (P0 56-71) induced EAN was 1-3 days later than in P0 peptide 180-199(P0 180-199) induced EAN at all immunizing doses, whereas the peak of the disease occurred at a similartime point post immunization (p.i.), i.e. at days 14-16 p.i. in P0 56-71 induced EAN and at day 16 p.i. inP0 180-199 induced EAN. (2) Intramolecular epitope spreading as assessed by delayed typehypersensitivity response occurred in P0 56-71 induced EAN at both low and high antigen doses and in P0180-199 induced EAN at high antigen dose (250 microg/rat) only. (3) P0 180-199 stimulated higherlevels of interferon-gamma production in P0 180-199 induced EAN than in P0 56-71 induced EAN and viceversa. (4) Histopathologic evaluation revealed a similar grade of mononuclear cell infiltration in the sciaticnerves of both types of EAN, but more severe demyelination was found in P0 180-199 induced EANcompared to P0 56-71 induced EAN. The results support the hypothesis that high dose autoantigenimmunization induces extensive determinant spreading and chronic course of autoimmune diseases.", "metadata": {}}
+{"_id": "35186640", "title": "", "text": "Interaction between broad-spectrum antibiotics and the combined oral contraceptive pill. A literaturereview.There is considerable variation in opinion about the importance of drug interactions between thecombined oral contraceptive pill (COCP) and broad-spectrum antibiotics. Clinical practice varies widely,especially between doctors in Europe and those in the US. Rifampicin and griseofulvin induce hepaticenzymes and do appear to have a genuine interaction with the COCP, leading to reduced efficacy. Thesituation with the broad-spectrum antibiotics is less clear. There are relatively few prospective studies ofthe pharmacokinetics of concurrent COCP and antibiotic use and few, if any, demonstrate a convincingbasis for any reduced contraceptive efficacy. There is evidence, however, that variable contraceptivesteroid handling could make some women, at some times, more susceptible to COCP failure. Given theserious consequences of unwanted pregnancy, the cautious approach of using additional or alternativecontraception during short courses of broad-spectrum antibiotics and the initial weeks of long-termantibiotic administration may be justified to safeguard the few unidentifiable women who may be at risk.Conflicting opinion and advice is potentially confusing to both professionals and patients, and instructionsfor additional precautions during and after concurrent COCP and antibiotic use are complicated. Manywomen are ignorant of, or confused about, the circumstances that can cause OC to fail. Healthprofessionals who prescribe the COCP must continue to strive to educate women about the mode ofaction and about the times when there is the greatest danger of failure. Professionals who feel thatconcurrent antibiotic use represents a real threat to contraceptive efficacy of the COCP should beprepared to present the advice for additional contraceptive precautions in a simple and consistent way,backed up with written information and reinforced at regular intervals.", "metadata": {}}
+{"_id": "35231675", "title": "", "text": "CLIP-170 interacts with dynactin complex and the APC-binding protein EB1 by differentmechanisms.CLIP-170 is a \"cytoplasmic linker protein\" implicated in endosome-microtubule interactionsand in control of microtubule dynamics. CLIP-170 localizes dynamically to growing microtubule plus ends,colocalizing with the dynein activator dynactin and the APC-binding protein EB1. This shared \"plus-endtracking\" behavior suggests that CLIP-170 might interact with dynactin and/or EB1. We have usedsite-specific mutagenesis of CLIP-170 and a transfection/colocalization assay to address this question inmammalian tissue culture cells. Our results indicate that CLIP-170 interacts, directly or indirectly, withboth dynactin and EB1. We find that the CLIP-170/dynactin interaction is mediated by the second metalbinding motif of the CLIP-170 tail. In contrast, the CLIP-170/EB1 interaction requires neither metalbinding motif. In addition, our experiments suggest that the CLIP-170/dynactin interaction occurs via theshoulder/sidearm subcomplex of dynactin and can occur in the cytosol (i.e., it does not requiremicrotubule binding). These results have implications for the targeting of both dynactin and EB1 tomicrotubule plus ends. Our data suggest that the CLIP-170/dynactin interaction can target dynactincomplex to microtubule plus ends, although dynactin likely also targets MT plus ends directly via themicrotubule binding motif of the p150(Glued) subunit. We find that CLIP-170 mutants alter p150(Glued)localization without affecting EB1, indicating that EB1 can target microtubule plus ends independently ofdynactin.", "metadata": {}}
+{"_id": "35256900", "title": "", "text": "Subcapsular encounter and complement-dependent transport of immune complexes by lymph node BcellsThe mechanism of B cell–antigen encounter in lymphoid tissues is incompletely understood. It is alsounclear how immune complexes are transported to follicular dendritic cells. Here, using real-timetwo-photon microscopy we noted rapid delivery of immune complexes through the lymph to macrophagesin the lymph node subcapsular sinus. B cells captured immune complexes by a complementreceptor–dependent mechanism from macrophage processes that penetrated the follicle and transportedthe complexes to follicular dendritic cells. Furthermore, cognate B cells captured antigen-containingimmune complexes from macrophage processes and migrated to the T zone. Our findings identifymacrophages lining the subcapsular sinus as an important site of B cell encounter with immunecomplexes and show that intrafollicular B cell migration facilitates the transport of immune complexes aswell as encounters with cognate antigen.", "metadata": {}}
+{"_id": "35271381", "title": "", "text": "Exercise training-induced adaptations in the coronary circulation.Aerobic exercise training induces anincrease in coronary blood flow capacity that is associated with altered control of coronary vascularresistance and, therefore, coronary blood flow. The relative importance of metabolic, myogenic,endothelium-mediated, and neurohumoral control systems varies throughout the coronary arterial tree,and these control systems contribute in parallel to regulating coronary vascular resistance to differingdegrees at each level in the coronary arterial tree. In addition to this nonuniformity of the relativeimportance of vascular control systems in the coronary arterial tree, it appears that exercisetraining-induced adaptations are also distributed spatially, in a nonuniform manner throughout thecoronary tree. As a result, it is necessary to examine training-induced adaptations throughout thecoronary arterial tree. Adaptations in endothelium-mediated control play a role in training-inducedchanges in control of coronary vascular resistance, and there is evidence that the effects of training maybe different in large coronary arteries than in the microcirculation. Also, there is evidence that the mode,frequency, and intensity of exercise training bouts and duration of training may influence the adaptivechanges in endothelial function. Exercise training has also been shown to induce changes in responses ofcoronary vascular smooth muscle to vasoactive agents and alterations in the cellular-molecular control ofintracellular Ca2+ in coronary vascular smooth muscle of conduit coronary arteries and to enhancemyogenic reactivity of coronary resistance arteries. Exercise training also appears to have differenteffects on vascular smooth muscle in large coronary arteries than in the microcirculation. For example,adenosine sensitivity is increased in conduit coronary arteries and large resistance arteries after trainingbut is not altered in small coronary resistance arteries of trained animals. Although much remains to bestudied, evidence clearly indicates that chronic exercise alters the phenotype of coronary endothelial andvascular smooth muscle cells and that plasticity of these cells plays a role in adaptation of thecardiovascular system in exercise training.", "metadata": {}}
+{"_id": "35301079", "title": "", "text": "Hepatic intra-arterial versus intravenous fotemustine in patients with liver metastases from uvealmelanoma (EORTC 18021): a multicentric randomized trial.BACKGROUND In uveal melanoma (UM) withmetastatic disease limited to the liver, the effect of an intrahepatic treatment on survival is unknown. Weinvestigated prospectively the efficacy and toxicity of hepatic intra-arterial (HIA) versus systemic (IV)fotemustine in patients with liver metastases from UM. PATIENTS AND METHODS Patients were randomlyassigned to receive either IV or HIA fotemustine at 100 mg/m(2) on days 1, 8, 15 (and 22 in HIA armonly) as induction, and after a 5-week rest period every 3 weeks as maintenance. Primary end point wasoverall survival (OS). Response rate (RR), progression-free survival (PFS) and safety were secondary endpoints. RESULTS Accrual was stopped after randomization of 171 patients based on the results of a futilityOS analysis. A total of 155 patients died and 16 were still alive [median follow-up 1.6 years (range0.25-6 years)]. HIA did not improve OS (median 14.6 months) when compared with the IV arm (median13.8 months), hazard ratio (HR) 1.09; 95% confidence interval (CI) 0.79-1.50, log-rank P = 0.59.However, there was a significant benefit on PFS for HIA compared with IV with a median of 4.5 versus 3.5months, respectively (HR 0.62; 95% CI 0.45-0.84, log-rank P = 0.002). The 1-year PFS rate was 24% inthe HIA arm versus 8% in the IV arm. An improved RR was seen in the HIA (10.5%) compared with IVtreatment (2.4%). In the IV arm, the most frequent grade ≥3 toxicity was thrombocytopenia (42.1%)and neutropenia (62.6%), compared with 21.2% and 28.7% in the HIA arm. The main grade ≥3 toxicityrelated to HIA was catheter complications (12%) and liver toxicity (4.5%) apart from two toxic deaths.CONCLUSION HIA treatment with fotemustine did not translate into an improved OS compared with IVtreatment, despite better RR and PFS. Intrahepatic treatment should still be considered as experimental.EUDRACT NUMBER AND CLINICALTRIALSGOV IDENTIFIER 2004-002245-12 and NCT00110123.", "metadata": {}}
+{"_id": "35314705", "title": "", "text": "Comparison of survival between cerebellar and supratentorial glioblastoma patients: surveillance,epidemiology, and end results (SEER) analysis.BACKGROUND Cerebellar glioblastoma multiforme (cGBM)is rare, and although there is a general belief that these tumors have a worse prognosis thansupratentorial GBM (sGBM), few studies have been published to support this belief. OBJECTIVE Toinvestigate the effect of cerebellar location on survival through a case-control design comparing overallsurvival time of cGBM and sGBM patients. METHODS The Surveillance, Epidemiology, and End Results(SEER) registry was used to identify 132 patients with cGBM (1973-2008). Each cGBM patient wasmatched with an sGBM patient from among 20,848 sGBM patients on the basis of age, extent ofresection, decade of diagnosis, and radiation therapy using propensity score matching. RESULTS Withinthe cGBM, 37% were older than 65 years of age, 62% were men, and 87% were white. Most patientsunderwent surgery and radiation (74%), whereas only 26% underwent surgical resection only. Themedian survival time for the cGBM and sGBM matched cohort was 8 months; however, the survivaldistributions differed (log-rank P = .04). Survival time for cGBM vs sGBM at 2 years was 21.5% vs 8.0%,and 12.7% vs 5.3% at 3 years. Multivariate analysis of survival among cGBM patients showed thatyounger age (P < .0001) and having radiation therapy (P < .0001) were significantly associated withreduced hazard of mortality. Among all patients, multivariate analysis showed that tumor location (P =.03), age (P < .0001), tumor size (P = .009), radiation (P < .0001), and resection (P < .0001) wereassociated with survival time in the unmatched cohort. CONCLUSION Median survival time for cGBM andsGBM patients was 8 months, but cGBM patients had a survival time advantage as the study progressed.These findings suggest that cGBM patients should be treated as aggressively as sGBM patients withsurgical resection and radiation therapy.", "metadata": {}}
+{"_id": "35321950", "title": "", "text": "Staphylococcus aureus and Candida albicans infection (animal experiments).During a certain period ofthe course of infection in white mice inoculated intraperitoneally with the pure culture of a proteolysingstrain of Candida albicans, Staphylococcus aureus and C. albicans both, were isolated simultaneouslyfrom the peritoneal abscesses, especially those adhering to the stomach, duodenum, pancreas and theupper part of small intestine. This concommitant occurrence of the two pathogens was furthercorroborated by histopathological examination which revealed large number of staphylococci present inthe close neighbourhood of Candida cells, usually in the center of the granulomata caused by the fungus.In view of the facts that the proteolytic end-products of C. albicans can offer a good substratum for thegrowth of S. aureus and the latter may be isolated from the intestinal tract of apparently healthy mice,possibly as a constituent of the transient microflora, the co-existence of these two important aetiologicagents of endogenous infections as encountered during this study appears to be of great clinical interest.Furthermore, these observations also demonstrate the importance of controlling the bacterial flora ofmice for pure mycological studies.", "metadata": {}}
+{"_id": "35329820", "title": "", "text": "Three common functional polymorphisms in microRNA encoding genes in the susceptibility tohepatocellular carcinoma: a systematic review and meta-analysis.Emerging evidences have shown thatcommon genetic polymorphisms in microRNAs may be associated with the development of hepatocellularcarcinoma (HCC); but individually published studies and previous meta-analyses revealed inconclusiveresults. The aims of this review and meta-analysis are to assess whether common single-nucleotidepolymorphisms (SNPs) in the genes encoding the microRNAs are associated with susceptibility to HCCdevelopment and clinicopathologic characteristics of hepatitis B virus (HBV) related HCC. A computerizedsearch was performed in PubMed, Embase, Web of Science and China BioMedicine (CBM) databases toidentify relevant articles published before January 1st 2013. Ten case-control studies were assessed witha total of 3437 cases and 3437 healthy controls. Three common functional SNPs in miRNA-encodinggenes were found, including miR-146a G>C (rs2910164), miR-196a-2 C>T (rs11614913) and miR-499T>C (rs3746444). This meta-analysis revealed that the miR-146a C variant was associated with adecrease in HCC risk, especially among Asian and male populations; while the miR-196a-2 T variant wasassociated with susceptibility to HCC among Caucasian populations. However, we failed to find anysignificant correlations between the miR-499 C polymorphism and HCC risks. When further stratificationon HBV status was conducted, a similar trend of association between the three SNPs and the HBV-relatedHCC risks was observed, but these results were not statistically significant due to small sample sizes. Thecurrent meta-analysis demonstrates that SNPs contained in the genes encoding miR-146a andmiR-196a-2 may play a major role in genetic susceptibility to HCC.", "metadata": {}}
+{"_id": "35345807", "title": "", "text": "Isonicotinamide enhances Sir2 protein-mediated silencing and longevity in yeast by raising intracellularNAD+ concentration.Sirtuins are an evolutionarily conserved family of NAD(+)-dependent proteindeacetylases that function in the regulation of gene transcription, cellular metabolism, and aging. Theiractivity requires the maintenance of an adequate intracellular NAD(+) concentration through thecombined action of NAD(+) biosynthesis and salvage pathways. Nicotinamide (NAM) is a key NAD(+)precursor that is also a byproduct and feedback inhibitor of the deacetylation reaction. In Saccharomycescerevisiae, the nicotinamidase Pnc1 converts NAM to nicotinic acid (NA), which is then used as asubstrate by the NAD(+) salvage pathway enzyme NA phosphoribosyltransferase (Npt1). Isonicotinamide(INAM) is an isostere of NAM that stimulates yeast Sir2 deacetylase activity in vitro by alleviating theNAM inhibition. In this study, we determined that INAM stimulates Sir2 through an additional mechanismin vivo, which involves elevation of the intracellular NAD(+) concentration. INAM enhanced normalsilencing at the rDNA locus but only partially suppressed the silencing defects of an npt1Δ mutant. Yeastcells grown in media lacking NA had a short replicative life span, which was extended by INAM in aSIR2-dependent manner and correlated with increased NAD(+). The INAM-induced increase in NAD(+)was strongly dependent on Pnc1 and Npt1, suggesting that INAM increases flux through the NAD(+)salvage pathway. Part of this effect was mediated by the NR salvage pathways, which generate NAM as aproduct and require Pnc1 to produce NAD(+). We also provide evidence suggesting that INAM influencesthe expression of multiple NAD(+) biosynthesis and salvage pathways to promote homeostasis duringstationary phase.", "metadata": {}}
+{"_id": "35395662", "title": "", "text": "Similar activation of signal transduction pathways by the herpesvirus-encoded chemokine receptors US28and ORF74.The virally encoded chemokine receptors US28 from human cytomegalovirus and ORF74 fromhuman herpesvirus 8 are both constitutively active. We show that both receptors constitutively activatethe transcription factors nuclear factor of activated T cells (NFAT) and cAMP response element bindingprotein (CREB) and that both pathways are modulated by their respective endogenous receptor ligands.By addition of specific pathway modulators against the G protein subunit Galphai, phospholipase C,protein kinase C, calcineurin, p38 MAP kinase, and MEK1, we find that the constitutive andligand-dependent inductions are mediated by multiple yet similar pathways in both receptors. The NFATand CREB transcription factors and their upstream activators are known inducers of host and virallyencoded genes. We propose that the activity of these virally encoded chemokine receptors coordinateshost and potentially viral gene expression similarly. As ORF74 is a known inducer of neoplasia, thesefindings may have important implications for cytomegalovirus-associated pathogenicity.", "metadata": {}}
+{"_id": "35443524", "title": "", "text": "The therapeutic promise of the cancer stem cell concept.Cancer stem cells (CSCs) are a subpopulation oftumor cells that selectively possess tumor initiation and self-renewal capacity and the ability to give riseto bulk populations of nontumorigenic cancer cell progeny through differentiation. As we discuss here,they have been prospectively identified in several human malignancies, and their relative abundance inclinical cancer specimens has been correlated with malignant disease progression in human patients.Furthermore, recent findings suggest that clinical cancer progression driven by CSCs may contribute tothe failure of existing therapies to consistently eradicate malignant tumors. Therefore, CSC-directedtherapeutic approaches might represent translationally relevant strategies to improve clinical cancertherapy, in particular for those malignancies that are currently refractory to conventional anticanceragents directed predominantly at tumor bulk populations.", "metadata": {}}
+{"_id": "35448676", "title": "", "text": "3'-End processing of pre-mRNA in eukaryotes.3'-Ends of almost all eukaryotic mRNAs are generated byendonucleolytic cleavage and addition of a poly(A) tail. In mammalian cells, the reaction depends on thesequence AAUAAA upstream of the cleavage site, a degenerate GU-rich sequence element downstream ofthe cleavage site and stimulatory sequences upstream of AAUAAA. Six factors have been identified thatcarry out the two reactions. With a single exception, they have been purified to homogeneity and cDNAsfor 11 subunits have been cloned. Some of the cooperative RNA-protein and protein-protein interactionswithin the processing complex have been analyzed, but many details, including the identity of theendonuclease, remain unknown. Several examples of regulated polyadenylation are being analyzed at themolecular level. In the yeast Saccharomyces cerevisiae, sequences directing cleavage andpolyadenylation are more degenerate than in metazoans, and a downstream element has not beenidentified. The list of processing factors may be complete now with approximately a dozen polypeptides,but their functions in the reaction are largely unknown. 3'-Processing is known to be coupled totranscription. This connection is thought to involve interactions of processing factors with the mRNA capas well as with RNA polymerase II.", "metadata": {}}
+{"_id": "35467590", "title": "", "text": "Structure and developmental regulation of Golli-mbp, a 105-kilobase gene that encompasses the myelinbasic protein gene and is expressed in cells in the oligodendrocyte lineage in the brain.We have identifieda novel transcription unit of 105 kilobases (called the Golli-mbp gene) that encompasses the mousemyelin basic protein (MBP) gene. Three unique exons within this gene are alternatively spliced into MBPexons and introns to produce a family of MBP gene-related mRNAs that are under individualdevelopmental regulation. These mRNAs are temporally expressed within cells of the oligodendrocytelineage at progressive stages of differentiation. Thus, the MBP gene is a part of a more complex genestructure, the products of which may play a role in oligodendrocyte differentiation prior to myelination.One Golli-mbp mRNA that encodes a protein antigenically related to MBP is also expressed in the spleenand other non-neural tissues.", "metadata": {}}
+{"_id": "35495268", "title": "", "text": "Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes.BACKGROUND Weight loss isrecommended for overweight or obese patients with type 2 diabetes on the basis of short-term studies,but long-term effects on cardiovascular disease remain unknown. We examined whether an intensivelifestyle intervention for weight loss would decrease cardiovascular morbidity and mortality among suchpatients. METHODS In 16 study centers in the United States, we randomly assigned 5145 overweight orobese patients with type 2 diabetes to participate in an intensive lifestyle intervention that promotedweight loss through decreased caloric intake and increased physical activity (intervention group) or toreceive diabetes support and education (control group). The primary outcome was a composite of deathfrom cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for anginaduring a maximum follow-up of 13.5 years. RESULTS The trial was stopped early on the basis of a futilityanalysis when the median follow-up was 9.6 years. Weight loss was greater in the intervention groupthan in the control group throughout the study (8.6% vs. 0.7% at 1 year; 6.0% vs. 3.5% at study end).The intensive lifestyle intervention also produced greater reductions in glycated hemoglobin and greaterinitial improvements in fitness and all cardiovascular risk factors, except for low-density-lipoproteincholesterol levels. The primary outcome occurred in 403 patients in the intervention group and in 418 inthe control group (1.83 and 1.92 events per 100 person-years, respectively; hazard ratio in theintervention group, 0.95; 95% confidence interval, 0.83 to 1.09; P=0.51). CONCLUSIONS An intensivelifestyle intervention focusing on weight loss did not reduce the rate of cardiovascular events inoverweight or obese adults with type 2 diabetes. (Funded by the National Institutes of Health and others;Look AHEAD ClinicalTrials.gov number, NCT00017953.).", "metadata": {}}
+{"_id": "35520219", "title": "", "text": "Early loss of interneurons and delayed subunit-specific changes in GABA(A)-receptor expression in amouse model of mesial temporal lobe epilepsy.Unilateral injection of kainic acid (KA) into the dorsalhippocampus of adult mice induces spontaneous recurrent partial seizures and replicateshistopathological changes observed in human mesial temporal lobe epilepsy (MTLE) (Bouilleret V et al.,Neuroscience 1999; 89:717-729). Alterations in pre- and postsynaptic components of GABAergicneurotransmission were investigated immunohistochemically at different time points (1-120 days) in thismouse model of MTLE. Markers of GABAergic interneurons (parvalbumin, calbindin-D28k, and calretinin),the type-1 GABA transporter (GAT1), and major GABA(A)-receptor subunits expressed in thehippocampal formation were analyzed. Acutely, KA injection produced a profound loss of hilar cells butonly limited damage to CA1 and CA3 pyramidal cells. In addition, parvalbumin and calbindin-D28kstaining of interneurons disappeared irreversibly in CA1 and dentate gyrus (DG), whereas calretininstaining was spared. The prominent GABA(A)-receptor alpha1 subunit staining of interneurons alsodisappeared after KA treatment, suggesting acute degeneration of these cells. Likewise, GAT1immunoreactivity revealed degenerating terminals at 24 h post-KA in CA1 and DC and subsided almostcompletely thereafter. Loss of CA1 and, to a lesser extent, CA3 neurons became evident at 7-15 dayspost-KA. It was more accentuated after 1 month, accompanied by a corresponding reduction ofGABA(A)-receptor staining. In contrast, DC granule cells were markedly enlarged and dispersed in themolecular layer and exhibited a prominent increase in GABA(A)-receptor subunit staining. After 4months, the dorsal CA1 area was lost almost entirely, CA3 was reduced, and the DG represented most ofthe remaining dorsal hippocampal formation. No significant morphological alterations were detectedcontralaterally. These results suggest that loss of hilar cells and GABAergic neurons contributes toepileptogenesis in this model of MTLE. In contrast, long-term degeneration of pyramidal cells and granulecell dispersion may reflect distinct responses to recurrent seizures. Finally, GABA(A)-receptorupregulation in the DG may represent a compensatory response persisting for several months in epilepticmice.", "metadata": {}}
+{"_id": "35521287", "title": "", "text": "Cardiorespiratory adaptation during sleep in infants and children.The cardiorespiratory control systemundergoes functional maturation after birth. Until this process is completed, the cardiorespiratory systemis unstable, placing infants at risk for cardiorespiratory disturbances, especially during sleep. Theprofound influence of states of alertness on respiratory and cardiac control has been the focus of intensescrutiny during the last decade. The effects of rapid-eye movement (REM) sleep on various mechanismsinvolved in cardiorespiratory control are of particular significance during the postnatal period sincenewborns spend much of their time in this sleep state. In fullterm newborns, REM sleep occupies morethan 50% of total sleep time, and this percentage is even greater in preterm newborns. From term to sixmonths of age, the proportion of REM sleep decreases. Since respiratory and cardiac disturbances areknown to occur selectively during REM sleep, the predominance of REM sleep may be a risk factor forabnormal sleep-related events during early infancy. Awareness of these developmental changes in sleeppatterns is important for clinicians dealing with problems such as apparent life-threatening events (ALTE),sudden infant death syndrome (SIDS), and/or cardiorespiratory responses to respiratory disorders. Ourcurrent understanding of respiratory and cardiac control rests mainly on studies conducted during thefirst months of life. There is a paucity of data on late infancy and early childhood. The present paper willreview available data on how sleep affects 1) ventilatory mechanics, in particular of the upper airwaysand the chest wall; ventilation and apnea; gas exchange; chemoreceptor function; and arousalresponses; 2) changes in heart rate and heart rate variability, and the occurrence and mechanisms ofbradycardia.", "metadata": {}}
+{"_id": "35531883", "title": "", "text": "A Common Signal Patch Drives AP-1 Protein-dependent Golgi Export of Inwardly Rectifying PotassiumChannels.Nearly all members of the inwardly rectifying potassium (Kir) channel family share acytoplasmic domain structure that serves as an unusual AP-1 clathrin adaptor-dependent Golgi exportsignal in one Kir channel, Kir2.1 (KCNJ2), raising the question whether Kir channels share a commonGolgi export mechanism. Here we explore this idea, focusing on two structurally and functionallydivergent Kir family members, Kir2.3 (KCNJ4) and Kir4.1/5.1 (KCNJ10/16), which have \u000050% aminoidentity. We found that Golgi export of both channels is blocked upon siRNA-mediated knockdown of theAP-1 γ subunit, as predicted for the common AP-1-dependent trafficking process. A comprehensivemutagenic analysis, guided by homology mapping in atomic resolution models of Kir2.1, Kir2.3, andKir4.1/5.1, identified a common structure that serves as a recognition site for AP-1 binding and governsGolgi export. Larger than realized from previous studies with Kir2.1, the signal is created by a patch ofresidues distributed at the confluence of cytoplasmic N and C termini. The signal involves a stretch ofhydrophobic residues from the C-terminal region that form a hydrophobic cleft, an adjacent cluster ofbasic residues within the N terminus, and a potential network of salt bridges that join the N- andC-terminal poles together. Because patch formation and AP-1 binding are dependent on proper folding ofthe cytoplasmic domains, the signal provides a common quality control mechanism at the Golgi for Kirchannels. These findings identify a new proteostatic mechanism that couples protein folding of channelsto forward trafficking in the secretory pathway.", "metadata": {}}
+{"_id": "35534019", "title": "", "text": "Statins in the treatment of polycythaemia vera and allied disorders: an antithrombotic and cytoreductivepotential?Thrombohaemorrhagic complications are major clinical problems in the classical chronicPh-negative myeloproliferative disorders (CMPDs), polycytaemia vera (PV), essential thrombocythaemia(ET) and idiopathic myelofibrosis (IMF), contributing significantly to morbidity and mortality.Pathophysiologically these disorders are characterized by clonal myeloproliferation, myeloaccumulationand a propensity to develop myelofibrosis and neoangiogenesis in both the bone marrow and spleen.Based upon in vitro and in vivo studies of the effects of statins (antithrombotic, antiproliferative,proapoptotic and antiangiogenic), this review focuses on the translation of these effects into potentialclinical benefits of statin therapy in patients with CMPDs.", "metadata": {}}
+{"_id": "35543846", "title": "", "text": "Metabolic analysis of senescent human fibroblasts reveals a role for AMP in cellular senescence.Cellularsenescence is considered a major tumour-suppressor mechanism in mammals, and many oncogenicinsults, such as the activation of the ras proto-oncogene, trigger initiation of the senescence programme.Although it was shown that activation of the senescence programme involves the up-regulation ofcell-cycle regulators such as the inhibitors of cyclin-dependent kinases p16INK4A and p21CIP-1, themechanisms underlying the senescence response remain to be resolved. In the case of stress-inducedpremature senescence, reactive oxygen species are considered important intermediates contributing tothe phenotype. Moreover, distinct alterations of the cellular carbohydrate metabolism are known tocontribute to oncogenic transformation, as is best documented for the phenomenon of aerobic glycolysis.These findings suggest that metabolic alterations are involved in tumourigenesis and tumoursuppression; however, little is known about the metabolic pathways that contribute to these processes.Using the human fibroblast model of in vitro senescence, we analysed age-dependent changes in thecellular carbohydrate metabolism. Here we show that senescent fibroblasts enter into a metabolicimbalance, associated with a strong reduction in the levels of ribonucleotide triphosphates, including ATP,which are required for nucleotide biosynthesis and hence proliferation. ATP depletion in senescentfibroblasts is due to dysregulation of glycolytic enzymes, and finally leads to a drastic increase in cellularAMP, which is shown here to induce premature senescence. These results suggest that metabolicregulation plays an important role during cellular senescence and hence tumour suppression.", "metadata": {}}
+{"_id": "35612665", "title": "", "text": "Identification of an H2-M3-restricted Listeria epitope: implications for antigen presentation by M3.Usingexpression cloning, we have identified an H2-M3-restricted epitope of the intracellular bacterial pathogenListeria monocytogenes. Picomolar concentrations of an amino-terminal N-formylated hexapeptide,fMIGWII, targeted cells for lysis by CD8+ cytotoxic T cells, while the nonformylated peptide wasapproximately 100-fold less active. The sequence of the 185 aa protein source of this epitope predicts atransmembrane protein that retains its N terminus and assumes an N(out)-C(in) topology. Thismembrane orientation offers an explanation for the protection of the epitope from deformylases presentin the bacterial cell and suggests an explanation for the ability of phagocytes to present H2-M3-restrictedbacterial epitopes via a vacuolar TAP-independent mechanism.", "metadata": {}}
+{"_id": "35621259", "title": "", "text": "High-resolution peripheral quantitative computed tomographic imaging of cortical and trabecular bonemicroarchitecture in patients with type 2 diabetes mellitus.CONTEXT Cross-sectional epidemiologicalstudies have found that patients with type 2 diabetes mellitus (T2DM) have a higher incidence of certainfragility fractures despite normal or elevated bone mineral density (BMD). OBJECTIVE In this study,high-resolution peripheral quantitative computed tomography was applied to characterize cortical andtrabecular microarchitecture and biomechanics in the peripheral skeleton of female patients with T2DM.DESIGN AND SETTING A cross-sectional study was conducted in patients with T2DM recruited from adiabetic outpatient clinic. PARTICIPANTS Elderly female patients (age, 62.9 ± 7.7 yr) with a history ofT2DM (n = 19) and age- and height-matched controls (n = 19) were recruited. OUTCOME MEASURESSubjects were imaged using high-resolution peripheral quantitative computed tomography at the distalradius and tibia. Quantitative measures of volumetric (BMD), cross-sectional geometry, trabecular andcortical microarchitecture were calculated. Additionally, compressive mechanical properties weredetermined by micro-finite element analysis. RESULTS Compared to the controls, the T2DM cohort had10% higher trabecular volumetric BMD (P < 0.05) adjacent to the cortex and higher trabecular thicknessin the tibia (13.8%; P < 0.05). Cortical porosity differences alone were consistent with impaired bonestrength and were significant in the radius (>+50%; P < 0.05), whereas pore volume approachedsignificance in the tibia (+118%; P = 0.1). CONCLUSION The results of this pilot investigation provide apotential explanation for the inability of standard BMD measures to explain the elevated fractureincidence in patients with T2DM. The findings suggest that T2DM may be associated with impairedresistance to bending loads due to inefficient redistribution of bone mass, characterized by loss ofintracortical bone offset by an elevation in trabecular bone density.", "metadata": {}}
+{"_id": "35651106", "title": "", "text": "Critical role of CD28 in protective immunity against Salmonella typhimurium.Efficient T cell activationrequires both TCR signals and costimulatory signals. CD28 is one of the molecules that providecostimulatory signals for T cells. We used mice deficient in CD28 expression (CD28-/- mice) to analyzethe role of CD28 in the immune response against the intracellular bacterium Salmonella typhimurium, thecausative agent of murine typhoid fever. CD28-/- mice were highly susceptible to infection with wild-typeS. typhimurium and even failed to control infection with attenuated aroA- S. typhimurium. More detailedanalysis revealed that CD28-/- animals did not mount a T-dependent Ab response and were highlyimpaired in the production of IFN-gamma. Thus, CD28 cosignaling is crucial for immunity against S.typhimurium. To our knowledge, this is the first report describing an essential role for CD28 in protectiveimmunity against an intracellular microbial pathogen.", "metadata": {}}
+{"_id": "35660758", "title": "", "text": "D3 phosphoinositides and outside-in integrin signaling by glycoprotein IIb-IIIa mediate platelet actinassembly and filopodial extension induced by phorbol 12-myristate 13-acetate.Phorbol 12-myristate13-acetate (PMA) uncaps a small number of the fast-growing (barbed) ends of actin filaments, therebyeliciting slow actin assembly and extension of filopodia in human blood platelets. These reactions, whichalso occur in response to immunologic perturbation of the integrin glycoprotein (GP) IIb-IIIa, aresensitive to the phosphoinositide 3-kinase inhibitor wortmannin. Platelets deficient in GPIIb-IIIa integrinsor with GPIIb-IIIa function inhibited by calcium chelation or the peptide RGDS have diminished PMAresponsiveness. The effects of PMA contrast with thrombin receptor stimulation by >/=5 microM thrombinreceptor-activating peptide (TRAP), which causes rapid and massive wortmannin-insensitive actinassembly and lamellar and filopodial extension. However, we show here that wortmannin can inhibitfilopod formation if the thrombin receptor is ligated using suboptimal doses (<1 microM) of TRAP.Phosphatidylinositol 3,4-bisphosphate inhibits actin filament severing and capping by human gelsolin invitro. The findings implicate D3 polyphosphoinositides and integrin signaling in PMA-mediated plateletstimulation and implicate D3 containing phosphoinositides generated in response to protein kinase Cactivation and GPIIb-IIIa signaling as late-acting intermediates leading to filopodial actin assembly.", "metadata": {}}
+{"_id": "35684881", "title": "", "text": "`Gain of function' phenotype of tumor-derived mutant p53 requires theoligomerization/nonsequence-specific nucleic acid-binding domainTumor-derived p53 mutants cantranscriptionally activate a number of promoters of genes involved in cellular proliferation. For thistransactivation, mutant p53 does not use the wild-type p53 DNA-binding site, suggesting a mechanism oftransactivation that is independent of direct DNA binding. Here we describe our analysis of the domainrequirements for mutant p53 to transactivate promoters of the human epidermal growth factor receptor(EGFR), human multiple drug resistance 1 (MDR-1) and human proliferating cell nuclear antigen (PCNA)genes. We also report the identification of a structural domain required for the `gain of function' propertyof mutant p53-281G. `Gain of function' is measured as the tumorigenicity (in nude mice) of 10(3) murinecells expressing mutant p53 constitutively. We have generated internal deletion mutants of p53-281Gdeleting conserved domains I, II, III, IV and V, individually. We have also generated one deletion mutanteliminating amino acids 100 through 300 that removes four of the five conserved domains (II–V);another mutant, p53-281G del 393-327, deletes the oligomerization and nonsequence-specific nucleicacid-binding domains of p53. For the EGFR and MDR-1 promoters, all these mutants have significantlylower transactivation ability than intact p53-281G. These deletion mutants, however, significantlyactivated the pCNA promoter, suggesting that the mechanism of transactivation of the PCNA promoter isdifferent from that of the EGFR and MDR-1 promoters. When expressed constitutively in 10(3) cells,p53-281G del 393-327 was found to be defective in inducing tumor formation in nude mice althoughintact p53-281G was very efficient. Thus, our results suggest that structural domains near the C-terminusare needed for `gain of function'.", "metadata": {}}
+{"_id": "35711485", "title": "", "text": "Banana contains a diverse array of endogenous badnaviruses.Banana streak disease is caused by severaldistinct badnavirus species, one of which is Banana streak Obino l'Ewai virus. Banana streak Obino l'Ewaivirus has severely hindered international banana (Musa spp.) breeding programmes, as new hybrids arefrequently infected with this virus, curtailing any further exploitation. This infection is thought to arisefrom viral DNA integrated in the nuclear genome of Musa balbisiana (B genome), one of the wild speciescontributing to many of the banana cultivars currently grown. In order to determine whether the DNA ofother badnavirus species is integrated in the Musa genome, PCR-amplified DNA fragments from Musaacuminata, M. balbisiana and Musa schizocarpa, as well as cultivars 'Obino l'Ewai' and 'Klue Tiparot', werecloned. In total, 103 clones were sequenced and all had similarity to open reading frame III in thebadnavirus genome, although there was remarkable variation, with 36 distinct sequences beingrecognized with less than 85 % nucleotide identity to each other. There was no commonality in thesequences amplified from M. acuminata and M. balbisiana, suggesting that integration occurred followingthe separation of these species. Analysis of rates of non-synonymous and synonymous substitutionsuggested that the integrated sequences evolved under a high degree of selective constraint as might beexpected for a living badnavirus, and that each distinct sequence resulted from an independentintegration event.", "metadata": {}}
+{"_id": "35714909", "title": "", "text": "Pregnancy in women with type 1 diabetes: have the goals of St. Vincent declaration been met concerningfoetal and neonatal complications?OBJECTIVE In 1989 the St. Vincent declaration set a five-year targetfor approximating outcomes of pregnancies in women with diabetes to those of the backgroundpopulation. We investigated and quantified the risk of adverse pregnancy outcomes in pregnant womenwith type 1 diabetes (T1DM) to evaluate if the goals of the 1989 St. Vincent Declaration have beenobtained concerning foetal and neonatal complications. METHODS Twelve population-based studiespublished within the last 10 years with in total 14,099 women with T1DM and 4,035,373 women from thebackground population were identified. The prevalence of four foetal and neonatal complications wascompared. RESULTS In women with T1DM versus the background population, congenital malformationsoccurred in 5.0% (2.2-9.0) (weighted mean and range) versus 2.1% (1.5-2.9), relative risk (RR) = 2.4,perinatal mortality in 2.7% (2.0-6.6) versus 0.72% (0.48-0.9), RR = 3.7, preterm delivery in 25.2%(13.0-41.7) versus 6.0% (4.7-7.1), RR = 4.2 and delivery of large for gestational infants in 54.2%(45.1-62.5) versus 10.0%, RR = 4.5. Early pregnancy HbA1c was positively associated with adversepregnancy outcomes. CONCLUSION The risk of adverse pregnancy outcomes was two to five timesincreased in women with T1DM compared with the general population. The goals of the St. Vincentdeclaration have not been achieved.", "metadata": {}}
+{"_id": "35724562", "title": "", "text": "BP control and left ventricular hypertrophy regression in children with CKD.In adult patients with CKD,hypertension is linked to the development of left ventricular hypertrophy, but whether this associationexists in children with CKD has not been determined conclusively. To assess the relationship between BPand left ventricular hypertrophy, we prospectively analyzed data from the Chronic Kidney Disease inChildren cohort. In total, 478 subjects were enrolled, and 435, 321, and 142 subjects remained enrolledat years 1, 3, and 5, respectively. Echocardiograms were obtained 1 year after study entry and thenevery 2 years; BP was measured annually. A linear mixed model was used to assess the effect of BP onleft ventricular mass index, which was measured at three different visits, and a mixed logistic model wasused to assess left ventricular hypertrophy. These models were part of a joint longitudinal and survivalmodel to adjust for informative dropout. Predictors of left ventricular mass index included systolic BP,anemia, and use of antihypertensive medications other than angiotensin-converting enzyme inhibitors orangiotensin receptor blockers. Predictors of left ventricular hypertrophy included systolic BP, female sex,anemia, and use of other antihypertensive medications. Over 4 years, the adjusted prevalence of leftventricular hypertrophy decreased from 15.3% to 12.6% in a systolic BP model and from 15.1% to12.6% in a diastolic BP model. These results indicate that a decline in BP may predict a decline in leftventricular hypertrophy in children with CKD and suggest additional factors that warrant additionalinvestigation as predictors of left ventricular hypertrophy in these patients.", "metadata": {}}
+{"_id": "35747505", "title": "", "text": "Nicotinic Acid Adenine Dinucleotide 2'-Phosphate (NAADP) Binding Proteins in T-Lymphocytes.Nicotinicacid adenine dinucleotide phosphate (NAADP) is a messenger that regulates calcium release fromintracellular acidic stores. Although several channels, including two-pore channels (TPC), ryanodinereceptor (RYR) and mucolipin (TRP-ML1) have been implicated in NAADP regulation of calcium signaling,the NAADP receptor has not been identified. In this study, the photoaffinity probe, [32P]-5-azido-NAADP([32P]-5-N3-NAADP), was used to study NAADP binding proteins in extracts from NAADP responsiveJurkat T-lymphocytes. [32P]-5-N3-NAADP photolabeling of Jurkat S100 cytosolic fractions resulted in thelabeling of at least ten distinct proteins. Several of these S100 proteins, including a doublet at 22/23 kDaand small protein at 15 kDa displayed selectivity for NAADP as the labeling was protected by inclusion ofunlabeled NAADP, whereas the structurally similar NADP required much higher concentrations forprotection. Interestingly, the labeling of several S100 proteins (60, 45, 33 and 28 kDa) was stimulated bylow concentrations of unlabeled NAADP, but not by NADP. The effect of NAADP on the labeling of the 60kDa protein was biphasic, peaking at 100 nM with a five-fold increase and displaying no change at 1 µMNAADP. Several proteins were also photolabeled when the P100 membrane fraction from Jurkat cells wasexamined. Similar to the results with S100, a 22/23 kDa doublet and a 15 kDa protein appeared to beselectively labeled. NAADP did not increase the labeling of any P100 proteins as it did in the S100fraction. The photolabeled S100 and P100 proteins were successfully resolved by two-dimensional gelelectrophoresis. [32P]-5-N3-NAADP photolabeling and two-dimensional electrophoresis should representa suitable strategy in which to identify and characterize NAADP binding proteins.", "metadata": {}}
+{"_id": "35760786", "title": "", "text": "Loss of subcellular lipid transport due to ARV1 deficiency disrupts organelle homeostasis and activates theunfolded protein response.The ARV1-encoded protein mediates sterol transport from the endoplasmicreticulum (ER) to the plasma membrane. Yeast ARV1 mutants accumulate multiple lipids in the ER andare sensitive to pharmacological modulators of both sterol and sphingolipid metabolism. Using fluorescentand electron microscopy, we demonstrate sterol accumulation, subcellular membrane expansion,elevated lipid droplet formation, and vacuolar fragmentation in ARV1 mutants. Motif-based regressionanalysis of ARV1 deletion transcription profiles indicates activation of Hac1p, an integral component ofthe unfolded protein response (UPR). Accordingly, we show constitutive splicing of HAC1 transcripts,induction of a UPR reporter, and elevated expression of UPR targets in ARV1 mutants. IRE1, encoding theunfolded protein sensor in the ER lumen, exhibits a lethal genetic interaction with ARV1, indicating aviability requirement for the UPR in cells lacking ARV1. Surprisingly, ARV1 mutants expressing a variantof Ire1p defective in sensing unfolded proteins are viable. Moreover, these strains also exhibitconstitutive HAC1 splicing that interacts with DTT-mediated perturbation of protein folding. These datasuggest that a component of UPR induction in arv1Δ strains is distinct from protein misfolding. DecreasedARV1 expression in murine macrophages also results in UPR induction, particularly up-regulation ofactivating transcription factor-4, CHOP (C/EBP homologous protein), and apoptosis. Cholesterol loadingor inhibition of cholesterol esterification further elevated CHOP expression in ARV1 knockdown cells.Thus, loss or down-regulation of ARV1 disturbs membrane and lipid homeostasis, resulting in a disruptionof ER integrity, one consequence of which is induction of the UPR.", "metadata": {}}
+{"_id": "35764259", "title": "", "text": "IL-28, IL-29 and their class II cytokine receptor IL-28RCytokines play a critical role in modulating theinnate and adaptive immune systems. Here, we have identified from the human genomic sequence afamily of three cytokines, designated interleukin 28A (IL-28A), IL-28B and IL-29, that are distantlyrelated to type I interferons (IFNs) and the IL-10 family. We found that like type I IFNs, IL-28 and IL-29were induced by viral infection and showed antiviral activity. However, IL-28 and IL-29 interacted with aheterodimeric class II cytokine receptor that consisted of IL-10 receptor β (IL-10Rβ) and an orphan classII receptor chain, designated IL-28Rα. This newly described cytokine family may serve as an alternativeto type I IFNs in providing immunity to viral infection.", "metadata": {}}
+{"_id": "35766603", "title": "", "text": "High-dose recombinant tumor necrosis factor alpha in combination with interferon gamma and melphalanin isolation perfusion of the limbs for melanoma and sarcoma.PURPOSE To determine the toxicity and thetherapeutic efficacy of the combination of the recombinant tumor necrosis factor alpha (rTNF alpha),recombinant interferon gamma (rIFN-gamma), and melphalan, we designed a protocol using isolationlimb perfusion (ILP) with hyperthermia for in-transit metastases of melanoma and recurrent sarcoma.The triple combination was chosen because of the reported synergistic antitumor effect of rTNF alpha withIFN-gamma and of rTNF alpha with alkylating agents. PATIENTS AND METHODS Twenty-three patientsreceived a total of 25 ILPs with the triple combination. There were 19 females and four males with eithermultiple progressive in-transit melanoma metastases of the extremities (stage IIIa or IIIab; 19 patients)or recurrent soft tissue sarcoma (five). The rTNF alpha was injected as a bolus in the arterial line, andtotal dose ranged between 2 and 4 mg, under hyperthermic conditions (40 degrees C to 40.5 degrees C)for 90 minutes. The rIFN-gamma was given subcutaneously (SC) on days -2 and -1 and in the perfusate,with rTNF alpha at the dose of 0.2 mg. Melphalan (Alkeran; Burroughs Wellcome Co, London, England)was administered in the perfusate at 40 micrograms/mL.   RESULTS Toxicity observed during three ILPsin a pilot study with rTNF alpha included only two severe toxicities: one severe hypotension withtachycardia and transient oliguria and one moderate hypotension for 4 hours followed by severe kidneyfailure with complete recovery on day 29. In all 18 ILPs performed in the triple combination protocol, thepatients received continuous infusion dopamine at 3 micrograms/kg/min from the start of ILP and for 72hours and showed only mild hypotension and transient chills and temperature. Regional toxicityattributable to rTNF alpha was minimal. There have been 11 cases with hematologic toxicity consisting ofneutropenia (one grade 4 and one grade 3) and neutropenia with thrombocytopenia (one grade 4 andthree grade 2). Twelve patients had been previously treated with melphalan in ILP (11) or with cisplatin(one). The 23 patients are assessable: there have been 21 complete responses (CRs; range, 4 to 29months; 89%), two partial responses (PRs; range, 2 to 3 months), and no failures. Overall disease-freesurvival and survival have been 70% and 76%, respectively, at 12 months. In all cases, softening of thenodules was obvious within 3 days after ILP and time to definite response ranged between day 5 and 30.CONCLUSION This preliminary analysis of a phase II study suggests that high-dose rTNF alpha can beadministered with acceptable toxicity by ILP with dopamine and hyperhydration. Tumor responses can beevidenced in melanoma and sarcoma. Furthermore, combination of rTNF alpha, rIFN-gamma, andmelphalan seems to achieve high efficacy with minimal toxicity, even after failure of prior therapy withmelphalan alone.", "metadata": {}}
+{"_id": "35768199", "title": "", "text": "Methanosphaera stadtmaniae gen. nov., sp. nov.: a species that forms methane by reducing methanolwith hydrogenMethanosphaera stadtmaniae is a non-motile, Gram-positive spherical-shaped organismthat obtains energy for growth by using hydrogen to reduce methanol to methane. It does not producemethane from hydrogen and carbon dioxide, formate, acetate or methylamines and cannot grow withhydrogen and carbon monoxide, nitrate, fumarate, sulfate or choline. Its pH optimum is 6.5 to 6.9 and itstemperature optimum is 36° to 40° C. It is not inhibited by bile salts, inhibitors of the synthesis of folicacid coenzymes, cephalothin or clindamycin but is inhibited by metronidazole, bacitracin, monensin,lasalocid, or bromoethanesulfonate. It requires acetate, carbon dioxide, isoleucine, ammonium, andthiamin for growth and biotin is stimulatory. It does not contain cytochromes and the mol % G+C of itsDNA is 25.8. The composition of its cell wall and 16 S rRNA and its immunological fingerprint areconsistent with characterization of the organism as a member of a new genus of the familyMethanobacteriaceae. The habitat of the type strain is the human large intestine.", "metadata": {}}
+{"_id": "35777860", "title": "", "text": "Generation of induced pluripotent stem cells from Asian patients with chronic neurodegenerativediseases.Induced pluripotent stem (iPS) cells derived from disease patients are an invaluable resource forbiomedical research and may provide a source for replacement therapies. In this study, we havegenerated iPS cells from Asian patients with chronic degenerative diseases of the nervous system,including spinal muscular atrophy (SMA), Parkinson disease (PD) and amyotrophic lateral sclerosis (ALS)by transduction with four factors (KLF4, SOX2, OCT4 and c-MYC). All of the iPS cells showed pluripotencysimilar to that of human embryonic stem cells (hESCs) and were able to differentiate into various somaticcell types in vitro and in vivo. Furthermore, the iPS cells also can be committed to differentiate into neuralcells, the cell type that is affected in chronic degenerative diseases. Therefore, the patient-specific iPScells we generated offer a cellular model in which to investigate disease mechanisms, discover and testnovel drugs and develop new therapies for chronic neurodegenerative diseases.", "metadata": {}}
+{"_id": "35811036", "title": "", "text": "Embryonic-like stem cell derived from adult bone marrow: immature morphology, cell surface markers,ultramicrostructure and differentiation into multinucleated fibers in vitro.Embryonic-like stem cell (ELSC),expressing part of surface markers of human embryonic stem cells, may be a better candidate for celltherapy of degenerative muscular disease than mesenchymal stem cell (MSC). We isolated ELSC and MSCfrom bone marrow, respectively, and compared their differences in the characteristics and the capacity ofmyogenic differentiation. Results showed that ELSC could be isolated successfully from 3 adult bonemarrow samples by using serum-free medium with 10ng/ml basic fibroblast growth factor (bFGF). At thesame cell density, MSC could also be isolated from the same samples by using DMEM/F12 mediumcontaining 10% new cattle serum. However, ELSC appeared as small, morphologically slenderer,upregulated expression of SSEA-4 and ultramicroscopically more immature than MSC derived from thesame samples. Immunofluorescent staining and RT-PCR analysis showed ELSC weakly expressed Oct-4,Nanog-3 and Sox-2. Moreover, ELSC and MSC could be induced into long, multinucleated fibersexpressing myogenin and myosin heavy chain (MHC) in myogenic differentiation medium, but by day 10,proportion of multinucleated fibers positive for MHC was respectively 25.0%+/-6.9% and 13.8%+/-7.6%in ELSC and MSC culture. These data suggest that bone marrow derived ELSC represent an idealcandidate for cell therapy of degenerative muscular disease.", "metadata": {}}
+{"_id": "35828148", "title": "", "text": "Kinetic evidence for rapid oxidation of (-)-epicatechin by human myeloperoxidase.Apocynin has beenreported to require dimerization by myeloperoxidase (MPO) to inhibit leukocyte NADPH oxidase.(-)-Epicatechin, a dietary flavan-3-ol, has been identified as a 'prodrug' of apocynin-like metabolites thatinhibit endothelial NADPH oxidase activity and elevate the cellular level of nitric oxide. Since(-)-epicatechin has tentatively been identified as substrate of MPO, we studied the one-electron oxidationof (-)-epicatechin by MPO. By using multi-mixing stopped-flow technique, we demonstrate that(-)-epicatechin is one of the most efficient electron donors for heme peroxidases investigated so far.Second order rate constants for the (-)-epicatechin-mediated conversion of MPO-compound I tocompound II and compound II to resting enzyme were estimated to be 1.9 x 10(7) and 4.5 x 10(6)M(-1)s(-1), respectively (pH 7, 25 degrees C). The data indicate that (-)-epicatechin is capable ofundergoing fast MPO-mediated one-electron oxidation.", "metadata": {}}
+{"_id": "35861290", "title": "", "text": "Using the yeast gene deletion collection to customize gene expression.Substitute Teacher Despite therelative ease of genome manipulation in S. cerevisiae, researchers are always looking to learn still moreconvenient and rapid methods for substituting yeast promoters. Replacing a gene's native promoter witha heterolo-gous promoter of choice allows regulated expression and simplifies the task of discerningfunctional relevance. Although a host of clever chromosomal insertion strategies have been describedover the years, the advent of the S. cerevisiae Genome Deletion Project provides an incredible resourcefor a further streamlined workflow. The strategy, explained by Liko et al. on p. 728 is appealingly simple.The genome deletion project resulted in a collection of strains in which a single ORF is replaced with akanamycin resistance module. Although the purpose of the collection is to have a comprehensiveresource of essentially all possible knockouts, the authors point out that for almost any given yeastpromoter of interest there will be a strain in which the ORF imm...", "metadata": {}}
+{"_id": "35884026", "title": "", "text": "Tyrosine phosphorylation and regulation of the AMPA receptor by SRC family tyrosinekinases.Phosphorylation of AMPA receptors is a major mechanism for the regulation of receptor functionand underlies several forms of synaptic plasticity in the CNS. Although serine and threoninephosphorylation of AMPA receptors has been well studied, the potential role of tyrosine phosphorylation ofAMPA receptors has not been investigated. Here, we show that the GluR2 subunit of AMPA receptors istyrosine phosphorylated in vitro and in vivo by Src family tyrosine kinases on tyrosine 876 near its Cterminus. In addition, GluR agonist treatment of cultured cortical neurons increased phosphorylation oftyrosine 876. The association with GluR2-interacting molecules GRIP1/2 was decreased by tyrosinephosphorylation of GluR2, whereas PICK1 interaction was not influenced. Moreover, mutation of tyrosine876 eliminated AMPA- and NMDA-induced internalization of the GluR2 subunit. These data indicate thattyrosine phosphorylation of tyrosine 876 on the GluR2 C terminus by Src family tyrosine kinases isimportant for the regulation of AMPA receptor function and may be important for synaptic plasticity.", "metadata": {}}
+{"_id": "35962023", "title": "", "text": "tBid induces alterations of mitochondrial fatty acid oxidation flux by malonyl-CoA-independent inhibitionof carnitine palmitoyltransferase-1Recent studies suggest a close relationship between cell metabolismand apoptosis. We have evaluated changes in lipid metabolism on permeabilized hepatocytes treated withtruncated Bid (tBid) in the presence of caspase inhibitors and exogenous cytochrome c. Themeasurement of β-oxidation flux by labeled palmitate demonstrates that tBid inhibits β-oxidation,thereby resulting in the accumulation of palmitoyl-coenzyme A (CoA) and depletion of acetyl-carnitineand acylcarnitines, which is pathognomonic for inhibition of carnitine palmitoyltransferase-1 (CPT-1). Wealso show that tBid decreases CPT-1 activity by a mechanism independent of both malonyl-CoA, the keyinhibitory molecule of CPT-1, and Bak and/or Bax, but dependent on cardiolipin decrease. Overexpressionof Bcl-2, which is able to interact with CPT-1, counteracts the effects exerted by tBid on β-oxidation. Theunexpected role of tBid in the regulation of lipid β-oxidation suggests a model in which tBid-inducedmetabolic decline leads to the accumulation of toxic lipid metabolites such as palmitoyl-CoA, which mightbecome participants in the apoptotic pathway.", "metadata": {}}
+{"_id": "35987381", "title": "", "text": "CD8+ T cells are activated in an antigen-independent manner in HIV-infected individuals.Hyperactivationof T cells, particularly of CD8(+) T cells, is a hallmark of chronic HIV 1 (HIV-1) infection. Little is knownabout the antigenic specificities and the mechanisms by which HIV-1 causes activation of CD8(+) T cellsduring chronic infection. We report that CD8(+) T cells were activated during in vivo HIV-1 replicationirrespective of their Ag specificity. Cytokines present during untreated HIV-1 infection, most prominentlyIL-15, triggered proliferation and expression of activation markers in CD8(+) T cells, but not CD4(+) Tcells, in the absence of TCR stimulation. Moreover, LPS or HIV-1-activated dendritic cells (DCs)stimulated CD8(+) T cells in an IL-15-dependent but Ag-independent manner, and IL-15 expression washighly increased in DCs isolated from viremic HIV-1 patients, suggesting that CD8(+) T cells are activatedby inflammatory cytokines in untreated HIV-1 patients independent of Ag specificity. This findingcontrasts with CD4(+) T cells whose in vivo activation seems biased toward specificities for persistentAgs. These observations explain the higher abundance of activated CD8(+) T cells compared with CD4(+)T cells in untreated HIV-1 infection.", "metadata": {}}
+{"_id": "35993767", "title": "", "text": "Cancer-associated fibroblasts promote hepatocellular carcinoma metastasis through chemokine-activatedhedgehog and TGF-β pathways.Fibroblasts are rich in the surrounding microenvironment of hepatocellularcarcinoma (HCC) because most HCCs occur in fibrotic or cirrhotic livers. However, the role ofcancer-associated fibroblasts (CAFs) in HCC metastasis remains obscure. Here, we reported that CAFspromote the migration and invasion of HCC cells in vitro and facilitate the HCC metastasis to the bone,brain and lung in NOD/SCID mice. The RayBio human chemokine antibody array revealed that CAFssecret higher levels of CCL2, CCL5, CCL7 and CXCL16 than peri-tumor fibroblasts. CCL2 and CCL5increase the migration but not the invasion of HCC cells, while CCL7 and CXCL16 promote both migrationand invasion of HCC cells. Moreover, CCL2 and CCL5 stimulate the activation of the hedgehog (Hh)pathway, while CCL7 and CXCL16 enhance the activity of the transforming growth factor-β (TGF-β)pathway in HCC cells. The neutralizing antibodies of chemokines notably attenuate the effect of CAFs onHCC metastasis and compromised the activation of Hh and TGF-β pathways in HCC cells. In summary,CAF-secreted CCL2, CCL5, CCL7 and CXCL16 promote HCC metastasis through the coordinate activationof Hh and TGF-β pathways in HCC cells.", "metadata": {}}
+{"_id": "36003142", "title": "", "text": "Mortality risk in patients with dementia treated with antipsychotics versus other psychiatricmedications.OBJECTIVE Mortality rates in the year following new antipsychotic medication starts forneuropsychiatric symptoms of dementia were compared with rates after starts of other psychiatricmedications. METHOD The retrospective, cohort study used national data from the Department ofVeterans Affairs (fiscal years 2001-2005) on patients older than 65 years who began outpatienttreatment with psychiatric medication following a dementia diagnosis (N=10,615). Twelve-monthmortality rates were compared in patients taking antipsychotics and those taking other psychiatricmedications. The authors controlled for confounding by using multivariate models and propensity-scoringmethods. Secondary analyses included a no-medication group and examination of mortality causes.RESULTS All groups taking antipsychotics had significantly higher mortality rates (22.6%-29.1%) thanpatients taking nonantipsychotic medications (14.6%). Adjusted mortality risks for atypicals and forcombined atypical and conventional antipsychotics were similar to those for conventional antipsychotics.The mortality risk was significantly lower for nonantipsychotic medications than conventionalantipsychotics. Except for anticonvulsants, the adjusted risks for all individual classes ofnonantipsychotics were significantly lower than the risk for antipsychotics. Mortality risks did not changeover 12 months. The proportions of patients taking antipsychotics who died from cerebrovascular,cardiovascular, or infectious causes were not higher than rates for those taking nonantipsychoticpsychiatric medications. CONCLUSIONS Antipsychotic medications taken by patients with dementia wereassociated with higher mortality rates than were most other medications used for neuropsychiatricsymptoms. The association between mortality and antipsychotics is not well understood and may be dueto a direct medication effect or the pathophysiology underlying neuropsychiatric symptoms that promptantipsychotic use.", "metadata": {}}
+{"_id": "36025357", "title": "", "text": "Glutathione: overview of its protective roles, measurement, and biosynthesis.This review is theintroduction to a special issue concerning, glutathione (GSH), the most abundant low molecular weightthiol compound synthesized in cells. GSH plays critical roles in protecting cells from oxidative damage andthe toxicity of xenobiotic electrophiles, and maintaining redox homeostasis. Here, the functions and GSHand the sources of oxidants and electrophiles, the elimination of oxidants by reduction and electrophilesby conjugation with GSH are briefly described. Methods of assessing GSH status in the cells are alsodescribed. GSH synthesis and its regulation are addressed along with therapeutic approaches formanipulating GSH content that have been proposed. The purpose here is to provide a brief overview ofsome of the important aspects of glutathione metabolism as part of this special issue that will provide amore comprehensive review of the state of knowledge regarding this essential molecule.", "metadata": {}}
+{"_id": "36033696", "title": "", "text": "A wellness class for inpatients with psychotic disorders.OBJECTIVE The purpose of this project was toeducate inpatients with psychotic disorders, many of whom were taking second-generationantipsychotics, about lifestyle changes they can make to combat weight gain. METHOD All inpatients on aVeterans Affairs acute inpatient schizophrenia treatment unit were invited to a 30-minute, didacticpresentation given by a medical student and a psychology student under the supervision of the primaryinvestigator. The topics covered included the health benefits of maintaining an ideal body weight byselecting foods according to the USDA Food Pyramid, determining adequate food portions, choosinghealthy meals outside the home, and beginning and adhering to an exercise program. Subjectscompleted a 13-item quiz concerning their knowledge of food and nutrition before and after thepresentation to determine its efficacy in teaching patients the material. RESULTS Fifty patients completedboth the pre- and post-presentation tests. The mean percentage of correct answers on the pre-test was85.6%, which rose to 89.3% on the post-test. This difference of 3.7% was statistically significant (t =2.43, df = 49, p < 0.02), and the mean percent of improvement was 6.1%. CONCLUSIONS This studydemonstrates that psychotic individuals are able to benefit from educational presentations about nutritionand a healthy lifestyle. A statistically significant improvement in test scores suggests that subjects gainedan understanding of basic concepts related to food choices and fitness.", "metadata": {}}
+{"_id": "36066871", "title": "", "text": "Heterochromatin integrity affects chromosome reorganization after centromere dysfunction.Thecentromere is essential for the inheritance of genetic information on eukaryotic chromosomes. Epigeneticregulation of centromere identity has been implicated in genome stability, karyotype evolution, andspeciation. However, little is known regarding the manner in which centromere dysfunction affects thechromosomal architectures. Here we show that in the fission yeast Schizosaccharomyces pombe, theconditional deletion of the centromere produces survivors that carry either a neocentromere-acquiredchromosome at the subtelomeric region or an acentric chromosome rescued by intertelomere fusion witheither of the remaining chromosomes. The ratio of neocentromere formation to telomere fusion isconsiderably decreased by the inactivation of genes involved in RNA interference-dependentheterochromatin formation. By affecting the modes of chromosomal reorganization, the genomicdistribution of heterochromatin may influence the fate of karyotype evolution.", "metadata": {}}
+{"_id": "36082224", "title": "", "text": "Expansion and deletion of CTG repeats from human disease genes are determined by the direction ofreplication in E. coliSeveral human hereditary neurological and neurodegenerative disease genes areassociated with the expansion of CTG repeats. Here we show that the frequency of genetic expansions ordeletions in Escherichia coli depends on the direction of replication. Large expansions occurpredominantly when the CTGs are in the leading strand template rather than the lagging strand.However, deletions are more prominant when the CTGs are in the opposite orientation. Most deletionsgenerated products of defined size classes. Strand slippage coupled with non–classical DMA structuresmay account for these observations and relate to expansion–deletion mechanisms in eukaryoticchromosomes for disease genes.", "metadata": {}}
+{"_id": "36089763", "title": "", "text": "Neutrophil extracellular traps capture and kill Candida albicans yeast and hyphal forms.Neutrophilsphagocytose and kill microbes upon phagolysosomal fusion. Recently we found that activated neutrophilsform extracellular fibres that consist of granule proteins and chromatin. These neutrophil extracellulartraps (NETs) degrade virulence factors and kill Gram positive and negative bacteria. Here we show for thefirst time that Candida albicans, a eukaryotic pathogen, induces NET-formation and is susceptible toNET-mediated killing. C. albicans is the predominant aetiologic agent of fungal infections in humans,particularly in immunocompromised hosts. One major virulence trait of C. albicans is its ability toreversibly switch from singular budding cells to filamentous hyphae. We demonstrate that NETs kill bothyeast-form and hyphal cells, and that granule components mediate fungal killing. Taken together ourdata indicate that neutrophils trap and kill ascomycetous yeasts by forming NETs.", "metadata": {}}
+{"_id": "36111909", "title": "", "text": "Katanin p60-like1 promotes microtubule growth and terminal dendrite stability in the larval class IVsensory neurons of Drosophila.Dendrite shape is considered a defining component of neuronal function.Yet, the mechanisms specifying diverse dendritic morphologies, and the extent to which their functiondepends on these morphologies, remain unclear. Here, we demonstrate a requirement for themicrotubule-severing protein katanin p60-like 1 (Kat-60L1) in regulating the elaborate dendritemorphology and nocifensive functions of Drosophila larval class IV dendritic arborization neurons.Kat-60L1 mutants exhibit diminished responsiveness to noxious mechanical and thermal stimuli. Class IVdendrite branch number and length are also reduced, supporting a correspondence between neuronalfunction and the full extent of the dendritic arbor. These arborization defects occur particularly in latelarval development, and live imaging reveals that Kat-60L1 is required for dynamic, filopodia-like nascentbranches to stabilize during this stage. Mutant dendrites exhibit fewer EB1-GFP-labeled microtubules,suggesting that Kat-60L1 increases polymerizing microtubules to establish terminal branch stability andfull arbor complexity. Although loss of the related microtubule-severing protein Spastin also reduces theclass IV dendrite arbor, microtubule polymerization within dendrites is unaffected. Conversely, Spastinoverexpression destroys stable microtubules within these neurons, while Kat-60L1 has no effect.Kat-60L1 thus sculpts the class IV dendritic arbor through microtubule regulatory mechanisms distinctfrom Spastin. Our data support differential roles of microtubule-severing proteins in regulating neuronalmorphology and function, and provide evidence that dendritic arbor development is the product ofmultiple pathways functioning at distinct developmental stages.", "metadata": {}}
+{"_id": "36124058", "title": "", "text": "Update on technical issues concerning complementary feeding of young children in developing countriesand implications for intervention programs.This paper provides an update to the 1998 WHO/UNICEFreport on complementary feeding. New research findings are generally consistent with the guidelines inthat report, but the adoption of new energy and micronutrient requirements for infants and youngchildren will result in lower recommendations regarding minimum meal frequency and energy density ofcomplementary foods, and will alter the list of \"problem nutrients. \" Without fortification, the densities ofiron, zinc, and vitamin B6 in complementary foods are often inadequate, and the intake of other nutrientsmay also be low in some populations. Strategies for obtaining the needed amounts of problem nutrients,as well as optimizing breastmilk intake when other foods are added to the diet, are discussed. The impactof complementary feeding interventions on child growth has been variable, which calls attention to theneed for more comprehensive programs. A six-step approach to planning, implementing, and evaluatingsuch programs is recommended.", "metadata": {}}
+{"_id": "36178047", "title": "", "text": "Decrease of learning capacity in offspring with increasing paternal age in the rat.The same 15 maleWistar rats at the ages of 2.5, 6, 10, 14, 18, and 22 months were successively randomly mated with2.5-month-old females. In a separate experiment, 15 male Wistar rats at the age of 2.5 months and 15at the age of 23 months were simultaneously randomly mated with 2.5-month-old females. Offspringwere evaluated in regard to the mean number per litter, sex ratio, frequency of gross externalmalformations, growth pattern, and mortality in the first 13 weeks of life and reproductive capacity at 13weeks of age. They were also evaluated for spontaneous activity and emotionality with an open field testand for learning capacity with an avoidance conditioning test, both carried out between 10 and 13 weeksof age. Only learning capacity of the offspring, expressed in percentage of success for male or female,decreased consistently and significantly as the father's age increased. But females did not seem to beaffected in the same way as males. The genetic implications are briefly discussed.", "metadata": {}}
+{"_id": "36180468", "title": "", "text": "Processing of the beta-amyloid precursor. Multiple proteases generate and degrade potentiallyamyloidogenic fragments.Proteolytic processing of the beta-amyloid precursor proteins (APP) is requiredfor release of the beta/A4 protein and its deposition into the amyloid plaques characteristic of aging andAlzheimer's disease. We have examined the involvement of acidic intracellular compartments in APPprocessing in cultured human cells. The use of acidotropic agents and inhibitors to a specific class oflysosomal protease, coupled with metabolic labeling and immunoprecipitation, revealed that APP isdegraded within an acidic compartment to produce at least 12 COOH-terminal fragments. Nine likelycontain the entire beta/A4 domain and, therefore, are potentially amyloidogenic. Treatment with E64 orZ-Phe-Ala-CHN2 irreversibly blocked activities of the lysosomal cysteine proteases cathepsins B and L butdid not inhibit the lysosomal aspartic protease cathepsin D and did not alter the production of potentiallyamyloidogenic fragments. Instead, the inhibitors prevented further degradation of the fragments. Thus,large numbers of potentially amyloidogenic fragments of APP are routinely generated in an acidiccompartment by noncysteine proteases and then are eliminated within lysosomes by cysteine proteases.Immunoblot and immunohistochemical analyses confirmed that chronic cysteine protease inhibition leadsto accumulation of potentially amyloidogenic APP fragments in lysosomes. The results provide furthersupport for the hypothesis that an acidic compartment may be involved in amyloid formation and begin todefine the proteolytic events that may be important for amyloidogenesis.", "metadata": {}}
+{"_id": "36202354", "title": "", "text": "Pharmaceutical Public-Private Partnerships in the United States and Europe: Moving from the Bench tothe BedsideBoth to address unmet medical needs and to improve industry competitiveness, regulators inboth the United States and the European Union have taken bold steps to translate academic researchfrom the university lab to the patient. A pharmaceutical public-private partnership (PPPP), which is alegally binding contract between a private pharmaceutical enterprise and a public research university (ora private university doing research funded with public funds), can be a significant tool to ensure a moreefficient payoff in the highly regulated world of pharmaceuticals. In particular, a properly framed bindingcontract, coupled with respect for positive social norms, can move the parties away from an inefficientprisoners’ dilemma Nash Equilibrium to the Pareto Optimal Frontier. When coupled with appropriateattention to the difficult task of coordinating the actions of interdependent actors, a PPPP arrangementcan enhance the likelihood of successful commercialization by flipping the parties’ incentives as comparedwith more traditional contracts. Because PPPPs are less common in Europe than in the United States, akey purpose of this article is to provide an annotated roadmap that universities, private firms, and EUpolicy makers can use to create efficient PPPPs to enhance for-profit innovation in the pharmaceuticalindustry in Europe. A secondary purpose is to suggest amendments to the U.S. laws governing thepatenting of government-funded technology to prevent undue burdens on the sharing of certain upstreammedical discoveries and research tools. Our analysis is not only comparative; it also combines, we believefor the first time, a game theory and law and management approach to for-profit PPPPs.", "metadata": {}}
+{"_id": "36211049", "title": "", "text": "Chronic stress and psychological well-being: evidence from Thailand on household crowding.This paperexamines the effect of one form of chronic stress--household crowding--on psychological well-being, asmeasured by multiple inverse indicators of psychological well-being. We rely on data from a large (n =2017) random sample of households in Bangkok, Thailand, a context that has a higher level and broaderrange of crowding than typically found in the United States. Objective household crowding is found to bedetrimental to psychological well-being, controlling for a number of background characteristics. The effectof objective crowding is mediated by subjective crowding, which has strong, consistent and directdetrimental effects on well-being. There is no evidence of a gender effect. Extended family householdsare not uncommon in Bangkok, but the effects of objective and subjective crowding are similar in bothtwo- and three-generation households, as well as in one- and multiple-couple households. The argumentthat subjective crowding is an effect, rather than a cause, of psychological well-being is examined andrejected. The findings suggest that crowding, as a chronic source of stress, constitutes a major threat topsychological well-being. Although the empirical analyses are based on data from one city, we frame theissue of household crowding in a historical and theoretical context in order to suggest in which culturalsettings household crowding is most likely to have detrimental effects on psychological well-being.", "metadata": {}}
+{"_id": "36212758", "title": "", "text": "Age- and sex-specific genomic profiles in non-small cell lung cancer.CONTEXT Gene expression profilingmay be useful in examining differences underlying age- and sex-specific outcomes in non-small cell lungcancer (NSCLC). OBJECTIVE To describe clinically relevant differences in the underlying biology of NSCLCbased on patient age and sex. DESIGN, SETTING, AND PATIENTS Retrospective analysis of 787 patientswith predominantly early stage NSCLC performed at Duke University, Durham, North Carolina, from July2008 to June 2009. Lung tumor samples with corresponding microarray and clinical data were used. Allpatients were divided into subgroups based on age (< 70 vs > or = 70 years old) or sex. Gene expressionsignatures representing oncogenic pathway activation and tumor biology/microenvironment status wereapplied to these samples to obtain patterns of activation/deregulation. MAIN OUTCOME MEASURESPatterns of oncogenic and molecular signaling pathway activation that are reproducible and correlate with5-year recurrence-free patient survival. RESULTS Low- and high-risk patient clusters/cohorts wereidentified with the longest and shortest 5-year recurrence-free survival, respectively, within the age andsex NSCLC subgroups. These cohorts of NSCLC demonstrate similar patterns of pathway activation. Inpatients younger than 70 years, high-risk patients, with the shortest recurrence-free survival,demonstrated increased activation of the Src (25% vs 6%; P<.001) and tumor necrosis factor (76% vs42%; P<.001) pathways compared with low-risk patients. High-risk patients aged 70 years or olderdemonstrated increased activation of the wound healing (40% vs 24%; P = .02) and invasiveness (64%vs 20%; P<.001) pathways compared with low-risk patients. In women, high-risk patients demonstratedincreased activation of the invasiveness (99% vs 2%; P<.001) and STAT3 (72% vs 35%; P<.001)pathways while high-risk men demonstrated increased activation of the STAT3 (87% vs 18%; P<.001),tumor necrosis factor (90% vs 46%; P<.001), EGFR (13% vs 2%; P = .003), and wound healing (50% vs22%; P<.001) pathways. Multivariate analyses confirmed the independent clinical relevance of thepathway-based subphenotypes in women (hazard ratio [HR], 2.02; 95% confidence interval [CI],1.34-3.03; P<.001) and patients younger than 70 years (HR, 1.83; 95% CI, 1.24-2.71; P = .003). Allobservations were reproducible in split sample analyses. CONCLUSIONS Among a cohort of patients withNSCLC, subgroups defined by oncogenic pathway activation profiles were associated with recurrence-freesurvival. These findings require validation in independent patient data sets.", "metadata": {}}
+{"_id": "36216395", "title": "", "text": "Amelioration of colitis by genetically engineered murine regulatory T cells redirected by antigen-specificchimeric receptor.BACKGROUND & AIMS The therapeutic application of regulatory T cells (Tregs) for thetreatment of inflammatory diseases is limited by the scarcity of antigen-specific Tregs. A preferredapproach to endow effector T cells (Teff) with a desired specificity uses chimeric immune receptors withantibody-type specificity. Accordingly, employing such chimeric immune receptors to redirect Tregs tosites of inflammation may be a useful therapeutic approach to alleviate a broad scope of diseases inwhich an uncontrolled inflammatory response plays a major role. METHODS To enable application of theapproach in clinical setting, which requires the genetic modification of the patient's own Tregs, wedescribe here a novel protocol that allows the efficient retroviral transduction and2,4,6-trinitrophenol-specific expansion of murine naturally occurring regulatory T cells (nTregs), with a2,4,6-trinitrophenol-specific tripartite chimeric receptor. RESULTS Transduced Tregs maintained theirFoxp3 level, could undergo repeated expansion upon ex vivo encounter with their cognate antigen in amajor histocompatibility complex-independent, costimulation-independent, and contact-dependentmanner and specifically suppressed Teff cells. Adoptive transfer of small numbers of the transducednTregs was associated with antigen-specific, dose-dependent amelioration of trinitrobenzenesulphonicacid colitis. CONCLUSIONS This study demonstrates that nTregs can be efficiently transduced to expressfunctional, antigen-specific chimeric receptors that enable the specific suppression of effector T cells bothin vitro and in vivo. This approach may enable future cell-based therapeutic application in inflammatorybowel disease, as well as other inflammatory disorders.", "metadata": {}}
+{"_id": "36233757", "title": "", "text": "Purification and activation properties of UreD-UreF-urease apoprotein complexes.In vivo assembly of theKlebsiella aerogenes urease nickel metallocenter requires the presence of UreD, UreF, and UreGaccessory proteins and is further facilitated by UreE. Prior studies had shown that urease apoproteinexists in an uncomplexed form as well as in a series of UreD-urease (I.-S. Park, M.B. Carr, and R.P.Hausinger, Proc. Natl. Acad. Sci. USA 91:3233-3237, 1994) and UreD-UreF-UreG-urease (I.-S. Park andR.P. Hausinger, J. Bacteriol. 177:1947-1951, 1995) apoprotein complexes. This study demonstrates theexistence of a distinct series of complexes consisting of UreD, UreF, and urease apoprotein. These novelcomplexes exhibited activation properties that were distinct from urease and UreD-urease apoproteincomplexes. Unlike the previously described species, the UreD-UreF-urease apoprotein complexes wereresistant to inactivation by NiCl2. The bicarbonate concentration dependence for UreD-UreF-ureaseapoenzyme activation was significantly decreased compared with that of the urease and UreD-ureaseapoproteins. Western blot (immunoblot) analyses with polyclonal anti-urease and anti-UreD antibodiesindicated that UreD is masked in the UreD-UreF-urease complexes, presumably by UreF. We propose thatthe binding of UreF modulates the UreD-urease apoprotein activation properties by excluding nickel ionsfrom binding to the active site until after formation of the carbamylated lysine metallocenter ligand.", "metadata": {}}
+{"_id": "36242796", "title": "", "text": "Coordinate regulation of the IL-4, IL-13, and IL-5 cytokine cluster in Th2 clones revealed by allelicexpression patterns.The cytokines IL-4, IL-13, and IL-5 are markers for the Th2 subset of effector T cellsand are often expressed together. These cytokine genes are organized within 140 kb of orthologous DNAin both mouse and human. Using IL-4-expressing CD4+ T cell clones derived from F1 mice, we identifiedallelic polymorphisms for each of these cytokines and assessed the parental identity of the cytokinemRNAs. Both monoallelic and biallelic expression occurred for each gene and for an additional gene, IL-3,that lies with GM-CSF over 450 kb telomeric on the same chromosome. When coexpressed in T cellclones, IL-4 was expressed from the same allele as IL-13 or IL-5 in 81% of instances. In contrast, therewas only 52% concordance of these three cytokines at the allelic level among clones that expressed IL-3.Independent expression of the cytokine alleles occurs commonly in T cells, but the clustered locusencompassing IL-4, IL-13, and IL-5 is subject to coordinate regulation.", "metadata": {}}
+{"_id": "36271512", "title": "", "text": "T-cell activation.INTRODUCTION • • CELLULAR AND MOLECULAR REQUIREMENTS FOR T-CELLACTIVATION . The T-Cell Antigen Receptor Complex . . . .. . . . ..... . . . . . . . . . . . . . . . . ...... . . . T-CellActivation by Antibodies and Leetins . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . Other Cell Surface Structures (Accessory Molecules) Involved in Antigen Recognition andActivation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . Minimal Requirements/or T-Cell Activation . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CONSEQUE\u0000CES o\u0000, T-CELL AC::IV A TION ; .ExpressIOn of ActIVatIOn Anllgens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . Mechanisms of Signal Transmission via the TCR Complex . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . The Mode of Control of Gene Expression during T-Cell Activation . . . . .. . . . . . . . . . . . . . . . . . . . . The Mechanism of Action of IL-2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acquisition of Cytolytic Activity . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . .ANALOGIES WITH IMMATURE T CELLS .", "metadata": {}}
+{"_id": "36288526", "title": "", "text": "Effect of hydroxyethyl starch on bleeding after cardiopulmonary bypass: a meta-analysis of randomizedtrials.OBJECTIVE The effects of hydroxyethyl starch on bleeding after cardiopulmonary bypass weredetermined. METHODS A meta-analysis was performed of postoperative blood loss in randomized clinicaltrials of hydroxyethyl starch versus albumin for fluid management in adult cardiopulmonary bypasssurgery. Impacts of hydroxyethyl starch molecular weight and molar substitution were assessed.Randomized trials directly comparing different hydroxyethyl starch solutions were also included. RESULTSEighteen trials with 970 total patients were included. Compared with albumin, hydroxyethyl starchincreased postoperative blood loss by 33.3% of a pooled SD (95% confidence interval, 18.2%-48.3%; P< .001). Risk of reoperation for bleeding was more than doubled by hydroxyethyl starch (relative risk,2.24; 95% confidence interval, 1.14-4.40; P = .020). Hydroxyethyl starch increased transfusion of redblood cells by 28.4% of a pooled SD (95% confidence interval, 12.2%-44.6%; P < .001), of fresh-frozenplasma by 30.6% (95% confidence interval, 8.0%-53.1%; P = .008), and of platelets by 29.8% (95%confidence interval, 3.4%-56.2%; P = .027). None of these effects differed significantly betweenhydroxyethyl starch 450/0.7 and 200/0.5. Insufficient data were available for hydroxyethyl starch130/0.4 versus albumin; however, no significant differences were detected in head-to-head comparisonsof hydroxyethyl starch 130/0.4 with 200/0.5. Albumin improved hemodynamics. There were nodifferences in fluid balance, ventilator time, intensive care unit stay, or mortality. CONCLUSIONSHydroxyethyl starch increased blood loss, reoperation for bleeding, and blood product transfusion aftercardiopulmonary bypass. There was no evidence that these risks could be mitigated by lower molecularweight and substitution.", "metadata": {}}
+{"_id": "36310858", "title": "", "text": "Downstream of Mutant KRAS, the Transcription Regulator YAP Is Essential for Neoplastic Progression toPancreatic Ductal AdenocarcinomaPancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer withpoor survival rates and frequently carries oncogenic KRAS mutation. However, KRAS has thus far notbeen a viable therapeutic target. We found that the abundance of YAP mRNA, which encodesYes-associated protein (YAP), a protein regulated by the Hippo pathway during tissue development andhomeostasis, was increased in human PDAC tissue compared with that in normal pancreatic epithelia. Ingenetically engineered KrasG12D and KrasG12D:Trp53R172H mouse models, pancreas-specific deletionof Yap halted the progression of early neoplastic lesions to PDAC without affecting normal pancreaticdevelopment and endocrine function. Although Yap was dispensable for acinar to ductal metaplasia(ADM), an initial step in the progression to PDAC, Yap was critically required for the proliferation ofmutant Kras or Kras:Trp53 neoplastic pancreatic ductal cells in culture and for their growth andprogression to invasive PDAC in mice. Yap functioned as a critical transcriptional switch downstream ofthe oncogenic KRAS–mitogen-activated protein kinase (MAPK) pathway, promoting the expression ofgenes encoding secretory factors that cumulatively sustained neoplastic proliferation, a tumorigenicstromal response in the tumor microenvironment, and PDAC progression in Kras and Kras:Trp53 mutantpancreas tissue. Together, our findings identified Yap as a critical oncogenic KRAS effector and apromising therapeutic target for PDAC and possibly other types of KRAS-mutant cancers.", "metadata": {}}
+{"_id": "36345185", "title": "", "text": "Rho, Rac and Cdc42 regulate actin organization and cell adhesion in macrophages.Rho family proteins areknown to regulate actin organization in fibroblasts, but their functions in cells of haematopoietic originhave not been studied in detail. Bac1.2F5 cells are a colony-stimulating factor-1 (CSF-1)-dependentmurine macrophage cell line; CSF-1 stimulates their proliferation and motility, and acts as achemoattractant. CSF-1 rapidly induced actin reorganization in Bac1 cells: it stimulated the formation offilopodia, lamellipodia and membrane ruffles at the plasma membrane, as well as the appearance of fineactin cables within the cell interior. Microinjection of constitutively activated (V12)Rac1 stimulatedlamellipodium formation and membrane ruffling. The dominant inhibitory Rac mutant, N17Rac1, inhibitedCSF-1-induced lamellipodium formation, and also induced cell rounding. V12Cdc42 induced the formationof long filopodia, while the dominant inhibitory mutant N17Cdc42 prevented CSF-1-induced formation offilopodia but not lamellipodia. V14RhoA stimulated actin cable assembly and cell contraction, while theRho inhibitor, C3 transferase, induced the loss of actin cables. Bac1 cells had cell-to-substratum adhesionsites containing beta1 integrin, pp125FAK, paxillin, vinculin, and tyrosine phosphorylated proteins. These'focal complexes' were present in growing and CSF-1-starved cells, but were disassembled in cellsinjected with N17Cdc42 or N17Rac1. Interestingly, beta1 integrin did not disperse until long after focalphosphotyrosine and vinculin staining had disappeared. We conclude that in Bac1 macrophages Cdc42,Rac and Rho regulate the formation of distinct actin filament-based structures, and that Cdc42 and Racare also required for the assembly of adhesion sites to the extracellular matrix.", "metadata": {}}
+{"_id": "36345578", "title": "", "text": "Visualizing the function and fate of neutrophils in sterile injury and repairNeutrophils have beenimplicated as harmful cells in a variety of inappropriate inflammatory conditions where they injure thehost, leading to the death of the neutrophils and their subsequent phagocytosis by monocytes andmacrophages. Here we show that in a fully repairing sterile thermal hepatic injury, neutrophils alsopenetrate the injury site and perform the critical tasks of dismantling injured vessels and creatingchannels for new vascular regrowth. Upon completion of these tasks, they neither die at the injury sitenor are phagocytosed. Instead, many of these neutrophils reenter the vasculature and have apreprogrammed journey that entails a sojourn in the lungs to up-regulate CXCR4 (C-X-C motif chemokinereceptor 4) before entering the bone marrow, where they undergo apoptosis.", "metadata": {}}
+{"_id": "36355784", "title": "", "text": "The effect of mass screening on incidence and mortality of squamous and adenocarcinoma of cervixuteri.OBJECTIVE To describe the efficacy of the Finnish mass screening program for cervical squamouscarcinoma and adenocarcinoma, as reflected by changes of incidence and mortality rate. METHODSCervical cancer incidence and mortality data were obtained from the Finnish Cancer Registry. Data wereavailable from the year 1953, when the registry was established. The nationwide mass screeningprogram in Finland was started in the mid-1960s. A centralized organization administers this program.Women age 30-60 years are notified for screening every 5 years. RESULTS The mean incidence ofcervical carcinoma in the early 1960s was 15.4 per 10(5) woman-years. In 1991, it was only 2.7 per10(5) woman-years. The mortality rate has decreased in the same proportion since the mass screeningprogram. In the early 1960s, the mortality was 6.6 and in 1991 1.4 per 10(5) woman-years. However,the decrease of the incidence is seen almost exclusively in squamous cell carcinomas. The mortalitycaused by adenocarcinoma has decreased in screened birth cohorts, but the incidence rate has remainedthe same. CONCLUSIONS The Finnish mass screening program has been effective and its continuation isof utmost importance. In the future more attention should be given to glandular cell atypias in cervicalsmears. Thus, it might be possible to decrease the incidence of cervical adenocarcinoma.", "metadata": {}}
+{"_id": "36357627", "title": "", "text": "Role of 5-HT in the regulation of the brain-pituitary-adrenal axis: effects of 5-HT on adrenocorticalcells.Serotonin (5-HT) plays a pivotal role in the regulation of the brain-pituitary-adrenal axis. Inparticular, 5-HT has been shown to control the activity of hypothalamic CRF neurons and pituitarycorticotrope cells through activation of 5-HT1A and (or) 5-HT(2A/2C) receptor subtypes. 5-HT, actingthrough 5-HT2 receptors, can also trigger the renin-angiotensin system by stimulating renin secretionand consequently can enhance aldosterone production. At the adrenal level, 5-HT produced locallystimulates the secretory activity of adrenocortical cells through a paracrine mode of communication. Thepresence of 5-HT in the adrenal gland has been demonstrated immunohistochemically and biochemicallyin various species. In the frog, rat, and pig adrenal gland, 5-HT is synthesized by chromaffin cells, whilein the mouse adrenal cortex, 5-HT is contained in nerve fibers. In man, 5-HT is present in perivascularmast cells. In vivo and in vitro studies have shown that 5-HT stimulates corticosteroid secretion invarious species (including human). The type of receptor involved in the mechanism of action of 5-HTdiffers between the various species. In frogs and humans, the stimulatory effect of 5-HT onadrenocortical cells is mediated through a 5-HT4 receptor subtype positively coupled to adenylyl cyclaseand calcium influx. In the rat, the effect of 5-HT on aldosterone secretion is mediated via activation of5-HT7 receptors. Clinical studies indicate that 5-HT4 receptor agonists stimulate aldosterone secretion inhealthy volunteers and in patients with corticotropic insufficiency and primary hyperaldosteronism. Localserotonergic control of corticosteroid production may be involved in the physiological control of theactivity of the adrenal cortex as well as in the pathophysiology of cortisol and aldosterone disorders.", "metadata": {}}
+{"_id": "36386637", "title": "", "text": "Effect of interleukin-1 and tumor necrosis factor/cachectin on glucose turnover in the rat.We studied theeffect of recombinant human interleukin-1 beta (IL-1) and recombinant human tumor necrosis factoralpha/cachectin (TNF) on glucose kinetics in healthy rats by means of a primed constant infusion ofD-(6-3H)glucose and D-[U-14C]glucose. During the isotope (6-hour) and monokine (4-hour) infusion,plasma levels of glucagon and insulin were determined and correlated with changes in glucosemetabolism. The rates of glucose appearance (Ra) and disappearance (Rd) were elevated only with IL-1and were associated with an increase in glucagon and a concomitant decrease in the ratio of insulin toglucagon. Plasma glucose concentration was increased early after IL-1 administration and coincided withthe peak in the Ra. The augmentation of the metabolic clearance rate (MCR) and percent of flux oxidizedby IL-1 suggest that this monokine induces the utilization of glucose as a substrate. TNF administrationfailed to modify the Ra or Rd, percent of flux oxidized, or MCR. TNF-treated rats increased the percent ofglucose recycling, but not the total rate of glucose production. The results of this experiment suggest thatendogenous macrophage products participate in the diverse alterations of carbohydrate metabolism seenduring injury and/or infection.", "metadata": {}}
+{"_id": "36398420", "title": "", "text": "Human and murine very small embryonic-like cells represent multipotent tissue progenitors, in vitro andin vivo.The purpose of this study was to determine the lineage progression of human and murine verysmall embryonic-like (HuVSEL or MuVSEL) cells in vitro and in vivo. In vitro, HuVSEL and MuVSEL cellsdifferentiated into cells of all three embryonic germ layers. HuVSEL cells produced robust mineralizedtissue of human origin compared with controls in calvarial defects. Immunohistochemistry demonstratedthat the HuVSEL cells gave rise to neurons, adipocytes, chondrocytes, and osteoblasts within the calvarialdefects. MuVSEL cells were also able to differentiate into similar lineages. First round serial transplants ofMuVSEL cells into irradiated osseous sites demonstrated that \u000060% of the cells maintained their VSELcell phenotype while other cells differentiated into multiple tissues at 3 months. Secondary transplantsdid not identify donor VSEL cells, suggesting limited self renewal but did demonstrate VSEL cellderivatives in situ for up to 1 year. At no point were teratomas identified. These studies show that VSELcells produce multiple cellular structures in vivo and in vitro and lay the foundation for future cell-basedregenerative therapies for osseous, neural, and connective tissue disorders.", "metadata": {}}
+{"_id": "36399107", "title": "", "text": "High frequency of p16 (CDKN2/MTS-1/INK4A) inactivation in head and neck squamous cellcarcinoma.The tumor suppressor gene p16 (CDKN2/MTS-1/INK4A) can be inactivated by multiple geneticmechanisms. We analyzed 29 invasive primary head and neck squamous cell carcinomas (HNSCC) forp16 inactivation with immunohistochemistry utilizing a new monoclonal antibody (mAb), DCS-50. p16staining of the primary lesions was correlated with genetic analysis including: (a) detailed microsatelliteanalysis of markers at the p16 locus to detect homozygous deletion; (b) sequence analysis of p16; and(c) Southern blot analysis to determine the methylation status of the 5' CpG island of p16. Twenty-four of29 (83%) head and neck squamous cell carcinoma tumors displayed an absence of p16 nuclear stainingusing immunohistochemistry. Of these 24 tumors, we found that 16 (67%) harbored homozygousdeletions, 5 (21%) were methylated, 1 displayed a rearrangement at the p16 locus, and 1 displayed aframeshift mutation in exon 1. These data suggest that: (a) inactivation of the p16 tumor suppressorgene is a frequent event in squamous cell carcinomas of the head and neck; (b) p16 is inactivated byseveral distinct and exclusive events including homozygous deletion, point mutation, and promotermethylation; and (c) immunohistochemical analysis for expression of the p16 gene product is an accurateand relatively simple method for evaluating p16 gene inactivation.", "metadata": {}}
+{"_id": "36399109", "title": "", "text": "Genome-wide RNAi screen of Ca(2+) influx identifies genes that regulate Ca(2+) release-activatedCa(2+) channel activity.Recent studies by our group and others demonstrated a required and conservedrole of Stim in store-operated Ca(2+) influx and Ca(2+) release-activated Ca(2+) (CRAC) channelactivity. By using an unbiased genome-wide RNA interference screen in Drosophila S2 cells, we nowidentify 75 hits that strongly inhibited Ca(2+) influx upon store emptying by thapsigargin. Among thesehits are 11 predicted transmembrane proteins, including Stim, and one, olf186-F, that upon RNAinterference-mediated knockdown exhibited a profound reduction of thapsigargin-evoked Ca(2+) entryand CRAC current, and upon overexpression a 3-fold augmentation of CRAC current. CRAC currents werefurther increased to 8-fold higher than control and developed more rapidly when olf186-F wascotransfected with Stim. olf186-F is a member of a highly conserved family of four-transmembranespanning proteins with homologs from Caenorhabditis elegans to human. The endoplasmic reticulum (ER)Ca(2+) pump sarco-/ER calcium ATPase (SERCA) and the single transmembrane-solubleN-ethylmaleimide-sensitive (NSF) attachment receptor (SNARE) protein Syntaxin5 also were required forCRAC channel activity, consistent with a signaling pathway in which Stim senses Ca(2+) depletion withinthe ER, translocates to the plasma membrane, and interacts with olf186-F to trigger CRAC channelactivity.", "metadata": {}}
+{"_id": "36432234", "title": "", "text": "Wedelolactone induces growth of breast cancer cells by stimulation of estrogen receptorsignalling.Wedelolactone, a plant coumestan, was shown to act as anti-cancer agent for breast andprostate carcinomas in vitro and in vivo targeting multiple cellular proteins including androgen receptors,5-lipoxygenase and topoisomerase IIα. It is cytotoxic to breast, prostate, pituitary and myeloma cancercell lines in vitro at μM concentrations. In this study, however, a novel biological activity of nM dose ofwedelolactone was demonstrated. Wedelolactone acts as agonist of estrogen receptors (ER) α and β asdemonstrated by transactivation of estrogen response element (ERE) in cells transiently expressing eitherERα or ERβ and by molecular docking of this coumestan into ligand binding pocket of both ERα and ERβ.In breast cancer cells, wedelolactone stimulates growth of estrogen receptor-positive cells, expression ofestrogen-responsive genes and activates rapid non-genomic estrogen signalling. All these effects can beinhibited by pretreatment with pure ER antagonist ICI 182,780 and they are not observed in ER-negativebreast cancer cells. We conclude that wedelolactone acts as phytoestrogen in breast cancer cells bystimulating ER genomic and non-genomic signalling pathways.", "metadata": {}}
+{"_id": "36444198", "title": "", "text": "Subpopulations of mouse blood monocytes differ in maturation stage and inflammatory response.Bloodmonocytes are well-characterized precursors for macrophages and dendritic cells. Subsets of humanmonocytes with differential representation in various disease states are well known. In contrast, mousemonocyte subsets have been characterized minimally. In this study we identify three subpopulations ofmouse monocytes that can be distinguished by differential expression of Ly-6C, CD43, CD11c, MBR, andCD62L. The subsets share the characteristics of extensive phagocytosis, similar expression of M-CSFreceptor (CD115), and development into macrophages upon M-CSF stimulation. By eliminating bloodmonocytes with dichloromethylene-bisphosphonate-loaded liposomes and monitoring their repopulation,we showed a developmental relationship between the subsets. Monocytes were maximally depleted 18 hafter liposome application and subsequently reappeared in the circulation. These cells were exclusively ofthe Ly-6C(high) subset, resembling bone marrow monocytes. Serial flow cytometric analyses of newlyreleased Ly-6C(high) monocytes showed that Ly-6C expression on these cells was down-regulated whilein circulation. Under inflammatory conditions elicited either by acute infection with Listeriamonocytogenes or chronic infection with Leishmania major, there was a significant increase in immatureLy-6C(high) monocytes, resembling the inflammatory left shift of granulocytes. In addition, acuteperitoneal inflammation recruited preferentially Ly-6C(med-high) monocytes. Taken together, these dataidentify distinct subpopulations of mouse blood monocytes that differ in maturation stage and capacity tobecome recruited to inflammatory sites.", "metadata": {}}
+{"_id": "36450001", "title": "", "text": "Proteogenomics to discover the full coding content of genomes: a computationalperspective.Proteogenomics has emerged as a field at the junction of genomics and proteomics. It is aloose collection of technologies that allow the search of tandem mass spectra against genomic databasesto identify and characterize protein-coding genes. Proteogenomic peptides provide invaluable informationfor gene annotation, which is difficult or impossible to ascertain using standard annotation methods.Examples include confirmation of translation, reading-frame determination, identification of gene andexon boundaries, evidence for post-translational processing, identification of splice-forms includingalternative splicing, and also, prediction of completely novel genes. For proteogenomics to deliver on itspromise, however, it must overcome a number of technological hurdles, including speed and accuracy ofpeptide identification, construction and search of specialized databases, correction of sampling bias, andothers. This article reviews the state of the art of the field, focusing on the current successes, and therole of computation in overcoming these challenges. We describe how technological and algorithmicadvances have already enabled large-scale proteogenomic studies in many model organisms, includingarabidopsis, yeast, fly, and human. We also provide a preview of the field going forward, describing earlyefforts in tackling the problems of complex gene structures, searching against genomes of relatedspecies, and immunoglobulin gene reconstruction.", "metadata": {}}
+{"_id": "36464673", "title": "", "text": "The in vitro phosphorylation of p53 by calcium-dependent protein kinase C--characterization of aprotein-kinase-C-binding site on p53.We show that, in vitro, Ca2+-dependent protein kinase C (PKC)phosphorylates recombinant murine p53 protein on several residues contained within a conserved basicregion of 25 amino acids, located in the C-terminal part of the protein. Accordingly, syntheticp53-(357-381)-peptide is phosphorylated by PKC at multiple Ser and Thr residues, including Ser360,Thr365, Ser370 and Thr377. We also establish that p53-(357-381)-peptide at micromolar concentrationshas the ability to stimulate sequence-specific DNA binding by p53. That stimulation is lost uponphosphorylation by PKC. To further characterise the mechanisms that regulate PKC-dependentphosphorylation of p53-(357-381)-peptide, the phosphorylation of recombinant p53 andp53-(357-381)-peptide by PKC were compared. The results suggest that phosphorylation of full-lengthp53 on the C-terminal PKC sites is highly dependent on the accessibility of the phosphorylation sites andthat a domain on p53 distinct from p53-(357-381)-peptide is involved in binding PKC. Accordingly, wehave identified a conserved 27-amino-acid peptide, p53-(320-346)-peptide, within the C-terminal regionof p53 and adjacent to residues 357-381 that interacts with PKC in vitro. The interaction betweenp53-(320-346)-peptide and PKC inhibits PKC autophosphorylation and the phosphorylation of substrates,including p53-(357-381)-peptide, neurogranin and histone H1. Conventional Ca2+-dependent PKC alpha,beta and gamma and the catalytic fragment of PKC (PKM) were nearly equally susceptible to inhibition byp53-(320-346)-peptide. The Ca2+-independent PKC delta was much less sensitive to inhibition. Thesignificance of these findings for understanding the in vivo phosphorylation of p53 by PKC are discussed.", "metadata": {}}
+{"_id": "36480032", "title": "", "text": "Role of ocular pigment epithelial cells in immune privilegeThe ocular microenvironment is bothimmunosuppressive and anti-inflammatory in nature. Pigment epithelial (PE) cells isolated from the eyepossess the ability to suppress the T cell receptor-dependent activation of T cells and the induction ofregulatory T cells in vitro. This property is dependent on the cells’ capacity to produce cell-surface andsoluble inhibitory molecules, for example CD86 (B7-2), transforming growth factor (TGF)-β,thrombospondin-1, programmed cell death 1 ligand 1 (PD-L1/B7-H1), and cytotoxic Tlymphocyte-associated antigen 2α. Cultured ocular PE cells from the iris, ciliary body, and retina canindividually suppress T-cell activation via mechanisms that partially overlap. Moreover, PE-derivedregulatory T cells acquire functions that play a role in establishing immune regulation in the eye. Multiplestrategies are employed within the eye to control immune-mediated inflammation. This phenomenon isknown as immune privilege and is instrumental in helping to prevent extensive damage to bystander cellsthat would otherwise lead to blindness. This review focuses on the immunosuppressive property and roleof ocular PE cells in immune privileged sites.", "metadata": {}}
+{"_id": "36497180", "title": "", "text": "Drug-resistant Salmonella in the United States: an epidemiologic perspective.Salmonellosis poses ahealth problem of large proportions in the United States. Annually, it accounts for more than 40,000reported cases, 500 deaths, and financial costs well in excess of $50 million. Antimicrobial resistance isincreasing in Salmonella strains, a finding that has important public health implications. Although thechain of transmission of the bacteria is often complex, combined epidemiologic and laboratory studieswith the use of new methods in molecular biology make it possible to trace antimicrobial-resistantsalmonellae to their primary source--foods of animal origin. These studies suggest that the antimicrobialdrugs to which food animals are exposed provide selective pressure that leads to the appearance andpersistence of resistant strains.", "metadata": {}}
+{"_id": "36540079", "title": "", "text": "Glutamine-specific N-terminal amidase, a component of the N-end rule pathway.Deamidation ofN-terminal Gln by Nt(Q)-amidase, an N-terminal amidohydrolase, is a part of the N-end rule pathway ofprotein degradation. We detected the activity of Nt(Q)-amidase, termed Ntaq1, in mouse tissues, purifiedNtaq1 from bovine brains, identified its gene, and began analyzing this enzyme. Ntaq1 is highlyconserved among animals, plants, and some fungi, but its sequence is dissimilar to sequences of otheramidases. An earlier mutant in the Drosophila Cg8253 gene that we show here to encode Nt(Q)-amidasehas defective long-term memory. Other studies identified protein ligands of the uncharacterized humanC8orf32 protein that we show here to be the Ntaq1 Nt(Q)-amidase. Remarkably, \"high-throughput\"studies have recently solved the crystal structure of C8orf32 (Ntaq1). Our site-directed mutagenesis ofNtaq1 and its crystal structure indicate that the active site and catalytic mechanism of Nt(Q)-amidase aresimilar to those of transglutaminases.", "metadata": {}}
+{"_id": "36547290", "title": "", "text": "Brahma-related gene 1-dependent STAT3 recruitment at IL-6-inducible genes.IL-6 is animmunoregulatory cytokine with multiple functions in hemopoiesis, proliferation, and tumorigenesis. IL-6triggers phosphorylation, dimerization, and nuclear translocation of STAT3, which binds to targetpromoters and activates transcription. Brahma-related gene 1 (BRG1), the enzymatic engine of theyeast-mating type-switching and sucrose-nonfermenting chromatin-remodeling complex, is essential forrecruitment of STAT1 or STAT1/STAT2-containing complexes to IFN targets. We hypothesized that BRG1might also be required for STAT3 recruitment. In this study, we show that induction of a subset of humanIL-6-responsive genes is BRG1 dependent. BRG1 is constitutively present at these targets and is requiredfor STAT3 recruitment, downstream histone modifications, and IL-6-induced chromatin remodeling.IL-6-induced recruitment of STAT3 to the IFN regulatory factor 1 promoter and subsequent mRNAsynthesis is BRG1 dependent, even though IFN-gamma-mediated STAT1 recruitment to this locus isBRG1 independent. BRG1 also increased basal expression of IFN-induced transmembrane protein 3 andIFN-gamma-induced protein 16, and the basal chromatin accessibility at the promoter of IFN regulatoryfactor 1. The effect on basal expression was STAT3 independent, as revealed by small interfering RNAknockdown. Together with prior observations, these data reveal that BRG1 has a broad role in mediatingSTAT accessibility at multiple cytokine-responsive promoters and exposes promoter specific differences inboth the effect of BRG1 on basal chromatin accessibility and on access of different STAT proteins to thesame target.", "metadata": {}}
+{"_id": "36558211", "title": "", "text": "High and low fat consumers, their macronutrient intake and body mass index: further analysis of theNational Diet and Nutrition Survey of British Adults.OBJECTIVES To explore the different characteristics ofhigh and low fat consumers, in particular their macronutrient intake and body mass index. DESIGNReanalysis of data from the Dietary and Nutritional Survey of British Adults. Comparisons were madebetween groups defined as high and low fat consumers on the basis of 7-day weighed food recordsconsidered to be valid for energy intake. Individuals were classified in two ways according to thepercentage energy from fat (FAT%) and the absolute amount of fat consumed (FATg). The criteria forclassification of the high FAT% being > 45% (high fat) and < or = 35% (low fat). For the FATg group thethreshold for the high fat group was > 138 g/day (men) and > 102 g/day (women), and for the low fatgroup < 85 g/day (men) and < 70 g/day (women). SETTING Dietary data was collected from privatehouseholds in Great Britain between 1986 and 1987. SUBJECTS From the total population of 2197,individuals who were slimming, ill or had an EI: BMR of < 1.2 were excluded in order to use data whichwas most likely to represent habitual energy intakes. From the remaining 1240 subjects, 10.8% of thissample (6.1% of the total population) were classified as low fat consumers (76 men and 58 women) and15.4% high fat (8.7% of the total population, 93 men and 98 women). MAIN OUTCOME MEASURESMacronutrient consumption and body mass index (BMI). RESULTS 30% of the subjects changed fat groupclassification when the criteria of defining high and low fat groups altered from FAT% to FATg. Nutrientintakes differed according to definition of the groups. The high fat FATg group ate significantly more of allnutrients than the low fat FATg group. However, this was not seen for the FAT% analysis, with the highfat group eating more fat and less carbohydrate. The average BMI tended to be higher in the high fatthan the low fat groups, particularly in the FATg analysis. However, the high fat group contained a widerange of BMIs. Further exploration of BMI in the high fat groups, showed that age (an 11-year difference)was the only variable to distinguish individuals in the top and bottom quartiles of BMI. CONCLUSIONSHigh and low fat consumers differ according to a number of variables, and this is affected by how thesegroups are defined (FAT% or FATg). High fat consumers tend to have a higher BMI than low fatconsumers, but not all high fat consumers are overweight or obese.", "metadata": {}}
+{"_id": "36606083", "title": "", "text": "Quantitative, genome-wide analysis of eukaryotic replication initiation and termination.Many fundamentalaspects of DNA replication, such as the exact locations where DNA synthesis is initiated and terminated,how frequently origins are used, and how fork progression is influenced by transcription, are poorlyunderstood. Via the deep sequencing of Okazaki fragments, we comprehensively document replicationfork directionality throughout the S. cerevisiae genome, which permits the systematic analysis ofinitiation, origin efficiency, fork progression, and termination. We show that leading-strand initiationpreferentially occurs within a nucleosome-free region at replication origins. Using a strain in which lateorigins can be induced to fire early, we show that replication termination is a largely passive phenomenonthat does not rely on cis-acting sequences or replication fork pausing. The replication profile ispredominantly determined by the kinetics of origin firing, allowing us to reconstruct chromosome-widetiming profiles from an asynchronous culture.", "metadata": {}}
+{"_id": "36618603", "title": "", "text": "The murine H19 gene is activated during embryonic stem cell differentiation in vitro and at the time ofimplantation in the developing embryo.The differentiation in vitro of murine embryonic stem cells toembryoid bodies mimics events that occur in vivo shortly before and after embryonic implantation. Wehave used this system, together with differential cDNA cloning, to identify genes the expression of whichis regulated during early embryogenesis. Here we describe the isolation of several such cDNA clones, oneof which corresponds to the gene H19. This gene is activated in extraembryonic cell types at the time ofimplantation, suggesting that it may play a role at this stage of development, and is subsequentlyexpressed in all of the cells of the mid-gestation embryo with the striking exception of most of those ofthe developing central and peripheral nervous systems. After birth, expression of this gene ceases or isdramatically reduced in all tissues.", "metadata": {}}
+{"_id": "36623997", "title": "", "text": "Localization of Sir2p: the nucleolus as a compartment for silent information regulators.In wild-typebudding yeast strains, the proteins encoded by SIR3, SIR4 and RAP1 co-localize with telomeric DNA in alimited number of foci in interphase nuclei. Immunostaining of Sir2p shows that in addition to a punctatestaining that coincides with Rap1 foci, Sir2p localizes to a subdomain of the nucleolus. The presence ofSir2p at both the spacer of the rDNA repeat and at telomeres is confirmed by formaldehyde cross-linkingand immunoprecipitation with anti-Sir2p antibodies. In strains lacking Sir4p, Sir3p becomes concentratedin the nucleolus, by a pathway requiring SIR2 and UTH4, a gene that regulates life span in yeast. Theunexpected nucleolar localization of Sir2p and Sir3p correlates with observed effects of sir mutations onrDNA stability and yeast longevity, defining a new site of action for silent information regulatory factors.", "metadata": {}}
+{"_id": "36637129", "title": "", "text": "Optogenetics reveal delayed afferent synaptogenesis on grafted human-induced pluripotent stemcell-derived neural progenitors.Reprogramming of somatic cells into pluripotency stem cell state hasopened new opportunities in cell replacement therapy and disease modeling in a number of neurologicaldisorders. It still remains unknown, however, to what degree the grafted human-induced pluripotentstem cells (hiPSCs) differentiate into a functional neuronal phenotype and if they integrate into the hostcircuitry. Here, we present a detailed characterization of the functional properties and synapticintegration of hiPSC-derived neurons grafted in an in vitro model of hyperexcitable epileptic tissue,namely organotypic hippocampal slice cultures (OHSCs), and in adult rats in vivo. The hiPSCs were firstdifferentiated into long-term self-renewing neuroepithelial stem (lt-NES) cells, which are known to formprimarily GABAergic neurons. When differentiated in OHSCs for 6 weeks, lt-NES cell-derived neuronsdisplayed neuronal properties such as tetrodotoxin-sensitive sodium currents and action potentials (APs),as well as both spontaneous and evoked postsynaptic currents, indicating functional afferent synapticinputs. The grafted cells had a distinct electrophysiological profile compared to host cells in the OHSCswith higher input resistance, lower resting membrane potential, and APs with lower amplitude and longerduration. To investigate the origin of synaptic afferents to the grafted lt-NES cell-derived neurons, thehost neurons were transduced with Channelrhodopsin-2 (ChR2) and optogenetically activated by bluelight. Simultaneous recordings of synaptic currents in grafted lt-NES cell-derived neurons using whole-cellpatch-clamp technique at 6 weeks after grafting revealed limited synaptic connections from host neurons.Longer differentiation times, up to 24 weeks after grafting in vivo, revealed more mature intrinsicproperties and extensive synaptic afferents from host neurons to the lt-NES cell-derived neurons,suggesting that these cells require extended time for differentiation/maturation and synaptogenesis.However, even at this later time point, the grafted cells maintained a higher input resistance. These dataindicate that grafted lt-NES cell-derived neurons receive ample afferent input from the host brain. Sincethe lt-NES cells used in this study show a strong propensity for GABAergic differentiation, thehost-to-graft synaptic afferents may facilitate inhibitory neurotransmitter release, and normalizehyperexcitable neuronal networks in brain diseases, for example, such as epilepsy.", "metadata": {}}
+{"_id": "36642096", "title": "", "text": "Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus.BACKGROUND Type 1 diabetesmellitus is a chronic autoimmune disease caused by the pathogenic action of T lymphocytes oninsulin-producing beta cells. Previous clinical studies have shown that continuous immune suppressiontemporarily slows the loss of insulin production. Preclinical studies suggested that a monoclonal antibodyagainst CD3 could reverse hyperglycemia at presentation and induce tolerance to recurrent disease.METHODS We studied the effects of a nonactivating humanized monoclonal antibody againstCD3--hOKT3gamma1(Ala-Ala)--on the loss of insulin production in patients with type 1 diabetes mellitus.Within 6 weeks after diagnosis, 24 patients were randomly assigned to receive either a single 14-daycourse of treatment with the monoclonal antibody or no antibody and were studied during the first year ofdisease. RESULTS Treatment with the monoclonal antibody maintained or improved insulin productionafter one year in 9 of the 12 patients in the treatment group, whereas only 2 of the 12 controls had asustained response (P=0.01). The treatment effect on insulin responses lasted for at least 12 monthsafter diagnosis. Glycosylated hemoglobin levels and insulin doses were also reduced in themonoclonal-antibody group. No severe side effects occurred, and the most common side effects werefever, rash, and anemia. Clinical responses were associated with a change in the ratio of CD4+ T cells toCD8+ T cells 30 and 90 days after treatment. CONCLUSIONS Treatment with hOKT3gamma1(Ala-Ala)mitigates the deterioration in insulin production and improves metabolic control during the first year oftype 1 diabetes mellitus in the majority of patients. The mechanism of action of the anti-CD3 monoclonalantibody may involve direct effects on pathogenic T cells, the induction of populations of regulatory cells,or both.", "metadata": {}}
+{"_id": "36651210", "title": "", "text": "Establishment and in vitro differentiation of a new embryonic stem cell line from humanblastocyst.Embryonic stem cells have the ability to remain undifferentiated and proliferate indefinitely invitro while maintaining the potential to differentiate into derivatives of all three embryonic germ layers.These cells have, therefore, potential for in vitro differentiation studies, gene function, and so on. Theaim of this study was to produce a human embryonic stem cell line. An inner cell mass of a humanblastocyst was separated and cultured on mouse embryonic fibroblasts in embryonic stem cell mediumwith related additives. The established line was evaluated by morphology; passaging; freezing andthawing; alkaline phosphatase; Oct-4 expression; anti-surface markers including Tra-1-60 and Tra-1-81;and karyotype and spontaneous differentiation. Differentiated cardiomyocytes and neurons wereevaluated by transmission electron microscopy and immunocytochemistry. Here, we report the derivationof a new embryonic stem cell line (Royan H1) from a human blastocyst that remains undifferentiated inmorphology during continuous passaging for more than 30 passages, maintains a normal XX karyotype,is viable after freezing and thawing, and expresses alkaline phosphatase, Oct-4, Tra-1-60, and Tra-1-81.These cells remain undifferentiated when grown on mouse embryonic fibroblast feeder layers in thepresence or absence of recombinant human leukemia inhibitory factor. Royan H1 cells can differentiate invitro in the absence of feeder cells and can produce embryoid bodies that can further differentiate intobeating cardiomyocytes as well as neurons. These results define Royan H1 cells as a new humanembryonic stem cell line.", "metadata": {}}
+{"_id": "36653415", "title": "", "text": "Lactate Metabolism in Human Lung TumorsCancer cells consume glucose and secrete lactate in culture. Itis unknown whether lactate contributes to energy metabolism in living tumors. We previously reportedthat human non-small-cell lung cancers (NSCLCs) oxidize glucose in the tricarboxylic acid (TCA) cycle.Here, we show that lactate is also a TCA cycle carbon source for NSCLC. In human NSCLC, evidence oflactate utilization was most apparent in tumors with high 18fluorodeoxyglucose uptake and aggressiveoncological behavior. Infusing human NSCLC patients with 13C-lactate revealed extensive labeling of TCAcycle metabolites. In mice, deleting monocarboxylate transporter-1 (MCT1) from tumor cells eliminatedlactate-dependent metabolite labeling, confirming tumor-cell-autonomous lactate uptake. Strikingly,directly comparing lactate and glucose metabolism in vivo indicated that lactate's contribution to the TCAcycle predominates. The data indicate that tumors, including bona fide human NSCLC, can use lactate asa fuel in vivo.", "metadata": {}}
+{"_id": "36654066", "title": "", "text": "Increased lipid peroxidation as a mechanism of methionine-induced atherosclerosis in rabbits.Methionineis converted by the transmethylation/transsulfuration pathway to homocysteine which may exertatherogenic effects by several mechanisms, including lipid peroxidation. Therefore, the excessive dietarymethionine may induce the development of atherosclerosis. To test this hypothesis, plasma and aorticthiobarbituric acid reactive substances (TBARS), as well as activities of aortic and erythrocyte superoxidedismutase (SOD), catalase and selenium-dependent glutathione peroxidase (GPX) were measured inrabbits fed a diet enriched with 0.3% methionine for 6 or 9 months. Histological examinations of aortasalso were performed. Feeding rabbits a methionine-enriched diet for 6 or 9 months resulted in significantincreases in plasma and aortic TBARS levels and aortic antioxidant enzyme activities. However, adecrease in plasma antioxidant activity (AOA) was observed. In erythrocytes, SOD activity increased,catalase remained normal and GPX decreased in the treated animals. Histological examination of aortasshowed typical atherosclerotic changes, such as intimal thickening, deposition of cholesterol, andcalcification in methionine-fed rabbits. These results confirm that high-methionine diet may induceatherosclerosis in rabbits and indicate disturbances in lipid peroxidation and antioxidant processes aspossible mechanisms of its atherogenic influence.", "metadata": {}}
+{"_id": "36708463", "title": "", "text": "Sex differences in sex chromosome gene expression in mouse brain.A major question is whether genesencoded on the sex chromosomes act directly in non-gonadal tissues to cause sex differences indevelopment or function, or whether all sex differences in somatic tissues are induced by gonadalsecretions. As part of this question we asked whether mouse X-Y homologous gene pairs are expressed inbrain in a sex-specific fashion. Using RT-PCR and northern blot analysis, we assessed mRNA expression inbrain of eight Y-linked genes as well as their X-linked homologues, at three ages: 13.5 days post coitum,the day of birth (P1) and adult. Transcripts of six Y genes were expressed at one or more ages: Usp9y,Ube1y, Smcy, Eif2s3y, Uty and Dby. Their expression also occurred in XY female brain, and thereforedoes not require testicular secretions. Six X-linked homologues (Usp9x, Ube1x, Smcx, Eif2s3x, Utx andDbx) were also expressed in brain, and in adulthood all of these transcripts were expressed atsignificantly higher levels in brains of females than in brains of males, irrespective of their X-inactivationstatus. For five of these gene pairs, the expression of the Y-linked homologue in males was not sufficientto compensate for the female bias in X gene expression. Three X-Y gene pairs, Usp9x/y, Ube1x/y andEif2s3x/y, appeared to be differentially regulated (expressed in brain in a different age- ortissue-dependent pattern), and hence may not be functionally equivalent. These sex differences in X-Ygene expression suggest several mechanisms by which these genes may participate in sex differences inbrain development and function.", "metadata": {}}
+{"_id": "36713289", "title": "", "text": "Genome architecture, rearrangements and genomic disorders.An increasing number of human diseasesare recognized to result from recurrent DNA rearrangements involving unstable genomic regions. Theseare termed genomic disorders, in which the clinical phenotype is a consequence of abnormal dosage ofgene(s) located within the rearranged genomic fragments. Both inter- and intrachromosomalrearrangements are facilitated by the presence of region-specific low-copy repeats (LCRs) and result fromnonallelic homologous recombination (NAHR) between paralogous genomic segments. LCRs usually spanapproximately 10-400 kb of genomic DNA, share >or= 97% sequence identity, and provide thesubstrates for homologous recombination, thus predisposing the region to rearrangements. Moreover, ithas been suggested that higher order genomic architecture involving LCRs plays a significant role inkaryotypic evolution accompanying primate speciation.", "metadata": {}}
+{"_id": "36721932", "title": "", "text": "painDETECT: a new screening questionnaire to identify neuropathic components in patients with backpain.OBJECTIVE Nociceptive and neuropathic components both contribute to pain. Since thesecomponents require different pain management strategies, correct pain diagnosis before and duringtreatment is highly desirable. As low back pain (LBP) patients constitute an important subgroup of chronicpain patients, we addressed the following issues: (i) to establish a simple, validated screening tool todetect neuropathic pain (NeP) components in chronic LBP patients, (ii) to determine the prevalence ofneuropathic pain components in LBP in a large-scale survey, and (iii) to determine whether LBP patientswith an NeP component suffer from worse, or different, co-morbidities. METHODS In co-operation withthe German Research Network on Neuropathic Pain we developed and validated the painDETECTquestionnaire (PD-Q) in a prospective, multicentre study and subsequently applied it to approximately8000 LBP patients. RESULTS The PD-Q is a reliable screening tool with high sensitivity, specificity andpositive predictive accuracy; these were 84% in a palm-top computerised version and 85%, 80% and83%, respectively, in a corresponding pencil-and-paper questionnaire. In an unselected cohort of chronicLBP patients, 37% were found to have predominantly neuropathic pain. Patients with NeP showed higherratings of pain intensity, with more (and more severe) co-morbidities such as depression, panic/anxietyand sleep disorders. This also affected functionality and use of health-care resources. On the basis ofgiven prevalence of LBP in the general population, we calculated that 14.5% of all female and 11.4% ofall male Germans suffer from LBP with a predominant neuropathic pain component. CONCLUSION Simple,patient-based, easy-to-use screening questionnaires can determine the prevalence of neuropathic paincomponents both in individual LBP patients and in heterogeneous cohorts of such patients. Since NePcorrelates with more intense pain, more severe co-morbidity and poorer quality of life, accurate diagnosisis a milestone in choosing appropriate therapy.", "metadata": {}}
+{"_id": "36749390", "title": "", "text": "Scoring of dual fluorescein and ICG inflammatory angiographic signs for the grading of posterior segmentinflammation (dual fluorescein and ICG angiographic scoring system for uveitis)Purpose To propose asemiquantitative dual fluorescein angiography (FA) and indocyanine green angiography (ICGA) scoringsystem for uveitis that would assist in the follow-up of disease progression and monitoring response totreatment. Methods The scoring system was based on the FA scoring systems, the standardized ICGAprotocol, and schematic interpretation of ICGA findings in posterior uveitis that have been previouslypublished. We assigned scores to the fluorescein and ICG angiographic signs that represent ongoinginflammatory process in the posterior segment. We rated each angiographic sign according to the impactit has on our appreciation of active intraocular inflammation. In order to permit direct comparisonbetween FA and ICGA, we multiplied the total ICGA score by a coefficient of 2 to adjust to the total scoreof FA. Results A total maximum score of 40 was assigned to the FA signs, including optic dischyperfluorescence, macular edema, retinal vascular staining and/or leakage, capillary leakage, retinalcapillary nonperfusion, neovascularization of the optic disc, neovascularization elsewhere, pinpoint leaks,and retinal staining and/or subretinal pooling. A total maximum score of 20 was assigned to the ICGAsigns, including early stromal vessel hyperfluorescence, choroidal vasculitis, dark dots or areas (excludingatrophy), and optic disc hyperfluorescence. Conclusion The combined fluorescein and ICG angiographicscoring system proposed herein may help estimate the magnitude of retinal versus choroidalinflammation, monitor disease progression and response to treatment, and provide comparable data forclinical studies. The applicability of the proposed system needs to be tested in clinical settings, and intra-and interobserver variations need to be determined.", "metadata": {}}
+{"_id": "36799998", "title": "", "text": "Improving outcomes of acute kidney injury: report of an initiativeAcute kidney injury (AKI) is a complexdisorder comprising several etiological factors and occurring in multiple settings. The disorder has avariety of clinical manifestations that range from minimal elevation in serum creatinine level to anuricrenal failure. We describe the formation of a multidisciplinary collaborative network focused on AKI. ThisAcute Kidney Injury Network has proposed uniform standards for diagnosing and classifying AKI. Theseproposed standards will need to be validated in future studies, a process that will be facilitated by theAcute Kidney Injury Network, which offers a forum that encourages acquisition of knowledge to improvepatient outcomes.", "metadata": {}}
+{"_id": "36816310", "title": "", "text": "A Screen for Endocytic MotifsSorting signals for cargo selection into coated vesicles are usually in theform of short linear motifs. Three motifs for clathrin-mediated endocytosis have been identified: YXXPhi,[D/E]XXXL[L/I] and FXNPXY. To search for new endocytic motifs, we made a library of CD8 chimeras withrandom sequences in their cytoplasmic tails, and used a novel fluorescence-activated cell sorting(FACS)-based assay to select for endocytosed constructs. Out of the five tails that were most efficientlyinternalized, only one was found to contain a conventional motif. Two contain dileucine-like sequencesthat appear to be variations on the [D/E]XXXL[L/I] motif. Another contains a novel internalization signal,YXXXPhiN, which is able to function in cells expressing a mutant mu2 that cannot bind YXXPhi, indicatingthat it is not a variation on the YXXPhi motif. Similar sequences are present in endogenous proteins,including a functional YXXXPhiN (in addition to a classical YXXPhi) in cytotoxic T-lymphocyte-associatedprotein 4 (CTLA-4). Thus, the repertoire of endocytic motifs is more extensive than the threewell-characterized sorting signals.", "metadata": {}}
+{"_id": "36830715", "title": "", "text": "Microtubule stabilization reduces scarring and causes axon regeneration after spinal cordinjury.Hypertrophic scarring and poor intrinsic axon growth capacity constitute major obstacles for spinalcord repair. These processes are tightly regulated by microtubule dynamics. Here, moderate microtubulestabilization decreased scar formation after spinal cord injury in rodents through various cellularmechanisms, including dampening of transforming growth factor-β signaling. It prevented accumulationof chondroitin sulfate proteoglycans and rendered the lesion site permissive for axon regeneration ofgrowth-competent sensory neurons. Microtubule stabilization also promoted growth of central nervoussystem axons of the Raphe-spinal tract and led to functional improvement. Thus, microtubulestabilization reduces fibrotic scarring and enhances the capacity of axons to grow.", "metadata": {}}
+{"_id": "36831892", "title": "", "text": "Histone tails: Directing the chromatin response to DNA damage.Considerable energetic investment isdevoted to altering large stretches of chromatin adjacent to DNA double strand breaks (DSBs).Immediately ensuing DSB formation, a myriad of histone modifications are elicited to create a platformfor inducible and modular assembly of DNA repair protein complexes in the vicinity of the DNA lesion.This complex signaling network is critical to repair DNA damage and communicate with cellular processesthat occur in cis and in trans to the genomic lesion. Failure to properly execute DNA damage induciblechromatin changes is associated with developmental abnormalities, immunodeficiency, and malignancy inhumans and in genetically engineered mouse models. This review will discuss current knowledge of DNAdamage responsive histone changes that occur in mammalian cells, highlighting their involvement in themaintenance of genome integrity.", "metadata": {}}
+{"_id": "36838958", "title": "", "text": "Sestrin2 inhibits uncoupling protein 1 expression through suppressing reactive oxygen species.Uncouplingprotein 1 (Ucp1), which is localized in the mitochondrial inner membrane of mammalian brown adiposetissue (BAT), generates heat by uncoupling oxidative phosphorylation. Upon cold exposure or nutritionalabundance, sympathetic neurons stimulate BAT to express Ucp1 to induce energy dissipation andthermogenesis. Accordingly, increased Ucp1 expression reduces obesity in mice and is correlated withleanness in humans. Despite this significance, there is currently a limited understanding of how Ucp1expression is physiologically regulated at the molecular level. Here, we describe the involvement ofSestrin2 and reactive oxygen species (ROS) in regulation of Ucp1 expression. Transgenic overexpressionof Sestrin2 in adipose tissues inhibited both basal and cold-induced Ucp1 expression in interscapular BAT,culminating in decreased thermogenesis and increased fat accumulation. Endogenous Sestrin2 is alsoimportant for suppressing Ucp1 expression because BAT from Sestrin2(-/-) mice exhibited a highlyelevated level of Ucp1 expression. The redox-inactive mutant of Sestrin2 was incapable of regulatingUcp1 expression, suggesting that Sestrin2 inhibits Ucp1 expression primarily through reducing ROSaccumulation. Consistently, ROS-suppressing antioxidant chemicals, such as butylated hydroxyanisoleand N-acetylcysteine, inhibited cold- or cAMP-induced Ucp1 expression as well. p38 MAPK, a signalingmediator required for cAMP-induced Ucp1 expression, was inhibited by either Sestrin2 overexpression orantioxidant treatments. Taken together, these results suggest that Sestrin2 and antioxidants inhibit Ucp1expression through suppressing ROS-mediated p38 MAPK activation, implying a critical role of ROS inproper BAT metabolism.", "metadata": {}}
+{"_id": "36855703", "title": "", "text": "The non-catalytic function of XPG protein during dual incision in human nucleotide excision repair.XPG isa member of the FEN-1 structure-specific endonuclease family. It has 3'-junction cutting activity onbubble substrates and makes the 3'-incision in the human dual incision (excision nuclease) repair system.To investigate the precise role of XPG in nucleotide excision repair, we mutagenized two amino acidresidues thought to be involved in DNA binding and catalysis, overproduced the mutant proteins using abaculovirus/insect cell system, and purified and characterized the mutant proteins. The mutation D77Ahad a modest effect on junction cutting and excision activity and gave rise to uncoupled 5'-incision bymammalian cell-free extracts. The D812A mutation completely abolished the junction cutting and3'-incision activities of XPG, but the excision nuclease reconstituted with XPG (D812A) carried out normal5'-incision at the 23rd-24th phosphodiester bonds 5' to a (6-4) photoproduct without producing any3'-incision. It is concluded that Asp-812 is an active site residue of XPG and that in addition to making the3'-incision, the physical presence of XPG in the protein-DNA complex is required non-catalytically forsubsequent 5'-incision by XPF-ERCC1.", "metadata": {}}
+{"_id": "36860856", "title": "", "text": "A 40-Hz auditory potential recorded from the human scalp.Computer techniques readily extract from thebrainwaves an orderly sequence of brain potentials locked in time to sound stimuli. The potentials thatappear 8 to 80 msec after the stimulus resemble 3 or 4 cycles of a 40-Hz sine wave; we show here thatthese waves combined to form a single, stable, composite wave when the sounds are repeated at ratesaround 40 per sec. This phenomenon, the 40-Hz event-related potential (ERP), displays severalproperties of theoretical and practical interest. First, it reportedly disappears with surgical anesthesia,and it resembles similar phenomena in the visual and olfactory system, facts which suggest thatadequate processing of sensory information may require cyclical brain events in the 30- to 50-Hz range.Second, latency and amplitude measurements on the 40-Hz ERP indicate it may contain usefulinformation on the number and basilar membrane location of the auditory nerve fibers a given toneexcites. Third, the response is present at sound intensities very close to normal adult thresholds for theaudiometric frequencies, a fact that could have application in clinical hearing testing.", "metadata": {}}
+{"_id": "36889513", "title": "", "text": "Bile acids: natural ligands for an orphan nuclear receptor.Bile acids regulate the transcription of genesthat control cholesterol homeostasis through molecular mechanisms that are poorly understood.Physiological concentrations of free and conjugated chenodeoxycholic acid, lithocholic acid, anddeoxycholic acid activated the farnesoid X receptor (FXR; NR1H4), an orphan nuclear receptor. Asligands, these bile acids and their conjugates modulated interaction of FXR with a peptide derived fromsteroid receptor coactivator 1. These results provide evidence for a nuclear bile acid signaling pathwaythat may regulate cholesterol homeostasis.", "metadata": {}}
+{"_id": "36904081", "title": "", "text": "The yeast ribosomal protein L32 and its gene.The yeast ribosomal protein gene RPL32 of Saccharomycescerevisiae is of particular interest for two reasons: 1) it is adjacent to another ribosomal protein gene,RP29, whose divergent transcription may be driven from the same control sequences, and 2) it appearsthat the splicing of its transcript is regulated by the product of the gene, ribosomal protein in L32. RPL32has been analyzed in detail. It is essential for cell growth. Its sequence predicts L32 to be a protein of105 amino acids, somewhat basic near the NH2 terminus, rather acidic near the COOH terminus, andhomologous to ribosomal protein L30 of mammals. The reading frame has been confirmed by partialNH2-terminal analysis of L32. The nucleotide sequence also predicts an intron of 230 nucleotides, whichbegins with the unusual sequence GTCAGT and ends 40 nucleotides downstream of the consensussequence TAC-TAAC. The intron has been confirmed by determination of the sequence of a cDNA clone.Transcription initiates 58 nucleotides upstream of the AUG initiation codon, and the polyadenylation siteoccurs 100 nucleotides downstream of the termination codon. Regulation of the transcription of ribosomalprotein genes has been linked to two related consensus sequences. Analysis of the intergenic regionbetween RP29 and RPL32 reveals three copies of these sequences. A deletion removing all threesequences reduces synthesis of a L32-LacZ fusion protein by more than 90%. Some residual activity,however, remains.", "metadata": {}}
+{"_id": "36921186", "title": "", "text": "Derivation conditions impact X-inactivation status in female human induced pluripotent stem cells.Femalehuman induced pluripotent stem cell (hiPSC) lines exhibit variability in X-inactivation status. The majorityof hiPSC lines maintain one transcriptionally active X (Xa) and one inactive X (Xi) chromosome fromdonor cells. However, at low frequency, hiPSC lines with two Xas are produced, suggesting thatepigenetic alterations of the Xi occur sporadically during reprogramming. We show here thatX-inactivation status in female hiPSC lines depends on derivation conditions. hiPSC lines generated by theKyoto method (retroviral or episomal reprogramming), which uses leukemia inhibitory factor(LIF)-expressing SNL feeders, frequently had two Xas. Early passage Xa/Xi hiPSC lines generated onnon-SNL feeders were converted into Xa/Xa hiPSC lines after several passages on SNL feeders, andsupplementation with recombinant LIF caused reactivation of some of X-linked genes. Thus, feeders are asignificant factor affecting X-inactivation status. The efficient production of Xa/Xa hiPSC lines providesunprecedented opportunities to understand human X-reactivation and -inactivation.", "metadata": {}}
+{"_id": "36950726", "title": "", "text": "Loss of 5-hydroxymethylcytosine and ten-eleven translocation 2 protein expression in malignantmelanoma.Several research groups have recently reported on markedly reduced levels of5-hydroxymethylcytosine (5hmC) in human breast, liver, lung, pancreatic, colon, prostate, brain, andmyeloid cancers. We studied benign compound nevi (BCN, n=17), dysplastic compound nevi (DCN,n=15), superficial spreading melanomas [SSM, stratified in <1 mm (n=19) and >4 mm (n=18) Breslowtumor thickness], and cutaneous metastatic disease (CMD, n=24). Immunohistochemistry includedspecific antibodies against 5hmC, 5-methylcytosine (5mC), and ten-eleven translocation 2 protein(TET2). Immunohistological scoring showed significantly (P<0.0001) higher median 5hmC levels in BCNand DCN than in thin SSM, thick SSM, and CMD. 5mC immunoreactivity did not differ significantly(P=0.15) between nevi and melanoma. The intensity of TET2 expression was predominantly weak butwas found to be significantly (P<0.0001) more often in nevi than in thin SSM, thick SSM, and CMD. Wehave shown that 5hmC levels and TET2 expression are significantly reduced in advanced melanomascompared with nevi and thin melanomas. It is suggested that 5hmC and TET2 possibly play an importantrole in the epigenetic regulation of melanoma development and progression.", "metadata": {}}
+{"_id": "36960449", "title": "", "text": "Estimation of the dietary requirement for vitamin D in healthy adults.BACKGROUND Knowledge gapshave contributed to considerable variation among international dietary recommendations for vitaminD.   OBJECTIVE We aimed to establish the distribution of dietary vitamin D required to maintain serum25-hydroxyvitamin D [25(OH)D] concentrations above several proposed cutoffs (ie, 25, 37.5, 50, and 80nmol/L) during wintertime after adjustment for the effect of summer sunshine exposure and diet.DESIGN A randomized, placebo-controlled, double-blind 22-wk intervention study was conducted in menand women aged 20-40 y (n = 238) by using different supplemental doses (0, 5, 10, and 15 microg/d) ofvitamin D(3) throughout the winter. Serum 25(OH)D concentrations were measured by usingenzyme-linked immunoassay at baseline (October 2006) and endpoint (March 2007). RESULTS Therewere clear dose-related increments (P < 0.0001) in serum 25(OH)D with increasing supplemental vitaminD(3). The slope of the relation between vitamin D intake and serum 25(OH)D was 1.96 nmol x L(-1) xmicrog(-1) intake. The vitamin D intake that maintained serum 25(OH)D concentrations of >25 nmol/L in97.5% of the sample was 8.7 microg/d. This intake ranged from 7.2 microg/d in those who enjoyedsunshine exposure, 8.8 microg/d in those who sometimes had sun exposure, and 12.3 microg/d in thosewho avoided sunshine. Vitamin D intakes required to maintain serum 25(OH)D concentrations of >37.5,>50, and >80 nmol/L in 97.5% of the sample were 19.9, 28.0, and 41.1 microg/d, respectively.CONCLUSION The range of vitamin D intakes required to ensure maintenance of wintertime vitamin Dstatus [as defined by incremental cutoffs of serum 25(OH)D] in the vast majority (>97.5%) of20-40-y-old adults, considering a variety of sun exposure preferences, is between 7.2 and 41.1 microg/d.", "metadata": {}}
+{"_id": "36962270", "title": "", "text": "Rapid purification of homodimer and heterodimer HIV-1 reverse transcriptase by metal chelate affinitychromatography.We have modified an Escherichia coli vector expressing 66-kDa HIV-1 reversetranscriptase (p66) so that it simultaneously expresses this and the pol-coded protease. The twinexpression cassette yields high quantities of both reverse transcriptase and protease; however, underthese conditions, 50% of the over-expressed p66 reverse transcriptase is processed, resulting inaccumulation of large quantities of p66/p51 enzyme. Furthermore, addition of a poly(histidine) affinitylabel at the amino terminus of the reverse-transcriptase-coding sequence (His-p66) permits a simple,rapid purification of milligram quantities of either p66 or p66/p51 enzyme from a crude lysate by metalchelate affinity chromatography. Purified His-p66 and His-p66/His-p51 reverse transcriptase exhibit bothreverse transcriptase and RNase H activity. Purification by metal chelate chromatography of a p66/p51enzyme wherein only the p66 component is labelled strengthens the argument for the existence of aheterodimer.", "metadata": {}}
+{"_id": "36991551", "title": "", "text": "Polyphenols of Cocoa: Inhibition of Mammalian 15-LipoxygenaseAbstract Some cocoas and chocolates arerich in ()epicatechin and its related oligomers, the procyanidins. Fractions of these compounds, isolatedfrom the seeds of Theobroma cacao, caused dosedependent inhibition of isolated rabbit15-lipoxygenase-1 with the larger oligomers being more active; the decamer fraction revealed an IC 50of 0.8 M. Among the monomeric flavanols, epigallocatechin gallate (IC 50 = 4 M) and epicatechin gallate(5 M) were more potent than ()epicatechin (IC50 = 60 M). ()Epicatechin and procyanidin nonamer alsoinhibited the formation of 15-hydroxyeicosatetraenoic acid from arachidonic acid in rabbit smooth musclecells transfected with human 15-lipoxygenase-1. In contrast, inhibition of the lipoxygenase pathway inJ774A.1 cells transfected with porcine leukocytetype 12- lipoxygenase (another representative of the12/15- lipoxygenase family) was only observed upon sonication of the cells, suggesting a membranebarrier for flavanols in these cells. Moreover, epicatechin (IC50 approx. 15 M) and the procyanidindecamer inhibited recombinant human platelet 12-lipoxygenase. These observations suggest generallipoxygenase inhibitory potency of flavanols and procyanidins that may contribute to their putativebeneficial effects on the cardiovascular system in man. Thus, they may provide a plausible explanationfor recent literature reports indicating that procyanidins decrease the leukotriene/prostacyclin ratio inhumans and human aortic endothelial cells.", "metadata": {}}
+{"_id": "37029185", "title": "", "text": "Quality of life in patients with advanced heart failure.Although evaluation of the treatment of congestiveheart failure is usually based on objective clinical outcomes, patient self-assessment is increasinglyrecognized as an important component of evaluation. A study was designed to measure the quality of lifeof 134 patients with symptoms of advanced heart failure who were being evaluated for possible hearttransplantation. The patients' quality of life was assessed using a mix of subjective and objectivemeasures, including functional status, physical symptoms, emotional state, and psychosocial adaptation.There was no significant relationship between patients' cardiac ejection fraction and any quality-of-lifemeasures; however, the results of a 6-minute walking test, New York Heart Association classification, andself-reported functional status were all significantly correlated with psychosocial adjustment.Self-reported functional status, depression, and hostility accounted for 43% of the variance in totalpsychosocial adjustment to illness. These findings support the inclusion of quality of life as an outcomemeasure in any evaluation of treatment efficacy and suggest that interventions to improve the quality oflife of patients with advanced heart failure need to be targeted at reducing depression and hostility andincreasing daily activity levels.", "metadata": {}}
+{"_id": "37037012", "title": "", "text": "Regional vascular resistance during exercise: role of cardiac afferents and exercise training.This studywas designed to determine whether cardiac vagal afferents exert an inhibitory influence on increases inregional vascular resistance during exercise and to determine whether endurance exercise trainingenhances the inhibitory influence of cardiac vagal afferents. We measured changes in regional vascularresistance in 12 rabbits at rest and during running at 12.6 m/min, 20% grade, before and after reversibledenervation of cardiac afferents (intrapericardial procainamide HCl, 2%). In addition, these procedureswere repeated in five of these rabbits following an 8-wk endurance exercise training program. Becauseintrapericardial injections of procainamide anesthetize both the efferent as well as the afferentinnervation to the heart, it was necessary to determine the effects of blocking the efferent innervation onthe regulation of regional vascular resistance during exercise. Rabbits were instrumented with Dopplerultrasonic flow probes around the renal (R), mesenteric (M), ascending, and terminal aortic (TA) arteries.Catheters were positioned in the central ear artery and vein and pericardial sac. Mean arterial pressure,heart rate, cardiac output, R, M, TA, and systemic (S) resistances were determined. Exercise changed R(+37 +/- 4%), M (+88 +/- 9%), TA (-62 +/- 6%), and S (-34 +/- 3) resistances. Subsequent cardiacefferent blockade alone had no significant effect on regional vascular resistance during exercise.Combined efferent and afferent blockade resulted in significant increases in R (+62 +/- 6%) and Mresistance (+134 +/- 13%) but did not alter TA (-51 +/- 4%) or S (-27 +/- 2%) resistance duringexercise. Exercise training significantly enhanced the inhibitory influence of cardiac afferents on R and Mregional vascular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)", "metadata": {}}
+{"_id": "37065914", "title": "", "text": "Serum Soluble Corin is Decreased in Stroke.BACKGROUND AND PURPOSE Soluble corin was decreased incoronary heart disease. Given the connections between cardiac dysfunction and stroke, circulating corinmight be a candidate marker of stroke risk. However, the association between circulating corin and strokehas not yet been studied in humans. Here, we aimed to examine the association in patients wtith strokeand community-based healthy controls. METHODS Four hundred eighty-one patients with ischemicstroke, 116 patients with hemorrhagic stroke, and 2498 healthy controls were studied. Serum solublecorin and some conventional risk factors of stroke were examined. Because circulating corin was reportedto be varied between men and women, the association between serum soluble corin and stroke wasevaluated in men and women, respectively. RESULTS Patients with ischemic and hemorrhagic stroke hada significantly lower level of serum soluble corin than healthy controls in men and women (all P values,<0.05). In multivariate analysis, men in the lowest quartile of serum soluble corin were more likely tohave ischemic (odds ratio [OR], 4.90; 95% confidence interval, 2.99-8.03) and hemorrhagic (OR, 17.57;95% confidence interval, 4.85-63.71) stroke than men in the highest quartile. Women in the lowestquartile of serum soluble corin were also more likely to have ischemic (OR, 3.10; 95% confidenceinterval, 1.76-5.44) and hemorrhagic (OR, 8.54; 95% confidence interval, 2.35-31.02) stroke thanwomen in the highest quartile. ORs of ischemic and hemorrhagic stroke were significantly increased withthe decreasing levels of serum soluble corin in men and women (all P values for trend, <0.001).CONCLUSIONS Serum soluble corin was decreased in patients with stroke compared with healthycontrols. Our findings raise the possibility that serum soluble corin may have a pathogenic role in stroke.", "metadata": {}}
+{"_id": "37118634", "title": "", "text": "Topical application of chlorhexidine to neonatal umbilical cords for prevention of omphalitis and neonatalmortality in a rural district of Pakistan: a community-based, cluster-randomised trial.BACKGROUNDUmbilical cord infection (omphalitis) is a risk factor for neonatal sepsis and mortality in low-resourcesettings where home deliveries are common. We aimed to assess the effect of umbilical-cord cleansingwith 4% chlorhexidine (CHX) solution, with or without handwashing with antiseptic soap, on the incidenceof omphalitis and neonatal mortality. METHODS We did a two-by-two factorial, cluster-randomised trial inDadu, a rural area of Sindh province, Pakistan. Clusters were defined as the population covered by afunctional traditional birth attendant (TBA), and were randomly allocated to one of four groups (groups Ato D) with a computer-generated random number sequence. Implementation and data collection teamswere masked to allocation. Liveborn infants delivered by participating TBAs who received birth kits wereeligible for enrolment in the study. One intervention comprised birth kits containing 4% CHX solution forapplication to the cord at birth by TBAs and once daily by family members for up to 14 days along withsoap and educational messages promoting handwashing. One intervention was CHX solution only andanother was handwashing only. Standard dry cord care was promoted in the control group. The primaryoutcomes were incidence of neonatal omphalitis and neonatal mortality. The trial is registered withClinicalTrials.gov, number NCT00682006. FINDINGS 187 clusters were randomly allocated to one of thefour study groups. Of 9741 newborn babies delivered by participating TBAs, factorial analysis indicated areduction in risk of omphalitis with CHX application (risk ratio [RR]=0·58, 95% CI 0·41-0·82; p=0·002)but no evidence of an effect of handwashing (RR=0·83, 0·61-1·13; p=0·24). We recorded strongevidence of a reduction in neonatal mortality in neonates who received CHX cleansing (RR=0·62, 95 % CI0·45-0·85; p=0·003) but no evidence of an effect of handwashing promotion on neonatal mortality(RR=1·08, 0·79-1·48; p=0·62). We recorded no serious adverse events. INTERPRETATION Application of4% CHX to the umbilical cord was effective in reducing the risk of omphalitis and neonatal mortality inrural Pakistan. Provision of CHX in birth kits might be a useful strategy for the prevention of neonatalmortality in high-mortality settings. FUNDING The United States Agency for International Development.", "metadata": {}}
+{"_id": "37138639", "title": "", "text": "The IKK complex, a central regulator of NF-kappaB activation.The IKK kinase complex is the core elementof the NF-kappaB cascade. It is essentially made of two kinases (IKKalpha and IKKbeta) and a regulatorysubunit, NEMO/IKKgamma. Additional components may exist, transiently or permanently, but theircharacterization is still unsure. In addition, it has been shown that two separate NF-kappaB pathwaysexist, depending on the activating signal and the cell type, the canonical (depending on IKKbeta andNEMO) and the noncanonical pathway (depending solely on IKKalpha). The main question, which is stillonly partially answered, is to understand how an NF-kappaB activating signal leads to the activation ofthe kinase subunits, allowing them to phosphorylate their targets and eventually induce nucleartranslocation of the NF-kappaB dimers. I will review here the genetic, biochemical, and structural dataaccumulated during the last 10 yr regarding the function of the three IKK subunits.", "metadata": {}}
+{"_id": "37156349", "title": "", "text": "Cognitive predictors of young children's readiness for powered mobility.Independent mobility in earlychildhood has been associated with the development of various cognitive and psychosocial skills.However, children with physical disabilities are not always able to move independently and may be at riskfor delays in these areas. Early provision of powered mobility can offer young children an opportunity forindependent mobility. Despite this, there is little information to help determine when a young child hasthe cognitive skills necessary to operate a powered wheelchair safely. This current research aims toidentify these skills. A cognitive assessment battery and a wheelchair mobility training and assessmentprogram were developed. Twenty-six children with physical disabilities between the ages of 20 and 36months were evaluated on the cognitive assessment and participated in the wheelchair training andassessment program. A stepwise regression analysis was used to determine which of the cognitive skillspredicted wheelchair mobility performance. The cognitive domains of spatial relations and problemsolving were found to be significant and accounted for 57% of the variance in wheelchair skills.Developmental cut-off points on these scales as they relate to wheelchair skills are presented and clinicalapplications are discussed.", "metadata": {}}
+{"_id": "37164306", "title": "", "text": "Knockdown of the co-chaperone Hop promotes extranuclear accumulation of Stat3 in mouse embryonicstem cells.A key event in the mechanism of mouse embryonic stem cell (mESC) pluripotency isphosphorylation, dimerisation and translocation to the nucleus of the signal transducer and activator oftranscription3, Stat3. We used RNAi to suppress the levels of the co-chaperone Hsp70/Hsp90 organisingprotein (Hop) in an mESC line. Hop knockdown caused 68% depletion in Stat3 mRNA levels, decreasedsoluble pYStat3 levels, and led to an extranuclear accumulation of Stat3. The major binding partner ofHop, Hsp90, co-localised with a small non-nuclear fraction of Stat3 in mESCs, and both Stat3 and Hopco-precipitated with Hsp90. Hop knockdown did not affect Nanog and Oct4 protein levels; however,Nanog mRNA levels were decreased. We found that in the absence of Hop, mESCs lost their pluripotentability to form embryoid bodies with a basement membrane. These data suggest that Hop facilitates thephosphorylation and nuclear translocation of Stat3, implying a role for the Hsp70/Hsp90 chaperoneheterocomplex machinery in pluripotency signalling.", "metadata": {}}
+{"_id": "37182501", "title": "", "text": "B-cell self-tolerance in humans.Two mechanisms account for generation of the human antibodyrepertoire; V(D)J recombination during the early stages of B-cell development in the bone marrow andsomatic mutation of immunoglobulin genes in mature B cells responding to antigen in the periphery.V(D)J recombination produces diversity by random joining of gene segments and somatic mutation byintroducing random point mutations. Both are required to attain the degree of antigen receptordiversification that is necessary for immune protection: defects in either mechanism are associated withincreased susceptibility to infection. However, the downside of producing enormous random diversity inthe antibody repertoire is the generation of autoantibodies. To prevent autoimmunity B cells expressingautoantibodies are regulated by strict mechanisms that either modify the specificity of autoantibodies orthe fate of cells expressing such antibodies. Abnormalities in B-cell self-tolerance are associated with alarge number of autoimmune diseases, but the precise nature of the defects is less well defined. Here wesummarize recent data on the self-reactive B-cell repertoire in healthy humans and in patients withautoimmunity.", "metadata": {}}
+{"_id": "37204802", "title": "", "text": "JMJD6 Promotes Colon Carcinogenesis through Negative Regulation of p53 by HydroxylationJumonjidomain-containing 6 (JMJD6) is a member of the Jumonji C domain-containing family of proteins.Compared to other members of the family, the cellular activity of JMJD6 is still not clearly defined and itsbiological function is still largely unexplored. Here we report that JMJD6 is physically associated with thetumor suppressor p53. We demonstrated that JMJD6 acts as an α-ketoglutarate- and Fe(II)-dependentlysyl hydroxylase to catalyze p53 hydroxylation. We found that p53 indeed exists as a hydroxylatedprotein in vivo and that the hydroxylation occurs mainly on lysine 382 of p53. We showed that JMJD6antagonizes p53 acetylation, promotes the association of p53 with its negative regulator MDMX, andrepresses transcriptional activity of p53. Depletion of JMJD6 enhances p53 transcriptional activity, arrestscells in the G1 phase, promotes cell apoptosis, and sensitizes cells to DNA damaging agent-induced celldeath. Importantly, knockdown of JMJD6 represses p53-dependent colon cell proliferation andtumorigenesis in vivo, and significantly, the expression of JMJD6 is markedly up-regulated in varioustypes of human cancer especially in colon cancer, and high nuclear JMJD6 protein is strongly correlatedwith aggressive clinical behaviors of colon adenocarcinomas. Our results reveal a novel posttranslationalmodification for p53 and support the pursuit of JMJD6 as a potential biomarker for colon canceraggressiveness and a potential target for colon cancer intervention.", "metadata": {}}
+{"_id": "37205685", "title": "", "text": "Spread of chloroquine resistance in Plasmodium falciparum.Malaria resistant to chloroquine has now beenconfirmed in more than 40 countries. The drug was introduced in 1934, but was not in large-scale useuntil the early 1950s. Anecdotal reports suggest that resistance emerged as early as 1957 both inColombia and along the then Cambodia-Thailand border area. But by 1960, resistance in these areas wasconfirmed - and may represent two separate events. Resistance spread rapidly, with a new focus ofresistance confirmed in East Africa by 1977. Chloroquine resistance represents a severe problem both forprophylaxis and treatment of malaria. In this aricle, David Payne traces the spread of resistance anddiscusses some of its implications.", "metadata": {}}
+{"_id": "37205759", "title": "", "text": "Obesity occurring in apolipoprotein E-knockout mice has mild effects on fertility.The Apolipoprotein (Apo)family is implicated in lipid metabolism. There are five types of Apo: Apoa, Apob, Apoc, Apod, and Apoe.Apoe has been demonstrated to play a central role in lipoprotein metabolism and to be essential forefficient receptor-mediated plasma clearance of chylomicron remnants and VLDL remnant particles by theliver. Apoe-deficient (Apoe(-/-)) mice develop atherosclerotic plaques spontaneously, followed by obesity.In this study, we investigated whether lipid deposition caused by Apoe knockout affects reproduction infemale mice. The results demonstrated that Apoe(-/-) mice were severely hypercholesterolemic, withtheir cholesterol metabolism disordered, and lipid accumulating in the ovaries causing the ovaries to beheavier compared with the WT counterparts. In addition, estrogen and progesterone decreasedsignificantly at D 100. Quantitative PCR analysis demonstrated that at D 100 the expression ofcytochromeP450 aromatase (Cyp19a1), 3β-hydroxysteroid dehydrogenase (Hsd3b), mechanistic target ofrapamycin (Mtor), and nuclear factor-κB (Nfkb) decreased significantly, while that of BCL2-associatedagonist of cell death (Bad) and tuberous sclerosis complex 2 (Tsc2) increased significantly in theApoe(-/-) mice. However, there was no difference in the fertility rates of the Apoe(-/-) and WT mice; thatis, obesity induced by Apoe knockout has no significant effect on reproduction. However, the deletion ofApoe increased the number of ovarian follicles and the ratio of ovarian follicle atresia and apoptosis. Webelieve that this work will augment our understanding of the role of Apoe in reproduction.", "metadata": {}}
+{"_id": "37207226", "title": "", "text": "Lipid metabolism and toxicity in the heart.The heart has both the greatest caloric needs and the mostrobust oxidation of fatty acids (FAs). Under pathological conditions such as obesity and type 2 diabetes,cardiac uptake and oxidation are not balanced and hearts accumulate lipid potentially leading to cardiaclipotoxicity. We will first review the pathways utilized by the heart to acquire FAs from the circulation andto store triglyceride intracellularly. Then we will describe mouse models in which excess lipidaccumulation causes heart dysfunction and experiments performed to alleviate this toxicity. Finally, theknown relationships between heart lipid metabolism and dysfunction in humans will be summarized.", "metadata": {}}
+{"_id": "37248570", "title": "", "text": "Malaria eradication back on the table.After a lapse of almost 40 years, malaria eradication is back on theglobal health agenda. Inspired by the Gates Malaria Forum in October 2007,1,2 key organizations arestarting to debate the pros and cons of redefining eradication as an explicit goal of malaria control efforts.Attempts to eliminate malaria in southern Africa3 and Pacific Island states,4 and WHO’s Global MalariaProgramme agenda and field manual for malaria elimination,5,6 foreshadow this movement towardsanother global attempt at eradication. When marking 60 years of WHO’s commitment to fighting malaria,we must ask what has been achieved, but also what can we learn from the past. We now know so muchmore about the biology of parasite-host responses, the determinants of endemicity and transmissiondynamics, the social, economic and cultural implications of malaria at household, community and nationallevels, and the demands made upon health systems in endemic countries. We do not yet know how tosynthesize and integrate this knowledge to achieve elimination in different settings. Regional malariaelimination campaigns were first conducted in the late 1940s, preparing the ground for the Global MalariaEradication Program in 1955. This campaign succeeded in eliminating malaria from Europe, NorthAmerica, the Caribbean and parts of Asia and South-Central America.7 But no major success occurred insub-Saharan Africa, which accounts for 80% of today’s burden of malaria.8 When the aspiration of globaleradication was abandoned in 1969, the main reasons for failure were technical challenges of executingthe strategy especially in Africa. The post-eradication era from 1969 to 1991 focused on technical issues,and research and development for new tools, leading to advances in drug and vaccine development,vector control and insecticide-treated nets. These decades also brought a better understanding of thesocial, economic and cultural dimensions of malaria. There was little global support provided specificallyfor malaria control in the newly independent states of Africa that were struggling to establishbroad-based health systems and primary health care. By 1992, the combination of a worsening malariasituation and promising technical developments led to renewed global focus on malaria control. The RollBack Malaria initiative, launched by WHO in 1998, led to the Abuja Declaration in 2000, which definedprogressive intervention coverage targets for control designed to eliminate malaria as a public healthproblem, while emphasizing that this could only be achieved through vastly strengthened local healthsystems.9 Increased resources through the Global Fund to Fight AIDS, Tuberculosis and Malaria, theWorld Bank’s Booster Program, the US President’s Malaria Initiative and many others has meant that thispage is finally beginning to turn as intervention coverage is rising.10    It is against this background thatwe hear this call for elimination/eradication. The challenges remain formidable. We all know thatelimination in Africa is not possible with current tools. But efforts must focus beyond simply developingbetter tools, to include how existing and future tools can be strategically combined for maximumsynergistic effectiveness when integrated into different health and social systems prevailing in endemicareas. Aiming at elimination and eradication further implies the need for effective surveillance strategiesto monitor progress (again a challenge for health systems). This in turn requires a better understandingof malaria transmission heterogeneity in a globalized world with rapidly changing dynamics inenvironment, climate, migration and transnational cooperation. Maintaining long-term momentum in theface of success in regional elimination while waiting to achieve final eradication will be a major challenge.Shrinking the map by starting on the malaria margins with the “easy-to-eliminate” settings will boostmorale initially but may bring marginal benefits to such areas at the expense of those where the burdenof malaria is highest. Any strategic plan – and here we learn again from the past – needs to be asynchronous global effort, locally adapted in all endemic areas. Although we lack sufficient knowledge,systems and tools to eradicate malaria today, we do have a window of political will and financialresources to refocus on the goal of effective control through universal coverage of appropriateinterventions. The prerequisites for a successful start are: (i) a process of inclusive discourse to agree onglobal vision, goals and strategy; and (ii) a global plan for all endemic areas describing how, where andwhen we move from control towards elimination. What must distinguish the new era, especially in Africa,is a real rather than rhetorical emphasis on health systems. \u0000", "metadata": {}}
+{"_id": "37248765", "title": "", "text": "CI-994 (N-acetyl-dinaline) in combination with conventional anti-cancer agents is effective against acutemyeloid leukemia in vitro and in vivo.N-acetyl-dinaline (CI-994) is an investigational anti-cancer drugwhich inhibits histone deacetylases. We evaluated the interaction between CI-994 and conventionalchemotherapeutics used in acute myeloid leukemia (AML) in a rat model for AML and Brown Norway ratacute myelocytic leukemia (BNML). In vitro, CI-994 in combination with cytarabine (ara-C), daunorubicinand mitoxantrone, resulted in moderate synergism. In vivo, higher dosages of CI-994 induced completeremissions. CI-994/ara-C was very active against BNML. The combinations of CI-994/daunorubicin andCI-994/mitoxantrone were also active against BNML. This study demonstrates favorable in vitro and invivo interactions between CI-994 and conventional anti-cancer agents used for the treatment of AML.", "metadata": {}}
+{"_id": "37249641", "title": "", "text": "CTCF and Cohesin in Genome Folding and Transcriptional Gene Regulation.Genome function, replication,integrity, and propagation rely on the dynamic structural organization of chromosomes during the cellcycle. Genome folding in interphase provides regulatory segmentation for appropriate transcriptionalcontrol, facilitates ordered genome replication, and contributes to genome integrity by limitingillegitimate recombination. Here, we review recent high-resolution chromosome conformation captureand functional studies that have informed models of the spatial and regulatory compartmentalization ofmammalian genomes, and discuss mechanistic models for how CTCF and cohesin control the functionalarchitecture of mammalian chromosomes.", "metadata": {}}
+{"_id": "37256966", "title": "", "text": "Melatonin synthesized by T lymphocytes as a ligand of the retinoic acid-related orphan receptor.Melatoninmodulates a wide array of physiological events with pleiotropic effects on the immune system. While therelevance of specific melatonin membrane receptors has been well established for several biologicalfunctions, retinoic acid-related orphan receptor alpha (RORα) has been suggested as a mediator ofnuclear melatonin signalling by results obtained from pharmacological approaches. However, amelatonin-mediated downstream effect cannot be ruled out, and further evidence is needed to support adirect interaction between melatonin and RORα. Here, we show that RORα is mainly located in humanJurkat T-cell nucleus, and it is co-immunoprecipitated with melatonin. Moreover, immunocytochemistrystudies confirmed the co-localization of melatonin and RORα. Melatonin promoted a time-dependentdecrease in nuclear RORα levels, suggesting a role in the RORα transcriptional activity. Interestingly,RORα acts as a molecular switch implicated in the mutually exclusive generation of Th17 and Treg cells,both involved in the harm/protection balance of immune conditions such as autoimmunity or acutetransplant rejection. Therefore, the identification of melatonin as a natural modulator of RORα gives it atremendous therapeutic potential for a variety of clinical disorders.", "metadata": {}}
+{"_id": "37269418", "title": "", "text": "Age- and infection intensity-dependent cytokine and antibody production in human trichuriasis: theimportance of IgE.The cytokine and antibody response to Trichuris trichiura infection was determined for96 persons living in an area where the parasite is highly endemic and infection exhibits a convex ageintensity profile. In response to stimulation with T. trichiura antigen, a small proportion of the studygroup produced interleukin (IL)-4 (7%), IL-9 (5%), and IL-13 (17%). A larger proportion produced IL-10(97%), tumor necrosis factor (TNF)-alpha (93%), and interferon (IFN)-gamma (32%). The levels ofTNF-alpha (P =.016) and IFN-gamma (P =.012) significantly increased with age, suggesting a switch to amore chronic infection phenotype. The predominant parasite-specific antibodies produced were IgG1,IgG4, IgA, and IgE. Unlike the IgG subclasses and IgA, parasite-specific IgE correlated negatively withinfection intensity, as defined by egg output (P =.008), and positively with host age (P =.010). Thesefindings suggest a mixed cytokine response in trichuriasis and an IgE-associated level of protection.", "metadata": {}}
+{"_id": "37296667", "title": "", "text": "The cryoprotective effect of trehalose supplementation on boar spermatozoa quality.In order to improveboar sperm quality during frozen-thawed process, the influence of the presence of trehalose on success ofcryopreservation of boar sperm were investigated. We evaluated freeze-thawing tolerance of boarspermatozoa in a base cooling extender with the addition of different trehalose concentrations (0, 25, 50,100 and 200mmol/l), and tried to determine the optimum concentration of trehalose. We chose spermmotility, acrosome integrity, membrane integrity and cryocapacitation as parameters to evaluatecryopreservation capacity of boar spermatozoa. We obtained the best results for 100mmol/ltrehalose-supplemented extenders, with values of 49.89% for motility, 66.52% for acrosome integrityand 44.61% for membrane integrity, while freeze-thawing tolerance was diminished significantly for200mmol/l of trehalose. Before and after capacitation, the CTC score for semen diluted by extendercontaining 100mmol/l trehalose was 3.68% and 43.82%, respectively. In conclusion, trehalose couldconfer a greater cryoprotective capacity to boar spermatozoa. Trehalose-supplementation with100mmol/l concentration in basic extender could significantly improve sperm motility, membraneintegrity and acrosome integrity parameters, and reduce boar spermatozoa cryocapacitation during thecryopreservation process.", "metadata": {}}
+{"_id": "37297740", "title": "", "text": "Roads to polyploidy: the megakaryocyte example.Polyploidy, recognized by multiple copies of the haploidchromosome number, has been described in plants, insects, and in mammalian cells such as, the plateletprecursors, the megakaryocytes. Several of these cell types reach high ploidy via a different cell cycle.Megakaryocytes undergo an endomitotic cell cycle, which consists of an S phase interrupted by a gap,during which the cells enter mitosis but skip anaphase B and cytokinesis. Here, we review themechanisms that lead to this cell cycle and to polyploidy in megakaryocytes, while also comparing themto those described for other systems in which high ploidy is achieved. Overall, polyploidy is associatedwith an orchestrated change in expression of several genes, of which, some may be a result of highploidy and hence a determinant of a new cell physiology, while others are inducers of polyploidization.Future studies will aim to further explore these two groups of genes.", "metadata": {}}
+{"_id": "37311371", "title": "", "text": "Central memory and effector memory T cell subsets: function, generation, and maintenance.The memoryT cell pool functions as a dynamic repository of antigen-experienced T lymphocytes that accumulate overthe lifetime of the individual. Recent studies indicate that memory T lymphocytes contain distinctpopulations of central memory (TCM) and effector memory (TEM) cells characterized by distinct homingcapacity and effector function. This review addresses the heterogeneity of TCM and TEM, theirdifferentiation stages, and the current models for their generation and maintenance in humans and mice.", "metadata": {}}
+{"_id": "37328025", "title": "", "text": "The Werner and Bloom syndrome proteins help resolve replication blockage by converting (regressed)holliday junctions to functional replication forks.Cells cope with blockage of replication fork progression ina manner that allows DNA synthesis to be completed and genomic instability minimized. Models forresolution of blocked replication involve fork regression to form Holliday junction structures. The humanRecQ helicases WRN and BLM (deficient in Werner and Bloom syndromes, respectively) are critical formaintaining genomic stability and thought to function in accurate resolution of replication blockage.Consistent with this notion, WRN and BLM localize to sites of blocked replication after certainDNA-damaging treatments and exhibit enhanced activity on replication and recombination intermediates.Here we examine the actions of WRN and BLM on a special Holliday junction substrate reflective of aregressed replication fork. Our results demonstrate that, in reactions requiring ATP hydrolysis, both WRNand BLM convert this Holliday junction substrate primarily to a four-stranded replication fork structure,suggesting they target the Holliday junction to initiate branch migration. In agreement, the Hollidayjunction binding protein RuvA inhibits the WRN- and BLM-mediated conversion reactions. Importantly,this conversion product is suitable for replication with its leading daughter strand readily extended byDNA polymerases. Furthermore, binding to and conversion of this Holliday junction are optimal at lowMgCl(2) concentrations, suggesting that WRN and BLM preferentially act on the square planar (open)conformation of Holliday junctions. Our findings suggest that, subsequent to fork regression events, WRNand/or BLM could re-establish functional replication forks to help overcome fork blockage. Such a functionis highly consistent with phenotypes associated with WRN- and BLM-deficient cells.", "metadata": {}}
+{"_id": "37336085", "title": "", "text": "Do Montelukast Sodium and N-Acetylcysteine Have a Nephroprotective Effect on Unilateral UreteralObstruction? A Placebo Controlled Trial in a Rat Model.PURPOSE We assessed the nephroprotectiveeffects of montelukast sodium and N-acetylcysteine on secondary renal damage due to unilateral ureteralobstruction in a rat model. MATERIALS AND METHODS In this study 30 Wistar albino male rats wererandomized into 3 groups, including placebo, N-acetylcysteine and montelukast sodium. Three ratsserved as the control group. The left ureter of the rats was sutured with 4-zero polyglactin sutures.Medications were given 3 days before obstruction and continued for 15 days. Dimercaptosuccinic acidrenal scintigraphy was performed before obstruction and on day 15. Rats were sacrificed on day 15 andhistopathological examinations were done. We biochemically assessed oxidative stress markers(myeloperoxidase and malondialdehyde), sulfhydryl and total nitrite for lipid peroxidation, oxidativeprotein damage and antioxidant levels, respectively. RESULTS On pathological examination inflammationand tubular epithelial damage in the N-acetylcysteine and montelukast sodium groups were less than inthe placebo group (p <0.05). No difference was seen in normal kidneys. Myeloperoxidase,malondialdehyde and total nitrite levels in the N-acetylcysteine group, and myeloperoxidase andmalondialdehyde levels in the montelukast sodium group were lower than in the placebo group (p<0.05). No statistical difference was seen in sulfhydryl levels (p >0.05) or among the N-acetylcysteine,montelukast sodium and placebo groups on scintigraphy (p >0.05). No pathological, chemical andscintigraphic differences were seen among the N-acetylcysteine, montelukast sodium and sham treatedgroups (p >0.05). CONCLUSIONS N-acetylcysteine and montelukast sodium have a protective effectagainst obstructive damage of the kidney. However, further investigations are needed.", "metadata": {}}
+{"_id": "37362689", "title": "", "text": "Oxidative phosphorylation: synthesis of mitochondrially encoded proteins and assembly of individualstructural subunits into functional holoenzyme complexes.The bulk of ATP consumed by various cellularprocesses in higher eukaryotes is normally produced by five multimeric protein complexes (I-V)embedded within the inner mitochondrial membrane, in a process known as oxidative phosphorylation(OXPHOS). Maintenance of energy homeostasis under most physiological conditions is thereforecontingent upon the ability of OXPHOS to meet cellular changes in bioenergetic demand, with a chronicfailure to do so being a frequent cause of human disease. With the exception of Complex II, the structuralsubunits of OXPHOS complexes are encoded by both the nuclear and the mitochondrial genomes. Thephysical separation of the two genomes necessitates that the expression of the 13 mitochondriallyencoded polypeptides be co-ordinated with that of relevant nuclear-encoded partners in order toassemble functional holoenzyme complexes. Complex biogenesis is a highly ordered process, and severalnuclear-encoded factors that function at distinct stages in the assembly of individual OXPHOS complexeshave been identified.", "metadata": {}}
+{"_id": "37405449", "title": "", "text": "Familial gastroesophageal reflux and development of Barrett's esophagus.The family of an elderly manwith Barrett's esophagus was examined for gastroesophageal reflux and development of Barrett'sesophagus. All five living children have gastroesophageal reflux or esophagitis, or both, and three haveunequivocal Barrett's esophagus. Two third-generation descendents have gastroesophageal reflux. Thispattern suggests autosomal dominant transmission of the gastroesophageal reflux trait. The family alsohas a high prevalence of cancer, which may represent the cancer family syndrome.", "metadata": {}}
+{"_id": "37424881", "title": "", "text": "The effect of folate fortification on folic acid-based homocysteine-lowering intervention and stroke risk: ameta-analysis.OBJECTIVE Folate and vitamin B12 are two vital regulators in the metabolic process ofhomocysteine, which is a risk factor of atherothrombotic events. Low folate intake or low plasma folateconcentration is associated with increased stroke risk. Previous randomized controlled trials presenteddiscordant findings in the effect of folic acid supplementation-based homocysteine lowering on strokerisk. The aim of the present review was to perform a meta-analysis of relevant randomized controlledtrials to check the how different folate fortification status might affect the effects of folic acidsupplementation in lowering homocysteine and reducing stroke risk. DESIGN Relevant randomizedcontrolled trials were identified through formal literature search. Homocysteine reduction was comparedin subgroups stratified by folate fortification status. Relative risks with 95 % confidence intervals wereused as a measure to assess the association between folic acid supplementation and stroke risk. SETTINGThe meta-analysis included fourteen randomized controlled trials,   SUBJECTS A total of 39 420 patients.RESULTS Homocysteine reductions were 26·99 (sd 1·91) %, 18·38 (sd 3·82) % and 21·30 (sd 1·98) %,respectively, in the subgroups without folate fortification, with folate fortification and with partial folatefortification. Significant difference was observed between the subgroups with folate fortification andwithout folate fortification (P=0·05). The relative risk of stroke was 0·88 (95 % CI 0·77, 1·00, P=0·05) inthe subgroup without folate fortification, 0·94 (95 % CI 0·58, 1·54, P=0·82) in the subgroup with folatefortification and 0·91 (95 % CI 0·82, 1·01, P=0·09) in the subgroup with partial folate fortification.CONCLUSIONS Folic acid supplementation might have a modest benefit on stroke prevention in regionswithout folate fortification.", "metadata": {}}
+{"_id": "37437064", "title": "", "text": "On the origin and impact of mesenchymal stem cell heterogeneity: new insights and emerging tools forsingle cell analysis.Mesenchymal stem cells (MSCs) display substantial cell-to-cell variation. Thisheterogeneity manifests among donors, among tissue sources, and within cell populations. Suchpervasive variability complicates the use of MSCs in regenerative applications and may limit theirtherapeutic efficacy. Most conventional assays measure MSC properties in bulk and, as a consequence,mask this cell-to-cell variation. Recent studies have identified extensive variability amongst and withinclonal MSC populations, in dimensions including functional differentiation capacity, molecular state (e.g.epigenetic, transcriptomic, and proteomic status), and biophysical properties. While the origins of thesevariations remain to be elucidated, potential mechanisms include in vivo micro-anatomical heterogeneity,epigenetic bistability, and transcriptional fluctuations. Emerging tools for single cell analysis of MSC geneand protein expression may yield further insight into the mechanisms and implications of single cellvariation amongst these cells, and ultimately improve the clinical utility of MSCs in tissue engineering andregenerative medicine applications. This review outlines the dimensions across which MSC heterogeneityis present, defines some of the known mechanisms that govern this heterogeneity, and highlightsemerging technologies that may further refine our understanding and improve our clinical application ofthis unique cell type.", "metadata": {}}
+{"_id": "37438296", "title": "", "text": "Altered microRNA expression in bovine skeletal muscle with age.Age-dependent decline in skeletal musclefunction leads to several inherited and acquired muscular disorders in elderly individuals. The levels ofmicroRNAs (miRNAs) could be altered during muscle maintenance and repair. We therefore performed acomprehensive investigation for miRNAs from five different periods of bovine skeletal muscledevelopment using next-generation small RNA sequencing. In total, 511 miRNAs, including one putativelynovel miRNA, were identified. Thirty-six miRNAs were differentially expressed between prenatal andpostnatal stages of muscle development including several myomiRs (miR-1, miR-206 and let-7 families).Compared with miRNA expression between different muscle tissues, 14 miRNAs were up-regulated and22 miRNAs were down-regulated in the muscle of postnatal stage. In addition, a novel miRNA waspredicted and submitted to the miRBase database as bta-mir-10020. A dual luciferase reporter assay wasused to demonstrate that bta-mir-10020 directly targeted the 3'-UTR of the bovine ANGPT1 gene. Theoverexpression of bta-mir-10020 significantly decreased the DsRed fluorescence in the wild-typeexpression cassette compared to the mutant type. Using three computational approaches - miranda, pitaand rnahybrid - these differentially expressed miRNAs were also predicted to target 3609 bovine genes.Disease and biological function analyses and the KEGG pathway analysis revealed that these targets werestatistically enriched in functionality for muscle growth and disease. Our miRNA expression analysisfindings from different states of muscle development and aging significantly expand the repertoire ofbovine miRNAs now shown to be expressed in muscle and could contribute to further studies on growthand developmental disorders in this tissue type.", "metadata": {}}
+{"_id": "37444589", "title": "", "text": "Apoptosis occurs predominantly in bystander cells and not in productively infected cells of HIV- andSIV-infected lymph nodesAlthough 13 years have passed since identification of human immunodeficiencyvirus-1 (HIV-1) as the cause of AIDS, we do not yet know how HIV kills its primary target, the T cell thatcarries the CD4 antigen. We and others have shown an increase in the percentage of apoptotic cellsamong circulating CD4+ (and CD8+) T cells of HIV-seropositive individuals and an increase in frequencyof apoptosis with disease progression. However, it is not known if this apoptosis occurs in infected oruninfected T cells. We show here, using in situ labelling of lymph nodes from HIV-infected children andSIV-infected macaques, that apoptosis occurs predominantly in bystander cells and not in theproductively infected cells themselves. These data have implications for pathogenesis and therapy,namely, arguing that rational drug therapy may involve combination agents targeting viral replication ininfected cells and apoptosis of uninfected cells.", "metadata": {}}
+{"_id": "37450671", "title": "", "text": "Neuronal origin of a cerebral amyloid: neurofibrillary tangles of Alzheimer's disease contain the sameprotein as the amyloid of plaque cores and blood vessels.The protein component of Alzheimer's diseaseamyloid [neurofibrillary tangles (NFT), amyloid plaque core and congophilic angiopathy] is an aggregatedpolypeptide with a subunit mass of 4 kd (the A4 monomer). Based on the degree of N-terminalheterogeneity, the amyloid is first deposited in the neuron, and later in the extracellular space. Usingantisera raised against synthetic peptides, we show that the N terminus of A4 (residues 1-11) contains anepitope for neurofibrillary tangles, and the inner region of the molecule (residues 11-23) contains anepitope for plaque cores and vascular amyloid. The non-protein component of the amyloid (aluminumsilicate) may form the basis for the deposition or amplification (possible self-replication) of theaggregated amyloid protein. The amyloid of Alzheimer's disease is similar in subunit size, composition butnot sequence to the scrapie-associated fibril and its constituent polypeptides. The sequence andcomposition of NFT are not homologous to those of any of the known components of normalneurofilaments.", "metadata": {}}
+{"_id": "37480103", "title": "", "text": "Pregnancy characteristics and maternal risk of breast cancer.CONTEXT During pregnancy, serum levels ofestrogen, progesterone, and other hormones are markedly higher than during other periods of life.Pregnancy hormones primarily are produced in the placenta, and signs of placental impairment mayserve as indirect markers of hormone exposures during pregnancy. During pregnancy, these markershave been inconsistently associated with subsequent risk of breast cancer in the mother. OBJECTIVE Toexamine associations between indirect markers of hormonal exposures, such as placental weight andother pregnancy characteristics, and maternal risk of developing breast cancer. DESIGN AND SETTINGPopulation-based cohort study using data from the Swedish Birth Register, the Swedish Cancer Register,the Swedish Cause of Death Register, and the Swedish Register of Population and Population Changes.PARTICIPANTS Women included in the Sweden Birth Register who delivered singletons between 1982 and1989, with complete information on date of birth and gestational age. Women were followed up until theoccurrence of breast cancer, death, or end of follow-up (December 31, 2001). Cox proportional hazardsmodels were used to estimate associations between hormone exposures and risks of breast cancer. MAINOUTCOME MEASURE Incidence of invasive breast cancer. RESULTS Of 314,019 women in the cohort,2216 (0.7%) developed breast cancer during the follow-up through 2001, of whom 2100 (95%) werediagnosed before age 50 years. Compared with women who had placentas weighing less than 500 g in 2consecutive pregnancies, the risk of breast cancer was increased among women whose placentasweighed between 500 and 699 g in their first pregnancy and at least 700 g in their second pregnancy (orvice versa) (adjusted hazard ratio, 1.82; 95% confidence interval [CI], 1.07-3.08), and thecorresponding risk was doubled among women whose placentas weighed at least 700 g in bothpregnancies (adjusted hazard ratio, 2.05; 95% CI, 1.15-3.64). A high birth weight (> or =4000 g) in 2successive births was associated with an increased risk of breast cancer before but not after adjusting forplacental weight and other covariates (adjusted hazard ratio, 1.10; 95% CI, 0.76-1.59). CONCLUSIONSPlacental weight is positively associated with maternal risk of breast cancer. These results further supportthe hypothesis that pregnancy hormones are important modifiers of subsequent maternal breast cancerrisk.", "metadata": {}}
+{"_id": "37488367", "title": "", "text": "Attention-deficit hyperactivity disorder: a category or a continuum? Genetic analysis of a large-scale twinstudy.OBJECTIVE To investigate heritability and continuum versus categorical approaches toattention-deficit hyperactivity disorder (ADHD), using a large-scale twin sample. METHOD A cohort of1,938 families with twins and siblings aged 4 to 12 years, recruited from the Australian National Healthand Medical Research Council Twin Registry, was assessed for ADHD using a DSM-III-R-based maternalrating scale. Probandwise concordance rates and correlations in monozygotic and dizygotic twins andsiblings were calculated, and heritability was examined using the De Fries and Fulker regressiontechnique. RESULTS There was a narrow (additive) heritability of 0.75 to 0.91 which was robust acrossfamilial relationships (twin, sibling, and twin-sibling) and across definitions of ADHD as part of acontinuum or as a disorder with various symptom cutoffs. There was no evidence for nonadditive geneticvariation or for shared family environmental effects. CONCLUSIONS These findings suggest that ADHD isbest viewed as the extreme of a behavior that varies genetically throughout the entire population ratherthan as a disorder with discrete determinants. This has implications for the classification of ADHD and forthe identification of genes for this behavior, as well as implications for diagnosis and treatment.", "metadata": {}}
+{"_id": "37549932", "title": "", "text": "Antiapoptotic BCL-2 is required for maintenance of a model leukemia.Resistance to apoptosis, oftenachieved by the overexpression of antiapoptotic proteins, is common and perhaps required in the genesisof cancer. However, it remains uncertain whether apoptotic defects are essential for tumor maintenance.To test this, we generated mice expressing a conditional BCL-2 gene and constitutive c-myc that developlymphoblastic leukemia. Eliminating BCL-2 yielded rapid loss of leukemic cells and significantly prolongedsurvival, formally validating BCL-2 as a rational target for cancer therapy. Loss of this single moleculeresulted in cell death, despite or perhaps attributable to the presence of other oncogenic events. Thissuggests a generalizable model in which aberrations inherent to cancer generate tonic death signals thatwould otherwise kill the cell if not opposed by a requisite apoptotic defect(s).", "metadata": {}}
+{"_id": "37562370", "title": "", "text": "Cellular and histopathological changes in the infrapatellar fat pad in the monoiodoacetate model ofosteoarthritis pain.OBJECTIVE The infrapatellar fat pad (IPFP) has been identified as a source of anteriorknee pain. Fibrosis and marked inflammatory infiltrate in the IPFP of patients with arthritis of the kneeand reduction in pain post knee replacement in patients following resection of the IPFP have beenobserved. We have investigated changes in the IPFP of rats undergoing the monoiodoacetate (MIA)model of degenerative joint disease, a model that exhibits some histopathological similarities toosteoarthritis (OA). METHODS Rats were injected intra-articularly with MIA and the development ofweight bearing asymmetry was followed for 21 days as compared to vehicle-injected animals. In addition,IPFPs were removed from both ipsilateral and contralateral joints. Both inflammatory infiltrate andhistopathological changes were analysed. RESULTS MIA injection caused marked weight bearingasymmetry. Ipsilateral IPFP wet weights were significantly increased on days 1 and 3 in MIA-treatedanimals. MIA treatment also resulted in significant increases in IPFP total white blood cells and monocyteson days 1, 3, and 7 and neutrophils on days 1 and 3. This was supported by histopathological findings atearly time points which progressed to adipocyte necrosis, IPFP fibrosis, patellar cartilage and subchondralbone necrosis with synovial hyperplasia at later timepoints. CONCLUSIONS The current study clearlydemonstrated that marked inflammatory changes in the IPFP occur during the early stage of the MIAmodel of OA which may contribute to the pain observed at this early stage. The role of the IPFP in laterstages of the model needs to be further explored.", "metadata": {}}
+{"_id": "37578311", "title": "", "text": "Angiogenesis therapy: amidst the hype, the neglected potential for serious side effects.Althoughessentially unknown as a therapeutic concept as recently as a decade ago, it is difficult now to open acardiology journal, attend a cardiology meeting, or scan a newspaper without being caught up in theexcitement generated by the thought that angiogenesis therapy may soon have a major impact on thetreatment of patients with atherosclerotic lesions obstructing arteries that supply the myocardium or legs.Potent therapeutic interventions, however, are rarely free of at least the potential for causing harmfuleffects. Angiogenesis therapy is no exception. Despite this and despite the fact that the only reasonablypowered, randomized, double-blind clinical studies to date have failed to demonstrate primary end-pointefficacy,1 thoughtful consideration of the serious side effects that might accompany any therapeuticbenefit has been largely missing from scientific communications. For the lay media, a switch from thisunbounded enthusiasm to profound skepticism occurred recently after a report of the tragic death of ayoung man caused by injection of large amounts of an adenoviral vector into the hepatic artery(unrelated to angiogenesis therapy).2 For the scientific community, however, there has been a generallack of in-depth discussion of the potential dangers inherent in angiogenesis interventions. Such adiscussion is appropriate not only because of the event cited above but also because considerablemechanistic data are available that actually permit us to identify specific side effects that we mightanticipate as potential complications of angiogenesis therapy. The following therefore is a discussion ofpotential complications based predominantly on our knowledge of the underlying biological activities of 2of the most potent angiogenic cytokines, vascular endothelial growth factor (VEGF) and fibroblast growthfactor (FGF). Angiogenic agents are thought to have the potential to induce neovascularization in manydifferent tissues. This becomes important in that under clinical circumstances it …", "metadata": {}}
+{"_id": "37583120", "title": "", "text": "Body mass index and magnetic resonance markers of brain integrity in adults.OBJECTIVE Obesity andbeing overweight during adulthood have been consistently linked to increased risk for development ofdementia later in life, especially Alzheimer's disease. They have also been associated with cognitivedysfunction and brain structural alterations in otherwise healthy adults. Although proton magneticresonance spectroscopy may distinguish between neuronal and glial components of the brain and maypoint to neurobiological mechanisms underlying brain atrophy and cognitive changes, no spectroscopicstudies have yet assessed the relationships between adiposity and brain metabolites. METHODS We haveutilized magnetic resonance imaging and proton magnetic resonance spectroscopic imaging data from 50healthy middle-aged participants (mean age, 41.7 +/- 8.5 years; 17 women), who were scanned ascontrol subjects for another study. RESULTS After adjustment for age and sex, greater body mass indices(BMIs) correlated with: (1) lower concentrations of N-acetylaspartate (spectroscopic marker of neuronalviability) in frontal (p = 0.001), parietal (p = 0.006), and temporal (p = 0.008) white matter; (2) lowerN-acetylaspartate in frontal gray matter (p = 0.01); and (3) lower concentrations of choline-containingmetabolites (associated with membrane metabolism) in frontal white matter (p = 0.05).INTERPRETATION These results suggest that increased BMI at midlife is associated with neuronal and/ormyelin abnormalities, primarily in the frontal lobe. Because white matter in the frontal lobes is moreprone to the effects of aging than in other lobes, our results may reflect accelerated aging in individualswith high levels of adiposity. Thus, greater BMI may increase the odds of developing an age-relateddisease, such as Alzheimer's disease.", "metadata": {}}
+{"_id": "37592824", "title": "", "text": "Characteristics of medial temporal lobe epilepsy: II. Interictal and ictal scalp electroencephalography,neuropsychological testing, neuroimaging, surgical results, and pathology.Sixty-seven patients withtemporal lobe epilepsy without circumscribed, potentially epileptogenic lesions, who were studied withintracranial electrodes and who became seizure free following temporal lobectomy were retrospectivelyevaluated with regard to preoperative scalp electroencephalographic (EEG) findings, neuropsychologicaltest results, neuroimaging findings, results of surgery, and pathology of resected tissue. Interictal scalpEEG showed paroxysmal abnormalities during prolonged monitoring in 64 patients (96%). These werelocalized in the anterior temporal region in 60 (94%) of these 64 patients. Bilateral independentparoxysmal activity occurred in 42% of the patients and was preponderant over the side of seizure originin half. Ictal EEG changes were rarely detected at the time of clinical seizure onset, but lateralized buildupof rhythmic seizure activity during the seizure occurred in 80% of patients. In 13%, the scalp EEG seizurebuildup was, however, contralateral to the side of seizure origin as subsequently determined by depthEEG and curative surgery. Lateralized postictal slowing, when present, was a very reliable lateralizingfinding. Neuropsychological testing provided lateralizing findings concordant with the side of seizureorigin in 73% of patients. When neuropsychological testing produced discordant results or nonlateralizingfindings, those patients were usually found to have right temporal seizure origin. Intracarotid amobarbital(Amytal) testing demonstrated absent or marginal memory functions on the side of seizure onset in 63%of patients, but 26 patients (37%) had bilaterally intact memory. In those patients who had magneticresonance imaging, it was very sensitive in detecting subtle medial temporal abnormalities. Theseabnormalities were present in 23 of 28 magnetic resonance images, and corresponded with mesialtemporal sclerosis on pathological examination in all but 2 patients.(ABSTRACT TRUNCATED AT 250WORDS)", "metadata": {}}
+{"_id": "37608303", "title": "", "text": "OPA1-dependent cristae modulation is essential for cellular adaptation to metabolic demand.Cristae, theorganized invaginations of the mitochondrial inner membrane, respond structurally to the energeticdemands of the cell. The mechanism by which these dynamic changes are regulated and theconsequences thereof are largely unknown. Optic atrophy 1 (OPA1) is the mitochondrial GTPaseresponsible for inner membrane fusion and maintenance of cristae structure. Here, we report that OPA1responds dynamically to changes in energetic conditions to regulate cristae structure. This cristaeregulation is independent of OPA1's role in mitochondrial fusion, since an OPA1 mutant that can stilloligomerize but has no fusion activity was able to maintain cristae structure. Importantly, OPA1 wasrequired for resistance to starvation-induced cell death, for mitochondrial respiration, for growth ingalactose media and for maintenance of ATP synthase assembly, independently of its fusion activity. Weidentified mitochondrial solute carriers (SLC25A) as OPA1 interactors and show that their pharmacologicaland genetic blockade inhibited OPA1 oligomerization and function. Thus, we propose a novel way in whichOPA1 senses energy substrate availability, which modulates its function in the regulation of mitochondrialarchitecture in a SLC25A protein-dependent manner.", "metadata": {}}
+{"_id": "37619697", "title": "", "text": "Phenylpropanolamine and the risk of hemorrhagic stroke.BACKGROUND Phenylpropanolamine iscommonly found in appetite suppressants and cough or cold remedies. Case reports have linked the useof products containing phenylpropanolamine to hemorrhagic stroke, often after the first use of theseproducts. To study the association, we designed a case-control study. METHODS Men and women 18 to49 years of age were recruited from 43 U.S. hospitals. Eligibility criteria included the occurrence of asubarachnoid or intracerebral hemorrhage within 30 days before enrollment and the absence of apreviously diagnosed brain lesion. Random-digit dialing identified two matched control subjects perpatient. RESULTS There were 702 patients and 1376 control subjects. For women, the adjusted oddsratio was 16.58 (95 percent confidence interval, 1.51 to 182.21; P=0.02) for the association between theuse of appetite suppressants containing phenylpropanolamine and the risk of a hemorrhagic stroke and3.13 (95 percent confidence interval, 0.86 to 11.46; P=0.08) for the association with the first use of aproduct containing phenylpropanolamine. All first uses of phenylpropanolamine involved cough or coldremedies. For men and women combined, the adjusted odds ratio was 1.49 (95 percent confidenceinterval, 0.84 to 2.64; P=0.17) for the association between the use of a product containingphenylpropanolamine and the risk of a hemorrhagic stroke, 1.23 (95 percent confidence interval, 0.68 to2.24; P=0.49) for the association with the use of cough or cold remedies that containedphenylpropanolamine, and 15.92 (95 percent confidence interval, 1.38 to 184.13; P=0.03) for theassociation with the use of appetite suppressants that contained phenylpropanolamine. An analysis inmen showed no increased risk of a hemorrhagic stroke in association with the use of cough or coldremedies containing phenylpropanolamine. No men reported the use of appetite suppressants.CONCLUSIONS The results suggest that phenylpropanolamine in appetite suppressants, and possibly incough and cold remedies, is an independent risk factor for hemorrhagic stroke in women.", "metadata": {}}
+{"_id": "37628989", "title": "", "text": "The safety of intravenous fluorescein for confocal laser endomicroscopy in the gastrointestinaltract.BACKGROUND Confocal laser endomicroscopy (CLE) is rapidly emerging as a valuable tool forgastrointestinal endoscopic imaging. Fluorescent contrast agents are used to optimize imaging with CLE,and intravenous fluorescein is the most widely used contrast agent. Fluorescein is FDA-cleared fordiagnostic angiography of the retina. For these indications, the safety profile of fluorescein has beenwell-documented; however, to date, fluorescein is not cleared for use with CLE. AIMS To estimate therate of serious and total adverse events attributable to intravenous fluorescein when used forgastrointestinal CLE. METHODS We performed a cross sectional survey of 16 International AcademicMedical Centres with active research protocols in CLE that involved intravenous fluorescein. Centres usingi.v. fluorescein for CLE who were actively monitored for adverse events were included. RESULTS Sixteencentres performed 2272 gastrointestinal CLE procedures. The most common dose of contrast agent was2.5-5 mL of 10% sodium fluorescein. No serious adverse events were reported. Mild adverse eventsoccurred in 1.4% of individuals, including nausea/vomiting, transient hypotension without shock,injection site erythema, diffuse rash and mild epigastric pain. The limitation is that only immediate postprocedure events were actively monitored. CONCLUSIONS Use of intravenous fluorescein forgastrointestinal CLE appears to be safe with few acute complications.", "metadata": {}}
+{"_id": "37641175", "title": "", "text": "Metabolic DNA as the origin of spontaneously released DNA?A DNA fraction is spontaneously releasedfrom living, but not dead or dying, human, other mammalian, avian, amphibian, plant, and prokaryotecells. The spontaneously released DNA fraction has been shown to be (a) present in both actively dividingand nondividing, differentiated cell populations; (b) labile; (c) associated with DNA-dependent RNA orDNA polymerase; (d) associated with an RNA fraction; and to have (e) a lower molecular weight than thetypical genetic DNA fraction; and (f) Alu repeat sequences in increased proportions compared to a uniquegene in plasma/serum. On the other hand, early autoradiographic and biochemical and quantitativecytochemical and cytophysical studies on DNA permitted the identification of a DNA fraction which was(1) present in both actively dividing and nondividing, differentiated cell populations; (2) labile; and (3)had a lower molecular weight than the typical genetic DNA fraction. This DNA fraction was termedmetabolic DNA (m-DNA) and was proposed as possibly forming extra gene copies for the rapid productionof m-RNA, to be destroyed subsequently. Therefore, we suggest that the metabolic DNA fraction mightrepresent the precursor to the formation of the spontaneously released DNA fraction.", "metadata": {}}
+{"_id": "37643601", "title": "", "text": "The flavivirus precursor membrane-envelope protein complex: structure and maturation.Many viruses gothrough a maturation step in the final stages of assembly before being transmitted to another host. Thematuration process of flaviviruses is directed by the proteolytic cleavage of the precursor membraneprotein (prM), turning inert virus into infectious particles. We have determined the 2.2 angstromresolution crystal structure of a recombinant protein in which the dengue virus prM is linked to theenvelope glycoprotein E. The structure represents the prM-E heterodimer and fits well into thecryo-electron microscopy density of immature virus at neutral pH. The pr peptide beta-barrel structurecovers the fusion loop in E, preventing fusion with host cell membranes. The structure provides a basisfor identifying the stages of its pH-directed conformational metamorphosis during maturation, endingwith release of pr when budding from the host.", "metadata": {}}
+{"_id": "37673301", "title": "", "text": "Peptide and non-peptide G-protein coupled receptors (GPCRs) in skeletal muscle.G-protein coupledreceptors (GPCRs) represent a large class of cell surface receptors that mediate a multitude of functions.Over the years, a number of GPCRs and ancillary proteins have been shown to be expressed in skeletalmuscle. Unlike the case with other muscle tissues like cardiac and vascular smooth muscle cells, therehas been little attempt at systematically analyzing GPCRs in skeletal muscle. Here we have compiled allthe GPCRs that are expressed in skeletal muscle. In addition, we review the known function of thesereceptors in both skeletal muscle tissue and in cultured skeletal muscle cells.", "metadata": {}}
+{"_id": "37677954", "title": "", "text": "Characterization of complete genome and small RNA profile of pagoda yellow mosaic associated virus, anovel badnavirus in China.A new badnavirus was discovered from pagoda trees showing yellow mosaicsymptoms on the leaves by high throughput sequencing of small RNAs. The complete genome of thisvirus was determined to comprise 7424 nucleotides, and the virus shared 40.4-45.1% identity with thatof other badnaviruses. The genome encodes five open reading frames (ORFs) on the plus strand, whichincludes three conserved badnaviral ORFs. These results suggest that this virus is a new member of thegenus Badnavirus in the family Caulimoviridae. The virus is tentatively named pagoda yellow mosaicassociated virus (PYMAV). Phylogenetic analysis suggested that this virus together with gooseberry veinbanding virus (GVBV) and grapevine vein-clearing virus (GVCV) forms a separate group that is distincttwo other well characterized badnaviral groups. Additionally, the viral derived small RNA (vsRNA) profileof PYMAV was analyzed and compared with that of viruses within the same family. Results showed thatthe most abundant PYMAV vsRNAs were 21-nt, whereas other viruses in the same family have apredominance of 22- or 24-nt vsRNA. The percentage of sense PYMAV vsRNA was almost equal to that ofantisense vsRNA, whereas vsRNAs of other viruses in the family display preferences toward the sensestrand of their genome. Furthermore, PYMAV vsRNAs were symmetrically distributed along the genomewith no obvious vsRNA generating hotspots.", "metadata": {}}
+{"_id": "37686718", "title": "", "text": "Experimental approaches for the treatment of malignant gliomas.Malignant gliomas, which includeglioblastomas and anaplastic astrocytomas, are the most common primary tumors of the brain. Over thepast 30 years, the standard treatment for these tumors has evolved to include maximal safe surgicalresection, radiation therapy and temozolomide chemotherapy. While the median survival of patients withglioblastomas has improved from 6 months to 14.6 months, these tumors continue to be lethal for thevast majority of patients. There has, however, been recent substantial progress in our mechanisticunderstanding of tumor development and growth. The translation of these genetic, epigenetic andbiochemical findings into therapies that have been tested in clinical trials is the subject of this review.", "metadata": {}}
+{"_id": "37699461", "title": "", "text": "Reversal of hyperglycemia in mice by using human expandable insulin-producing cells differentiated fromfetal liver progenitor cells.Beta-cell replacement is considered to be the most promising approach fortreatment of type 1 diabetes. Its application on a large scale is hindered by a shortage of cells fortransplantation. Activation of insulin expression, storage, and regulated secretion in stem/progenitor cellsoffers novel ways to overcome this shortage. We explored whether fetal human progenitor liver cells (FH)could be induced to differentiate into insulin-producing cells after expression of the pancreatic duodenalhomeobox 1 (Pdx1) gene, which is a key regulator of pancreatic development and insulin expression inbeta cells. FH cells possess a considerable replication capacity, and this was further extended byintroduction of the gene for the catalytic subunit of human telomerase. Immortalized FH cells expressingPdx1 activated multiple beta-cell genes, produced and stored considerable amounts of insulin, andreleased insulin in a regulated manner in response to glucose. When transplanted into hyperglycemicimmunodeficient mice, the cells restored and maintained euglycemia for prolonged periods. Quantitationof human C-peptide in the mouse serum confirmed that the glycemia was normalized by the transplantedhuman cells. This approach offers the potential of a novel source of cells for transplantation into patientswith type 1 diabetes.", "metadata": {}}
+{"_id": "37722384", "title": "", "text": "A review of the methods for human iPSC derivation.The ability to reprogram somatic cells to inducedpluripotent stem cells (iPSCs) offers an opportunity to generate pluripotent patient-specific cell lines thatcan help model human diseases. These iPSC lines could also be powerful tools for drug discovery and thedevelopment of cellular transplantation therapies. Many methods exist for generating iPSC lines but thosebest suited for use in studying human diseases and developing therapies must be of adequate efficiencyto produce iPSCs from samples that may be of limited abundance, capable of reprogramming cells fromboth skin fibroblasts and blood, and footprint-free. Several reprogramming techniques meet these criteriaand can be utilized to derive iPSCs in projects with both basic scientific and therapeutic goals. Combiningthese reprogramming methods with small molecule modulators of signaling pathways can lead tosuccessful generation of iPSCs from even the most recalcitrant patient-derived somatic cells.", "metadata": {}}
+{"_id": "37727521", "title": "", "text": "EB virus-encoded RNAs are recognized by RIG-I and activate signaling to induce type I IFN.Epstein-Barrvirus (EBV)-encoded small RNAs (EBERs) are nonpolyadenylated, untranslated RNAs, exist mostabundantly in latently EBV-infected cells, and are expected to show secondary structures with many shortstem-loops. Retinoic acid-inducible gene I (RIG-I) is a cytosolic protein that detects viral double-strandedRNA (dsRNA) inside the cell and initiates signaling pathways leading to the induction of protective cellulargenes, including type I interferons (IFNs). We investigated whether EBERs were recognized by RIG-I asdsRNA. Transfection of RIG-I plasmid induced IFNs and IFN-stimulated genes (ISGs) in EBV-positiveBurkitt's lymphoma (BL) cells, but not in their EBV-negative counterparts or EBER-knockout EBV-infectedBL cells. Transfection of EBER plasmid or in vitro-synthesized EBERs induced expression of type I IFNsand ISGs in RIG-I-expressing, EBV-negative BL cells, but not in RIG-I-minus counterparts. EBERsactivated RIG-I's substrates, NF-kappaB and IFN regulatory factor 3, which were necessary for type I IFNactivation. It was also shown that EBERs co-precipitated with RIG-I. These results indicate that EBERs arerecognized by RIG-I and activate signaling to induce type I IFN in EBV-infected cells.", "metadata": {}}
+{"_id": "37731372", "title": "", "text": "Pregnancy in dialysis patients: a review of outcomes, complications, and management.Althoughuncommon, pregnancy occurs in women on chronic dialysis. In 1980 the incidence of pregnancy inwomen on dialysis was 0.9%. Studies from 1992 to 2003 indicate that pregnancy occurred in 1-7% ofwomen on chronic dialysis. Half of the infants born to women on chronic dialysis survive. Of importance isthat \"intensive dialysis\" of 16-24 hr/week is associated with improved infant survival. In this article, theincidence, duration, fetal and maternal complications, and outcomes of pregnancy in women on chronicdialysis are reviewed. The management of anemia, hypertension, electrolytes, bone minerals, andacid-base parameters in the pregnant dialysis patient is also summarized. Recommendations regardingthe dialysis prescription for the pregnant woman on hemodialysis (HD) or peritoneal dialysis (PD) are alsomade. The complex and precarious condition of the pregnant woman on dialysis requires closecollaboration between the patient, nephrologist, dialysis staff, obstetrician, and neonatologist tomaximize the chance of a successful pregnancy.", "metadata": {}}
+{"_id": "37762357", "title": "", "text": "Potent immunosuppressive activities of cytomegalovirus-encoded interleukin-10.Cytomegalovirus (CMV)has highly evolved mechanisms for avoiding detection by the host immune system. Recently, in thegenomes of human and primate CMV, a novel gene comprising segments of noncontiguous open readingframes was identified and found to have limited predicted homology to endogenous cellular interleukin-10(IL-10). Here we investigate the biological activities of the CMV IL-10-like gene product and show it topossess potent immunosuppressive properties. Both purified bacterium-derived recombinant CMV IL-10and CMV IL-10 expressed in supernatants of human cells were found to inhibit proliferation ofmitogen-stimulated peripheral blood mononuclear cells (PBMCs), with specific activity comparable to thatof recombinant human IL-10. In addition, CMV IL-10 expressed from human cells inhibited cytokinesynthesis, as treatment of stimulated PBMCs and monocytes with CMV IL-10 led to a marked decrease inproduction of proinflammatory cytokines. Finally, CMV IL-10 was observed to decrease cell surfaceexpression of both major histocompatibility complex (MHC) class I and class II molecules, whileconversely increasing expression of the nonclassical MHC allele HLA-G. These results demonstrate for thefirst time that CMV has a biologically active IL-10 homolog that may contribute to immune evasion duringvirus infection.", "metadata": {}}
+{"_id": "37768883", "title": "", "text": "Evidence for the presence of urease apoprotein complexes containing UreD, UreF, and UreG in cells thatare competent for in vivo enzyme activation.In vivo activation of Klebsiella aerogenes urease, anickel-containing enzyme, requires the presence of functional UreD, UreF, and UreG accessory proteinsand is further facilitated by UreE. These accessory proteins are proposed to be involved in metallocenterassembly (M. H. Lee, S. B. Mulrooney, M. J. Renner, Y. Markowicz, and R. P. Hausinger, J. Bacteriol.174:4324-4330, 1992). A series of three UreD-urease apoprotein complexes are present in cells thatexpress ureD at high levels, and these complexes are thought to be essential for in vivo activation of theenzyme (I.-S. Park, M. B. Carr, and R. P. Hausinger, Proc. Natl. Acad. Sci. USA 91:3233-3237, 1994). Inthis study, we describe the effect of accessory gene deletions on urease complex formation. The ureE,ureF, and ureG gene products were found not to be required for formation of the UreD-urease complexes;however, the complexes from the ureF deletion mutant exhibited delayed elution during size exclusionchromatography. Because these last complexes were of typical UreD-urease sizes according to native gelelectrophoretic analysis, we propose that UreF alters the conformation of the UreD-urease complexes.The same studies revealed the presence of an additional series of urease apoprotein complexes presentonly in cells containing ureD, ureF, and ureG, along with the urease subunit genes. These new complexeswere shown to contain urease, UreD, UreF, and UreG. We propose that the UreD-UreF-UreG-ureaseapoprotein complexes represent the activation-competent form of urease apoprotein in the cell.", "metadata": {}}
+{"_id": "37822406", "title": "", "text": "Human somatic cell nuclear transfer using adult cells.Derivation of patient-specific human pluripotentstem cells via somatic cell nuclear transfer (SCNT) has the potential for applications in a range oftherapeutic contexts. However, successful SCNT with human cells has proved challenging to achieve, andthus far has only been reported with fetal or infant somatic cells. In this study, we describe theapplication of a recently developed methodology for the generation of human ESCs via SCNT usingdermal fibroblasts from 35- and 75-year-old males. Our study therefore demonstrates the applicability ofSCNT for adult human cells and supports further investigation of SCNT as a strategy for regenerativemedicine.", "metadata": {}}
+{"_id": "37895688", "title": "", "text": "\"Natural\" killer cells in the mouse. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells.Specificity and distribution according to genotype.In the spleens of young, adult mice there existnaturally occurring killer lymphocytes with specificity for mouse Moloney leukemia cells. The lytic activitywas directed against syngeneic or allogeneic Moloney leukemia cells to a similar extent, but was primarilyexpressed when tested against in vitro grown leukemia cells. Two leukemias of non-Moloney origin wereresistant and so was the mastocytoma line P815. Although killer activity varied between different strainsof mice, the specificity of lysis was the same as indicated by competition experiments using unlabeledMoloney or other tumor cells as inhibitors in the cytotoxic assays. Capacity to compete and sensitivy tolysis by the killer cells were found to be highly positively correlated. Analysis of the kinetics of thecytotoxic assay revealed a rapid induction of lysis within one to four hours, arguing against anyconventional in vitro induction of immune response. No evidence was found of soluble factors playing anyrole in the cytolytic assay.", "metadata": {}}
+{"_id": "37912677", "title": "", "text": "Dose-response study on thyrotoxic patients undergoing positron emission tomography and radioiodinetherapyWith the acknowledged problems associated with assessment of functioning thyroid mass andhence radiation dose, our policy had been to give 75 MBq iodine-131 at 6-monthly intervals to patientswith Graves' disease until they became euthyroid. Since positron emission tomography (PET) has beenavailable at this hospital, the radiation dose to the thyroid has been calculated with an accuracy of\u000020%, the thyroid mass being determined from an iodine-124 PET scan. A dose-response study hasbeen carried out on 65 patients who have received single or cumulative radiation doses of <80 Gy. Theresults show that patients who receive a low radiation dose (<20 Gy) at their first treatment have a highprobability of remaining toxic at 12 months. In contrast, patients who receive higher radiation doses (>40Gy) at their first treatment have a high probability of control. The probability of becoming euthyroidincreases more rapidly with increasing radiation dose than the probability of becoming hypothyroid.Following this dose-response study, a new treatment protocol has been introduced. A 124I PET tracerstudy prior to 131I therapy will be performed to enable a prescribed thyroid dose of 50 Gy to be deliveredto patients with Graves' disease. Further 131I therapy will only be considered if patients are still toxic at12 months.", "metadata": {}}
+{"_id": "37916361", "title": "", "text": "Increased serum soluble corin in mid pregnancy is associated with hypertensive disorders ofpregnancy.OBJECTIVE The study of soluble corin in the circulation before hypertensive disorders ofpregnancy (HDP) has been limited. Here we aimed to study serum soluble corin in mid pregnancy inpatients with HDP and their age- and gestational weeks-matched controls. METHODS Sixty-eight pairs ofcases of HDP and controls were studied. Blood samples were obtained in mid pregnancy between 16 and20 gestational weeks. Serum soluble corin was examined by enzyme-linked immunosorbent assaymethods. The relationship between serum soluble corin and HDP was examined using conditional logisticregression models. RESULTS Serum soluble corin in mid pregnancy was increased in cases with HDPcompared with controls (median [interquartile range]: 1968 [1644-2332] pg/mL vs. 1700 [1446-2056]pg/mL, p=0.002). Participants were categorized into quartiles of serum soluble corin distributed incontrols. Compared with the lowest quartile, participants in the highest quartile had a significantlyincreased risk for HDP (odds ratio [OR], 4.21; 95% confidence interval [95% CI], 1.31-13.53) aftermultivariate adjustment. Nevertheless, we did not find a significantly increased risk for participants in thesecond (OR, 1.75; 95% CI, 0.44-7.02) and third (OR, 2.80; 95% CI, 0.70-11.18) quartiles. Then the firstthree quartiles were merged as a reference group to calculate the OR of HDP for participants in thehighest quartile and we found a significantly increased risk for HDP in individuals in the highest quartile(OR, 2.28, 95% CI, 1.02-5.06). CONCLUSION Increased serum soluble corin in mid pregnancy wasassociated with an increased risk for HDP. Our findings suggest that increased serum soluble corin in midpregnancy could be an indicator for HDP.", "metadata": {}}
+{"_id": "37949139", "title": "", "text": "The in vitro effect of dandelions antioxidants on microsomal lipid peroxidation.Dandelions have long beenused in herbal medicine for their choleretic, diuretic, antiinflammatory, appetite-stimulating and laxativeproperties. An antioxidant property can be supposed as a basis of their-therapeutic effects. Tounderstand the mechanism of the drug's action, the effects of natural extracts on a microsomal fractionof rat liver were examined. The extracts diminished the enzymatically induced-lipid peroxidation andreduced the cytochrome c with and without NADPH in a concentration dependent manner.", "metadata": {}}
+{"_id": "37964706", "title": "", "text": "Local Ca2+ influx through Ca2+ release-activated Ca2+ (CRAC) channels stimulates production of anintracellular messenger and an intercellular pro-inflammatory signal.Ca2+ entry through store-operatedCa2+ channels drives the production of the pro-inflammatory molecule leukotriene C4 (LTC4) from mastcells through a pathway involving Ca2+-dependent protein kinase C, mitogen-activated protein kinasesERK1/2, phospholipase A2, and 5-lipoxygenase. Here we examine whether local Ca2+ influx throughstore-operated Ca2+ release-activated Ca2+ (CRAC) channels in the plasma membrane stimulates thissignaling pathway. Manipulating the amplitude and spatial extent of Ca2+ entry by altering chemical andelectrical gradients for Ca2+ influx or changing the Ca2+ buffering of the cytoplasm all impacted onprotein kinase C and ERK activation, generation of arachidonic acid and LTC4 secretion, with little changein the bulk cytoplasmic Ca2+ rise. Similar bulk cytoplasmic Ca2+ concentrations were achieved whenCRAC channels were activated in 0.25 mm external Ca2+ versus 2 mm Ca2+ and 100 nm La3+, aninhibitor of CRAC channels. However, despite similar bulk cytoplasmic Ca2+, protein kinase C activationand LTC4 secretion were larger in 2 mm Ca2+ and La3+ than in 0.25 mm Ca2+, consistent with thecentral involvement of a subplasmalemmal Ca2+ rise. The nonreceptor tyrosine kinase Syk coupled CRACchannel opening to protein kinase C and ERK activation. Recombinant TRPC3 channels also activatedprotein kinase C, suggesting that subplasmalemmal Ca2+ rather than a microdomain exclusive to CRACchannels is the trigger. Hence a subplasmalemmal Ca2+ increase in mast cells is highly versatile in that ittriggers cytoplasmic responses through generation of intracellular messengers as well as long distancechanges through increased secretion of paracrine signals.", "metadata": {}}
+{"_id": "37969403", "title": "", "text": "Cytokine production patterns and lymphoproliferative responses in volunteers orally immunized withattenuated vaccine strains of Salmonella typhi.New recombinant strains of attenuated Salmonella typhiused as live oral vaccines elicit potent immune responses. This study examined the patterns of cytokineproduction and proliferation to specific S. typhi antigens in subjects orally immunized with attenuated S.typhi vaccines CVD 906, CVD 908, and CVD 908 expressing the circumsporozoite protein of Plasmodiumfalciparum. After immunization, sensitized lymphocytes were found in subjects' blood that exhibitedsignificantly increased proliferative responses and interferon-gamma production to purified S. typhiflagella when compared with preimmunization levels. Significant negative correlations were observedbetween interleukin-4 production and both interferon-gamma production and proliferation to S. typhiflagella. These results demonstrate that oral immunization with attenuated S. typhi strains alone or withthose carrying a foreign gene elicits strong systemic cell-mediated immunity to purified S. typhi antigens,including the production of cytokines compatible with T1-type responses.", "metadata": {}}
+{"_id": "38009906", "title": "", "text": "Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7in transcriptional silencing of INK4a.Expression of the INK4b/ARF/INK4a tumor suppressor locus innormal and cancerous cell growth is controlled by methylation of histone H3 at lysine 27 (H3K27me) asdirected by the Polycomb group proteins. The antisense noncoding RNA ANRIL of the INK4b/ARF/INK4alocus is also important for expression of the protein-coding genes in cis, but its mechanism has remainedelusive. Here we report that chromobox 7 (CBX7) within the polycomb repressive complex 1 binds toANRIL, and both CBX7 and ANRIL are found at elevated levels in prostate cancer tissues. In concert withH3K27me recognition, binding to RNA contributes to CBX7 function, and disruption of either interactionimpacts the ability of CBX7 to repress the INK4b/ARF/INK4a locus and control senescence.Structure-guided analysis reveals the molecular interplay between noncoding RNA and H3K27me asmediated by the conserved chromodomain. Our study suggests a mechanism by which noncoding RNAparticipates directly in epigenetic transcriptional repression.", "metadata": {}}
+{"_id": "38023457", "title": "", "text": "Tumor necrosis factor alpha mediates apoptosis of brown adipocytes and defective brown adipocytefunction in obesity.Severe quantitative and qualitative brown adipocyte defects are common in obesity.To investigate whether aberrant expression of tumor necrosis factor alpha (TNF-alpha) in obesity isinvolved in functional brown fat atrophy, we have studied genetically obese (ob/ob) mice with targetednull mutations in the genes encoding the two TNF receptors. The absence of both TNF receptors or p55receptor alone resulted in a significant reduction in brown adipocyte apoptosis and an increase inbeta(3)-adrenoreceptor and uncoupling protein-1 expression in obese mice. Increased numbers ofmultilocular functionally active brown adipocytes, and improved thermoregulation was also observed inobese animals lacking TNF-alpha function. These results indicate that TNF-alpha plays an important rolein multiple aspects of brown adipose tissue biology and mediates the abnormalities that occur at this sitein obesity.", "metadata": {}}
+{"_id": "38025907", "title": "", "text": "Engineered FGF19 eliminates bile acid toxicity and lipotoxicity leading to resolution of steatohepatitis andfibrosis in miceNonalcoholic fatty liver disease (NAFLD) is an increasingly prevalent chronic liver diseasefor which no approved therapies are available. Despite intensive research, the cellular mechanisms thatmediate NAFLD pathogenesis and progression are poorly understood. Although obesity, diabetes, insulinresistance, and related metabolic syndrome, all consequences of a Western diet lifestyle, arewell-recognized risk factors for NAFLD development, dysregulated bile acid metabolism is emerging as anovel mechanism contributing to NAFLD pathogenesis. Notably, NAFLD patients exhibit a deficiency infibroblast growth factor 19 (FGF19), an endocrine hormone in the gut-liver axis that controls de novo bileacid synthesis, lipogenesis, and energy homeostasis. Using a mouse model that reproduces the clinicalprogression of human NAFLD, including the development of simple steatosis, nonalcoholic steatohepatitis(NASH), and advanced \"burnt-out\" NASH with hepatocellular carcinoma, we demonstrate that FGF19 aswell as an engineered nontumorigenic FGF19 analogue, M70, ameliorate bile acid toxicity and lipotoxicityto restore liver health. Mass spectrometry-based lipidomics analysis of livers from mice treated withFGF19 or M70 revealed significant reductions in the levels of toxic lipid species (i.e., diacylglycerols,ceramides and free cholesterol) and an increase in levels of unoxidized cardiolipins, an importantcomponent of the inner mitochondrial membrane. Furthermore, treatment with FGF19 or M70 rapidly andprofoundly reduced levels of liver enzymes, resolved the histologic features of NASH, and enhancedinsulin sensitivity, energy homeostasis, and lipid metabolism. Whereas FGF19 induced hepatocellularcarcinoma formation following prolonged exposure in these mice, animals expressing M70 showed noevidence of liver tumorigenesis in this model. Conclusion: We have engineered an FGF19 hormone that iscapable of regulating multiple pathways to deliver antisteatotic, anti-inflammatory, and antifibroticactivities and that represents a potentially promising therapeutic for patients with NASH. (HepatologyCommunications 2017;1:1024-1042).", "metadata": {}}
+{"_id": "38028419", "title": "", "text": "Leptin deficiency contributes to the pathogenesis of alcoholic fatty liver disease in mice.White adiposetissue (WAT) secretes adipokines, which critically regulate lipid metabolism. The present studyinvestigated the effects of alcohol on adipokines and the mechanistic link between adipokinedysregulation and alcoholic fatty liver disease. Mice were fed alcohol for 2, 4, or 8 weeks to documentchanges in adipokines over time. Alcohol exposure reduced WAT mass and body weight in associationwith hepatic lipid accumulation. The plasma adiponectin concentration was increased at 2 weeks, butdeclined to normal at 4 and 8 weeks. Alcohol exposure suppressed leptin gene expression in WAT andreduced the plasma leptin concentration at all times measured. There is a highly positive correlationbetween plasma leptin concentration and WAT mass or body weight. To determine whether leptindeficiency mediates alcohol-induced hepatic lipid dyshomeostasis, mice were fed alcohol for 8 weeks withor without leptin administration for the last 2 weeks. Leptin administration normalized the plasma leptinconcentration and reversed alcoholic fatty liver. Alcohol-perturbed genes involved in fatty acidβ-oxidation, very low-density lipoprotein secretion, and transcriptional regulation were attenuated byleptin. Leptin also normalized alcohol-reduced phosphorylation levels of signal transducer Stat3 andadenosine monophosphate-activated protein kinase. These data demonstrated for the first time thatleptin deficiency in association with WAT mass reduction contributes to the pathogenesis of alcoholic fattyliver disease.", "metadata": {}}
+{"_id": "38037690", "title": "", "text": "Three-dimensional chemical imaging of skin using stimulated Raman scattering microscopyAbstract.Stimulated Raman scattering (SRS) microscopy is used to generate structural and chemicalthree-dimensional images of native skin. We employed SRS microscopy to investigate themicroanatomical features of skin and penetration of topically applied materials. Image depth stacks arecollected at distinct wavelengths corresponding to vibrational modes of proteins, lipids, and water in theskin. We observed that corneocytes in stratum corneum are grouped together in clusters, 100 to 250 μmin diameter, separated by 10- to 25-μm-wide microanatomical skin-folds called canyons. These canyonsoccasionally extend down to depths comparable to that of the dermal–epidermal junction below the flatsurface regions in porcine and human skin. SRS imaging shows the distribution of chemical species withincell clusters and canyons. Water is predominately located within the cell clusters, and its concentrationrapidly increases at the transition from stratum corneum to viable epidermis. Canyons do not containdetectable levels of water and are rich in lipid material. Oleic acid-d34 applied to the skin surface linesthe canyons down to a depth of 50 μm below the surface of the skin. This observation could haveimplications on the evaluation of penetration profiles of bioactive materials measured using traditionalmethods, such as tape-stripping.", "metadata": {}}
+{"_id": "38040186", "title": "", "text": "Familial amyloidosis: a study of 52 North American-born patients examined during a 30-yearperiod.Between 1961 and 1990, 52 patients with biopsy-proven familial amyloidosis born in NorthAmerica were examined at the Mayo Clinic. At the time of diagnosis of familial amyloidosis, 83% of thesepatients had peripheral neuropathy, 33% had autonomic neuropathy, and 27% had cardiomyopathy.Renal disease was noted in fewer than 10%, and liver involvement was rare. The median age at diagnosiswas 64 years. The sensitivity of various diagnostic biopsies was similar to that for primary amyloidosis:deposits of amyloid were found in 77 and 78% of the subcutaneous fat aspirates or rectal biopsyspecimens, respectively, and in 41% of specimens of bone marrow. The median duration of survival of5.8 years for patients with inherited amyloidosis was superior to that for patients with primaryamyloidosis. When patients were stratified by organ involvement, the survival of patients with familialamyloidosis remained superior. The presence of cardiomyopathy and an interactive variable of age andthe presence of autonomic neuropathy were powerful predictors of survival. Of the 52 patients, 22 died,12 (55%) of cardiac failure or cardiac arrhythmia. Nine patients (41%) died of inanition in conjunctionwith progressive peripheral or autonomic neuropathy. Transthyretin was identified byimmunohistochemical studies in 31 of the 34 tissue specimens tested. A transthyretin mutation wasidentified in 24 of the 31. A transthyretin mutation was found in five additional patients for whom tissuewas unavailable for immunostaining.", "metadata": {}}
+{"_id": "38043606", "title": "", "text": "Mycobacterium tuberculosis and the environment within the phagosome.Once across the barrier of theepithelium, macrophages constitute the primary defense against microbial invasion. For most microbes,the acidic, hydrolytically competent environment of the phagolysosome is sufficient to kill them. Despiteour understanding of the trafficking events that regulate phagosome maturation, our appreciation of thelumenal environment within the phagosome is only now becoming elucidated through real-time functionalassays. The assays quantify pH change, phagosome/lysosome fusion, proteolysis, lipolysis, andbeta-galactosidase activity. This information is particularly important for understanding pathogens thatsuccessfully parasitize the endosomal/lysosomal continuum. Mycobacterium tuberculosis infectsmacrophages through arresting the normal maturation process of the phagosome, retaining its vacuole atpH 6.4 with many of the characteristics of an early endosome. Current studies are focusing on thetranscriptional response of the bacterium to the changing environment in the macrophage phagosome.Manipulation of these environmental cues, such as preventing the pH drop to pH 6.4 with concanamycinA, abrogates the majority of the transcriptional response in the bacterium, showing that pH is thedominant signal that the bacterium senses and responds to. These approaches represent our ongoingattempts to unravel the discourse that takes place between the pathogen and its host cell.", "metadata": {}}
+{"_id": "38076716", "title": "", "text": "High density DNA methylation array with single CpG site resolution.We have developed a new generationof genome-wide DNA methylation BeadChip which allows high-throughput methylation profiling of thehuman genome. The new high density BeadChip can assay over 480K CpG sites and analyze twelvesamples in parallel. The innovative content includes coverage of 99% of RefSeq genes with multipleprobes per gene, 96% of CpG islands from the UCSC database, CpG island shores and additional contentselected from whole-genome bisulfite sequencing data and input from DNA methylation experts. Thewell-characterized Infinium® Assay is used for analysis of CpG methylation using bisulfite-convertedgenomic DNA. We applied this technology to analyze DNA methylation in normal and tumor DNA samplesand compared results with whole-genome bisulfite sequencing (WGBS) data obtained for the samesamples. Highly comparable DNA methylation profiles were generated by the array and sequencingmethods (average R2 of 0.95). The ability to determine genome-wide methylation patterns will rapidlyadvance methylation research.", "metadata": {}}
+{"_id": "38127792", "title": "", "text": "Acentrosomal Microtubule Assembly in Mitosis: The Where, When, and How.In mitosis the cell assemblesthe bipolar spindle, a microtubule (MT)-based apparatus that segregates the duplicated chromosomesinto two daughter cells. Most animal cells enter mitosis with duplicated centrosomes that provide anactive source of dynamic MTs. However, it is now established that spindle assembly relies on thenucleation of acentrosomal MTs occurring around the chromosomes after nuclear envelope breakdown,and on pre-existing microtubules. Where chromosome-dependent MT nucleation occurs, when MTamplification takes place and how the two pathways function are still key questions that generate somecontroversies. We reconcile the data and present an integrated model accounting for acentrosomalmicrotubule assembly in the dividing cell.", "metadata": {}}
+{"_id": "38131471", "title": "", "text": "Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints.DNA damage is arelatively common event in the life of a cell and may lead to mutation, cancer, and cellular or organismicdeath. Damage to DNA induces several cellular responses that enable the cell either to eliminate or copewith the damage or to activate a programmed cell death process, presumably to eliminate cells withpotentially catastrophic mutations. These DNA damage response reactions include: (a) removal of DNAdamage and restoration of the continuity of the DNA duplex; (b) activation of a DNA damage checkpoint,which arrests cell cycle progression so as to allow for repair and prevention of the transmission ofdamaged or incompletely replicated chromosomes; (c) transcriptional response, which causes changes inthe transcription profile that may be beneficial to the cell; and (d) apoptosis, which eliminates heavilydamaged or seriously deregulated cells. DNA repair mechanisms include direct repair, base excisionrepair, nucleotide excision repair, double-strand break repair, and cross-link repair. The DNA damagecheckpoints employ damage sensor proteins, such as ATM, ATR, the Rad17-RFC complex, and the 9-1-1complex, to detect DNA damage and to initiate signal transduction cascades that employ Chk1 and Chk2Ser/Thr kinases and Cdc25 phosphatases. The signal transducers activate p53 and inactivatecyclin-dependent kinases to inhibit cell cycle progression from G1 to S (the G1/S checkpoint), DNAreplication (the intra-S checkpoint), or G2 to mitosis (the G2/M checkpoint). In this review the molecularmechanisms of DNA repair and the DNA damage checkpoints in mammalian cells are analyzed.", "metadata": {}}
+{"_id": "38143689", "title": "", "text": "Characterization of serotonin 5-HT2C receptor signaling to extracellular signal-regulated kinases 1 and2.Serotonin 5-HT2C receptors (5-HT(2C)Rs) are almost exclusively expressed in the CNS, and implicatedin disorders such as obesity, depression, and schizophrenia. The present study investigated themechanisms governing the coupling of the 5-HT(2C)R to the extracellular signal-regulated kinases (ERKs)1/2, using a Chinese hamster ovary (CHO) cell line stably expressing the receptor at levels comparable tothose found in the brain. Using the non-RNA-edited isoform of the 5-HT(2C)R, constitutive ERK1/2phosphorylation was observed and found to be modulated by full, partial and inverse agonists.Interestingly, agonist-directed trafficking of receptor stimulus was also observed when comparing effectson phosphoinositide accumulation and intracellular Ca2+ elevation to ERK1/2 phosphorylation, wherebythe agonists, [+/-]-2,5-dimethoxy-4-iodoamphetamine (DOI) and quipazine, showed reversal of efficacybetween the phosphoinositide/Ca2+ pathways, on the one hand, and the ERK1/2 pathway on the other.Subsequent molecular characterization found that 5-HT-stimulated ERK1/2 phosphorylation in thiscellular background requires phospholipase D, protein kinase C, and activation of the Raf/MEK/ERKmodule, but is independent of both receptor- and non-receptor tyrosine kinases, phospholipase C,phosphoinositide 3-kinase, and endocytosis. Our findings underscore the potential for exploitingpathway-selective receptor states in the differential modulation of signaling pathways that play prominentroles in normal and abnormal neuronal signaling.", "metadata": {}}
+{"_id": "38180456", "title": "", "text": "Short-term medical service trips: a systematic review of the evidence.Short-term medical service trips(MSTs) aim to address unmet health care needs of low- and middle-income countries. The lack ofcritically reviewed empirical evidence of activities and outcomes is a concern. Developing evidence-basedrecommendations for health care delivery requires systematic research review. I focused on MSTpublications with empirical results. Searches in May 2013 identified 67 studies published since 1993, only6% of the published articles on the topic in the past 20 years. Nearly 80% reported on surgical trips.Although the MST field is growing, its medical literature lags behind, with nearly all of the scholarlypublications lacking significant data collection. By incorporating data collection into service trips, groupscan validate practices and provide information about areas needing improvement.", "metadata": {}}
+{"_id": "38211681", "title": "", "text": "Comparison of Beck Depression Inventories -IA and -II in psychiatric outpatients.The amended (revised)Beck Depression Inventory (BDI-IA; Beck & Steer, 1993b) and the Beck Depression Inventory-II (BDI-II;Beck, Steer, & Brown, 1996) were self-administered to 140 psychiatric outpatients with variouspsychiatric disorders. The coefficient alphas of the BDI-IA and the BDI-II were, respectively, .89 and .91.The mean rating for Sadness on the BDI-IA was higher than it was on the BDI-II, but the mean ratingsfor Past Failure, Self-Dislike, Change in Sleeping Pattern, and Change in Appetite were higher on theBDI-II than they were on the BDI-IA. The mean BDI-II total score was approximately 2 points higherthan it was for the BDI-IA, and the outpatients also endorsed approximately one more symptom on theBDI-II than they did on the BDI-IA. The correlations of BDI-IA and BDI-II total scores with sex, ethnicity,age, the diagnosis of a mood disorder, and the Beck Anxiety Inventory (Beck & Steer, 1993a) were within1 point of each other for the same variables.", "metadata": {}}
+{"_id": "38243984", "title": "", "text": "Tumor engraftment in nude mice and enrichment in stroma- related gene pathways predict poor survivaland resistance to gemcitabine in patients with pancreatic cancer.PURPOSE The goal of this study was toevaluate prospectively the engraftment rate, factors influencing engraftment, and predictability of clinicaloutcome of low-passage xenografts from patients with resectable pancreatic ductal adenocarcinoma(PDA) and to establish a bank of PDA xenografts. EXPERIMENTAL DESIGN Patients with resectable PDAscheduled for resection at the Johns Hopkins Hospital were eligible. Representative pieces of tumor wereimplanted in nude mice. The status of the SMAD4 gene and content of tumor-generating cells weredetermined by immunohistochemistry. Gene expression was carried out by using a U133 Plus 2.0 array.Patients were followed for progression and survival. RESULTS A total of 94 patients with PDA wereresected, 69 tumors implanted in nude mice, and 42 (61%) engrafted. Engrafted carcinomas were moreoften SMAD4 mutant, and had a metastatic gene expression signature and worse prognosis. Tumors frompatients resistant to gemcitabine were enriched in stroma-related gene pathways. Tumors sensitive togemcitabine were enriched in cell cycle and pyrimidine gene pathways. The time to progression forpatients who received treatment with gemcitabine for metastatic disease (n = 7) was double in patientswith xenografts sensitive to gemcitabine. CONCLUSION A successful xenograft was generated in 61% ofpatients attempted, generating a pool of 42 PDA xenografts with significant biological information andannotated clinical data. Patients with PDA and SMAD4 inactivation have a better engraftment rate.Engraftment is a poor prognosis factor, and engrafted tumors have a metastatic gene expressionsignature. Tumors from gemcitabine-resistant patients were enriched in stromal pathways.", "metadata": {}}
+{"_id": "38252314", "title": "", "text": "The MCM8-MCM9 complex promotes RAD51 recruitment at DNA damage sites to facilitate homologousrecombination.The minichromosome maintenance protein homologs MCM8 and MCM9 have previouslybeen implicated in DNA replication elongation and prereplication complex (pre-RC) formation,respectively. We found that MCM8 and MCM9 physically associate with each other and that MCM8 isrequired for the stability of MCM9 protein in mammalian cells. Depletion of MCM8 or MCM9 in humancancer cells or the loss of function MCM9 mutation in mouse embryo fibroblasts sensitizes cells to theDNA interstrand cross-linking (ICL) agent cisplatin. Consistent with a role in the repair of ICLs byhomologous recombination (HR), knockdown of MCM8 or MCM9 significantly reduces HR repair efficiency.Chromatin immunoprecipitation analysis using human DR-GFP cells or Xenopus egg extract demonstratedthat MCM8 and MCM9 proteins are rapidly recruited to DNA damage sites and promote RAD51recruitment. Thus, these two metazoan-specific MCM homologs are new components of HR and mayrepresent novel targets for treating cancer in combination with DNA cross-linking agents.", "metadata": {}}
+{"_id": "38296571", "title": "", "text": "The 5TMM series: a useful in vivo mouse model of human multiple myeloma.The present inventionprovides a combination sink and dishwashing apparatus having a sink sharing a common side wall with acabinet which defines a closed space. The cabinet has a wire basket for holding and washing a plurality ofdishes within the cabinet. The common side wall is a part of the cabinet that defines the closed space andis positioned to form one side of the sink. The common side wall can be opened to allow the wire basketto slide from within the cabinet and into the sink, for loading and unloading the dishes. Within thecabinet, the invention contains a pump powered by a motor, the pump spraying water through arotatably mounted spray arm onto the dishes to wash them, as with traditional dishwashing machines.The invention preferably includes a garbage disposal which is also powered by the motor. In analternative embodiment, this invention can include two cabinets as described above, each located onopposing sides of the sink.", "metadata": {}}
+{"_id": "38300781", "title": "", "text": "Ionic protein-lipid interaction at the plasma membrane: what can the charge do?Phospholipids are themajor components of cell membranes, but they have functional roles beyond forming lipid bilayers. Inparticular, acidic phospholipids form microdomains in the plasma membrane and can ionically interactwith proteins via polybasic sequences, which can have functional consequences for the protein. The list ofproteins regulated by ionic protein-lipid interaction has been quickly expanding, and now includesmembrane proteins, cytoplasmic soluble proteins, and viral proteins. Here we review how acidicphospholipids in the plasma membrane regulate protein structure and function via ionic interactions, andhow Ca(2+) regulates ionic protein-lipid interactions via direct and indirect mechanisms.", "metadata": {}}
+{"_id": "38355793", "title": "", "text": "A20 is overexpressed in glioma cells and may serve as a potential therapeutic target.OBJECTIVE A20 is aTNF-inducible primary response gene, which has been found to have antiapoptotic function in severalcancer cells. This study investigates A20 expression in human glioma tissues and four glioma cell lines,and its effect on tumorigenesis of glioma cells and a mouse tumor model. METHODS Human glioma tissuesamples and cells were subject to reverse transcription-PCR (RT-PCR), western blotting andimmunohistochemistry. Glioma cells was tested by flow cytometry. A xenograft tumor model in mice wasutilized to examine the knock-down effect of specific A20 siRNAs on tumorigenesis. RESULTS A20 wasoverexpressed in clinical glioma tissue samples (63.9%) and correlated with clinical staging. All fourhuman glioma cell lines expressed A20, among which U87 displayed the strongest expression signals.Inhibiting A20 expression by siRNAs in vitro reduced the growth rates of glioma cells and resulted in G1/Sarrest and increased apoptosis. In a mouse tumor model, local administration of siRNA significantlysuppressed solid tumor growth. CONCLUSIONS A20 was overexpressed both in human glioma tissues andcell lines, and inhibiting A20 expression greatly slowed tumor cell growth in culture and in mice. Thesefindings indicated that A20 is involved in tumorigenesis of human glioma, and may serve as a futuretherapeutic target.", "metadata": {}}
+{"_id": "38369817", "title": "", "text": "Prevalence and size of directly detected patent foramen ovale in migraine with aura.BACKGROUNDTranscranial contrast Doppler studies have shown an increased prevalence of right-to-left shunts inpatients with migraine with aura compared with controls. The anatomy and size of these right-to-leftshunts have never been directly assessed. METHODS In a cross-sectional case-control study, the authorsperformed transesophageal contrast echocardiography in 93 consecutive patients with migraine with auraand 93 healthy controls. RESULTS A patent foramen ovale was present in 44 (47% [95% CI 37 to 58%])patients with migraine with aura and 16 (17% [95% CI 10 to 26%]) control subjects (OR 4.56 [95% CI1.97 to 10.57]; p < 0.001). A small shunt was equally prevalent in migraineurs (10% [95% CI 5 to18%]) and controls (10% [95% CI 5 to 18%]), but a moderate-sized or large shunt was found moreoften in the migraine group (38% [95% CI 28 to 48%] vs 8% [95% CI 2 to 13%] in controls; p < 0.001).The presence of more than a small shunt increased the odds of having migraine with aura 7.78-fold (95%CI 2.53 to 29.30; p < 0.001). Besides patent foramen ovale prevalence and shunt size, no otherechocardiographic differences were found between the study groups. Headache and baselinecharacteristics did not differ in migraine patients with and without shunt. CONCLUSIONS Nearly half of allpatients with migraine with aura have a right-to-left shunt due to a patent foramen ovale. Shunt size islarger in migraineurs than controls. The clinical presentation of migraine is identical in patients with andwithout a patent foramen ovale.", "metadata": {}}
+{"_id": "38376189", "title": "", "text": "A Live Attenuated Chimeric West Nile Virus Vaccine, rWN/DEN4&Dgr;30, Is Well Tolerated andImmunogenic in Flavivirus-Naive Older Adult VolunteersWest Nile virus (WNV) is a major cause ofmosquito-borne illness in the United States. Human disease ranges from mild febrile illness to severefatal neurologic infection. Adults aged >60 years are more susceptible to neuroinvasive diseaseaccompanied by a high mortality rate or long-lasting neurologic sequelae. A chimeric live attenuated WestNile virus vaccine, rWN/DEN4&Dgr;30, was shown to be safe and immunogenic in healthy adults aged18–50 years. This study evaluated rWN/DEN4&Dgr;30 in flavivirus-naive adults aged 50–65 years andfound it to be safe and immunogenic. Outbreaks of WNV infection tend to be unpredictable, and a safeand effective vaccine will be an important public health tool.", "metadata": {}}
+{"_id": "38380061", "title": "", "text": "Localization and requirement for Myosin II at the dorsal-ventral compartment boundary of the Drosophilawing.As organisms develop, their tissues can become separated into distinct cell populations through theestablishment of compartment boundaries. Compartment boundaries have been discovered in a widevariety of tissues, but in many cases the molecular mechanisms that separate cells remain poorlyunderstood. In the Drosophila wing, a stripe of Notch activation maintains the dorsal-ventralcompartment boundary, through a process that depends on the actin cytoskeleton. Here, we show thatthe dorsal-ventral boundary exhibits a distinct accumulation of Myosin II, and that this accumulation isregulated downstream of Notch signaling. Conversely, the dorsal-ventral boundary is depleted for thePar-3 homologue Bazooka. We further show that mutations in the Myosin heavy chain subunit encodedby zipper can impair dorsal-ventral compartmentalization without affecting anterior-posteriorcompartmentalization. These observations identify a distinct accumulation and requirement for Myosinactivity in dorsal-ventral compartmentalization, and suggest a novel mechanism in which contractiletension along an F-actin cable at the compartment boundary contributes to compartmentalization.", "metadata": {}}
+{"_id": "38401028", "title": "", "text": "The cause of hepatic accumulation of fructose 1-phosphate on fructose loading.1. The changes in themetabolite content in freeze-clamped livers of fed rats occurring on perfusion with 10mm-d-fructose havebeen examined. 2. The most striking effects of fructose were an accumulation of fructose 1-phosphate, asalready known, up to 8.7mumol/g of liver within 10min, a loss of total adenine nucleotides (up to 35%after 40min) with a decrease in the ATP content to 23% within 10min, a sevenfold rise in theconcentration of IMP to 1.1mumol/g and an eightfold rise of alpha-glycerophosphate to 1.1mumol/g. 3.There was a transient decrease in P(i) from 4.2 to 1.7mumol/g. Within 40min the P(i) content recoveredto the normal value, probably because of an uptake of P(i) from the perfusion medium. 4. Thedegradation of the adenine nucleotides beyond the stage of AMP can be accounted for by the decrease ofATP and P(i). As ATP inhibits 5-nucleotidase, and as P(i) inhibits AMP deaminase any AMP arising in thetissue is liable to undergo dephosphorylation or deamination under the conditions occurring after fructoseloading. 5. The content of lactate increased to 4.3mumol/g at 80min; pyruvate also increased and the[lactate]/[pyruvate] ratio remained within physiological limits. 6. The concentration of free fructosewithin the liver remained much below that in the perfusion medium, indicating that the rate ofpenetration of fructose into the tissue was lower than the rate of utilization. 7. The fission of fructose1-phosphate by liver aldolase is inhibited by several phosphorylated intermediates, especially by IMP.This inhibition is competitive with a K(i) of 0.1mm. 8. The maximal rates of the enzymes synthesizing andsplitting fructose 1-phosphate are about equal. The accumulation of fructose 1-phosphate on fructoseloading is due to the inhibition of the fission of fructose 1-phosphate by the IMP arising from thedegradation of the adenine nucleotides.", "metadata": {}}
+{"_id": "38410121", "title": "", "text": "Reported side effects to chloroquine, chloroquine plus proguanil, and mefloquine as chemoprophylaxisagainst malaria in Danish travelers.BACKGROUND The aim of the study was to provide data on therelative frequency of reported symptoms in travelers using chloroquine, chloroquine plus proguanil, andmefloquine. METHOD The study was an open, nonrandomized study recording self-reported events intravelers recruited consecutively from two travel clinics in Copenhagen, Denmark. The main outcomemeasures were the relative proportion of travelers reporting particular symptoms in the three prophylaxisgroups, compliance, hospitalization and premature termination of the travel. RESULTS From May 1996 toApril 1998 5, 446 travelers were included and 4,158 questionnaires (76.3%) returned. Compliance wassignificantly better in mefloquine users with 83.3% of short term travelers compared to 76.3% inchloroquine plus proguanil users. Also, 84.8%, 59.3% and 69.5% using chloroquine, chloroquine plusproguanil, and mefloquine respectively reported no symptoms and 0.6%, 1.1% and 2.8% reported\"unacceptable\" symptoms. Compared to chloroquine, mefloquine users had a significantly higher risk ofreporting depression, RR 5.06 (95% CI 2.71 - 9.45), \"strange thoughts,\" RR 6.36 (95% CI 2.52 - 16.05)and altered spatial perception, RR 3.00 (95% CI 1.41 - 6.41). CONCLUSION Overall mefloquine istolerated at least as well as chloroquine plus proguanil and shows better compliance, however, symptomsrelated to the central nervous system are more prevalent in mefloquine users and when symptomsdevelop, they are perceived as more severe.", "metadata": {}}
+{"_id": "38477436", "title": "", "text": "Ubiquitinylation of the cytosolic domain of a type I membrane protein is not required to initiate itsdislocation from the endoplasmic reticulum.Human cytomegalovirus US2 and US11 target newlysynthesized class I major histocompatibility complex (MHC) heavy chains for rapid degradation by theproteasome through a process termed dislocation. The presence of US2 induces the formation of class IMHC heavy chain conjugates of increased molecular weight that are recognized by aconformation-specific monoclonal antibody, W6/32, suggesting that these class I MHC molecules retaintheir proper tertiary structure. These conjugates are properly folded glycosylated heavy chains modifiedby attachment of an estimated one, two, and three ubiquitin molecules. The folded ubiquitinated class IMHC heavy chains are not observed in control cells or in cells transfected with US11, suggesting that US2targets class I MHC heavy chains for dislocation in a manner distinct from that used by US11. This isfurther supported by the fact that US2 and US11 show different requirements in terms of theconformation of the heavy chain molecule. Although ubiquitin conjugation may occur on the cytosolic tailof the class I MHC molecule, replacement of lysines in the cytosolic tail of heavy chains with arginine doesnot prevent their degradation by US2. In an in vitro system that recapitulates US2-mediated dislocation,heavy chains that lack these lysines still occur in an ubiquitin-modified form, but in the soluble(cytoplasmic) fraction. Such ubiquitin conjugation can only occur on the class I MHC lumenal domain andis likely to take place once class I MHC heavy chains have been discharged from the endoplasmicreticulum. We conclude that ubiquitinylation of class I MHC heavy chain is not required during the initialstep of the US2-mediated dislocation reaction.", "metadata": {}}
+{"_id": "38485364", "title": "", "text": "The adaptor protein Tks5/Fish is required for podosome formation and function, and for theprotease-driven invasion of cancer cells.Tks5/Fish is a scaffolding protein with five SH3 domains and onePX domain. In Src-transformed cells, Tks5/Fish localizes to podosomes, discrete protrusions of the ventralmembrane. We generated Src-transformed cells with reduced Tks5/Fish levels. They no longer formedpodosomes, did not degrade gelatin, and were poorly invasive. We detected Tks5/Fish expression inpodosomes in invasive cancer cells, as well as in human breast cancer and melanoma samples. Tks5/Fishexpression was also required for protease-driven matrigel invasion in human cancer cells. Finally,coexpression of Tks5/Fish and Src in epithelial cells resulted in the appearance of podosomes. Thus,Tks5/Fish appears to be required for podosome formation, for degradation of the extracellular matrix,and for invasion of some cancer cells.", "metadata": {}}
+{"_id": "38493521", "title": "", "text": "Corticosteroid injections for shoulder pain.BACKGROUND While many treatments, including corticosteroidinjections in and around the shoulder, are advocated to be of benefit for shoulder pain, few are of provenefficacy. This review of corticosteroid injections for shoulder pain is one in a series of reviews of varyinginterventions for shoulder disorders. OBJECTIVES To determine the efficacy and safety of corticosteroidinjections in the treatment of adults with shoulder pain. SEARCH STRATEGY MEDLINE, EMBASE, CINAHL,Central and Science Citation Index were searched up to and including June 2002. SELECTION CRITERIARandomised and pseudo-randomised trials in all languages of corticosteroid injections compared toplacebo or another intervention, or of varying types and dosages of steroid injection in adults withshoulder pain. Specific exclusions were duration of shoulder pain less than three weeks, rheumatoidarthritis, polymyalgia rheumatica and fracture. DATA COLLECTION AND ANALYSIS Trial inclusion andmethodological quality was assessed by two independent reviewers according to predetermined criteria.Results are presented separately for rotator cuff disease, adhesive capsulitis, full thickness rotator cufftear and mixed diagnoses, and, where possible, combined in meta-analysis. MAIN RESULTS Twenty-sixtrials met inclusion criteria. The number, site and dosage of injections varied widely between studies. Thenumber of participants per trial ranged from 20 to 114 (median 52 participants). Methodological qualitywas variable. For rotator cuff disease, subacromial steroid injection was demonstrated to have a smallbenefit over placebo in some trials however no benefit of subacromial steroid injection over NSAID wasdemonstrated based upon the pooled results of three trials. For adhesive capsulitis, two trials suggested apossible early benefit of intra-articular steroid injection over placebo but there was insufficient data forpooling of any of the trials. One trial suggested short-term benefit of intra-articular corticosteroidinjection over physiotherapy in the short-term (success at seven weeks RR=1.66 (1.21, 2.28).REVIEWER'S CONCLUSIONS Despite many RCTs of corticosteroid injections for shoulder pain, their smallsample sizes, variable methodological quality and heterogeneity means that there is little overall evidenceto guide treatment. Subacromial corticosteroid injection for rotator cuff disease and intra-articularinjection for adhesive capsulitis may be beneficial although their effect may be small and notwell-maintained. There is a need for further trials investigating the efficacy of corticosteroid injections forshoulder pain. Other important issues that remain to be clarified include whether the accuracy of needleplacement, anatomical site, frequency, dose and type of corticosteroid influences efficacy.", "metadata": {}}
+{"_id": "38502066", "title": "", "text": "IL-2 receptor signaling is essential for the development of Klrg1+ terminally differentiated T regulatorycells.Thymic-derived natural T regulatory cells (Tregs) are characterized by functional and phenotypicheterogeneity. Recently, a small fraction of peripheral Tregs has been shown to express Klrg1, but itremains unclear as to what extent Klrg1 defines a unique Treg subset. In this study, we show thatKlrg1(+) Tregs represent a terminally differentiated Treg subset derived from Klrg1(-) Tregs. This subsetis a recent Ag-responsive and highly activated short-lived Treg population that expresses enhanced levelsof Treg suppressive molecules and that preferentially resides within mucosal tissues. The development ofKlrg1(+) Tregs also requires extensive IL-2R signaling. This activity represents a distinct function forIL-2, independent from its contribution to Treg homeostasis and competitive fitness. These and otherproperties are analogous to terminally differentiated short-lived CD8(+) T effector cells. Our findingssuggest that an important pathway driving Ag-activated conventional T lymphocytes also operates forTregs.", "metadata": {}}
+{"_id": "38528892", "title": "", "text": "The aurora B kinase promotes inner and outer kinetochore interactions in budding yeast.The kinetochoreis the macromolecular protein complex that mediates chromosome segregation. The Dsn1 component iscrucial for kinetochore assembly and is phosphorylated by the Aurora B kinase. We found that Aurora Bphosphorylation of Dsn1 promotes the interaction between outer and inner kinetochore proteins inbudding yeast.", "metadata": {}}
+{"_id": "38533515", "title": "", "text": "AMP-activated/SNF1 protein kinases: conserved guardians of cellular energyThe SNF1/AMP-activatedprotein kinase (AMPK) family maintains the balance between ATP production and consumption in alleukaryotic cells. The kinases are heterotrimers that comprise a catalytic subunit and regulatory subunitsthat sense cellular energy levels. When energy status is compromised, the system activates catabolicpathways and switches off protein, carbohydrate and lipid biosynthesis, as well as cell growth andproliferation. Surprisingly, recent results indicate that the AMPK system is also important in functions thatgo beyond the regulation of energy homeostasis, such as the maintenance of cell polarity in epithelialcells.", "metadata": {}}
+{"_id": "38551172", "title": "", "text": "Mammographic density, plasma vitamin D levels and risk of breast cancer in postmenopausalwomen.Mammographic density is a strong risk factor for breast cancer, but the underlying biology for thisassociation is unknown. Studies suggest that vitamin D may reduce breast cancer risk and dietaryvitamin D intake has been associated with reduced breast density. We conducted a case-control studynested within the Nurses' Health Study cohort consisting of 463 and 497 postmenopausal cases andcontrols, respectively. We examined the association between mammographic density and plasma levelsof 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)(2)D]. We assessed whetherplasma vitamin D metabolites modify the association between breast density and breast cancer. Percentmammographic density was measured from digitized film mammograms. Generalized linear models wereused to determine mean percent breast density per quartile of vitamin D metabolite. Logistic regressionmodels were used to calculate relative risks and confidence intervals. All models were adjusted formatching variables and potential confounders. We found no cross-sectional association betweencirculating levels of 25(OH)D or 1,25(OH)(2)D with mammographic density. Women in the highest tertileof mammographic density and lowest tertile of plasma 25(OH)D had 4 times greater risk of breast cancerthan women with the lowest mammographic density and highest plasma 25(OH)D levels (RR = 3.8; 95%CI: 2.0-7.3). The overall interaction between mammographic density and plasma 25(OH)D wasnonsignificant (p-het = 0.20). These results indicate that the association between mammographic densityand breast cancer is independent of plasma vitamin D metabolites in postmenopausal women. Furtherresearch examining vitamin D, mammographic density and breast cancer risk is warranted.", "metadata": {}}
+{"_id": "38587347", "title": "", "text": "Finding the right niche: B-cell migration in the early phases of T-dependent antibody responses.Humoralimmune responses depend on B cells encountering antigen, interacting with helper T cells, proliferatingand differentiating into low-affinity plasma cells or, after organizing into a germinal center (GC),high-affinity plasma cells and memory B cells. Remarkably, each of these events occurs in associationwith distinct stromal cells in separate subcompartments of the lymphoid tissue. B cells must migrate fromniche to niche in a rapid and highly regulated manner to successfully mount a response. The chemokine,CXCL13, plays a central role in guiding B cells to follicles whereas T-zone chemokines guide activated Bcells to the T zone. Sphingosine-1-phosphate (S1P) promotes cell egress from the tissue, as well asmarginal-zone B-cell positioning in the spleen. Recent studies have identified a role for the orphanreceptor, EBV-induced molecule 2 (EBI2; GPR183), in guiding activated B cells to inter and outer follicularniche(s) and down-regulation of this receptor is essential for organizing cells into GCs. In this review, wediscuss current understanding of the roles played by chemokines, S1P and EBI2 in the migration eventsthat underlie humoral immune responses.", "metadata": {}}
+{"_id": "38623601", "title": "", "text": "Arginine Starvation Impairs Mitochondrial Respiratory Function in ASS1-Deficient Breast CancerCellsAutophagy is the principal catabolic response to nutrient starvation and is necessary to cleardysfunctional or damaged organelles, but excessive autophagy can be cytotoxic or cytostatic andcontributes to cell death. Depending on the abundance of enzymes involved in molecule biosynthesis,cells can be dependent on uptake of exogenous nutrients to provide these molecules. Argininosuccinatesynthetase 1 (ASS1) is a key enzyme in arginine biosynthesis, and its abundance is reduced in many solidtumors, making them sensitive to external arginine depletion. We demonstrated that prolonged argininestarvation by exposure to ADI-PEG20 (pegylated arginine deiminase) induced autophagy-dependentdeath of ASS1-deficient breast cancer cells, because these cells are arginine auxotrophs (dependent onuptake of extracellular arginine). Indeed, these breast cancer cells died in culture when exposed toADI-PEG20 or cultured in the absence of arginine. Arginine starvation induced mitochondrial oxidativestress, which impaired mitochondrial bioenergetics and integrity. Furthermore, arginine starvation killedbreast cancer cells in vivo and in vitro only if they were autophagy-competent. Thus, a key mechanismunderlying the lethality induced by prolonged arginine starvation was the cytotoxic autophagy thatoccurred in response to mitochondrial damage. Last, ASS1 was either low in abundance or absent in morethan 60% of 149 random breast cancer biosamples, suggesting that patients with such tumors could becandidates for arginine starvation therapy.", "metadata": {}}
+{"_id": "38630735", "title": "", "text": "A prospective natural-history study of coronary atherosclerosis.BACKGROUND Atherosclerotic plaquesthat lead to acute coronary syndromes often occur at sites of angiographically mild coronary-arterystenosis. Lesion-related risk factors for such events are poorly understood. METHODS In a prospectivestudy, 697 patients with acute coronary syndromes underwent three-vessel coronary angiography andgray-scale and radiofrequency intravascular ultrasonographic imaging after percutaneous coronaryintervention. Subsequent major adverse cardiovascular events (death from cardiac causes, cardiacarrest, myocardial infarction, or rehospitalization due to unstable or progressive angina) were adjudicatedto be related to either originally treated (culprit) lesions or untreated (nonculprit) lesions. The medianfollow-up period was 3.4 years. RESULTS The 3-year cumulative rate of major adverse cardiovascularevents was 20.4%. Events were adjudicated to be related to culprit lesions in 12.9% of patients and tononculprit lesions in 11.6%. Most nonculprit lesions responsible for follow-up events wereangiographically mild at baseline (mean [±SD] diameter stenosis, 32.3±20.6%). However, onmultivariate analysis, nonculprit lesions associated with recurrent events were more likely than those notassociated with recurrent events to be characterized by a plaque burden of 70% or greater (hazard ratio,5.03; 95% confidence interval [CI], 2.51 to 10.11; P<0.001) or a minimal luminal area of 4.0 mm(2) orless (hazard ratio, 3.21; 95% CI, 1.61 to 6.42; P=0.001) or to be classified on the basis ofradiofrequency intravascular ultrasonography as thin-cap fibroatheromas (hazard ratio, 3.35; 95% CI,1.77 to 6.36; P<0.001). CONCLUSIONS In patients who presented with an acute coronary syndrome andunderwent percutaneous coronary intervention, major adverse cardiovascular events occurring duringfollow-up were equally attributable to recurrence at the site of culprit lesions and to nonculprit lesions.Although nonculprit lesions that were responsible for unanticipated events were frequentlyangiographically mild, most were thin-cap fibroatheromas or were characterized by a large plaqueburden, a small luminal area, or some combination of these characteristics, as determined by gray-scaleand radiofrequency intravascular ultrasonography. (Funded by Abbott Vascular and Volcano;ClinicalTrials.gov number, NCT00180466.).", "metadata": {}}
+{"_id": "38664102", "title": "", "text": "What do medical schools teach about women's health and gender differences?PURPOSE To examine thecurricula of U.S. medical schools to assess the inclusion of women's health and gender-specificinformation and identify institutional characteristics associated with this content. METHOD Using datafrom the Association of American Medical Colleges' Curriculum Management and Information Tool(CurrMIT), in November 2003 to February 2004 the authors performed a curriculum search of schoolsthat entered course/clerkships in CurrMIT to identify interdisciplinary women's health or gender-specificcourses/clerkships. A subset of schools that entered comprehensive information in CurrMIT was searchedfor a specified list of women's health topics and or gender-specific content on any topic. Statisticalanalyses were performed to assess the relationship between frequency of topics and schoolcharacteristics. RESULTS The authors identified 95 schools that entered related courses/clerkships. Tencourses/clerkships at nine schools met criteria for an interdisciplinary women's health course/clerkship. Inthe subset of 60 schools with comprehensive CurrMIT information, 18 specified women's health topicswere identified, as well as 24 topics on gender-specific content, for a total of 42 topics. The number oftopics taught ranged from zero to 26 (mean = 11). More than 50% of these schools taught 11 of the 18specified topics, while fewer than 30% included gender-specific topics. There was no association inbivariate analysis between the mean number of topics taught and schools' characteristics; however, awomen's health program (p= .01) and female dean (p= .06) were positively associated in a regressionmodel. CONCLUSIONS Few schools offer interdisciplinary women's health courses/clerkships or includegender-specific information in their curricula. A designated women's health program may increase thiscontent in schools' curricula.", "metadata": {}}
+{"_id": "38675228", "title": "", "text": "A molecular framework for plant regeneration.Plants and some animals have a profound capacity toregenerate organs from adult tissues. Molecular mechanisms for regeneration have, however, beenlargely unexplored. Here we investigate a local regeneration response in Arabidopsis roots. Laser-inducedwounding disrupts the flow of auxin-a cell-fate-instructive plant hormone-in root tips, and wedemonstrate that resulting cell-fate changes require the PLETHORA, SHORTROOT, and SCARECROWtranscription factors. These transcription factors regulate the expression and polar position of PIN auxinefflux-facilitating membrane proteins to reconstitute auxin transport in renewed root tips. Thus, aregeneration mechanism using embryonic root stem-cell patterning factors first responds to andsubsequently stabilizes a new hormone distribution.", "metadata": {}}
+{"_id": "38712515", "title": "", "text": "Cocoa flavonols and procyanidins promote transforming growth factor-beta1 homeostasis in peripheralblood mononuclear cells.Evidence suggests that certain flavan-3-ols and procyanidins (FP) can have apositive influence on cardiovascular health. It has been previously reported that FP isolated from cocoacan potentially modulate the level and production of several signaling molecules associated with immunefunction and inflammation, including several cytokines and eicosanoids. In the present study, weexamined whether FP fractions monomers through decamers modulate secretion of the cytokinetransforming growth factor (TGF)-beta(1) from resting human peripheral blood mononuclear cells(PBMC). A total of 13 healthy subjects were studied and grouped according to their baseline production ofTGF-beta(1). When cells from individuals with low baseline levels of TGF-beta(1) (n = 7) were stimulatedby individual FP fractions (25 microg/ml), TGF-beta(1) release was enhanced in the range of 15%-66%over baseline (P < 0.05; monomer, dimer, and tetramer). The low-molecular-weight FP fractions(<or=pentamer) were more effective at augmenting TGF-beta(1) secretion than their larger counterparts(>or=hexamer), with the monomer and dimer inducing the greatest increases (66% and 68%,respectively). In contrast to the above, TGF-beta(1) secretion from high TGF-beta(1) baseline subjects (n= 6) was inhibited by individual FP fractions (P < 0.05; trimer through decamer). The inhibition was mostpronounced with trimeric through decameric fractions (28%-42%), and monomers and dimersmoderately inhibited TGF-beta(1) release (17% and 23%, respectively). Given the vascular actionsassociated with TGF-beta(1), we suggest that in healthy individuals, homeostatic modulation of itsproduction by FP offers an additional mechanism by which FP-rich foods can potentially benefitcardiovascular health.", "metadata": {}}
+{"_id": "38727075", "title": "", "text": "BMP receptor IA is required in mammalian neural crest cells for development of the cardiac outflow tractand ventricular myocardium.The neural crest is a multipotent, migratory cell population arising from theborder of the neural and surface ectoderm. In mouse, the initial migratory neural crest cells occur at thefive-somite stage. Bone morphogenetic proteins (BMPs), particularly BMP2 and BMP4, have beenimplicated as regulators of neural crest cell induction, maintenance, migration, differentiation andsurvival. Mouse has three known BMP2/4 type I receptors, of which Bmpr1a is expressed in the neuraltube sufficiently early to be involved in neural crest development from the outset; however, earlier rolesin other domains obscure its requirement in the neural crest. We have ablated Bmpr1a specifically in theneural crest, beginning at the five-somite stage. We find that most aspects of neural crest developmentoccur normally; suggesting that BMPRIA is unnecessary for many aspects of early neural crest biology.However, mutant embryos display a shortened cardiac outflow tract with defective septation, a processknown to require neural crest cells and to be essential for perinatal viability. Surprisingly, these embryosdie in mid-gestation from acute heart failure, with reduced proliferation of ventricular myocardium. Themyocardial defect may involve reduced BMP signaling in a novel, minor population of neural crestderivatives in the epicardium, a known source of ventricular myocardial proliferation signals. Theseresults demonstrate that BMP2/4 signaling in mammalian neural crest derivatives is essential for outflowtract development and may regulate a crucial proliferation signal for the ventricular myocardium.", "metadata": {}}
+{"_id": "38735355", "title": "", "text": "Early intermittent noninvasive ventilation for acute chest syndrome in adults with sickle cell disease: apilot studyAlveolar hypoxia and hypoxic vasoconstriction lead to trapping of sickle cells within thepulmonary vasculature. Improving alveolar ventilation and oxygenation may improve the outcome ofacute chest syndrome (ACS). Prospective randomized single-center open study from November 1998 toFebruary 2002 to test whether noninvasive ventilation (NIV) was more effective than oxygen alone inimproving oxygenation on day 3 in adults with ACS and to evaluate the effects on pain, transfusionrequirements, and length of stay. Seventy-one consecutive ACS episodes in 67 patients were randomlyallocated to oxygen (n = 36) or NIV (n = 35) for 3 days in a medical step-down unit. Baseline respiratoryrate and pain score were higher in the NIV group. NIV promptly lowered the respiratory rate, raised $${\\text{Pa}}_{{\\text{O}_{2}}} $$ , and decreased alveolar–arterial oxygen gradient $$ (({\\text{A}} -{\\text{a}})_{{{\\text{O}}_{ 2} }} ) $$ , which remained unchanged with oxygen alone. $${\\text{Pa}}_{{{\\text{CO}}_{ 2} }} $$ significantly worsened only in the oxygen group. On day 3, thegroups did not differ regarding the proportion of episodes with normal $$ {\\text{Pa}}_{{{\\text{O}}_{2} }} $$ (35% with NIV and 25% with oxygen; P = 0.5) or $$ (({\\text{A}} -{\\text{a}})_{{{\\text{O}}_{ 2} }} ) $$ . Patient satisfaction and compliance were lower with NIV. Nodifferences were noted in pain relief, transfusions, or length of stay. In the subgroup of patients withsevere hypoxemia $$ ( {\\text{Pa}}_{{{\\text{O}}_{ 2} }} \\le 6 5\\,{\\text{mmHg)}} $$ , physiologicalvariables also improved faster with NIV, the differences being slightly more pronounced. Respiratory rateand gas exchange improved faster with NIV. However, NIV failed to significantly reduce the number ofpatients remaining hypoxemic at day 3, and was associated with greater patient discomfort.", "metadata": {}}
+{"_id": "38745690", "title": "", "text": "Serum Exosome MicroRNA as a Minimally-Invasive Early Biomarker of AMLRelapse remains the majorcause of mortality for patients with Acute Myeloid Leukemia (AML). Improved tracking of minimal residualdisease (MRD) holds the promise of timely treatment adjustments to preempt relapse. Currentsurveillance techniques detect circulating blasts that coincide with advanced disease and poorly reflectMRD during early relapse. Here, we investigate exosomes as a minimally invasive platform for amicroRNA (miRNA) biomarker. We identify a set of miRNA enriched in AML exosomes and track levels ofcirculating exosome miRNA that distinguish leukemic xenografts from both non-engrafted and humanCD34+ controls. We develop biostatistical models that reveal circulating exosomal miRNA at low marrowtumor burden and before circulating blasts can be detected. Remarkably, both leukemic blasts andmarrow stroma contribute to serum exosome miRNA. We propose development of serum exosome miRNAas a platform for a novel, sensitive compartment biomarker for prospective tracking and early detectionof AML recurrence.", "metadata": {}}
+{"_id": "38747567", "title": "", "text": "Human cytomegalovirus encodes an MHC class I-like molecule (UL142) that functions to inhibit NK celllysis.Clinical and low passage strains of human CMV (HCMV) encode an additional MHC class I-relatedmolecule UL142, in addition to the previously described UL18. The UL142 open reading frame is encodedwithin the ULb' region which is missing from a number of common high passage laboratory strains. Cellsexpressing UL142 following transfection, and fibroblasts infected with a recombinantadenovirus-expressing UL142, were used to screen both polyclonal NK cells and NK cell clones, in acompletely autologous system. Analysis of 100 NK cell clones derived from five donors, revealed 23clones that were inhibited by fibroblasts expressing UL142 alone. Small-interfering RNA-mediatedknockdown of UL142 mRNA expression in HCMV-infected cells resulted in increased sensitivity to lysis.From these data we conclude that UL142 is a novel HCMV-encoded MHC class I-related molecule whichinhibits NK cell killing in a clonally dependent manner.", "metadata": {}}
+{"_id": "38751591", "title": "", "text": "Identification of the conserved serine/threonine residues important for gibberellin-sensitivity ofArabidopsis RGL2 protein.The DELLA proteins GAI, RGA, RGL1 and RGL2 in Arabidopsis are plant growthrepressors, repressing diverse developmental processes. Studies have shown that gibberellin (GA)attenuates the repressive function of DELLA proteins by triggering their degradation via the proteasomepathway. However, it is not known if GA-induced protein degradation is the only pathway for regulatingthe bioactivity of DELLA proteins. We show here that tobacco BY2 cells represent a suitable system forstudying GA signaling. RGL2 exists in a phosphorylated form in BY2 cells. RGL2 undergoes GA-induceddegradation, and this process is blocked by proteasome inhibitors and serine/threonine phosphataseinhibitors; however, serine/threonine kinase inhibitors had no detectable effect, suggesting thatdephosphorylation of serine/threonine is probably a prerequisite for degradation of RGL2 via theproteasome pathway. Site-directed substitution of all 17 conserved serine and threonine residues showedthat six mutants (RGL2(S441D, RGL2(S542D), RGL2(T271E), RGL2(T319E), RGL2(T411E) andRGL2(T535E)) mimicking the status of constitutive phosphorylation are resistant to GA-induceddegradation. This suggests that these sites are potential phosphorylation sites. A functional assay basedon the expression of GA 20-oxidase revealed that RGL2(T271E) is probably a null mutant, RGL2(S441D),RGL2(S542D), RGL2(T319E) and RGL2(T411E) only retained about 4-17% of the activity of the wild typeRGL2, whereas RGL2(T535E) retained about 66% of the activity of the wild type RGL2. However,expression of GA 20-oxidase in BY2 cells expressing these mutant proteins is still responsive to GA,suggesting that the stabilization of RGL2 protein is not the only pathway for regulating its bioactivity.", "metadata": {}}
+{"_id": "38752049", "title": "", "text": "A chart review of cyproheptadine for stimulant-induced weight loss.Youths with attention deficithyperactivity disorder often experience weight loss on stimulants, which may limit optimal dosing andcompliance. Cyproheptadine has been shown in medical samples to stimulate weight gain. We conducteda retrospective chart review of 28 consecutive pediatric psychiatry outpatients prescribed cyproheptadinefor weight loss or insomnia while on stimulants. Of these, 4 patients never took cyproheptadineconsistently, and 3 discontinued it within the first 7 days due to intolerable side effects. Data wereanalyzed for 21 other patients (age range 4-15 years) who continued with 4-8 mg of cyproheptadinenightly (mean final dose = 4.9 mg/day) for at least 14 days (mean duration = 104.7 days). Most had lostweight on stimulant alone (mean weight loss was 2.1 kg, mean weight velocity was -19.3 g/day). All 21gained weight taking concomitant cyproheptadine, with a mean gain of 2.2 kg (paired t = 6.87, p <0.0001) and a mean weight velocity of 32.3 g/day. Eleven of 17 patients who had reported initialinsomnia on stimulant alone noted significant improvements in sleep with cyproheptadine added. Weconclude that concomitant cyproheptadine may be useful in youths with attention deficit hyperactivitydisorder for stimulant-induced weight loss, pending future randomized controlled trials.", "metadata": {}}
+{"_id": "38784540", "title": "", "text": "Life course breast cancer risk factors and adult breast density (United Kingdom)Objective To determinewhether risk factors in childhood and early adulthood affect later mammographic breast density.Methods: Subjects were 628 women who attended a medical examination at the University of GlasgowStudent Health Service (1948–1968), responded to a questionnaire (2001) and had a screeningmammogram in Scotland (1989–2002). Mammograms (median age of 59years) were classified using asix category classification (SCC) of breast density percent. Logistic regression was used to determineassociations between risk factors and having a high-risk mammogram (≥25 dense). Results: Inmulti-variable analyses, high-risk mammograms were associated with parity (adjusted odds ratio (OR)per child: 0.77 (95 confidence interval (CI) 0.61–0.99)), age at first birth, OR per year: 1.05(0.99–1.11), smoking at university, OR smokers versus non-smokers: 0.58 (0.36–0.92) and body massindex (BMI) while at university, OR per 1kg/m20.75 (0.69–0.82). No associations with SCC were foundfor age at menarche, birth weight, oral contraceptive (OC) use, height, leg length or exercise at age 20.Conclusions: We confirm previous findings that breast density is affected by reproductive events andsome anthropometric measures, however most of the risk factors acting throughout the life course whichwe examined were not closely related to adult breast density.", "metadata": {}}
+{"_id": "38793927", "title": "", "text": "Osteoclast nuclei of myeloma patients show chromosome translocations specific for the myeloma cellclone: a new type of cancer-host partnership?A major clinical manifestation of bone cancers is bonedestruction. It is widely accepted that this destruction is not caused by the malignant cells themselves,but by osteoclasts, multinucleated cells of monocytic origin that are considered to be the only cells able todegrade bone. The present study demonstrates that bone-resorbing osteoclasts from myeloma patientscontain nuclei with translocated chromosomes of myeloma B-cell clone origin, in addition to nucleiwithout these translocations, by using combined FISH and immunohistochemistry on bone sections.These nuclei of malignant origin are transcriptionally active and appear fully integrated amongst the othernuclei. The contribution of malignant nuclei to the osteoclast population analysed in this study wasgreater than 30%. Osteoclast-myeloma clone hybrids contained more nuclei than normal osteoclasts andtheir occurrence correlated with the proximity of myeloma cells. Similar hybrid cells were generated inmyeloma cell-osteoclast co-cultures, as revealed by tracing myeloma nuclei using translocations,bromo-deoxyuridine, or the Y chromosome of male myeloma cells in female osteoclasts. Theseobservations indicate that hybrid cells can originate through fusion between myeloma cells andosteoclasts. In conclusion, malignant cells contribute significantly to the formation of bone-resorbingosteoclasts in multiple myeloma. Osteoclast-myeloma clone hybrids reflect a previously unrecognizedmechanism of bone destruction in which malignant cells participate directly. The possibility that malignantcells corrupt host cells by the transfer of malignant DNA may have been underestimated to date in cancerresearch.", "metadata": {}}
+{"_id": "38794814", "title": "", "text": "Frequency modulation entrains slow neural oscillations and optimizes human listening behavior.Thehuman ability to continuously track dynamic environmental stimuli, in particular speech, is proposed toprofit from \"entrainment\" of endogenous neural oscillations, which involves phase reorganization suchthat \"optimal\" phase comes into line with temporally expected critical events, resulting in improvedprocessing. The current experiment goes beyond previous work in this domain by addressing two thus farunanswered questions. First, how general is neural entrainment to environmental rhythms: Can neuraloscillations be entrained by temporal dynamics of ongoing rhythmic stimuli without abrupt onsets?Second, does neural entrainment optimize performance of the perceptual system: Does human auditoryperception benefit from neural phase reorganization? In a human electroencephalography study, listenersdetected short gaps distributed uniformly with respect to the phase angle of a 3-Hz frequency-modulatedstimulus. Listeners' ability to detect gaps in the frequency-modulated sound was not uniformly distributedin time, but clustered in certain preferred phases of the modulation. Moreover, the optimal stimulusphase was individually determined by the neural delta oscillation entrained by the stimulus. Finally, deltaphase predicted behavior better than stimulus phase or the event-related potential after the gap. Thisstudy demonstrates behavioral benefits of phase realignment in response to frequency-modulatedauditory stimuli, overall suggesting that frequency fluctuations in natural environmental input provide apacing signal for endogenous neural oscillations, thereby influencing perceptual processing.", "metadata": {}}
+{"_id": "38799797", "title": "", "text": "Interventions by pharmacists in out-patient pharmaceutical care.Interventions by the pharmacists havealways been considered as a valuable input by the health care community in the patient care process byreducing the medication errors, rationalizing the therapy and reducing the cost of therapy. The primaryobjective of this study was to determine the number and types of medication errors intervened by thedispensing pharmacists at OPD pharmacy in the Khoula Hospital during 2009 retrospectively. Theinterventions filed by the pharmacists and assistant pharmacists in OPD pharmacy were collected. Thenthey were categorized and analyzed after a detailed review. The results show that 72.3% of theinterventions were minor of which 40.5% were about change medication order. Comparatively morenumbers of prescriptions were intervened in female patients than male patients. 98.2% of theinterventions were accepted by the prescribers reflecting the awareness of the doctors about theimportance of the pharmacy practice. In this study only 688 interventions were due to prescribing errorsof which 40.5% interventions were done in changing the medication order of clarifying the medicine.14.9% of the interventions were related to administrative issues, 8.7% of the interventions were relatedto selection of medications as well as errors due to ignorance of history of patients. 8.2% of theinterventions were to address the overdose of medications. Moderately significant interventions wereobserved in 19.4% and 7.5% of them were having the impact on major medication errors. Pharmacistshave intervened 20.8% of the prescriptions to prevent complications, 25.1% were to rationalize thetreatment, 7.9% of them were to improve compliance. Based on the results we conclude that the role ofpharmacist in improving the health care system is vital. We recommend more number of such researchbased studies to bring awareness among health care professionals, provide solution to the prescriptionand dispensing problems, as it can also improve the documentation system, emphasize the importance ofit, reduce prescribing errors, and update the knowledge of pharmacists and other health careprofessionals.", "metadata": {}}
+{"_id": "38805486", "title": "", "text": "Biochemical studies on Mycobacterium tuberculosis UreG and comparative modeling reveal structural andfunctional conservation among the bacterial UreG family.Nickel is a fundamental micronutrient for cellularlife, but it is toxic in soluble form at nonphysiological concentrations. Such potentially contradictoryfeatures required living organisms to develop efficient systems for nickel utilization and homeostasis. Thisis the case for incorporation of nickel into the active site of urease, a multistep, tightly regulated process,requiring the interplay of various accessory proteins. The understanding of this activation mechanismmay find medical applications against ureolytic bacteria, among which Mycobacterium tuberculosis is adeadly pathogen for humans. The topic of this study is UreG, an essential chaperone in the in vivoactivation of urease upon insertion of Ni2+ into the active site. The protein was examined using bothexperimental and computational approaches. In particular, the soluble M. tuberculosis UreG (MtUreG)was overexpressed in Escherichia coli and purified to homogeneity. The identity of the isolated proteinwas established by mass spectrometry. On-line size-exclusion chromatography and light scatteringindicated that MtUreG exists as a dimeric form in solution. Determination of the free thiol concentrationrevealed that a disulfide bond is present in the dimer. The isolated MtUreG shows low GTPase activityunder native conditions, with a kcat of 0.01 min-1. Circular dichroism spectroscopy demonstrated thepresence of a well-defined secondary structure (8% alpha-helices, 29% beta-strands) in MtUreG,whereas NMR spectroscopy indicated that this protein does not behave as a rigid three-dimensional foldand thus can be assigned to the class of intrinsically unstructured polypeptides. The molecular model ofMtUreG in the fully folded and functional form was built using fold recognition algorithms. An extensivesimilarity search was performed to determine conservation patterns in all known bacterial UreGsequences. The generation of a multiple-sequence alignment and the related phylogenetic tree allowed usto recognize key residues and motifs that are likely important for protein function. A structural databasecontaining the homology-built models of the most representative UreG proteins was created, confirmingthe structural analogies among the UreG family. A flexible region, likely to be important for proteinfunction, is identified. The structural conservation among this class of GTPases is discussed on the basisof their function in the urease assembly process.", "metadata": {}}
+{"_id": "38808600", "title": "", "text": "(99m)Tc-HisoDGR as a Potential SPECT Probe for Orthotopic Glioma Detection via Targeting of Integrinα5β1.Integrins, a large family of cell adhesion receptors, have been shown to play an important role forglioma proliferation and invasion. Several integrin receptors, including αvβ3, αvβ5, and α5β1, havegenerated clinical interest for glioma diagnosis and antitumor therapy. Integrin α5β1 has beenhighlighted as a prognostic and diagnostic marker in glioma, and its expression is correlated with a worseprognosis in high-grade glioma. However, unlike extensively studied integrins αvβ3 and αvβ5, very fewintegrin α5β1-specific radiotracers have been reported. Developing α5β1-specific radiotracers mayprovide alternative diagnosis and evaluation options in addition to well-studied αvβ3/αvβ5-specifictracers, and they may add new documents for profiling tumor progression. Here, a novel integrinα5β1-specific probe (99m)Tc-HisoDGR was fabricated for SPECT (single-photon emission computedtomography) imaging of glioma. To confirm its selective targeting of integrin α5β1 in vivo, the mousemodels of α5β1-positive U87MG human glioma were subjected to SPECT/CT scans, and biodistributionexperiments and blocking studies were performed. Small-animal SPECT/CT imaging experimentsdemonstrated that the tumors were clearly visualized in both subcutaneous and orthotopic glioma tumormodels with clear background at 0.5, 1, and 2 h p.i. The tumor accumulation of (99m)Tc-HisoDGRshowed significant reduction when excess cold isoDGR peptide was coinjected, suggesting that the tumoruptake was specifically mediated. Our work revealed that (99m)Tc-HisoDGR represented a powerfulmolecular probe for integrin α5β1-positive cancer imaging; moreover, it might be a promising tool forevaluating malignancy, predicting prognosis, selecting subpopulations of patients who might be sensitiveto integrin α5β1-targeted drugs, and assessing and monitoring the response to integrin α5β1-targeteddrugs in clinical trials.", "metadata": {}}
+{"_id": "38811597", "title": "", "text": "Effect of cyclic AMP-dependent protein phosphorylating conditions on the pH-dependent activity oftyrosine hydroxylase from beef and rat striata.Tyrosine hydroxylase (TH, EC 1.14.16.2) from beef brainstriata was purified 23-fold from an extract of an acetone powder. If this enzyme preparation is treatedwith a cyclic AMP[-dependent protein phosphorylation system, there is a change in the pH dependence ofthe enzyme activity. The pH optimum at saturating tetrahydrobiopterin (BH4) concentration is shiftedfrom below pH 6 to about pH 6.7. At pH 7, activation is expressed mainly as an increase in Vmax,whereas at pH 6, activation is expressed mainly as a decrease in Km for the pterin cofactor. Further, evenwith the control enzyme the Km for pterin cofactor declines precipitously as the pH is increased from 6toward neutrality. Similar data were obtained with G-25 Sephadex-treated rat striatal TH. Experiments inwhich rat striatal synaptosomes were used demonstrated that the in situ activation of TH byphosphorylating conditions is expressed primarily as an increase in the maximum rate of dopaminesynthesis. These results indicate that changes in TH activity caused by cyclic AMP-dependent proteinphosphorylation will depend to a large extent on the pH of the TH environment.", "metadata": {}}
+{"_id": "38830961", "title": "", "text": "Interaction of TNF with TNF receptor type 2 promotes expansion and function of mouse CD4+CD25+ Tregulatory cells.Although TNF is a major proinflammatory cytokine, increasing evidence indicates thatTNF also has immunosuppressive feedback effects. We have demonstrated in this study that, in bothresting and activated states, mouse peripheral CD4(+)CD25(+) T regulatory cells (Tregs) expressedremarkably higher surface levels of TNFR2 than CD4(+)CD25(-) T effector cells (Teffs). In cocultures ofTregs and Teffs, inhibition of proliferation of Teffs by Tregs was initially transiently abrogated by exposureto TNF, but longer exposure to TNF restored suppressive effects. Cytokine production by Teffs remainedcontinually suppressed by Tregs. The profound anergy of Tregs in response to TCR stimulation wasovercome by TNF, which expanded the Treg population. Furthermore, in synergy with IL-2, TNF expandedTregs even more markedly up-regulated expression of CD25 and FoxP3 and phosphorylation of STAT5,and enhanced the suppressive activity of Tregs. Unlike TNF, IL-1beta and IL-6 did not up-regulateFoxP3-expressing Tregs. Furthermore, the number of Tregs increased in wild-type mice, but not inTNFR2(-/-) mice following sublethal cecal ligation and puncture. Depletion of Tregs significantlydecreased mortality following cecal ligation and puncture. Thus, the stimulatory effect of TNF on Tregsresembles the reported costimulatory effects of TNF on Teffs, but is even more pronounced because ofthe higher expression of TNFR2 by Tregs. Moreover, our study suggests that the slower response of Tregsthan Teffs to TNF results in delayed immunosuppressive feedback effects.", "metadata": {}}
+{"_id": "38844612", "title": "", "text": "The basics of epithelial-mesenchymal transition.The origins of the mesenchymal cells participating intissue repair and pathological processes, notably tissue fibrosis, tumor invasiveness, and metastasis, arepoorly understood. However, emerging evidence suggests that epithelial-mesenchymal transitions (EMTs)represent one important source of these cells. As we discuss here, processes similar to the EMTsassociated with embryo implantation, embryogenesis, and organ development are appropriated andsubverted by chronically inflamed tissues and neoplasias. The identification of the signaling pathways thatlead to activation of EMT programs during these disease processes is providing new insights into theplasticity of cellular phenotypes and possible therapeutic interventions.", "metadata": {}}
+{"_id": "38873881", "title": "", "text": "Child maltreatment, other trauma exposure, and posttraumatic symptomatology among children withoppositional defiant and attention deficit hyperactivity disorders.Consecutive child psychiatric outpatientadmissions with disruptive behavior or adjustment disorders were assessed by validated instruments fortrauma exposure and posttraumatic stress disorder (PTSD) symptoms and other psychopathology. Fourreliably diagnosed groups were defined in a retrospective case-control design: Attention DeficitHyperactivity Disorder (ADHD), Oppositional Defiant Disorder (ODD), comorbid ADHD-ODD, andadjustment disorder controls. ODD and (although to a lesser extent) ADHD were associated with a historyof physical or sexual maltreatment. PTSD symptoms were most severe if (a) ADHD and maltreatmentco-occurred or (b) ODD and accident/illness trauma co-occurred. The association between ODD and PTSDCriterion D (hyperarousal/hypervigilance) symptoms remained after controlling for overlappingsymptoms, but the association of ADHD with PTSD symptoms was largely due to an overlappingsymptom. These findings suggest that screening for maltreatment, other trauma, and PTSD symptomsmay enhance prevention, treatment, and research concerning childhood disruptive behavior disorders.", "metadata": {}}
+{"_id": "38882175", "title": "", "text": "Exercise-induced asthma screening of elite athletes: field versus laboratory exercise challenge.PURPOSEThe purpose of this study was to compare a laboratory based exercise challenge (LBC) to a field basedexercise challenge (FBC) for pulmonary function test (PFT) exercise-induced asthma (EIA) screening ofelite athletes. METHODS Twenty-three elite cold weather athletes (14 men, 9 women) PFT positive forEIA (FBC screened) served as subjects. Twenty-three gender and sport matched controls (nonasthmatics)were randomly selected to establish PFT reference values for normal elite athletes. Before FBC, athletescompleted a medical history questionnaire for EIA symptoms. FBC evaluations consisted of baselinespirometry, actual or simulated competition, and 5, 10, and 15 min postexercise spirometry. PFT positiveathletes were evaluated in the laboratory using an exercise challenge simulating race intensity (ambientconditions: 21 degrees C, 60% relative humidity). PFT procedures were identical to FBC. RESULTS 91%of PFT positive and 48% of PFT normal athletes reported at least one symptom of EIA, with postracecough most frequent. Baseline spirometry was the same for PFT positives and normal controls. Lowerlimit reference range (MN - 2 SD) of FEV1 for controls suggests that postexercise decrements of greaterthan approximately -7% indicate abnormal airway response in this population. Exercise time duration didnot effect bronchial reactivity; 78% of FBC PFT positives were PFT normal post-LBC. CONCLUSIONSelf-reported symptoms by elite athletes are not reliable in identifying EIA. Reference range criterion forFEV1 decrement in the elite athlete postexercise contrasts current recommended guidelines. Moreover, alarge number of false negatives may occur in this population if EIA screening is performed withinadequate exercise and environmental stress.", "metadata": {}}
+{"_id": "38886345", "title": "", "text": "Use of a targeted oncolytic poxvirus, JX-594, in patients with refractory primary or metastatic livercancer: a phase I trial.BACKGROUND JX-594 is a targeted oncolytic poxvirus designed to selectivelyreplicate in and destroy cancer cells with cell-cycle abnormalities and epidermal growth factor receptor(EGFR)-ras pathway activation. Direct oncolysis plus granulocyte-macrophage colony-stimulating factor(GM-CSF) expression also stimulates shutdown of tumour vasculature and antitumoral immunity. Weaimed to assess intratumoral injection of JX-594 in patients with refractory primary or metastatic livercancer. METHODS Between Jan 4, 2006, and July 4, 2007, 14 patients with histologically confirmedrefractory primary or metastatic liver tumours (up to 10.9 cm total diameter) that were amenable toimage-guided intratumoral injections were enrolled into this non-comparative, open-label, phase Idose-escalation trial (standard 3x3 design; two to six patients for each dose with 12-18 estimated totalpatients). Patients received one of four doses of intratumoral JX-594 (10(8) plaque-forming units [pfu],3x10(8) pfu, 10(9) pfu, or 3x10(9) pfu) every 3 weeks at Dong-A University Hospital (Busan, SouthKorea). Patients were monitored after treatment for at least 48 h in hospital and for at least 4 weeks asout-patients. Adverse event-monitoring according to the National Cancer Institute Common ToxicityCriteria (version 3) and standard laboratory toxicity grading for haematology, liver and renal function,coagulation studies, serum chemistry, and urinalysis were done. The primary aims were to ascertain themaximum-tolerated dose (MTD) and safety of JX-594 treatment. Data were also collected onpharmacokinetics, pharmacodynamics, and efficacy. Analysis was per protocol. This study is registeredwith ClinicalTrials.gov, number NCT00629759. FINDINGS Of 22 patients with liver tumours who wereassessed for eligibility, eight patients did not meet inclusion criteria. Therefore, 14 patients, includingthose with hepatocellular, colorectal, melanoma, and lung cancer, were enrolled. Patients were heavilypretreated (5.6 previous treatments, SD 2.8, range 2.0-12.0) and had large tumours (7.0 cm diameter,SD 2.7, range 1.8-10.9). Patients received a mean of 3.4 (SD 2.2, range 1.0-8.0) cycles of JX-594. Allpatients were evaluable for toxicity. All patients experienced grade I-III flu-like symptoms, and four hadtransient grade I-III dose-related thrombocytopenia. Grade III hyperbilirubinaemia was dose-limiting inboth patients at the highest dose; the MTD was therefore 1x10(9) pfu. JX-594 replication-dependentdissemination in blood was shown, with resultant infection of non-injected tumour sites. GM-CSFexpression resulted in grade I-III increases in neutrophil counts in four of six patients at the MTD.Tumour responses were shown in injected and non-injected tumours. Ten patients were radiographicallyevaluable for objective responses; non-evaluable patients had contraindications to contrast medium(n=2) or no post-treatment scans (n=2). According to Response Evaluation Criteria in Solid Tumors(RECIST), three patients had partial response, six had stable disease, and one had progressive disease.INTERPRETATION Intratumoral injection of JX-594 into primary or metastatic liver tumours was generallywell-tolerated. Direct hyperbilirubinaemia was the dose-limiting toxicity. Safety was acceptable in thecontext of JX-594 replication, GM-CSF expression, systemic dissemination, and JX-594 had anti-tumoraleffects against several refractory carcinomas. Phase II trials are now underway.", "metadata": {}}
+{"_id": "38899659", "title": "", "text": "PTH Signaling in Osteoprogenitors Is Essential for B-Lymphocyte Differentiation and Mobilization.Cells ofthe osteoblast lineage provide critical support for B lymphopoiesis in the bone marrow (BM). Parathyroidhormone (PTH) signaling in osteoblastic cells through its receptor (PPR) is an important regulator ofhematopoietic stem cells; however, its role in regulation of B lymphopoiesis is not clear. Here wedemonstrate that deletion of PPR in osteoprogenitors results in a significant loss of trabecular and corticalbone. PPR signaling in osteoprogenitors, but not in mature osteoblasts or osteocytes, is critical for B-cellprecursor differentiation via IL-7 production. Interestingly, despite a severe reduction in B-cellprogenitors in BM, mature B-lymphocytes were increased 3.5-fold in the BM of mice lacking PPR inosteoprogenitors. This retention of mature IgD(+) B cells in the BM was associated with increasedexpression of vascular cell adhesion molecule 1 (VCAM1) by PPR-deficient osteoprogenitors, andtreatment with VCAM1 neutralizing antibody increased mobilization of B lymphocytes from mutant BM.Our results demonstrate that PPR signaling in early osteoblasts is necessary for B-cell differentiation viaIL-7 secretion and for B-lymphocyte mobilization via VCAM1.", "metadata": {}}
+{"_id": "38919140", "title": "", "text": "Snail coordinately regulates downstream pathways to control multiple aspects of mammalian neuralprecursor development.The Snail transcription factor plays a key role in regulating diverse developmentalprocesses but is not thought to play a role in mammalian neural precursors. Here, we have examinedradial glial precursor cells of the embryonic murine cortex and demonstrate that Snail regulates theirsurvival, self-renewal, and differentiation into intermediate progenitors and neurons via two distinct andseparable target pathways. First, Snail promotes cell survival by antagonizing a p53-dependent deathpathway because coincident p53 knockdown rescues survival deficits caused by Snail knockdown.Second, we show that the cell cycle phosphatase Cdc25b is regulated by Snail in radial precursors andthat Cdc25b coexpression is sufficient to rescue the decreased radial precursor proliferation anddifferentiation observed upon Snail knockdown. Thus, Snail acts via p53 and Cdc25b to coordinatelyregulate multiple aspects of mammalian embryonic neural precursor biology.", "metadata": {}}
+{"_id": "38944245", "title": "", "text": "Endothelial KLF2 links local arterial shear stress levels to the expression of vascular tone-regulatinggenes.Lung Krüppel-like factor (LKLF/KLF2) is an endothelial transcription factor that is crucially involvedin murine vasculogenesis and is specifically regulated by flow in vitro. We now show a relation to localflow variations in the adult human vasculature: decreased LKLF expression was noted at the aortabifurcations to the iliac and carotid arteries, coinciding with neointima formation. The direct involvementof shear stress in the in vivo expression of LKLF was determined independently by in situ hybridizationand laser microbeam microdissection/reverse transcriptase-polymerase chain reaction in a murine carotidartery collar model, in which a 4- to 30-fold induction of LKLF occurred at the high-shear sites. Dissectionof the biomechanics of LKLF regulation in vitro demonstrated that steady flow and pulsatile flow inducedbasal LKLF expression 15- and 36-fold at shear stresses greater than approximately 5 dyne/cm2,whereas cyclic stretch had no effect. Prolonged LKLF induction in the absence of flow changed theexpression of angiotensin-converting enzyme, endothelin-1, adrenomedullin, and endothelial nitric oxidesynthase to levels similar to those observed under prolonged flow. LKLF repression by siRNA suppressedthe flow response of endothelin-1, adrenomedullin, and endothelial nitric oxide synthase (P < 0.05).Thus, we demonstrate that endothelial LKLF is regulated by flow in vivo and is a transcriptional regulatorof several endothelial genes that control vascular tone in response to flow.", "metadata": {}}
+{"_id": "39048693", "title": "", "text": "Synapsin I Cre transgene expression in male mice produces germline recombination in progeny.Thecre/LoxP system can produce conditional loss of gene function in specific cell types such as neurons. Atransgenic mouse line, utilized by multiple studies, used the Synapsin I promoter to drive expression ofcre (SynCre) to achieve neuronal-specific cre expression. Herein we describe that cre expression can alsobe observed in SynCre mice within the testes after being bred into a floxed transgenic mouse line. Cretranscript was expressed in testes resulting in recombination of the floxed substrate in testes. In themajority of cases, progeny of male SynCre mice inherited a germline recombined floxed allele, while thiswas never observed in progeny from female mice carrying the SynCre allele. This observation should alertinvestigators to a potential confound using these mice and enables male germ cell \"deletor\" strategies.", "metadata": {}}
+{"_id": "39059143", "title": "", "text": "Hospital mortality, length of stay, and preventable complications among critically ill patients before andafter tele-ICU reengineering of critical care processes.CONTEXT The association of an adult tele-intensivecare unit (ICU) intervention with hospital mortality, length of stay, best practice adherence, andpreventable complications for an academic medical center has not been reported. OBJECTIVE To quantifythe association of a tele-ICU intervention with hospital mortality, length of stay, and complications thatare preventable by adherence to best practices. DESIGN, SETTING, AND PATIENTS Prospectivestepped-wedge clinical practice study of 6290 adults admitted to any of 7 ICUs (3 medical, 3 surgical, and1 mixed cardiovascular) on 2 campuses of an 834-bed academic medical center that was performed fromApril 26, 2005, through September 30, 2007. Electronically supported and monitored processes for bestpractice adherence, care plan creation, and clinician response times to alarms were evaluated. MAINOUTCOME MEASURES Case-mix and severity-adjusted hospital mortality. Other outcomes includedhospital and ICU length of stay, best practice adherence, and complication rates. RESULTS The hospitalmortality rate was 13.6% (95% confidence interval [CI], 11.9%-15.4%) during the preinterventionperiod compared with 11.8% (95% CI, 10.9%-12.8%) during the tele-ICU intervention period (adjustedodds ratio [OR], 0.40 [95% CI, 0.31-0.52]). The tele-ICU intervention period compared with thepreintervention period was associated with higher rates of best clinical practice adherence for theprevention of deep vein thrombosis (99% vs 85%, respectively; OR, 15.4 [95% CI, 11.3-21.1]) andprevention of stress ulcers (96% vs 83%, respectively; OR, 4.57 [95% CI, 3.91-5.77], best practiceadherence for cardiovascular protection (99% vs 80%, respectively; OR, 30.7 [95% CI, 19.3-49.2]),prevention of ventilator-associated pneumonia (52% vs 33%, respectively; OR, 2.20 [95% CI,1.79-2.70]), lower rates of preventable complications (1.6% vs 13%, respectively, forventilator-associated pneumonia [OR, 0.15; 95% CI, 0.09-0.23] and 0.6% vs 1.0%, respectively, forcatheter-related bloodstream infection [OR, 0.50; 95% CI, 0.27-0.93]), and shorter hospital length ofstay (9.8 vs 13.3 days, respectively; hazard ratio for discharge, 1.44 [95% CI, 1.33-1.56]). The resultsfor medical, surgical, and cardiovascular ICUs were similar. CONCLUSION In a single academic medicalcenter study, implementation of a tele-ICU intervention was associated with reduced adjusted odds ofmortality and reduced hospital length of stay, as well as with changes in best practice adherence andlower rates of preventable complications.", "metadata": {}}
+{"_id": "39084565", "title": "", "text": "CD11b+ monocytes abrogate Th17 CD4+ T cell-mediated experimental autoimmunemyocarditis.Experimental autoimmune myocarditis (EAM) represents a Th17 T cell-mediated mousemodel of postinflammatory heart disease. In BALB/c wild-type mice, EAM is a self-limiting disease,peaking 21 days after alpha-myosin H chain peptide (MyHC-alpha)/CFA immunization and largelyresolving thereafter. In IFN-gammaR(-/-) mice, however, EAM is exacerbated and shows a chronicprogressive disease course. We found that this progressive disease course paralleled persistentlyelevated IL-17 release from T cells infiltrating the hearts of IFN-gammaR(-/-) mice 30 days afterimmunization. In fact, IL-17 promoted the recruitment of CD11b(+) monocytes, the majorheart-infiltrating cells in EAM. In turn, CD11b(+) monocytes suppressed MyHC-alpha-specific Th17 T cellresponses IFN-gamma-dependently in vitro. In vivo, injection of IFN-gammaR(+/+)CD11b(+), but notIFN-gammaR(-/-)CD11b(+), monocytes, suppressed MyHC-alpha-specific T cells, and abrogated theprogressive disease course in IFN-gammaR(-/-) mice. Finally, coinjection of MyHC-alpha-specific, but notOVA-transgenic, IFN-gamma-releasing CD4(+) Th1 T cell lines, together with MyHC-alpha-specific Th17 Tcells protected RAG2(-/-) mice from EAM. In conclusion, CD11b(+) monocytes play a dual role in EAM: asa major cellular substrate of IL-17-induced inflammation and as mediators of an IFN-gamma-dependentnegative feedback loop confining disease progression.", "metadata": {}}
+{"_id": "39128592", "title": "", "text": "The cytokine RANKL produced by positively selected thymocytes fosters medullary thymic epithelial cellsthat express autoimmune regulator.The thymic medulla provides a microenvironment where medullarythymic epithelial cells (mTECs) express autoimmune regulator and diverse tissue-restricted genes,contributing to launching self-tolerance. Positive selection is essential for thymic medulla formation via apreviously unknown mechanism. Here we show that the cytokine RANK ligand (RANKL) was produced bypositively selected thymocytes and regulated the cellularity of mTEC by interacting with RANK andosteoprotegerin. Forced expression of RANKL restored thymic medulla in mice lacking positive selection,whereas RANKL perturbation impaired medulla formation. These results indicate that RANKL produced bypositively selected thymocytes is responsible for fostering thymic medulla formation, thereby establishingcentral tolerance.", "metadata": {}}
+{"_id": "39164524", "title": "", "text": "Fibrosis and adipogenesis originate from a common mesenchymal progenitor in skeletalmuscle.Accumulation of adipocytes and collagen type-I-producing cells (fibrosis) is observed in musculardystrophies. The origin of these cells had been largely unknown, but recently we identified mesenchymalprogenitors positive for platelet-derived growth factor receptor alpha (PDGFRα) as the origin ofadipocytes in skeletal muscle. However, the origin of muscle fibrosis remains largely unknown. In thisstudy, clonal analyses show that PDGFRα(+) cells also differentiate into collagen type-I-producing cells.In fact, PDGFRα(+) cells accumulated in fibrotic areas of the diaphragm in the mdx mouse, a model ofDuchenne muscular dystrophy. Furthermore, mRNA of fibrosis markers was expressed exclusively in thePDGFRα(+) cell fraction in the mdx diaphragm. Importantly, TGF-β isoforms, known as potent profibroticcytokines, induced expression of markers of fibrosis in PDGFRα(+) cells but not in myogenic cells.Transplantation studies revealed that fibrogenic PDGFRα(+) cells mainly derived from pre-existingPDGFRα(+) cells and that the contribution of PDGFRα(-) cells and circulating cells was limited. Theseresults indicate that mesenchymal progenitors are the main origin of not only fat accumulation but alsofibrosis in skeletal muscle.", "metadata": {}}
+{"_id": "39174007", "title": "", "text": "The pecking order of free radicals and antioxidants: lipid peroxidation, alpha-tocopherol, andascorbate.Free radicals vary widely in their thermodynamic properties, ranging from very oxidizing tovery reducing. These thermodynamic properties can be used to predict a pecking order, or hierarchy, forfree radical reactions. Using one-electron reduction potentials, the predicted pecking order is inagreement with experimentally observed free radical electron (hydrogen atom) transfer reactions. Thesepotentials are also in agreement with experimental data that suggest that vitamin E, the primary lipidsoluble small molecule antioxidant, and vitamin C, the terminal water soluble small molecule antioxidant,cooperate to protect lipids and lipid structures against peroxidation. Although vitamin E is located inmembranes and vitamin C is located in aqueous phases, vitamin C is able to recycle vitamin E; i.e.,vitamin C repairs the tocopheroxyl (chromanoxyl) radical of vitamin E, thereby permitting vitamin E tofunction again as a free radical chain-breaking antioxidant. This review discusses: (i) the thermodynamicsof free radical reactions that are of interest to the health sciences; (ii) the fundamental thermodynamicand kinetic properties that are associated with chain-breaking antioxidants; (iii) the unique interfacialnature of the apparent reaction of the tocopherol free radical (vitamin E radical) and vitamin C; and (iv)presents a hierarchy, or pecking order, for free radical electron (hydrogen atom) transfer reactions.", "metadata": {}}
+{"_id": "39187170", "title": "", "text": "Mitochondrial respiration in subcutaneous and visceral adipose tissue from patients with morbidobesity.Adipose tissue exerts important endocrine and metabolic functions in health and disease. Yet thebioenergetics of this tissue is not characterized in humans and possible regional differences are notelucidated. Using high resolution respirometry, mitochondrial respiration was quantified in humanabdominal subcutaneous and intra-abdominal visceral (omentum majus) adipose tissue from biopsiesobtained in 20 obese patients undergoing bariatric surgery. Mitochondrial DNA (mtDNA) and genomicDNA (gDNA) were determined by the PCR technique for estimation of mitochondrial density. Adiposetissue samples were permeabilized and respirometric measurements were performed in duplicate at 37degrees C. Substrates (glutamate (G) + malate (M) + octanoyl carnitine (O) + succinate (S)) were addedsequentially to provide electrons to complex I + II. ADP ((D)) for state 3 respiration was added after GM.Uncoupled respiration was measured after addition of FCCP. Visceral fat contained more mitochondria permilligram of tissue than subcutaneous fat, but the cells were smaller. Robust, stable oxygen fluxes werefound in both tissues, and coupled state 3 (GMOS(D)) and uncoupled respiration were significantly (P <0.05) higher in visceral (0.95 +/- 0.05 and 1.15 +/- 0.06 pmol O(2) s(1) mg(1), respectively) comparedwith subcutaneous (0.76 +/- 0.04 and 0.98 +/- 0.05 pmol O(2) s(1) mg(1), respectively) adipose tissue.Expressed per mtDNA, visceral adipose tissue had significantly (P < 0.05) lower mitochondrialrespiration. Substrate control ratios were higher and uncoupling control ratio lower (P < 0.05) in visceralcompared with subcutaneous adipose tissue. We conclude that visceral fat is bioenergetically more activeand more sensitive to mitochondrial substrate supply than subcutaneous fat. Oxidative phosphorylationhas a higher relative activity in visceral compared with subcutaneous adipose tissue.", "metadata": {}}
+{"_id": "39225849", "title": "", "text": "Endogenous gamma-H2AX-ATM-Chk2 checkpoint activation in Bloom's syndrome helicase deficient cellsis related to DNA replication arrested forks.The Bloom syndrome helicase (BLM) is critical for genomicstability. A defect in BLM activity results in the cancer-predisposing Bloom syndrome (BS). Here, wereport that BLM-deficient cell lines and primary fibroblasts display an endogenously activated DNAdouble-strand break checkpoint response with prominent levels of phosphorylated histone H2AX(gamma-H2AX), Chk2 (p(T68)Chk2), and ATM (p(S1981)ATM) colocalizing in nuclear foci. Interestingly,the mitotic fraction of gamma-H2AX foci did not seem to be higher in BLM-deficient cells, indicating thatthese lesions form transiently during interphase. Pulse labeling with iododeoxyuridine andimmunofluorescence microscopy showed the colocalization of gamma-H2AX, ATM, and Chk2 togetherwith replication foci. Those foci costained for Rad51, indicating homologous recombination at thesereplication sites. We therefore analyzed replication in BS cells using a single molecule approach oncombed DNA fibers. In addition to a higher frequency of replication fork barriers, BS cells displayed areduced average fork velocity and global reduction of interorigin distances indicative of an elevatedfrequency of origin firing. Because BS is one of the most penetrant cancer-predisposing hereditarydiseases, it is likely that the lack of BLM engages the cells in a situation similar to precancerous tissueswith replication stress. To our knowledge, this is the first report of high ATM-Chk2 kinase activation andits linkage to replication defects in a BS model.", "metadata": {}}
+{"_id": "39264456", "title": "", "text": "Impact of TNF-alpha and IL-6 levels on development of cachexia in newly diagnosed NSCLCpatients.OBJECTIVES We investigated the role of cytokines tumor necrosis factor-alpha (TNF-alpha) andinterleukin-6 (IL-6) in cachexia development in newly diagnosed nonsmall cell lung cancer (NSCLC)patients. METHODS : We evaluated 44 (M/F:41/3) NSCLC patients and 12 (M/F:10/2) age matchedhealthy smokers. NSCLC cases with a weight loss of > or =10% consisted the cachectic group (n:23,M/F:21/2) and the ones with <10% weight loss consisted the noncachectic group (n:21, M/F:19/2).RESULTS Body mass index (BMI) of cachectics was significantly lower than that of noncachectics (21.0+/- 2.9 versus 24.5 +/- 3.6, P = 0.02) and controls (21.0 +/- 2.9 versus 25.5 +/- 2.6, P = 0.01). SerumTNF-alpha level did not differ between cachectic and noncachectics (37.3 +/- 39.1 and 51.6 +/- 84.2pg/mL, respectively). However, it was significantly higher in NSCLC patients compared with controls(44.1 +/- 64.3 and 15.1 +/- 14.3 pg/mL, P = 0.03). Serum IL-6 level was not different between 3 groups(6.4 +/- 4.1, 8.9 +/- 16.3, and 4.1 +/- 3.5 pg/mL, respectively) but it correlated significantly withTNF-alpha (r = 0.4, P = 0.006) and BMI (r = -0.3, P = 0.03). Erythrocyte sedimentation rate (ESR)correlated significantly with TNF-alpha (r = 0.4, P = 0.003) and BMI (r = -0.3, P = 0.03). Among 44cases, survival of 12 and 17 patients was recorded in cachectics and noncachectics, with no statisticaldifference (12.2 +/- 3.7 and 11.2 +/- 1.0 months, respectively). CONCLUSIONS TNF-alpha and IL-6levels did not differ significantly between cachectics and noncachectics. However, significant correlationsbetween IL-6, BMI, and TNF-alpha suggested that these cytokines acted as cofactors in weight loss.Survival was neither influenced by BMI, nor the cytokine levels in the present study. The significantcorrelation of ESR with TNF-alpha suggested that ESR could provide valuable clue for considerable weightloss in the follow-up of NSCLC patients.", "metadata": {}}
+{"_id": "39281140", "title": "", "text": "Treatment of antidepressant-associated sexual dysfunction with sildenafil: a randomized controlledtrial.CONTEXT Sexual dysfunction is a common adverse effect of antidepressants that frequently resultsin treatment noncompliance. OBJECTIVE To assess the efficacy of sildenafil citrate in men with sexualdysfunction associated with the use of selective and nonselective serotonin reuptake inhibitor (SRI)antidepressants. DESIGN, SETTING, AND PATIENTS Prospective, parallel-group, randomized,double-blind, placebo-controlled trial conducted between November 1, 2000, and January 1, 2001, at 3US university medical centers among 90 male outpatients (mean [SD] age, 45 [8] years) with majordepression in remission and sexual dysfunction associated with SRI antidepressant treatment.INTERVENTION Patients were randomly assigned to take sildenafil (n = 45) or placebo (n = 45) at aflexible dose starting at 50 mg and adjustable to 100 mg before sexual activity for 6 weeks. MAINOUTCOME MEASURES The primary outcome measure was score on the Clinical Global Impression-SexualFunction (CGI-SF); secondary measures were scores on the International Index of Erectile Function,Arizona Sexual Experience Scale, Massachusetts General Hospital-Sexual Functioning Questionnaire, andHamilton Rating Scale for Depression (HAM-D). RESULTS Among the 90 randomized patients, 93%(83/89) of patients treated per protocol took at least 1 dose of study drug and 85% (76/89) completedweek 6 end-point assessments with last observation carried forward analyses. At a CGI-SF score of 2 orlower, 54.5% (24/44) of sildenafil compared with 4.4% (2/45) of placebo patients were much or verymuch improved (P<.001). Erectile function, arousal, ejaculation, orgasm, and overall satisfaction domainmeasures improved significantly in sildenafil compared with placebo patients. Mean depression scoresremained consistent with remission (HAM-D score < or =10) in both groups for the study duration.CONCLUSION In our study, sildenafil effectively improved erectile function and other aspects of sexualfunction in men with sexual dysfunction associated with the use of SRI antidepressants. Theseimprovements may allow patients to maintain adherence with effective antidepressant treatment.", "metadata": {}}
+{"_id": "39281166", "title": "", "text": "Noncoding transcription at enhancers: general principles and functional models.Mammalian genomes areextensively transcribed outside the borders of protein-coding genes. Genome-wide studies recentlydemonstrated that cis-regulatory genomic elements implicated in transcriptional control, such asenhancers and locus-control regions, represent major sites of extragenic noncoding transcription.Enhancer-templated transcripts provide a quantitatively small contribution to the total amount of cellularnonribosomal RNA; nevertheless, the possibility that enhancer transcription and the resulting enhancerRNAs may, in some cases, have functional roles, rather than represent mere transcriptional noise ataccessible genomic regions, is supported by an increasing amount of experimental data. In this article wereview the current knowledge on enhancer transcription and its functional implications.", "metadata": {}}
+{"_id": "39285547", "title": "", "text": "Microarray analysis of pneumococcal gene expression during invasive disease.Streptococcus pneumoniaeis a leading cause of invasive bacterial disease. This is the first study to examine the expression of S.pneumoniae genes in vivo by using whole-genome microarrays available from The Institute for GenomicResearch. Total RNA was collected from pneumococci isolated from infected blood, infected cerebrospinalfluid, and bacteria attached to a pharyngeal epithelial cell line in vitro. Microarray analysis ofpneumococcal genes expressed in these models identified body site-specific patterns of expression forvirulence factors, transporters, transcription factors, translation-associated proteins, metabolism, andgenes with unknown function. Contributions to virulence predicted for several unknown genes withenhanced expression in vivo were confirmed by insertion duplication mutagenesis and challenge of micewith the mutants. Finally, we cross-referenced our results with previous studies that usedsignature-tagged mutagenesis and differential fluorescence induction to identify genes that arepotentially required by a broad range of pneumococcal strains for invasive disease.", "metadata": {}}
+{"_id": "39291138", "title": "", "text": "Integration of Smad and MAPK pathways: a link and a linker revisited.Cells develop by reading mixedsignals. Nowhere is this clearer than in the highly dynamic processes that propel embryogenesis, whencritical cell-fate decisions are made swiftly in response to well-orchestrated growthfactor combinations.Learning how diverse signaling pathways are integrated is therefore essential for understandingphysiology. This requires the identification, in tangible molecular terms, of key nodes for pathwayintegration that operate in vivo. A report in this issue, on the integration of Smad and Ras/MAPKpathways during neural induction (Pera et al. 2003), provides timely insights into the relevance of onesuch node. Pera et al. (2003) report that FGF8 and IGF2—two growth factors that activate the Ras/MAPKpathway— favor neural differentiation and mesoderm dorsalization in Xenopus by inhibiting BMP (BoneMorphogenetic Protein) signaling. Mesoderm is formed from ectoderm in response to Nodal-relatedsignals from the endoderm at the blastula stage and beyond (Fig. 1; for review, see De Robertis et al.2000). BMP induces differentiation of ectoderm into epidermal cell fates at the expense of neural fates,and it ventralizes the mesoderm at the expense of dorsal fates (for review, see Weinstein andHemmatiBrivanlou 1999; De Robertis et al. 2000). Accordingly, neural differentiation and dorsalmesoderm formation are favored when BMP signaling is attenuated. Noggin, Chordin, Cerberus, andFollistatin, secreted by the Spemann organizer on the dorsal side at the gastrula stage, facilitate theformation of neural tissue by sequestering BMP (Weinstein and Hemmati-Brivanlou 1999; De Robertis etal. 2000). Experimentally blocking BMP signaling with a dominant-negative BMP receptor has a similareffect of promoting ectoderm neuralization (Weinstein and Hemmati-Brivanlou 1999). As it turns out,neural induction can also be achieved with FGF (fibroblast growth factor; Kengaku and Okamoto 1993;Lamb and Harland 1995; Hongo et al. 1999; Hardcastle et al. 2000; Streit et al. 2000; Wilson et al.2000) and IGF (insulin-like growth factor; Pera et al. 2001; Richard-Parpaillon et al. 2002). Injection oftranscripts encoding FGF8 or IFG2 into one animal-pole blastomere of a fourto eight-cell embryo resultsin an expanded neural plate at the injected side (Pera et al. 2003). Surprisingly, expression of adominant-negative FGF receptor prevents neuralization of ectoderm explants by the BMP blocker Noggin(Launay et al. 1996). Likewise, the potent neuralizing effect of Chordin can be blocked by adominant-negative FGF receptor or a morpholino oligonucleotide targeting the IGF receptor (Pera et al.2003). Thus, the neuralizing effect of BMP inhibitors is somehow tied to FGF and IFG signaling. Thequestion is, how? Because FGF8 and IFG2 activate MAPK, Pera et al. (2003) took heed from previouswork showing that MAPK inhibits the BMP signal-transduction factor Smad1 (Kretzschmar et al. 1997a).Smad1 is directly phosphorylated by the BMP receptor, resulting in Smad1 activation (Kretzschmar et al.1997b), and by MAPK in response to EGF, resulting in Smad1 inhibition (Kretzschmar et al. 1997a; Fig.2). Smad transcription factors mediate gene responses to the entire TGF (Transforming Growth Factor)family, to which the BMPs belong (for review, see Massague 2000; Derynck and Zhang 2003). Smads 1,5, and 8 act primarily downstream of BMP receptors and Smads 2 and 3 downstream of TGF , Activin andNodal receptors. Smad proteins have two conserved globular domains—the MH1 and MH2 domains (Fig.2). The MH1 domain is involved in DNA binding and the MH2 domain in binding to cytoplasmic retentionfactors, activated receptors, nucleoporins in the nuclear pore, and DNA-binding cofactors, coactivators,and corepressors in the nucleus (for review, see Shi and Massague 2003). Receptor-mediatedphosphorylation occurs at the carboxy-terminal sequence SXS. This enables the nuclear accumulation ofSmads and their association with the shared partner Smad4 to form transcriptional complexes that areinterpreted by the cell as a function of the context (Massague 2000). Between the MH1 and MH2 domainslies a linker region of variable sequence and length. Attention was drawn to this region when it was foundthat EGF (epidermal growth factor), a classical activator of the Ras/ MAPK pathway, causesphosphorylation of the Smad1 linker at four MAPK sites (PXSP sequences; Kretzschmar et al. 1997a).This prevents the nuclear localization of Smad1 and inhibits BMP signaling. Mutation of these E-MAILj-massague@ski.mskcc.org; FAX (212) 717-3298. Article and publication are athttp://www.genesdev.org/cgi/doi/10.1101/ gad.1167003.", "metadata": {}}
+{"_id": "39300105", "title": "", "text": "A brief analysis of clinical pharmacy interventions undertaken in an Australian teaching hospital.Selectedclinical pharmacy interventions undertaken during a 30-day data capture period were analysed, seekingto gain a greater understanding of the nature of the drug-related problems involved. Pharmacists wereasked to record only interventions that were of potentially major significance. A total of 67 interventionswere submitted for analysis. In 28 cases (41.7% of the initial total) the intervention reports wereexcluded from further analysis after initial review. For the remaining 39 interventions, 20 patients (51%)were under the care of a medical unit, and cardiovascular/antithrombotic agents accounted for 17 reports(43.5%). The majority of interventions were implemented at the time of inpatient medication orderreview by the clinical pharmacist (n=25, 64%). The most common category of drug-related problemaddressed in the interventions related to the prescription of inappropriately high doses of the correct drugfor the patient (n=17, 43.6%). Deficiencies in technical knowledge accounted for less than 25% of allcases.", "metadata": {}}
+{"_id": "39304380", "title": "", "text": "Lethal complications of typhoid-cholera-vaccination. (Case report and review of theliterature).Simultaneous parenteral vaccination against typhoid and cholera lead to death through eitheranaphylactic shock or endotoxic shock in a 36-year-old male. At autopsy the charactertic features ofshock as well as chronic interstitial myocarditis were noted. Moreover, fresh histiocytic and lymphocyticnodules were found in the liver, heart and meninges. A review of the literature dealing with lethalcomplications following parenteral tyhoid vaccinations shows an increased risk in debilitated persons(emaciation, stress, cold). Most of the fatalities occurred in persons who had previous disturbances of thecardiovascular system, as in the case reviewed here. Cardiac failure, Landry's paralysis, renal failure anddisturbances of skin, joints and intestines may also follow typhoid vaccinations. However, these lattercomplications are usually not lethal. The patients presented here had many of the conditions which areknown to aggravate the situation and to lead to a lethal culmination. The review of this case and thedisucussion following it shows that only healthy persons should receive the parenteral typhoidvaccination. Hopefully, the presentation of this material will help prevent fatalities of this type in thefuture.", "metadata": {}}
+{"_id": "39326723", "title": "", "text": "Functional genomics and proteomics approaches to study the ERBB network in cancer.Substantialprogress in functional genomic and proteomic technologies has opened new perspectives in biomedicalresearch. The sequence of the human genome has been mostly determined and opened new visions onits complexity and regulation. New technologies, like RNAi and protein arrays, allow gathering knowledgebeyond single gene analysis. Increasingly, biological processes are studied with systems biologicalapproaches, where qualitative and quantitative data of the components are utilized to model therespective processes, to predict effects of perturbations, and to then refine these models afterexperimental testing. Here, we describe the potential of applying functional genomics and proteomics,taking the ERBB family of growth-factor receptors as an example to study the signaling network and itsimpact on cancer.", "metadata": {}}
+{"_id": "39334724", "title": "", "text": "Evaluation of spatial filters to create smoothed maps of health data.Spatial filters have been used as aneasy and intuitive way to create smoothed disease maps. Birth weight data from New York State for 1994and 1995 are used to compare the traditional filter type of fixed geographical size with a filter size ofconstant or nearly constant population size. The latter are more appropriate for mapping disease ingeographic areas with widely varying population density, such as New York State. Issues such as thechoice of population size for the filter, the scale of smoothing, the ability to detect true spatial variationand the ability to smooth over random spatial noise are evaluated and discussed.", "metadata": {}}
+{"_id": "39368721", "title": "", "text": "Glucose tolerance and blood pressure: long term follow up in middle aged men.OBJECTIVE to investigatethe role of glucose tolerance in the development of hypertension. DESIGN Retrospective analysis of theresults of a health check up in a group of clinically healthy middle aged men in the late 1960s (medianyear 1968). The subjects were invited to enter into a primary prevention trial for cardiovascular diseasein 1974, when they underwent clinical examination for risk factors. The trial was completed in 1979,when the men were re-examined. Follow up was in 1986. SETTING Institute of Occupational Health,Helsinki, Finland and second department of medicine, University of Helsinki. SUBJECTS In all, 3490 menborn during 1919-34 participated in a health check up in the late 1960s. In 1974, 1815 of these men whowere clinically healthy were entered into a primary prevention trial for cardiovascular disease. On clinicalexamination 1222 of the men were considered at high risk of cardiovascular disease. Of these, 612received an intervention and were excluded from the study. A total of 593 men were without risk factors.The study comprised all of the men who did not have an intervention (n = 1203). In 1979, 1120 menwere re-examined, and in 1986 945 men attended follow up. There were two groups for analysis: onecomprising all subjects and the other comprising only men who were normotensive in 1968 and for whomcomplete information was available. INTERVENTIONS By 1979, 103 men were taking antihypertensivedrugs, and by 1986, 131 were taking antihypertensive drugs and 12 were taking drugs forhyperglycaemia. MAIN OUTCOME MEASURES Blood glucose concentration one hour after a glucose load,blood pressure, and body weight were measured in 1968, 1974, and 1979. In 1986 blood pressure andbody weight were recorded. RESULTS Men who were hypertensive in 1986 had significantly higher bloodpressures (p less than 0.0001) and (after adjustment for body mass index and alcohol intake)significantly higher blood glucose concentrations one hour after a glucose load at all examinations thanthose who were normotensive in 1986. Regression analysis showed that the higher the blood glucoseconcentration after a glucose load in 1968 the higher the blood pressure during the following years.Those men between the second and third tertiles of blood glucose concentration in 1968 had asignificantly higher risk of developing hypertension (odds ratio 1.71, 95% confidence interval 1.05 to2.77) compared with those below the first tertile. CONCLUSION In this study men who developedhypertension tended to have shown an increased intolerance to glucose up to 18 years before the clinicalmanifestation of their disorder. Blood glucose concentration one hour after a glucose load was anindependent predictor of future hypertension.", "metadata": {}}
+{"_id": "39381118", "title": "", "text": "At the gates of death.Apoptosis that proceeds via the mitochondrial pathway involves mitochondrial outermembrane permeabilization (MOMP), responsible for the release of cytochrome c and other proteins ofthe mitochondrial intermembrane space. This essential step is controlled and mediated by proteins of theBcl-2 family. The proapoptotic proteins Bax and Bak are required for MOMP, while the antiapoptotic Bcl-2proteins, including Bcl-2, Bcl-xL, Mcl-1, and others, prevent MOMP. Different proapoptotic BH3-onlyproteins act to interfere with the function of the antiapoptotic Bcl-2 members and/or activate Bax andBak. Here, we discuss an emerging view, proposed by Certo et al. in this issue of Cancer Cell, on howthese interactions result in MOMP and apoptosis.", "metadata": {}}
+{"_id": "39389082", "title": "", "text": "Structure of human RNase H1 complexed with an RNA/DNA hybrid: insight into HIV reversetranscription.We report here crystal structures of human RNase H1 complexed with an RNA/DNAsubstrate. Unlike B. halodurans RNase H1, human RNase H1 has a basic protrusion, which forms aDNA-binding channel and together with the conserved phosphate-binding pocket confers specificity forthe B form and 2'-deoxy DNA. The RNA strand is recognized by four consecutive 2'-OH groups andcleaved by a two-metal ion mechanism. Although RNase H1 is overall positively charged, the substrateinterface is neutral to acidic in character, which likely contributes to the catalytic specificity. Positions ofthe scissile phosphate and two catalytic metal ions are interdependent and highly coupled. Modeling ofHIV reverse transcriptase (RT) with RNA/DNA in its RNase H active site suggests that the substratecannot simultaneously occupy the polymerase active site and must undergo a conformational change totoggle between the two catalytic centers. The region that accommodates this conformational changeoffers a target to develop HIV-specific inhibitors.", "metadata": {}}
+{"_id": "39390206", "title": "", "text": "A diffusion tensor magnetic resonance imaging study of brain tissue from patients withmigraine.OBJECTIVE To measure in vivo, using diffusion tensor magnetic resonance imaging (DT-MRI)the extent of pathological damage of normal appearing brain tissue (NABT) from patients with migraine.METHODS Dual echo and DT-MRI scans of the brain were acquired from 34 patients with migraine and 17sex and age matched healthy volunteers. Mean diffusivity (MD) and fractional anisotropy (FA) histogramsof the NABT were obtained from all subjects and the histograms' peak heights and average NABT MD andFA measured. When present, average MD and FA values of T2 visible lesions were also measured.RESULTS In comparison with healthy volunteers, patients with migraine had lower MD histogram peakheight (p=0.02) of the NABT. No differences were found in FA histogram derived metrics betweenmigraine patients and healthy subjects. No difference was found for any MD and FA histogram derivedmetrics between migraine patients with and without brain MRI lesions, and between patients with andwithout aura. CONCLUSIONS This study shows that, although brain damage may extend beyond T2weighted abnormalities in patients with migraine, the severity of these \"occult\" changes is mild comparedwith that found in other diseases associated with white matter abnormality.", "metadata": {}}
+{"_id": "39391953", "title": "", "text": "Determination of chloramphenicol residues in milk by enzyme-linked immunosorbent assay: improvementby biotin-streptavidin-amplified system.A sensitive biotin-streptavidin amplified enzyme-linkedimmunosorbent assay (BA-ELISA) method was developed for the determination of chloramphenicolresidues in milk. The biotin-streptavidin system was applied to enhance the sensitivity. Afteroptimization, the detection limit of the method was found to be 0.042 +/- 0.006 ng mL(-1), which is8-fold more sensitive than the traditional competitive ELISA using the same antibody and coatingantigen. The amplification mechanism of the biotin-streptavidin system and the major factors affectingthe sensitivity of detection are discussed. This method was successfully applied to determine thechloramphenicol residues in milk samples with a simple and rapid extraction procedure, and goodrecoveries (85.66-109.67%) were obtained. The result indicated that the biotin-streptavidin system maybe a valuable tool to improve the specific detection of trace veterinary drug residues and could be widelyused for routine monitoring of food samples.", "metadata": {}}
+{"_id": "39424916", "title": "", "text": "Wedelolactone exhibits anti-fibrotic effects on human hepatic stellate cell line LX-2.Wedelolactone is amajor coumarin of Eclipta prostrata, which is used for preventing liver damage. However the effects ofwedelolactone on hepatic fibrosis remained unexplored. The purpose of this study was to demonstrate theanti-fibrotic effects of wedelolactone on activated human hepatic stellate cell (HSC) line LX-2 and thepossible underlying mechanisms by means of MTT assay, Hoechst staining, as well as real-timequantitative PCR and western blot. The results showed that wedelolactone reduced the cellular viability ofLX-2 in a time and dose-dependent manner. After treatment of wedelolactone, the expressions ofcollagen I and α-smooth muscle actin, two biomarkers of LX-2 activation, were remarkably decreased.The apoptosis of LX-2 cells was induced by wedelolactone accompanied with the decreasing expression ofanti-apoptotic Bcl-2 and increasing expression of pro-apoptotic Bax. In addition, phosphorylated status ofextracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) was up-regulated, but notin p38. Moreover, wedelolactone significantly repressed the level of phosphorylated inhibitor of nuclearfactor κB (IκB) and p65 in nucleus in spite of tumor necrosis factor-α stimulation. In conclusion,wedelolactone could significantly inhibit the activation of LX-2 cells, the underlying mechanisms of whichincluded inducing Bcl-2 family involved apoptosis, up-regulating phosphorylated status of ERK and JNKexpressions, and inhibiting nuclear factor-κB (NF-κB) mediated activity. Wedelolactone might present asa useful tool for the prevention and treatment of hepatic fibrosis.", "metadata": {}}
+{"_id": "39426225", "title": "", "text": "Adipose stem cells originate from perivascular cells.Recent research has shown that adipose tissuescontain abundant MSCs (mesenchymal stem cells). The origin and location of the adipose stem cells,however, remain unknown, presenting an obstacle to the further purification and study of these cells. Inthe present study, we aimed at investigating the origins of adipose stem cells. α-SMA (α-smooth muscleactin) is one of the markers of pericytes. We harvested ASCs (adipose stromal cells) from α-SMA-GFP(green fluorescent protein) transgenic mice and sorted them into GFP-positive and GFP-negative cells byFACS. Multilineage differentiation tests were applied to examine the pluripotent ability of theα-SMA-GFP-positive and -negative cells. Immunofluorescent staining for α-SMA and PDGF-Rβ(platelet-derived growth factor receptor β) were applied to identify the α-SMA-GFP-positive cells. Thenα-SMA-GFP-positive cells were loaded on a collagen-fibronectin gel with endothelial cells to test theirvascularization ability both in vitro and in vivo. Results show that, in adipose tissue, all of theα-SMA-GFP-positive cells congregate around the blood vessels. Only the α-SMA-GFP-positive cells havemultilineage differentiation ability, while the α-SMA-GFP-negative cells can only differentiate in anadipogenic direction. The α-SMA-GFP-positive cells maintained expression of α-SMA during multilineagedifferentiation. The α-SMA-GFP-positive cells can promote the vascularization of endothelial cells inthree-dimensional culture both in vitro and in vivo. We conclude that the adipose stem cells originatefrom perivascular cells and congregate around blood vessels.", "metadata": {}}
+{"_id": "39443128", "title": "", "text": "Interferon alpha and zidovudine therapy in adult T-cell leukaemia lymphoma: response and outcome in15 patients.Adult T-cell leukaemia lymphoma (ATLL) is an aggressive disease caused by the humanT-lymphotropic virus 1 (HTLV-I) with a short survival. Responses to interferon alpha (IFN-alpha) andzidovudine (AZT) have been documented but not with long-term follow-up. We treated 15 ATLL patientswith IFN and AZT. Eleven patients had acute ATLL, two had lymphoma and two smouldering ATLL, withprogression. The main features were: organomegaly (14), skin lesions (10), high white blood cell (WBC)count (11) and hypercalcaemia (9). Eleven patients had previously received chemotherapy and one hadreceived an autograft. At the time of the study, seven patients had progressive disease and eight were inpartial or complete clinical remission. Responses (PR) lasting 2+ to 44+ months were seen in 67%; 26%did not respond (NR) and one patient was not evaluable. Hypercalcaemia predicted a poor outcome butdifferences were not significant. Eight of the 15 patients have died 3-41 months from diagnosis. Mediansurvival for the 15 patients was 18 months. Survival of the NR ranged from 4 to 20 months; six PRpatients are alive 8-82 months from diagnosis. The differences in survival between NR (median: 6months) and PR (55% of patients alive at 4 years) were statistically significant (P = 0.002). Inconclusion, IFN and AZT improves the outcome of ATLL patients and helps maintain responses.", "metadata": {}}
+{"_id": "39462488", "title": "", "text": "Replisome stalling and stabilization at CGG repeats, which are responsible for chromosomalfragilityExpanded CGG repeats cause chromosomal fragility and hereditary neurological disorders inhumans. Replication forks stall at CGG repeats in a length-dependent manner in primate cells and inyeast. Saccharomyces cerevisiae proteins Tof1 and Mrc1 facilitate replication fork progression throughCGG repeats. Remarkably, the fork-stabilizing role of Mrc1 does not involve its checkpoint function. Thus,chromosomal fragility might occur when forks stalled at expanded CGG repeats escape the S-phasecheckpoint.", "metadata": {}}
+{"_id": "39465575", "title": "", "text": "Direct reprogramming of fibroblasts into neural stem cells by defined factors.Recent studies have shownthat defined sets of transcription factors can directly reprogram differentiated somatic cells to a differentdifferentiated cell type without passing through a pluripotent state, but the restricted proliferative andlineage potential of the resulting cells limits the scope of their potential applications. Here we show that acombination of transcription factors (Brn4/Pou3f4, Sox2, Klf4, c-Myc, plus E47/Tcf3) induces mousefibroblasts to directly acquire a neural stem cell identity-which we term as induced neural stem cells(iNSCs). Direct reprogramming of fibroblasts into iNSCs is a gradual process in which the donortranscriptional program is silenced over time. iNSCs exhibit cell morphology, gene expression, epigeneticfeatures, differentiation potential, and self-renewing capacity, as well as in vitro and in vivo functionalitysimilar to those of wild-type NSCs. We conclude that differentiated cells can be reprogrammed directlyinto specific somatic stem cell types by defined sets of specific transcription factors.", "metadata": {}}
+{"_id": "39481265", "title": "", "text": "Epigenetics in lung fibrosis: from pathobiology to treatment perspective.PURPOSE OF REVIEW Idiopathicpulmonary fibrosis (IPF) is a fatal disease with limited treatment options and extensive gene expressionchanges identified in the lung parenchyma. Multiple lines of evidence suggest that epigenetic factorscontribute to dysregulation of gene expression in IPF lung. Most importantly, risk factors that predisposeto IPF - age, sex, cigarette smoke, and genetic variants - all influence epigenetic marks. This reviewsummarizes recent findings of association of DNA methylation and histone modifications with thepresence of disease and fibroproliferation. RECENT FINDINGS In addition to targeted studies focused onspecific gene loci, genome-wide profiles of DNA methylation demonstrate widespread DNA methylationchanges in IPF lung tissue and a substantial effect of these methylation changes on gene expression.Genetic loci that have been recently associated with IPF also contain differentially methylated regions,suggesting that genetic and epigenetic factors act in concert to dysregulate gene expression in IPF lung.SUMMARY Although we are in very early stages of understanding the role of epigenetics in IPF, thepotential for the use of epigenetic marks as biomarkers and therapeutic targets is high and discoveriesmade in this field will likely bring us closer to better prognosticating and treating this fatal disease.", "metadata": {}}
+{"_id": "39506601", "title": "", "text": "Novel roles for KLF1 in erythropoiesis revealed by mRNA-seq.KLF1 (formerly known as EKLF) regulatesthe development of erythroid cells from bi-potent progenitor cells via the transcriptional activation of adiverse set of genes. Mice lacking Klf1 die in utero prior to E15 from severe anemia due to the inadequateexpression of genes controlling hemoglobin production, cell membrane and cytoskeletal integrity, and thecell cycle. We have recently described the full repertoire of KLF1 binding sites in vivo by performing KLF1ChIP-seq in primary erythroid tissue (E14.5 fetal liver). Here we describe the KLF1-dependent erythroidtranscriptome by comparing mRNA-seq from Klf1(+/+) and Klf1(-/-) erythroid tissue. This has revealednovel target genes not previously obtainable by traditional microarray technology, and provided novelinsights into the function of KLF1 as a transcriptional activator. We define a cis-regulatory module boundby KLF1, GATA1, TAL1, and EP300 that coordinates a core set of erythroid genes. We also describe anovel set of erythroid-specific promoters that drive high-level expression of otherwise ubiquitouslyexpressed genes in erythroid cells. Our study has identified two novel lncRNAs that are dynamicallyexpressed during erythroid differentiation, and discovered a role for KLF1 in directing apoptotic geneexpression to drive the terminal stages of erythroid maturation.", "metadata": {}}
+{"_id": "39532074", "title": "", "text": "Self-assembling peptides optimize the post-traumatic milieu and synergistically enhance the effects ofneural stem cell therapy after cervical spinal cord injury.INTRODUCTION The hostile environment afterspinal cord injury (SCI) can compromise effects of regenerative therapies. We hypothesized thatoptimizing the post-traumatic environment with QL6 self-assembling peptides (SAPs) before neuralprecursor cell (NPC) transplantation would improve cell survival, differentiation and functional recovery.METHODS A total of 90 Wistar rats received a clip-compression SCI at C7. Within each of two study arms,animals were randomized into 5 groups (NPC, SAP, NPC+SAP, vehicle, and sham). SAPs and NPCs wereinjected into the spinal cord 1day and 14days post-injury, respectively. Animals received growth factorsover 7days and were immunosuppressed. Rats were sacrificed at 4weeks and sections of the cervicalspinal cord prepared for immunohistochemistry (first study arm). Neurological function was assessedweekly for 8weeks using a battery of behavioral tests. Nine weeks post-SCI, the corticospinal tract wasassessed using fiber-tracking (second arm). RESULTS SAP-treated animals had significantly moresurviving NPCs which showed increased differentiation to neurons and oligodendrocytes compared tocontrols. SAPs alone or in combination with NPCs resulted in smaller intramedullary cysts and largervolume of preserved tissue compared to other groups. The combined treatment group showed reducedastrogliosis and chondroitin sulfate proteoglycan deposition. Synaptic connectivity was increased in theNPC and combined treatment groups. Corticospinal tract preservation and behavioral outcomes improvedwith combinatorial treatment. CONCLUSION Injecting SAPs after SCI enhances subsequent NPC survival,integration and differentiation and improves functional recovery. STATEMENT OF SIGNIFICANCE Thehostile environment after spinal cord injury (SCI) can compromise effects of regenerative therapies. Wehypothesized that improving this environment with self-assembling peptides (SAPs) before neuralprecursor cell (NPC) transplantation would support their beneficial effects. SAPs assemble once injected,providing a supportive scaffold for repair and regeneration. We investigated this in a rat model of spinalcord injury. More NPCs survived in SAP-treated animals and these showed increased differentiationcompared to controls. SAPS alone or in combination with NPCs resulted in smaller cysts and largervolume of preserved tissue with the combined treatment also reducing scarring and improving behavioraloutcomes. Overall, injection of SAPs was shown to improve the efficacy of NPC treatment, a promisingfinding for those with SCIs.", "metadata": {}}
+{"_id": "39539647", "title": "", "text": "A direct role for IFN-gamma in regulation of Th1 cell development.IL-12 has been identified as a majorcytokine influencing the differentiation of CD4 cells to a Th1 phenotype, whereas a role for IFN-gamma iscontroversial. We investigated the interrelationship between IL-12 and IFN-gamma in promoting Th1responses using naive CD4 cells reactive with pigeon cytochrome c from TCR transgenics and memoryCD4 cells derived by in vivo priming with KLH. Without exogenous rIL-12 or rIFN-gamma, primary andmemory effectors induced by Ag or anti-CD3 and anti-CD28 secreted variable levels of IL-2 andIFN-gamma. The level of IFN-gamma secreted by effectors correlated with endogenous IFN-gammaproduced in primary cultures, and anti-IFN-gamma largely inhibited the development of effectorsproducing IFN-gamma. With optimal TCR stimulation and costimulation, endogenous IFN-gamma,without IL-12, was sufficient to elicit Th1 cells via an autocrine mechanism, whereas with suboptimalstimulation, exogenous rIFN-gamma or rIL-12 was required for Th1 development. However, rIL-12 wasmore effective than rIFN-gamma, partially because rIL-12 greatly enhanced autocrine production ofIFN-gamma, and optimal development of the Th1 phenotype was mediated by the synergistic actions ofboth cytokines. Thus, both IFN-gamma and IL-12 can independently regulate Th1 development, butbecause of IFN-gamma-mediated feedback, their relative contributions are determined by the conditionsof T cell stimulation. The extent of differentiation to a Th1 phenotype may, therefore, depend on theavailability of both APC-derived IL-12 and autocrine IFN-gamma consequent to the overall strength of Tcell stimulation.", "metadata": {}}
+{"_id": "39545358", "title": "", "text": "Neuregulin 1 promotes excitatory synapse development and function in GABAergicinterneurons.Neuregulin 1 (NRG1) and its receptor ErbB4 are both susceptibility genes of schizophrenia.However, little is known about the underlying mechanisms of their malfunction. Although ErbB4 isenriched in GABAergic interneurons, the role of NRG1 in excitatory synapse formation in these neuronsremains poorly understood. We showed that NRG1 increased both the number and size of PSD-95 punctaand the frequency and amplitude of miniature EPSCs (mEPSCs) in GABAergic interneurons, indicatingthat NRG1 stimulates the formation of new synapses and strengthens existing synapses. In contrast,NRG1 treatment had no effect on either the number or size of excitatory synapses in glutamatergicneurons, suggesting its synaptogenic effect is specific to GABAergic interneurons. Ecto-ErbB4 treatmentdiminished both the number and size of excitatory synapses, suggesting that endogenous NRG1 may becritical for basal synapse formation. NRG1 could stimulate the stability of PSD-95 in the manner thatrequires tyrosine kinase activity of ErbB4. Finally, deletion of ErbB4 in parvalbumin-positive interneuronsled to reduced frequency and amplitude of mEPSCs, providing in vivo evidence that ErbB4 is important inexcitatory synaptogenesis in interneurons. Together, our findings suggested a novel synaptogenic role ofNRG1 in excitatory synapse development, possibly via stabilizing PSD-95, and this effect is specific toGABAergic interneurons. In light of the association of the genes of both NRG1 and ErbB4 withschizophrenia and dysfunction of GABAergic system in this disorder, these results provide insight into itspotential pathological mechanism.", "metadata": {}}
+{"_id": "39550665", "title": "", "text": "Tolerance rather than immunity protects from Helicobacter pylori-induced gastricpreneoplasia.BACKGROUND & AIMS Chronic infection with the bacterial pathogen Helicobacter pyloricauses gastric disorders, ranging from chronic gastritis to gastric adenocarcinoma. Only a subset ofinfected persons will develop overt disease; most remains asymptomatic despite lifelong colonization.This study aims to elucidate the differential susceptibility to H pylori that is found both across and withinpopulations. METHODS We have established a C57BL/6 mouse model of H pylori infection with a strainthat is capable of delivering the virulence factor cytotoxin-associated gene A (CagA) into host cellsthrough the activity of a Cag-pathogenicity island-encoded type IV secretion system. RESULTS Miceinfected at 5-6 weeks of age with CagA(+)H pylori rapidly develop gastritis, gastric atrophy, epithelialhyperplasia, and metaplasia in a type IV secretion system-dependent manner. In contrast, mice infectedduring the neonatal period with the same strain are protected from preneoplastic lesions. Their protectionresults from the development of H pylori-specific peripheral immunologic tolerance, which requirestransforming growth factor-β signaling and is mediated by long-lived, inducible regulatory T cells, andwhich controls the local CD4(+) T-cell responses that trigger premalignant transformation. Tolerance to Hpylori develops in the neonatal period because of a biased ratio of T-regulatory to T-effector cells and isfavored by prolonged low-dose exposure to antigen. CONCLUSIONS Using a novel CagA(+)H pyloriinfection model, we report here that the development of tolerance to H pylori protects from gastric cancerprecursor lesions. The age at initial infection may thus account for the differential susceptibility ofinfected persons to H pylori-associated disease manifestations.", "metadata": {}}
+{"_id": "39558597", "title": "", "text": "Impaired mitochondrial fatty acid oxidation and insulin resistance in aging: novel protective role ofglutathione.Aging is associated with impaired fasted oxidation of nonesterified fatty acids (NEFA)suggesting a mitochondrial defect. Aging is also associated with deficiency of glutathione (GSH), animportant mitochondrial antioxidant, and with insulin resistance. This study tested whether GSHdeficiency in aging contributes to impaired mitochondrial NEFA oxidation and insulin resistance, andwhether GSH restoration reverses these defects. Three studies were conducted: (i) in 82-week-oldC57BL/6 mice, the effect of naturally occurring GSH deficiency and its restoration on mitochondrial (13)C1 -palmitate oxidation and glucose metabolism was compared with 22-week-old C57BL/6 mice; (ii) in20-week C57BL/6 mice, the effect of GSH depletion on mitochondrial oxidation of (13) C1 -palmitate andglucose metabolism was studied; (iii) the effect of GSH deficiency and its restoration on fasted NEFAoxidation and insulin resistance was studied in GSH-deficient elderly humans, and compared withGSH-replete young humans. Chronic GSH deficiency in old mice and elderly humans was associated withdecreased fasted mitochondrial NEFA oxidation and insulin resistance, and these defects were reversedwith GSH restoration. Acute depletion of GSH in young mice resulted in lower mitochondrial NEFAoxidation, but did not alter glucose metabolism. These data suggest that GSH is a novel regulator ofmitochondrial NEFA oxidation and insulin resistance in aging. Chronic GSH deficiency promotes impairedNEFA oxidation and insulin resistance, and GSH restoration reverses these defects. Supplementing dietsof elderly humans with cysteine and glycine to correct GSH deficiency could provide significant metabolicbenefits.", "metadata": {}}
+{"_id": "39559521", "title": "", "text": "Control of central and peripheral tolerance by Aire.The negative selection of self-reactive thymocytesdepends on the expression of tissue-specific antigens by medullary thymic epithelial cells. Theautoimmune regulator (Aire) protein plays an important role in turning on these antigens, and theabsence of even one Aire-induced tissue-specific antigen in the thymus can lead to autoimmunity in theantigen-expressing target organ. Recently, Aire protein has been detected in peripheral lymphoid organs,suggesting that peripheral Aire plays a complementary role here. In these peripheral sites, Aire wasfound to regulate the expression of a group of tissue-specific antigens that is distinct from thoseexpressed in the thymus. Furthermore, transgenic antigen expression in extrathymic Aire-expressingcells (eTACs) can mediate deletional tolerance, but the immunological relevance of Aire-dependent,endogenous tissue-specific antigens remains to be determined.", "metadata": {}}
+{"_id": "39571812", "title": "", "text": "Congenital Hypogonadotropic Hypogonadism: A Trait Shared by Several Complex NeurodevelopmentalDisorders.Reproductive function depends on the activity of the gonadotropic axis, which is controlled by ahypothalamic neural network whose main function is to regulate the secretion of gonadotropin-releasinghormone (GnRH). This endocrine network is not mature at birth, and several phases ofactivation-inactivation of the gonadotropic axis are necessary for its normal development. The postnatalmaturation of the GnRH network lies under the control of a neurodevelopmental program that starts infetal life and ends at puberty. There are many clinical situations in which this program is interrupted,leading to congenital hypogonadotropic hypogonadism (CHH) and an absence of puberty. For manyyears, attention has mainly been focused on the genetics of isolated CHH. More recently, the emergenceof new genomics techniques has led to the description of genetic defects in very rare syndromes in whichCHH is associated with complex neurological dysfunctions. Here, we review the clinical phenotype andgenetic defects linked to such syndromic CHH. This analysis highlights the close link between theubiquitin pathway, synaptic proteins and CHH, as well as unexpected mutations in genes encodingnucleolar proteins.", "metadata": {}}
+{"_id": "39580129", "title": "", "text": "Elevated expression of miR-24-3p is a potentially adverse prognostic factor in colorectaladenocarcinoma.OBJECTIVES Several miRNAs are aberrantly expressed in cancer. miR-24-3p is involvedin cancer-related cellular processes, including cell cycle control, cell growth, proliferation, and apoptosis.In this study, we examined the potential diagnostic and prognostic significance of miR-24-3p expressionin colorectal adenocarcinoma. DESIGN AND METHODS Total RNA was isolated from 182 colorectaladenocarcinoma specimens and 86 paired non-cancerous colorectal mucosae. After polyadenylation of2μg total RNA and reverse transcription into first-strand cDNA using an oligo-dT-adapter primer,miR-24-3p expression was quantified using an in-house-developed reverse-transcription real-timequantitative PCR method, based on the SYBR Green chemistry. SNORD43 (RNU43) was used as areference gene. RESULTS miR-24-3p levels do not significantly differ between colorectal adenocarcinomaand non-cancerous colorectal mucosae. Thus, miR-24-3p expression cannot be used for diagnosticpurposes. However, high miR-24-3p expression predicts poor disease-free survival (DFS) and overallsurvival (OS) of colorectal adenocarcinoma patients. Multivariate Cox regression analysis confirmed thatmiR-24-3p overexpression is a significant predictor of relapse in colorectal adenocarcinoma and that itsprognostic significance is independent of other established prognostic factors and treatment of patients.Of note, miR-24-3p overexpression retains its rather unfavorable prognostic value in the subgroup ofpatients with advanced yet locally restricted colorectal adenocarcinoma (T3) and in those without distantmetastasis (M0). Moreover, miR-24-3p overexpression is a potentially unfavorable prognosticator forpatients who were not treated with radiotherapy. CONCLUSIONS Strong expression of miR-24-3p predictspoor DFS and OS of colorectal adenocarcinoma patients, independently of clinicopathological parametersthat are currently used for prognosis in this human malignancy.", "metadata": {}}
+{"_id": "39593548", "title": "", "text": "Reforming the health sector in developing countries: the central role of policy analysis.Policy analysis isan established discipline in the industrialized world, yet its application to developing countries has beenlimited. The health sector in particular appears to have been neglected. This is surprising because there isa well recognized crisis in health systems, and prescriptions abound of what health policy reformscountries should introduce. However, little attention has been paid to how countries should carry outreforms, much less who is likely to favour or resist such policies. This paper argues that much healthpolicy wrongly focuses attention on the content of reform, and neglects the actors involved in policyreform (at the international, national sub-national levels), the processes contingent on developing andimplementing change and the context within which policy is developed. Focus on policy content divertsattention from understanding the processes which explain why desired policy outcomes fail to emerge.The paper is organized in 4 sections. The first sets the scene, demonstrating how the shift fromconsensus to conflict in health policy established the need for a greater emphasis on policy analysis. Thesecond section explores what is meant by policy analysis. The third investigates what other disciplineshave written that help to develop a framework of analysis. And the final section suggests how policyanalysis can be used not only to analyze the policy process, but also to plan.", "metadata": {}}
+{"_id": "39637840", "title": "", "text": "The processing of Holliday junctions by BLM and WRN helicases is regulated by p53.BLM, WRN, and p53are involved in the homologous DNA recombination pathway. The DNA structure-specific helicases, BLMand WRN, unwind Holliday junctions (HJ), an activity that could suppress inappropriate homologousrecombination during DNA replication. Here, we show that purified, recombinant p53 binds to BLM andWRN helicases and attenuates their ability to unwind synthetic HJ in vitro. The p53 248W mutant reducesabilities of both to bind HJ and inhibit helicase activities, whereas the p53 273H mutant loses theseabilities. Moreover, full-length p53 and a C-terminal polypeptide (residues 373-383) inhibit the BLM andWRN helicase activities, but phosphorylation at Ser(376) or Ser(378) completely abolishes this inhibition.Following blockage of DNA replication, Ser(15) phospho-p53, BLM, and RAD51 colocalize in nuclear foci atsites likely to contain DNA replication intermediates in cells. Our results are consistent with a novelmechanism for p53-mediated regulation of DNA recombinational repair that involves p53post-translational modifications and functional protein-protein interactions with BLM and WRN DNAhelicases.", "metadata": {}}
+{"_id": "39652608", "title": "", "text": "Trim and fill: A simple funnel-plot-based method of testing and adjusting for publication bias inmeta-analysis.We study recently developed nonparametric methods for estimating the number of missingstudies that might exist in a meta-analysis and the effect that these studies might have had on itsoutcome. These are simple rank-based data augmentation techniques, which formalize the use of funnelplots. We show that they provide effective and relatively powerful tests for evaluating the existence ofsuch publication bias. After adjusting for missing studies, we find that the point estimate of the overalleffect size is approximately correct and coverage of the effect size confidence intervals is substantiallyimproved, in many cases recovering the nominal confidence levels entirely. We illustrate the trim and fillmethod on existing meta-analyses of studies in clinical trials and psychometrics.", "metadata": {}}
+{"_id": "39661951", "title": "", "text": "Familial Barrett's esophagus associated with adenocarcinoma.A family with six cases of Barrett'sesophagus over three generations is described. The Barrett's esophagus affected only males, and therewere three associated adenocarcinomas. The mechanism of inheritance is compatible with an autosomaldominant pattern with nearly complete penetrance. Other case reports in the literature are comparedwith this familial case of Barrett's esophagus with associated adenocarcinomas.", "metadata": {}}
+{"_id": "39668245", "title": "", "text": "Development of an insect model for the in vivo pathogenicity testing of yeasts.Conventional in vivoassays to determine the relative pathogenicity of yeast isolates rely upon the use of a range ofmammalian species. The purpose of the work presented here was to investigate the possibility of usingan insect (Galleria mellonella) as a model system for in vivo pathogenicity testing. The haemolymph of G.mellonella larvae was inoculated with PBS containing different concentrations of stationary phase yeastsof the genus Candida by injection at the last pro-leg. Larvae were incubated at 30 degrees C andmonitored over 72 hours. Results indicate that G. mellonella can be killed by the pathogenic yeastCandida albicans and by a range of other Candida species but not to a significant extent by the yeastSaccharomyces cerevisiae. The kill kinetics for larvae inoculated with clinical and laboratory isolates of C.albicans indicate the former class of isolates to be more pathogenic. Differences in the relativepathogenicity of a range of Candida species may be distinguished using G. mellonella as a model. Thiswork indicates that G. mellonella may be employed to give results consistent with data previouslyobtained using mammals in conventional in vivo pathogenicity testing. Larvae of G. mellonella areinexpensive to culture, easy to manipulate and their use may reduce the need to employ mammals forroutine in vivo pathogenicity testing with a concomitant reduction in mammalian suffering.", "metadata": {}}
+{"_id": "39728826", "title": "", "text": "Use of TLS parameters to model anisotropic displacements in macromolecular refinement.An essentialstep in macromolecular refinement is the selection of model parameters which give as good a descriptionof the experimental data as possible while retaining a realistic data-to-parameter ratio. This is particularlytrue of the choice of atomic displacement parameters, where the move from individual isotropic toindividual anisotropic refinement involves a sixfold increase in the number of required displacementparameters. The number of refinement parameters can be reduced by using collective variables ratherthan independent atomic variables and one of the simplest examples of this is the TLS parameterizationfor describing the translation, libration and screw-rotation displacements of a pseudo-rigid body. Thisarticle describes the implementation of the TLS parameterization in the macromolecular refinementprogram REFMAC. Derivatives of the residual with respect to the TLS parameters are expanded in termsof the derivatives with respect to individual anisotropic U values, which in turn are calculated using a fastFourier transform technique. TLS refinement is therefore fast and can be used routinely. Examples of TLSrefinement are given for glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and a transcriptionactivator GerE, for both of which there is data to only 2.0 A, so that individual anisotropic refinement isnot feasible. GAPDH has been refined with between one and four TLS groups in the asymmetric unit andGerE with six TLS groups. In both cases, inclusion of TLS parameters gives improved refinement statisticsand in particular an improvement in R and free R values of several percent. Furthermore, GAPDH andGerE have two and six molecules in the asymmetric unit, respectively, and in each case the displacementparameters differ significantly between molecules. These differences are well accounted for by the TLSparameterization, leaving residual local displacements which are very similar between molecules and towhich NCS restraints can be applied.", "metadata": {}}
+{"_id": "39729277", "title": "", "text": "Sequence features surrounding the translation initiation sites assigned on the genome sequence ofSynechocystis sp. strain PCC6803 by amino-terminal protein sequencing.To characterize the sequencefeatures surrounding the translation initiation sites on the genome of Synechocystis sp. strain 6803, thetotal proteins extracted from the cell were resolved by two-dimensional electrophoresis, and theamino-terminal sequences of the relatively abundant protein spots were determined. By comparison ofthe determined amino-terminal sequences with the nucleotide sequence of the entire genome, thetranslation initiation sites of a total of 72 proteins were successfully assigned on the genome. Thesequence features emerged from the nucleotide sequences at and surrounding the translation initiationsites were as follows: (1) In addition to the three initiation codons, ATG, GTG, and TTG, evidence wasobtained that ATT was also used as a rare initiation codon; (2) the core sequences (GAGG, GGAG andAGGA) of the Shine-Dalgarno sequence were identified in the appropriate position preceding the 35initiation sites (48.6%); and (3) the preferential sequence surrounding the initiation codons wasformulated as 5'-YY[...]R-3' where Y and R denote pyrimidine and purine nucleotides, respectively, andthree dots represent the initiation codons. The result obtained would provide valuable information forimprovement of the gene-finding software, and the approach used in this study should be applicable forcomprehensive analysis of the expression profiles of cellular proteins.", "metadata": {}}
+{"_id": "39758684", "title": "", "text": "Deregulated DNA polymerase beta induces chromosome instability and tumorigenesis.To reach thebiological alterations that characterize cancer, the genome of tumor cells must acquire increasedmutability resulting from a malfunction of a network of genome stability systems, e.g., cell cycle arrest,DNA repair, and high accuracy of DNA synthesis during DNA replication. Numeric chromosomalimbalance, referred to as aneuploidy, is the most prevalent genetic changes recorded among many typesof solid tumors. We report here that ectopic expression in cells of DNA polymerase beta, an error-proneenzyme frequently over-regulated in human tumors, induces aneuploidy, an abnormal localization of thecentrosome-associated gamma-tubulin protein during mitosis, a deficient mitotic checkpoint, andpromotes tumorigenesis in nude immunodeficient mice. Thus, we find that alteration of polymerase betaexpression appears to induce major genetic changes associated with a malignant phenotype.", "metadata": {}}
+{"_id": "39763465", "title": "", "text": "Combinatorial signaling by Sonic hedgehog and Wnt family members induces myogenic bHLH geneexpression in the somite.We have demonstrated previously that a combination of signals from the neuraltube and the floor plate/notochord complex synergistically induce the expression of myogenic bHLHgenes and myogenic differentiation markers in unspecified somites. In this study we demonstrate thatSonic hedgehog (Shh), which is expressed in the floor plate/notochord, and a subset of Wnt familymembers (Wnt-1, Wnt-3, and Wnt-4), which are expressed in dorsal regions of the neural tube, mimicthe muscle inducing activity of these tissues. In combination, Shh and either Wnt-1 or Wnt-3 aresufficient to induce myogenesis in somitic tissue in vitro. Therefore, we propose that myotome formationin vivo may be directed by the combinatorial activity of Shh secreted by ventral midline tissues (floorplate and notochord) and Wnt ligands secreted by the dorsal neural tube.", "metadata": {}}
+{"_id": "39776978", "title": "", "text": "Advances in osteoclast biology: old findings and new insights from mouse modelsThe maintenance ofadequate bone mass is dependent upon the controlled and timely removal of old, damaged bone. Thiscomplex process is performed by the highly specialized, multinucleated osteoclast. Over the past 15years, a detailed picture has emerged describing the origins, differentiation pathways and activationstages that contribute to normal osteoclast function. This information has primarily been obtained by thedevelopment and skeletal analysis of genetically modified mouse models. Mice harboring mutations inspecific genetic loci exhibit bone defects as a direct result of aberrations in normal osteoclast recruitment,formation or function. These findings include the identification of the RANK–RANKL–OPG system as aprimary mediator of osteoclastogenesis, the characterization of ion transport and cellular attachmentmechanisms and the recognition that matrix-degrading enzymes are essential components of resorptiveactivity. This Review focuses on the principal observations in osteoclast biology derived from geneticmouse models, and highlights emerging concepts that describe how the osteoclast is thought tocontribute to the maintenance of adequate bone mass and integrity throughout life.", "metadata": {}}
+{"_id": "39801095", "title": "", "text": "DNA methylation in embryonic stem cells.Embryonic stem cells (ESCs) are pluripotent, self-renewingcells. These cells can be used in applications such as cell therapy, drug development, disease modeling,and the study of cellular differentiation. Investigating the interplay of epigenetics, genetics, and geneexpression in control of pluripotence and differentiation could give important insights on how these cellsfunction. One of the best known epigenetic factors is DNA methylation, which is a major mechanism forregulation of gene expression. This phenomenon is mostly seen in imprinted genes and X-chromosomeinactivation where DNA methylation of promoter regions leads to repression of gene expression.Differential DNA methylation of pluripotence-associated genes such as Nanog and Oct4/Pou5f1 has beenobserved between pluripotent and differentiated cells. It is clear that tight regulation of DNA methylationis necessary for normal development. As more associations between aberrant DNA methylation anddisease are reported, the demand for high-throughput approaches for DNA methylation analysis hasincreased. In this article, we highlight these methods and discuss recent DNA methylation studies onESCs.", "metadata": {}}
+{"_id": "39851630", "title": "", "text": "Reserves, functional, immunoregulatory, and cytogenetic properties of bone marrow mesenchymal stemcells in patients with myelodysplastic syndromes.Defective hematopoiesis supporting capacity of bonemarrow (BM) stroma has been implicated in the pathophysiology of myelodysplastic syndromes (MDS).The aim of this study is to explore whether the BM stroma progenitors, namely the mesenchymal stemcells (MSCs), are primarily affected in MDS by evaluating the reserves, the functional properties, as wellas the cytogenetic characteristics, in comparison to BM hematopoietic cells, in patients with de novo MDS(n = 13). The number, differentiation potential toward adipocytes/chondrocytes/osteoblasts andimmunosuppressive function in terms of inhibition of mitogen-induced T-cell proliferation did not differsignificantly between patient and normal (n = 20) MSCs. Patient MSCs did not show any aberrations inthe production of proinflammatory or growth-promoting cytokines and did not harbor the cytogeneticabnormalities present in hematopoietic cells. Occasional patient and normal MSC cultures, however,developed irrelevant chromosomal alterations (trisomies 5 and 7) with uncertain pathophysiologicsignificance. Compared to controls, patient MSCs displayed impaired proliferative and clonogenic potentialthrough passages that might represent a nonspecific abnormality associated with the chronicinflammatory process present in patients' BM. These data suggest that BM MSCs from MDS patients donot belong to the abnormal clone and do not represent the main cellular source contributing to theinflammatory marrow microenvironment.", "metadata": {}}
+{"_id": "39859981", "title": "", "text": "Symmetric signalling within asymmetric dimers of the Staphylococcus aureus receptor histidine kinaseAgrC.Virulence in Staphylococcus aureus is largely under control of the accessory gene regulator (agr)quorum-sensing system. The AgrC receptor histidine kinase detects its autoinducing peptide (AIP) ligandand generates an intracellular signal resulting in secretion of virulence factors. Although agr is awell-studied quorum-sensing system, little is known about the mechanism of AgrC activation. Byco-immunoprecipitation analysis and intermolecular complementation of receptor mutants, we showedthat AgrC forms ligand-independent dimers that undergo trans-autophosphorylation upon interaction withAIP. Remarkably, addition of specific AIPs to AgrC mutant dimers with only one functional sensor domaincaused symmetric activation of either kinase domain despite the sensor asymmetry. Furthermore, mutantdimers involving one constitutive protomer demonstrated ligand-independent activity, irrespective ofwhich protomer was kinase deficient. These results demonstrate that signalling through either individualAgrC protomer causes symmetric activation of both kinase domains. We suggest that such signallingacross the dimer interface may be an important mechanism for dimeric quorum-sensing receptors torapidly elicit a response upon signal detection.", "metadata": {}}
+{"_id": "39863735", "title": "", "text": "Attachment of the ubiquitin-related protein Urm1p to the antioxidant protein Ahp1p.Urm1p is aubiquitin-related protein that serves as a posttranslational modification of other proteins. Urm1pconjugation has been implicated in the budding process and in nutrient sensing. Here, we have identifiedthe first in vivo target for the urmylation pathway as the antioxidant protein Ahp1p. The attachment ofUrm1p to Ahp1p requires the E1 for the urmylation pathway, Uba4p. Loss of the urmylation pathwaycomponents results in sensitivity to a thiol-specific oxidant, as does loss of Ahp1p, implying thaturmylation has a role in an oxidative-stress response. Moreover, treatment of cells with thiol-specificoxidants affects the abundance of Ahp1p-Urm1p conjugates. These results suggest that the conjugationof Urm1p to Ahp1p could regulate the function of Ahp1p in antioxidant stress response in Saccharomycescerevisiae.", "metadata": {}}
+{"_id": "39892135", "title": "", "text": "Sulfasalazine in the treatment of spondylarthropathy. A randomized, multicenter, double-blind,placebo-controlled study.OBJECTIVE To assess the efficacy and tolerability of sulfasalazine (SSZ) in thetreatment of spondylarthropathy. METHODS We conducted a 6-month randomized, placebo-controlled,double-blind, multicenter study of patients with spondylarthropathy whose disease had remained activedespite treatment with nonsteroidal antiinflammatory drugs. Patients were treated with SSZ (3 gm/day)or placebo. The primary efficacy variables were the physician's and patient's overall assessments, pain,and morning stiffness. End points were analyzed in the intent-to-treat and completer patient populations;the time course of effect was analyzed in the completer patient population. RESULTS Of the 351 patientsenrolled, 263 (75%) completed the 6-month treatment period. The withdrawal rates were 35 (20%) and53 (30%) in the placebo and SSZ groups, respectively. In the intent-to-treat analysis of end pointefficacy, the between-treatment difference reached statistical significance only for 1 of the 4 primaryoutcome variables, the patient's overall assessment of disease activity, for which 60% of the patientstaking SSZ improved by at least 1 point on a 5-point scale, in contrast to 44% of the patients takingplacebo. Laboratory markers of inflammation also showed statistically significant change in favor of SSZ.In subgroup analysis, the most impressive effects were seen in patients with psoriatic arthritis, both forthe 4 primary efficacy variables and for secondary efficacy variables such as the number of inflamedjoints. Adverse events were more frequent in the SSZ group than the placebo group, but all weretransient or reversible after cessation of treatment. CONCLUSION The results of this study show that SSZhad greater efficacy than placebo in the treatment of active spondylarthropathy, notably in patients withpsoriatic arthritis.", "metadata": {}}
+{"_id": "39903312", "title": "", "text": "A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectalcancer.BACKGROUND Experimental studies in animals and observational studies in humans suggest thatregular aspirin use may decrease the risk of colorectal adenomas, the precursors to most colorectalcancers. METHODS We conducted a randomized, double-blind trial to determine the effect of aspirin onthe incidence of colorectal adenomas. We randomly assigned 635 patients with previous colorectal cancerto receive either 325 mg of aspirin per day or placebo. We determined the proportion of patients withadenomas, the number of recurrent adenomas, and the time to the development of adenoma betweenrandomization and subsequent colonoscopic examinations. Relative risks were adjusted for age, sex,cancer stage, the number of colonoscopic examinations, and the time to a first colonoscopy. The studywas terminated early by an independent data and safety monitoring board when statistically significantresults were reported during a planned interim analysis. RESULTS A total of 517 randomized patients hadat least one colonoscopic examination a median of 12.8 months after randomization. One or moreadenomas were found in 17 percent of patients in the aspirin group and 27 percent of patients in theplacebo group (P=0.004). The mean (+/-SD) number of adenomas was lower in the aspirin group thanthe placebo group (0.30+/-0.87 vs. 0.49+/-0.99, P=0.003 by the Wilcoxon test). The adjusted relativerisk of any recurrent adenoma in the aspirin group, as compared with the placebo group, was 0.65 (95percent confidence interval, 0.46 to 0.91). The time to the detection of a first adenoma was longer in theaspirin group than in the placebo group (hazard ratio for the detection of a new polyp, 0.64; 95 percentconfidence interval, 0.43 to 0.94; P=0.022). CONCLUSIONS Daily use of aspirin is associated with asignificant reduction in the incidence of colorectal adenomas in patients with previous colorectal cancer.", "metadata": {}}
+{"_id": "39929509", "title": "", "text": "The Wilms tumour suppressor protein WT1 (+KTS isoform) binds alpha-actinin 1 mRNA via its zinc-fingerdomain.Mutations in WT1 are associated with developmental syndromes that affect the urogenital systemand neoplasms, including Wilms tumour, acute myeloid leukemia, and breast and prostate cancers. TheWT1 protein belongs to the early growth response family of zinc-finger transcription factors. Uniquely toWT1, an evolutionarily conserved alternative splice event inserts the tripeptide KTS, between zinc fingers3 and 4. Whereas -KTS isoforms bind DNA and activate or repress transcription, +KTS isoforms bind DNAless efficiently and interact with splice factors and RNA in vitro and in vivo. Although candidate DNAtargets have been found, physiological mRNA targets are yet to be defined. We examined the distributionof WT1 in ribonucleoprotein (RNP) complexes in nuclear extract prepared from M15 cells, a mousemesonephric fetal kidney cell line. WT1 cofractionated with the splice factor PSF in large RNP particles>or=2 MDa. We also found that PSF co-immunoprecipitated with WT1, suggesting a functional interactionbetween these 2 multifunctional proteins. Using yeast three-hybrid library constructed from theco-immunoprecipitated RNA we found that WT1 (+KTS) binds close to or at the start codon ofalpha-actinin 1 (ACTN1) mRNA. A band shift assay confirmed the ability of the WT1 zinc-finger domain(+KTS) to bind this sequence in vitro. ACTN1 is the first likely physiological mRNA target of WT1.", "metadata": {}}
+{"_id": "39970500", "title": "", "text": "How safe are psychiatric medications after a voluntary overdose?PURPOSE This study assessedpsychiatric medications and their potential lethality in a representative sample of suicide attempts.MATERIALS AND METHODS During 1996-98, 563 suicide attempts were studied in a general hospital inMadrid (Spain). Medication overdose was used in 456 suicide attempts (81%). The ratio between dosetaken and maximum prescription dose recommended was used to evaluate the medication toxicity.RESULTS Benzodiazepines were the drugs most often used in self-poisoning (65% of overdoses), followedby new antidepressants (11%), tricyclic antidepressants (TCAs) (10%), and antipsychotics (8%). Anoverdose with any of the three latter psychiatric medications was significantly more frequent in patientsprescribed those medications. The overdoses for TCA were potentially lethal in 47% of the cases.However, all patients who overdosed on psychiatric medications recovered well and were dischargedwithout any sequelae. DISCUSSION This study suggests that psychiatric medications, particularlybenzodiazepines, new antidepressants and antipsychotics, are relatively safe when they are used forself-poisoning. If patients with mental illnesses are under treated, there is a clear and documented higherrisk for suicide. CONCLUSION It is better to prescribe psychiatric medications, particularly the new ones,rather than withhold them due to an exaggerated fear of a lethal overdose", "metadata": {}}
+{"_id": "39984099", "title": "", "text": "Health benefits, costs, and cost-effectiveness of earlier eligibility for adult antiretroviral therapy andexpanded treatment coverage: a combined analysis of 12 mathematical models.BACKGROUND New WHOguidelines recommend ART initiation for HIV-positive persons with CD4 cell counts ≤500 cells/µL, ahigher threshold than was previously recommended. Country decision makers must consider whether tofurther expand ART eligibility accordingly. METHODS We used multiple independent mathematical modelsin four settings-South Africa, Zambia, India, and Vietnam-to evaluate the potential health impact, costs,and cost-effectiveness of different adult ART eligibility criteria under scenarios of current and expandedtreatment coverage, with results projected over 20 years. Analyses considered extending eligibility toinclude individuals with CD4 ≤500 cells/µL or all HIV-positive adults, compared to the previousrecommendation of initiation with CD4 ≤350 cells/µL. We assessed costs from a health systemperspective, and calculated the incremental cost per DALY averted ($/DALY) to compare competingstrategies. Strategies were considered 'very cost-effective' if the $/DALY was less than the country's percapita gross domestic product (GDP; South Africa: $8040, Zambia: $1425, India: $1489, Vietnam:$1407) and 'cost-effective' if $/DALY was less than three times per capita GDP. FINDINGS In SouthAfrica, the cost per DALY averted of extending ART eligibility to CD4 ≤500 cells/µL ranged from $237 to$1691/DALY compared to 2010 guidelines; in Zambia, expanded eligibility ranged from improving healthoutcomes while reducing costs (i.e. dominating current guidelines) to $749/DALY. Results were similar inscenarios with substantially expanded treatment access and for expanding eligibility to all HIV-positiveadults. Expanding treatment coverage in the general population was therefore found to be cost-effective.In India, eligibility for all HIV-positive persons ranged from $131 to $241/DALY and in Vietnam eligibilityfor CD4 ≤500 cells/µL cost $290/DALY. In concentrated epidemics, expanded access among keypopulations was also cost-effective. INTERPRETATION Earlier ART eligibility is estimated to be verycost-effective in low- and middle-income settings, although these questions should be revisited as furtherinformation becomes available. Scaling-up ART should be considered among other high-priority healthinterventions competing for health budgets. FUNDING The Bill and Melinda Gates Foundation and WorldHealth Organization.", "metadata": {}}
+{"_id": "39985001", "title": "", "text": "Chronic daily headache: long-term prognosis following inpatient treatment with repetitive IV DHE.Weretrospectively studied the long-term (2-year) outcome of 50 consecutive patients admitted to ourinpatient headache program because of chronic daily headache (CDH) associated with the overuse ofanalgesics, ergotamine, or both. They had been detoxified, given repetitive intravenousdihydroergotamine (IV DHE) and prophylactic medications as part of the program, and had becomeheadache-free on this regimen. At the time of admission, 37 of the 50 patients had transformed migraine(TM), 12 had new daily persistent headache (NDPH), and 1 had chronic tension-type headache; 29 of thepatients with TM, 7 of those with NDPH, and the single patient with chronic tension-type headache hadcoexistent migraine. Substances abused, alone or in combination, included: caffeine in 39 patients (av.441 mg/d), acetaminophen in 32 (av. 2187 mg/d), aspirin in 24 (av. 1807 mg/d), ibuprofen in 9 (av.1156 mg/d), narcotics in 7 (av. 10.1 mg morphine equivalents/d) and ergotamine in 11 (av. 2.3 mg/d).Twenty patients were using preventive medication at the time of admission. Follow-up evaluations wereperformed at 3, 6, 12, and 24 months after discharge. Forty-three patients were analyzed at 3 months.Of these, 44% had an excellent or good result and 28% a fair result; 3 were overusing analgesics. At 24months, 39 patients were analyzed: 59% had a good or excellent result and 28% a fair result; 5 wereoverusing analgesics, 4 of whom were doing poorly.(ABSTRACT TRUNCATED AT 250 WORDS)", "metadata": {}}
+{"_id": "40005757", "title": "", "text": "Survival in a case of massive paraquat ingestion.Serious exposure to the herbicide paraquat usuallyresults in death, either due to gastrointestinal caustic lesions, shock, and acute respiratory distresssyndrome or related to the progressive development of pulmonary fibrosis associated with refractoryhypoxemia. We report a case of suicidal paraquat ingestion in a 59-year-old man. Most of the indicatorsof poor prognosis were encountered in this patient. Treatment consisted of early digestivedecontamination and hemodialysis, followed by antioxidant therapy, including the administration ofdeferoxamine (100 mg/kg in 24 h) and a continuous infusion of acetylcysteine (300 mg/kg/d during 3weeks). The patient only developed a nonoliguric acute renal failure, a mild alteration of liver tests, andan impairment of CO transfer factor without any respiratory complaint. Renal and hepatic disturbancescompletely resolved within 1 month, whereas CO transfer factor remained altered 14 months later. Thisobservation suggests that early administration of an antioxidant therapy, including deferoxamine andacetylcysteine could be usefully associated with measures that prevent digestive absorption or enhanceelimination to limit systemic toxicity in potentially fatal paraquat poisoning.", "metadata": {}}
+{"_id": "40044800", "title": "", "text": "Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway.Thepresence of DNA in the cytoplasm of mammalian cells is a danger signal that triggers host immuneresponses such as the production of type I interferons. Cytosolic DNA induces interferons through theproduction of cyclic guanosine monophosphate-adenosine monophosphate (cyclic GMP-AMP, or cGAMP),which binds to and activates the adaptor protein STING. Through biochemical fractionation andquantitative mass spectrometry, we identified a cGAMP synthase (cGAS), which belongs to thenucleotidyltransferase family. Overexpression of cGAS activated the transcription factor IRF3 and inducedinterferon-β in a STING-dependent manner. Knockdown of cGAS inhibited IRF3 activation andinterferon-β induction by DNA transfection or DNA virus infection. cGAS bound to DNA in the cytoplasmand catalyzed cGAMP synthesis. These results indicate that cGAS is a cytosolic DNA sensor that inducesinterferons by producing the second messenger cGAMP.", "metadata": {}}
+{"_id": "40078758", "title": "", "text": "Eating pathology, emotion regulation, and emotional overeating in obese adults with Binge EatingDisorder.OBJECTIVE The purpose of the current study was to examine the relationship among emotionalregulation, emotional overeating, and general eating pathology in a treatment seeking sample of adultswith Binge Eating Disorder (BED). METHOD The sample was composed of 326 adults (248 women, 78men) who were obese and met DSM-IV-TR criteria for BED. Prior to treatment, participants completed theDifficulties in Emotion Regulation Scale (DERS), Emotional Overeating Questionnaire (EOQ), BeckDepression Inventory (BDI), and Eating Disorder Examination-Questionnaire (EDE-Q) as part of a largerassessment battery. RESULTS A series of hierarchical regression analyses indicated that difficulties withemotion regulation accounted for unique variance in both emotional overeating and general eatingpathology above and beyond sex and negative affect. DISCUSSION Emotion regulation may play asignificant role in the maintenance of emotional overeating and eating pathology in obese adults withBED.", "metadata": {}}
+{"_id": "40087494", "title": "", "text": "Monoallelic expression and methylation of imprinted genes in human and mouse embryonic germ celllineages.Imprinting is an epigenetic modification leading to monoallelic expression of some genes, anddisrupted imprinting is believed to be a barrier to human stem cell transplantation, based on studies thatsuggest that epigenetic marks are unstable in mouse embryonic germ (EG) and embryonic stem (ES)cells. However, stem cell imprinting has not previously been examined directly in humans. We found thatthree imprinted genes, TSSC5, H19, and SNRPN, show monoallelic expression in in vitro differentiatedhuman EG-derived cells, and a fourth gene, IGF2, shows partially relaxed imprinting at a ratio from 4:1to 5:1, comparable to that found in normal somatic cells. In addition, we found normal methylation of animprinting control region (ICR) that regulates H19 and IGF2 imprinting, suggesting that imprinting maynot be a significant epigenetic barrier to human EG cell transplantation. Finally, we were able to constructan in vitro mouse model of genomic imprinting, by generating EG cells from 8.5-day embryos of aninterspecific cross, in which undifferentiated cells show biallelic expression and acquire preferentialparental allele expression after differentiation. This model should allow experimental manipulation ofepigenetic modifications of cultured EG cells that may not be possible in human stem cell studies.", "metadata": {}}
+{"_id": "40090058", "title": "", "text": "Functional in vivo interactions between JNK1 and JNK2 isoforms in obesity and insulin resistance.Thec-Jun N-terminal kinases (JNKs) are key regulators of inflammation and interfere with insulin action incultured cells and whole animals. Obesity increases total JNK activity, and JNK1, but not JNK2, deficiencyresults in reduced adiposity and improved insulin sensitivity. Interestingly, a higher-than-normal level ofJNK activation is observed in Jnk2(-/-) mice, particularly in the liver, indicating an interaction betweenthe isoforms that might have masked the metabolic activity of JNK2 in isolated mutant mice. To addressthe role of the JNK2 isoform in metabolic homeostasis, we intercrossed Jnk1(-/-) and Jnk2(-/-) mice andexamined body weight and glucose metabolism in the resulting mutant allele combinations. Among all ofthe viable genotypes examined, we observed only reduced body weight and increased insulin sensitivityin Jnk1(-/-) and Jnk1(+/-)Jnk2(-/-) mice. These two groups of mice also exhibited reduced total JNKactivity and cytokine expression in liver tissue compared with all other genotypes examined. These dataindicate that the JNK2 isoform is also involved in metabolic regulation, but its function is not obviouswhen JNK1 is fully expressed because of regulatory crosstalk between the two isoforms.", "metadata": {}}
+{"_id": "40094786", "title": "", "text": "The immunological synapse of CTL contains a secretory domain and membrane bridges.Cytotoxic Tlymphocytes (CTL) rapidly destroy their targets. Here we show that although target cell death occurswithin 5 min of CTL-target cell contact, an immunological synapse similar to that seen in CD4 cells rapidlyforms in CTL, with a ring of adhesion proteins surrounding an inner signaling molecule domain. Lyticgranule secretion occurs in a separate domain within the adhesion ring, maintaining signaling proteinorganization during exocytosis. Live and fixed cell studies show target cell plasma membrane markers aretransferred to the CTL as the cells separate. Electron microscopy reveals continuities forming membranebridges between the CTL and target cell membranes, suggesting a possible mechanism for this transfer.", "metadata": {}}
+{"_id": "40096222", "title": "", "text": "Compromised intestinal epithelial barrier induces adaptive immune compensation that protects fromcolitis.Mice lacking junctional adhesion molecule A (JAM-A, encoded by F11r) exhibit enhanced intestinalepithelial permeability, bacterial translocation, and elevated colonic lymphocyte numbers, yet do notdevelop colitis. To investigate the contribution of adaptive immune compensation in response toincreased intestinal epithelial permeability, we examined the susceptibility of F11r(-/-)Rag1(-/-) mice toacute colitis. Although negligible contributions of adaptive immunity in F11r(+/+)Rag1(-/-) mice wereobserved, F11r(-/-)Rag1(-/-) mice exhibited increased microflora-dependent colitis. Elimination of T cellsubsets and cytokine analyses revealed a protective role for TGF-β-producing CD4(+) T cells in F11r(-/-)mice. Additionally, loss of JAM-A resulted in elevated mucosal and serum IgA that was dependent uponCD4(+) T cells and TGF-β. Absence of IgA in F11r(+/+)Igha(-/-) mice did not affect disease, whereasF11r(-/-)Igha(-/-) mice displayed markedly increased susceptibility to acute injury-induced colitis. Thesedata establish a role for adaptive immune-mediated protection from acute colitis under conditions ofintestinal epithelial barrier compromise.", "metadata": {}}
+{"_id": "40127292", "title": "", "text": "Apoptosis and chemoresistance in transgenic cancer modelsMultidrug resistance remains an unresolvedproblem in clinical oncology. Over a decade ago genes encoding cellular efflux pumps were shown toconfer resistance to a broad spectrum of biochemically unrelated anticancer drugs even before thecompounds reached their intracellular targets. More recently it has become apparent that many drugsinduce a common apoptotic program, such that mutations in this program can also produce multidrugresistance. However, a thorough evaluation of the contribution of apoptotic defects to this \"postdamage\"drug resistant phenotype is technically complicated, and this has led to uncertainty about the overallsignificance of apoptosis in therapy-induced cell death. For example, correlative analyses using patientspecimens are limited by unknown background mutations in the biopsy material, and assays using cancercell lines can be biased by unphysiological conditions. We sought to circumvent these restrictions byutilizing a tractable transgenic cancer model to examine the impact of apoptosis on treatment outcome.Here we discuss potential caveats of cell culture based assays, highlight features of geneticallyengineered mice as potential model systems, and describe a tractable transgenic mouse model to studydrug responses in a series of primary lymphomas with genetically defined lesions treated at their naturalsite.", "metadata": {}}
+{"_id": "40145839", "title": "", "text": "NC-100717: a versatile RGD peptide scaffold for angiogenesis imaging.Targeting the molecular pathwaysassociated with angiogenesis offers great potential in detecting disease pathology using in vivo imagingtechnologies. Initiation of angiogenesis requires activation and migration of endothelial cells in order forneovascularization to proceed. Endothelial cells associate with the extracellular matrix through specificinteractions with a variety of cell adhesion receptors known as integrins. Peptides containing thetripeptide sequence RGD are known to bind with high affinity to the alphavbeta3 and alphavbeta5integrins associated with angiogenesis. We present herein the synthesis and in vitro binding affinity of theRGD-containing peptide NC-100717 and a range of molecular probes derived from this intermediate.", "metadata": {}}
+{"_id": "40156901", "title": "", "text": "Dose-dependent effect of statins on the incidence of acute kidney injury after cardiacsurgery.BACKGROUND Acute kidney injury (AKI) after cardiac surgery is associated with increasedmorbidity and mortality. METHODS We assessed whether statin treatment is associated with a lowerincidence of postoperative AKI in 2,104 consecutive patients who underwent coronary artery bypass graftor valve surgery at the Minneapolis Veterans Administration Medical Center. Acute kidney injury wasdefined as absolute increase greater than 0.3 mg/dL or relative increase greater than 50% in serumcreatinine from baseline, within 48 hours after surgery or requiring postoperative hemodialysis per AKInetwork. Propensity scores were utilized to adjust for the differences between the statin and the no-statintreatment groups. All statins were converted to equivalent-dose simvastatin and divided at the median toconstruct high-dose (≥40 mg) and low-dose (<40 mg) statin groups. RESULTS Of the 2,104 patients,1,435 (68%) were taking statins (638 high-dose) and 495 (24%) developed AKI (25% high-dose vs 40%low-dose vs 35% no-statin; p = 0.014). Estimated preoperative glomerular filtration rate (p = 0.003),diabetes mellitus (p=0.02), valve surgery with or without coronary artery bypass graft (p = 0.024),cardiopulmonary bypass time (p = 0.001), and intraaortic balloon pump (p = 0.055) were independentpredictors of AKI. After propensity adjustment statin treatment was not associated with postoperativeAKI (odds ratio 0.79; 95% confidence interval 0.59 to 1.06; p = 0.11 for high-dose v. no-statin). Afterfull adjustment for all independent predictors of AKI, the results did not change. Statins also had noeffect on the incidence of postoperative hemodialysis (0.8% high-dose vs 1.9% low-dose vs 1%no-statin; p = 0.15). CONCLUSIONS Statin treatment is not associated with a lower incidence of AKI aftercardiac surgery.", "metadata": {}}
+{"_id": "40164383", "title": "", "text": "Comparison of allogeneic vs autologous bone marrow–derived mesenchymal stem cells delivered bytransendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomizedtrial.CONTEXT Mesenchymal stem cells (MSCs) are under evaluation as a therapy for ischemiccardiomyopathy (ICM). Both autologous and allogeneic MSC therapies are possible; however, their safetyand efficacy have not been compared. OBJECTIVE To test whether allogeneic MSCs are as safe andeffective as autologous MSCs in patients with left ventricular (LV) dysfunction due to ICM. DESIGN,SETTING, AND PATIENTS A phase 1/2 randomized comparison (POSEIDON study) in a US tertiary-carereferral hospital of allogeneic and autologous MSCs in 30 patients with LV dysfunction due to ICMbetween April 2, 2010, and September 14, 2011, with 13-month follow-up. INTERVENTION Twentymillion, 100 million, or 200 million cells (5 patients in each cell type per dose level) were delivered bytransendocardial stem cell injection into 10 LV sites. MAIN OUTCOME MEASURES Thirty-daypostcatheterization incidence of predefined treatment-emergent serious adverse events (SAEs). Efficacyassessments included 6-minute walk test, exercise peak VO2, Minnesota Living with Heart FailureQuestionnaire (MLHFQ), New York Heart Association class, LV volumes, ejection fraction (EF), earlyenhancement defect (EED; infarct size), and sphericity index. RESULTS Within 30 days, 1 patient in eachgroup (treatment-emergent SAE rate, 6.7%) was hospitalized for heart failure, less than the prespecifiedstopping event rate of 25%. The 1-year incidence of SAEs was 33.3% (n = 5) in the allogeneic group and53.3% (n = 8) in the autologous group (P = .46). At 1 year, there were no ventricular arrhythmia SAEsobserved among allogeneic recipients compared with 4 patients (26.7%) in the autologous group (P =.10). Relative to baseline, autologous but not allogeneic MSC therapy was associated with animprovement in the 6-minute walk test and the MLHFQ score, but neither improved exercise VO2 max.Allogeneic and autologous MSCs reduced mean EED by −33.21% (95% CI, −43.61% to −22.81%; P <.001) and sphericity index but did not increase EF. Allogeneic MSCs reduced LV end-diastolic volumes.Low-dose concentration MSCs (20 million cells) produced greatest reductions in LV volumes andincreased EF. Allogeneic MSCs did not stimulate significant donor-specific alloimmune reactions.CONCLUSIONS In this early-stage study of patients with ICM, transendocardial injection of allogeneic andautologous MSCs without a placebo control were both associated with low rates of treatment-emergentSAEs, including immunologic reactions. In aggregate, MSC injection favorably affected patient functionalcapacity, quality of life, and ventricular remodeling. TRIAL REGISTRATION clinicaltrials.gov Identifier:NCT01087996.", "metadata": {}}
+{"_id": "40212412", "title": "", "text": "Periosteal bone formation--a neglected determinant of bone strength.Life forms that have low body masscan hunt for food on the undersurface of branches or along shear cliff faces quite unperturbed by gravity.For larger animals, the hunt for dinner and the struggle to avoid becoming someone else's meal requirerapid movement against gravity. This need is met by the lever function of long bones, three-dimensionalmasterpieces of biomechanical engineering that, by their material composition and structural design,achieve the contradictory properties of stiffness and flexibility, strength and lightness.1 Material stiffnessresults from the encrusting of the triple-helical structure of collagen type I with hydroxyapatite crystals,which confers . . .", "metadata": {}}
+{"_id": "40232172", "title": "", "text": "Triglyceride depletion of brown adipose tissue enables analysis of mitochondrial respiratory function inpermeabilized biopsies.The research on mitochondrial functions in adipocytes has increasingly evidencedthat mitochondria plays an important role in the onset and/or progression of obesity and relatedpathologies. Mitochondrial function in brown adipose tissue (BAT) has been classically assessed bymeasuring either the levels/activity of mitochondrial enzymes, or the respiration in isolated mitochondria.Isolation of mitochondria is not advantageous because it demands significant time and amount of tissueand, as tissue homogenates, disrupts biochemical and physical connections of mitochondria within thecell. Here, we described a new and efficient protocol to analyze the mitochondrial respiratory states inBAT biopsies that relies on intracellular triglyceride depletion followed by tissue permeabilization. Inaddition to minimizing tissue requirements to \u000017 mg wet weight, the proposed protocol enabledanalysis of all mitochondrial respiratory states, including phosphorylation (OXPHOS), no-phosphorylation(LEAK), and uncoupled (ETS) states, as well as the use of substrates for complex I, complex II, andcytochrome c; together, these features demonstrated mitochondrial integrity and validated thepreparation efficacy. Therefore, the protocol described here increases the possibilities of answeringphysiological questions related to small BAT regions of human and animal models, which shall help tounravel the mechanisms that regulate mitochondrial function in health and disease.", "metadata": {}}
+{"_id": "40234452", "title": "", "text": "HES-1 preserves purified hematopoietic stem cells ex vivo and accumulates side population cells invivo.Mouse long-term hematopoietic reconstituting cells exist in the c-Kit+Sca-1+Lin- (KSL) cellpopulation; among them, CD34(low/-) cells represent the most highly purified population ofhematopoietic stem cells in the adult bone marrow. Here, we demonstrate that retrovirus-mediatedtransduction of CD34(low/-)c-Kit+Sca-1+Lin- (34-KSL) cells with the HES-1 gene, which encodes a basichelix-loop-helix transcription factor functioning downstream of the Notch receptor, and is a key moleculefor the growth phase of neural stem cells in the embryo, preserves the long-term reconstituting activityof these cells in vitro. We also show that cells derived from the HES-1-transduced 34-KSL populationproduce progenies characterized by negative Hoechst dye staining, which defines the side population, andby CD34(low/-) profile in the bone marrow KSL population in each recipient mouse at ratios 3.5- and7.8-fold those produced by nontransduced 34-KSL-derived competitor cells. We conclude that HES-1preserves the long-term reconstituting hematopoietic activity of 34-KSL stem cells ex vivo. Up-regulationof HES-1 protein in the 34-KSL population before unnecessary cell division, that is, without retrovirustransduction, may represent a potent approach to absolute expansion of hematopoietic stem cells.", "metadata": {}}
+{"_id": "40254495", "title": "", "text": "Measuring Absolute RNA Copy Numbers at High Temporal Resolution Reveals Transcriptome Kinetics inDevelopment.Transcript regulation is essential for cell function, and misregulation can lead to disease.Despite technologies to survey the transcriptome, we lack a comprehensive understanding of transcriptkinetics, which limits quantitative biology. This is an acute challenge in embryonic development, whererapid changes in gene expression dictate cell fate decisions. By ultra-high-frequency sampling of Xenopusembryos and absolute normalization of sequence reads, we present smooth gene expression trajectoriesin absolute transcript numbers. During a developmental period approximating the first 8 weeks of humangestation, transcript kinetics vary by eight orders of magnitude. Ordering genes by expression dynamics,we find that \"temporal synexpression\" predicts common gene function. Remarkably, a single parameter,the characteristic timescale, can classify transcript kinetics globally and distinguish genes regulatingdevelopment from those involved in cellular metabolism. Overall, our analysis provides unprecedentedinsight into the reorganization of maternal and embryonic transcripts and redefines our ability to performquantitative biology.", "metadata": {}}
+{"_id": "40312663", "title": "", "text": "Inflammasome activation by adenylate cyclase toxin directs Th17 responses and protection againstBordetella pertussis.Inflammasome-mediated IL-1beta production is central to the innate immune defectsthat give rise to certain autoinflammatory diseases and may also be associated with the generation ofIL-17-producing CD4(+) T (Th17) cells that mediate autoimmunity. However, the role of theinflammasome in driving adaptive immunity to infection has not been addressed. In this article, wedemonstrate that inflammasome-mediated IL-1beta plays a critical role in promoting Ag-specific Th17cells and in generating protective immunity against Bordetella pertussis infection. Using a murinerespiratory challenge model, we demonstrated that the course of B. pertussis infection was significantlyexacerbated in IL-1R type I-defective (IL-1RI(-/-)) mice. We found that adenylate cyclase toxin (CyaA), akey virulence factor secreted by B. pertussis, induced robust IL-1beta production by dendritic cellsthrough activation of caspase-1 and the NALP3-containing inflammasome complex. Using mutant toxins,we demonstrate that CyaA-mediated activation of caspase-1 was not dependent on adenylate cyclaseenzyme activity but was dependent on the pore-forming capacity of CyaA. In addition, CyaA promotedthe induction of Ag-specific Th17 cells in wild-type but not IL-1RI(-/-) mice. Furthermore, the bacterialload was enhanced in IL-17-defective mice. Our findings demonstrate that CyaA, a virulence factor fromB. pertussis, promotes innate IL-1beta production via activation of the NALP3 inflammasome and,thereby, polarizes T cell responses toward the Th17 subtype. In addition to its known role in subvertinghost immunity, our findings suggest that CyaA can promote IL-1beta-mediated Th17 cells, which promoteclearance of the bacteria from the respiratory tract.", "metadata": {}}
+{"_id": "40323148", "title": "", "text": "Infection and apoptosis as a combined inflammatory trigger.While inflammatory phagocytosis of microbialpathogens and non-inflammatory phagocytosis of apoptotic cells have each been studied extensively, theconsequences of innate immune recognition of host cells undergoing apoptosis as a direct result ofinfection are unclear. In this situation, the innate immune system is confronted with mixed signals, thosefrom apoptotic cells and those from the infecting pathogen. Nuclear receptor activation has beenimplicated downstream of apoptotic cell recognition while Toll-like receptors are the prototypicalinflammatory receptors engaged during infection. When the two signals combine, a new set of eventstakes place beginning with transrepression of a subset of inflammatory-response genes and ending withthe induction of a T helper-17 adaptive immune response. This response is best suited for clearing theinfecting pathogen and repairing the damage that occurred to the host tissue during infection.", "metadata": {}}
+{"_id": "40323454", "title": "", "text": "Chronic lymphocytic leukemia with t(14;19)(q32;q13) is characterized by atypical morphologic andimmunophenotypic features and distinctive genetic features.The t(14;19)(q32;q13) involving the IGH@and BCL3 loci is an infrequent cytogenetic abnormality detected in B-cell malignancies. We describe theclinicopathologic, cytogenetic, and molecular genetic characteristics of 14 cases of chronic lymphocyticleukemia/small lymphocytic lymphoma (CLL/SLL) with t(14;19)(q32;q13). All patients (10 men and 4women) had lymphocytosis; 10 had lymphadenopathy. Blood and bone marrow lymphocytes werepredominantly small, but cytologically and immunophenotypically atypical. In all cases, t(14;19) wasfound in the neoplastic stem line; it was the sole abnormality in 4. Ten cases showed additionalcytogenetic abnormalities, including trisomy 12 in 9 and complex karyotypes in 7. Fluorescence in situhybridization demonstrated IGH@/BCL3 fusion gene in all cases. In all cases, the IGHV genes wereunmutated, but only 7 expressed ZAP70. Seven cases preferentially used IGHV4-39. Our results indicatethat t(14;19)(q32;q13) identifies a subset of CLL/SLL with distinctive clinicopathologic and geneticfeatures. Furthermore, t(14;19) may represent an early, possibly primary, genetic event.", "metadata": {}}
+{"_id": "40343416", "title": "", "text": "Risk factors for the development of gallstone recurrence following medical dissolution. The British-ItalianGallstone Study Group.OBJECTIVE To assess risk factors for gallstone recurrence following non-surgicaltreatment. DESIGN A prospective follow-up of a multicentre cohort of post-dissolution gallstone patients.SETTING Six gastroenterology units in the UK and Italy. PARTICIPANTS One hundred and sixty-threepatients with confirmed gallstone dissolution following non-surgical therapy (bile acids or lithotripsy plusbile acids), followed up by ultrasound scan and clinical assessment at 6-monthly intervals for up to 6years (median, 25 months; range, 6-70 months). OUTCOME MEASURES Subject-related variables (sex,age, height, weight, body mass index), gallstone-related variables (number, diameter, presence ofsymptoms, months to complete stone clearance), treatment modalities (bile acid therapy, extracorporealshock wave lithotripsy) and follow-up related variables (weight change, use of non-steroidalanti-inflammatory agents, statins, pregnancies and/or use of oestrogens) were assessed by univariateand multivariate analysis as putative risk factors for gallstone recurrence. RESULTS Forty-five gallstonerecurrences were observed during the follow-up period. Multiple primary gallstones and length of time toachieve gallstone dissolution were the only variables associated with a significant increase in therecurrence rate. Appearance of biliary sludge during follow-up was also significantly related todevelopment of gallstone recurrence. Use of statins or non-steroidal anti-inflammatory agents did notconfer protection against recurrence. CONCLUSIONS Patients with primary single stones are the bestcandidates for non-surgical treatment of gallstones, because of a low risk of gallstone recurrence. Thepositive association of recurrence with biliary sludge formation and time to dissolution of primary stonesmay provide indirect confirmation for the role of impaired gallbladder motility in the pathogenesis of thiscondition.", "metadata": {}}
+{"_id": "40349336", "title": "", "text": "Deletion of the developmentally essential gene ATR in adult mice leads to age-related phenotypes andstem cell loss.Developmental abnormalities, cancer, and premature aging each have been linked todefects in the DNA damage response (DDR). Mutations in the ATR checkpoint regulator causedevelopmental defects in mice (pregastrulation lethality) and humans (Seckel syndrome). Here we showthat eliminating ATR in adult mice leads to defects in tissue homeostasis and the rapid appearance ofage-related phenotypes, such as hair graying, alopecia, kyphosis, osteoporosis, thymic involution,fibrosis, and other abnormalities. Histological and genetic analyses indicate that ATR deletion causesacute cellular loss in tissues in which continuous cell proliferation is required for maintenance.Importantly, thymic involution, alopecia, and hair graying in ATR knockout mice were associated withdramatic reductions in tissue-specific stem and progenitor cells and exhaustion of tissue renewal andhomeostatic capacity. In aggregate, these studies suggest that reduced regenerative capacity in adultsvia deletion of a developmentally essential DDR gene is sufficient to cause the premature appearance ofage-related phenotypes.", "metadata": {}}
+{"_id": "40365566", "title": "", "text": "Conventional and monocyte-derived CD11b(+) dendritic cells initiate and maintain T helper 2cell-mediated immunity to house dust mite allergen.Dendritic cells (DCs) are crucial for mounting allergicairway inflammation, but it is unclear which subset of DCs performs this task. By using CD64 and MAR-1staining, we reliably separated CD11b(+) monocyte-derived DCs (moDCs) from conventional DCs (cDCs)and studied antigen uptake, migration, and presentation assays of lung and lymph node (LN) DCs inresponse to inhaled house dust mite (HDM). Mainly CD11b(+) cDCs but not CD103(+) cDCs induced Thelper 2 (Th2) cell immunity in HDM-specific T cells in vitro and asthma in vivo. Studies in Flt3l(-/-) mice,lacking all cDCs, revealed that moDCs were also sufficient to induce Th2 cell-mediated immunity but onlywhen high-dose HDM was given. The main function of moDCs was the production of proinflammatorychemokines and allergen presentation in the lung during challenge. Thus, we have identified migratoryCD11b(+) cDCs as the principal subset inducing Th2 cell-mediated immunity in the LN, whereas moDCsorchestrate allergic inflammation in the lung.", "metadata": {}}
+{"_id": "40367499", "title": "", "text": "Interplay between the dividing cell and its neighbors regulates adherens junction formation duringcytokinesis in epithelial tissue.How adherens junctions (AJs) are formed upon cell division is largelyunexplored. Here, we found that AJ formation is coordinated with cytokinesis and relies on an interplaybetween the dividing cell and its neighbors. During contraction of the cytokinetic ring, the neighboringcells locally accumulate Myosin II and produce the cortical tension necessary to set the initial geometry ofthe daughter cell interface. However, the neighboring cell membranes impede AJ formation. Uponmidbody formation and concomitantly to neighboring cell withdrawal, Arp2/3-dependent actinpolymerization oriented by the midbody maintains AJ geometry and regulates AJ final length and theepithelial cell arrangement upon division. We propose that cytokinesis in epithelia is a multicellularprocess, whereby the cooperative actions of the dividing cell and its neighbors define a two-tieredmechanism that spatially and temporally controls AJ formation while maintaining tissue cohesiveness.", "metadata": {}}
+{"_id": "40382183", "title": "", "text": "Cancer stem cells in solid tumours: accumulating evidence and unresolved questionsSolid tumours are anenormous cancer burden and a major therapeutic challenge. The cancer stem cell (CSC) hypothesisprovides an attractive cellular mechanism to account for the therapeutic refractoriness and dormantbehaviour exhibited by many of these tumours. There is increasing evidence that diverse solid tumoursare hierarchically organized and sustained by a distinct subpopulation of CSCs. Direct evidence for theCSC hypothesis has recently emerged from mouse models of epithelial tumorigenesis, althoughalternative models of heterogeneity also seem to apply. The clinical relevance of CSCs remains afundamental issue but preliminary findings indicate that specific targeting may be possible.", "metadata": {}}
+{"_id": "40383969", "title": "", "text": "The structure of the follistatin:activin complex reveals antagonism of both type I and type II receptorbinding.TGF-beta ligands stimulate diverse cellular differentiation and growth responses by signalingthrough type I and II receptors. Ligand antagonists, such as follistatin, block signaling and are essentialregulators of physiological responses. Here we report the structure of activin A, a TGF-beta ligand, boundto the high-affinity antagonist follistatin. Two follistatin molecules encircle activin, neutralizing the ligandby burying one-third of its residues and its receptor binding sites. Previous studies have suggested thattype I receptor binding would not be blocked by follistatin, but the crystal structure reveals that thefollistatin N-terminal domain has an unexpected fold that mimics a universal type I receptor motif andoccupies this receptor binding site. The formation of follistatin:BMP:type I receptor complexes can beexplained by the stoichiometric and geometric arrangement of the activin:follistatin complex. The modeof ligand binding by follistatin has important implications for its ability to neutralize homo- andheterodimeric ligands of this growth factor family.", "metadata": {}}
+{"_id": "40412980", "title": "", "text": "The activity of siRNA in mammalian cells is related to structural target accessibility: a comparison withantisense oligonucleotides.The biological activity of siRNA seems to be influenced by local characteristicsof the target RNA, including local RNA folding. Here, we investigated quantitatively the relationshipbetween local target accessibility and the extent of inhibition of the target gene by siRNA. Targetaccessibility was assessed by a computational approach that had been shown earlier to be consistent withexperimental probing of target RNA. Two sites of ICAM-1 mRNA predicted to serve as accessible motifsand one site predicted to adopt an inaccessible structure were chosen to test siRNA constructs forsuppression of ICAM-1 gene expression in ECV304 cells. The local target-dependent effectiveness ofsiRNA was compared with antisense oligonucleotides (asON). The concentration dependency ofsiRNA-mediated suppression indicates a >1000-fold difference between active siRNAs (IC50approximately 0.2-0.5 nM) versus an inactive siRNA (IC50 > or = 1 microM) which is consistent with theactivity pattern of asON when relating target suppression to predicted local target accessibility. Theextremely high activity of the siRNA si2B (IC50 = 0.24 nM) indicates that not all siRNAs shown to beactive at the usual concentrations of >10-100 nM belong to this highly active species. The observationsdescribed here suggest an option to assess target accessibility for siRNA and, thus, support the design ofactive siRNA constructs. This approach can be automated, work at high throughput and is open to includeadditional parameters relevant to the biological activity of siRNA.", "metadata": {}}
+{"_id": "40429879", "title": "", "text": "Rapid accumulation of mutations during seed-to-seed propagation of mismatch-repair-defectiveArabidopsis.During the many cell divisions that precede formation of plant gametes, theirapical-meristem and floral antecedents are continually exposed to endogenous and environmentalmutagenic threats. Although some deleterious recessive mutations may be eliminated during growth ofhaploid gametophytes and functionally haploid early embryos (\"haplosufficiency quality-checking\"), themultiplicity of plant genome-maintenance systems suggests aggressive quality control during prior diploidgrowth. To test in Arabidopsis a hypothesis that prior mismatch repair (MMR) is paramount in defense ofplant genetic fidelity, we propagated in parallel 36 MMR-defective (Atmsh2-1) and 36 wild-type lines. TheAtmsh2-1 lines rapidly accumulated a wide variety of mutations: fifth-generation (G5) plants showedabnormalities in morphology and development, fertility, germination efficiency, seed/silique development,and seed set. Only two Atmsh2-1, but all 36 wild-type lines, appeared normal at G5. Analyses ofinsertion/deletion mutation at six repeat-sequence (microsatellite) loci showed each Atmsh2-1 line tohave evolved its own \"fingerprint,\" the results of as many as 10 microsatellite mutations in a single line.Thus, MMR during diploid growth is essential for plant genomic integrity.", "metadata": {}}
+{"_id": "40447899", "title": "", "text": "Archaeal chromatin and transcription.Archaea contain a variety of sequence-independent DNA bindingproteins consistent with the evolution of several different, sometimes overlapping and exchangeablesolutions to the problem of genome compaction. Some of these proteins undergo residue-specificpost-translational lysine acetylation or methylation, hinting at analogues of the histone modifications thatregulate eukaryotic chromatin structure and transcription. Archaeal transcription initiation most closelyresembles the eukaryotic RNA polymerase II (RNAPII) system, but Archaea do not appear to havehomologues of the multisubunit complexes that remodel eukaryotic chromatin and activate RNAPIIinitiation. In contrast, they have sequence-specific regulators that repress and perhaps activate archaealtranscription by mechanisms superficially similar to the bacterial paradigm of regulating promoter bindingby RNAP. Repressors compete with archaeal TATA-box binding protein (TBP) and TFB for the TATA-boxand TFB-recognition elements (BRE) of the archaeal promoter, or with archaeal RNAP for the site oftranscription initiation. Transcript-specific regulation by repressors binding to sites of transcript initiationis consistent with such sites having very little sequence conservation. However, most Archaea have onlyone TBP and/or TFB that presumably must therefore bind to similar TATA-box and BRE sequencesupstream of most genes. Repressors that function by competing with TBP and/or TFB binding musttherefore also make additional contacts with transcript-specific regulatory sites adjacent or remote fromthe TATA-box/BRE region. The fate of the archaeal TBP and TFB following transcription initiation remainsto be determined. Based on functional homology with their eukaryotic RNAPII-system counterparts,archaeal TBP and possibly also TFB should remain bound to the TATA-box/BRE region after transcriptioninitiation. However, this seems unlikely as it might limit repressor competition at this site to only the firstround of transcription initiation.", "metadata": {}}
+{"_id": "40473317", "title": "", "text": "Temporal segregation of 4-1BB versus CD28-mediated costimulation: 4-1BB ligand influences T cellnumbers late in the primary response and regulates the size of the T cell memory response followinginfluenza infection.In this report, we demonstrate that CD28(-/-) mice are severely impaired in the initialexpansion of D(b)/NP366-374-specific CD8 T cells in response to influenza virus infection, whereas 4-1BBligand (4-1BBL)(-/-) mice show no defect in primary T cell expansion to influenza virus. In contrast,4-1BBL(-/-) mice show a decrease in D(b)/NP366-374-specific T cells late in the primary response. Uponsecondary challenge with influenza virus, 4-1BBL(-/-) mice show a decrease in the number ofD(b)/NP366-374-specific T cells compared to wild-type mice such that the level of the CD8 T cellexpansion during the in vivo secondary response is reduced to the level of a primary response, withconcomitant reduction of CTL effector function. In contrast, Ab responses, as well as secondary CD4 T cellresponses, to influenza are unaffected by 4-1BBL deficiency. Thus, CD28 is critical for initial T cellexpansion, whereas 4-1BB/4-1BBL signaling affects T cell numbers much later in the response and isessential for the survival and/or responsiveness of the memory CD8 T cell pool.", "metadata": {}}
+{"_id": "40476126", "title": "", "text": "Functional role of high-affinity anandamide transport, as revealed by selective inhibition.Anandamide, anendogenous ligand for central cannabinoid receptors, is released from neurons on depolarization andrapidly inactivated. Anandamide inactivation is not completely understood, but it may occur by transportinto cells or by enzymatic hydrolysis. The compound N-(4-hydroxyphenyl)arachidonylamide (AM404) wasshown to inhibit high-affinity anandamide accumulation in rat neurons and astrocytes in vitro, anindication that this accumulation resulted from carrier-mediated transport. Although AM404 did notactivate cannabinoid receptors or inhibit anandamide hydrolysis, it enhanced receptor-mediatedanandamide responses in vitro and in vivo. The data indicate that carrier-mediated transport may beessential for termination of the biological effects of anandamide, and may represent a potential drugtarget.", "metadata": {}}
+{"_id": "40500438", "title": "", "text": "Silibinin inhibits the invasion of IL-6-stimulated colon cancer cells via selective JNK/AP-1/MMP-2modulation in vitro.Silibinin is a flavonoid with antihepatotoxic properties and pleiotropic anticancercapabilities. This study investigated silibinin inhibition of cell invasion by down-regulating matrixmetalloproteinase-2 (MMP-2) expression, via attenuation of activator protein-1 (AP-1) in IL-6-stimulatedLoVo colon cancer cells. Western blot data showed that the expression of MMP-2 protein was reduced 1.6-or 1.7-fold over the control by treatment with silibinin or JNK inhibitor in the models. Similar results wererevealed in zymography and confocal microscopy. Pretreatment with silibinin also abolished the bindingactivity of AP-1 and MMP-2 promoter activity via AP-1 binding, as observed by EMSA and luciferaseassay. Finally, a [(3)H]-thymidine incorporation proliferation assay and cell migration assaydemonstrated that silibinin inhibited IL-6-stimulated LoVo cell proliferation and invasion. Taken together,these data indicated that silibinin inhibits LoVo cell invasion with the reduction of MMP-2 presentation byattenuating AP-1 binding activity, suggesting a novel antimetastatic application for silibinin in coloncancer chemoprevention.", "metadata": {}}
+{"_id": "40500723", "title": "", "text": "Immigration cohorts and residential overcrowding in southern CaliforniaTo what degree do immigrantsreduce their high rates of residential overcrowding with increasing length of residence in the UnitedStates? This question is addressed through the application of a “double cohort” method that nests birthcohorts within immigration cohorts. This method enables duration of immigration effects to be separatedfrom aging effects as cohorts pass through life course phases, when family sizes may be growing orshrinking. The analysis finds that cohort trends differ sharply from the cross-sectional pattern observed ata single point in time. Cohorts’ growth in income is found to contribute substantially to the decline inovercrowding over time. Cohort trends among Hispanic immigrants, however, diverge from those amongothers, indicating much less decrease in overcrowding and even increases over certain age spans.", "metadata": {}}
+{"_id": "40558887", "title": "", "text": "Expression of green fluorescent protein in the ureteric bud of transgenic mice: a new tool for the analysisof ureteric bud morphogenesis.The growth and branching of the ureteric bud is a complex process that isultimately responsible for the organization of the collecting duct system as well as the number ofnephrons in the metanephric kidney. While the genes involved in the regulation of this process havebegun to be elucidated, our understanding of the cellular and molecular basis of ureteric budmorphogenesis remains rudimentary. Furthermore, the timing and sequence of branching and elongationthat gives rise to the collecting system of the kidney can only be inferred from retrospective staining ormicrodissection of fixed preparations. To aid in the investigation of these issues, we developed strains oftransgenic mice in which a green fluorescent protein (GFP) is expressed in the ureteric bud under thecontrol of the Hoxb7 promoter. In these mice, GFP is expressed in every branch of the ureteric budthroughout renal development, and in its derivative epithelia in the adult kidney. As GFP fluorescence canbe easily visualized in living tissue, this allows the dynamic pattern of ureteric bud growth and branchingto be followed over several days when the kidneys are cultured in vitro. Using confocal microscopy,branching of the ureteric bud in all three dimensions can be analyzed. These mice represent an extremelypowerful tool to characterize the normal patterns of ureteric bud morphogenesis and to investigate theresponse of the bud to growth factors, matrix elements, and other agents that regulate its growth andbranching.", "metadata": {}}
+{"_id": "40584205", "title": "", "text": "Biological properties of herpes simplex virus 2 replication-defective mutant strains in a murine nasalinfection model.We used a mouse nasal model of herpes simplex virus 2 (HSV-2) infection to examine thebiological properties of HSV-2 wild-type (wt), TK-negative, and replication-defective strains in vivo. Nasalsepta tissue is the major site of wt viral replication post intranasal (i.n.) inoculation. The HSV-2 strain186 syn(+)-1 wt virus caused lethal encephalitis at doses of 10(4) PFU and above per nostril, and atlower doses no neurons in the trigeminal ganglia were positive for the latency-associated transcript,indicating a lack of latent infection. The 186DeltaKpn TK-negative mutant virus replicated in nasal septatissue but showed low-level replication in trigeminal ganglia at only one timepoint. In situ hybridization oftrigeminal ganglia showed that the number of LAT-positive neurons was proportional to the inoculumdose from 10(3) to 10(6) PFU per nare. The replication-defective mutant virus 5BlacZ showed noreplication in nasal septa tissue and no persistence of viral DNA at the inoculation site or the trigeminalganglia. Nevertheless, inoculation of 5BlacZ or the double-mutant dl5-29 at distal sites reduced acutereplication and latent infection of 186DeltaKpn following intranasal challenge. This infection modelprovides a biological system to test the properties of HSV-2 strains and shows that replication-defectivemutant strains do not persist at sites of inoculation or in sensory ganglia but can induce immuneprotection that reduces the latent viral load of a challenge virus.", "metadata": {}}
+{"_id": "40590358", "title": "", "text": "The sphingosine-1-phosphate receptor agonist FTY720 modulates dendritic cell trafficking in vivo.Thepro-drug FTY720 is undergoing phase III clinical trials for prevention of allograft rejection. Afterphosphorylation, FTY720 targets the G protein-coupled-sphingosine-1-phosphate receptor 1 (S1PR1) onlymphocytes, thereby inhibiting their egress from lymphoid organs and their recirculation to inflammatorysites. Potential effects on dendritic cell (DC) trafficking have not been evaluated. Here, we demonstratethe expression of all five S1PR subtypes (S1PR1-5) by murine DCs. Administration of FTY720 toC57BL/10 mice markedly reduced circulating T and B lymphocytes within 24 h, but not blood-borne DCs,which were enhanced significantly for up to 96 h, while DCs in lymph nodes and spleen were reduced.Numbers of adoptively transferred, fluorochrome-labeled syngeneic or allogeneic DCs in blood wereincreased significantly in FTY720-treated animals, while donor-derived DCs and allostimulatory activityfor host naïve T cells within the spleen were reduced. Administration of the selective S1PR1 agonistSEW2871 significantly enhanced circulating DC numbers. Flow analysis revealed that CD11b,CD31/PECAM-1, CD54/ICAM-1 and CCR7 expression on blood-borne DCs was downregulated followingFTY720 administration. Transendothelial migration of FTY720-P-treated immature DCs to the CCR7 ligandCCL19 was reduced. These novel data suggest that modulation of DC trafficking by FTY720 maycontribute to its immunosuppressive effects.", "metadata": {}}
+{"_id": "40608679", "title": "", "text": "Sustained survivin expression from OX40 costimulatory signals drives T cell clonal expansion.Sustainedsignaling from the T cell receptor (TCR) and costimulatory molecules is thought necessary for generatinghigh numbers of effector T cells. Here, we show that Survivin is controlled in peripheral T cells by OX40cosignaling via sustained PI3k and PKB activation. Survivin is induced by OX40 independent of mitoticprogression in late G1, and blocking Survivin suppresses S-phase transition and division of T cells andleads to apoptosis. Moreover, Survivin expression alone is sufficient to restore proliferation and toantagonize apoptosis in costimulation-deficient T cells and can rescue T cell expansion in vivo. Survivinallows effector T cells to accumulate in large numbers, but Bcl-2 family proteins are required for T cellsurvival after the phase of active division. Thus, sustained Survivin expression from costimulatorysignaling maintains T cell division over time and regulates the extent of clonal expansion.", "metadata": {}}
+{"_id": "40631095", "title": "", "text": "The Combination of Exercise and Respiratory Training Improves Respiratory Muscle Function inPulmonary HypertensionIncreased dyspnea and reduced exercise capacity in pulmonary arterialhypertension (PAH) can be partly attributed to impaired respiratory muscle function. This prospectivestudy was designed to assess the impact of exercise and respiratory training on respiratory musclestrength and 6-min walking distance (6MWD) in PAH patients. Patients with invasively confirmed PAHunderwent 3 weeks of in-hospital exercise and respiratory training, which was continued at home foranother 12 weeks. Medication remained constant during the study period. Blinded observers assessedefficacy parameters at baseline (I) and after 3 (II) and 15 weeks (III). Respiratory muscle function wasassessed by twitch mouth pressure (TwPmo) during nonvolitional supramaximal magnetic phrenic nervestimulation. Seven PAH patients (4 women; mean pulmonary artery pressure 45 ± 11 mmHg, medianWHO functional class 3.1 ± 0.4, idiopathic/associated PAH n = 5/2) were included. The training programwas feasible and well tolerated by all patients with excellent compliance. TwPmo was I: 0.86 ± 0.37 kPa,II: 1.04 ± 0.29 kPa, and III: 1.27 ± 0.44 kPa, respectively. 6MWD was I: 417 ± 51 m, II: 509 ± 39 m,and III: 498 ± 39 m, respectively. Both TwPmo (+0.41 ± 0.34 kPa, +56 ± 39 %) and 6MWD (+81 ± 30m, +20 ± 9 %) increased significantly in the period between baseline and the final assessment (pairwisecomparison: p = 0.012/<0.001; RM-ANOVA considering I, II, III: p = 0.037/<0.001). Exercise andrespiratory training as an adjunct to medical therapy may be effective in patients with PAH to improverespiratory muscle strength and exercise capacity. Future, randomized, controlled trials should be carriedout to further investigate these findings.", "metadata": {}}
+{"_id": "40632104", "title": "", "text": "Dual role of the IL-12/IFN-gamma axis in the development of autoimmune myocarditis: induction byIL-12 and protection by IFN-gamma.IL-12 and IFN-gamma positively regulate each other and type 1inflammatory responses, which are believed to cause tissue damage in autoimmune diseases. Weinvestigated the role of the IL-12/IFN-gamma (Th1) axis in the development of autoimmune myocarditis.IL-12p40-deficient mice on a susceptible background resisted myocarditis. In the absence of IL-12,autospecific CD4(+) T cells proliferated poorly and showed increased Th2 cytokine responses. However,IFN-gamma-deficient mice developed fatal autoimmune disease, and blockade of IL-4R signaling did notconfer susceptibility to myocarditis in IL-12p40-deficient mice, demonstrating that IL-12 triggersautoimmunity by a mechanism independent of the effector cytokines IFN-gamma and IL-4. In conclusion,our results suggest that the IL-12/IFN-gamma axis is a double-edged sword for the development ofautoimmune myocarditis. Although IL-12 mediates disease by induction/expansion of Th1-type cells,IFN-gamma production from these cells limits disease progression.", "metadata": {}}
+{"_id": "40655970", "title": "", "text": "Somatic and Germline Diversification of a Putative Immunoreceptor within One Phylum: Dscam inArthropods.Arthropod Dscam, the homologue of the human Down Syndrome cell adhesion molecule, is areceptor used by the nervous and immune systems. Unlike in vertebrates, evolutionary pressure hasselected and maintained a vast Dscam diversity of isoforms, known to specifying neuronal identity duringthe nervous system differentiation. This chapter examines the different modes of Dscam diversification inthe context of arthropods' evolution and that of their immune system, where its role is controversial. Inthe single Dscam gene of insects and crustaceans, mutually exclusive alternative splicing affects threeclusters of duplicated exons encoding the variable parts of the receptor. The Dscam gene produces over10,000 isoforms. In the more basal arthropods such as centipedes, Dscam diversity results from acombination of many germline genes (over 80) with, in about half of those, the possibility of alternativesplicing affecting only one exon cluster. In the even more basal arthropods, such as chelicerates, nosplicing possibility is detected, but there exist dozens of germline Dscam genes. Compared to controllingthe expression of multiple germline genes, the somatic mutually alternative splicing within a single genemay offer a simplified way of expressing a large Dscam repertoire. Expressed by hemocytes, Dscam isconsidered a phagocytic receptor but is also encountered in solution. More information is necessary aboutits binding to pathogens, its role in phagocytosis, its possible role in specifying hemocyte identity, itskinetics of expression, and the regulation of its RNA splicing to understand how its diversity is linked toimmunity.", "metadata": {}}
+{"_id": "40666943", "title": "", "text": "Epidemiology, health-related quality of life and economic burden of binge eating disorder: a systematicliterature reviewPURPOSE To perform a systematic review on the epidemiology, the health-related qualityof life (HRQoL) and economic burden of binge eating disorder (BED). METHODS A systematic literaturesearch of English-language articles was conducted using Medline, Embase, PsycINFO, PsycARTICLES,Academic Search Complete, CINAHL Plus, Business Source Premier and Cochrane Library. Literaturesearch on epidemiology was limited to studies published between 2009 and 2013. Cost data were inflatedand converted to 2012 US$ purchasing power parities. All of the included studies were assessed forquality. RESULTS Forty-nine articles were included. Data on epidemiology were reported in 31, HRQoLburden in 16, and economic burden in 7 studies. Diagnosis of BED was made using 4th Edition of TheDiagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria in 46 studies. Lifetime prevalenceof BED was 1.1-1.9% in the general population (DSM-IV). BED was associated with significantimpairment in aspects of HRQoL relating to both physical and mental health; the Short Form 36 Physicaland Mental Component Summary mean scores varied between 31.1 to 47.3 and 32.0 to 49.8,respectively. Compared to individuals without eating disorder, BED was related to increased healthcareutilization and costs. Annual direct healthcare costs per BED patient ranged between $2,372 and $3,731.CONCLUSIONS BED is a serious eating disorder that impairs HRQoL and is related to increased healthcareutilization and healthcare costs. The limited literature warrants further research, especially to betterunderstand the long-term HRQoL and economic burden of BED.", "metadata": {}}
+{"_id": "40667066", "title": "", "text": "Subcellular steroid/nuclear receptor dynamics.Steroid hormones, thyroid hormones, retinoic acids, andvitamin D bind to their receptors, which are now called steroid/nuclear receptors, and liganded receptorstranslocate either intracellularly or intranuclearly and form large protein complexes with cofactors toinduce or repress gene transcription. Therefore, steroid/nuclear receptors are ligand-dependenttranscription factors. With the advent of green fluorescent protein (GFP) and its color variants, thesubcellular distribution of many steroid/nuclear receptors has been found to be much more dynamic thanpreviously thought, with some of the receptors shuttling between the cytoplasm and nucleus.Steroid/nuclear receptors can be divided into three categories based on their unliganded distribution:those that are primarily in the nucleus, those in the cytoplasm, and those with mixed cytoplasmic andnuclear distributions. However, in all cases, the addition of a ligand leads to almost complete nucleartranslocation of the receptors. Hormonal stimulation induces intranuclear receptor distribution from ahomogeneous pattern to a heterogeneous dot-like image. Ligand binding to steroid/nuclear receptorsleads to the recruitment of many proteins including cofactors to provoke the redistribution of receptorcomplexes in the nucleus. This focal organization could involve more complex events than simple DNAbinding sites for transcription. Protein activities and interactions of steroid/nuclear receptors can beimaged and localized in a single cell.", "metadata": {}}
+{"_id": "40667577", "title": "", "text": "EMT, the cytoskeleton, and cancer cell invasionThe metastatic process, i.e. the dissemination of cancercells throughout the body to seed secondary tumors at distant sites, requires cancer cells to leave theprimary tumor and to acquire migratory and invasive capabilities. In a process of epithelial-mesenchymaltransition (EMT), besides changing their adhesive repertoire, cancer cells employ developmentalprocesses to gain migratory and invasive properties that involve a dramatic reorganization of the actincytoskeleton and the concomitant formation of membrane protrusions required for invasive growth. Themolecular processes underlying such cellular changes are still only poorly understood, and the variousmigratory organelles, including lamellipodia, filopodia, invadopodia and podosomes, still require a betterfunctional and molecular characterization. Notably, direct experimental evidence linking the formation ofmigratory membrane protrusions and the process of EMT and tumor metastasis is still lacking. In thisreview, we have summarized recent novel insights into the molecular processes and players underlyingEMT on one side and the formation of invasive membrane protrusions on the other side.", "metadata": {}}
+{"_id": "40710501", "title": "", "text": "Different response of human glioma tumor-initiating cells to epidermal growth factor receptor kinaseinhibitors.Because a subpopulation of cancer stem cells (tumor-initiating cells, TICs) is believed to beresponsible for the development, progression, and recurrence of many tumors, we evaluated the in vitrosensitivity of human glioma TICs to epidermal growth factor receptor (EGFR) kinase inhibitors (erlotiniband gefitinib) and possible molecular determinants for their effects. Cells isolated from sevenglioblastomas (GBM 1-7) and grown using neural stem cell permissive conditions were characterized forin vivo tumorigenicity, expression of tumor stem cell markers (CD133, nestin), and multilineagedifferentiation properties, confirming that these cultures are enriched in TICs. TIC cultures werechallenged with increasing concentrations of erlotinib and gefitinib, and their survival was evaluated after1-4 days. In most cases, a time- and concentration-dependent cell death was observed, although GBM 2was completely insensitive to both drugs, and GBM 7 was responsive only to the highest concentrationstested. Using a radioligand binding assay, we show that all GBM TICs express EGFR. Erlotinib andgefitinib inhibited EGFR and ERK1/2 phosphorylation/activation in all GBMs, irrespective of theantiproliferative response observed. However, under basal conditions GBM 2 showed a high Aktphosphorylation that was completely insensitive to both drugs, whereas GBM 7 was completelyinsensitive to gefitinib, and Akt inactivation occurred only for the highest erlotinib concentration tested,showing a precise relationship with the antiproliferative effects of the drug. Interestingly, in GBM 2,phosphatase and tensin homolog expression was significantly down-regulated, possibly accounting for theinsensitivity to the drugs. In conclusion, glioma TICs are responsive to anti-EGFR drugs, but phosphataseand tensin homolog expression and Akt inhibition seem to be necessary for such effect.", "metadata": {}}
+{"_id": "40721190", "title": "", "text": "Structural features of the interaction of the 3'-untranslated region of mRNA containing exosomalRNA-specific motifs with YB-1, a potential mediator of mRNA sorting.We have previously shown that YB-1is the only protein of the HEK293 cell cytoplasmic (S100) extract that specifically interacts with RNAhairpins each containing one of the motifs ACCAGCCU (1), CAGUGAGC (2) and UAAUCCCA (3), which hadbeen identified as often found in exosomal RNA and proposed as potential cis-acting elements targetingRNAs into exosomes. Here we explored the interactions of YB-1 with a fragment of the 3'-untranslatedregion (UTR) of septin 14 mRNA (SEPT14 RNA), which contains all three motifs. We demonstrated theoccurrence of YB-1 among proteins pulled down from the HEK293 S100 extract using biotinylated SEPT14RNA. With recombinant YB-1, it was found that SEPT14 RNA can bind up to 5 moles of protein per mole ofRNA in a cooperative manner, which was shown to be mainly facilitated by the presence of the abovemotifs. RNA hairpins with motifs 1 and 2 competed with SEPT14 RNA for binding to the protein, whereasthat with motif 3 was less competitive, in accordance with the affinity of YB-1 for these RNA hairpins.With YB-1-bound RNA, nucleotides protected from attack by hydroxyl radicals were revealed in all threemotifs, although hairpins with motif 2 and especially with motif 1 contained many protected nucleotidesoutside the motifs, suggesting that the specific environments of these motifs contribute significantly tothe YB-1 binding. An analysis of the environments of motifs 1-3 in the HEK293 cell mRNA 3' UTRs gainedfrom RNA-seq data led us to conclude that the primary binding sites of YB-1 in the 3' UTRs are hairpinscontaining some part of the motif along with its specific surroundings; the consensus sequences of thesehairpins were derived. Thus, our findings provide a new understanding of the structural basis of theinteractions between YB-1 and mRNAs carrying the aforementioned motifs.", "metadata": {}}
+{"_id": "40735046", "title": "", "text": "Periodic screening for breast cancer: the HIP Randomized Controlled Trial. Health Insurance Plan.Thispaper summarizes the findings of the first breast cancer screening trial, which was initiated in December1963 to explore the efficacy of screening. Women aged 40-64 years were selected from enrollees in theHealth Insurance Plan (HIP) of Greater New York and were randomly assigned to study and controlgroups. Study group women were invited for screening, an initial examination, and three annualreexaminations. Screening consisted of film mammography (cephalocaudal and lateral views of eachbreast) and clinical examination of breasts. Breast cancer and mortality from breast cancer wereexamined by treatment group (study vs. control) and by entry-age subgroup. By the end of 18 yearsfrom entry, the study group had about a 25% lower breast cancer mortality among women aged 40-49and 50-59 at time of entry than did the control group. However, to a large extent the difference amongthe 40-49-year-olds occurred in the subgroup with breast cancer diagnosed after these women hadpassed their 50th birthday, and utility of screening women in their forties is questionable.", "metadata": {}}
+{"_id": "40754510", "title": "", "text": "Staphylococcus aureus infections.Micrococcus, which, when limited in its extent and activity, causes acutesuppurative inflammation (phlegmon), produces, when more extensive and intense in its action on thehuman system, the most virulent forms of septicaemia and pyaemia.1 In an elegant series of clinicalobservations and laboratory studies published in 1880 and 1882, Ogston described staphylococcaldisease and its role in sepsis and abscess formation.1,2 More than 100 years later, Staphylococcusaureus remains a versatile and dangerous pathogen in humans. The frequencies of bothcommunity-acquired and hospital-acquired staphylococcal infections have increased steadily, with littlechange in overall mortality. Treatment of these infections . . .", "metadata": {}}
+{"_id": "40760684", "title": "", "text": "Structural overview of the nuclear receptor superfamily: insights into physiology and therapeutics.Asligand-regulated transcription factors, the nuclear hormone receptors are nearly ideal drug targets, withinternal pockets that bind to hydrophobic, drug-like molecules and well-characterized ligand-inducedconformational changes that recruit transcriptional coregulators to promoter elements. Yet, due to themultitude of genes under the control of a single receptor, the major challenge has been the identificationof ligands with gene-selective actions, impacting disease outcomes through a narrow subset of targetgenes and not across their entire gene-regulatory repertoire. Here, we summarize the concepts and workto date underlying the development of steroidal and nonsteroidal receptor ligands, including the use ofcrystal structures, high-throughput screens, and rational design approaches for finding useful therapeuticmolecules. Difficulties in finding selective receptor modulators require a more complete understanding ofreceptor interdomain communications, posttranslational modifications, and receptor-protein interactionsthat could be exploited for target gene selectivity.", "metadata": {}}
+{"_id": "40769868", "title": "", "text": "Differential assembly of inwardly rectifying K+ channel subunits, Kir4.1 and Kir5.1, in brainastrocytes.The inwardly rectifying K+ channel subunit Kir5.1 is expressed abundantly in the brain, but itsprecise distribution and function are still largely unknown. Because Kir5.1 is co-expressed with Kir4.1 inretinal glial Muller cells, we have compared the biochemical and immunological properties of Kir5.1 andKir4.1 in the mouse brain. Immunoprecipitation experiments suggested that brain expressed at least twosubsets of Kir channels, heteromeric Kir4.1/5.1 and homomeric Kir4.1. Immunolabeling using specificantibodies showed that channels comprising Kir4.1 and Kir5.1 subunits were assembled in aregion-specific fashion. Heteromeric Kir4.1/5.1 was identified in the neocortex and in the glomeruli of theolfactory bulb. Homomeric Kir4.1 was confined to the hippocampus and the thalamus. Homomeric Kir5.1was not identified. Kir4.1/5.1 and Kir4.1 expression appeared to occur only in astrocytes, specifically inthe membrane domains facing the pia mater and blood vessels or in the processes surrounding synapses.Both Kir4.1/5.1 and Kir4.1 could be associated with PDZ domain-containing syntrophins, which might beinvolved in the subcellular targeting of these astrocyte Kir channels. Because heteromeric Kir4.1/5.1 andhomomeric Kir4.1 have distinct ion channel properties (Tanemoto, M., Kittaka, N., Inanobe, A., andKurachi, Y. (2000) J. Physiol. (Lond.) 525, 587-592 and Tucker, S. J., Imbrici, P., Salvatore, L., D'Adamo,M. C., and Pessia, M. (2000) J. Biol. Chem. 275, 16404-16407), it is plausible that these channels playdifferential physiological roles in the K+ -buffering action of brain astrocytes in a region-specific manner.", "metadata": {}}
+{"_id": "40781557", "title": "", "text": "Low-grade serous ovarian cancer: a unique disease.Low-grade serous carcinomas representapproximately 10% of all serous ovarian carcinomas. A growing body of research has demonstratedseveral important differences between the clinical and molecular characteristics of these tumors andthose of high-grade serous ovarian carcinomas. Patients with low-grade serous ovarian tumors arediagnosed at a younger age, have a longer overall survival, and have lower response rates toconventional chemotherapy. In addition, low-grade serous ovarian carcinomas have pathologic andmolecular characteristics distinct from high-grade serous carcinomas, yet similar to serous tumors of lowmalignant potential. This suggests a common pathogenesis and a continuum of disease from seroustumors of low malignant potential to low-grade serous carcinomas. Further study, focusing specifically onlow-grade serous carcinomas, is needed to determine the role of other chemotherapeutic agents,hormonal therapy, or targeted biologic agents in the treatment of this disease.", "metadata": {}}
+{"_id": "40790033", "title": "", "text": "Renal outcomes with different fixed-dose combination therapies in patients with hypertension at high riskfor cardiovascular events (ACCOMPLISH): a prespecified secondary analysis of a randomised controlledtrial.BACKGROUND The Avoiding Cardiovascular Events through Combination Therapy in Patients Livingwith Systolic Hypertension (ACCOMPLISH) trial showed that initial antihypertensive therapy withbenazepril plus amlodipine was superior to benazepril plus hydrochlorothiazide in reducing cardiovascularmorbidity and mortality. We assessed the effects of these drug combinations on progression of chronickidney disease. METHODS ACCOMPLISH was a double-blind, randomised trial undertaken in five countries(USA, Sweden, Norway, Denmark, and Finland). 11 506 patients with hypertension who were at high riskfor cardiovascular events were randomly assigned via a central, telephone-based interactive voiceresponse system in a 1:1 ratio to receive benazepril (20 mg) plus amlodipine (5 mg; n=5744) orbenazepril (20 mg) plus hydrochlorothiazide (12.5 mg; n=5762), orally once daily. Drug doses wereforce-titrated for patients to attain recommended blood pressure goals. Progression of chronic kidneydisease, a prespecified endpoint, was defined as doubling of serum creatinine concentration or end-stagerenal disease (estimated glomerular filtration rate <15 mL/min/1.73 m(2) or need for dialysis). Analysiswas by intention to treat (ITT). This trial is registered with ClinicalTrials.gov, number NCT00170950.FINDINGS The trial was terminated early (mean follow-up 2.9 years [SD 0.4]) because of superiorefficacy of benazepril plus amlodipine compared with benazepril plus hydrochlorothiazide. At trialcompletion, vital status was not known for 143 (1%) patients who were lost to follow-up (benazepril plusamlodipine, n=70; benazepril plus hydrochlorothiazide, n=73). All randomised patients were included inthe ITT analysis. There were 113 (2.0%) events of chronic kidney disease progression in the benazeprilplus amlodipine group compared with 215 (3.7%) in the benazepril plus hydrochlorothiazide group (HR0.52, 0.41-0.65, p<0.0001). The most frequent adverse event in patients with chronic kidney diseasewas peripheral oedema (benazepril plus amlodipine, 189 of 561, 33.7%; benazepril plushydrochlorothiazide, 85 of 532, 16.0%). In patients with chronic kidney disease, angio-oedema was morefrequent in the benazepril plus amlodipine group than in the benazepril plus hydrochlorothiazide group. Inpatients without chronic kidney disease, dizziness, hypokalaemia, and hypotension were more frequent inthe benazepril plus hydrochlorothiazide group than in the benazepril plus amlodipine group.INTERPRETATION Initial antihypertensive treatment with benazepril plus amlodipine should be consideredin preference to benazepril plus hydrochlorothiazide since it slows progression of nephropathy to agreater extent. FUNDING Novartis.", "metadata": {}}
+{"_id": "40817021", "title": "", "text": "Effects of exercise training on health status in patients with chronic heart failure: HF-ACTION randomizedcontrolled trial.CONTEXT Findings from previous studies of the effects of exercise training onpatient-reported health status have been inconsistent. OBJECTIVE To test the effects of exercise trainingon health status among patients with heart failure. DESIGN, SETTING, AND PATIENTS Multicenter,randomized controlled trial among 2331 medically stable outpatients with heart failure with leftventricular ejection fraction of 35% or less. Patients were randomized from April 2003 through February2007. INTERVENTIONS Usual care plus aerobic exercise training (n = 1172), consisting of 36 supervisedsessions followed by home-based training, vs usual care alone (n = 1159). Randomization was stratifiedby heart failure etiology, which was a covariate in all models. MAIN OUTCOME MEASURES Kansas CityCardiomyopathy Questionnaire (KCCQ) overall summary scale and key subscales at baseline, every 3months for 12 months, and annually thereafter for up to 4 years. The KCCQ is scored from 0 to 100 withhigher scores corresponding to better health status. Treatment group effects were estimated using linearmixed models according to the intention-to-treat principle. RESULTS Median follow-up was 2.5 years. At3 months, usual care plus exercise training led to greater improvement in the KCCQ overall summaryscore (mean, 5.21; 95% confidence interval, 4.42 to 6.00) compared with usual care alone (3.28; 95%confidence interval, 2.48 to 4.09). The additional 1.93-point increase (95% confidence interval, 0.84 to3.01) in the exercise training group was statistically significant (P < .001). After 3 months, there were nofurther significant changes in KCCQ score for either group (P = .85 for the difference between slopes),resulting in a sustained, greater improvement overall for the exercise group (P < .001). Results weresimilar on the KCCQ subscales, and no subgroup interactions were detected. CONCLUSIONS Exercisetraining conferred modest but statistically significant improvements in self-reported health statuscompared with usual care without training. Improvements occurred early and persisted over time. TRIALREGISTRATION clinicaltrials.gov Identifier: NCT00047437.", "metadata": {}}
+{"_id": "40867854", "title": "", "text": "Acute respiratory failure in patients with severe community-acquired pneumonia: a prospectiverandomized evaluation of noninvasive ventilation.In uncontrolled studies, noninvasive positive pressureventilation (NPPV) was found useful in avoiding endotracheal intubation in patients with acute respiratoryfailure (ARF) caused by severe community-acquired pneumonia (CAP). We conducted a prospective,randomized study comparing standard treatment plus NPPV delivered through a face mask to standardtreatment alone in patients with severe CAP and ARF. Patients fitting the American Thoracic Societycriteria for severe CAP were included in presence of ARF (refractory hypoxemia and/or hypercapnia withacidosis). Exclusion criteria were: severe hemodynamic instability, requirement for emergentcardiopulmonary resuscitation, home mechanical ventilation or oxygen long-term supplementation,concomitant severe disease with a low expectation of life, inability to expectorate or contraindications tothe use of the mask. Fifty-six consecutive patients (28 in each arm) were enrolled, and the two groupswere similar at study entry. The use of NPPV was well tolerated, safe, and associated with a significantreduction in respiratory rate, need for endotracheal intubation (21% versus 50%; p = 0.03), andduration of intensive care unit (ICU) stay (1.8 ± 0.7 d versus 6 ± 1.8 d; p = 0.04). The two groups had asimilar intensity of nursing care workload, time interval from study entry to endotracheal intubation,duration of hospitalization, and hospital mortality. Among patients with chronic obstructive pulmonarydisease (COPD), those randomized to NPPV had a lower intensity of nursing care workload (p = 0.04) andimproved 2-mo survival (88.9% versus 37.5%; p = 0.05). We conclude that in selected patients with ARFcaused by severe CAP, NPPV was associated with a significant reduction in the rate of endotrachealintubation and duration of ICU stay. A 2-mo survival advantage was seen in patients with COPD.", "metadata": {}}
+{"_id": "40900242", "title": "", "text": "Smallest angiosperm genomes found in lentibulariaceae, with chromosomes of bacterial size.Nuclearholoploid genome sizes (C-values) have been estimated to vary about 800-fold in angiosperms, with thesmallest established 1C-value of 157 Mbp recorded in Arabidopsis thaliana. In the highly specializedcarnivorous family Lentibulariaceae now three taxa have been found that exhibit significantly lowervalues: Genlisea margaretae with 63 Mbp, G. aurea with 64 Mbp, and Utricularia gibba with 88 Mbp. Thesmallest mitotic anaphase chromatids in G. aurea have 2.1 Mbp and are thus of bacterial size (NB: E. colihas ca. 4 Mbp). Several Utricularia species range somewhat lower than A. thaliana or are similar ingenome size. The highest 1C-value known from species of Lentibulariaceae was found in Genliseahispidula with 1510 Mbp, and results in about 24-fold variation for Genlisea and the Lentibulariaceae.Taking into account these new measurements, genome size variation in angiosperms is now almost2000-fold. Genlisea and Utricularia are plants with terminal positions in the phylogeny of the eudicots, sothat the findings are relevant for the understanding of genome miniaturization. Moreover, theGenlisea-Utricularia clade exhibits one of the highest mutational rates in several genomic regions inangiosperms, what may be linked to specialized patterns of genome evolution. Ultrasmall genomes havenot been found in Pinguicula, which is the sister group of the Genlisea-Utricularia clade, and which doesnot show accelerated mutational rates. C-values in Pinguicula varied only 1.7-fold from 487 to 829 Mbp.", "metadata": {}}
+{"_id": "40900567", "title": "", "text": "Parasite multiplication potential and the severity of Falciparum malaria.The multiplication rates andinvasiveness of Plasmodium falciparum parasites isolated from adult Thai patients hospitalized withuncomplicated malaria (n=34) were compared with those from persons with severe malaria (n=42). Tosimulate severe malaria and control for host effects, the in vitro cultures were adjusted to 1%parasitemia and used the same red blood cell donor. P. falciparum isolates from persons with severemalaria had initial cycle multiplication rates in vitro that were 3-fold higher than those fromuncomplicated malaria (median [95% confidence interval], 8.3 [7. 1-10.5] vs. 2.8 [1.7-3.9]; P=.001).Parasites causing severe malaria exhibited unrestricted red blood cell invasion, whereas those fromuncomplicated malaria were restricted to a geometric mean of 40 (31%-53%) of red blood cells. P.falciparum parasites causing severe malaria were less selective and multiplied more at high parasitemiasthan those causing uncomplicated malaria.", "metadata": {}}
+{"_id": "40901687", "title": "", "text": "PHD3-dependent hydroxylation of HCLK2 promotes the DNA damage response.The DNA damageresponse (DDR) is a complex regulatory network that is critical for maintaining genome integrity.Posttranslational modifications are widely used to ensure strict spatiotemporal control of signal flow, buthow the DDR responds to environmental cues, such as changes in ambient oxygen tension, remainspoorly understood. We found that an essential component of the ATR/CHK1 signaling pathway, thehuman homolog of the Caenorhabditis elegans biological clock protein CLK-2 (HCLK2), associated withand was hydroxylated by prolyl hydroxylase domain protein 3 (PHD3). HCLK2 hydroxylation wasnecessary for its interaction with ATR and the subsequent activation of ATR/CHK1/p53. Inhibiting PHD3,either with the pan-hydroxylase inhibitor dimethyloxaloylglycine (DMOG) or through hypoxia, preventedactivation of the ATR/CHK1/p53 pathway and decreased apoptosis induced by DNA damage. Consistentwith these observations, we found that mice lacking PHD3 were resistant to the effects of ionizingradiation and had decreased thymic apoptosis, a biomarker of genomic integrity. Our identification ofHCLK2 as a substrate of PHD3 reveals the mechanism through which hypoxia inhibits the DDR,suggesting hydroxylation of HCLK2 is a potential therapeutic target for regulating the ATR/CHK1/p53pathway.", "metadata": {}}
+{"_id": "40905302", "title": "", "text": "Economic implications of nighttime attending intensivist coverage in a medical intensive careunit.OBJECTIVE Our objective was to assess the cost implications of changing the intensive care unitstaffing model from on-demand presence to mandatory 24-hr in-house critical care specialist presence.DESIGN A pre-post comparison was undertaken among the prospectively assessed cohorts of patientsadmitted to our medical intensive care unit 1 yr before and 1 yr after the change. Our data were stratifiedby Acute Physiology and Chronic Health Evaluation III quartile and whether a patient was admitted duringthe day or at night. Costs were modeled using a generalized linear model with log-link and γ-distributederrors. SETTING A large academic center in the Midwest. PATIENTS All patients admitted to the adultmedical intensive care unit on or after January 1, 2005 and discharged on or before December 31, 2006.Patients receiving care under both staffing models were excluded. INTERVENTION Changing the intensivecare unit staffing model from on-demand presence to mandatory 24-hr in-house critical care specialistpresence. MEASUREMENTS AND MAIN RESULTS Total cost estimates of hospitalization were calculated foreach patient starting from the day of intensive care unit admission to the day of hospital discharge.Adjusted mean total cost estimates were 61% lower in the post period relative to the pre period forpatients admitted during night hours (7 pm to 7 am) who were in the highest Acute Physiology andChronic Health Evaluation III quartile. No significant differences were seen at other severity levels. Theunadjusted intensive care unit length of stay fell in the post period relative to the pre period (3.5 vs. 4.8)with no change in non-intensive care unit length of stay. CONCLUSIONS We find that 24-hr intensive careunit intensivist staffing reduces lengths of stay and cost estimates for the sickest patients admitted atnight. The costs of introducing such a staffing model need to be weighed against the potential totalsavings generated for such patients in smaller intensive care units, especially ones that predominantlycare for lower-acuity patients.", "metadata": {}}
+{"_id": "40913091", "title": "", "text": "GENOTYPING OF THALASSEMIA IN MICROCYTIC HYPOCHROMIC ANEMIA PATIENTS FROM SOUTHWESTREGION OF IRANObjective: To evaluate the frequency of α -gene, s-gene, and hemoglobin variantnumbers in subjects with Microcytic hypochromic anemia. Methodology: In total out of 850, 340 subjectswith microcytic hypochromic anemia [MCV<80fl; MCH<27pg] from Southwest part of Iran, were studiedin Research Center of Thalassemia and Hemoglobinopathies (RCTH) which is the only center working onhematology and oncology in Southwest (Khuzestan) region of Iran. These include 325 individuals: 171with Beta-thalassemia trait, 88 with Alpha-thalassemia trait, 13 with thalassemia major, 11 withhemoglobin variants (HbS, HbC, and HbD Punjab ) and 42 with iron-deficiency anemia. The rest 15patients diagnosed with no definite etiology. Results: Genotyping for -α 3.7 , -α 4.2 , – α PA , - α 5NT and- - MED was done with gap-PCR. The overall frequency of - α 3.7 deletion in 325 individuals is 20%.Genotyping for 23 most known s-gene mutations was done with direct mutation analysis by AmplificationRefractory Mutation System (ARMS). The most frequent mutations were CD 36/37, IVS II-I, and IVSI-110 with 9.7%, 11.7%, and 3.5% respected frequencies in 340 patients. There was statisticallysignificant difference between Beta-thalassemia trait and Beta-thalassemia Major in case of MCV (p-value = 0.25) and MCH (P–value =0.23) indices, and also MCH index between Beta-thalassemia trait andHb Variants (P-value = 0.04). Conclusion: The α -gene and s-gene mutation is quite common in theSouthwest part of Iran. Molecular genotyping of α -thalassemia and s-thalassemia help to diagnoseunexplained microcytosis, and thus prevent unnecessary iron supplementation.", "metadata": {}}
+{"_id": "40935722", "title": "", "text": "Systemic biomarkers in exacerbations of COPD: the evolving clinical challenge.BACKGROUNDExacerbations of COPD (ECOPD) remain a major cause of mortality and morbidity. Despite advances inthe understanding of their pathophysiology, their assessment relies primarily on clinical presentation,which can be variable and difficult to predict. A large number of biomarkers already have been assessedin this context, and some appear to be promising. METHODS An online search for articles published untilDecember 2010 was conducted using three terms for ECOPD, five terms for biomarkers, and five termsfor the sampling method. Biomarkers were evaluated for their potential role in the establishment andconfirmation of the diagnosis of ECOPD, the evaluation of etiology and severity, the prediction ofprognosis, and the guidance of treatment decisions. RESULTS Several systemic biomarkers have beenmeasured in the context of ECOPD, and most have been found to increase at ECOPD onset and to subsideduring the course of exacerbations. Correlations have been reported among these biomarkers, but directassociations with clinical variables have been more difficult to establish. Although there are severallimitations yet to be addressed, some of the biomarkers, most notably C-reactive protein for theidentification of an ECOPD and procalcitonin for antibiotic guidance, may provide clinically relevantinformation. CONCLUSIONS So far , no single biomarker has been able to gain wide acceptance, butsome provide clinically useful information. The evaluation of such biomarkers in large decision-makingstudies is expected to become an area of intense investigation in the near future.", "metadata": {}}
+{"_id": "40949706", "title": "", "text": "Preoperative Predictors of Weight Loss Following Bariatric Surgery: Systematic ReviewObesity affects32% of adults in the USA. Surgery generates substantial weight loss, but 20–30% fails to achievesuccessful weight loss. Our objective was to identify preoperative psychosocial factors associated withweight loss following bariatric surgery. We performed a literature search of PubMed® and the CochraneDatabase of Reviews of Effectiveness between 1988 and April 2010. Articles were screened for bariatricsurgery and weight loss if they included a preoperative predictor of weight loss: body mass index (BMI),preoperative weight loss, eating disorders, or psychiatric disorder/substance abuse. One thousand seventitles were reviewed, 534 articles screened, and 115 included in the review. Factors that may bepositively associated with weight loss after surgery include mandatory preoperative weight loss (7 of 14studies with positive association). Factors that may be negatively associated with weight loss includepreoperative BMI (37 out of 62 studies with negative association), super-obesity (24 out of 33 studies),and personality disorders (7 out of 14 studies). Meta-analysis revealed a decrease of 10.1% excessweight loss (EWL) for super-obese patients (95% confidence interval (CI) [3.7–16.5%]), though therewas significant heterogeneity in the meta-analysis, and an increase of 5.9% EWL for patients with bingeeating at 12 months after surgery (95% CI [1.9–9.8%]). Further studies are necessary to investigatewhether preoperative factors can predict a clinically meaningful difference in weight loss after bariatricsurgery. The identification of predictive factors may improve patient selection and help developinterventions targeting specific needs of patients.", "metadata": {}}
+{"_id": "40963697", "title": "", "text": "The tumor necrosis factor receptor stalk regions define responsiveness to soluble versusmembrane-bound ligand.The family of tumor necrosis factor receptors (TNFRs) and their ligands form aregulatory signaling network that controls immune responses. Various members of this receptor familyrespond differently to the soluble and membrane-bound forms of their respective ligands. However, thedetermining factors and underlying molecular mechanisms of this diversity are not yet understood. Usingan established system of chimeric TNFRs and novel ligand variants mimicking the bioactivity ofmembrane-bound TNF (mTNF), we demonstrate that the membrane-proximal extracellular stalk regionsof TNFR1 and TNFR2 are crucial in controlling responsiveness to soluble TNF (sTNF). We show that thestalk region of TNFR2, in contrast to the corresponding part of TNFR1, efficiently inhibits both thereceptor's enrichment/clustering in particular cell membrane regions and ligand-independent homotypicreceptor preassembly, thereby preventing sTNF-induced, but not mTNF-induced, signaling. Thus, thestalk regions of the two TNFRs not only have implications for additional TNFR family members, but alsoprovide potential targets for therapeutic intervention.", "metadata": {}}
+{"_id": "40971746", "title": "", "text": "A bird's-eye view of sex chromosome dosage compensation.Intensive study of a few genetically tractablespecies with XX/XY sex chromosomes has produced generalizations about the process of sexchromosome dosage compensation that do not fare well when applied to ZZ/ZW sex chromosomesystems, such as those in birds. The inherent sexual imbalance in dose of sex chromosome genes has ledto the evolution of sex-chromosome-wide mechanisms for balancing gene dosage between the sexes andrelative to autosomal genes. Recent advances in our knowledge of avian genomes have led to areexamination of sex-specific dosage compensation (SSDC) in birds, which is less effective than in knownXX/XY systems. Insights about the mechanisms of SSDC in birds also suggest similarities to anddifferences from those in XX/XY species. Birds are thus offering new opportunities for studying dosagecompensation in a ZZ/ZW system, which should shed light on the evolution of SSDC more broadly.", "metadata": {}}
+{"_id": "40987633", "title": "", "text": "The role of CHMP2BIntron5 in autophagy and frontotemporal dementia.Charged multivesicular bodyprotein 2B (CHMP2B) - a component of the endosomal complex required for transport-III (ESCRT-III) - isresponsible for the vital membrane deformation functions in autophagy and endolysosomal trafficking. Adominant mutation in CHMP2B (CHMP2BIntron5) is associated with a subset of heritable frontotemporaldementia - frontotemporal dementia linked to chromosome 3 (FTD-3). ESCRT-III recruits Vps4, anAAA-ATPase that abscises the membrane during various cellular processes including autophagy andintraluminal vesicle formation. CHMP2BIntron5 results in a C-terminus truncation removing an importantVps4 binding site as well as eliminating the normal autoinhibitory resting state of CHMP2B. CHMP2B isexpressed in most cell types but seems to be especially vital for proper neuronal function.CHMP2BIntron5-mediated phenotypes include misregulation of transmembrane receptors, accumulationof multilamellar structures, abnormal lysosomal morphology, down regulation of a brain-specific microRNA (miRNA-124), abnormal dendritic spine morphology, decrease in dendritic arborization, and celldeath. Currently, transgenic-fly,-mouse, and -human cell lines are being used to better understand thediverse phenotypes and develop therapeutic approaches for the CHMP2BIntron5-induced FTD-3. Thisarticle is part of a Special Issue entitled SI:Autophagy.", "metadata": {}}
+{"_id": "40996863", "title": "", "text": "Restless legs syndrome and attention-deficit/hyperactivity disorder: a review of the literature.STUDYOBJECTIVE To review evidence on the association between restless legs syndrome (RLS) andattention-deficit/hyperactivity disorder (ADHD), to discuss the hypothetical mechanisms underlying thisassociation, and to consider the potential interest for common pharmacologic treatments of RLS andADHD when co-occurring. METHOD A PubMed search. RESULTS In clinical samples, up to 44% of subjectswith ADHD have been found to have RLS or RLS symptoms, and up to 26% of subjects with RLS havebeen found to have ADHD or ADHD symptoms. Several mechanisms may explain this association. Sleepdisruption associated with RLS might lead to inattentiveness, moodiness, and paradoxical overactivity.Diurnal manifestations of RLS, such as restlessness and inattention, might mimic ADHD symptoms.Alternatively, RLS might be comorbid with idiopathic ADHD. Subjects with RLS and a subset of subjectswith ADHD might share a common dopamine dysfunction. Limited evidence suggests that somedopaminergic agents, such as levodopa/carbidopa, pergolide, and ropinirole, may be effective in childrenwith RLS associated with ADHD symptoms. CONCLUSIONS Although still limited, evidence from clinicalstudies demonstrates an association between RLS and ADHD or ADHD symptoms. Further clinical studiesusing standard criteria and procedures are needed to better estimate the degree of association.Epidemiologic studies are required to assess the relationship between ADHD and RLS symptoms innonclinical samples. Further investigations should address the mechanisms underlying the relationshipbetween RLS and ADHD. Several dopaminergic agents seem to be promising treatment for RLSassociated with ADHD symptoms. To date, however, the absence of randomized and blinded controlledstudies does not allow evidence-based recommendations.", "metadata": {}}
+{"_id": "41022628", "title": "", "text": "Impact of the KU80 pathway on NHEJ-induced genome rearrangements in mammalian cells.Using asubstrate measuring deletion or inversion of an I-SceI-excised fragment and both accurate andinaccurate rejoining, we determined the impact of non-homologous end-joining (NHEJ) on mammalianchromosome rearrangements. Deletion is 2- to 8-fold more efficient than inversion, independent of theDNA ends structure. KU80 controls accurate rejoining, whereas in absence of KU mutagenic rejoining,particularly microhomology-mediated repair, occurs efficiently. In cells bearing both the NHEJ and ahomologous recombination (HR) substrate containing a third I-SceI site, we show that NHEJ is at least3.3-fold more efficient than HR, and translocation of the I-SceI fragment from the NHEJ substrate locusinto the HR-I-SceI site can occur, but 50- to 100-fold less frequently than deletion. Deletions andtranslocations show both accurate and inaccurate rejoining, suggesting that they correspond to a mix ofKU-dependent and KU-independent processes. Thus these processes should represent prominentpathways for DSB-induced genetic instability in mammalian cells.", "metadata": {}}
+{"_id": "41024260", "title": "", "text": "The multi-zinc finger protein ZNF217 contacts DNA through a two-finger domain.Classical C2H2 zincfinger proteins are among the most abundant transcription factors found in eukaryotes, and themechanisms through which they recognize their target genes have been extensively investigated. Ingeneral, a tandem array of three fingers separated by characteristic TGERP links is required forsequence-specific DNA recognition. Nevertheless, a significant number of zinc finger proteins do notcontain a hallmark three-finger array of this type, raising the question of whether and how they contactDNA. We have examined the multi-finger protein ZNF217, which contains eight classical zinc fingers.ZNF217 is implicated as an oncogene and in repressing the E-cadherin gene. We show that two of its zincfingers, 6 and 7, can mediate contacts with DNA. We examine its putative recognition site in theE-cadherin promoter and demonstrate that this is a suboptimal site. NMR analysis and mutagenesis isused to define the DNA binding surface of ZNF217, and we examine the specificity of the DNA bindingactivity using fluorescence anisotropy titrations. Finally, sequence analysis reveals that a variety ofmulti-finger proteins also contain two-finger units, and our data support the idea that these mayconstitute a distinct subclass of DNA recognition motif.", "metadata": {}}
+{"_id": "41074251", "title": "", "text": "Knowledge, attitudes, risk perception, and cancer screening behaviors among cancersurvivors.BACKGROUND Knowledge, attitudes, and risk perception in relation to second primary cancer(SPC) screening and their impact on screening practices in cancer survivors are largely unknown.METHODS A total of 326 cancer survivors who had completed primary treatment for cancer >1 yearpreviously were recruited from 6 oncology care outpatient clinics in the Republic of Korea. Survivors'knowledge, attitudes, perceived risk, and screening practices were assessed along withsociodemographic, behavioral, and clinical characteristics. Multivariate logistic regression was used toexamine behavioral factors associated with the completion of all appropriate SPC screening according tonational guidelines. RESULTS Approximately 37.7% of survivors had undergone all appropriate SPCscreening tests. Survivors were found to have a high perceived risk of SPC, high perceived benefits ofscreening, and positive attitudes toward cancer screening. However, they had limited knowledgeregarding SPC screening tests and few had received a recommendation from a physician to undergo SPCscreening. Although there was no association found between perceived risk and positive attitudes withscreening behavior, higher knowledge was noted to be significantly associated with the completion of allappropriate SPC screening (adjusted odds ratio, 1.81; 95% confidence interval, 1.03-3.33).CONCLUSIONS In the current study, cancer survivors were found to have limited knowledge regardingsecond cancer screening tests, which may have resulted in lower rates of completion of screeningpractices in this population.", "metadata": {}}
+{"_id": "41087952", "title": "", "text": "Ria1p (Ynl163c), a protein similar to elongation factors 2, is involved in the biogenesis of the 60S subunitof the ribosome in Saccharomyces cerevisiaeRIA1 (YNL163c) is a quasi-essential gene that encodes aprotein with strong similarities to elongation factors 2. Small C-terminal deletions in the protein lead to asevere growth defect. In the case of a 22-residue C-terminal deletion this can be suppressed byintragenic mutations in the RIA1 gene or dominant extragenic mutations in TIF6, which is thought to beinvolved in the biogenesis of the 60S subunit of the ribosome. The dominant TIF6 alleles can alsosuppress the phenotype associated with a complete deletion of the RIA1 gene. Depletion of Ria1p has adramatic effect on the polysome profile: there is a severe reduction in the level of the 80S monosomes,an imbalance in the 40S/60S ratio, and halfmers appear. Dissociation of the monosomes and polysomesin the Ria1p depletion mutant revealed a specific reduction in the amount of 60S subunits. Localizationexperiments with HA-tagged derivatives of Ria1p did not detect any stable association of Ria1p withribosome subunits, 80S monosomes or polysomes. Cell fractionation experiments show that Ria1p isfound in both the cytoplasmic fraction and the nuclear fraction. Taken together, these data suggest thatRia1p is involved in the biogenesis of the 60S subunit of the ribosome.", "metadata": {}}
+{"_id": "41120293", "title": "", "text": "The Intestinal Immune System in Obesity and Insulin Resistance.Obesity and insulin resistance areassociated with chronic inflammation in metabolic tissues such as adipose tissue and the liver. Recently,growing evidence has implicated the intestinal immune system as an important contributor to metabolicdisease. Obesity predisposes to altered intestinal immunity and is associated with changes to the gutmicrobiota, intestinal barrier function, gut-residing innate and adaptive immune cells, and oral toleranceto luminal antigens. Accordingly, the gut immune system may represent a novel therapeutic target forsystemic inflammation in insulin resistance. This review discusses the emerging field of intestinalimmunity in obesity-related insulin resistance and how it affects metabolic disease.", "metadata": {}}
+{"_id": "41131087", "title": "", "text": "Human placental lactogen and unconjugated estriol concentrations in twin pregnancy: monitoring of fetaldevelopment in intrauterine growth retardation and single intrauterine fetal death.Human placentallactogen and unconjugated estriol concentrations in maternal serum were evaluated in 100 uneventfultwin pregnancies, and these values were compared with those observed in 16 twin pregnanciesassociated with intrauterine growth retardation or single intrauterine fetal death. In pregnanciesassociated with intrauterine growth retardation (n = 8), human placental lactogen levels were at thelower limit of normal range for singleton pregnancies, whereas estriol levels were normal in most cases.When one of the fetuses had died before week 33 of pregnancy (n = 5), both human placental lactogenand estriol levels were low and they were almost at the levels in singleton pregnancy. When intrauterinefetal death occurred after week 36 of pregnancy (n = 3), both hormone levels remained normal untilterm. Thus human placental lactogen rather than estriol is a good indicator of intrauterine growthretardation in twin pregnancy. Both human placental lactogen and estriol are useful for the monitoring ofthe surviving fetus in the case of single intrauterine fetal death.", "metadata": {}}
+{"_id": "41133176", "title": "", "text": "Low antioxidant enzyme gene expression in pancreatic islets compared with various other mousetissues.Using a sensitive Northern blot hybridization technique, gene expression of superoxide dismutase(SOD), catalase, and glutathione peroxidase was studied in pancreatic islets and for comparison invarious other mouse tissues (liver, kidney, brain, lung, skeletal muscle, heart muscle, adrenal gland, andpituitary gland). Gene expression of the antioxidant enzymes was usually in the range of +/- 50% of thatin the liver. Only in pancreatic islets gene expression was substantially lower. The levels of thecytoplasmic Cu/Zn SOD and the mitochondrial Mn SOD gene expression were in the range of 30-40% ofthose in the liver. Glutathione peroxidase gene expression was 15%, and catalase gene expression wasnot at all detectable in pancreatic islets. These low levels of antioxidant enzyme gene expression mayprovide an explanation for the extraordinary sensitivity of pancreatic beta cells towards cytotoxic damageby diabetogenic compounds and during the development of human and animal diabetes.", "metadata": {}}
+{"_id": "41159361", "title": "", "text": "Cyclic nucleotide phosphodiesterase isozymes expressed in mouse skeletal muscle.To understandchanges in cyclic nucleotide metabolism in muscle disease states, the expression of phosphodiesterase(PDE) isozymes in normal mouse leg muscle was examined. Four subcellular fractions were generated bydifferential centrifugation at 10,000 x g and 100,000 x g. cAMP PDE activity was found predominately inthe soluble fractions, while cGMP PDE activity was more evenly distributed amongst soluble andparticulate fractions. Pharmacological inhibitors demonstrate that PDE4 represents the major cAMPhydrolyzing activity and PDE2 represents the major cGMP hydrolyzing activity in mouse leg muscle. PDE1is expressed at low levels, while PDE3 and PDE5 are intermediate. Between 20 and 40% of total PDEactivity remained in the presence of inhibitors for PDE1-PDE5, indicating that other PDE familiescontribute to the total PDE pool. Reverse-transcription PCR with family-specific primers showedexpression of mRNA for PDE7-PDE9, supporting this conclusion. Total PDE activity was found to beelevated in tissue extracts from a mouse model of Duchenne's muscular dystrophy.", "metadata": {}}
+{"_id": "41161366", "title": "", "text": "Exercise-induced asthma.The effect of exercise on ventilatory function was studied in 7 patients withasthma. Three showed appreciable decrease in forced expiratory volume in one second (FEV 1) afterexercise. The degree of hyperventilation produced by exercise correlated with the postexercise decreasein FEV 1. Voluntary hyperventilation at rest produced a decrease in FEV 1 in all patients with asthma.Breathing 5.6 per cent carbon dioxide during voluntary hyperventilation instead of room air induced alarger ventilation and greater decrease in FEV1. Neither exercise nor voluntary hyperventilation had anysignificant effect on the FEV 1 in normal subjects and patients with chronic bronchitis. Bothexercise·induced and hyperventilation-induced decrease in FEV 1 were inhibited by prior administration ofisoproterenol but not by atropine. It is postulated that exercise-induced asthma is probablyhyperventilation-induced asthma. Several underlying mechanisms by which airway obstruction isproduced are possible.", "metadata": {}}
+{"_id": "41165286", "title": "", "text": "An antimicrobial protein of the gut symbiont Bacteroides fragilis with a MACPF domain of host immuneproteins.Bacteroidales are the most abundant Gram-negative bacteria of the human intestinal microbiotacomprising more than half of the bacteria in many individuals. Some of the factors that these bacteria useto establish and maintain themselves in this ecosystem are beginning to be identified. However,ecological competition, especially interference competition where one organism directly harms another, islargely unexplored. To begin to understand the relevance of this ecological principle as it applies to theseabundant gut bacteria and factors that may promote such competition, we screened Bacteroides fragilisfor the production of antimicrobial molecules. We found that the production of extracellularly secretedantimicrobial molecules is widespread in this species. The first identified molecule, described in thismanuscript, contains a membrane attack complex/perforin (MACPF) domain present in host immunemolecules that kill bacteria and virally infected cells by pore formation, and mutations affecting keyresidues of this domain abrogated its activity. This antimicrobial molecule, termed BSAP-1, is secretedfrom the cell in outer membrane vesicles and no additional proteins are required for its secretion,processing or immunity of the producing cell. This study provides the first insight into secreted moleculesthat promote competitive interference among Bacteroidales strains of the human gut.", "metadata": {}}
+{"_id": "41182002", "title": "", "text": "Directional perception of distributed sound sources.The perception of spatially distributed sound sourceswas investigated by conducting two listening experiments in anechoic conditions with 13 loudspeakersevenly distributed in the frontal horizontal plane emitting incoherent noise signals. In the firstexperiment, widely distributed sound sources with gaps in their distribution emitted pink noise. Theresults indicated that the exact loudspeaker distribution could not be perceived accurately and that thewidth of the distribution was perceived to be narrower than it was in reality. Up to three spatiallydistributed loudspeakers that were simultaneously emitting sound could be individually perceived. Inaddition, the number of loudspeakers that were indicated as emitting sound was smaller than the actualnumber. In the second experiment, a reference with 13 loudspeakers and test cases with fewerloudspeakers were presented and their perceived spatial difference was rated. The effect of the noisebandwidth was of particular interest. Noise with different bandwidths centered around 500 and 4000 Hzwas used. The results indicated that when the number of loudspeakers was increased from four to seven,the perceived auditory event was very similar to that perceived with 13 loudspeakers at all bandwidths.The perceived differences were larger in wideband noise than in narrow-band noise.", "metadata": {}}
+{"_id": "41226276", "title": "", "text": "Adoptive T cell transfer for cancer immunotherapy in the era of synthetic biology.Adoptive T cell transferfor cancer and chronic infection is an emerging field that shows promise in recent trials.Synthetic-biology-based engineering of T lymphocytes to express high-affinity antigen receptors canovercome immune tolerance, which has been a major limitation of immunotherapy-based strategies.Advances in cell engineering and culture approaches to enable efficient gene transfer and ex vivo cellexpansion have facilitated broader evaluation of this technology, moving adoptive transfer from a\"boutique\" application to the cusp of a mainstream technology. The major challenge currently facing thefield is to increase the specificity of engineered T cells for tumors, because targeting shared antigens hasthe potential to lead to on-target off-tumor toxicities, as observed in recent trials. As the field of adoptivetransfer technology matures, the major engineering challenge is the development of automated cellculture systems, so that the approach can extend beyond specialized academic centers and becomewidely available.", "metadata": {}}
+{"_id": "41233511", "title": "", "text": "Bruce treadmill test in children: normal values in a clinic population.The Bruce treadmill protocol issuitable for children as young as age 4 years. Maximal endurance time may be used as the sole criterionof exercise capacity, and normal values were established with 327 children having an innocent heartmurmur. Mean endurance time in boys increased from 10.4 minutes at age 4 to 5 years, to 14.1 minutesat age 13 to 15 years. Mean endurance time in girls increased from 9.5 minutes at age 4 to 5 years to12.3 minutes at age 10 to 12 years. Mean maximal heart rate ranged from 193 to 206 beats/min. Agedifferences in mean maximal and submaximal heart rates were small. There were negative correlationsbetween endurance time and the ratio of weight to height. There were negative correlations betweenheart rates at treadmill stages 1 to 3 and the endurance times. The correlation coefficient of endurancetime with maximal oxygen uptake was 0.88, but for clinical purposes endurance time alone is asatisfactory indicator of exercise performance.", "metadata": {}}
+{"_id": "41239107", "title": "", "text": "Immunoproteasome and LMP2 polymorphism in aged and Alzheimer's disease brains.In this study, weinvestigated the presence and role of immunoproteasome and its LMP2 subunit polymorphism at codon60 in Alzheimer's disease (AD). Immunoproteasome was present in brain areas such as hippocampus andcerebellum and localized in neurons, astrocytes and endothelial cells. A higher expression ofimmunoproteasome was found in brain of AD patients than in brain of non-demented elderly, being itsexpression in young brain negligible or absent. Furthermore, AD affected regions showed a partialdecrease in proteasome trypsin-like activity. The study of LMP2 polymorphism (R/H) showed that it doesnot influence LMP2 expression (neither the mRNA nor mature protein) in brain tissue. However, controlbrain areas of AD patients carrying the RR genotype showed an increased proteasome activity incomparison with RH carriers. To test whether this effect of the genotype might be related to AD onset weperformed a genetic study, which allowed us to exclude an association of LMP2 codon 60 polymorphismwith AD onset, despite its influence on the proteasome activity in human brain.", "metadata": {}}
+{"_id": "41256402", "title": "", "text": "The centrosome and its mode of inheritance: the reduction of the centrosome during gametogenesis andits restoration during fertilization.Neither the restoration of the centrosome during fertilization nor itsreduction during gametogenesis is fully understood, but both are pivotal events in development. Duringeach somatic cell cycle, the chromosomes, cytoplasm, and centrosomes duplicate in interphase, and allthree split in two during each cell division. While it has long been recognized that both the sperm and theegg contribute equal haploid genomes during fertilization and that the vast majority of the cytoplasm iscontributed by the egg, the relative contributions of the centrosome by each gamete are still in question.This article explores centrosome inheritance patterns and considers nine integral and secondarily derivedactivities of the centrosome. Boveri once hypothesized that \"The ripe egg possesses all of the elementsnecessary for development save an active division-center. The sperm, on the other hand, possesses sucha center but lacks the protoplasmic substratum in which to operate. In this respect the egg and spermare complementary structures; their union in syngamy thus restores to each the missing elementnecessary to further development. \" This article reviews the evidence gathered from 11 experimentalstrategies used to test this theory. While the majority of these approaches supports the hypothesis thatthe sperm introduces the centrosome at fertilization, the pattern did not reveal itself as universal, sinceparthenogenesis occurs in nature and can be induced artificially, since centrosome and centriole form denovo in extracts from unfertilized eggs and since the centrosome is derived from maternal sources duringfertilization in some systems--notably, in mice. Models of the centrosome are proposed, along withspeculative mechanisms which might lead to the cloaking of the reproducing element of the maternalcentrosome during oogenesis and the retention of this structure by the paternal centrosome duringspermatogenesis. Proteins essential for microtubule nucleation, like gamma-tubulin, are retained in thecytoplasm during oogenesis, but are largely lost during spermatogenesis. It is further postulated that therestoration of the zygotic centrosome at fertilization requires the attraction of maternal centrosomalcomponents (in particular, gamma-tubulin and the 25S \"gamma-some\" particle) to the paternalreproducing element; this, along with post-translational modifications (including phosphorylation,disulfide reduction, and calcium ion binding), creates a functional zygote centrosome by blending bothmaternal and paternal constituents.(ABSTRACT TRUNCATED AT 400 WORDS)", "metadata": {}}
+{"_id": "41264017", "title": "", "text": "Aggregation of vascular risk factors and risk of incident Alzheimer disease.BACKGROUND The prevalenceof Alzheimer disease (AD) is increasing in the elderly, and vascular risk factors may increase its risk.OBJECTIVE To explore the association of the aggregation of vascular risk factors with AD. METHODS Theauthors followed 1,138 individuals without dementia at baseline (mean age 76.2) for a mean of 5.5years. The presence of vascular risk factors was related to incident possible and probable AD. RESULTSFour risk factors (diabetes, hypertension, heart disease, and current smoking) were associated with ahigher risk of AD (p < 0.10) when analyzed individually. The risk of AD increased with the number of riskfactors (diabetes + hypertension + heart disease + current smoking). The adjusted hazards ratio ofprobable AD for the presence of three or more risk factors was 3.4 (95% CI: 1.8, 6.3; p for trend <0.0001) compared with no risk factors. Diabetes and current smoking were the strongest risk factors inisolation or in clusters, but hypertension and heart disease were also related to a higher risk of AD whenclustered with diabetes, smoking, or each other. CONCLUSIONS The risk of Alzheimer disease (AD)increased with the number of vascular risk factors. Diabetes and current smoking were the strongest riskfactors, but clusters including hypertension and heart disease also increased the risk of AD. Theseassociations are unlikely to be explained by misclassification of the outcome, given strong associationswhen only probable AD is considered.", "metadata": {}}
+{"_id": "41293601", "title": "", "text": "Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups ofglioblastoma.Glioblastoma (GBM) is a brain tumor that carries a dismal prognosis and displaysconsiderable heterogeneity. We have recently identified recurrent H3F3A mutations affecting two criticalamino acids (K27 and G34) of histone H3.3 in one-third of pediatric GBM. Here, we show that each H3F3Amutation defines an epigenetic subgroup of GBM with a distinct global methylation pattern, and that theyare mutually exclusive with IDH1 mutations, which characterize a third mutation-defined subgroup. Threefurther epigenetic subgroups were enriched for hallmark genetic events of adult GBM and/or establishedtranscriptomic signatures. We also demonstrate that the two H3F3A mutations give rise to GBMs inseparate anatomic compartments, with differential regulation of transcription factors OLIG1, OLIG2, andFOXG1, possibly reflecting different cellular origins.", "metadata": {}}
+{"_id": "41294031", "title": "", "text": "Glucocorticoid with cyclophosphamide for paraquat-induced lung fibrosis.BACKGROUND Paraquat is aneffective and widely used herbicide but is also a lethal poison. In many developing countries paraquat iswidely available and inexpensive, making poisoning prevention difficult. However most of the people whobecome poisoned from paraquat have taken it as a means of suicide. Standard treatment for paraquatpoisoning both prevents further absorption and reduces the load of paraquat in the blood throughhaemoperfusion or haemodialysis. The effectiveness of standard treatments is extremely limited. Theimmune system plays an important role in exacerbating paraquat-induced lung fibrosis.Immunosuppressive treatment using glucocorticoid and cyclophosphamide in combination is beingdeveloped and studied. OBJECTIVES To assess the effects of glucocorticoid with cyclophosphamide onmortality in patients with paraquat-induced lung fibrosis. SEARCH METHODS To identify randomisedcontrolled trials (RCTs) on this topic, we searched the Cochrane Injuries Group's Specialised Register(searched 1 February 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) (The CochraneLibrary 2012, Issue 1), MEDLINE (Ovid SP) (1946 January Week 3 2012), EMBASE (Ovid SP) (1947 toWeek 4 2012), ISI Web of Science: Science Citation Index Expanded (SCI-EXPANDED) (1970 to January2012), ISI Web of Science: Conference Proceedings Citation Index - Science (CPCI-S) (1990 to January2012), Chinese Biomedical Literature and Retrieval System (CBM) (1978 to April 2012), Chinese MedicalCurrent Contents (CMCC) (1995 to April 2012), and Chinese Medical Academic Conference (CMAC) (1994to April 2012). Searches were completed on English language databases on 1 February 2012 and onChinese language databases on 12 April 2012. SELECTION CRITERIA RCTs were included in this review.All patients were to receive standard care, plus the intervention or control. The intervention wasglucocorticoid with cyclophosphamide in combination versus a control of a placebo, standard care aloneor any other therapy in addition to standard care. DATA COLLECTION AND ANALYSIS The mortality riskratio (RR) and 95% confidence interval (CI) was calculated for each study on an intention-to-treat basis.Data for all-cause mortality at final follow-up were summarised in a meta-analysis using a fixed-effectmodel. MAIN RESULTS This systematic review includes three trials with a combined total of 164participants who had moderate to severe paraquat poisoning. Patients who received glucocorticoid withcyclophosphamide in addition to standard care had a lower risk of death at final follow-up than thosereceiving standard care only (RR 0.72; 95% CI 0.59 to 0.89). AUTHORS' CONCLUSIONS Based on thefindings of three small RCTs of moderate to severely poisoned patients, glucocorticoid withcyclophosphamide in addition to standard care may be a beneficial treatment for patients withparaquat-induced lung fibrosis. To enable further study of the effects of glucocorticoid withcyclophosphamide for patients with moderate to severe paraquat poisoning, hospitals may provide thistreatment as part of an RCT with allocation concealment.", "metadata": {}}
+{"_id": "41298619", "title": "", "text": "Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function.BACKGROUNDHydroxyethyl starches (HES) are synthetic colloids commonly used for fluid resuscitation, yet controversyexists about their impact on kidney function. OBJECTIVES To examine the effects of HES on kidneyfunction compared to other fluid resuscitation therapies in different patient populations. SEARCHSTRATEGY We searched the Cochrane Renal Group's specialised register, the Cochrane Central Registerof Controlled Trials (CENTRAL, in The Cochrane Library), MEDLINE, EMBASE, MetaRegister and referencelists of articles. SELECTION CRITERIA Randomised controlled trials (RCTs) and quasi-RCTs in which HESwas compared to an alternate fluid therapy for the prevention or treatment of effective intravascularvolume depletion. Primary outcomes were renal replacement therapy (RRT), author-defined kidney failureand acute kidney injury (AKI) as defined by the RIFLE criteria. Secondary outcomes included serumcreatinine and creatinine clearance. DATA COLLECTION AND ANALYSIS Screening, selection, dataextraction and quality assessments for each retrieved article were carried out by two authors usingstandardised forms. Authors were contacted when published data were incomplete. Preplanned sensitivityand subgroup analyses were performed after data were analysed with a random effects model. MAINRESULTS The review included 34 studies (2607 patients). Overall, the RR of author-defined kidney failurewas 1.50 (95% CI 1.20 to 1.87; n = 1199) and 1.38 for requiring RRT (95% CI 0.89 to 2.16; n = 1236)in HES treated individuals compared with other fluid therapies. Subgroup analyses suggested increasedrisk in septic patients compared to non-septic (surgical/trauma) patients. Non-septic patient studies weresmaller and had lower event rates, so subgroup differences may have been due to lack of statisticalpower in these studies. Only limited data was obtained for analysis of kidney outcomes by the RIFLEcriteria. Overall, methodological quality of studies was good but subjective outcomes were potentiallybiased because most studies were unblinded. AUTHORS' CONCLUSIONS Potential for increased risk of AKIshould be considered when weighing the risks and benefits of HES for volume resuscitation, particularly inseptic patients. Large studies with adequate follow-up are required to evaluate the renal safety of HESproducts in non-septic patient populations. RIFLE criteria should be applied to evaluate kidney function infuture studies of HES and, where data is available, to re-analyse those studies already published. There isinadequate clinical data to address the claim that safety differences exist between different HES products.", "metadata": {}}
+{"_id": "41310252", "title": "", "text": "Dietary fat and obesity: evidence from epidemiology.The epidemiological evidence that a high-fat dietpromotes the development of obesity is considered suggestive but not definitive. The purpose of thispaper is to provide a review of various epidemiological methods that have been used to address this issueas well as an updated summary of the existing evidence. Ecological studies describing dietary fat intakeand obesity at the population level provide mixed results and are likely to be biased by both confoundingand unknown data quality factors that differ systematically across the populations studied.Cross-sectional studies are generally in agreement that the concentration of fat in the diet is positivelyassociated with relative weight. Prospective studies of diet in relation to subsequent weight change giveinconsistent results. This may be due to behavioural factors such as dieting in response to weight gain; inaddition, this type of study rarely takes into account the possible interaction between geneticpredisposition and dietary fat in promoting weight gain. Finally, intervention studies in free-living subjectsare considered, providing evidence of a consistent but short-lived period of active weight loss on low-fatdiets. The experimental evidence on this relationship is more conclusive than the epidemiologicalevidence, although biological mechanisms remain controversial. Some areas for future epidemiologicalresearch involve: longitudinal studies of dietary fat intake as a predictor of growth in children;observational studies relating total dietary fat and specific types of fat to overall as well as regionaladiposity; and randomized intervention studies of the effect of low-fat diets with particular emphasis onand familial predisposition to obesity and other possible modifying factors.", "metadata": {}}
+{"_id": "41314611", "title": "", "text": "Uncoupling of leading- and lagging-strand DNA replication during lesion bypass in vivo.Numerous agentsattack DNA, forming lesions that impair normal replication. Specialized DNA polymerases transientlyreplace the replicative polymerase and copy past lesions, thus generating mutations, the major initiatingcause of cancer. We monitored, in Escherichia coli, the kinetics of replication of both strands of DNAmolecules containing a single replication block in either the leading or lagging strand. Despite a block inthe leading strand, lagging-strand synthesis proceeded further, implying transient uncoupling ofconcurrent strand synthesis. Replication through the lesion requires specialized DNA polymerases and isachieved with similar kinetics and efficiencies in both strands.", "metadata": {}}
+{"_id": "41325555", "title": "", "text": "Phosphoinositide 3-kinase signalling--which way to target?Abstract Phosphoinositide 3-kinases (PI3Ks)are central to the control of cell growth, proliferation and survival, and drive the progression of tumoursby activating phosphoinositide-dependent kinase, protein kinase B and the target of rapamycin. Otherdownstream effectors link PI3K to cell motility and the control of cardiovascular parameters. Currentknowledge indicates that PI3Ks might qualify as drug targets for the treatment of cancer, chronicinflammation, allergy and cardiovascular failure. However, PI3Ks also modulate vital processes such asmetabolic control and nutrient uptake. Here, mechanistic data and mouse phenotypic analyses aresummarised, and the possible success of therapeutic inhibition of distinct PI3K isoforms is discussed.", "metadata": {}}
+{"_id": "41329220", "title": "", "text": "Determination of the time course of capacitation in mouse spermatozoa using a chlortetracyclinefluorescence assay.The heads of mouse spermatozoa obtained 5 min after release from the excisedcaudae epididymides showed a characteristic fluorescence pattern in the presence of the fluorophorechlortetracycline (CTC). There was uniform fluorescence over the entire head with about half the spermpopulation showing a brighter line of fluorescence across the equatorial segment; this fluorescencepattern was designated \"F\". After 90-min incubation in culture medium (CM) containing 2% (w/v) bovineserum albumin, most of the sperm heads showed a dark band of nonfluorescence over the equatorial andpostequatorial segment, while the anterior portion of the head showed bright fluorescence. Thisfluorescence pattern was designated \"B.\" The time course for the disappearance of pattern F matched thetime course of the appearance of pattern B, with a half-time of 30 min. The transformation was completein 90 min. At longer times of incubation in CM, the percentage of spermatozoa showing pattern Bdeclined; fluorescence over the entire head was lost, characteristic of the pattern for acrosome-reactedsperm (P. M. Saling and B. T. Storey (1979). J. Cell Biol. 83, 544-555). Mouse sperm showing pattern Bwere able to undergo the acrosome reaction, either spontaneously or by induction with acid-solubilizedzonae pellucidae from mouse eggs (H.M. Florman and B. T. Storey (1982). Dev. Biol. 91, 121-130). Thelatter reaction was blocked by its specific inhibitor 3-quinuclidinyl benzilate (QNB). Mouse sperm showingpattern F could not be induced to undergo the acrosome reaction by exposure to solubilized zonae. Thisimplies that the change from fluorescence pattern F to fluorescence pattern B corresponds with changesin the sperm which make them susceptible to undergo the acrosome reaction. This change occurs duringthe time interval previously determined to be needed for capacitation of mouse sperm in vitro in CM (M.Inoue and D. P. Wolf (1975). Biol. Reprod. 13, 340-346). These results imply that spermatozoa showingCTC fluorescence pattern B can be considered to be capacitated and that a functional definition forcapacitation is the acquired ability to undergo the acrosome reaction rapidly when treated withacid-solubilized zonae pellucidae. The CTC fluorescence assay provides for the first time a means tomonitor the time course of epididymal mouse sperm capacitation in vitro.", "metadata": {}}
+{"_id": "41329906", "title": "", "text": "[Detection of CRISPR and its relationship to drug resistance in Shigella].OBJECTIVE To detect clusteredregularly interspaced short palindromic repeats (CRISPR) in Shigella, and to analyze its relationship todrug resistance. METHODS Four pairs of primers were used for the detection of convincing CRISPRstructures CRISPR-S2 and CRISPR-S4, questionable CRISPR structures CRISPR-S1 and CRISPR-S3 in 60Shigella strains. All primers were designed using sequences in CRISPR database. CRISPR Finder was usedto analyze CRISPR and susceptibilities of Shigella strains were tested by agar diffusion method.Furthermore, we analyzed the relationship between drug resistance and CRISPR-S4. RESULTS Thepositive rate of convincing CRISPR structures was 95%. The four CRISPR loci formed 12 spectral patterns(A-L), all of which contained convincing CRISPR structures except type K. We found one new repeat and12 new spacers. The multi-drug resistance rate was 53. 33% . We found no significant differencebetween CRISPR-S4 and drug resistant. However, the repeat sequence of CRISPR-S4 in multi- orTE-resistance strains was mainly R4.1 with AC deletions in the 3' end, and the spacer sequences ofCRISPR-S4 in multi-drug resistance strains were mainly Sp5.1, Sp6.1 and Sp7. CONCLUSION CRISPRwas common in Shigella. Variations df repeat sequences and diversities of spacer sequences might berelated to drug resistance in Shigella.", "metadata": {}}
+{"_id": "41337677", "title": "", "text": "The helicase DDX41 senses intracellular DNA mediated by the adaptor STING in dendritic cellsTherecognition of pathogenic DNA is important to the initiation of antiviral responses. Here we report theidentification of DDX41, a member of the DEXDc family of helicases, as an intracellular DNA sensor inmyeloid dendritic cells (mDCs). Knockdown of DDX41 expression by short hairpin RNA blocked the abilityof mDCs to mount type I interferon and cytokine responses to DNA and DNA viruses. Overexpression ofboth DDX41 and the membrane-associated adaptor STING together had a synergistic effect in promotingIfnb promoter activity. DDX41 bound both DNA and STING and localized together with STING in thecytosol. Knockdown of DDX41 expression blocked activation of the mitogen-activated protein kinase TBK1and the transcription factors NF-κB and IRF3 by B-form DNA. Our results suggest that DDX41 is anadditional DNA sensor that depends on STING to sense pathogenic DNA.", "metadata": {}}
+{"_id": "41340212", "title": "", "text": "Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma.BACKGROUND Glioblastoma,the most common primary brain tumor in adults, is usually rapidly fatal. The current standard of care fornewly diagnosed glioblastoma is surgical resection to the extent feasible, followed by adjuvantradiotherapy. In this trial we compared radiotherapy alone with radiotherapy plus temozolomide, givenconcomitantly with and after radiotherapy, in terms of efficacy and safety. METHODS Patients with newlydiagnosed, histologically confirmed glioblastoma were randomly assigned to receive radiotherapy alone(fractionated focal irradiation in daily fractions of 2 Gy given 5 days per week for 6 weeks, for a total of60 Gy) or radiotherapy plus continuous daily temozolomide (75 mg per square meter of body-surfacearea per day, 7 days per week from the first to the last day of radiotherapy), followed by six cycles ofadjuvant temozolomide (150 to 200 mg per square meter for 5 days during each 28-day cycle). Theprimary end point was overall survival. RESULTS A total of 573 patients from 85 centers underwentrandomization. The median age was 56 years, and 84 percent of patients had undergone debulkingsurgery. At a median follow-up of 28 months, the median survival was 14.6 months with radiotherapyplus temozolomide and 12.1 months with radiotherapy alone. The unadjusted hazard ratio for death inthe radiotherapy-plus-temozolomide group was 0.63 (95 percent confidence interval, 0.52 to 0.75;P<0.001 by the log-rank test). The two-year survival rate was 26.5 percent with radiotherapy plustemozolomide and 10.4 percent with radiotherapy alone. Concomitant treatment with radiotherapy plustemozolomide resulted in grade 3 or 4 hematologic toxic effects in 7 percent of patients. CONCLUSIONSThe addition of temozolomide to radiotherapy for newly diagnosed glioblastoma resulted in a clinicallymeaningful and statistically significant survival benefit with minimal additional toxicity.", "metadata": {}}
+{"_id": "41354899", "title": "", "text": "Drug interactions between oral contraceptives and antibiotics.OBJECTIVE To evaluate the evidence onpossible drug interactions between antibiotics and oral contraceptives (OCs) that may lead to OC failure.DATA SOURCES MEDLINE and Lexis/Nexis Medical Library searches for 1966-1999 using the key word\"oral contraceptives,\" cross-indexed with the terms \"antibiotics,\" \"adverse effects,\" and \"pregnancy,\" andMEDLINE search using the additional MeSH term \"drug interactions. \" No language restrictions were used.METHODS OF STUDY SELECTION A total of 167 articles were retrieved for analysis. Another 32 articleswere identified by review of the references cited in these publications. Articles were selected based ontheir ability to provide information on the relationship between antibiotic therapy and OC efficacy inotherwise compliant users (defined as women with unplanned pregnancies who reported compliance withtheir OC regimen). Additionally, studies that either directly measured the effects of antibiotics on thepharmacokinetics of OC components, or that analyzed the effects of antibiotics on measures of ovulationin OC users were accepted. TABULATION, INTEGRATION, AND RESULTS At least 30 cases have beenreported of pregnancies occurring in women taking OCs and antibiotics, particularly rifampin.Approximately 20% of pregnant women reporting to family planning or abortion clinics reportedconcomitant OC and antibiotic use. Information from adverse event reporting databases generally mirrorsthe types of information gleaned from these case reports and clinical surveys and accounts forapproximately one-third of reported cases. Retrospective surveys, primarily from dermatology-basedpractices, also have reported 24 pregnancies in OC users who concomitantly received therapy withantibiotics, most commonly tetracyclines and penicillins. Apparent OC failure rates in clinical surveys werewithin the usual range expected for patterns of typical use. In pooled results obtained from relativelysmall populations, oral antibiotics, with the exception of rifampin, have not significantly affected thepharmacokinetics of ethinyl estradiol, levonorgestrel, and norethindrone or reduced the serumconcentrations of gonadotropins. However, individual patients have been identified who experiencedsignificant decreases in the plasma concentration of these components of OCs and who appeared toovulate. CONCLUSION Rifampin impairs the effectiveness of OCs. Pharmacokinetic studies of otherantibiotics have not shown any systematic interaction between antibiotics and OC steroids. However,individual patients do show large decreases in the plasma concentrations of ethinyl estradiol when theytake certain other antibiotics, notably tetracycline and penicillin derivatives. Because it is not possible toidentify these women in advance, a cautious approach is advised.", "metadata": {}}
+{"_id": "41380943", "title": "", "text": "Male Japanese quails with female brains do not show male sexual behaviors.During embryonicdevelopment, gonadal steroid hormones (androgens and estrogens) are thought to organize the sexualdifferentiation of the brain in the heterogametic sexes of higher vertebrates (males in mammals, femalesin birds). Brain differentiation of the homogametic sexes is thought to proceed by default, not requiringsex hormones for sex-specific organization. In gallinaceous birds such as the Japanese quail, female brainorganization is thought to develop via estrogen-dependent demasculinization of a default male brainphenotype. We performed male donor-to-female host (MF), female-to-male (FM), male-to-male (MM),and female-to-female (FF) isotopic, isochronic transplantation of the forebrain primordium in Japanesequail embryos before gonadal differentiation had occurred; brain chimeras had a forebrain (including thehypothalamus) originating exclusively from donor cells. MM, FF, and MF chimeras all showed sexualbehavior governed by the genetic sex of the host. In contrast, FM chimeras (genetically female forebrain,all other tissues genetically male) showed no mounting and only rudimentary crowing behavior. AlthoughMM, FF, MF, and FM chimeras all showed host-typical production of steroid hormones during embryoniclife, only FM chimeras were hypogonadal, had atypical low levels of circulating testosterone in adulthood,and showed reduction (crowing) or absence (mounting) of reproductive behaviors. Morphological featuresof the medial preoptic nucleus (a sexually dimorphic brain area) also were not male-like in FM males.These data demonstrate a brain-intrinsic, genetically determined component that organizes thesex-typical production of gonadal hormones in adulthood and call for a reevaluation of the mechanismsunderlying brain sexual differentiation in other higher-vertebrate species.", "metadata": {}}
+{"_id": "41403996", "title": "", "text": "DNA joint dependence of pol X family polymerase action in nonhomologous end joining.DNA doublestrand breaks (DSBs) can be rejoined directly by the nonhomologous end-joining (NHEJ) pathway ofrepair. Nucleases and polymerases are required to promote accurate NHEJ when the terminal bases ofthe DSB are damaged. The same enzymes also participate in imprecise rejoining and joining ofincompatible ends, important mutagenic events. Previous work has shown that the Pol X familypolymerase Pol4 is required for some but not all NHEJ events that require gap filling in Saccharomycescerevisiae. Here, we systematically analyzed DSB end configurations and found that gaps on both strandsand overhang polarity are the principal factors that determine whether a joint requires Pol4. DSBs with3'-overhangs and a gap on each strand strongly depended on Pol4 for repair, DSBs with 5'-overhangs ofthe same sequence did not. Pol4 was not required when 3'-overhangs contained a gap on only onestrand, however. Pol4 was equally required at 3'-overhangs of all lengths within the NHEJ-dependentrange but was dispensable outside of this range, indicating that Pol4 is specific to NHEJ. Loss of Pol4 didnot affect the rejoining of DSBs that utilized a recessed microhomology or DSBs bearing 5'-hydroxyls butno gap. Finally, mammalian Pol X polymerases were able to differentially complement a pol4 mutationdepending on the joint structure, demonstrating that these polymerases can participate in yeast NHEJ butwith distinct properties.", "metadata": {}}
+{"_id": "41493639", "title": "", "text": "ABC of burns. Introduction.Burns are one of the most devastating conditions encountered in medicine.The injury represents an assault on all aspects of the patient, from the physical to the psychological. Itaffects all ages, from babies to elderly people, and is a problem in both the developed and developingworld. All of us have experienced the severe pain that even a small burn can bring. However the pain anddistress caused by a large burn are not limited to the immediate event. The visible physical and theinvisible psychological scars are long lasting and often lead to chronic disability. Burn injuries represent adiverse and varied challenge to medical and paramedical staff. Correct management requires a skilledmultidisciplinary approach that addresses all the problems facing a burn patient. This series provides anoverview of the most important aspects of burn injuries for hospital and non-hospital healthcareworkers.workers. Figure 1    Top: Child with 70% full thickness burns, which required resuscitation,intensive care support, and extensive debridement and skin grafting. Left: The same child one year laterat a burns camp, having made a good recovery. A reasonable outcome is possible ...", "metadata": {}}
+{"_id": "41496215", "title": "", "text": "DNA methylation is a critical cell-intrinsic determinant of astrocyte differentiation in the fetalbrain.Astrocyte differentiation, which occurs late in brain development, is largely dependent on theactivation of a transcription factor, STAT3. We show that astrocytes, as judged by glial fibrillary acidicprotein (GFAP) expression, never emerge from neuroepithelial cells on embryonic day (E) 11.5 evenwhen STAT3 is activated, in contrast to E14.5 neuroepithelial cells. A CpG dinucleotide within a STAT3binding element in the GFAP promoter is highly methylated in E11.5 neuroepithelial cells, but isdemethylated in cells responsive to the STAT3 activation signal to express GFAP. This CpG methylationleads to inaccessibility of STAT3 to the binding element. We suggest that methylation of a celltype-specific gene promoter is a pivotal event in regulating lineage specification in the developing brain.", "metadata": {}}
+{"_id": "41548287", "title": "", "text": "DNMT1 Inhibition Reprograms Pancreatic Cancer Stem Cells via Upregulation of the miR-17-92Cluster.Pancreatic ductal adenocarcinoma (PDAC) and other carcinomas are hierarchically organized, withcancer stem cells (CSC) residing at the top of the hierarchy, where they drive tumor progression,metastasis, and chemoresistance. As CSC and non-CSC share an identical genetic background, wehypothesize that differences in epigenetics account for the striking functional differences between thesetwo cell populations. Epigenetic mechanisms, such as DNA methylation, play an important role inmaintaining pluripotency and regulating the differentiation of stem cells, but the role of DNA methylationin pancreatic CSC is obscure. In this study, we investigated the genome-wide DNA methylation profile ofPDAC CSC, and we determined the importance of DNA methyltransferases for CSC maintenance andtumorigenicity. Using high-throughput methylation analysis, we discovered that sorted CSCs have ahigher level of DNA methylation, regardless of the heterogeneity or polyclonality of the CSC populationspresent in the tumors analyzed. Mechanistically, CSC expressed higher DNMT1 levels than non-CSC.Pharmacologic or genetic targeting of DNMT1 in CSCs reduced their self-renewal and in vivo tumorigenicpotential, defining DNMT1 as a candidate CSC therapeutic target. The inhibitory effect we observed wasmediated in part through epigenetic reactivation of previously silenced miRNAs, in particular themiR-17-92 cluster. Together, our findings indicate that DNA methylation plays an important role in CSCbiology and also provide a rationale to develop epigenetic modulators to target CSC plasticity andimprove the poor outcome of PDAC patients. Cancer Res; 76(15); 4546-58. ©2016 AACR.", "metadata": {}}
+{"_id": "41599676", "title": "", "text": "Mutation spectrum in the nephrin gene (NPHS1) in congenital nephrotic syndrome.Congenital nephroticsyndrome, Finnish type (CNF or NPHS1), is an autosomal recessive disease characterized by massiveproteinuria and development of nephrotic syndrome shortly after birth. The disease is most common inFinland, but many patients have been identified in other populations. The disease is caused by mutationsin the gene for nephrin which is a key component of the glomerual ultrafilter, the podocyte slitdiaphragm. A total of 30 mutations have been reported in the nephrin gene in patients with congenitalnephrotic syndrome worldwide. In the Finnish population, two main mutations have been found. Thesetwo nonsense mutations account for over 94% of all mutations in Finland. Most mutations found innon-Finnish patients are missense mutations, but they include also nonsense and splice site mutations,as well as deletions and insertions. This mutation update summarizes the nature of all previouslyreported nephrin mutations and, additionally, describes 20 novel mutations recently identified in ourlaboratory.", "metadata": {}}
+{"_id": "41620295", "title": "", "text": "The HSA domain binds nuclear actin-related proteins to regulate chromatin-remodeling ATPasesWeidentify the helicase-SANT–associated (HSA) domain as the primary binding platform for nuclearactin-related proteins (ARPs) and actin. Individual HSA domains from chromatin remodelers (RSC, yeastSWI-SNF, human SWI-SNF, SWR1 and INO80) or modifiers (NuA4) reconstitute their respective ARP–ARPor ARP–actin modules. In RSC, the HSA domain resides on the catalytic ATPase subunit Sth1. The Sth1HSA is essential in vivo, and its omission causes the specific loss of ARPs and a moderate reduction inATPase activity. Genetic selections for arp suppressors yielded specific gain-of-function mutations in twonew domains in Sth1, the post-HSA domain and protrusion 1, which are essential for RSC function in vivobut not ARP association. Taken together, we define the role of the HSA domain and provide evidence for aregulatory relationship involving the ARP–HSA module and two new functional domains conserved inremodeler ATPases that contain ARPs.", "metadata": {}}
+{"_id": "41644178", "title": "", "text": "Increased dendritic complexity and axonal length in cultured mouse cortical neurons overexpressingmethyl-CpG-binding protein MeCP2Rett syndrome is caused by loss-of-function mutations in the geneencoding the methyl DNA-binding factor MeCP2. As brain mass and neuronal complexity tend to bediminished in Rett patients, we tested whether MeCP2 directly influences the morphological complexity ofdeveloping neurons. Our results show that cultured mouse neurons overexpressing MeCP2beta (MECP2A)develop more complex morphologies, having longer axonal and dendritic processes, and an increasednumber of axonal and dendritic terminal endings. We then tested whether overexpressing a mutant formof MeCP2beta lacking its carboxyl terminus would elicit the same effects. Interestingly, while neuronsoverexpressing this mutant failed to enhance axonal and dendritic process elongation, the complexity oftheir axonal and dendritic processes remained significantly elevated. Taken together, these data supportthe hypothesis that MeCP2 directly regulates neuronal maturation and/or synaptogenesis, and providesevidence that MeCP2 may influence neuritic elongation and process branching through differentmechanisms.", "metadata": {}}
+{"_id": "41646286", "title": "", "text": "Folate affects apoptosis in human trophoblastic cells.Effects of folate deficiency on the rate of apoptosis inhuman cytotrophoblastic cells has been investigated. Apoptosis was determined in cytotrophoblastic cellsafter culture in 1. control medium, 2. folate-free medium and 3. folate-free medium plus 10% fetal calfserum. Apoptosis rates in cells cultured in mediums 2 and 3 were significantly higher than those culturedin the control medium (P<0.02 and P<0.03, respectively). In conclusion, human cytotrophoblastic cellsshow a significantly increased rate of apoptosis in vitro after culture in a folate-free medium. Possibleexplanations for the association between folate deficiency and pregnancy complications are suggested.", "metadata": {}}
+{"_id": "41650417", "title": "", "text": "Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of CanadaClinical Trials Group Study BR.21.PURPOSE To evaluate the effect of KRAS and epidermal growth factorreceptor (EGFR) genotype on the response to erlotinib treatment in the BR.21, placebo-controlled trial.PATIENTS AND METHODS We analyzed 206 tumors for KRAS mutation, 204 tumors for EGFR mutation,and 159 tumors for EGFR gene copy by fluorescent in situ hybridization (FISH). We reanalyzed EGFRdeletion/mutation using two highly sensitive techniques that detect abnormalities in samples with 5% to10% tumor cellularity. KRAS mutation was analyzed by direct sequencing. RESULTS Thirty patients(15%) had KRAS mutations, 34 (17%) had EGFR exon 19 deletion or exon 21 L858R mutations, and 61(38%) had high EGFR gene copy (FISH positive). Response rates were 10% for wild-type and 5% formutant KRAS (P = .69), 7% for wild-type and 27% for mutant EGFR (P = .03), and 5% for EGFRFISH-negative and 21% for FISH-positive patients (P = .02). Significant survival benefit from erlotinibtherapy was observed for patients with wild-type KRAS (hazard ratio [HR] = 0.69, P = .03) and EGFRFISH positivity (HR = 0.43, P = .004) but not for patients with mutant KRAS (HR = 1.67, P = .31),wild-type EGFR (HR = 0.74, P = .09), mutant EGFR (HR = 0.55, P = .12), and EGFR FISH negativity (HR= 0.80, P = .35). In multivariate analysis, only EGFR FISH-positive status was prognostic for poorersurvival (P = .025) and predictive of differential survival benefit from erlotinib (P = .005). CONCLUSIONEGFR mutations and high copy number are predictive of response to erlotinib. EGFR FISH is the strongestprognostic marker and a significant predictive marker of differential survival benefit from erlotinib.", "metadata": {}}
+{"_id": "41707539", "title": "", "text": "Immune dysregulation in major depression: a critical review of existing evidence.It is now wellestablished that depression is associated with immune dysregulation. It is not, however, known whetherthis immune dysregulation plays a role in the pathophysiology of major depression or whether itincreases the susceptibility of the depressed patient to immune-related disorders. This article presents acritical review of existing evidence for immune dysregulation in major depression, including changes inleucocyte trafficking, lymphocyte function, and markers of immune activation. Possible mediators ofimmune dysregulation in major depression are briefly discussed. Finally, the relationship between majordepression and several medical conditions such as infection, allergy and autoimmune disorders,cardiovascular diseases, cancer and AIDS is critically reviewed.", "metadata": {}}
+{"_id": "41710132", "title": "", "text": "Regulation of E2Fs and senescence by PML nuclear bodies.The tumor suppressor PML (promyelocyticleukemia protein) regulates cellular senescence and terminal differentiation, two processes that implicatea permanent exit from the cell cycle. Here, we show that the mechanism by which PML induces apermanent cell cycle exit and activates p53 and senescence involves a recruitment of E2F transcriptionfactors bound to their promoters and the retinoblastoma (Rb) proteins to PML nuclear bodies enriched inheterochromatin proteins and protein phosphatase 1α. Blocking the functions of the Rb protein family oradding back E2Fs to PML-expressing cells can rescue their defects in E2F-dependent gene expression andcell proliferation, inhibiting the senescent phenotype. In benign prostatic hyperplasia, a neoplasticdisease that displays features of senescence, PML was found to be up-regulated and forming nuclearbodies. In contrast, PML bodies were rarely visualized in prostate cancers. The newly defined PML/Rb/E2Fpathway may help to distinguish benign tumors from cancers, and suggest E2F target genes as potentialtargets to induce senescence in human tumors.", "metadata": {}}
+{"_id": "41735503", "title": "", "text": "The International Classification of Headache Disorders.A set of related medical disorders that lack aproper classification system and diagnostic criteria is like a society without laws. The result is incoherenceat best, chaos at worst. For this reason, the International Classification of Headache Disorders (ICHD) isarguably the single most important breakthrough in headache medicine over the last 50 years. The ICHDidentifies and categorizes more than a hundred different kinds of headache in a logical, hierarchalsystem. Even more important, it has provided explicit diagnostic criteria for all of the headache disorderslisted. The ICHD quickly became universally accepted, and criticism of the classification has been minorrelative to that directed at other disease classification systems. Over the 20 years following publication ofthe first edition of the ICHD, headache research has rapidly accelerated despite sparse allocation ofresources to that effort. In summary, the ICHD has attained widespread acceptance at the internationallevel and has substantially facilitated both clinical research and clinical care in the field of headachemedicine.", "metadata": {}}
+{"_id": "41774099", "title": "", "text": "Call to Develop a Standard Acquisition Charge Model for Kidney Paired DonationWe propose a MedicareDemonstration Project to develop a standard acquisition charge for kidney paired donation. A newpayment strategy is required because Medicare and commercial insurance companies may not directlypay living donor costs intended to lead to transplantation of a beneficiary of a different insuranceprovider. Until the 1970s, when organ procurement organizations were empowered to serve as financialintermediaries to pay the upfront recovery expenses for deceased donor kidneys before knowing theidentity of the recipient, there existed similar limitations in the recovery and placement of deceaseddonor organs. Analogous to the recovery of deceased donor kidneys, kidney paired donation requires theevaluation of living donors before identifying their recipient. Tissue typing, crossmatching andtransportation of living donors or their kidneys represent additional financial barriers. Finally, theadministrative expenses of the organizations that identify and coordinate kidney paired donationtransplantation require reimbursement akin to that necessary for organ procurement organizations. Toexpand access to kidney paired donation for more patients, we propose a model to reimburse paireddonation expenses analogous to the proven strategy used for over 30 years to pay for deceased donorsolid organ transplantation in America.", "metadata": {}}
+{"_id": "41781905", "title": "", "text": "Oxidant stress promotes disease by activating CaMKII.CaMKII is activated by oxidation of methionineresidues residing in the regulatory domain. Oxidized CaMKII (ox-CaMKII) is now thought to participate incardiovascular and pulmonary diseases and cancer. This invited review summarizes current evidence forthe role of ox-CaMKII in disease, considers critical knowledge gaps and suggests new areas for inquiry.", "metadata": {}}
+{"_id": "41782935", "title": "", "text": "Genetic diagnosis and prognosis of Alzheimer's disease: challenges and opportunities.Alzheimer's disease(AD), the most common form of dementia in western societies, is a pathologically and clinicallyheterogeneous disease with a strong genetic component. The recent advances in high-throughputgenome technologies allowing for the rapid analysis of millions of polymorphisms in thousands of subjectshas significantly advanced our understanding of the genomic underpinnings of AD susceptibility. Duringthe last 5 years, genome-wide association and whole-exome- and whole-genome sequencing studieshave mapped more than 20 disease-associated loci, providing insights into the molecular pathwaysinvolved in AD pathogenesis and hinting at potential novel therapeutic targets. This review articlesummarizes the challenges and opportunities of when using genomic information for the diagnosis andprognosis of AD.", "metadata": {}}
+{"_id": "41790911", "title": "", "text": "WNT5A regulates adipose tissue angiogenesis via antiangiogenic VEGF-A165b in obesehumans.Experimental studies have suggested that Wingless-related integration site 5A (WNT5A) is aproinflammatory secreted protein that is associated with metabolic dysfunction in obesity. Impairedangiogenesis in fat depots has been implicated in the development of adipose tissue capillary rarefaction,hypoxia, inflammation, and metabolic dysfunction. We have recently demonstrated that impaired adiposetissue angiogenesis is associated with overexpression of antiangiogenic factor VEGF-A165b in human fatand the systemic circulation. In the present study, we postulated that upregulation of WNT5A isassociated with angiogenic dysfunction and examined its role in regulating VEGF-A165b expression inhuman obesity. We biopsied subcutaneous and visceral adipose tissue from 38 obese individuals (bodymass index: 44 ± 7 kg/m2, age: 37 ± 11 yr) during planned bariatric surgery and characterizeddepot-specific protein expression of VEGF-A165b and WNT5A using Western blot analysis. In bothsubcutaneous and visceral fat, VEGF-A165b expression correlated strongly with WNT5A protein (r = 0.9,P < 0.001). In subcutaneous adipose tissue where angiogenic capacity is greater than in the visceraldepot, exogenous human recombinant WNT5A increased VEGF-A165b expression in both whole adiposetissue and isolated vascular endothelial cell fractions (P < 0.01 and P < 0.05, respectively). This wasassociated with markedly blunted angiogenic capillary sprout formation in human fat pad explants.Moreover, recombinant WNT5A increased secretion of soluble fms-like tyrosine kinase-1, a negativeregulator of angiogenesis, in the sprout media (P < 0.01). Both VEGF-A165b-neutralizing antibody andsecreted frizzled-related protein 5, which acts as a decoy receptor for WNT5A, significantly improvedcapillary sprout formation and reduced soluble fms-like tyrosine kinase-1 production (P < 0.05). Wedemonstrated a significant regulatory nexus between WNT5A and antiangiogenic VEGF-A165b in theadipose tissue of obese subjects that was linked to angiogenic dysfunction. Elevated WNT5A expression inobesity may function as a negative regulator of angiogenesis. NEW & NOTEWORTHY Wingless-relatedintegration site 5a (WNT5A) negatively regulates adipose tissue angiogenesis via VEGF-A165b in humanobesity.", "metadata": {}}
+{"_id": "41811327", "title": "", "text": "At least 1400 base pairs of 5'-flanking DNA is required for the correct expression of the HO gene inyeast.Homothallic yeast cells undergo a specific pattern of mating-type switching initiated by anendonuclease encoded by the HO gene. HO transcription is affected by cell type (a, alpha, and a/alpha),by cell age (mother or daughter), and by the cell cycle. This paper investigates the sequences involved inHO transcription by replacing genomic DNA with copies mutated in vitro. A region between -1000 and1400 (called URS1) is necessary for transcription in addition to a \"TATA\"-like region at -90. The 900 bp ofDNA separating URS1 from the \"TATA\" box is not necessary for transcription nor for a/alpha repressionand some measure of mother/daughter control, but it is necessary for correct cell cycle control.", "metadata": {}}
+{"_id": "41822527", "title": "", "text": "Inflammation and its role in neuroprotection, axonal regeneration and functional recovery after spinalcord injury.Trauma to the central nervous system (CNS) triggers intraparenchymal inflammation andactivation of systemic immunity with the capacity to exacerbate neuropathology and stimulatemechanisms of tissue repair. Despite our incomplete understanding of the mechanisms that control thesedivergent functions, immune-based therapies are becoming a therapeutic focus. This review will addressthe complexities and controversies of post-traumatic neuroinflammation, particularly in spinal cord. Inaddition, current therapies designed to target neuroinflammatory cascades will be discussed.", "metadata": {}}
+{"_id": "41852733", "title": "", "text": "Order of intron removal influences multiple splice outcomes, including a two-exon skip, in a COL5A1acceptor-site mutation that results in abnormal pro-alpha1(V) N-propeptides and Ehlers-Danlossyndrome type I.Ehlers-Danlos syndrome (EDS) type I (the classical variety) is a dominantly inherited,genetically heterogeneous connective-tissue disorder. Mutations in the COL5A1 and COL5A2 genes, whichencode type V collagen, have been identified in several individuals. Most mutations affect either thetriple-helical domain of the protein or the expression of one COL5A1 allele. We identified a novelsplice-acceptor mutation (IVS4-2A-->G) in the N-propeptide-encoding region of COL5A1, in one patientwith EDS type I. The outcome of this mutation was complex: In the major product, both exons 5 and 6were skipped; other products included a small amount in which only exon 5 was skipped and an evensmaller amount in which cryptic acceptor sites within exon 5 were used. All products were in frame.Pro-alpha1(V) chains with abnormal N-propeptides were secreted and were incorporated into extracellularmatrix, and the mutation resulted in dramatic alterations in collagen fibril structure. The two-exon skipoccurred in transcripts in which intron 5 was removed rapidly relative to introns 4 and 6, leaving a large(270 nt) composite exon that can be skipped in its entirety. The transcripts in which only exon 5 wasskipped were derived from those in which intron 6 was removed prior to intron 5. The use of crypticacceptor sites in exon 5 occurred in transcripts in which intron 4 was removed subsequent to introns 5and 6. These findings suggest that the order of intron removal plays an important role in the outcome ofsplice-site mutations and provide a model that explains why multiple products derive from a mutation ata single splice site.", "metadata": {}}
+{"_id": "41877386", "title": "", "text": "Kruppel-like factor KLF10 targets transforming growth factor-beta1 to regulate CD4(+)CD25(-) T cellsand T regulatory cells.CD4(+)CD25(+) regulatory T cells (T regs) play a major role in the maintenance ofself-tolerance and immune suppression, although the mechanisms controlling T reg development andsuppressor function remain incompletely understood. Herein, we provide evidence that Kruppel-like factor10 (KLF10/TIEG1) constitutes an important regulator of T regulatory cell suppressor function andCD4(+)CD25(-) T cell activation through distinct mechanisms involving transforming growth factor(TGF)-beta1 and Foxp3. KLF10 overexpressing CD4(+)CD25(-) T cells induced both TGF-beta1 and Foxp3expression, an effect associated with reduced T-Bet (Th1 marker) and Gata3 (Th2 marker) mRNAexpression. Consistently, KLF10(-/-) CD4(+)CD25(-) T cells have enhanced differentiation along both Th1and Th2 pathways and elaborate higher levels of Th1 and Th2 cytokines. Furthermore, KLF10(-/-)CD4(+)CD25(-) T cell effectors cannot be appropriately suppressed by wild-type T regs. Surprisingly,KLF10(-/-) T reg cells have reduced suppressor function, independent of Foxp3 expression, withdecreased expression and elaboration of TGF-beta1, an effect completely rescued by exogenoustreatment with TGF-beta1. Mechanistic studies demonstrate that in response to TGF-beta1, KLF10 cantransactivate both TGF-beta1 and Foxp3 promoters, implicating KLF10 in a positive feedback loop thatmay promote cell-intrinsic control of T cell activation. Finally, KLF10(-/-) CD4(+)CD25(-) T cells promotedatherosclerosis by approximately 2-fold in ApoE(-/-)/scid/scid mice with increased leukocyteaccumulation and peripheral pro-inflammatory cytokines. Thus, KLF10 is a critical regulator in thetranscriptional network controlling TGF-beta1 in both CD4(+)CD25(-) T cells and T regs and plays animportant role in regulating atherosclerotic lesion formation in mice.", "metadata": {}}
+{"_id": "41900731", "title": "", "text": "Synchrotron radiation solution X-ray scattering study of the pH dependence of the quaternary structure ofyeast pyruvate decarboxylase.The pH dependence of the quaternary structure of pyruvate decarboxylasefrom yeast was studied in the range 6.2 less than pH less than 8.4. There is an equilibrium with amidpoint around pH 7.5 between tetramers and dimers, and the catalytic activity of the enzyme dependson the volume fraction of tetramer. This equilibrium may provide an additional regulating mechanismbesides substrate activation since accumulation of pyruvate would lead to a reduction in pH and hence anincrease of the concentration of the catalytically active tetramer. Radiation damage during the X-rayscattering experiments results in a shift of this equilibrium and in the formation of octamers. Theseeffects could be circumvented and analyzed using experimental and data processing methods which canbe readily applied to other radiation-sensitive systems. The low-resolution shapes of the dimers andtetramers were determined from the scattering curves using spherical harmonics. The results indicatethat a conformational change must occur in the dimers upon formation of the tetramers, in agreementwith earlier circular dichroism measurements.", "metadata": {}}
+{"_id": "41911192", "title": "", "text": "Enhancement of anxiety-like responsiveness to the cannabinoid CB(1) receptor agonist HU-210 followingchronic stress.The effect that chronic unpredictable stress had on the anxiety-like response elicited by thecannabinoid receptor agonist HU-210 [3-(1,1-dimethylheptyl)-(-)-11-hydroxy-delta8-tetrahydrocannabinol] in the elevated plus maze was investigated here. Male Long-Evans rats wereeither unstressed or were subjected to a 21-day regimen of chronic unpredictable stress, andsubsequently were subdivided into three testing groups (vehicle, 10 and 50 microg/kg of HU-210) andtested on the elevated plus maze. Results demonstrated that in unstressed animals, a low dose ofHU-210 induced an anxiolytic response, whereas a high dose induced an anxiogenic response. Further, instressed animals both the low and the high doses of HU-210 induced anxiogenic responses. Thesefindings suggest that chronic stress enhances either cannabinoid receptor responsivity or one of theinteracting systems implicated in emotional states.", "metadata": {}}
+{"_id": "41913714", "title": "", "text": "Cardiac glycosides inhibit TNF-α/NF-κB signaling by blocking recruitment of TNF receptor-associateddeath domain to the TNF receptorDigitoxin and structurally related cardiac glycoside drugs potently blockactivation of the TNF-α/NF-κB signaling pathway. We have hypothesized that the mechanism might bediscovered by searching systematically for selective inhibitory action through the entire pathway. Wereport that the common action of these drugs is to block the TNF-α-dependent binding of TNF receptor 1to TNF receptor-associated death domain. This drug action can be observed with native cells, such asHeLa, and reconstituted systems prepared in HEK293 cells. All other antiinflammatory effects of digitoxinon NF-κB and c-Jun N-terminal kinase pathways appear to follow from the blockade of this initialupstream signaling event.", "metadata": {}}
+{"_id": "41915616", "title": "", "text": "Zinc supplementation during lactation: effects on maternal status and milk zinc concentrations.Theeffects of a zinc supplement on maternal zinc status and milk zinc concentrations through > or = 7 mo oflactation were examined. Seventy-one lactating women received either a daily 15-mg zinc supplement(ZS, n = 40) or placebo (NZS, n = 31) started by 2 wk postpartum in a double-blind, randomized design.Overall mean zinc intakes were 13.0 +/- 3.4 mg/d for the NZS group and 25.7 +/- 3.9 mg/d (includingsupplement) for the ZS group. Plasma zinc concentrations of the ZS group were significantly higher thanthose of the NZS group (P = 0.05). Milk zinc concentrations declined significantly over the course of thestudy for all subjects but were not affected by zinc supplementation. The mean dietary zinc intakeobserved in the nonsupplemented group was adequate to maintain normal maternal zinc status and milkzinc concentrations through > or = 7 mo lactation. Similar controlled intervention trials in lesswell-nourished populations will be required to assess the impact of lower zinc intakes on milk zincconcentrations.", "metadata": {}}
+{"_id": "41925568", "title": "", "text": "DMSO as a vehicle for central injections: tests with feeding elicited by norepinephrine injected into theparaventricular nucleus.Dimethyl sulfoxide (DMSO) is becoming increasingly popular as a vehicle instudies employing central injections. The aim of the present study was to determine whether the vehiclerequired for solubilization of substances for central injection [75% DMSO and 25% artificial CSF (aCSF)]would alter the well-characterized stimulatory response to norepinephrine (NE) injected into theparaventricular nucleus (PVN) on short-term food intake. To evaluate its suitability, we compared theeffects of repeated unilateral injections of NE dissolved in two different vehicles (100% aCSF or 75%DMSO, 25% aCSF), in separate groups of animals every 48 h over a 30-day period. NE (40 nmol)stimulated food intake by approximately sevenfold compared to either vehicle alone, and the stimulatoryeffect was similar whether aCSF or 75% DMSO was used as a vehicle. Furthermore, the NE-inducedfeeding did not vary in magnitude across a series of 13 tests. These results suggest that 75% DMSO is asuitable vehicle for administering NE (and likely other water-insoluble substances)in small volumes of 0.3microl into specific brain regions.", "metadata": {}}
+{"_id": "41928290", "title": "", "text": "Dodecameric structure and ATPase activity of the human TIP48/TIP49 complex.TIP48 and TIP49 are tworelated and highly conserved eukaryotic AAA(+) proteins with an essential biological function and acritical role in major pathways that are closely linked to cancer. They are found together as componentsof several highly conserved chromatin-modifying complexes. Both proteins show sequence homology tobacterial RuvB but the nature and mechanism of their biochemical role remain unknown. Recombinanthuman TIP48 and TIP49 were assembled into a stable high molecular mass equimolar complex and testedfor activity in vitro. TIP48/TIP49 complex formation resulted in synergistic increase in ATPase activity butATP hydrolysis was not stimulated in the presence of single-stranded, double-stranded or four-wayjunction DNA and no DNA helicase or branch migration activity could be detected. Complexes withcatalytic defects in either TIP48 or TIP49 had no ATPase activity showing that both proteins within theTIP48/TIP49 complex are required for ATP hydrolysis. The structure of the TIP48/TIP49 complex wasexamined by negative stain electron microscopy. Three-dimensional reconstruction at 20 A resolutionrevealed that the TIP48/TIP49 complex consisted of two stacked hexameric rings with C6 symmetry. Thetop and bottom rings showed substantial structural differences. Interestingly, TIP48 formed oligomers inthe presence of adenine nucleotides, whilst TIP49 did not. The results point to biochemical differencesbetween TIP48 and TIP49, which may explain the structural differences between the two hexameric ringsand could be significant for specialised functions that the proteins perform individually.", "metadata": {}}
+{"_id": "41976370", "title": "", "text": "Associations between work-related factors and specific disorders of the shoulder--a systematic review ofthe literature.OBJECTIVE Our aim was to provide a quantitative assessment of the exposure-responserelationships between work-related physical and psychosocial factors and the occurrence of specificshoulder disorders in occupational populations. METHODS A systematic review of the literature wasconducted on the associations between type of work, physical load factors, and psychosocial aspects atwork, on the one hand, and the occurrence of tendinitis of the biceps tendon, rotator cuff tears,subacromial impingement syndrome (SIS), and suprascapular nerve compression, on the other hand.Associations between work factors and shoulder disorders were expressed in quantitative measures asodds ratio (OR) or relative risk (RR). RESULTS The occurrence of SIS was associated with forcerequirements >10% maximal voluntary contraction (MVC), lifting >20 kg >10 times/day, and high-levelof hand force >1 hour/day (OR 2.8-4.2). Repetitive movements of the shoulder, repetitive motion of thehand/wrist >2 hours/day, hand-arm vibration, and working with hand above shoulder level showed anassociation with SIS (OR 1.04-4.7) as did upper-arm flexion > or =45 degrees > or =15% of time (OR2.43) and duty cycle of forceful exertions > or =9% time or duty cycle of forceful pinch >0% of time (OR2.66). High psychosocial job demand was also associated with SIS (OR 1.5-3.19). Jobs in the fishprocessing industry had the highest risk for both tendinitis of the biceps tendon as well as SIS (OR 2.28and 3.38, respectively). Work in a slaughterhouse and as a betel pepper leaf culler were associated withthe occurrence of SIS only (OR 5.27 and 4.68, respectively). None of the included articles described theassociation between job title/risk factors and the occurrence of rotator cuff tears or suprascapular nervecompression. CONCLUSIONS Highly repetitive work, forceful exertion in work, awkward postures, andhigh psychosocial job demand are associated with the occurrence of SIS.", "metadata": {}}
+{"_id": "41982985", "title": "", "text": "Altered TCR signaling from geometrically repatterned immunological synapses.The immunologicalsynapse is a specialized cell-cell junction that is defined by large-scale spatial patterns of receptors andsignaling molecules yet remains largely enigmatic in terms of formation and function. We used supportedbilayer membranes and nanometer-scale structures fabricated onto the underlying substrate to imposegeometric constraints on immunological synapse formation. Analysis of the resulting alternativelypatterned synapses revealed a causal relation between the radial position of T cell receptors (TCRs) andsignaling activity, with prolonged signaling from TCR microclusters that had been mechanically trapped inthe peripheral regions of the synapse. These results are consistent with a model of the synapse in whichspatial translocation of TCRs represents a direct mechanism of signal regulation.", "metadata": {}}
+{"_id": "42009630", "title": "", "text": "Molecular regulation of histone H3 trimethylation by COMPASS and the regulation of gene expression.TheSet1-containing complex COMPASS, which is the yeast homolog of the human MLL complex, is requiredfor mono-, di-, and trimethylation of lysine 4 of histone H3. We have performed a comparative globalproteomic screen to better define the role of COMPASS in histone trimethylation. We report that bothCps60 and Cps40 components of COMPASS are required for proper histone H3 trimethylation, but not forproper regulation of telomere-associated gene silencing. Purified COMPASS lacking Cps60 can mono- anddimethylate but is not capable of trimethylating H3(K4). Chromatin immunoprecipitation (ChIP) studiesindicate that the loss subunits of COMPASS required for histone trimethylation do not affect thelocalization of Set1 to chromatin for the genes tested. Collectively, our results suggest a molecularrequirement for several components of COMPASS for proper histone H3 trimethylation and regulation oftelomere-associated gene expression, indicating multiple roles for different forms of histone methylationby COMPASS.", "metadata": {}}
+{"_id": "42035464", "title": "", "text": "Mitosis-specific anchoring of gamma tubulin complexes by pericentrin controls spindle organization andmitotic entry.Microtubule nucleation is the best known function of centrosomes. Centrosomal microtubulenucleation is mediated primarily by gamma tubulin ring complexes (gamma TuRCs). However, little isknown about the molecules that anchor these complexes to centrosomes. In this study, we show that thecentrosomal coiled-coil protein pericentrin anchors gamma TuRCs at spindle poles through an interactionwith gamma tubulin complex proteins 2 and 3 (GCP2/3). Pericentrin silencing by small interfering RNAs insomatic cells disrupted gamma tubulin localization and spindle organization in mitosis but had no effecton gamma tubulin localization or microtubule organization in interphase cells. Similarly, overexpression ofthe GCP2/3 binding domain of pericentrin disrupted the endogenous pericentrin-gamma TuRC interactionand perturbed astral microtubules and spindle bipolarity. When added to Xenopus mitotic extracts, thisdomain uncoupled gamma TuRCs from centrosomes, inhibited microtubule aster assembly, and inducedrapid disassembly of preassembled asters. All phenotypes were significantly reduced in a pericentrinmutant with diminished GCP2/3 binding and were specific for mitotic centrosomal asters as we observedlittle effect on interphase asters or on asters assembled by the Ran-mediated centrosome-independentpathway. Additionally, pericentrin silencing or overexpression induced G2/antephase arrest followed byapoptosis in many but not all cell types. We conclude that pericentrin anchoring of gamma tubulincomplexes at centrosomes in mitotic cells is required for proper spindle organization and that loss of thisanchoring mechanism elicits a checkpoint response that prevents mitotic entry and triggers apoptotic celldeath.", "metadata": {}}
+{"_id": "42065070", "title": "", "text": "High levels of viral replication contrast with only transient changes in CD4(+) and CD8(+) cell numbersduring the early phase of experimental infection with simian immunodeficiency virus SIVmnd-1 inMandrillus sphinx.Early events during human immunodeficiency virus infections are considered to reflectthe capacity of the host to control infection. We have studied early virus and host parameters during theearly phase of simian immunodeficiency virus SIVmnd-1 nonpathogenic infection in its natural host,Mandrillus sphinx. Four mandrills were experimentally infected with a primary SIVmnd-1 strain derivedfrom a naturally infected mandrill. Two noninfected control animals were monitored in parallel. Blood andlymph nodes were collected at three time points before infection, twice a week during the first month,and at days 60, 180, and 360 postinfection (p.i.). Anti-SIVmnd-1 antibodies were detected starting fromdays 28 to 32 p.i. Neither elevated temperature nor increased lymph node size were observed. The viralload in plasma peaked between days 7 to 10 p.i. (2 x 10(6) to 2 x 10(8) RNA equivalents/ml). Viremiathen decreased 10- to 1,000-fold, reaching the viral set point between days 30 to 60 p.i. The levelsduring the chronic phase of infection were similar to that in the naturally infected donor mandrill (2 x10(5) RNA equivalents/ml). The CD4(+) cell numbers and percentages in blood and lymph nodesdecreased slightly (<10%) during primary infection, and CD8(+) cell numbers increased transiently. Allvalues returned to preinfection infection levels by day 30 p.i. CD8(+) cell numbers or percentages, inperipheral blood and lymph nodes, did not increase during the 1 year of follow-up. In conclusion,SIVmnd-1 has the capacity for rapid and extensive replication in mandrills. Despite high levels of viremia,CD4(+) and CD8(+) cell numbers remained stable in the post-acute phase of infection, raising questionsregarding the susceptibility of mandrill T cells to activation and/or cell death in response to SIVmnd-1infection in vivo.", "metadata": {}}
+{"_id": "42080024", "title": "", "text": "Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and boneturnover.Several growth factors are expressed in distinct temporal and spatial patterns during fracturerepair. Of these, vascular endothelial growth factor, VEGF, is of particular interest because of its ability toinduce neovascularization (angiogenesis). To determine whether VEGF is required for bone repair, weinhibited VEGF activity during secondary bone healing via a cartilage intermediate (endochondralossification) and during direct bone repair (intramembranous ossification) in a novel mouse model.Treatment of mice with a soluble, neutralizing VEGF receptor decreased angiogenesis, bone formation,and callus mineralization in femoral fractures. Inhibition of VEGF also dramatically inhibited healing of atibial cortical bone defect, consistent with our discovery of a direct autocrine role for VEGF in osteoblastdifferentiation. In separate experiments, exogenous VEGF enhanced blood vessel formation, ossification,and new bone (callus) maturation in mouse femur fractures, and promoted bony bridging of a rabbitradius segmental gap defect. Our results at specific time points during the course of healing underscorethe role of VEGF in endochondral vs. intramembranous ossification, as well as skeletal development vs.bone repair. The responses to exogenous VEGF observed in two distinct model systems and speciesindicate that a slow-release formulation of VEGF, applied locally at the site of bone damage, may prove tobe an effective therapy to promote human bone repair.", "metadata": {}}
+{"_id": "42095718", "title": "", "text": "Psychiatric comorbidity in chronic daily headache.Clinical evidence suggests that chronic daily headache(CDH) occurs in association with psychopathologies: previous studies have focused particularly onmigraine. To evaluate this association, we studied, using the DSM-IIIR criteria, a population of 88patients (18M, 70F) affected by CDH (mean duration 7.4 +/- 8.7 years). We documented the presence ofa psychiatric disorder in 90% of this population. The most frequent diagnosis was a comorbidity ofanxiety and mood disorders. The comorbidity of psychiatric disorders and headache has importantimplications as far as treatment is concerned.", "metadata": {}}
+{"_id": "42106119", "title": "", "text": "An Expanded Oct4 Interaction Network: Implications for Stem Cell Biology, Development, andDiseaseThe transcription factor Oct4 is key in embryonic stem cell identity and reprogramming. Insightinto its partners should illuminate how the pluripotent state is established and regulated. Here, weidentify a considerably expanded set of Oct4-binding proteins in mouse embryonic stem cells. We findthat Oct4 associates with a varied set of proteins including regulators of gene expression and modulatorsof Oct4 function. Half of its partners are transcriptionally regulated by Oct4 itself or other stem celltranscription factors, whereas one-third display a significant change in expression upon celldifferentiation. The majority of Oct4-associated proteins studied to date show an early lethal phenotypewhen mutated. A fraction of the human orthologs is associated with inherited developmental disorders orcausative of cancer. The Oct4 interactome provides a resource for dissecting mechanisms of Oct4function, enlightening the basis of pluripotency and development, and identifying potential additionalreprogramming factors.", "metadata": {}}
+{"_id": "42150015", "title": "", "text": "Reproductive and lifestyle determinants of anti-Müllerian hormone in a large population-basedstudy.CONTEXT Anti-müllerian hormone (AMH) is an ovarian reserve marker that is increasingly appliedin clinical practice as a prognostic and diagnostic tool. Despite increased use of AMH in clinical practice,large-scale studies addressing the influence of possible determinants on AMH levels are scarce.OBJECTIVE We aimed to address the role of reproductive and lifestyle determinants of AMH in a largepopulation-based cohort of women. DESIGN In this cross-sectional study, age-specific AMH percentileswere calculated using general linear modeling with CG-LMS (Cole and Green, Lambda, Mu, and Sigmamodel, an established method to calculate growth curves for children). SETTING Women from the generalcommunity participating in the Doetinchem Cohort study were assessed. PARTICIPANTS Two thousandthree hundred twenty premenopausal women were included. MAIN OUTCOME MEASURE The effect offemale reproductive and lifestyle factors on shifts in age-specific AMH percentiles was studied. RESULTSIn comparison to women with a regular menstrual cycle, current oral contraceptive (OC) users, womenwith menstrual cycle irregularity, and pregnant women had significantly lower age-specific AMHpercentiles (for OC use, 11 percentiles lower; for cycle irregularity, 11 percentiles lower; and forpregnancy, 17 percentiles lower [P value for all <.0001]). Age at menarche and age at first childbirthwere not associated with the age-specific AMH percentile. Higher parity was associated with 2 percentileshigher age-specific AMH (P = .02). Of the lifestyle factors investigated, current smoking was associatedwith 4 percentiles lower age-specific AMH percentiles (P = .02), irrespective of the smoking dose. Bodymass index, waist circumference, alcohol consumption, physical exercise, and socioeconomic status werenot significantly associated with age-specific AMH percentiles. CONCLUSIONS This study demonstratesthat several reproductive and lifestyle factors are associated with age-specific AMH levels. The lower AMHlevels associated with OC use and smoking seem reversible, as effects were confined to current use of OCor cigarettes. It is important to give careful consideration to the effect of such determinants wheninterpreting AMH in a clinical setting and basing patient management on AMH.", "metadata": {}}
+{"_id": "42185082", "title": "", "text": "Primary care and health insurance among women released from New York City jails.Factors associatedwith primary care utilization and health insurance coverage were examined among 511 women leavingjail in New York City from 1997-2001. One year after release, roughly half of the sample reported primarycare utilization (47%) and health insurance coverage (56%). Neither outcome was more likely amongthose reporting diabetes, asthma, or depression. Primary care utilization was more likely among thosereporting receipt of public benefits, health insurance coverage, moderate social support, avoidance ofillegal activity, and HIV seropositivity. Health insurance coverage was associated with receipt of publicbenefits, hospitalization, primary care, and avoiding re-arrest. This study demonstrated that a majority ofwomen leaving jail, including those with chronic diseases, lack primary care. These data highlight theneed to plan for continuity of care from corrections to the community and suggest further that this can befacilitated with provision of health benefits and social support.", "metadata": {}}
+{"_id": "42240424", "title": "", "text": "The effects of prion protein proteolysis and disaggregation on the strain properties of hamsterscrapie.Native mammalian prions exist in self-propagating strains that exhibit distinctive clinical,pathological and biochemical characteristics. Prion strain diversity is associated with variations in PrP(Sc)conformation, but it remains unknown precisely which physical properties of the PrP(Sc) molecules arerequired to encipher mammalian prion strain phenotypes. In this study, we subjected prion-infected brainhomogenates derived from three different hamster scrapie strains to either (i) proteinase K digestion or(ii) sonication, and inoculated the modified samples into normal hamsters. The results show that thestrain-specific clinical features and neuropathological profiles of inoculated animals were not affected byeither treatment. Similarly, the strain-dependent biochemical characteristics of the PrP(Sc) molecules(including electrophoretic mobility, glycoform composition, conformational stability and susceptibility toprotease digestion) in infected animals were unaffected by either proteolysis or sonication of the originalinocula. These results indicate that the infectious strain properties of native prions do not appear to bealtered by PrP(Sc) disaggregation, and that maintenance of such properties does not require theN-domain (approximately residues 23-90) of the protease-resistant PrP(Sc) molecules orprotease-sensitive PrP(Sc) molecules.", "metadata": {}}
+{"_id": "42267740", "title": "", "text": "Methylation of histone H3 lysine-79 by Dot1p plays multiple roles in the response to UV damage inSaccharomyces cerevisiae.Various proteins have been found to play roles in both the repair of UVdamaged DNA and heterochromatin-mediated silencing in the yeast Saccharomyces cerevisiae. Inparticular, factors that are involved in the methylation of lysine-79 of histone H3 by Dot1p have beenimplicated in both processes, suggesting a bipartite function for this modification. We find that a dot1 nullmutation and a histone H3 point mutation at lysine-79 cause increased sensitivity to UV radiation,suggesting that lysine-79 methylation is important for efficient repair of UV damage. Epistasis analysisbetween dot1 and various UV repair genes indicates that lysine-79 methylation plays overlapping roleswithin the nucleotide excision, post-replication and recombination repair pathways, as well asRAD9-mediated checkpoint function. In contrast, epistasis analysis with the H3 lysine-79 point mutationindicates that the lysine-to-glutamic acid substitution exerts specific effects within the nucleotide excisionrepair and post-replication repair pathways, suggesting that this allele only disrupts a subset of thefunctions of lysine-79 methylation. The overall results indicate the existence of distinct and separableroles of histone H3 lysine-79 methylation in the response to UV damage, potentially serving to coordinatethe various repair processes.", "metadata": {}}
+{"_id": "42278130", "title": "", "text": "Unmet need for personal assistance with activities of daily living among older adults.PURPOSE This studyexamined the prevalence, correlates, and negative consequences of unmet need for personal assistancewith activities of daily living (ADLs) among older adults. DESIGN AND METHODS The authors analyzedcross-sectional data from the 1994 National Health Interview Survey's Supplement on Aging. Data wereweighted to be representative of the noninstitutionalized population aged 70 years and older. RESULTSOverall, 20.7% of those needing help to perform 1 or more ADLs (an estimated 629,000 persons)reported receiving inadequate assistance; for individual ADLs, the prevalence of unmet need ranged from10.2% (eating) to 20.1% (transferring). The likelihood of having 1 or more unmet needs was associatedwith lower household income, multiple ADL difficulties, and living alone. Nearly half of those with unmetneeds reported experiencing a negative consequence (e.g., unable to eat when hungry) as a result oftheir unmet need. IMPLICATIONS Greater, targeted efforts are needed to reduce the prevalence andconsequences of unmet need for ADL assistance in elderly persons.", "metadata": {}}
+{"_id": "42279414", "title": "", "text": "Multi-stage chemical carcinogenesis in mouse skin: Fundamentals and applicationsFor more than 60years, the chemical induction of tumors in mouse skin has been used to study mechanisms of epithelialcarcinogenesis and evaluate modifying factors. In the traditional two-stage skin carcinogenesis model,the initiation phase is accomplished by the application of a sub-carcinogenic dose of a carcinogen.Subsequently, tumor development is elicited by repeated treatment with a tumor-promoting agent. Theinitiation protocol can be completed within 1–3 h depending on the number of mice used; whereas thepromotion phase requires twice weekly treatments (1–2 h) and once weekly tumor palpation (1–2 h) forthe duration of the study. Using the protocol described here, a highly reproducible papilloma burden isexpected within 10–20 weeks with progression of a portion of the tumors to squamous cell carcinomaswithin 20–50 weeks. In contrast to complete skin carcinogenesis, the two-stage model allows for greateryield of premalignant lesions, as well as separation of the initiation and promotion phases.", "metadata": {}}
+{"_id": "42291761", "title": "", "text": "Preventing deaths by drowning in children in the United Kingdom: have we made progress in 10 years?Population based incidence study.Detailed information on drowning in children is not routinely collectedby offices of national statistics. Few studies have been carried out in the United Kingdom, and none hasbeen done on British children abroad. In 1988-9, two of the authors (AMK and JRS) combined informationfrom national statistical offices, police forces (Royal Life Saving Society), and from a press cutting service(Royal Society for Prevention of Accidents) for a detailed analysis of deaths by drowning in children.1, 2,3 This analysis found that 149 children had drowned in the United Kingdom during 1998-9. It alsoidentified a safety agenda, which focused on young children in garden ponds and pools and on olderchildren swimming without supervision. Over the past 10 years there have been initiatives on children'ssafety in water, particularly swimming. We obtained similar information for 1998-9 to identify changesthat have …", "metadata": {}}
+{"_id": "42298280", "title": "", "text": "Hypoxic heterogeneity in human tumors: EF5 binding, vasculature, necrosis, and proliferation.Weevaluated the levels and distribution of hypoxia in 31 human tumors using fluorescentimmunohistochemical detection of binding by the 2-nitroimidazole, EF5. Hypoxia was found to be aheterogeneous property of human tumors. Necrosis was usually found adjacent to the highest level ofbinding in an individual patient's tumor. However, hypoxia often occurred without necrosis. In the groupof tumors studied, the most common relationship between blood vessels (PECAM/CD31) and EF5 stainingwas consistent with diffusion-limited hypoxia; acute hypoxia occurred infrequently. Within a givenpatient's tumor, there was an inverse correlation between regions of proliferation (Ki-67) and regions ofhypoxia. Again, however, when these parameters were examined in a group of patients, the absence ofproliferation did not predict the presence of hypoxia. The relationships between hypoxia and otherbiologic endpoints are complex, but, within a given tumor's spatial relationships, they are in accord withknown physiologic principles. Thus, our data emphasize that the relationships between hypoxia and otherbiologic parameters vary between patients. Necrosis, proliferation, and blood vessel distribution cannotpredict the level or presence of hypoxia in an individual patient's tumor.", "metadata": {}}
+{"_id": "42314147", "title": "", "text": "The Sp1-like protein BTEB3 inhibits transcription via the basic transcription element box by interactingwith mSin3A and HDAC-1 co-repressors and competing with Sp1.Sp1-like proteins are characterized bythree conserved C-terminal zinc finger motifs that bind GC-rich sequences found in promoters ofnumerous genes essential for mammalian cell homeostasis. These proteins behave as transcriptionalactivators or repressors. Although significant information has been reported on the molecularmechanisms by which Sp1-like activators function, relatively little is known about mechanisms forrepressor proteins. Here we report the functional characterization of BTEB3, a ubiquitously expressedSp1-like transcriptional repressor. GAL4 assays show that the N terminus of BTEB3 contains regions thatcan act as direct repressor domains. Immunoprecipitation assays reveal that BTEB3 interacts with theco-repressor mSin3A and the histone deacetylase protein HDAC-1. Gel shift assays demonstrate thatBTEB3 specifically binds the BTE site, a well characterized GC-rich DNA element, with an affinity similar tothat of Sp1. Reporter and gel shift assays in Chinese hamster ovary cells show that BTEB3 can alsomediate repression by competing with Sp1 for BTE binding. Thus, the characterization of this proteinexpands the repertoire of BTEB-like members of the Sp1 family involved in transcriptional repression.Furthermore, our results suggest a mechanism of repression for BTEB3 involving direct repression by theN terminus via interaction with mSin3A and HDAC-1 and competition with Sp1 via the DNA-bindingdomain.", "metadata": {}}
+{"_id": "42330403", "title": "", "text": "Perceptual limits in a simulated \"Cocktail party\".Numerosity judgments of simultaneous talkers wereexamined. Listeners were required to report the number of talkers heard when this number varied (1 to13). Spatial location of talkers (1 or 6 locations), duration of talker voices (0.8 s, 5.0 s, and 15.0 s), andgender arrangement of talkers also were manipulated in four experiments. In all experiments, theproportion of correct numerosity judgments monotonically decreased as talker numbers increased.Perceptual limits, defined as talker numbers with proportion correct scores of 0.5, varied between 3 to 5talkers, on average, depending on listening conditions, and were significantly higher for spatiallyseparated talkers, for the longer voices, and for the mixed gender voices (Experiments 1, 2, and 3). Inaddition, Experiment 4 found that average numerosity response times increased monotonically over arange of one to four talkers. These results support the idea that, before counting talkers, listenersperceptually segregate talkers to render numerosity judgments. They also suggest that our functionalauditory world for simultaneous voices may consist of, at most, three to five talkers depending onlistening situations. In light of these results, possible causes for such perceptual limits are discussed.", "metadata": {}}
+{"_id": "42373087", "title": "", "text": "The MOS social support survey.This paper describes the development and evaluation of a brief,multidimensional, self-administered, social support survey that was developed for patients in the MedicalOutcomes Study (MOS), a two-year study of patients with chronic conditions. This survey was designedto be comprehensive in terms of recent thinking about the various dimensions of social support. Inaddition, it was designed to be distinct from other related measures. We present a summary of the majorconceptual issues considered when choosing items for the social support battery, describe the items, andpresent findings based on data from 2987 patients (ages 18 and older). Multitrait scaling analysessupported the dimensionality of four functional support scales (emotional/informational, tangible,affectionate, and positive social interaction) and the construction of an overall functional social supportindex. These support measures are distinct from structural measures of social support and from relatedhealth measures. They are reliable (all Alphas greater than 0.91), and are fairly stable over time.Selected construct validity hypotheses were supported.", "metadata": {}}
+{"_id": "42373943", "title": "", "text": "Can hematological parameters discriminate malaria from nonmalarious acute febrile illness in thetropics?BACKGROUND Malaria is considered as the main differential diagnosis of acute febrile illness inthe tropics, and alteration of various hematological parameters has been observed in patients withmalaria. AIM To ascertain if certain hematological parameters increase the probability of malaria inpatients with acute febrile illnesses. SETTINGS AND DESIGN Hospital based, prospective cohort study.METHODS AND MATERIAL All consecutive in patients with fever of less than seven days in duration wereincluded in the study. Patients where localizing cause for fever could be determined were excluded.Hematological parameters (Hemoglobin, Red cell distribution width (RDW), Leukocyte count, and plateletcounts) were determined by using automated counter, and peripheral smear examination for malarialparasite was taken as gold standard for the diagnosis of malaria. STATISTICAL ANALYSIS USEDDiagnostic accuracy was measured by computing sensitivity, specificity, predictive values and likelihoodratios. The precision of these estimates was evaluated using 95% confidence intervals. RESULTS ANDCONCLUSIONS A total of 184 patients were included in the study and 70 (38%) had a positive peripheralsmear for malarial parasite. Thrombocytopenia alone (platelet countless than 150,000/mm3) was apredictor for malaria (Sn 60%, Sp 88%, LR+ 5.04) and in combination with anemia (Hb < 10 g/dl) it wasnext best parameter (Sn 69%, Sp 74%, LR+ 2.77). RDW and leukocyte count were not predictive. Theconclusion of this study is that the presence of thrombocytopenia in a patient with acute febrile illnessincreases the probability of malarial infection.", "metadata": {}}
+{"_id": "42377686", "title": "", "text": "14q deletions are associated with trisomy 12, NOTCH1 mutations and unmutated IGHV genes in chroniclymphocytic leukemia and small lymphocytic lymphoma.Deletions of the long arm of chromosome 14[del(14q)] are rare but recurrently observed in mature B-cell neoplasms, particularly in chroniclymphocytic leukemia (CLL). To further characterize this aberration, we studied 81 cases with del(14q):54 of CLL and 27 of small lymphocytic lymphoma (SLL), the largest reported series to date. Usingkaryotype and fluorescence in situ hybridization (FISH), the most frequent additional abnormality wastrisomy 12 (tri12), observed in 28/79 (35%) cases, followed by del13q14 (12/79, 15%), delTP53 (11/80,14%) delATM (5/79, 6%), and del6q21 (3/76, 4%). IGHV genes were unmutated in 41/53 (77%)patients, with a high frequency of IGHV1-69 (21/52, 40%). NOTCH1 gene was mutated in 14/45 (31%)patients. There was no significant difference in cytogenetic and molecular abnormalities between CLL andSLL. Investigations using FISH and SNP-array demonstrated the heterogeneous size of the 14q deletions.However, a group with the same del(14)(q24.1q32.33) was identified in 48% of cases. In this group,tri12 (P = 0.004) and NOTCH1 mutations (P = 0.02) were significantly more frequent than in the otherpatients. In CLL patients with del(14q), median treatment-free survival (TFS) was 27 months. Inconclusion, del(14q) is associated with tri12 and with pejorative prognostic factors: unmutated IGHVgenes (with over-representation of the IGHV1-69 repertoire), NOTCH1 mutations, and a short TFS.", "metadata": {}}
+{"_id": "42387637", "title": "", "text": "Rapid DNA methylation changes after exposure to traffic particles.RATIONALE Exposure to particulate airpollution has been related to increased hospitalization and death, particularly from cardiovasculardisease. Lower blood DNA methylation content is found in processes related to cardiovascular outcomes,such as oxidative stress, aging, and atherosclerosis. OBJECTIVES We evaluated whether particulatepollution modifies DNA methylation in heavily methylated sequences with high representation throughoutthe human genome. METHODS We measured DNA methylation of long interspersed nucleotide element(LINE)-1 and Alu repetitive elements by quantitative polymerase chain reaction-pyrosequencing of 1,097blood samples from 718 elderly participants in the Boston area Normative Aging Study. We usedcovariate-adjusted mixed models to account for within-subject correlation in repeated measures. Weestimated the effects on DNA methylation of ambient particulate pollutants (black carbon, particulatematter with aerodynamic diameter < or = 2.5 microm [PM2.5], or sulfate) in multiple time windows (4 hto 7 d) before the examination. We estimated standardized regression coefficients (beta) expressing thefraction of a standard deviation change in DNA methylation associated with a standard deviation increasein exposure. MEASUREMENTS AND MAIN RESULTS Repetitive element DNA methylation varied inassociation with time-related variables, such as day of the week and season. LINE-1 methylationdecreased after recent exposure to higher black carbon (beta = -0.11; 95% confidence interval [CI],-0.18 to -0.04; P = 0.002) and PM2.5 (beta = -0.13; 95% CI, -0.19 to -0.06; P < 0.001 for the 7-dmoving average). In two-pollutant models, only black carbon, a tracer of traffic particles, wassignificantly associated with LINE-1 methylation (beta = -0.09; 95% CI, -0.17 to -0.01; P = 0.03). Noassociation was found with Alu methylation (P > 0.12). CONCLUSIONS We found decreasedrepeated-element methylation after exposure to traffic particles. Whether decreased methylationmediates exposure-related health effects remains to be determined.", "metadata": {}}
+{"_id": "42404093", "title": "", "text": "Incidence of adverse drug events and potential adverse drug events. Implications for prevention. ADEPrevention Study Group.OBJECTIVES To assess incidence and preventability of adverse drug events(ADEs) and potential ADEs. To analyze preventable events to develop prevention strategies. DESIGNProspective cohort study. PARTICIPANTS All 4031 adult admissions to a stratified random sample of 11medical and surgical units in two tertiary care hospitals over a 6-month period. Units included twomedical and three surgical intensive care units and four medical and two surgical general care units.MAIN OUTCOME MEASURES Adverse drug events and potential ADEs. METHODS Incidents were detectedby stimulated self-report by nurses and pharmacists and by daily review of all charts by nurseinvestigators. Incidents were subsequently classified by two independent reviewers as to whether theyrepresented ADEs or potential ADEs and as to severity and preventability. RESULTS Over 6 months, 247ADEs and 194 potential ADEs were identified. Extrapolated event rates were 6.5 ADEs and 5.5 potentialADEs per 100 nonobstetrical admissions, for mean numbers per hospital per year of approximately 1900ADEs and 1600 potential ADEs. Of all ADEs, 1% were fatal (none preventable), 12% life-threatening,30% serious, and 57% significant. Twenty-eight percent were judged preventable. Of the life-threateningand serious ADEs, 42% were preventable, compared with 18% of significant ADEs. Errors resulting inpreventable ADEs occurred most often at the stages of ordering (56%) and administration (34%);transcription (6%) and dispensing errors (4%) were less common. Errors were much more likely to beintercepted if the error occurred earlier in the process: 48% at the ordering stage vs 0% at theadministration stage. CONCLUSION Adverse drug events were common and often preventable; seriousADEs were more likely to be preventable. Most resulted from errors at the ordering stage, but many alsooccurred at the administration stage. Prevention strategies should target both stages of the drug deliveryprocess.", "metadata": {}}
+{"_id": "42421723", "title": "", "text": "Induction of galactokinase in Saccharomyces cerevisiae: kinetics of induction and glucose effects.Theinduced synthesis of galactokinase and the repressing effects of glucose on this synthesis have beeninvestigated in whole yeast cells rendered permeable by treatment with dimethyl sulfoxide. It was foundthat the induction response of uninduced cells to galactose is clearly dependent on the nature of thecarbon source upon which the culture was grown prior to exposure to galactose. Glucose-grown cellsexhibited a long lag before induction, whereas lactate-grown cells exhibited induced synthesis within 8min. A concentration of 0.5% galactose was found to be optimal for induction. The addition of glucose toyeast cultures growing on galactose resulted in a severe transient repression of synthesis which wasfollowed by a resumed rate of synthesis characteristic of a weaker permanent catabolite repression.Neither 2-deoxygalactose nor fucose acted as gratuitous inducers of the pathway, nor did they serve as asubstrates for galactokinase.", "metadata": {}}
+{"_id": "42441846", "title": "", "text": "Gene--nutrition interactions in coronary artery disease: correlation between the MTHFR C677Tpolymorphism and folate and homocysteine status in a Korean population.INTRODUCTION Elevatedplasma total homocysteine is a major risk for coronary artery disease (CAD). Methyltetrahydrofolatereductase (MTHFR) is a main regulatory enzyme in homocysteine metabolism; a common C677Tmutation in the MTHFR gene results in decreased enzyme activity, and contributes to increasedhomocysteine levels and decreased folate levels. We investigated the frequency of MTHFR C677T allelesin a Korean population, determined the genotype-specific threshold levels of folate or vitamin B12, andinvestigated the relationship between the TT genotype and the risk of CAD. MATERIALS AND METHODSWe enrolled a study population of 163 CAD patients and 50 control subjects, and screened the MTHFRC677T polymorphism using real-time PCR with melting point analysis. Levels of plasma homocysteine,folate and vitamin B12 were also determined. We then defined the genotype-specific threshold values offolate and vitamin B12 required to keep homocysteine levels in a normal range for individuals of eachMTHFR C677T genotype. RESULTS The frequency of the TT genotype was 18% in control subjects and26% in patients group (P>0.05). Individuals homozygous for the TT genotype had significantly elevatedhomocysteine levels (P<0.05). The genotype-specific folate threshold level was significantly higher in TTindividuals than in the CC or CT genotypes. The OR of individuals with low folate status and the TTgenotype to estimate the relative risk of CAD was 2.2 and the OR of those with high folate status and theTT genotype was 1.5 (95% CI, 0.5-9.6 and 0.7-3.2, respectively). CONCLUSION We were able to define agene-nutrient interaction that shows a higher risk for CAD based on specific threshold folate levelsrequired by different MTHFR C677T genotypes in a Korean population.", "metadata": {}}
+{"_id": "42465769", "title": "", "text": "Human bone marrow adipocytes block granulopoiesis through neuropilin-1-induced granulocytecolony-stimulating factor inhibition.Adipocytes are part of hematopoietic microenvironment, even thoughup to now in humans, their role in hematopoiesis is still questioned. We have previously shown thataccumulation of fat cells in femoral bone marrow (BM) coincides with increased expression of neuropilin-1(NP-1), while it is weakly expressed in hematopoietic iliac crest BM. Starting from this observation, wepostulated that adipocytes might exert a negative effect on hematopoiesis mediated through NP-1. Totest this hypothesis, we set up BM adipocytes differentiated into fibroblast-like fat cells (FLFC), whichshare the major characteristics of primitive unilocular fat cells, as an experimental model. As expected,FLFCs constitutively produced macrophage colony stimulating factor and induced CD34(+) differentiationinto macrophages independently of cell-to-cell contact. By contrast, granulopoiesis was hampered bycell-to-cell contact but could be restored in transwell culture conditions, together with granulocyte colonystimulating factor production. Both functions were also recovered when FLFCs cultured in contact withCD34(+) cells were treated with an antibody neutralizing NP-1, which proved its critical implication incontact inhibition. An inflammatory cytokine such as interleukin-1 beta or dexamethasone modulatesFLFC properties to restore granulopoiesis. Our data provide the first evidence that primary adipocytesexert regulatory functions during hematopoiesis that might be implicated in some pathological processes.Disclosure of potential conflicts of interest is found at the end of this article.", "metadata": {}}
+{"_id": "42484543", "title": "", "text": "The transcriptome profile of human embryonic stem cells as defined by SAGE.Human embryonic stem(ES) cell lines that have the ability to self-renew and differentiate into specific cell types have beenestablished. The molecular mechanisms for self-renewal and differentiation, however, are poorlyunderstood. We determined the transcriptome profiles for two proprietary human ES cell lines (HES3 andHES4, ES Cell International), and compared them with murine ES cells and other human tissues. Humanand mouse ES cells appear to share a number of expressed gene products although there are numerousnotable differences, including an inactive leukemia inhibitory factor pathway and the high preponderanceof several important genes like POU5F1 and SOX2 in human ES cells. We have established a list of genescomprised of known ES-specific genes and new candidates that can serve as markers for human ES cellsand may also contribute to the \"stemness\" phenotype. Of particular interest was the downregulation ofDNMT3B and LIN28 mRNAs during ES cell differentiation. The overlapping similarities and differences ingene expression profiles of human and mouse ES cells provide a foundation for a detailed and concerteddissection of the molecular and cellular mechanisms governing their pluripotency, directed differentiationinto specific cell types, and extended ability for self-renewal.", "metadata": {}}
+{"_id": "42489926", "title": "", "text": "Small-molecule antagonists of p53-MDM2 binding: research tools and potential therapeutics.p53regulates a key pathway which protects normal tissues from tumor development that may result fromdiverse forms of stress. In the absence of stress, growth suppressive and proapoptotic activity of p53 isinhibited by MDM2 which binds p53 and negatively regulates its activity and stability. MDM2 antagonistscould activate p53 and may offer a novel therapeutic approach to cancer. Recently, we identified the firstpotent and selective low molecular weight inhibitors of MDM2-p53 binding, the Nutlins. These moleculesactivate the p53 pathway and suppress tumor growth in vitro and in vivo. They represent valuable newtools for studying the p53 pathway and its defects in cancer. Nutlins induce p53-dependent apoptosis inhuman cancer cells but appear cytostatic to proliferating normal cells. Their potent activity againstosteosarcoma xenografts suggests that MDM2 antagonists may have clinical utility in the treatment oftumors with wild-type p53.", "metadata": {}}
+{"_id": "42520882", "title": "", "text": "Slipped (CTG)•(CAG) repeats can be correctly repaired, escape repair or undergo error-pronerepairExpansion of (CTG)•(CAG) repeats, the cause of 14 or more diseases, is presumed to arise throughescaped repair of slipped DNAs. We report the fidelity of slipped-DNA repair using human cell extractsand DNAs with slip-outs of (CAG)20 or (CTG)20. Three outcomes occurred: correct repair, escaped repairand error-prone repair. The choice of repair path depended on nick location and slip-out composition(CAG or CTG). A new form of error-prone repair was detected whereby excess repeats were incompletelyexcised, constituting a previously unknown path to generate expansions but not deletions. Neuron-likecell extracts yielded each of the three repair outcomes, supporting a role for these processes in(CTG)•(CAG) instability in patient post-mitotic brain cells. Mismatch repair (MMR) and nucleotide excisionrepair (NER) proteins hMSH2, hMSH3, hMLH1, XPF, XPG or polymerase β were not required—indicatingthat their role in instability may precede that of slip-out processing. Differential processing of slippedrepeats may explain the differences in mutation patterns between various disease loci or tissues.", "metadata": {}}
+{"_id": "42565477", "title": "", "text": "High Dub3 expression in mouse ESCs couples the G1/S checkpoint to pluripotency.The molecularmechanism underlying G1/S checkpoint bypass in mouse embryonic stem cells (ESCs) remains unknown.DNA damage blocks S phase entry by inhibiting the CDK2 kinase through destruction of its activator, theCdc25A phosphatase. We observed high Cdc25A levels in G1 that persist even after DNA damage inmouse ESCs. We also found higher expression of Dub3, a deubiquitylase that controls Cdc25A proteinabundance. Moreover, we demonstrate that the Dub3 gene is a direct target of Esrrb, a key transcriptionfactor of the self-renewal machinery. We show that Dub3 expression is strongly downregulated duringneural conversion and precedes Cdc25A destabilization, while forced Dub3 expression in ESCs becomeslethal upon differentiation, concomitant to cell-cycle remodeling and lineage commitment. Finally,knockdown of either Dub3 or Cdc25A induced spontaneous differentiation of ESCs. Altogether, thesefindings couple the self-renewal machinery to cell-cycle control through a deubiquitylase in ESCs.", "metadata": {}}
+{"_id": "42601237", "title": "", "text": "Paracrine effects of direct intramyocardial implantation of bone marrow derived cells to enhanceneovascularization in chronic ischaemic myocardium.OBJECTIVE To determine the optimal bone marrow(BM) cell types, and their potential mechanisms of action for neovascularization in chronic ischaemicmyocardium. METHODS AND RESULTS The functional effects, angiogenic potential and cytokineexpression of direct intramyocardial implantation of autologous BM CD31-positive endothelial progenitorcells (EPC, n=9), BM mononuclear cells (MNCs, n=9), and saline (n=9) were compared in a swine modelof chronic ischaemic myocardium. Autologous BM cells were harvested and catheter-basedelectromechanical mapping-guided direct intramyocardial injection was performed to target ischaemicmyocardium. After 12 weeks, injection of BM-MNC resulted in significant improvements in left ventriculardP/dt (+21+/-8%, P=0.032), left ventricular pressure (+17+/-4%, P=0.048) and regional microspheremyocardial perfusion over ischaemic endocardium (+74+/-28%, P<0.05) and epicardium (+73+/-29%,P<0.05). No significant effects were observed following injection of BM-EPC or saline. Capillary density(1132+/-69 versus 903+/-44 per mm(2), P=0.047) and expression of mRNA of vascular endothelialgrowth factor (VEGF, 32.3+/-5.6 versus 13.1+/-3.7, P<0.05,) and angiopoietin-2 (23.9+/-3.6 versus13.7+/-3.1, P<0.05) in ischaemic myocardium was significantly greater in the BM-MNC group than thesaline group. The capillary density in ischaemic myocardium demonstrated a significant positivecorrelation with VEGF expression (r=0.61, P<0.001). CONCLUSION Catheter-based direct intramyocardialinjection of BM-MNC enhanced angiogenesis more effectively than BM-EPC or saline, possibly via aparacrine effect, with increased expression of VEGF that subsequently improved cardiac performance ofischaemic myocardium.", "metadata": {}}
+{"_id": "42662816", "title": "", "text": "Endogenous miRNA sponge lincRNA-RoR regulates Oct4, Nanog, and Sox2 in human embryonic stem cellself-renewal.The embryonic stem cell (ESC) transcriptional and epigenetic networks are controlled by amultilayer regulatory circuitry, including core transcription factors (TFs), posttranscriptional modifiermicroRNAs (miRNAs), and some other regulators. However, the role of large intergenic noncoding RNAs(lincRNAs) in this regulatory circuitry and their underlying mechanism remains undefined. Here, wedemonstrate that a lincRNA, linc-RoR, may function as a key competing endogenous RNA to link thenetwork of miRNAs and core TFs, e.g., Oct4, Sox2, and Nanog. We show that linc-RoR sharesmiRNA-response elements with these core TFs and that linc-RoR prevents these core TFs frommiRNA-mediated suppression in self-renewing human ESC. We suggest that linc-RoR forms a feedbackloop with core TFs and miRNAs to regulate ESC maintenance and differentiation. These results mayprovide insights into the functional interactions of the components of genetic networks duringdevelopment and may lead to new therapies for many diseases.", "metadata": {}}
+{"_id": "42693833", "title": "", "text": "Foxp3(+) T cells regulate immunoglobulin a selection and facilitate diversification of bacterial speciesresponsible for immune homeostasis.Foxp3(+) T cells play a critical role for the maintenance of immunetolerance. Here we show that in mice, Foxp3(+) T cells contributed to diversification of gut microbiota,particularly of species belonging to Firmicutes. The control of indigenous bacteria by Foxp3(+) T cellsinvolved regulatory functions both outside and inside germinal centers (GCs), consisting of suppression ofinflammation and regulation of immunoglobulin A (IgA) selection in Peyer's patches, respectively.Diversified and selected IgAs contributed to maintenance of diversified and balanced microbiota, which inturn facilitated the expansion of Foxp3(+) T cells, induction of GCs, and IgA responses in the gut througha symbiotic regulatory loop. Thus, the adaptive immune system, through cellular and molecularcomponents that are required for immune tolerance and through the diversification as well as selection ofantibody repertoire, mediates host-microbial symbiosis by controlling the richness and balance ofbacterial communities required for homeostasis.", "metadata": {}}
+{"_id": "42708716", "title": "", "text": "The isolation and characterization of a cDNA encoding phospholipid-specific inositol polyphosphate5-phosphatase.We report the cDNA cloning and characterization of a novel human inositol polyphosphate5-phosphatase (5-phosphatase) that has substrate specificity unlike previously described members of thislarge gene family. All previously described members hydrolyze water soluble inositol phosphates. Thisenzyme hydrolyzes only lipid substrates, phosphatidylinositol 3,4,5-trisphosphate andphosphatidylinositol 4,5-bisphosphate. The cDNA isolated comprises 3110 base pairs and predicts aprotein product of 644 amino acids and M(r) = 70,023. We designate this 5-phosphatase as type IV. It isa highly basic protein (pI = 8.8) and has the greatest affinity toward phosphatidylinositol3,4,5-trisphosphate of known 5-phosphatases. The K(m) is 0.65 micrometer, 1/10 that of SHIP (5.95micrometer), another 5-phosphatase that hydrolyzes phosphatidylinositol 3,4,5-trisphosphate. Theactivity of 5-phosphatase type IV is sensitive to the presence of detergents in the in vitro assay. Thus theenzyme hydrolyzes lipid substrates in the absence of detergents or in the presence of n-octylbeta-glucopyranoside or Triton X-100, but not in the presence of cetyltriethylammonium bromide, thedetergent that has been used in other studies of the hydrolysis of phosphatidylinositol 4,5-bisphosphate.Remarkably SHIP, a 5-phosphatase previously characterized as hydrolyzing only substrates with d-3phosphates, also readily hydrolyzed phosphatidylinositol 4,5-bisphosphate in the presence of n-octylbeta-glucopyranoside but not cetyltriethylammonium bromide. We used antibodies prepared against apeptide predicted by the cDNA to identify the 5-phosphatase type IV enzyme in human tissues and findthat it is highly expressed in the brain as determined by Western blotting. We also performed Westernblotting of mouse tissues and found high levels of expression in the brain, testes, and heart with lowerlevels of expression in other tissues. mRNA was detected in many tissues and cell lines as determined byNorthern blotting.", "metadata": {}}
+{"_id": "42731834", "title": "", "text": "Lack of Absent in Melanoma 2 (AIM2) expression in tumor cells is closely associated with poor survival incolorectal cancer patients.Functional studies on colorectal cancer cells indicated a protective role of theinterferon-inducible dsDNA sensor Absent in Melanoma 2 (AIM2) in cancer progression. Given that a highmutation rate and lack of AIM2 expression was previously detected in a subset of colorectal cancers, wehere investigated the association of AIM2 expression in tumor cells and patient prognosis (5-yearfollow-up). A tissue microarray analysis of 476 matched tissue pairs (colorectal tumor and adjacentnormal colon epithelium) was performed by two independent observers. Samples from 62 patients wereexcluded because of missing follow-up information or due to neo-adjuvant therapy before tissuesampling. Out of the remaining 414 tissue pairs, 279 (67.4%) displayed reduced AIM2 expression incancer cells when compared to epithelial cells of their normal counterpart. Thirty-eight patients (9.18%)had completely lost AIM2 expression in tumor cells. After adjustment for sex, age, cancer stage, tumorsite, tumor grade and chemotherapy, complete lack of AIM2 expression was associated with an up to3-fold increase in overall mortality (HR=2.40; 95% CI=1.44-3.99) and disease specific mortality(HR=3.14; 95% CI=1.75-5.65) in comparison to AIM2-positive tumor samples. Our results demonstratethat lack of AIM2 expression is closely associated with poor outcome in colorectal cancer. The data thusstrongly substantiate a protective role of AIM2 against progression of colorectal tumors. Further studiesare required to assess whether lack of AIM2 expression may be used as a biomarker for the identificationof colorectal cancer patients with poor prognosis.", "metadata": {}}
+{"_id": "42782688", "title": "", "text": "VSL#3 probiotic upregulates intestinal mucosal alkaline sphingomyelinase and reducesinflammation.BACKGROUND Alkaline sphingomyelinase, an enzyme found exclusively in bile and theintestinal brush border, hydrolyzes sphingomyelin into ceramide, sphingosine andsphingosine-1-phosphate, thereby inducing epithelial apoptosis. Reduced levels of alkalinesphingomyelinase have been found in premalignant and malignant intestinal epithelia and in ulcerativecolitis tissue. Probiotic bacteria can be a source of sphingomyelinase. OBJECTIVE To determine the effectof VSL#3 probiotic therapy on mucosal levels of alkaline sphingomyelinase, both in a mouse model ofcolitis and in patients with ulcerative colitis. METHODS Interleukin-10 gene-deficient (IL10KO) and wildtype control mice were treated with VSL#3 (10(9) colony-forming units per day) for three weeks, afterwhich alkaline sphingomyelinase activity was measured in ileal and colonic tissue. As well, 15 patientswith ulcerative colitis were treated with VSL#3 (900 billion bacteria two times per day for five weeks).Alkaline sphingomyelinase activity was measured through biopsies and comparison of ulcerative colitisdisease activity index scores obtained before and after treatment. RESULTS Lowered alkalinesphingomyelinase levels were seen in the colon (P=0.02) and ileum (P=0.04) of IL10KO mice, ascompared with controls. Treatment of these mice with VSL#3 resulted in upregulation of mucosal alkalinesphingomyelinase activity in both the colon (P=0.04) and the ileum (P=0.01). VSL#3 treatment of humanpatients who had ulcerative colitis decreased mean (+/- SEM) ulcerative colitis disease activity indexscores from 5.3+/-1.8946 to 0.70+/-0.34 (P=0.02) and increased mucosal alkaline sphingomyelinaseactivity. CONCLUSION Mucosal alkaline sphingomyelinase activity is reduced in the intestine of IL10KOmice with colitis and in humans with ulcerative colitis. VSL#3 probiotic therapy upregulates mucosalalkaline sphingomyelinase activity.", "metadata": {}}
+{"_id": "42787108", "title": "", "text": "Nodal/Activin signaling predicts human pluripotent stem cell lines prone to differentiate toward thehematopoietic lineage.Lineage-specific differentiation potential varies among different human pluripotentstem cell (hPSC) lines, becoming therefore highly desirable to prospectively know which hPSC linesexhibit the highest differentiation potential for a certain lineage. We have compared the hematopoieticpotential of 14 human embryonic stem cell (hESC)/induced pluripotent stem cell (iPSC) lines. Theemergence of hemogenic progenitors, primitive and mature blood cells, and colony-forming unit (CFU)potential was analyzed at different time points. Significant differences in the propensity to differentiatetoward blood were observed among hPSCs: some hPSCs exhibited good blood differentiation potential,whereas others barely displayed blood-differentiation capacity. Correlation studies revealed that the CFUpotential robustly correlates with hemogenic progenitors and primitive but not mature blood cells.Developmental progression of mesoendodermal and hematopoietic transcription factors expressionrevealed no correlation with either hematopoietic initiation or maturation efficiency. Microarray studiesshowed distinct gene expression profile between hPSCs with good versus poor hematopoietic potential.Although neuroectoderm-associated genes were downregulated in hPSCs prone to hematopoieticdifferentiation many members of the Nodal/Activin signaling were upregulated, suggesting that thissignaling predicts those hPSC lines with good blood-differentiation potential. The association betweenNodal/Activin signaling and the hematopoietic differentiation potential was confirmed using loss- andgain-of-function functional assays. Our data reinforce the value of prospective comparative studies aimedat determining the lineage-specific differentiation potential among different hPSCs and indicate thatNodal/Activin signaling seems to predict those hPSC lines prone to hematopoietic specification.", "metadata": {}}
+{"_id": "42800527", "title": "", "text": "Addition of a Gastrointestinal Microbiome Modulator to Metformin Improves Metformin Tolerance andFasting Glucose Levels.BACKGROUND Adverse effects of metformin are primarily related togastrointestinal (GI) intolerance that could limit titration to an efficacious dose or cause discontinuation ofthe medication. Because some metformin side effects may be attributable to shifts in the GI microbiome,we tested whether a GI microbiome modulator (GIMM) used in combination with metformin wouldameliorate the GI symptoms. METHODS A 2-period crossover study design was used with 2 treatmentsequences, either placebo in period 1 followed by GIMM in period 2 or vice versa. Study periods lasted for2 weeks, with a 2-week washout period between. During the first week, type 2 diabetes patients (T2D)who experienced metformin GI intolerance took 500 mg metformin along with their assigned NM504(GIMM) or placebo treatment with breakfast and with dinner. In the second week, the 10 subjects took500 mg metformin (t.i.d.), with GIMM or placebo consumed with the first and third daily metformindoses. Subjects were permitted to discontinue metformin dosing if it became intolerable. RESULTS Thecombination of metformin and GIMM treatment produced a significantly better tolerance score tometformin than the placebo combination (6.78 ± 0.65 [mean ± SEM] versus 4.45 ± 0.69, P = .0006).Mean fasting glucose levels were significantly (P < .02) lower with the metformin-GIMM combination(121.3 ± 7.8 mg/dl) than with metformin-placebo (151.9 ± 7.8 mg/dl). CONCLUSION Combining a GImicrobiome modulator with metformin might allow the greater use of metformin in T2D patients andimprove treatment of the disease.", "metadata": {}}
+{"_id": "42836872", "title": "", "text": "Diverse tumorigenic pathways in ovarian serous carcinoma.This study was undertaken to analyze geneticalterations in 108 sporadic serous ovarian neoplasms to elucidate ovarian serous carcinogenesis. Ourresults demonstrate that K-ras mutations occur in approximately 50% of serous borderline tumors(SBTs), non-invasive micropapillary serous carcinomas (MPSCs), and invasive micropapillary serouscarcinomas, which represent a morphological continuum of tumor progression. Moreover, progressiveincrease in the degree of allelic imbalance of chromosomes 1p, 5q, 8p, 18q, 22q, and Xp was observedcomparing serous borderline tumors to noninvasive and invasive micropapillary serous carcinomas. Incontrast, high-grade (conventional serous carcinoma) tumors contained wild-type K-ras in all 23 casesstudied and a high frequency of allelic imbalance even in small (early) primary tumors similar to thatfound in advanced stage tumors. Based on these findings, we propose a dualistic model for ovarianserous carcinogenesis. One pathway involves a stepwise progression from SBT to noninvasive and theninvasive MPSC. The other pathway is characterized by rapid progression from the ovarian surfaceepithelium or inclusion cysts to a conventional (high-grade) serous carcinoma.", "metadata": {}}
+{"_id": "42855554", "title": "", "text": "Tissue-inherent fate of GPI revealed by GPI-anchored GFP transgenesis.To clarify the fate ofglycosylphosphatidylinositol (GPI) in mammals, we developed GPI-anchored enhanced green fluorescentprotein (EGFP-GPI) and transgenic mice carrying this fusion construct. When it was introduced to culturecells, the EGFP-GPI protein was correctly sorted to plasma membranes and microsomes depending onGPI biosynthesis. Transgenic mice carrying EGFP-GPI were found to show a broad transgene expression.Histologically, a prominent polarized localization of EGFP-GPI protein was observed in various epithelia,the nervous system and liver and secreted from some exocrine glands, as well as non-polarized presencein non-epithelial tissues, demonstrating a tissue-inherent manner of GPI sorting.", "metadata": {}}
+{"_id": "42865134", "title": "", "text": "Essential role for the SANT domain in the functioning of multiple chromatin remodeling enzymes.TheSANT domain is a novel motif found in a number of eukaryotic transcriptional regulatory proteins that wasidentified based on its homology to the DNA binding domain of c-myb. Here we show that the SANTdomain is essential for the in vivo functions of yeast Swi3p, Ada2p, and Rsc8p, subunits of three distinctchromatin remodeling complexes. We also find that the Ada2p SANT domain is essential for histoneacetyltransferase activity of native, Gcn5p-containing HAT complexes. Furthermore, kinetic analysesindicate that an intact SANT domain is required for an Ada2p-dependent enhancement of histone tailbinding and enzymatic catalysis by Gcn5p. Our results are consistent with a general role for SANTdomains in functional interactions with histone N-terminal tails.", "metadata": {}}
+{"_id": "42873134", "title": "", "text": "Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences, fewsimilarities.Type 1 and type 2 diabetes are characterized by progressive beta-cell failure. Apoptosis isprobably the main form of beta-cell death in both forms of the disease. It has been suggested that themechanisms leading to nutrient- and cytokine-induced beta-cell death in type 2 and type 1 diabetes,respectively, share the activation of a final common pathway involving interleukin (IL)-1beta, nuclearfactor (NF)-kappaB, and Fas. We review herein the similarities and differences between the mechanismsof beta-cell death in type 1 and type 2 diabetes. In the insulitis lesion in type 1 diabetes, invadingimmune cells produce cytokines, such as IL-1beta, tumor necrosis factor (TNF)-alpha, and interferon(IFN)-gamma. IL-1beta and/or TNF-alpha plus IFN-gamma induce beta-cell apoptosis via the activationof beta-cell gene networks under the control of the transcription factors NF-kappaB and STAT-1.NF-kappaB activation leads to production of nitric oxide (NO) and chemokines and depletion ofendoplasmic reticulum (ER) calcium. The execution of beta-cell death occurs through activation ofmitogen-activated protein kinases, via triggering of ER stress and by the release of mitochondrial deathsignals. Chronic exposure to elevated levels of glucose and free fatty acids (FFAs) causes beta-celldysfunction and may induce beta-cell apoptosis in type 2 diabetes. Exposure to high glucose has dualeffects, triggering initially \"glucose hypersensitization\" and later apoptosis, via different mechanisms.High glucose, however, does not induce or activate IL-1beta, NF-kappaB, or inducible nitric oxidesynthase in rat or human beta-cells in vitro or in vivo in Psammomys obesus. FFAs may cause beta-cellapoptosis via ER stress, which is NF-kappaB and NO independent. Thus, cytokines and nutrients triggerbeta-cell death by fundamentally different mechanisms, namely an NF-kappaB-dependent mechanismthat culminates in caspase-3 activation for cytokines and an NF-kappaB-independent mechanism fornutrients. This argues against a unifying hypothesis for the mechanisms of beta-cell death in type 1 andtype 2 diabetes and suggests that different approaches will be required to prevent beta-cell death in type1 and type 2 diabetes.", "metadata": {}}
+{"_id": "42913391", "title": "", "text": "Health-related quality of life among children with acute lymphoblastic leukemia.BACKGROUND Theobjective was to quantify the health-related quality of life (HRQL) of children treated for acutelymphoblastic leukemia (ALL) and identify specific disabilities for remediation. PROCEDURE Two types ofsubjects were included: ALL patients 5 plus years old in a multi-center clinical trial and general populationcontrol groups. Patients were assessed during all four major phases of active treatment andapproximately 2 years after treatment. Health status and HRQL were measured using HEALTH UTILITIESINDEX® (HUI®) Mark 2 (HUI2) and Mark 3 (HUI3). HRQL scores were used to calculate quality-adjustedlife years (QALYs). Excess disability rates identified attributes for remediation. RESULTS HUI assessments(n = 749) were collected during the five phases. Mean HRQL increased from induction through thepost-treatment phase (P < 0.001). There were no significant demographic or treatment effects on HRQL,except for type of asparaginase during continuation therapy (P = 0.005 for HUI2 and P = 0.007 forHUI3). Differences in mean HRQL scores between patients and controls were important (P < 0.001)during the active treatment phases but not during the post-treatment phase. Relative to controls,patients lost approximately 0.2 QALYs during active treatment. Disability was evident inmobility/ambulation, emotion, self-care and pain, and declined over time. CONCLUSIONS Patients withALL experienced important but declining deficits in HRQL during active treatment phases: Equivalent tolosing approximately 2 months of life in perfect health. HRQL within the 2-years post-treatment phasewas similar to controls. The policy challenge is to develop new treatment protocols producing fewerdisabilities in mobility/ambulation, emotion, self-care, and pain without compromising survival.", "metadata": {}}
+{"_id": "42944505", "title": "", "text": "JUVENILE MORTALITY INCREASES WITH CLUTCH SIZE IN A NEOTROPICAL BIRDThe change in avianclutch size with latitude is a celebrated example of geographic variation in a vertebrate life-history trait.Alternative hypotheses for this pattern invoke nest predation, limited food for nestlings, or post-fledgingjuvenile mortality as selection pressures leading to small clutch size of tropical birds. We manipulated theclutch size of Spotted Antbirds (Hylophylax naevioides) in central Panama to test these hypotheses. Weobserved that rates of nest predation were not influenced by parental activity at nests and parents couldsuccessfully feed nestlings in enlarged broods. Although larger broods produced the most fledgedjuveniles, these individuals were less likely to survive to dispersal than were juveniles that fledged fromsmaller broods. Consequently, nest productivity did not vary with clutch size. Post-fledging mortality wasnot related to nestling mass two to three days prior to fledging. Rather, differences in the allocation ofparental investment per juvenile among differently sized broods appeared to influence juvenile survivalprobability. These results identify parental care during the post-fledging period as a potential key factorinfluencing the evolution of small clutch size in tropical birds.", "metadata": {}}
+{"_id": "42950029", "title": "", "text": "Diagnosis of rotator cuff tears.Rotator cuff tears account for almost 50% of major shoulder injuries butare sometimes difficult to diagnose. To aid diagnosis, we did a prospective study, comparing results of 23clinical tests from 400 patients with and without rotator cuff tears. Three simple tests were predictive forrotator cuff tear: supraspinatus weakness, weakness in external rotation, and impingement. When allthree were positive, or if two tests were positive and the patient was aged 60 or older, the individual hada 98% chance of having a rotator cuff tear; combined absence of these features excluded this diagnosis.", "metadata": {}}
+{"_id": "43014661", "title": "", "text": "Increased susceptibility to UV-induced skin carcinogenesis in polymerase eta-deficient mice.Xerodermapigmentosum variant (XPV) patients with mutations in the DNA polymerase eta (pol eta) gene arehypersensitive to sunlight and have greatly increased susceptibility to sunlight-induced skin cancer.Consistent with the ability of Pol eta to efficiently bypass UV light-induced cyclobutane pyrimidine dimers,XPV cells lacking Pol eta have diminished capacity to replicate UV-damaged DNA and are sensitive to UVlight-induced killing and mutagenesis. To better understand these and other Pol eta functions, wegenerated Pol eta-deficient mice. Mice homozygous for a null mutation in pol eta are viable, fertile, anddo not show any obvious spontaneous defects during the first year of life. However, fibroblasts derivedfrom these mutant mice are sensitive to killing by exposure to UV light, and all Pol eta-deficient micedevelop skin tumors after UV irradiation, in contrast to the wild-type littermate controls that did notdevelop such tumors. These results and biochemical studies of translesion synthesis by mouse Pol etaindicate that Pol eta-dependent bypass of cyclobutane pyrimidine dimers suppresses UV light-inducedskin cancer in mice. Moreover, 37.5% of pol eta heterozygous mice also developed skin cancer during 5months after a 5-month exposure to UV light, suggesting that humans who are heterozygous formutations in pol eta may also have an increased risk of skin cancer.", "metadata": {}}
+{"_id": "43048059", "title": "", "text": "Hydrogen sulfide interacts with nitric oxide in the heart: possible involvement of nitroxyl.AIMS Thepresent study aims to investigate the interaction between nitric oxide (NO) and hydrogen sulfide (H(2)S),the two important gaseous mediators in rat hearts. METHODS AND RESULTS Intracellular calcium inisolated cardiomyocytes was measured with a spectrofluorometric method using Fura-2. Myocytecontractility was measured with a video edge system. NaHS (50 µM, an H(2)S donor) had no significanteffect on the resting calcium level, electrically induced (EI) calcium transients, and cell contractility inventricular myocytes. Stimulating endogenous NO production with l-arginine or exogenous application ofNO donors [sodium nitroprusside (SNP) and 2-(N,N-diethylamino)-diazenolate-2-oxide] decreasedmyocyte twitch amplitudes accompanied by slower velocities of both cell contraction and relaxation.Surprisingly, NaHS reversed the negative inotropic and lusitropic effects of the above three NO-increasingagents. In addition, the mixture of SNP + NaHS increased, whereas SNP alone decreased, the restingcalcium level and the amplitudes of EI calcium transients. Angeli's salt, a nitroxyl anion (HNO) donor,mimicked the effect of SNP + NaHS on calcium handling and myocyte contractility. Three thiols,N-acetyl-cysteine, l-cysteine, and glutathione, abolished the effects of HNO and SNP + NaHS on myocytecontraction. Neither Rp-cAMP [a protein kinase A (PKA) inhibitor] nor Rp-cGMP [a protein kinase G (PKG)inhibitor] affected the effects of SNP + NaHS, suggesting a cAMP/PKA- or cGMP/PKG-independentmechanism. CONCLUSION H(2)S may interact with NO to form a thiol sensitive molecule (probably HNO)which produces positive inotropic and lusitropic effects. Our findings may shed light on the interaction ofNO and H(2)S and provide new clues to treat cardiovascular diseases.", "metadata": {}}
+{"_id": "43054703", "title": "", "text": "A novel mechanism of rapid nuclear neutrophil extracellular trap formation in response to Staphylococcusaureus.Neutrophil extracellular traps (NETs) are webs of DNA covered with antimicrobial molecules thatconstitute a newly described killing mechanism in innate immune defense. Previous publications reportedthat NETs take up to 3-4 h to form via an oxidant-dependent event that requires lytic death ofneutrophils. In this study, we describe neutrophils responding uniquely to Staphylococcus aureus via anovel process of NET formation that did not require neutrophil lysis or even breach of the plasmamembrane. The multilobular nucleus rapidly became rounded and condensed. During this process, weobserved the separation of the inner and outer nuclear membranes and budding of vesicles, and theseparated membranes and vesicles were filled with nuclear DNA. The vesicles were extruded intact intothe extracellular space where they ruptured, and the chromatin was released. This entire processoccurred via a unique, very rapid (5-60 min), oxidant-independent mechanism. Mitochondrial DNAconstituted very little if any of these NETs. They did have a limited amount of proteolytic activity andwere able to kill S. aureus. With time, the nuclear envelope ruptured, and DNA filled the cytoplasmpresumably for later lytic NET production, but this was distinct from the vesicular release mechanism.Panton-Valentine leukocidin, autolysin, and a lipase were identified in supernatants with NET-inducingactivity, but Panton-Valentine leukocidin was the dominant NET inducer. We describe a new mechanismof NET release that is very rapid and contributes to trapping and killing of S. aureus.", "metadata": {}}
+{"_id": "43122426", "title": "", "text": "131-I radioiodine therapy for hyperthyroidism in patients with Graves' disease, uninodular goitre andmultinodular goitre.We studied 201 consecutive patients who received a relatively fixed dose ofradioiodine for the treatment of hyperthyroidism between the years 1981-6. Patients with Graves' disease(170) were initially treated with a mean (SE) dose of 369 (10) MBq 131-I with a remission rate of 94% at6 months and a cumulative relapse rate of 12% at one year and 21% at 5 years. The cumulativeincidence of hypothyroidism was 26% at 3 months, 55% at 6 months, 61% at 1 year and 66% at 5years. Patients with a uninodular goitre (10) were initially treated with a mean (SE) dose of 438 (85) MBq131-I with a remission rate of 100% at 6 months, without relapse at 1 year but relapsing in 17% at 5years. The cumulative incidence of hypothyroidism was 26% at 3 months, 30% at 6 months, 40% at 1year and 40% at 5 years. Patients with a multinodular goitre (21) were initially treated with a mean (SE)dose of 613 (77) MBq 131-I with a remission rate of 79% at 6 months and a cumulative relapse rate of26% at 1 year and 39% at 5 years. The cumulative incidence of hypothyroidism was 5% at 3 months,14% at 6 months, 24% at 1 year and 24% at 5 years.", "metadata": {}}
+{"_id": "43128141", "title": "", "text": "Enteral nutrition in the critically ill patient.Timing and route of nutrition provided to critically ill patientscan affect their outcome. Early enteral nutrition has been shown to decrease specifically infectiousmorbidity in the critically ill patient. There is a small group of patients who are malnourished on arrival tothe intensive care unit and in these patients parenteral nutrition is beneficial.", "metadata": {}}
+{"_id": "43156471", "title": "", "text": "Genomewide analysis of nucleosome density histone acetylation and HDAC function in fission yeast.Wehave conducted a genomewide investigation into the enzymatic specificity, expression profiles, andbinding locations of four histone deacetylases (HDACs), representing the three different phylogeneticclasses in fission yeast (Schizosaccharomyces pombe). By directly comparing nucleosome density,histone acetylation patterns and HDAC binding in both intergenic and coding regions with geneexpression profiles, we found that Sir2 (class III) and Hos2 (class I) have a role in preventing histoneloss; Clr6 (class I) is the principal enzyme in promoter-localized repression. Hos2 has an unexpected rolein promoting high expression of growth-related genes by deacetylating H4K16Ac in their open readingframes. Clr3 (class II) acts cooperatively with Sir2 throughout the genome, including the silent regions:rDNA, centromeres, mat2/3 and telomeres. The most significant acetylation sites are H3K14Ac for Clr3and H3K9Ac for Sir2 at their genomic targets. Clr3 also affects subtelomeric regions which containclustered stress- and meiosis-induced genes. Thus, this combined genomic approach has uncovereddifferent roles for fission yeast HDACs at the silent regions in repression and activation of geneexpression.", "metadata": {}}
+{"_id": "43165768", "title": "", "text": "In vitro antimicrobial activity of mangrove plant Sonneratia alba.OBJECTIVE To investigate theantimicrobial property of mangrove plant Sonneratia alba (S. alba). METHODS The antimicrobial activitywas evaluated using disc diffusion and microdilution methods against six microorganisms. Soxhletapparatus was used for extraction with a series of solvents, n-hexane, ethyl acetate and methanol insequence of increasing polarity. RESULTS Methanol extract appeared to be the most effective extractwhile n-hexane extract showed no activity. The antimicrobial activities were observed against the grampositive bacteria Staphylococcus aureus (S. aureus) and Bacillus cereus (B. cereus), the gram negativeEscherichia coli (E. coli) and the yeast Cryptococcus neoformans. Pseudomonas aeruginosa and Candidaalbicans appeared to be not sensitive to the concentrations tested since no inhibition zone was observed.E. coli (17.5 mm) appeared to be the most sensitive strain followed by S. aureus (12.5 mm) and B.cereus (12.5 mm). CONCLUSIONS From this study, it can be concluded that S. alba exhibits antimicrobialactivities against certain microorganisms.", "metadata": {}}
+{"_id": "43192375", "title": "", "text": "Obesity induces a phenotypic switch in adipose tissue macrophage polarization.Adipose tissuemacrophages (ATMs) infiltrate adipose tissue during obesity and contribute to insulin resistance. Wehypothesized that macrophages migrating to adipose tissue upon high-fat feeding may differ from thosethat reside there under normal diet conditions. To this end, we found a novel F4/80(+)CD11c(+)population of ATMs in adipose tissue of obese mice that was not seen in lean mice. ATMs from lean miceexpressed many genes characteristic of M2 or \"alternatively activated\" macrophages, including Ym1,arginase 1, and Il10. Diet-induced obesity decreased expression of these genes in ATMs while increasingexpression of genes such as those encoding TNF-alpha and iNOS that are characteristic of M1 or\"classically activated\" macrophages. Interestingly, ATMs from obese C-C motif chemokine receptor 2-KO(Ccr2-KO) mice express M2 markers at levels similar to those from lean mice. The antiinflammatorycytokine IL-10, which was overexpressed in ATMs from lean mice, protected adipocytes fromTNF-alpha-induced insulin resistance. Thus, diet-induced obesity leads to a shift in the activation state ofATMs from an M2-polarized state in lean animals that may protect adipocytes from inflammation to an M1proinflammatory state that contributes to insulin resistance.", "metadata": {}}
+{"_id": "43220289", "title": "", "text": "Psychological Outcome 4 Years after Restrictive Bariatric SurgeryExtreme obesity is associated withsevere psychiatric and somatic comorbidity and impairment of psychosocial functioning. Bariatric surgeryis the most effective treatment not only with regard to weight loss but also with obesity-associatedillnesses. Health-related psychological and psychosocial variables have been increasingly considered asimportant outcome variables of bariatric surgery. However, the long-term impact of bariatric surgery onpsychological and psychosocial functioning is largely unclear. The aim of this study was to evaluate therelationship between the course of weight and psychological variables including depression, anxiety,health-related quality of life (HRQOL), and self-esteem up to 4 years after obesity surgery. Bystandardized questionnaires prior to (T1) and 1 year (T2), 2 years (T3), and 4 years (T4) after surgery,148 patients (47 males (31.8 %), 101 females (68.2 %), mean age 38.8 ± 10.2 years) were assessed.On average, participants lost 24.6 % of their initial weight 1 year after surgery, 25.1 % after 2 years, and22.3 % after 4 years. Statistical analysis revealed significant improvements in depressive symptoms,physical dimension of quality of life, and self-esteem with peak improvements 1 year after surgery. Theseimprovements were largely maintained. Significant correlations between weight loss and improvements indepression, physical aspects of HRQOL (T2, T3, and T4), and self-esteem (T3) were observed.Corresponding to the considerable weight loss after bariatric surgery, important aspects of mental healthimproved significantly during the 4-year follow-up period. However, parallel to weight regain,psychological improvements showed a slow but not significant decline over time.", "metadata": {}}
+{"_id": "43224840", "title": "", "text": "Dynamics of Microvillus Extension and Tether Formation in Rolling Leukocytes.P-selectin glycoproteinligand-1 (PSGL-1) binding to P-selectin mediates leukocyte rolling under conditions of flow. In humanneutrophils, a type of leukocyte belonging to the innate immune system, PSGL-1 molecules are locatedon the neutrophil's surface ruffles, called microvilli. Each newly formed P-selectin-PSGL-1 bond canbecome load bearing, imposing on its microvillus a pulling force that deforms the microvillus. Dependingon the magnitude of the bond force, a microvillus can be extended, or a thin membrane cylinder (atether) can be formed at the tip of the microvillus. Here we propose a Kelvin-Voigt viscoelastic materialas an improved model for microvillus extension. Using a modified version of our Event-Tracking Model ofAdhesion (ETMA), we demonstrate how P-selectin-PSGL-1 load-bearing bonds shape microvillusdeformation during neutrophil rolling at low shear (wall shear rate of 50 s(-1), P-selectin site density of150 molecules μm(-2)). We also discuss the impact of microvillus deformability on neutrophil rolling. Wefind that the average microvillus extension constitutes 65% of the total microvillus-tether complexextension, and that the rolling neutrophil may never fully rest. A quantitative comparison with thecorresponding non-deformable microvilli case supports a concept that the ability of the microvillus todeform stabilizes cell rolling.", "metadata": {}}
+{"_id": "43226130", "title": "", "text": "Female Gender and Reproductive Factors Affecting Risk, Relapses and Progression in MultipleSclerosisMultiple sclerosis (MS), a chronic inflammatory demyelina-ting and degenerative disease of thecentral nervous system, is a frequent cause of neurological disability in young adults. Femalepredominance has increased over the last decades. Although female gender carries a higher risk ofdeveloping relapsing remitting MS, being female and at child-bearing age also appears to provide someprotection against cognitive decline and against progressive onset MS, an adverse predictive factor whenconsidering long-term disability in MS. The risk of MS in women has been associated with an earlier ageat menarche. In most studies, parity did not impact MS risk. However, the recently published associationof higher parity and offspring number with a reduced risk of a first demyelinating event suggests apotential suppressive effect. Pregnancy in MS patients has been associated with a reduced relapse rateand a reduction of neurological symptoms, especially in the third trimester. Despite the increased relapserisk in the postpartum period, there is no indication of an adverse effect of childbirth on the long-termcourse of MS. Fertility treatment in MS has been associated with an increased relapse risk in the following3-month period, especially when the procedure did not result in pregnancy and gonadotrophin-releasinghormone agonists were used. Altogether, there is substantial evidence to support a regulatory role of sexsteroid hormones in MS. In the absence of correlations with single hormone blood levels, we can onlyspeculate about the underlying mechanisms. In conclusion, the increased MS risk in women and thechanges in relapse and progression risk in association with reproductive events suggest significant andcomplex interactions between immune, neuroendocrine and reproductive systems in MS.", "metadata": {}}
+{"_id": "43283375", "title": "", "text": "Spatial release from masking based on binaural processing for up to six maskers.Spatial Release fromMasking (SRM) was measured for identification of a female target word spoken in the presence of malemasker words. Target words from a single loudspeaker located at midline were presented when two, four,or six masker words were presented either from the same source as the target or from spatiallyseparated masker sources. All masker words were presented from loudspeakers located symmetricallyaround the centered target source in the front azimuth hemifield. Three masking conditions wereemployed: speech-in-speech masking (involving both informational and energetic masking),speech-in-noise masking (involving energetic masking), and filtered speech-in-filtered speech masking(involving informational masking). Psychophysical results were summarized as three-point psychometricfunctions relating proportion of correct word identification to target-to-masker ratio (in decibels) for boththe co-located and spatially separated target and masker sources cases. SRM was then calculated bycomparing the slopes and intercepts of these functions. SRM decreased as the number of symmetricallyplaced masker sources increased from two to six. This decrease was independent of the type of masking,with almost no SRM measured for six masker sources. These results suggest that when SRM is dependentprimarily on binaural processing, SRM is effectively limited to fewer than six sound sources.", "metadata": {}}
+{"_id": "43311750", "title": "", "text": "Nephrin mutations cause childhood- and adult-onset focal segmental glomerulosclerosis.Mutations in theNPHS1 gene cause congenital nephrotic syndrome of the Finnish type presenting before the first 3months of life. Recently, NPHS1 mutations have also been identified in childhood-onset steroid-resistantnephrotic syndrome and milder courses of disease, but their role in adults with focal segmentalglomerulosclerosis remains unknown. Here we developed an in silico scoring matrix to evaluate thepathogenicity of amino-acid substitutions using the biophysical and biochemical difference betweenwild-type and mutant amino acid, the evolutionary conservation of the amino-acid residue in orthologs,and defined domains, with the addition of contextual information. Mutation analysis was performed in 97patients from 89 unrelated families, of which 52 presented with steroid-resistant nephrotic syndromeafter 18 years of age. Compound heterozygous or homozygous NPHS1 mutations were identified in fivefamilial and seven sporadic cases, including one patient 27 years old at onset of the disease.Substitutions were classified as 'severe' or 'mild' using this in silico approach. Our results suggest anearlier onset of the disease in patients with two 'severe' mutations compared to patients with at least one'mild' mutation. The finding of mutations in a patient with adult-onset focal segmental glomerulosclerosisindicates that NPHS1 analysis could be considered in patients with later onset of the disease.", "metadata": {}}
+{"_id": "43329366", "title": "", "text": "Use of clomifene during early pregnancy and risk of hypospadias: population based case-controlstudy.Clomifene is widely used for inducing ovulation.1 It is structurally related to diethylstilbestrol,which has been linked to vaginal and cervical clear cell adenocarcinoma in women exposed in utero. Theadverse effect is less severe in sons, although links to testicular cancer and urogenital anomalies, such asepididymal cysts, have been reported.2 3 A recent study also found an increased risk of hypospadias inthe sons of women exposed to diethylstilbestrol in utero.4 Clomifene has a half life of about five days, butits metabolites have been found in blood samples on day 22 of the menstrual cycle and in faeces up to sixweeks after administration.5 The occurrence of hypospadias may be increasing. Little is known about therisk of hypospadias in boys born to women who have used clomifene to induce ovulation. ### Methodsand results  Our case-control study was done in the Danish counties of North Jutland, Aarhus, Viborg, and…", "metadata": {}}
+{"_id": "43334921", "title": "", "text": "Association of aspirin and NSAID use with risk of colorectal cancer according to geneticvariants.IMPORTANCE Use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) isassociated with lower risk of colorectal cancer. OBJECTIVE To identify common genetic markers that mayconfer differential benefit from aspirin or NSAID chemoprevention, we tested gene × environmentinteractions between regular use of aspirin and/or NSAIDs and single-nucleotide polymorphisms (SNPs)in relation to risk of colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS Case-control study usingdata from 5 case-control and 5 cohort studies initiated between 1976 and 2003 across the United States,Canada, Australia, and Germany and including colorectal cancer cases (n=8634) and matched controls(n=8553) ascertained between 1976 and 2011. Participants were all of European descent. EXPOSURESGenome-wide SNP data and information on regular use of aspirin and/or NSAIDs and other risk factors.MAIN OUTCOMES AND MEASURES Colorectal cancer. RESULTS Regular use of aspirin and/or NSAIDs wasassociated with lower risk of colorectal cancer (prevalence, 28% vs 38%; odds ratio [OR], 0.69 [95% CI,0.64-0.74]; P = 6.2 × 10(-28)) compared with nonregular use. In the conventional logistic regressionanalysis, the SNP rs2965667 at chromosome 12p12.3 near the MGST1 gene showed a genome-widesignificant interaction with aspirin and/or NSAID use (P = 4.6 × 10(-9) for interaction). Aspirin and/orNSAID use was associated with a lower risk of colorectal cancer among individuals with rs2965667-TTgenotype (prevalence, 28% vs 38%; OR, 0.66 [95% CI, 0.61-0.70]; P = 7.7 × 10(-33)) but with a higherrisk among those with rare (4%) TA or AA genotypes (prevalence, 35% vs 29%; OR, 1.89 [95% CI,1.27-2.81]; P = .002). In case-only interaction analysis, the SNP rs16973225 at chromosome 15q25.2near the IL16 gene showed a genome-wide significant interaction with use of aspirin and/or NSAIDs (P =8.2 × 10(-9) for interaction). Regular use was associated with a lower risk of colorectal cancer amongindividuals with rs16973225-AA genotype (prevalence, 28% vs 38%; OR, 0.66 [95% CI, 0.62-0.71]; P =1.9 × 10(-30)) but was not associated with risk of colorectal cancer among those with less common (9%)AC or CC genotypes (prevalence, 36% vs 39%; OR, 0.97 [95% CI, 0.78-1.20]; P = .76). CONCLUSIONSAND RELEVANCE In this genome-wide investigation of gene × environment interactions, use of aspirinand/or NSAIDs was associated with lower risk of colorectal cancer, and this association differed accordingto genetic variation at 2 SNPs at chromosomes 12 and 15. Validation of these findings in additionalpopulations may facilitate targeted colorectal cancer prevention strategies.", "metadata": {}}
+{"_id": "43378932", "title": "", "text": "Intravaginal ring eluting tenofovir disoproxil fumarate completely protects macaques from multiplevaginal simian-HIV challenges.Topical preexposure prophylaxis interrupts HIV transmission at the site ofmucosal exposure. Intermittently dosed vaginal gels containing the HIV-1 reverse transcriptase inhibitortenofovir protected pigtailed macaques depending on the timing of viral challenge relative to gelapplication. However, modest or no protection was observed in clinical trials. Intravaginal rings (IVRs)may improve efficacy by providing long-term sustained drug delivery leading to constant mucosalantiretroviral concentrations and enhancing adherence. Although a few IVRs have entered the clinicalpipeline, 100% efficacy in a repeated macaque vaginal challenge model has not been achieved. Here wedescribe a reservoir IVR technology that delivers the tenofovir prodrug tenofovir disoproxil fumarate(TDF) continuously over 28 d. With four monthly ring changes in this repeated challenge model, TDF IVRsgenerated reproducible and protective drug levels. All TDF IVR-treated macaques (n = 6) remainedseronegative and simian-HIV RNA negative after 16 weekly vaginal exposures to 50 tissue cultureinfectious dose SHIV162p3. In contrast, 11/12 control macaques became infected, with a median of fourexposures assuming an eclipse of 7 d from infection to virus RNA detection. Protection was associatedwith tenofovir levels in vaginal fluid [mean 1.8 × 10(5) ng/mL (range 1.1 × 10(4) to 6.6 × 10(5) ng/mL)]and ex vivo antiviral activity of cervicovaginal lavage samples. These observations support furtheradvancement of TDF IVRs as well as the concept that extended duration drug delivery devices deliveringtopical antiretrovirals could be effective tools in preventing the sexual transmission of HIV in humans.", "metadata": {}}
+{"_id": "43385013", "title": "", "text": "Epithelial and mesenchymal subpopulations within normal basal breast cell lines exhibit distinct stemcell/progenitor properties.It has been proposed that epithelial-mesenchymal transition (EMT) inmammary epithelial cells and breast cancer cells generates stem cell features, and that the presence ofEMT characteristics in claudin-low breast tumors reveals their origin in basal stem cells. It remains to bedetermined, however, whether EMT is an inherent property of normal basal stem cells, and if thepresence of a mesenchymal-like phenotype is required for the maintenance of all their stem cellproperties. We used nontumorigenic basal cell lines as models of normal stem cells/progenitors anddemonstrate that these cell lines contain an epithelial subpopulation (\"EpCAM+,\" epithelial cell adhesionmolecule positive [EpCAM(pos)]/CD49f(high)) that spontaneously generates mesenchymal-like cells(\"Fibros,\" EpCAM(neg)/CD49f(med/low)) through EMT. Importantly, stem cell/progenitor properties suchas regenerative potential, high aldehyde dehydrogenase 1 activity, and formation of three-dimensionalacini-like structures predominantly reside within EpCAM+ cells, while Fibros exhibit invasive behavior andmammosphere-forming ability. A gene expression profiling meta-analysis established that EpCAM+ cellsshow a luminal progenitor-like expression pattern, while Fibros most closely resemble stromal fibroblastsbut not stem cells. Moreover, Fibros exhibit partial myoepithelial traits and strong similarities withclaudin-low breast cancer cells. Finally, we demonstrate that Slug and Zeb1 EMT-inducers control theprogenitor and mesenchymal-like phenotype in EpCAM+ cells and Fibros, respectively, by inhibitingluminal differentiation. In conclusion, nontumorigenic basal cell lines have intrinsic capacity for EMT, buta mesenchymal-like phenotype does not correlate with the acquisition of global stem cell/progenitorfeatures. Based on our findings, we propose that EMT in normal basal cells and claudin-low breastcancers reflects aberrant/incomplete myoepithelial differentiation.", "metadata": {}}
+{"_id": "43390777", "title": "", "text": "Involvement of members of the Rab family and related small GTPases in autophagosome formation andmaturationMacroautophagy, the process by which cytosolic components and organelles are engulfed anddegraded by a double-membrane structure, could be viewed as a specialized, multistep membranetransport process. As such, it intersects with the exocytic and endocytic membrane trafficking pathways.A number of Rab GTPases which regulate secretory and endocytic membrane traffic have been shown toplay either critical or accessory roles in autophagy. The biogenesis of the pre-autophagosomal isolationmembrane (or phagophore) is dependent on the functionality of Rab1. A non-canonical,Atg5/Atg7-independent mode of autophagosome generation from the trans-Golgi or endosome requiresRab9. Other Rabs, such as Rab5, Rab24, Rab33, and Rab7 have all been shown to be required, orinvolved at various stages of autophagosomal genesis and maturation. Another small GTPase, RalB, wasvery recently demonstrated to induce isolation membrane formation and maturation via its engagementof the exocyst complex, a known Rab effector. We summarize here what is now known about theinvolvement of Rabs in autophagy, and discuss plausible mechanisms with future perspectives.", "metadata": {}}
+{"_id": "43417006", "title": "", "text": "Comparative risk of new-onset diabetes mellitus for antihypertensive drugs: A networkmeta-analysis.New-onset diabetes mellitus (NOD) refers to forms of diabetes mellitus that develop duringthe therapeutic processes of other diseases such as hypertension. This study has been conducted in anetwork meta-analysis to compare antihypertensive drugs by identifying both the advantages anddisadvantages on NOD by focusing on their respective effect rates. Odd ratios and corresponding 95%confidence intervals or credible intervals were calculated within pairwise and network meta-analysis. Atotal of 38 articles with 224 140 patients were included to evaluate the preventive effect of hypertensiondrugs on NOD. From the network meta-analysis it was evident that both angiotensin-converting enzymeinhibitor as well as angiotensin receptor blocker treatments are associated with a lower risk of developingNOD compared with placebo, with ranking probabilities of 79.81% and 72.77%, respectively, whileβ-blockers and calcium channel blockers may significantly increase the probability of developing NOD(β-blockers: odds ratio, 2.18 [95% credible intervals: 1.36-3.50]; calcium channel blockers: odds ratio,1.16 [95% credible intervals, 1.05-1.29]). In conclusion, angiotensin receptor blockers have anadvantage over the other treatments regarding the NOD.", "metadata": {}}
+{"_id": "43419566", "title": "", "text": "Transformation of mammalian cells by constitutively active MAP kinase kinase.Mitogen-activated protein(MAP) kinase kinase (MAPKK) activates MAP kinase in a signal transduction pathway that mediatescellular responses to growth and differentiation factors. Oncogenes such as ras, src, raf, and mos havebeen proposed to transform cells by prolonging the activated state of MAPKK and of componentsdownstream in the signaling pathway. To test this hypothesis, constitutively active MAPKK mutants weredesigned that had basal activities up to 400 times greater than that of the unphosphorylated wild-typekinase. Expression of these mutants in mammalian cells activated AP-1-regulated transcription. The cellsformed transformed foci, grew efficiently in soft agar, and were highly tumorigenic in nude mice. Thesefindings indicate that constitutive activation of MAPKK is sufficient to promote cell transformation.", "metadata": {}}
+{"_id": "43427621", "title": "", "text": "Psychological treatment of malignant vasovagal syncope due to bloodphobia.A 17-year-old boy withfrequent faints due to blood-injury phobia was studied. During cardiovascular reflex investigation in oursyncope unit, 50 seconds of asystole were recorded. He was treated using systematic desensitization withmuscular tension and cognitive techniques by the Pediatric Psychosocial Department and has notexperienced syncopal events again.", "metadata": {}}
+{"_id": "43483151", "title": "", "text": "QT and QTc dispersion are accurate predictors of cardiac death in newly diagnosed non-insulin dependentdiabetes: cohort study.Patients with non-insulin dependent diabetes mellitus have an excess risk of dyingfrom cardiovascular disease. One small study suggested that a prolonged QT interval could predictcardiac death in patients with diabetic nephropathy who have received insulin treatment. The questionnow is whether the same is true in newly diagnosed diabetes in patients who have no apparentcomplications. In addition, QT dispersion, a new but related electrocardiographic variable, predictscardiac death in patients who have chronic heart failure, peripheral vascular disease, or essentialhypertension.1–3 We investigated whether it also predicted cardiac death in diabetic patients. The studygroup of 182 patients with non-insulin dependent diabetes mellitus (103 men; mean age 52.8 (SD 8.5)years) represented the Dundee cohort of the United Kingdom prospective diabetes study, which wasrecruited between 1982 and 1988. Patients were followed up for a mean of 10.3 (1.7) years. …", "metadata": {}}
+{"_id": "43534665", "title": "", "text": "Recombinant human IL-10 prevents the onset of diabetes in the nonobese diabetic mouse.The role ofIL-10 in the pathogenesis of autoimmune diabetes mellitus was assessed in the nonobese diabetic (NOD)mouse. In these studies the effect of IL-10 was determined on three parameters of diabetes: Thedevelopment of hyperglycemia, the development of insulitis, and the production of insulin by beta cells.Initial experiments investigated the effect of anticytokine antibodies on the development of disease.These results indicated that monoclonal anti-IFN-gamma antibody greatly reduced the incidence ofhyperglycemia in female NOD mice, while anti-IL-4, IL-5, and IL-10 were ineffective. In subsequentstudies, daily subcutaneous administration of IL-10, a known potent inhibitor of IFN-gamma productionby TH1 T cells, to 9 and 10-week-old NODs was shown to delay the onset of disease and significantlyreduce the incidence of diabetes. Histopathology performed on pancreatic tissue demonstrated thattreatment with IL-10 reduced the severity of insulitis, prevented cellular infiltration of islet cells, andpromoted normal insulin production by beta cells. Taken together these results indicate IL-10 suppressesthe induction and progression of autoimmune pathogenesis associated with diabetes mellitus and suggesta potential therapeutic role for this cytokine in this autoimmune disease.", "metadata": {}}
+{"_id": "43557480", "title": "", "text": "Arterial hypertension and progression of chronic kidney disease in children during 10-year ambulatoryobservation.The aim of this study was the long-term retrospective analysis of chronic kidney disease(CKD) progression in children, especially with regard to the presence of hypertension (HTN). The averagerate of progression of CKD was higher in patients with HTN than without HTN. Hypertension treatmentrequires multidrug schemes which need to be intensified with extended time of CKD duration.", "metadata": {}}
+{"_id": "43566999", "title": "", "text": "Exercise blood flow patterns within and among rat muscles after training.This study was designed todetermine the influence of a long-term, moderate-intensity treadmill training program on the distributionof blood flow within and among muscles of rats during exercise. One group (T) of male Sprague-Dawleyrats trained for 1 h/day for 13-17 wk at 30 m/min on a motor-driven treadmill. A second group (UT) ofrats was conditioned for 10 min/day for 4 wk at the same speed. Muscle succinate dehydrogenaseactivities were higher in T than UT rats indicating a significant training effect. Blood flows (BFs) in 32hindlimb muscles or muscle parts and other selected organs were measured in the two groups withradiolabeled microspheres during preexercise and while the rats ran for 30 s, 5 min, or 15 min at 30m/min on the treadmill. The data indicate 1) there were no differences in total hindlimb muscle BFbetween UT and T rats at any time; however, 2) T rats had higher preexercise heart rates and highermuscle BFs in the deep red extensor muscles, suggesting a greater anticipatory response to theimpending exercise; 3) T rats demonstrated more rapid elevations in BF in the red extensor muscles atthe commencement of exercise; 4) T rats had higher BFs in red extensor muscles during exercise,whereas UT rats had higher BFs in white muscles; and 5) T rats maintained higher BFs in the visceralorgans during exercise. These findings demonstrate that exercise training results in changes in thedistribution of BF within and among muscles and among organs during exercise. Specifically, dataindicate the high-oxidative motor units that are primarily recruited in the muscles during the initial stagesof moderate treadmill exercise receive higher blood flows in the trained rats; this presumably contributesto increased resistance to fatigue.", "metadata": {}}
+{"_id": "43587663", "title": "", "text": "Serious infections after unrelated donor transplantation in 136 children: impact of stem cell source.Howthe infection risks compare after umbilical cord blood (UCB) and bone marrow (BM) transplantation is notknown. Therefore, we compared serious infections in the 2 years after pediatric myeloablative unrelateddonor transplantation with unmanipulated BM (n = 52), T cell-depleted (TCD) BM (n = 24), or UCB (n =60) for the treatment of hematologic malignancy. Overall, the cumulative incidence of 1 or more seriousinfections was comparable between groups (BM, 81%; TCD, 83%; UCB, 90%; P = .12). Furthermore, bytaking all serious infections into account and using multivariate techniques with unmanipulated BM as thereference, there were also no significant differences between groups (TCD relative risk [RR], 1.6; P =.10; UCB RR, 1.0; P = .84). Within the time periods days 0 to 42, days 43 to 100, and days 101 to 180,the only difference was a greater risk of viral infections from days 0 to 42 in TCD recipients (RR, 3.5; P =.02). Notably, after day 180, TCD recipients had a significantly increased infection risk (RR, 3.1; P = .03),whereas the risk in UCB recipients (RR, 0.5; P = .23) was comparable to that in BM recipients. Otherfactors associated with an increased infection risk in the 2 years after transplantation were age > or = 8years, graft failure, and severe acute graft-versus-host disease. These data suggest that the risk ofserious infection after pediatric UCB transplantation is comparable to that with unmanipulated BM.", "metadata": {}}
+{"_id": "43602749", "title": "", "text": "The NBS1–Treacle complex controls ribosomal RNA transcription in response to DNAdamageChromosome breakage elicits transient silencing of ribosomal RNA synthesis, but the mechanismsinvolved remained elusive. Here we discover an in trans signalling mechanism that triggers pan-nuclearsilencing of rRNA transcription in response to DNA damage. This is associated with transient recruitmentof the Nijmegen breakage syndrome protein 1 (NBS1), a central regulator of DNA damage responses,into the nucleoli. We further identify TCOF1 (also known as Treacle), a nucleolar factor implicated inribosome biogenesis and mutated in Treacher Collins syndrome, as an interaction partner of NBS1, anddemonstrate that NBS1 translocation and accumulation in the nucleoli is Treacle dependent. Finally, weprovide evidence that Treacle-mediated NBS1 recruitment into the nucleoli regulates rRNA silencing intrans in the presence of distant chromosome breaks.", "metadata": {}}
+{"_id": "43619625", "title": "", "text": "Inflammatory T cells rapidly induce differentiation of human bone marrow stromal cells into matureosteoblasts.Activated T cells secrete multiple osteoclastogenic cytokines which play a major role in thebone destruction associated with rheumatoid arthritis. While the role of T cells in osteoclastogenesis hasreceived much attention recently, the effect of T cells on osteoblast formation and activity is poorlydefined. In this study, we investigated the hypothesis that in chronic inflammation activated T cellscontribute to enhanced bone turnover by promoting osteoblastic differentiation. We show that T cellsproduce soluble factors that induce alkaline phosphatase activity in bone marrow stromal cells andelevated expression of mRNA for Runx2 and osteocalcin. This data indicate that T cell derived factorshave the capacity to stimulate the differentiation of bone marrow stromal cells into the osteoblastphenotype. RANKL mRNA was undetectable under any conditions in highly purified bone marrow stromalcells. In contrast, RANKL was constitutively expressed in primary osteoblasts and only moderatelyup-regulated by activated T cell conditioned medium. Interestingly, both bone marrow stromal cells andosteoblasts expressed mRNA for RANK, which was strongly up-regulated in both cell types by activated Tcell conditioned medium. Although, mRNA for the RANKL decoy receptor, osteoprotegerin, was alsoup-regulated by activated T cell conditioned medium, it's inhibitory effects may be mitigated by asimultaneous rise in the osteoprotegerin competitor TNF-related apoptosis-inducing ligand. Based on ourdata we propose that during chronic inflammation, T cells regulate bone loss by a dual mechanisminvolving both direct stimulation of osteoclastogenesis, by production of osteoclastogenic cytokines, andindirectly by induction of osteoblast differentiation and up-regulation of bone turnover via coupling.", "metadata": {}}
+{"_id": "43629704", "title": "", "text": "Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West ofScotland Coronary Prevention Study Group.BACKGROUND Lowering the blood cholesterol level mayreduce the risk of coronary heart disease. This double-blind study was designed to determine whether theadministration of pravastatin to men with hypercholesterolemia and no history of myocardial infarctionreduced the combined incidence of nonfatal myocardial infarction and death from coronary heart disease.METHODS We randomly assigned 6595 men, 45 to 64 years of age, with a mean (+/- SD) plasmacholesterol level of 272 +/- 23 mg per deciliter (7.0 +/- 0.6 mmol per liter) to receive pravastatin (40 mgeach evening) or placebo. The average follow-up period was 4.9 years. Medical records,electrocardiographic recordings, and the national death registry were used to determine the clinical endpoints. RESULTS Pravastatin lowered plasma cholesterol levels by 20 percent and low-density-lipoproteincholesterol levels by 26 percent, whereas there was no change with placebo. There were 248 definitecoronary events (specified as nonfatal myocardial infarction or death from coronary heart disease) in theplacebo group, and 174 in the pravastatin group (relative reduction in risk with pravastatin, 31 percent;95 percent confidence interval, 17 to 43 percent; P < 0.001). There were similar reductions in the risk ofdefinite nonfatal myocardial infarctions (31 percent reduction, P < 0.001), death from coronary heartdisease (definite cases alone: 28 percent reduction, P = 0.13; definite plus suspected cases: 33 percentreduction, P = 0.042), and death from all cardiovascular causes (32 percent reduction, P = 0.033). Therewas no excess of deaths from noncardiovascular causes in the pravastatin group. We observed a 22percent reduction in the risk of death from any cause in the pravastatin group (95 percent confidenceinterval, 0 to 40 percent; P = 0.051). CONCLUSIONS Treatment with pravastatin significantly reduced theincidence of myocardial infarction and death from cardiovascular causes without adversely affecting therisk of death from noncardiovascular causes in men with moderate hypercholesterolemia and no historyof myocardial infarction.", "metadata": {}}
+{"_id": "43647194", "title": "", "text": "Validation of a migraine-specific questionnaire for use in family studies.The availability of validmigraine-specific questionnaires is important when large numbers of migraine patients have to beanalysed. The Finnish Migraine-Specific Questionnaire has been validated in two stages. In the first, aclinical diagnosis of migraine was reached, using International Headache Society criteria, in 100consecutive patients. Migraine was then diagnosed independently on the basis of responses to the FinnishMigraine-Specific Questionnaire. In the second stage, responses to 100 questionnaires returnedconsecutively in a family study in progress were analysed, and respondents were contacted by telephonefor interview and diagnosis of migraine. Contact proved impossible in six cases. The sensitivity of thequestionnaire for migraine was 0.99 (167 out of 168; validation stages 1 and 2 combined) and specificitywas 0.96 (25 out of 26 cases; validation stage 2). It also proved possible to differentiate betweenmigraine with and without aura on the basis of responses to the Finnish Migraine-Specific Questionnaire:chance-corrected agreement (Cohen's kappa) was 0.804 in relation to diagnoses reached on the basis ofresponses to the Finnish Migraine-Specific Questionnaire and clinically was 0.858 in relation to diagnosesreached on the basis of responses to the Finnish Migraine-Specific Questionnaire combined with theresults of the telephone interviews. A value for Cohen's kappa > 0.75 indicates good agreement.Therefore, use of the Finnish Migraine-Specific Questionnaire in research into migraine genetics isjustified.", "metadata": {}}
+{"_id": "43661837", "title": "", "text": "Defining early lineage specification of human embryonic stem cells by the orchestrated balance ofcanonical Wnt/beta-catenin, Activin/Nodal and BMP signaling.The canonical Wnt/beta-catenin signalinghas remarkably diverse roles in embryonic development, stem cell self-renewal and cancer progression.Here, we show that stabilized expression of beta-catenin perturbed human embryonic stem (hES)-cellself-renewal, such that up to 80% of the hES cells developed into the primitive streak (PS)/mesodermprogenitors, reminiscent of early mammalian embryogenesis. The formation of the PS/mesodermprogenitors essentially depended on the cooperative action of beta-catenin together with Activin/Nodaland BMP signaling pathways. Intriguingly, blockade of BMP signaling completely abolished mesodermgeneration, and induced a cell fate change towards the anterior PS progenitors. The PI3-kinase/Akt, butnot MAPK, signaling pathway had a crucial role in the anterior PS specification, at least in part, byenhancing beta-catenin stability. In addition, Activin/Nodal and Wnt/beta-catenin signaling synergisticallyinduced the generation and specification of the anterior PS/endoderm. Taken together, our findingsclearly demonstrate that the orchestrated balance of Activin/Nodal and BMP signaling defines the cell fateof the nascent PS induced by canonical Wnt/beta-catenin signaling in hES cells.", "metadata": {}}
+{"_id": "43700577", "title": "", "text": "Sphingosine can pre- and post-condition heart and utilizes a different mechanism from sphingosine1-phosphate.Consistent with previous reports, sphingosine at a high concentration (5 microM) wascardiotoxic as evidenced by increased infarct size in response to ischemia/reperfusion in an ex vivo ratheart. Sphingosine 1-phosphate (S1P) at 5 microM was cardioprotective. However, at a physiologicconcentration (0.4 microM) sphingosine as well as S1P was effective in protecting the heart fromischemia/reperfusion injury both when perfused prior to 40 min of ischemia (preconditioning) or whenadded to reperfusion media following ischemia (postconditioning). Protection by sphingosine and S1P wasevidenced with both pre- and post-conditioning by a >75% recovery of left ventricular developedpressure during reperfusion and a decrease in infarct size from 45% of the risk area to less than 8%.When VPC23019, an S1P(1and3)G-protein coupled receptor antagonist, was added to the preconditioningor postconditioning medium along with S1P, it completely blocked S1P-induced protection. However, VPC23019 did not affect the ability of 0.4 microM sphingosine to either precondition or postcondition hearts.Studies of preconditioning revealed that inhibition of protein kinase C with GF109203X blockedpreconditioning by S1P. However, GF109203X did not affect preconditioning by 0.4 microM sphingosine.Likewise, cotreatment with the PI3 kinase inhibitor wortmanin blocked preconditioning by S1P but not bysphingosine. By contrast, inhibition of protein kinase G with KT5823 had no effect on S1P preconditioningbut completely eliminated preconditioning by sphingosine. Also, the protein kinase A inhibitory peptide14-22 amide blocked preconditioning by sphingosine but not S1P. These data reveal for the first time thatsphingosine is not toxic at physiologic concentrations but rather is a potent cardioprotectant that utilizesa completely different mechanism than S1P; one that is independent of G-protein coupled receptors andutilizes cyclic nucleotide-dependent pathways.", "metadata": {}}
+{"_id": "43711341", "title": "", "text": "Coordination of p300-mediated chromatin remodeling and TRAP/mediator function through coactivatorPGC-1alpha.Transcriptional coactivators showing physical and functional interactions with PPARgammainclude the protein acetyl transferase p300, the TRAP/Mediator complex that interacts with the generaltranscription machinery, and the highly regulated PGC-1alpha. We show that PGC-1alpha directlyinteracts with TRAP/Mediator, through the PPARgamma-interacting subunit TRAP220, and stimulatesTRAP/Mediator-dependent function on DNA templates. Further, while ineffective by itself, PGC-1alphastimulates p300-dependent histone acetylation and transcription on chromatin templates in response toPPARgamma. These functions are mediated by largely independent PPARgamma, p300, and TRAP220interaction domains in PGC-1alpha, whereas p300 and TRAP220 show ligand-dependent interactions witha common region of PPARgamma. Apart from showing PGC-1alpha functions both in chromatinremodeling and in preinitiation complex formation or function (transcription), these results suggest a keyrole for PGC-1alpha, through concerted but dynamic interactions, in coordinating these steps.", "metadata": {}}
+{"_id": "43752562", "title": "", "text": "Phospholipid synthesis and lipid composition of subcellular membranes in the unicellular eukaryoteSaccharomyces cerevisiae.Subcellular membranes of Saccharomyces cerevisiae, including mitochondria,microsomes, plasma membranes, secretory vesicles, vacuoles, nuclear membranes, peroxisomes, andlipid particles, were isolated by improved procedures and analyzed for their lipid composition and theircapacity to synthesize phospholipids and to catalyze sterol delta 24-methylation. The microsomal fractionis heterogeneous in terms of density and classical microsomal marker proteins and also with respect tothe distribution of phospholipid-synthesizing enzymes. The specific activity of phosphatidylserinesynthase was highest in a microsomal subfraction which was distinct from heavier microsomes harboringphosphatidylinositol synthase and the phospholipid N-methyltransferases. The exclusive location ofphosphatidylserine decarboxylase in mitochondria was confirmed. CDO-diacylglycerol synthase activitywas found both in mitochondria and in microsomal membranes. Highest specific activities ofglycerol-3-phosphate acyltransferase and sterol delta 24-methyltransferase were observed in the lipidparticle fraction. Nuclear and plasma membranes, vacuoles, and peroxisomes contain only marginalactivities of the lipid-synthesizing enzymes analyzed. The plasma membrane and secretory vesicles areenriched in ergosterol and in phosphatidylserine. Lipid particles are characterized by their high content ofergosteryl esters. The rigidity of the plasma membrane and of secretory vesicles, determined bymeasuring fluorescence anisotropy by using trimethylammonium diphenylhexatriene as a probe, can beattributed to the high content of ergosterol.", "metadata": {}}
+{"_id": "43855756", "title": "", "text": "Use of health services by prison inmates: comparisons with the community.The future organisation ofprison health care 1 recommends that the NHS and the Prison Service work together to plan and providehealth care services for prisoners. Whereas previously the Prison Service had this responsibility alone.The NHS will therefore have to take stock of the current level at which prison health care is demandedand provided. A key part of the information base for joint planning therefore includes data on currentservice utilisation. This paper compares primary care and inpatient health service utilisation data for UKprisoners with health services utilisation data for equivalent community populations. In the community,primary care is provided principally by general practitioners and professions allied to medicine (mostlynurses). Residents in the community have access to the full range of NHS outpatient and inpatientfacilities. Within prisons, primary care is provided by medical officers (some of whom are generalpractitioners), nursing grades and health care officers (who have received some training in health care).Some prisons have their own inpatient facilities (health care centre beds). These provide a low level ofinpatient care and do not have a direct equivalent in the community. Prisoners also have access to NHSoutpatient and inpatient facilities and to visiting specialists. The prison population has a high turnover andvaries from day to day. Because of this, the prison population is expressed as an average daily populationduring a one year period. …", "metadata": {}}
+{"_id": "43880096", "title": "", "text": "Regulation of p53 in response to DNA damageActivation of p53 can occur in response to a number ofcellular stresses, including DNA damage, hypoxia and nucleotide deprivation. Several forms of DNAdamage have been shown to activate p53, including those generated by ionising radiation (IR),radio-mimetic drugs, ultraviolet light (UV) and chemicals such as methyl methane sulfonate (MMS).Under normal conditions, p53 levels are maintained at a low state by virtue of the extremely short-halflife of the polypeptide. In addition to this, p53 normally exists in an largely inactive state that is relativelyinefficient at binding to DNA and activating transcription. Activation of p53 in response to DNA damage isassociated with a rapid increase in its levels and with an increased ability of p53 to bind DNA and mediatetranscriptional activation. This then leads to the activation of a number of genes whose products triggercell-cycle arrest, apoptosis, or DNA repair. Recent work has suggested that this regulation is broughtabout largely through DNA damage triggering a series of phosphorylation, de-phosphorylation andacetylation events on the p53 polypeptide. Here, we discuss the nature of these modifications, theenzymes that bring them about, and how changes in p53 modification lead to p53 activation.", "metadata": {}}
+{"_id": "43890638", "title": "", "text": "Hydrogen sulphide regulates intracellular pH in vascular smooth muscle cells.We investigated the role ofhydrogen sulphide (H(2)S) in intracellular pH (pH(i)) regulation in vascular smooth muscle cells and itscontribution on vasodilation. NaHS, a H(2)S donor, decreased pH(i) in a concentration-dependent mannerranging from 10 microM to 1mM. Neither inhibition of the Na(+)/H(+) exchanger with5-(N-ethyl-N-isopropyl) amiloride, (EIPA, 10 microM), nor plasmalemmal Ca(2+)-ATPase with CdCl(2)(20nM) alters the effect of NaHS on pH(i). Blockade of the Cl(-)/HCO3- exchanger with4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) significantly attenuated the pH(i) lowering effectof NaHS. Moreover, NaHS significantly increased the activity of Cl(-)/HCO3- exchanger when measuredwith NH(4)Cl prepulse method. DIDS attenuated the vasorelaxation induced by NaHS whereas EIPA andCdCl(2) did not cause any change. In conclusion, H(2)S induced intracellular acidification via activation ofCl(-)/HCO3- exchanger, which is, at least partially, responsible for H(2)S-mediated vasorelaxation.", "metadata": {}}
+{"_id": "43990286", "title": "", "text": "Cell and biomolecule delivery for tissue repair and regeneration in the central nervous system.Tissueengineering frequently involves cells and scaffolds to replace damaged or diseased tissue. It originated, inpart, as a means of effecting the delivery of biomolecules such as insulin or neurotrophic factors, giventhat cells are constitutive producers of such therapeutic agents. Thus cell delivery is intrinsic to tissueengineering. Controlled release of biomolecules is also an important tool for enabling cell delivery sincethe biomolecules can enable cell engraftment, modulate inflammatory response or otherwise benefit thebehavior of the delivered cells. We describe advances in cell and biomolecule delivery for tissueregeneration, with emphasis on the central nervous system (CNS). In the first section, the focus is onencapsulated cell therapy. In the second section, the focus is on biomolecule delivery in polymericnano/microspheres and hydrogels for the nerve regeneration and endogenous cell stimulation. In thethird section, the focus is on combination strategies of neural stem/progenitor cell or mesenchymal stemcell and biomolecule delivery for tissue regeneration and repair. In each section, the challenges andpotential solutions associated with delivery to the CNS are highlighted.", "metadata": {}}
+{"_id": "44030361", "title": "", "text": "The angiotensin II type 1 receptor blocker olmesartan preferentially improves nocturnal hypertension andproteinuria in chronic kidney diseaseAccumulated evidence suggests that an altered ambulatory bloodpressure (BP) profile, particularly elevated nighttime BP, reflects target organ injury and is a betterpredictor of further cardiorenal risk than the clinic BP or daytime BP in hypertensive patients complicatedby chronic kidney disease (CKD). In this study, we examined the beneficial effects of olmesartan, anangiotensin II type 1 receptor blocker (ARB), on ambulatory BP profiles and renal function inhypertensive CKD patients. Forty-six patients were randomly assigned to the olmesartan add-on group(n=23) or the non-ARB group (n=23). At baseline and after the 16-week treatment period, ambulatoryBP monitoring was performed and renal function parameter measurements were collected. Although thebaseline clinic BP levels and the after-treatment/baseline (A/B) ratios of clinic BP levels were similar inthe olmesartan add-on and non-ARB groups, the A/B ratios of ambulatory 24-h and nighttime BP levels inthe olmesartan add-on group were significantly lower. Furthermore, the A/B ratios of urinary protein,albumin and type IV collagen excretion in the olmesartan add-on group were significantly lower thanthose in the non-ARB group (urinary protein excretion, 0.72±0.41 vs. 1.45±1.48, P=0.030; urinaryalbumin excretion, 0.73±0.37 vs. 1.50±1.37, P=0.005; urinary type IV collagen excretion, 0.87±0.42 vs.1.48±0.87, P=0.014) despite comparable A/B ratios for the estimated glomerular filtration rate in the twogroups. These results indicate that in hypertensive patients with CKD, olmesartan add-on therapyimproves the ambulatory BP profile via a preferential reduction in nighttime BP with concomitant renalinjury inhibition.", "metadata": {}}
+{"_id": "44048701", "title": "", "text": "Surgical vs nonsurgical treatment of adults with displaced fractures of the proximal humerus: thePROFHER randomized clinical trial.IMPORTANCE The need for surgery for the majority of patients withdisplaced proximal humeral fractures is unclear, but its use is increasing. OBJECTIVE To evaluate theclinical effectiveness of surgical vs nonsurgical treatment for adults with displaced fractures of theproximal humerus involving the surgical neck. DESIGN, SETTING, AND PARTICIPANTS A pragmatic,multicenter, parallel-group, randomized clinical trial, the Proximal Fracture of the Humerus Evaluation byRandomization (PROFHER) trial, recruited 250 patients aged 16 years or older (mean age, 66 years[range, 24-92 years]; 192 [77%] were female; and 249 [99.6%] were white) who presented at theorthopedic departments of 32 acute UK National Health Service hospitals between September 2008 andApril 2011 within 3 weeks after sustaining a displaced fracture of the proximal humerus involving thesurgical neck. Patients were followed up for 2 years (up to April 2013) and 215 had complete follow-updata. The data for 231 patients (114 in surgical group and 117 in nonsurgical group) were included in theprimary analysis. INTERVENTIONS Fracture fixation or humeral head replacement were performed bysurgeons experienced in these techniques. Nonsurgical treatment was sling immobilization. Standardizedoutpatient and community-based rehabilitation was provided to both groups. MAIN OUTCOMES ANDMEASURES Primary outcome was the Oxford Shoulder Score (range, 0-48; higher scores indicate betteroutcomes) assessed during a 2-year period, with assessment and data collection at 6, 12, and 24months. Sample size was based on a minimal clinically important difference of 5 points for the OxfordShoulder Score. Secondary outcomes were the Short-Form 12 (SF-12), complications, subsequenttherapy, and mortality. RESULTS There was no significant mean treatment group difference in the OxfordShoulder Score averaged over 2 years (39.07 points for the surgical group vs 38.32 points for thenonsurgical group; difference of 0.75 points [95% CI, -1.33 to 2.84 points]; P = .48) or at individual timepoints. There were also no significant between-group differences over 2 years in the mean SF-12 physicalcomponent score (surgical group: 1.77 points higher [95% CI, -0.84 to 4.39 points]; P = .18); the meanSF-12 mental component score (surgical group: 1.28 points lower [95% CI, -3.80 to 1.23 points]; P =.32); complications related to surgery or shoulder fracture (30 patients in surgical group vs 23 patients innonsurgical group; P = .28), requiring secondary surgery to the shoulder (11 patients in both groups),and increased or new shoulder-related therapy (7 patients vs 4 patients, respectively; P = .58); andmortality (9 patients vs 5 patients; P = .27). Ten medical complications (2 cardiovascular events, 2respiratory events, 2 gastrointestinal events, and 4 others) occurred in the surgical group during thepostoperative hospital stay. CONCLUSIONS AND RELEVANCE Among patients with displaced proximalhumeral fractures involving the surgical neck, there was no significant difference between surgicaltreatment compared with nonsurgical treatment in patient-reported clinical outcomes over 2 yearsfollowing fracture occurrence. These results do not support the trend of increased surgery for patientswith displaced fractures of the proximal humerus. TRIAL REGISTRATION isrctn.com Identifier:ISRCTN50850043.", "metadata": {}}
+{"_id": "44172171", "title": "", "text": "Kinetics and Fidelity of the Repair of Cas9-Induced Double-Strand DNA BreaksThe RNA-guided DNAendonuclease Cas9 is a powerful tool for genome editing. Little is known about the kinetics and fidelity ofthe double-strand break (DSB) repair process that follows a Cas9 cutting event in living cells. Here, wedeveloped a strategy to measure the kinetics of DSB repair for single loci in human cells. Quantitativemodeling of repaired DNA in time series after Cas9 activation reveals variable and often slow repair rates,with half-life times up to \u000010 hr. Furthermore, repair of the DSBs tends to be error prone. Both classicaland microhomology-mediated end joining pathways contribute to the erroneous repair. Estimation oftheir individual rate constants indicates that the balance between these two pathways changes over timeand can be altered by additional ionizing radiation. Our approach provides quantitative insights into DSBrepair kinetics and fidelity in single loci and indicates that Cas9-induced DSBs are repaired in an unusualmanner.", "metadata": {}}
+{"_id": "44264297", "title": "", "text": "Network meta-analysis for indirect treatment comparisons.I present methods for assessing the relativeeffectiveness of two treatments when they have not been compared directly in a randomized trial buthave each been compared to other treatments. These network meta-analysis techniques allow estimationof both heterogeneity in the effect of any given treatment and inconsistency ('incoherence') in theevidence from different pairs of treatments. A simple estimation procedure using linear mixed models isgiven and used in a meta-analysis of treatments for acute myocardial infarction.", "metadata": {}}
+{"_id": "44265107", "title": "", "text": "Liver transplantation and opioid dependence.ContextChronic hepatitis C is the leading cause for livertransplantation in the United States. Intravenous drug use, the major risk factor, accounts forapproximately 60% of hepatitis C virus transmission. Information from the United Network of OrganSharing (UNOS) does not address substance use among liver transplantation patients. ObjectiveToidentify addiction-related criteria for admission to the UNOS liver transplantation waiting list andposttransplantation problems experienced by patients who are prescribed maintenance methadone.Design, Setting, and ParticipantsMail survey of all 97 adult US liver transplantation programs (belongingto UNOS) in March 2000 with telephone follow-up conducted in May and June 2000.Main OutcomeMeasuresPrograms' acceptance and management of patients with past or present substance use disorder.ResultsOf the 97 programs surveyed, 87 (90%) responded. All accept applicants with a history ofalcoholism or other addictions, including heroin dependence. Eighty-eight percent of the respondingprograms require at least 6 months of abstinence from alcohol; 83% from illicit drugs. Ninety-fourpercent have addiction treatment requirements. Consultations from substance abuse specialists areobtained by 86%. Patients receiving methadone maintenance are accepted by 56% of the respondingprograms. Approximately 180 patients receiving methadone maintenance are reported to haveundergone liver transplantation. ConclusionsMost liver transplantation programs have established policiesfor patients with substance use disorders. Opiate-dependent patients receiving opiate replacementtherapy seem underrepresented in transplantation programs. Little anecdotal evidence for negativeimpact of opiate replacement therapy on liver transplantation outcome was found. Policies requiringdiscontinuation of methadone in 32% of all programs contradict the evidence base for efficacy oflong-term replacement therapies and potentially result in relapse of previously stable patients.", "metadata": {}}
+{"_id": "44366096", "title": "", "text": "RIG-I-mediated antiviral responses to single-stranded RNA bearing 5'-phosphates.Double-stranded RNA(dsRNA) produced during viral replication is believed to be the critical trigger for activation of antiviralimmunity mediated by the RNA helicase enzymes retinoic acid-inducible gene I (RIG-I) and melanomadifferentiation-associated gene 5 (MDA5). We showed that influenza A virus infection does not generatedsRNA and that RIG-I is activated by viral genomic single-stranded RNA (ssRNA) bearing 5'-phosphates.This is blocked by the influenza protein nonstructured protein 1 (NS1), which is found in a complex withRIG-I in infected cells. These results identify RIG-I as a ssRNA sensor and potential target of viralimmune evasion and suggest that its ability to sense 5'-phosphorylated RNA evolved in the innateimmune system as a means of discriminating between self and nonself.", "metadata": {}}
+{"_id": "44384384", "title": "", "text": "In-hospital switching between adenosine diphosphate receptor inhibitors in patients with acutemyocardial infarction treated with percutaneous coronary intervention: Insights into contemporarypractice from the TRANSLATE-ACS study.AIMS While randomized clinical trials have compared clopidogrelwith higher potency adenosine diphosphate (ADP) receptor inhibitors among patients with acutemyocardial infarction, little is known about the frequency, effectiveness and safety of switching betweenADP receptor inhibitors in routine clinical practice. METHODS AND RESULTS We studied 11,999myocardial infarction patients treated with percutaneous coronary intervention at 230 hospitals from April2010 to October 2012 in the TRANSLATE-ACS study. Multivariable Cox regression was used to comparesix-month post-discharge risks of major adverse cardiovascular events (MACE: death, myocardialinfarction, stroke, or unplanned revascularization) and Global Utilization of Streptokinase and t-PA forOccluded Coronary Arteries (GUSTO)-defined bleeding between in-hospital ADP receptor inhibitorswitching versus continuation of the initially selected therapy. Among 8715 patients treated initially withclopidogrel, 994 (11.4%) were switched to prasugrel or ticagrelor; switching occurred primarily afterpercutaneous coronary intervention (60.9%) and at the time of hospital discharge (26.7%). Among 3284patients treated initially with prasugrel or ticagrelor, 448 (13.6%) were switched to clopidogrel; 48.2% ofswitches occurred after percutaneous coronary intervention and 48.0% at hospital discharge. Switchingto prasugrel or ticagrelor was not associated with increased bleeding when compared with continuationon clopidogrel (2.7% vs. 3.3%, adjusted hazard ratio 0.96, 95% confidence interval 0.64-1.42, p=0.82).Switching from prasugrel or ticagrelor to clopidogrel was not associated with increased MACE (8.9% vs.7.7%, adjusted hazard ratio 1.06, 95% confidence interval 0.75-1.49, p=0.76) when compared withcontinuation on the higher potency agent. CONCLUSIONS In-hospital ADP receptor inhibitor switchingoccurs in more than one in 10 myocardial infarction patients in contemporary practice. In thisobservational study, ADP receptor inhibitor switching does not appear to be significantly associated withincreased hazard of MACE or bleeding.", "metadata": {}}
+{"_id": "44387884", "title": "", "text": "Platelet activation in type 2 diabetes mellitus.The abnormal metabolic state that accompanies diabetesrenders arteries susceptible to atherosclerosis, being capable of altering the functional properties ofmultiple cell types, including endothelium and platelets. In particular, an altered platelet metabolism andchanges in intraplatelet signaling pathways may contribute to the pathogenesis of atherothromboticcomplications of diabetes. A variety of mechanisms may be responsible for enhanced plateletaggregation. Among them, hyperglycemia may represent a causal factor for in vivo platelet activation,and may be responsible for nonenzymatic glycation of platelet glycoproteins, causing changes in theirstructure and conformation, as well as alterations of membrane lipid dynamics. Furthermore,hyperglycemia-induced oxidative stress is responsible for enhanced peroxidation of arachidonic acid toform biologically active isoprostanes, which represents an important biochemical link between impairedglycemic control and persistent platelet activation. Finally, increased oxidative stress is responsible foractivation of transcription factors and expression of redox-sensitive genes leading to a phenotypic switchof endothelium toward an adhesive, pro-thrombotic condition, initial platelet activation, adhesion andsubsequent platelet aggregate formation. All this evidence is strengthened by the results of clinical trialsdocumenting the beneficial effects of metabolic control on platelet function, and by the finding thataspirin treatment may even be more beneficial in diabetic than in high-risk non-diabetic patients.Attention to appropriate medical management of diabetic patients will have great impact on long-termoutcome in this high-risk population.", "metadata": {}}
+{"_id": "44408494", "title": "", "text": "Nicotinic receptor-mediated neuroprotection in neurodegenerative disease models.Multiple lines ofevidence, from molecular and cellular to epidemiological, have implicated nicotinic transmission in thepathology of Alzheimer's disease (AD) and Parkinson's disease (PD). This review article presents evidencefor nicotinic acetylcholine receptor (nAChR)-mediated protection and the signal transduction involved inthis mechanism. The data is based mainly on our studies using rat-cultured primary neurons.Nicotine-induced protection was blocked by an alpha7 nAChR antagonist, a phosphatidylinositol 3-kinase(PI3K) inhibitor, and an Src inhibitor. Levels of phosphorylated Akt, an effector of PI3K, Bcl-2 and Bcl-xwere increased by nicotine administration. From these experimental data, our hypothesis for themechanism of nAChR-mediated survival signal transduction is that the alpha7 nAChR stimulates the Srcfamily, which activates PI3K to phosphorylate Akt, which subsequently transmits the signal to up-regulateBcl-2 and Bcl-x. Up-regulation of Bcl-2 and Bcl-x could prevent cells from neuronal death induced bybeta-amyloid (Abeta), glutamate and rotenone. These findings suggest that protective therapy withnAChR stimulation could delay the progress of neurodegenerative diseases such as AD and PD.", "metadata": {}}
+{"_id": "44409062", "title": "", "text": "High-throughput parallel proteogenomics: a bacterial case study.In recent years, a new paradigm forgenome annotation has emerged, termed \"proteogenomics,\" that leverages peptide MS to annotate agenome. This is achieved by mapping peptides to a six-frame translation of a genome, including availablesplice databases, which may suggest refinements to gene models. Using this approach, it is possible torefine gene regions such as exon boundaries, novel genes, gene boundaries, frame shifts, reversestrands, translated UTRs, and novel splice junctions. One of the challenges of proteogenomics is how bestto (1) tackle assigning confidence to any resulting annotation and (2) apply these gene modelrefinements, either through manual annotation or through an automated process via training geneprediction tools. This is not a straightforward process, as many gene prediction tools have their definedsuitability for niche genomes (either eukaryotic or prokaryotic) trained on and refined with modelorganisms such as Arabidopsis thaliana and Escherichia coli, and varying degrees of features that canleverage the use of external evidence. In this study, we outline a suitable approach toward preprocessingmass spectra and optimizing the MS/MS search for a given dataset. We also discuss future challenges,which continue to pose a problem in the field of proteogenomics, and better strategies to successfullytackle them with, using existing tools. We use Bradyrhizobium diazoefficiens (Nitrogen-fixing bacteria),with a 9.1 Mb genome as a case study, utilizing the latest in second-generation proteogenomics toolswith multiple gene models for cross-validation of proteogenomics annotations.", "metadata": {}}
+{"_id": "44420873", "title": "", "text": "Keratinocyte-specific transglutaminase of cultured human epidermal cells: relation to cross-linkedenvelope formation and terminal differentiation.The predominant form of the cross-linking enzyme,transglutaminase, in cultured normal human epidermal keratinocytes, is found in cell particulate materialand can be solubilized by nonionic detergent. It elutes as a single peak upon either anion-exchange orgel-filtration chromatography. Monoclonal antibodies raised to the particulate enzyme cross-react withone of two transglutaminases in the cell cytosol. The second cytosolic transglutaminase, which hasdistinct kinetic and physical properties from the first, does not cross-react and is not essential forformation of the keratinocyte cross-linked envelope in vitro. The anti-transglutaminase antibodies stainthe more differentiated layers of epidermis in a pattern similar to that given by anti-involucrin antiserum.These observations support the hypothesis that the transglutaminase so identified is involved incross-linked envelope formation in vivo.", "metadata": {}}
+{"_id": "44500794", "title": "", "text": "The effects of genetic and pharmacological blockade of the CB1 cannabinoid receptor on anxiety.The aimof this study was to compare the effects of the genetic and pharmacological disruption of CB1cannabinoid receptors on the elevated plus-maze test of anxiety. In the first experiment, the behaviour ofCB1-knockout mice and wild-type mice was compared. In the second experiment, the cannabinoidantagonist SR141716A (0, 1, and 3 mg/kg) was administered to both CB1-knockout and wild type mice.Untreated CB1-knockout mice showed a reduced exploration of the open arms of the plus-mazeapparatus, thus appearing more anxious than the wild-type animals, however no changes in locomotionwere noticed. The vehicle-injected CB1-knockout mice from the second experiment also showedincreased anxiety as compared with wild types. Surprisingly, the cannabinoid antagonist SR141716Areduced anxiety in both wild type and CB1 knockout mice. Locomotor behaviour was only marginallyaffected. Recent evidence suggests the existence of a novel cannabinoid receptor in the brain. It has alsobeen shown that SR141716A binds to both the CB1 and the putative novel receptor. The data presentedhere supports these findings, as the cannabinoid receptor antagonist affected anxiety in both wild typeand CB1-knockout mice. Tentatively, it may be suggested that the discrepancy between the effects of thegenetic and pharmacological blockade of the CB1 receptor suggests that the novel receptor plays a role inanxiety.", "metadata": {}}
+{"_id": "44562058", "title": "", "text": "Immune activation and HIV persistence: implications for curative approaches to HIV infection.Despitecomplete or near-complete suppression of human immunodeficiency virus (HIV) replication withcombination antiretroviral therapy, both HIV and chronic inflammation/immune dysfunction persistindefinitely. Untangling the association between the virus and the host immune environment duringtherapy might lead to novel interventions aimed at either curing the infection or preventing thedevelopment of inflammation-associated end-organ disease. Chronic inflammation and immunedysfunction might lead to HIV persistence by causing virus production, generating new target cells,enabling infecting of activated and resting target cells, altering the migration patterns of susceptibletarget cells, increasing the proliferation of infected cells, and preventing normal HIV-specific clearancemechanisms from function. Chronic HIV production or replication might contribute to persistentinflammation and immune dysfunction. The rapidly evolving data on these issues strongly suggest that avicious cycle might exist in which HIV persistence causes inflammation that in turn contributes to HIVpersistence.", "metadata": {}}
+{"_id": "44562221", "title": "", "text": "Tissue-specific alterations in the glucocorticoid sensitivity of immune cells following repeated social defeatin miceEndogenous glucocorticoids (GC) play an important role in the termination of the inflammatoryresponse following infection and tissue injury. However, recent findings indicate that stress can impair theanti-inflammatory capacities of these hormones. Lipopolysaccharide (LPS)-stimulated splenocytes of micethat were repeatedly subjected to social disruption (SDR) stress were less sensitive to theimmunosuppressive effects of corticosterone (CORT) as demonstrated by an increased production ofpro-inflammatory cytokines and enhanced cell survival. Myeloid cells expressing the marker CD11b wereshown to play a key role in this process. Here we investigated the role of the bone marrow as a potentialsource of the GC-insensitive cells. The study revealed that LPS-stimulated bone marrow cells, in theabsence of experimental stress, were virtually GC-resistant and retained high levels of cell viability aftertreatment with CORT. Recurrent exposure to the acute stressor over a period of 2, 4 or 6 days led to anincrease in the GC sensitivity of the bone marrow cells. This increase in GC sensitivity was associated withenhanced mRNA expression of granulocyte-macrophage colony-stimulating factor (GM-CSF), an increasein the number of myeloid progenitors, and a decrease in the proportion of mature CD11b+ cells. Thechanges in the cellular composition of the bone marrow were accompanied by an increase in splenicCD11b+ cell numbers. Simultaneous assessment of the GC sensitivity in bone marrow and spleenrevealed a significant negative correlation between both tissues suggesting that social stress causes theredistribution of GC-insensitive myeloid cells from the bone marrow to the spleen.", "metadata": {}}
+{"_id": "44562904", "title": "", "text": "Delays in the diagnosis of lung cancer.BACKGROUND Many patients with lung cancer report delays indiagnosing their disease. This may contribute to advanced stage at diagnosis and poor long term survival.This study explores the delays experienced by patients referred to a regional cancer centre with lungcancer. METHODS A prospective cohort of patients referred with newly diagnosed lung cancer weresurveyed over a 3 month period to assess delays in diagnosis. Patients were asked when they firstexperienced symptoms, saw their doctor, what tests were done, when they saw a specialist and whenthey started treatment. Descriptive statistics were used to summarize the different time intervals.RESULTS 56 of 73 patients consented (RR 77%). However only 52 patients (30M, 22F) were interviewedas 2 died before being interviewed and two could not be contacted. The mean age was 68yrs. Stagedistribution was as follows (IB/IIA 10%, stage IIIA 20%, IIIB/IV 70%). Patients waited a median of 21days (iqr 7-51d) before seeing a doctor and a further 22d (iqr 0-38d) to complete any investigations. Themedian time from presentation to specialist referral was 27d (iqr 12-49d) and a further 23.5d (iqr10-56d) to complete investigations. The median wait to start treatment once patients were seen at thecancer centre was 10d (iqr 2-28d). The overall time from development of first symptoms to startingtreatment was 138d (iqr 79-175d). CONCLUSIONS Lung cancer patients experience substantial delaysfrom development of symptoms to first initiating treatment. There is a need to promote awareness oflung cancer symptoms and develop and evaluate rapid assessment clinics for patients with suspectedlung cancers.", "metadata": {}}
+{"_id": "44572913", "title": "", "text": "Calcium and peak bone mass.On the basis of previous epidemiological, clinical and experimental studies,it was demonstrated that adequate calcium intake during growth may influence peak bone mass/density,and may be instrumental in preventing subsequent postmenopausal and senile osteoporosis. Calciumintake during adolescence appears to affect skeletal calcium retention directly, and a calcium intake of upto 1600 mg d-1 may be required. Therefore, adolescent females at the time of puberty probablyrepresent the optimal population for early prevention of osteoporosis with calcium. Young individualsmust be in positive calcium balance to provide the calcium necessary for skeletal modelling andconsolidation, but the degree of positive balance required to achieve peak bone mass and density isunknown. To assess calcium requirements in young individuals, and also to evaluate the determinants ofcalcium metabolism during the period of acquisition of peak bone mass, 487 calcium balances frompreviously published reports have been collected and analysed according to developmental phase andcalcium intake. The results of this analysis showed that calcium intake and skeletal modelling/turnoverare the most important determinants of calcium balance during growth. The highest requirements forcalcium are during infancy and adolescence, and then during childhood and young adulthood. Infants(adequate vitamin D supply) and adolescents have higher calcium absorption than children and youngadults to meet their high calcium requirements. Calcium absorption during the periods of rapid bonemodelling/turnover is probably mediated by Nicolaysen's endogenous factor. Urinary calcium increaseswith age, and reaches a maximum by the end of puberty. The results also show that calcium intake haslittle effect on urinary calcium excretion during the period of most rapid skeletal formation: a weakcorrelation is present in children and young adults. On the basis of the above studies it was suggestedthat the RDA for calcium should be higher than currently established for children, adolescents, and youngadults, in order to ensure a level of skeletal retention of calcium sufficient for maximal peak bone mass.In addition to nutrition, heredity (both parents) and endocrine factors (sexual development) appear tohave profound effects on peak bone mass formation. Most of the skeletal mass will be accumulated bylate adolescence, indicating early timing of peak bone mass.", "metadata": {}}
+{"_id": "44586415", "title": "", "text": "Most clinical tests cannot accurately diagnose rotator cuff pathology: a systematic review.QUESTION Doclinical tests accurately diagnose rotator cuff pathology? DESIGN A systematic review of investigationsinto the diagnostic accuracy of clinical tests for rotator cuff pathology. PARTICIPANTS People withshoulder pain who underwent clinical testing in order to diagnose rotator cuff pathology. OUTCOMEMEASURES The diagnostic accuracy of clinical tests was determined using likelihood ratios. RESULTSThirteen studies met the inclusion criteria. The 13 studies evaluated 14 clinical tests in 89 separateevaluations of diagnostic accuracy. Only one evaluation, palpation for supraspinatus ruptures, resulted insignificant positive and negative likelihood ratios. Eight of the 89 evaluations resulted in either significantpositive or negative likelihood ratios. However, none of these eight positive or negative likelihood ratioswere found in other studies. Of the 89 evaluations of clinical tests 71 (80%) did not result in eithersignificant positive or negative likelihood ratio evaluations across different studies. CONCLUSION Overall,most tests for rotator cuff pathology were inaccurate and cannot be recommended for clinical use. Atbest, suspicion of a rotator cuff tear may be heightened by a positive palpation, combinedHawkins/painful arc/infraspinatus test, Napoleon test, lift-off test, belly-press test, or drop-arm test, andit may be reduced by a negative palpation, empty can test or Hawkins-Kennedy test.", "metadata": {}}
+{"_id": "44614949", "title": "", "text": "Skeletal muscle interleukin\u00006 regulates metabolic factors in iWAT during HFD and exercisetrainingOBJECTIVE To investigate the role of skeletal muscle (SkM) interleukin (IL)-6 in the regulation ofadipose tissue metabolism. METHODS Muscle-specific IL-6 knockout (IL-6 MKO) and IL-6(loxP/loxP)(Floxed) mice were subjected to standard rodent diet (Chow), high-fat diet (HFD), or HFD in combinationwith exercise training (HFD ExTr) for 16 weeks. RESULTS Total fat mass increased (P < 0.05) in bothgenotypes with HFD. However, HFD IL-6 MKO mice had lower (P < 0.05) inguinal adipose tissue (iWAT)mass than HFD Floxed mice. Accordingly, iWAT glucose transporter 4 (GLUT4) protein content, 5'AMPactivated protein kinase (AMPK)(Thr172) phosphorylation, and fatty acid synthase (FAS) mRNA contentwere lower (P < 0.05) in IL-6 MKO than Floxed mice on Chow. In addition, iWAT AMPK(Thr172) andhormone-sensitive lipase (HSL)(Ser565) phosphorylation as well as perilipin protein content was higher(P < 0.05) in HFD IL-6 MKO than HFD Floxed mice, and pyruvate dehydrogenase E1α (PDH-E1α) proteincontent was higher (P < 0.05) in HFD ExTr IL-6 MKO than HFD ExTr Floxed mice. CONCLUSIONS Thesefindings indicate that SkM IL-6 affects iWAT mass through regulation of glucose uptake capacity as wellas lipogenic and lipolytic factors.", "metadata": {}}
+{"_id": "44624045", "title": "", "text": "Risk of hospitalization or death from ischemic heart disease among British vegetarians andnonvegetarians: results from the EPIC-Oxford cohort study.BACKGROUND Few previous prospectivestudies have examined differences in incident ischemic heart disease (IHD) risk between vegetarians andnonvegetarians. OBJECTIVE The objective was to examine the association of a vegetarian diet with risk ofincident (nonfatal and fatal) IHD. DESIGN A total of 44,561 men and women living in England andScotland who were enrolled in the European Prospective Investigation into Cancer and Nutrition(EPIC)-Oxford study, of whom 34% consumed a vegetarian diet at baseline, were part of the analysis.Incident cases of IHD were identified through linkage with hospital records and death certificates. Serumlipids and blood pressure measurements were available for 1519 non cases, who were matched to IHDcases by sex and age. IHD risk by vegetarian status was estimated by using multivariate Cox proportionalhazards models. RESULTS After an average follow-up of 11.6 y, there were 1235 IHD cases (1066hospital admissions and 169 deaths). Compared with nonvegetarians, vegetarians had a lower mean BMI[in kg/m(2); -1.2 (95% CI: -1.3, -1.1)], non-HDL-cholesterol concentration [-0.45 (95% CI: -0.60,-0.30) mmol/L], and systolic blood pressure [-3.3 (95% CI: -5.9, -0.7) mm Hg]. Vegetarians had a 32%lower risk (HR: 0.68; 95% CI: 0.58, 0.81) of IHD than did nonvegetarians, which was only slightlyattenuated after adjustment for BMI and did not differ materially by sex, age, BMI, smoking, or thepresence of IHD risk factors. CONCLUSION Consuming a vegetarian diet was associated with lower IHDrisk, a finding that is probably mediated by differences in non-HDL cholesterol, and systolic bloodpressure.", "metadata": {}}
+{"_id": "44629665", "title": "", "text": "The Supporting Independent Immunization and Vaccine Advisory Committees (SIVAC) initiative: acountry-driven, multi-partner program to support evidence-based decision making.Multiple healthpriorities, limited human resources and logistical capacities, as well as expensive vaccines with limitedfunds available increase the need for evidence-based decision making in immunization programs. The aimof the Supporting Independent Immunization and Vaccine Advisory Committees (SIVAC) Initiative is tosupport countries in the establishment or strengthening of National Immunization Technical AdvisoryGroups (NITAGs) that provide recommendations on immunization policies and programs (e.g.,vaccination schedules, improvements of routine immunization coverage, new vaccine introduction, etc.).SIVAC, a program funded by the Bill & Melinda Gates Foundation, is based on a country-driven,step-by-step process that ensures its support is tailored to country needs and emphasizes NITAGsustainability. SIVAC supports countries by reinforcing the capacities of the NITAG scientific and technicalsecretariat and by providing specific support activities established in consultation with the country andother international partners. Additionally, SIVAC and partners have built an electronic platform, theNITAG Resource Center, that provides information, tools, and briefings to NITAGs and the immunizationcommunity.", "metadata": {}}
+{"_id": "44640124", "title": "", "text": "Redox-relevant aspects of the extracellular matrix and its cellular contacts via integrins.SIGNIFICANCEThe extracellular matrix (ECM) fulfills essential functions in multicellular organisms. It provides themechanical scaffold and environmental cues to cells. Upon cell attachment, the ECM signals into the cells.In this process, reactive oxygen species (ROS) are physiologically used as signalizing molecules. RECENTADVANCES ECM attachment influences the ROS-production of cells. In turn, ROS affect the production,assembly and turnover of the ECM during wound healing and matrix remodeling. Pathological changes ofROS levels lead to excess ECM production and increased tissue contraction in fibrotic disorders anddesmoplastic tumors. Integrins are cell adhesion molecules which mediate cell adhesion and forcetransmission between cells and the ECM. They have been identified as a target of redox-regulation byROS. Cysteine-based redox-modifications, together with structural data, highlighted particular regionswithin integrin heterodimers that may be subject to redox-dependent conformational changes along withan alteration of integrin binding activity. CRITICAL ISSUES In a molecular model, a long-rangedisulfide-bridge within the integrin β-subunit and disulfide bridges within the genu and calf-2 domains ofthe integrin α-subunit may control the transition between the bent/inactive and upright/activeconformation of the integrin ectodomain. These thiol-based intramolecular cross-linkages occur in thestalk domain of both integrin subunits, whereas the ligand-binding integrin headpiece is apparentlyunaffected by redox-regulation. FUTURE DIRECTIONS Redox-regulation of the integrin activation statemay explain the effect of ROS in physiological processes. A deeper understanding of the underlyingmechanism may open new prospects for the treatment of fibrotic disorders.", "metadata": {}}
+{"_id": "44660616", "title": "", "text": "Prevalence of hypertension and pre-hypertension among adolescents.OBJECTIVE To determine theprevalence of hypertension and pre-hypertension on the basis of the 2004 National High Blood PressureEducation Program Working Group guidelines in an adolescent school-screening population. STUDYDESIGN Cross-sectional assessment of blood pressure (BP) in 6790 adolescents (11-17 years) in Houstonschools was conducted from 2003 to 2005. Initial measurements included height, weight, and 4oscillometric BP readings. Repeat measurements were obtained on 2 subsequent occasions in studentswith persistently elevated BP. Final prevalence was adjusted for loss to follow-up and logistic regressionused to assess risk factors. RESULTS BP distribution at initial screen was 81.1% normal, 9.5%pre-hypertension, and 9.4% hypertension (8.4% Stage 1; 1% Stage 2). Prevalence after 3 screeningswas 81.1% normal, 15.7% pre-hypertension, and 3.2% hypertension (2.6% Stage 1; 0.6% Stage 2).Hypertension and pre-hypertension increased with increasing body mass index. Sex, race, andclassification as either at-risk for overweight or overweight were independently associated withpre-hypertension. Only classification as overweight was associated with hypertension. CONCLUSIONSApplication of new classification guidelines for adolescents with elevated BP reveals approximately 20%are at risk for hypertension. Further research determining the significance of each BP category andrefining definitions to account for BP variability is warranted.", "metadata": {}}
+{"_id": "44672703", "title": "", "text": "Increased short- and long-term risk of inflammatory bowel disease after salmonella or campylobactergastroenteritis.BACKGROUND & AIMS Various commensal enteric and potentially pathogenic bacteria maybe involved in the pathogenesis of inflammatory bowel diseases (IBD). We compared the risk of IBDbetween a cohort of patients with documented Salmonella or Campylobacter gastroenteritis and an age-and gender-matched control group from the same population in Denmark. METHODS We identified13,324 patients with Salmonella/Campylobacter gastroenteritis from laboratory registries in North Jutlandand Aarhus counties, Denmark, from 1991 through 2003, and 26,648 unexposed controls from the samecounties. Of these, 176 exposed patients with IBD before the infection, their 352 unexposed controls, and80 unexposed individuals with IBD before the Salmonella/Campylobacter infection were excluded. Thefinal study cohort of 13,148 exposed and 26,216 unexposed individuals were followed for up to 15 years(mean, 7.5 years). RESULTS A first-time diagnosis of IBD was reported in 107 exposed (1.2%) and 73unexposed individuals (0.5%). By age, gender, and comorbidity adjusted Cox proportional hazardsregression analysis, the hazard ratio (95% confidence interval) for IBD was 2.9 (2.2-3.9) for the wholeperiod and 1.9 (1.4-2.6) if the first year after the Salmonella/Campylobacter infection was excluded. Theincreased risk in exposed subjects was observed throughout the 15-year observation period. Theincreased risk was similar for Salmonella (n = 6463) and Campylobacter (n = 6685) and for a first-timediagnosis of Crohn's disease (n = 47) and ulcerative colitis (n = 133). CONCLUSIONS In ourpopulation-based cohort study with complete follow-up, an increased risk of IBD was demonstrated inindividuals notified in laboratory registries with an episode of Salmonella/Campylobacter gastroenteritis.", "metadata": {}}
+{"_id": "44674301", "title": "", "text": "Establishment of a cell line (NPC/HK1) from a differentiated squamous carcinoma of the nasopharynx.Along-term cell culture epithelioid cell line was established from a recurrent squamous carcinoma of thenasopharynx of a Chinese male 17 1/2 years after radiation therapy. The cell line, designated NPC/HK1,has been passed 72 times over a period 1 year. The cells have been shown by light and electronmicroscopies to be of the squamous epithelial type. When they were transplanted subcutaneously into theback of athymic nude BALB/c (nu/nu) mice, tumors developed at the sites of inoculation, which onhistological examination were shown to be well-differentiated squamous carcinomas, similar inmorphology to the recurrent human tumor from which they were derived. Karyotypic analysis of cellsfrom the cell line demonstrates an aneuploid human type with a modal chromosome number of 74 withboth numerical and structural aberrations. Viral particles or Epstein-Barr viral nuclear antigen (EBNA) hasnot been demonstrated in the cells from the primary culture or several of the subcultures tested. Thepresence of EBNA in touch smears prepared from the biopsy tissue was inconclusive. Infection of thesubcultured cells with EBV from P3HR1 and B95-8 cells was unsuccessful.", "metadata": {}}
+{"_id": "44693226", "title": "", "text": "Effect of lipid restriction on mitochondrial free radical production and oxidative DNA damage.Many studieshave shown that caloric restriction (40%) decreases mitochondrial reactive oxygen species (ROS)generation in rodents. Moreover, we have recently found that 7 weeks of 40% protein restriction withoutstrong caloric restriction also decreases ROS production in rat liver. This is interesting since it has beenreported that protein restriction can also extend longevity in rodents. In the present study we haveinvestigated the possible role of dietary lipids in the effects of caloric restriction on mitochondrialoxidative stress. Using semipurified diets, the ingestion of lipids in male Wistar rats was decreased by40% below controls, while the other dietary components were ingested at exactly the same level as inanimals fed ad libitum. After 7 weeks of treatment the liver mitochondria of lipid-restricted animalsshowed significant increases in oxygen consumption with complex I-linked substrates (pyruvate/malateand glutamate/malate). Neither mitochondrial H(2)O(2) production nor oxidative damage tomitochondrial or nuclear DNA was modified in lipid-restricted animals. Oxidative damage to mitochondrialDNA was one order of magnitude higher than that of nuclear DNA in both dietary groups. These resultsdeny a role for lipids and reinforce the possible role of dietary proteins as being responsible for thedecrease in mitochondrial ROS production and DNA damage in caloric restriction.", "metadata": {}}
+{"_id": "44724517", "title": "", "text": "Kruppel-like factor 2 is a transcriptional regulator of chronic and acute inflammation.Although myeloid cellactivation is requisite for an optimal innate immune response, this process must be tightly controlled toprevent collateral host tissue damage. Kruppel-like factor 2 (KLF2) is a potent regulator of myeloid cellproinflammatory activation. As an approximately 30% to 50% reduction in KLF2 levels has been observedin human subjects with acute or chronic inflammatory disorders, we studied the biological response toinflammation in KLF2(+/-) mice. Herein, we show that partial deficiency of KLF2 modulates the in vivoresponse to acute (sepsis) and subacute (skin) inflammatory challenge. Mechanistically, we link theanti-inflammatory effects of KLF2 to the inhibition of NF-κB transcriptional activity. Collectively, theobservations provide biologically relevant insights into KLF2-mediated modulation of these inflammatoryprocesses that could potentially be manipulated for therapeutic gain.", "metadata": {}}
+{"_id": "44737533", "title": "", "text": "Simian immunodeficiency viruses replication dynamics in African non-human primate hosts: commonpatterns and species-specific differences.METHODS To define potential common features of simianimmunodeficiency virus (SIV) infections in different naturally infected host species, we compared thedynamics of viral replication in 31 African green monkeys (10 sabeus, 15 vervets and seven CaribbeanAGMs), 14 mandrills and three sooty mangabeys (SMs) that were experimentally infected with theirspecies-specific viruses. RESULTS After infection, these SIVs replicated rapidly reaching viral loads (VLs)of 10(5)-10(9) copies/ml of plasma between days 9-14 post-infection (p.i). Set point viremia wasestablished between days 42 and 60 p.i., with levels of approximately 10(5)-10(6) copies/ml in SM andmandrills, and lower levels (10(3)-10(5) copies/ml) in AGMs. VL during the chronic phase did notcorrelate with viral genome structure: SIVmnd-2 (a vpx-containing virus) and SIVmnd-1 (which does notcontain vpu or vpx) replicated to similar levels in mandrills. VL was dependent on virus strain: vervetsinfected with three different viral strains showed different patterns of viral replication. The pattern of viralreplication of SIVagm.sab, which uses both CCR5 and CXCR4 co-receptors was similar to those of theother viruses. CONCLUSIONS Our results show a common pattern of SIV replication in naturally andexperimentally infected hosts. This is similar overall to that observed in pathogenic SIV infection ofmacaques. This result indicates that differences in clinical outcome between pathogenic andnon-pathogenic infections rely on host responses rather than the characteristics of the virus itself.", "metadata": {}}
+{"_id": "44801733", "title": "", "text": "The role of the transcription factor KLF2 in vascular development and disease.The zinc-fingertranscription factor KLF2 transduces the physical forces exerted by blood flow into molecular signalsresponsible for a wide range of biological responses. Following its initial recognition as a flow-responsiveendothelial transcription factor, KLF2 is now known to be expressed in a range of cell types and toparticipate in a number of processes during development and disease such as endothelial homeostasis,vasoregulation, vascular growth/remodeling, and inflammation. In this review, we summarize the currentunderstanding about KLF2 with a focus on its effects on vascular biology.", "metadata": {}}
+{"_id": "44827480", "title": "", "text": "Implementation of contemporary oral antiplatelet treatment guidelines in patients with acute coronarysyndrome undergoing percutaneous coronary intervention: a report from the GReek AntiPlatelet rEgistry(GRAPE).BACKGROUND Few data exist about the implementation of contemporary oral antiplatelettreatment guidelines in patients with acute coronary syndrome (ACS) undergoing percutaneous coronaryintervention (PCI). METHODS GReek AntiPlatelet rEgistry (GRAPE), initiated on January 2012, is aprospective, observational, multicenter cohort study focusing on contemporary use of P2Y12 inhibitors. In1434 patients we evaluated appropriateness of P2Y12 selection initially and at discharge by applying aneligibility-assessing algorithm based on P2Y12 inhibitors' contraindications/specific warnings andprecautions. RESULTS Appropriate, less preferable and inappropriate P2Y12 inhibitor selections weremade initially in 45.8%, 47.2% and 6.6% and at discharge in 64.1%, 29.2% and 6.6% of patients,respectively. The selection of clopidogrel was most commonly less preferable, both initially (69.7%) andat discharge (75.6%). Appropriate selection of newer agents was high initially (79.2%-82.8%), withfurther increase as selection at discharge (89.4%-89.8%). Inappropriate selection of the newer agentswas 17.2%-20.8% initially, decreasing to 10.2%-10.6% at discharge. Conditions and co-medicationsrelated to increased bleeding risk, presentation with ST elevation myocardial infarction and the absenceof reperfusion within the first 24h were the most powerful predictors of appropriate P2Y12 selectioninitially, whereas age ≥75 years, conditions and co-medications related to increased bleeding risk andregional trends mostly affected appropriate P2Y12 selection at discharge. CONCLUSIONS In GRAPE,adherence with the recently released guidelines on oral antiplatelet therapy was satisfactory. Clopidogrelwas most commonly used as a less preferable selection, while prasugrel or ticagrelor selection wasmostly appropriate. Certain factors may predict initial and at discharge guideline implementation. ClinicalTrial Registration-clinicaltrials.gov Identifier: NCT01774955 http://clinicaltrials.gov/.", "metadata": {}}
+{"_id": "44830890", "title": "", "text": "Comorbidity of depressive and anxiety disorders in chronic daily headache and its subtypes.OBJECTIVETo investigate the frequency of depressive and anxiety disorders in patients with chronic daily headache.BACKGROUND There is a lack of data in the literature on the extent of psychiatric comorbidity in patientswith different subtypes of chronic daily headache. METHODS We recruited consecutive patients withchronic daily headache seen in a headache clinic from November 1998 to December 1999. The subtypesof chronic daily headache were classified according to the criteria proposed by Silberstein et al. Apsychiatrist evaluated the patients according to the structured Mini-International NeuropsychiatricInterview to assess the comorbidity of depressive and anxiety disorders. RESULTS Two hundred sixty-onepatients with chronic daily headache were recruited. The mean age was 46 years, and 80% were women.Transformed migraine was diagnosed in 152 patients (58%) and chronic tension-type headache in 92patients (35%). Seventy-eight percent of patients with transformed migraine had psychiatriccomorbidity, including major depression (57%), dysthymia (11%), panic disorder (30%), and generalizedanxiety disorder (8%). Sixty-four percent of patients with chronic tension-type headache had psychiatricdiagnoses, including major depression (51%), dysthymia (8%), panic disorder (22%), and generalizedanxiety disorder (1%). The frequency of anxiety disorders was significantly higher in patients withtransformed migraine after controlling for age and sex (P =.02). Both depressive and anxiety disorderswere significantly more frequent in women. CONCLUSION Psychiatric comorbidity, especially majordepression and panic disorders, was highly prevalent in patients with chronic daily headache seen in aheadache clinic. These results demonstrate that women and patients with transformed migraine are athigher risk of psychiatric comorbidity.", "metadata": {}}
+{"_id": "44935041", "title": "", "text": "The precursor form of IL-1alpha is an intracrine proinflammatory activator of transcription.Although mostcytokines are studied for biological effects after engagement of their specific cell surface membranereceptors, increasing evidence suggests that some function in the nucleus. In the present study, theprecursor form of IL-1alpha was overexpressed in various cells and assessed for activity in the presenceof saturating concentrations of IL-1 receptor antagonist to prevent receptor signaling. Initially diffuselypresent in the cytoplasm of resting cells, IL-1alpha translocated to the to nucleus after activation byendotoxin, a Toll-like receptor ligand. The IL-1alpha precursor, but not the C-terminal mature form,activated the transcriptional machinery in the GAL4 system by 90-fold; a 50-fold increase was observedusing only the IL-1alpha propiece, suggesting that transcriptional activation was localized to the Nterminus where the nuclear localization sequence resides. Under conditions of IL-1 receptor blockade,intracellular overexpression of the precursor and propiece forms of IL-1alpha were sufficient to activateNF-kappaB and AP-1. Stable transfectants overproducing precursor IL-1alpha released the cytokines IL-8and IL-6 but also exhibited a significantly lower threshold of activation to subpicomolar concentrations oftumor necrosis factor alpha or IFN-gamma. Thus, intracellular functions of IL-1alpha might play anunforeseen role in the genesis of inflammation. During disease-driven events, the cytosolic precursormoves to the nucleus, where it augments transcription of proinflammatory genes. Because thismechanism of action is not affected by extracellular inhibitors, reducing intracellular functions ofIL-1alpha might prove beneficial in some inflammatory conditions.", "metadata": {}}
+{"_id": "44947611", "title": "", "text": "Three-dimensional structure of the AAH26994.1 protein from Mus musculus, a putative eukaryoticUrm1.We have used NMR spectroscopy to determine the solution structure of protein AAH26994.1 fromMus musculus and propose that it represents the first three-dimensional structure of a ubiquitin-relatedmodifier 1 (Urm1) protein. Amino acid sequence comparisons indicate that AAH26994.1 belongs to theUrm1 family of ubiquitin-like modifier proteins. The best characterized member of this family has beenshown to be involved in nutrient sensing, invasive growth, and budding in yeast. Proteins in this familyhave only a weak sequence similarity to ubiquitin, and the structure of AAH26994.1 showed a muchcloser resemblance to MoaD subunits of molybdopterin synthases (known structures are of three bacterialMoaD proteins with 14%-26% sequence identity to AAH26994.1). The structures of AAH26994.1 and theMoaD proteins each contain the signature ubiquitin secondary structure fold, but all differ from ubiquitinlargely in regions outside of this fold. This structural similarity bolsters the hypothesis that ubiquitin andubiquitin-related proteins evolved from a protein-based sulfide donor system of the molybdopterinsynthase type.", "metadata": {}}
+{"_id": "45015767", "title": "", "text": "Concurrent endometrial carcinoma in women with a biopsy diagnosis of atypical endometrial hyperplasia:a Gynecologic Oncology Group study.BACKGROUND Adenocarcinoma of the endometrium is the mostcommon gynecologic malignancy in the United States, accounting for approximately 36,000 diagnoses ofinvasive carcinoma annually. The most common histologic type, endometrioid adenocarcinoma (EC),accounts for 75-80% of patients. The objective of this work was to estimate the prevalence of concurrentcarcinoma in women with a biopsy diagnosis of the precursor lesion, atypical endometrial hyperplasia(AEH). METHODS This prospective cohort study included women who had a community diagnosis of AEH.Diagnostic biopsy specimens were reviewed independently by three gynecologic pathologists who usedInternational Society of Gynecologic Pathologists/World Health Organization criteria. Study participantsunderwent hysterectomy within 12 weeks of entry onto protocol without interval treatment. Thehysterectomy slides also were reviewed by the study pathologists, and their findings were used in thesubsequent analyses. RESULTS Between November 1998 and June 2003, 306 women were enrolled onthe study. Of these, 17 women were not included in the analysis: Two patients had unreadable slidesbecause of poor processing or insufficient tissue, 2 patients had only slides that were not endometrial, theslides for 5 patients were not available for review, and 8 of the hysterectomy specimens were excludedbecause they showed evidence of interval intervention, either progestin effect or ablation. In total, 289patients were included in the current analysis. The study panel review of the AEH biopsy specimens wasinterpreted as follows: 74 of 289 specimens (25.6%) were diagnosed as less than AEH, 115 of 289specimens (39.8%) were diagnosed as AEH, and 84 of 289 specimens (29.1%) were diagnosed asendometrial carcinoma. In 5.5% (16 of 289 specimens), there was no consensus on the biopsy diagnosis.The rate of concurrent endometrial carcinoma for analyzed specimens was 42.6% (123 of 289specimens). Of these, 30.9% (38 of 123 specimens) were myoinvasive, and 10.6% (13 of 123specimens) involved the outer 50% of the myometrium. Among the women who had hysterectomyspecimens with carcinoma, 14 of 74 women (18.9%) had a study panel biopsy consensus diagnosis ofless than AEH, 45 of 115 women (39.1%) had a study panel biopsy consensus diagnosis of AEH, and 54of 84 women (64.3%) had a study panel diagnosis of carcinoma. Among women who had no consensus intheir biopsy diagnosis, 10 of 16 women (62.5%) had carcinoma in their hysterectomy specimens.CONCLUSIONS The prevalence of endometrial carcinoma in patients who had a community hospitalbiopsy diagnosis of AEH was high (42.6%). When considering management strategies for women whohave a biopsy diagnosis of AEH, clinicians and patients should take into account the considerable rate ofconcurrent carcinoma.", "metadata": {}}
+{"_id": "45027320", "title": "", "text": "The prevalence and clustering of four major lifestyle risk factors in an English adultpopulation.BACKGROUND The aim of this study was to examine the clustering of four major lifestyle riskfactors (smoking, heavy drinking, lack of fruit and vegetables consumption, and lack of physical activity),and to examine the variation across different socio-demographic groups in the English adult population.METHODS The study population was derived from the 2003 Health Survey for England (n=11,492).Clustering was examined by comparing the observed and expected prevalence of the different possiblecombinations. A multinomial multilevel regression model was conducted to examine thesocio-demographic variation in the clustering of the four risk factors. RESULTS The study found that,when using British health recommendations, a majority of the English population have multiple lifestylerisk factors at the same time. Clustering was found at both ends of the lifestyle spectrum and was morepronounced for women than for men. Overall, multiple risk factors were more prevalent among men,lower social class households, singles, and people who are economically inactive, but less prevalentamong home owners and older age groups. CONCLUSIONS The clustering of multiple risk factors providessupport for multiple-behavior interventions as opposed to single-behavior interventions.", "metadata": {}}
+{"_id": "45096063", "title": "", "text": "Cutting edge: interleukin 17 signals through a heteromeric receptor complex.IL-17 is an inflammatorycytokine produced primarily by a unique lineage of CD4 T cells that plays critical roles in the pathogenesisof multiple autoimmune diseases. IL-17RA is a ubiquitously expressed receptor that is essential for IL-17biologic activity. Despite widespread receptor expression, the activity of IL-17 is most classically definedby its ability to induce the expression of inflammatory cytokines, chemokines, and other mediators bystromal cells. The lack of IL-17 responsiveness in mouse stromal cells genetically deficient in IL-17RA ispoorly complemented by human IL-17RA, suggesting the presence of an obligate ancillary componentwhose activity is species specific. This component is IL-17RC, a distinct member of the IL-17R family.Thus, the biologic activity of IL-17 is dependent on a complex composed of IL-17RA and IL-17RC,suggesting a new paradigm for understanding the interactions between the expanded family of IL-17ligands and their receptors.", "metadata": {}}
+{"_id": "45143088", "title": "", "text": "Long non-coding RNAs with low expression levels in cells are enriched in secreted exosomes.Longnon-coding RNAs (lncRNAs) are involved in regulating chromatin modifications, gene transcription, mRNAtranslation, and protein function. We recently reported a high variation in the basal expression levels of apanel of lncRNAs in HeLa and MCF-7 cells and their differential response to DNA damage induction. Here,we hypothesized that lncRNA molecules with different cellular expression may have a differentialabundance in secreted exosomes, and their exosome levels would reflect cellular response to DNAdamage. MALAT1, HOTAIR, lincRNA-p21, GAS5, TUG1, CCND1-ncRNA in exosomes secreted fromcultured cells were characterized. A different expression pattern of lncRNAs in exosomes was seencompared to cells. RNA molecules with relative low expression levels (lincRNA-p21, HOTAIR,ncRNA-CCND1) were highly enriched in exosomes. TUG1 and GAS5 levels were moderately elevated inexosomes, whereas MALAT1--which was the most abundant molecule in cells--was present at levelscomparable to its cellular levels. lincRNA-p21 and ncRNA-CCND1 were the main molecules; exosomelevels of them best reflect the change of their cellular levels upon exposure of the cells tobleomycin-induced DNA damage. In conclusion, we provide evidence that lncRNAs have a differentialabundance in exosomes, indicating a selective loading.", "metadata": {}}
+{"_id": "45153864", "title": "", "text": "Olanzapine depot exposure in male rats: Dose-dependent lipogenic effects without concomitant weightgain.Treatment with second-generation antipsychotic agents such as olanzapine frequently results inmetabolic adverse effects, e.g. hyperphagia, weight gain and dyslipidaemia in patients of both genders.The molecular mechanisms underlying metabolic adverse effects are still largely unknown, and studies inrodents represent an important approach in their exploration. However, the validity of the rodent modelis hampered by the fact that antipsychotics induce weight gain in female, but not male, rats. Whenadministered orally, the short half-life of olanzapine in rats prevents stable plasma concentrations of thedrug. We recently showed that a single intramuscular injection of long-acting olanzapine formulationyields clinically relevant plasma concentrations accompanied by several dysmetabolic features in thefemale rat. In the current study, we show that depot injections of 100-250 mg/kg olanzapine yieldedclinically relevant plasma olanzapine concentrations also in male rats. In spite of transient hyperphagia,however, olanzapine resulted in weight loss rather than weight gain. The resultant negative feedefficiency was accompanied by a slight elevation of thermogenesis markers in brown adipose tissue forthe highest olanzapine dose, but the olanzapine-related reduction in weight gain remains to be explained.In spite of the absence of weight gain, an olanzapine dose of 200mg/kg or above induced significantlyelevated plasma cholesterol levels and pronounced activation of lipogenic gene expression in the liver.These results confirm that olanzapine stimulates lipogenic effects, independent of weight gain, and raisethe possibility that endocrine factors may influence gender specificity of metabolic effects ofantipsychotics in the rat.", "metadata": {}}
+{"_id": "45154987", "title": "", "text": "Glutamate mediates the function of melanocortin receptor 4 on Sim1 neurons in body weightregulation.The melanocortin receptor 4 (MC4R) is a well-established mediator of body weighthomeostasis. However, the neurotransmitter(s) that mediate MC4R function remain largely unknown; asa result, little is known about the second-order neurons of the MC4R neural pathway. Single-minded 1(Sim1)-expressing brain regions, which include the paraventricular nucleus of hypothalamus (PVH),represent key brain sites that mediate melanocortin action. We conditionally restored MC4R expression inSim1 neurons in the background of Mc4r-null mice. The restoration dramatically reduced obesity inMc4r-null mice. The anti-obesity effect was completely reversed by selective disruption of glutamaterelease from those same Sim1 neurons. The reversal was caused by lower energy expenditure andhyperphagia. Corroboratively, selective disruption of glutamate release from adult PVH neurons led torapid obesity development via reduced energy expenditure and hyperphagia. Thus, this study establishesglutamate as the primary neurotransmitter that mediates MC4Rs on Sim1 neurons in body weightregulation.", "metadata": {}}
+{"_id": "45166582", "title": "", "text": "Intracellular sterol dynamics.We review the cellular mechanisms implicated in cholesterol trafficking anddistribution. Recent studies have provided new information about the distribution of sterols within cells,including analysis of its transbilayer distribution. The cholesterol interaction with other lipids and itsengagement in various trafficking processes will determine its proper level in a specific membrane;making the cholesterol distribution uneven among the various intracellular organelles. The cholesterolcontent is important since cholesterol plays an essential role in membranes by controlling theirphysicochemical properties as well as key cellular events such as signal transduction and proteintrafficking. Cholesterol movement between cellular organelles is highly dynamic, and can be achieved byvesicular and non-vesicular processes. Various studies have analyzed the proteins that play a significantrole in these processes, giving us new information about the relative importance of these two traffickingpathways in cholesterol transport. Although still poorly characterized in many trafficking routes, severalpotential sterol transport proteins have been described in detail; as a result, molecular mechanisms forsterol transport among membranes start to be appreciated.", "metadata": {}}
+{"_id": "45199834", "title": "", "text": "A plasma membrane component able to bind and alter virions of poliovirus type 1: studies on cell-freealteration using a simplified assay.Abstract Intact HeLa cells can bind virions of poliovirus type 1 and cansubsequently convert them to altered particles by incubation at 37°. Altered particles sediment moreslowly than virions, have lost VP-4, and are disrupted by sodium dodecyl sulfate, but their RNA is intactand ribonuclease insensitive. These characteristics allow assay of altered particles and of particles thathave released their RNA, using nuclease digestion with or without sodium dodecyl sulfate treatment. Withthis simple assay procedure, quantitative parameters of binding and alteration can be measured. Thebinding-altering activity can be localized in plasma membranes, and pure membranes can be shown tocarry out alteration. The membrane-bound activity is abolished by proteases and by nonionic detergents.Only altered particles are formed by membranes; release of RNA is not caused by membranes but iscaused by intact cells. Binding and alteration are processes that are closely associated; it is possible thatalteration is a consequence of binding by multiple receptors in a fluid membrane.", "metadata": {}}
+{"_id": "45200347", "title": "", "text": "Resequencing studies of nonmodel organisms using closely related reference genomes: optimalexperimental designs and bioinformatics approaches for population genomics.Decreasing costs ofnext-generation sequencing (NGS) experiments have made a wide range of genomic questions open forstudy with nonmodel organisms. However, experimental designs and analysis of NGS data from lesswell-known species are challenging because of the lack of genomic resources. In this work, we investigatethe performance of alternative experimental designs and bioinformatics approaches in estimatingvariability and neutrality tests based on the site-frequency-spectrum (SFS) from individual resequencingdata. We pay particular attention to challenges faced in the study of nonmodel organisms, in particularthe absence of a species-specific reference genome, although phylogenetically close genomes areassumed to be available. We compare the performance of three alternative bioinformatics approaches –genotype calling, genotype–haplotype calling and direct estimation without calling genotypes. We findthat relying on genotype calls provides biased estimates of population genetic statistics at low tomoderate read depth (2–8X). Genotype–haplotype calling returns more accurate estimates irrespective ofthe divergence to the reference genome, but requires moderate depth (8–20X). Direct estimation withoutcalling genotypes returns the most accurate estimates of variability and of most SFS tests investigated,including at low read depth (2–4X). Studies without species-specific reference genome should thus aimfor low read depth and avoid genotype calling whenever individual genotypes are not essential.Otherwise, aiming for moderate to high depth at the expense of number of individuals, and usinggenotype–haplotype calling, is recommended.", "metadata": {}}
+{"_id": "45218443", "title": "", "text": "Thalassemia and malaria: new insights into an old problem.The hemoglobinopathies are probably theworld's most common genetic diseases: The World Health Organization has estimated that at least 5% ofthe population are carriers for one or other of the most serious forms, the alpha- and beta-thalassemiasand the structural variant hemoglobins S, C, and E, which are found at polymorphic frequencies in manycountries. All these hemoglobinopathies are believed to provide protection against malaria, and it isthought that, in malarial regions of the world, natural selection has been responsible for elevating andmaintaining their gene frequencies, an idea first proposed 50 years ago by J.B.S. Haldane.Epidemiological studies undertaken in the 1950s on hemoglobin S in Africa provided support for the\"malaria hypothesis,\" but until recently it has proved extremely difficult to verify it for the thalassemias.The application of molecular methods has, however, provided new opportunities to address this oldquestion. Population and molecular genetic analysis of thalassemia variants, and microepidemiologicalstudies of the relationship between alpha-thalassemia and malaria in the southwest Pacific, have providedunequivocal evidence for protection. Surprisingly, some of this protection appears to derive fromenhanced susceptibility in very young thalassemic children to both Plasmodium falciparum and,especially, P. vivax, and this early exposure appears to provide the basis for better protection in later life.", "metadata": {}}
+{"_id": "45244537", "title": "", "text": "Endocrine control of spermatogenesis: Role of FSH and LH/ testosterone.Evaluation of testicular functions(production of sperm and androgens) is an important aspect of preclinical safety assessment andtesticular toxicity is comparatively far more common than ovarian toxicity. This chapter focuses (1) onthe histological sequelae of disturbed reproductive endocrinology in rat, dog and nonhuman primates and(2) provides a review of our current understanding of the roles of gonadotropins and androgens. Theresponse of the rodent testis to endocrine disturbances is clearly different from that of dog and primateswith different germ cell types and spermatogenic stages being affected initially and also that theend-stage spermatogenic involution is more pronounced in dog and primates compared to rodents.Luteinizing hormone (LH)/testosterone and follicle-stimulating hormone (FSH) are the pivotal endocrinefactors controlling testicular functions. The relative importance of either hormone is somewhat differentbetween rodents and primates. Generally, however, both LH/testosterone and FSH are necessary forquantitatively normal spermatogenesis, at least in non-seasonal species.", "metadata": {}}
+{"_id": "45276789", "title": "", "text": "Extravasation injuries on regional neonatal units.This survey of regional neonatal intensive care unitsdetermined a prevalence of 38 per 1000 neonates who sustained an extravasation injury that caused skinnecrosis. Most injuries occurred in infants of 26 weeks gestation or less, with parenteral nutrition infusedthrough intravenous cannulae. Common treatments were exposing wounds to the air, infiltration withhyaluronidase and saline, and occlusive dressings.", "metadata": {}}
+{"_id": "45287266", "title": "", "text": "Nonstructural protein 3-4A: the Swiss army knife of hepatitis C virus.Hepatitis C virus (HCV)nonstructural protein 3-4A (NS3-4A) is a complex composed of NS3 and its cofactor NS4A. It harboursserine protease as well as NTPase/RNA helicase activities and is essential for viral polyprotein processing,RNA replication and virion formation. Specific inhibitors of the NS3-4A protease significantly improvesustained virological response rates in patients with chronic hepatitis C when combined with pegylatedinterferon-α and ribavirin. The NS3-4A protease can also target selected cellular proteins, therebyblocking innate immune pathways and modulating growth factor signalling. Hence, NS3-4A is not only anessential component of the viral replication complex and prime target for antiviral intervention but also akey player in the persistence and pathogenesis of HCV. This review provides a concise update on thebiochemical and structural aspects of NS3-4A, its role in the pathogenesis of chronic hepatitis C and theclinical development of NS3-4A protease inhibitors.", "metadata": {}}
+{"_id": "45336190", "title": "", "text": "Phase 2 safety trial targeting amyloid beta production with a gamma-secretase inhibitor in Alzheimerdisease.OBJECTIVE To evaluate the safety, tolerability, and amyloid beta (Abeta) response to thegamma-secretase inhibitor LY450139 in Alzheimer disease. DESIGN Multicenter, randomized,double-blind, dose-escalation, placebo-controlled trial. SETTING Community-based clinical researchcenters. Patients Fifty-one individuals with mild to moderate Alzheimer disease were randomized toreceive placebo (n=15) or LY450139 (100 mg [n=22] or 140 mg [n=14]), with 43 completing thetreatment phase. Intervention The LY450139 groups received 60 mg/d for 2 weeks, then 100 mg/d for 6weeks, and then either 100 or 140 mg/d for 6 additional weeks. MAIN OUTCOME MEASURES Primaryoutcome measures were adverse events, plasma and cerebrospinal fluid Abeta levels, vital signs,electrocardiographic data, and laboratory safety test results. Secondary outcome measures included theAlzheimer's Disease Assessment Scale cognitive subscale and the Alzheimer's Disease Cooperative StudyActivities of Daily Living Scale. RESULTS Group differences were seen in skin and subcutaneous tissueconcerns (P=.05), including 3 possible drug rashes and 3 reports of hair color change in the treatmentgroups. There were 3 adverse event-related discontinuations, including 1 transient bowel obstruction.The plasma Abeta(40) concentration was reduced by 58.2% for the 100-mg group and 64.6% for the140-mg group (P<.001). No significant reduction was seen in cerebrospinal fluid Abeta levels. No groupdifferences were seen in cognitive or functional measures. CONCLUSIONS LY450139 was generally welltolerated at doses of up to 140 mg/d for 14 weeks, with several findings indicating the need for closeclinical monitoring in future studies. Decreases in plasma Abeta concentrations were consistent withinhibition of gamma-secretase. Trial Registration clinicaltrials.gov Identifier: NCT00244322.", "metadata": {}}
+{"_id": "45341480", "title": "", "text": "Reduction in skin grafting after the introduction of hydrofiber dressings in partial thickness burns: acomparison between a hydrofiber and silver sulphadiazine.AIM/PURPOSE The aim of this study was tocompare clinical outcome of children with scald burns treated with a hydrofiber dressing (Aquacel(®),Convatec Inc.) with the former standard of care with silver sulfadiazine (Flammazine(®); SolvayPharmaceuticals), considering surgical intervention and length of stay (LOS). METHODS A retrospectivestudy of all consecutive children from zero to four years with primary scald burns up to 10% admitted tothe Burn Centre of the Maasstad Hospital Rotterdam between January 1987 and January 2010 werereviewed. For data collection a prospective computerized database was used. For comparison the studyperiod was divided into two periods representing the period before and after the introduction of thehydrofiber dressing (HFD), respectively 1987-1999 (period 1) and 1999-2010 (period 2). RESULTS Overthe whole study period 27.3% of 502 patients treated with silver sulfadiazine (Ag-SD) underwentsurgery, while before the introduction of HFD 30.5% of 338 Ag-SD treated patients were operated upon.After the introduction of the HFD 20.7% of 164 patients treated with Ag-SD eventually underwent skingrafting, a significant difference with the 11.6% of 302 patients whose wounds were dressed with HFD(p<0.01). CONCLUSIONS Compared to silver sulfadiazine treatment a reduced number of surgicalinterventions was observed in mixed partial thickness scald burns up to 10% TBSA burned in childrenaged 0-4 years after the introduction of hydrofiber dressings. The mode of treatment with this wounddressing also limited hospital length of stay.", "metadata": {}}
+{"_id": "45364685", "title": "", "text": "Induction of the heat-shock response by carbon dioxide in Chironomus thummi.The effects of a set ofstress treatments on gene expression of Chironomus thummi salivary gland cells have been analyzed.Among the treatments assayed, only during recovery from carbon dioxide have we observed a responsesimilar to that previously described after heat-shock treatment: induction of the heat-shock puffs andsynthesis of the heat-shock polypeptides. In these conditions, puffing and transcription of telomericregions were observed, which led to the appearance of the temperature-inducible telomeric Balbiani ringT-BR-III. Other treatments failed to induce the heat-shock response, despite promoting real stressconditions to C. thummi larvae or salivary gland cells.", "metadata": {}}
+{"_id": "45401535", "title": "", "text": "Candida albicans-Staphylococcus aureus polymicrobial peritonitis modulates host innateimmunity.Despite advances in medical device fabrication and antimicrobial treatment therapies,fungal-bacterial polymicrobial peritonitis remains a serious complication for surgery patients, those onperitoneal dialysis, and the critically ill. Using a murine model of peritonitis, we have demonstrated thatmonomicrobial infection with Candida albicans or Staphylococcus aureus is nonlethal. However,coinfection with these same doses leads to a 40% mortality rate and increased microbial burden in thespleen and kidney by day 1 postinfection. Using a multiplex enzyme-linked immunosorbent assay, wehave also identified a unique subset of innate proinflammatory cytokines (interleukin-6, granulocytecolony-stimulating factor, keratinocyte chemoattractant, monocyte chemoattractant protein-1, andmacrophage inflammatory protein-1α) that are significantly increased during polymicrobial versusmonomicrobial peritonitis, leading to increased inflammatory infiltrate into the peritoneum and targetorgans. Treatment of coinfected mice with the cyclooxygenase (COX) inhibitor indomethacin reduces theinfectious burden, proinflammatory cytokine production, and inflammatory infiltrate while simultaneouslypreventing any mortality. Further experiments demonstrated that the immunomodulatory eicosanoidprostaglandin E2 (PGE2) is synergistically increased during coinfection compared to monomicrobialinfection; indomethacin treatment also decreased elevated PGE2 levels. Furthermore, addition ofexogenous PGE2 into the peritoneal cavity during infection overrode the protection provided byindomethacin and restored the increased mortality and microbial burden. Importantly, these studieshighlight the ability of fungal-bacterial coinfection to modulate innate inflammatory events withdevastating consequences to the host.", "metadata": {}}
+{"_id": "45408403", "title": "", "text": "Techniques and probes for the study of Xenopus tropicalis development.The frog Xenopus laevis hasprovided significant insights into developmental and cellular processes. However, X. laevis has anallotetraploid genome precluding its use in forward genetic analysis. Genetic analysis may be applicableto Xenopus (Silurana) tropicalis, which has a diploid genome and a shorter generation time. Here, weshow that many tools for the study of X. laevis development can be applied to X. tropicalis. By using thedevelopmental staging system of Nieuwkoop and Faber, we find that X. tropicalis embryos develop atsimilar rates to X. laevis, although they tolerate a narrower range of temperatures. We also show thatmany of the analytical reagents available for X. laevis can be effectively transferred to X. tropicalis. TheX. laevis protocol for whole-mount in situ hybridization to mRNA transcripts can be successfully applied toX. tropicalis without alteration. Additionally, X. laevis probes often work in X. tropicalis--alleviating theimmediate need to clone the X. tropicalis orthologs before initiating developmental studies. Antibodiesthat react against X. laevis proteins can effectively detect the X. tropicalis protein by using establishedimmunohistochemistry procedures. Antisense morpholino oligonucleotides (MOs) offer a new alternativeto study loss of gene activity during development. We show that MOs function in X. tropicalis. Finally, X.tropicalis offers the possibility for forward genetics and genomic analysis.", "metadata": {}}
+{"_id": "45414636", "title": "", "text": "Requirement of c-myb in T cell development and in mature T cell function.Previous reports havesuggested that the protooncogene c-myb participates in T cell development in the thymus and mature Tcell proliferation. We have generated two T cell-specific c-myb knockout mouse models, myb/LckCre andmyb/CD4Cre. We have demonstrated that c-myb is required for the development of thymocytes at theDN3 stage, for survival and proliferation of double-positive thymocytes, for differentiation ofsingle-positive CD4 and CD8 T cells, and for the proliferative responses of mature T cells. In addition, ourdata show that c-myb is directly involved in the formation of double-positive CD4+CD8+CD25+,CD4+CD25+, and CD8+CD25+ T cells, developmental processes that may imply a role for c-myb inautoimmune dysfunction.", "metadata": {}}
+{"_id": "45447613", "title": "", "text": "Effect of losartan on ambulatory short-term blood pressure variability and cardiovascular remodeling inhypertensive patients on hemodialysis.OBJECTIVE Previous studies have shown increases in ambulatoryshort-term blood pressure (BP) variability to be related to cardiovascular disease. In this study, weexamined whether an angiotensin II type 1 receptor blocker losartan would improve ambulatoryshort-term BP variability in hypertensive patients on hemodialysis. METHODS Forty hypertensive patientson hemodialysis therapy were randomly assigned to the losartan treatment group (n=20) or the controltreatment group (n=20). At baseline and 6 and 12 months after the treatment, 24-h ambulatory BPmonitoring was performed. Echocardiography and measurements of brachial-ankle pulse wave velocity(baPWV) and biochemical parameters were also performed before and after therapy. RESULTS After 6-and 12-months of treatment, nighttime short-term BP variability, assessed on the basis of the coefficientof variation of ambulatory BP, was significantly decreased in the losartan group, but remained unchangedin the control group. Compared with the control group, losartan significantly decreased left ventricularmass index (LVMI), baPWV, and the plasma levels of brain natriuretic peptide and advanced glycationend products (AGE). Furthermore, multiple regression analysis showed significant correlations betweenchanges in LVMI and changes in nighttime short-term BP variability, as well as between changes in LVMIand changes in the plasma levels of AGE. CONCLUSION These results suggest that losartan is beneficialfor the suppression of pathological cardiovascular remodeling though its inhibitory effect on ambulatoryshort-term BP variability during nighttime.", "metadata": {}}
+{"_id": "45449835", "title": "", "text": "Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiplesclerosis.Myelin-directed autoimmunity is considered to play a key role in the pathogenesis of multiplesclerosis (MS). Increased production of both pro- and anti-inflammatory cytokines is a common finding inMS. Interleukin-17 (IL-17) is a recently described cytokine produced in humans almost exclusively byactivated memory T cells, which can induce the production of proinflammatory cytokines and chemokinesfrom parenchymal cells and macrophages. In situ hybridisation with synthetic oligonucleotide probes wasadopted to detect and enumerate IL-17 mRNA expressing mononuclear cells (MNC) in blood andcerebrospinal fluid (CSF) from patients with MS and control individuals. Numbers of IL-17 mRNAexpressing blood MNC were higher in patients with MS and acute aseptic meningoencephalitis (AM)compared to healthy individuals. Higher numbers of IL-17 mRNA expressing blood MNC were detected inMS patients examined during clinical exacerbation compared to remission. Patients with MS had highernumbers of IL-17 mRNA expressing MNC in CSF compared to blood. This increase in numbers of IL-17mRNA expressing MNC in CSF was not observed in patients with AM. Our results thus demonstrateincreased numbers of IL-17 mRNA expressing MNC in MS with higher numbers in CSF than blood, andwith the highest numbers in blood during clinical exacerbations.", "metadata": {}}
+{"_id": "45457778", "title": "", "text": "A European perspective on population studies of dementia.The change in the world's age demographicsand the predicted rise in the incidence of age-related diseases, including dementia, is a source of majorpublic health concern. Major research effort in both the United States and Europe has been targetedtoward understanding the pathogenesis and epidemiology of dementia. This article presents a generaloverview of the history of dementia research in Europe and how it compares with that in the UnitedStates. The review highlights the common issues which both U.S. and European researchers haveidentified and attempted to tackle. To maximize information gained from studies across the world, betterharmonization of methodology is needed, as informed from current research practice.", "metadata": {}}
+{"_id": "45461275", "title": "", "text": "The cost of providing comprehensive HIV treatment in PEPFAR-supported programs.BACKGROUNDPEPFAR, national governments, and other stakeholders are investing unprecedented resources to provideHIV treatment in developing countries. This study reports empirical data on costs and cost trends in alarge sample of HIV treatment sites. DESIGN In 2006-2007, we conducted cost analyses at 43PEPFAR-supported outpatient clinics providing free comprehensive HIV treatment in Botswana, Ethiopia,Nigeria, Uganda, and Vietnam. METHODS We collected data on HIV treatment costs over consecutive6-month periods starting from scale-up of dedicated HIV treatment services at each site. The studyincluded all patients receiving HIV treatment and care at study sites [62,512 antiretroviral therapy (ART)and 44,394 pre-ART patients]. Outcomes were costs per patient and total program costs, subdivided bymajor cost categories. RESULTS Median annual economic costs were US$ 202 (2009 USD) for pre-ARTpatients and US$ 880 for ART patients. Excluding antiretrovirals, per patient ART costs were US$ 298.Care for newly initiated ART patients cost 15-20% more than for established patients. Per patient costsdropped rapidly as sites matured, with per patient ART costs dropping 46.8% between first and second6-month periods after the beginning of scale-up, and an additional 29.5% the following year. PEPFARprovided 79.4% of funding for service delivery, and national governments provided 15.2%. CONCLUSIONTreatment costs vary widely between sites, and high early costs drop rapidly as sites mature. Treatmentcosts vary between countries and respond to changes in antiretroviral regimen costs and the package ofservices. Whereas cost reductions may allow near-term program growth, programs need to weigh thetrade-off between improving services for current patients and expanding coverage to new patients.", "metadata": {}}
+{"_id": "45487164", "title": "", "text": "A sperm cytoskeletal protein that signals oocyte meiotic maturation and ovulation.Caenorhabditis elegansoocytes, like those of most animals, arrest during meiotic prophase. Sperm promote the resumption ofmeiosis (maturation) and contraction of smooth muscle-like gonadal sheath cells, which are required forovulation. We show that the major sperm cytoskeletal protein (MSP) is a bipartite signal for oocytematuration and sheath contraction. MSP also functions in sperm locomotion, playing a role analogous toactin. Thus, during evolution, MSP has acquired extracellular signaling and intracellular cytoskeletalfunctions for reproduction. Proteins with MSP-like domains are found in plants, fungi, and other animals,suggesting that related signaling functions may exist in other phyla.", "metadata": {}}
+{"_id": "45548062", "title": "", "text": "Unmet need for mental health care among U.S. children: variation by ethnicity and insurancestatus.OBJECTIVE Policy discussions regarding the mental health needs of children and adolescentsemphasize a lack of use of mental health services among youth, but few national estimates are available.The authors use three national data sets and examine ethnic disparities in unmet need (defined as havinga need for mental health evaluation but not using any services in a 1-year period) to provide suchestimates. METHOD The authors conducted secondary data analyses in three nationally representativehousehold surveys fielded in 1996-1998: the National Health Interview Survey, the National Survey ofAmerican Families, and the Community Tracking Survey. They determined rates of mental health serviceuse by children and adolescents 3-17 years of age and differences by ethnicity and insurance status.Among the children defined as in need of mental health services, defined by an estimator of mentalhealth problems (selected items from the Child Behavior Checklist), they examined the association ofunmet need with ethnicity and insurance status. RESULTS In a 12-month period, 2%-3% of children 3-5years old and 6%-9% of children and adolescents 6-17 years old used mental health services. Of childrenand adolescents 6-17 years old who were defined as needing mental health services, nearly 80% did notreceive mental health care. Controlling for other factors, the authors determined that the rate of unmetneed was greater among Latino than white children and among uninsured than publicly insured children.CONCLUSIONS These findings reveal that most children who need a mental health evaluation do notreceive services and that Latinos and the uninsured have especially high rates of unmet need relative toother children. Rates of use of mental health services are extremely low among preschool children.Research clarifying the reasons for high rates of unmet need in specific groups can help inform policy andclinical programs.", "metadata": {}}
+{"_id": "45581752", "title": "", "text": "Conditional economic incentives for reducing HIV risk behaviors: integration of psychology and behavioraleconomics.OBJECTIVE This article reviews psychology and behavioral economic approaches to HIVprevention, and examines the integration and application of these approaches in conditional economicincentive (CEI) programs for reducing HIV risk behavior. METHODS We discuss the history of HIVprevention approaches, highlighting the important insights and limitations of psychological theories. Weprovide an overview of the theoretical tenets of behavioral economics that are relevant to HIV prevention,and utilize CEIs as an illustrative example of how traditional psychological theories and behavioraleconomics can be combined into new approaches for HIV prevention. RESULTS Behavioral economicinterventions can complement psychological frameworks for reducing HIV risk by introducing uniquetheoretical understandings about the conditions under which risky decisions are amenable to intervention.Findings from illustrative CEI programs show mixed but generally promising effects of economicinterventions on HIV and sexually transmitted infection (STI) prevalence, HIV testing, HIV medicationadherence, and drug use. CONCLUSIONS CEI programs can complement psychological interventions forHIV prevention and behavioral risk reduction. To maximize program effectiveness, CEI programs must bedesigned according to contextual and population-specific factors that may determine interventionapplicability and success.", "metadata": {}}
+{"_id": "45638119", "title": "", "text": "ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinicaloutcome.Application of stem cell biology to breast cancer research has been limited by the lack of simplemethods for identification and isolation of normal and malignant stem cells. Utilizing in vitro and in vivoexperimental systems, we show that normal and cancer human mammary epithelial cells with increasedaldehyde dehydrogenase activity (ALDH) have stem/progenitor properties. These cells contain thesubpopulation of normal breast epithelium with the broadest lineage differentiation potential and greatestgrowth capacity in a xenotransplant model. In breast carcinomas, high ALDH activity identifies thetumorigenic cell fraction, capable of self-renewal and of generating tumors that recapitulate theheterogeneity of the parental tumor. In a series of 577 breast carcinomas, expression of ALDH1 detectedby immunostaining correlated with poor prognosis. These findings offer an important new tool for thestudy of normal and malignant breast stem cells and facilitate the clinical application of stem cellconcepts.", "metadata": {}}
+{"_id": "45651303", "title": "", "text": "Interleukin-6 and interleukin-8 levels in serum and synovial fluid of patients withosteoarthritis.Concentrations of interleukin (IL)-6 and IL-8 in serum and synovial fluid obtained frompatients with osteoarthritis (OA) of the knee were determined by the chemiluminescence-ELISA(CL-ELISA) method, the sensitivity of which is 100-1,000 times greater than that of the conventionalELISA method. The results were compared with those obtained from patients with rheumatoid arthritis(RA) and from healthy subjects. The mean IL-6 and IL-8 levels in synovial fluid indicated higherconcentrations in RA than in OA. The IL-6 and IL-8 levels in serum were significantly higher in RA and OArelative to controls. Among OA patients in whom remarkable improvement was noted in hydrarthrosis,the synovial fluid IL-6 and IL-8 levels at the initial examination were relatively higher, and were markedlydecreased after treatment with sodium hyaluronate (NaHA). Among those in whom no improvement wasnoted in hydrarthrosis, the synovial fluid IL-6 and IL-8 levels at the time of initial examination wererelatively lower, and hydrarthrosis was not significantly improved even after treatment with NaHA. Inaddition, there was a tendency for the synovial fluid IL-6 and IL-8 levels to decrease as HA levelsincreased. Evaluation of X-ray findings revealed that the IL-6 levels in synovial fluid at the initialexamination in low-grade cases tended to be significantly higher than in high-grade cases. In low-gradecases, as determined by X-ray findings, there was a significant decrease in IL-6 levels in synovial fluidafter treatment with NaHA.", "metadata": {}}
+{"_id": "45764440", "title": "", "text": "Inhibition of SRC expression and activity inhibits tumor progression and metastasis of human pancreaticadenocarcinoma cells in an orthotopic nude mouse model.The nonreceptor protein tyrosine kinase Src isoverexpressed in 70% of pancreatic adenocarcinomas. Here, we describe the effect of molecular andpharmacological down-regulation of Src on incidence, growth, and metastasis of pancreatic tumor cells inan orthotopic model. Src expression in L3.6pl human pancreatic tumor cells was reduced by stableexpression of a plasmid encoding small interfering RNA (siRNA) to c-src. In stable siRNA clones, Srcexpression was reduced >80%, with no change in expression of the related kinases c-Yes and c-Lyn, andproliferation rates were similar in all clones. Phosphorylation of Akt and p44/42 Erk mitogen-activatedprotein kinase and production of VEGF and IL-8 in culture supernatants were also reduced (P < 0.005).On orthotopic implantation of varying cell numbers into nude mice, tumor incidence was unchanged;however, in the siRNA clones, large tumors failed to develop, and incidence of metastasis wassignificantly reduced, suggesting that c-Src activity is critical to tumor progression. To examine thispossibility further, animals bearing established wild-type tumors were treated with the Src/Abl-selectiveinhibitor BMS-354825 (dasatinib). Tumor size was decreased, and incidence of metastases wassignificantly reduced in treated mice compared with controls. These results demonstrate that Srcactivation contributes to pancreatic tumor progression in this model, offering Src as a candidate fortargeted therapy.", "metadata": {}}
+{"_id": "45770026", "title": "", "text": "Eicosapentaenoic acid is converted via ω-3 epoxygenation to the anti-inflammatory metabolite12-hydroxy-17,18-epoxyeicosatetraenoic acid.Eicosapentaenoic acid (EPA) has beneficial effects in manyinflammatory disorders. In this study, dietary EPA was converted to 17,18-epoxyeicosatetraenoic acid(17,18-EpETE) by ω-3 epoxygenation in the mouse peritoneal cavity. Mediator lipidomics revealed aseries of novel oxygenated metabolites of 17,18-EpETE, and one of the major metabolites,12-hydroxy-17,18-epoxyeicosatetraenoic acid (12-OH-17,18-EpETE), displayed a potentanti-inflammatory action by limiting neutrophil infiltration in murine zymosan-induced peritonitis.12-OH-17,18-EpETE inhibited leukotriene B4-induced neutrophil chemotaxis and polarization in vitro in alow nanomolar range (EC50 0.6 nM). The complete structures of two natural isomers were assigned as12S-OH-17R,18S-EpETE and 12S-OH-17S,18R-EpETE, using chemically synthesized stereoisomers.These natural isomers displayed potent anti-inflammatory action, whereas the unnatural stereoisomerswere essentially devoid of activity. These results demonstrate that 17,18-EpETE derived from dietary EPAis converted to a potent bioactive metabolite 12-OH-17,18-EpETE, which may generate an endogenousanti-inflammatory metabolic pathway.", "metadata": {}}
+{"_id": "45820464", "title": "", "text": "Scrapie in mice. Agent-strain differences in the distribution and intensity of grey matter vacuolation.Fivestrains of scrapie agent were used as intracerebral inocula for 2 inbred mouse strains, C57BL and VM,and their F1 cross. The degree of vacuolation in specified regions of the brain, and the relativedistribution of this damage in 9 regions represented as a “lesion profile”, was different for each agent.Any of the 5 scrapie agents could be distinguished from the others with a very high degree of reliabilitysolely on the basis of these histological parameters, using either strain of mouse. The lesion profile wasunaffected by the dose of the agent, using doses of ME7 agent ranging over 6 orders of magnitude inC57BL mice. The genotype of mouse had a marked effect on the overall degree of vacuolation and on theshape of the lesion profile: these effects were more profound with some agents than others. In certainareas of the brain, depending upon the strain of agent used, the (C57BL × VM)F1 cross was found tohave either significantly more or significantly less vacuolation than either parental genotype. The geneticcontrol of the lesion profile was found to be too complex for more detailed analysis in these data.", "metadata": {}}
+{"_id": "45875990", "title": "", "text": "Cyclin A2 is an RNA binding protein that controls Mre11 mRNA translationCyclin A2 activates thecyclin-dependent kinases Cdk1 and Cdk2 and is expressed at elevated levels from S phase until earlymitosis. We found that mutant mice that cannot elevate cyclin A2 are chromosomally unstable andtumor-prone. Underlying the chromosomal instability is a failure to up-regulate the meiotic recombination11 (Mre11) nuclease in S phase, which leads to impaired resolution of stalled replication forks, insufficientrepair of double-stranded DNA breaks, and improper segregation of sister chromosomes. Unexpectedly,cyclin A2 controlled Mre11 abundance through a C-terminal RNA binding domain that selectively anddirectly binds Mre11 transcripts to mediate polysome loading and translation. These data reveal cyclin A2as a mechanistically diverse regulator of DNA replication combining multifaceted kinase-dependentfunctions with a kinase-independent, RNA binding–dependent role that ensures adequate repair ofcommon replication errors.", "metadata": {}}
+{"_id": "45908102", "title": "", "text": "Cluster sampling to assess immunization coverage: a review of experience with a simplified samplingmethod.The Expanded Program on Immunization (EPI) is using a simplified cluster sampling method,based on the random selection of 210 children in 30 clusters of 7 children each, to estimate immunizationcoverage levels. This article analyzes the results of this method in actual and computer simulatedsurveys. Results from 60 actual surveys conducted in 25 countries were available for analysis, for a totalof 446 sample estimations of immunization coverage. 83% of the sample results had 95% confidencelimits within + or - 10%, and none of the surveys had 95% confidence limits exceeding + or - 13%. Inaddition, 12 hypothetical population strata with immunization coverage rates ranging from 10%-99%were established for the purposes of computer simulation, and 10 hypothetical communities wereestablished by allocating to them various proportions of each of the strata. These simulated surveys alsosupported the validity of the EPI method: over 95% of the results were less than + or - 10% from theactual population mean. The precision of this method, as estimated from the results of both actual andsimulated surveys, is considered satisfactory for the requirements of the EPI. Among the actual surveys,the proportion of results whose confidence limits exceeded + or - 10% was greatest (50%) whenimmunization coverage in the sample was 45%-54%.", "metadata": {}}
+{"_id": "45920278", "title": "", "text": "Gender differences in the utilization of health care services.BACKGROUND Studies have shown thatwomen use more health care services than men. We used important independent variables, such aspatient sociodemographics and health status, to investigate gender differences in the use and costs ofthese services. METHODS New adult patients (N = 509) were randomly assigned to primary carephysicians at a university medical center. Their use of health care services and associated charges weremonitored for 1 year of care. Self-reported health status was measured using the Medical OutcomesStudy Short Form-36 (SF-36). We controlled for health status, sociodemographic information, andprimary care physician specialty in the statistical analyses. RESULTS Women had significantly lowerself-reported health status and lower mean education and income than men. Women had a significantlyhigher mean number of visits to their primary care clinic and diagnostic services than men. Mean chargesfor primary care, specialty care, emergency treatment, diagnostic services, and annual total charges wereall significantly higher for women than men; however, there were no differences for mean hospitalizationsor hospital charges. After controlling for health status, sociodemographics, and clinic assignment, womenstill had higher medical charges for all categories of charges except hospitalizations. CONCLUSIONSWomen have higher medical care service utilization and higher associated charges than men. Althoughthe appropriateness of these differences was not determined, these findings have implications for healthcare.", "metadata": {}}
+{"_id": "46112052", "title": "", "text": "Recombinant human tumor necrosis factor administered as a 24-hour intravenous infusion. A phase I andpharmacologic study.Recombinant human tumor necrosis factor (rH-TNF) is a cytokine with directantitumor properties. In a phase I trial we continuously infused rH-TNF for 24 hours. We gave a total of115 courses of therapy to 50 patients. Doses ranged from 4.5 to 645 micrograms of rH-TNF/m2.Systemic toxicity, including fever, chills, fatigue, and hypotension, increased with the dose of rH-TNFadministered. Doses greater than 454 micrograms/m2 frequently caused severe lethargy and fatigue,which precluded hospital discharge of the patient at the completion of therapy. The dose-limiting toxicitywas hypotension, and five patients treated at the two highest dose levels required dopamine treatment.Other organ-specific toxicity was modest and spontaneously resolved after 48 hours. The 24-hourinfusions of rH-TNF were associated with significant decreases in serum cholesterol and high-densitylipoprotein levels. Pharmacokinetic studies using an enzyme-linked immunosorbent assay demonstratedpeak plasma rH-TNF levels of 90-900 pg/mL. Despite continuous infusion of rH-TNF, no steady-state levelwas achieved. The recommended phase II dose for rH-TNF as a 24-hour continuous infusion is 545micrograms/m2.", "metadata": {}}
+{"_id": "46127781", "title": "", "text": "Detection and comparison of epidermal growth factor receptor mutations in cells and fluid of malignantpleural effusion in non-small cell lung cancer.Cells or cell-free fluid of malignant pleural effusion could beimportant clinical specimen for epidermal growth factor receptor (EGFR) mutation screening in advancednon-small cell lung cancer (NSCLC) patients. However, their usefulness in mutation detection has notbeen well compared. In this study we recruited 26 East Asian NSCLC patients with malignant pleuraleffusion, determined the mutation status of EGFR in both cells and matched cell-free fluid with the use ofsequencing and mutant-enriched PCR. After comparing the mutation spectrums, we found both the cellsand cell-free pleural fluid may be feasible clinical specimen for EGFR mutation detection in unresectableNSCLC given sensitive genotyping assays employed. Direct sequencing could miss a significant portion ofmutations in these heterogeneous specimens. More sensitive methods, such as mutant-enriched PCR andgene scan, could provide more reliable mutational information.", "metadata": {}}
+{"_id": "46135768", "title": "", "text": "Materials and Methods Figs. S1 to S15 References Supporting Online MaterialsEndosomal Toll-likereceptors (TLRs) 7 and 9 recognize viral pathogens and induce signals leading to the activation of nuclearfactor κB (NF-κB)-dependent proinflammatory cytokines and interferon regulatory factor 7(IRF7)-dependent type I interferons (IFNs). Recognition of viral nucleic acids by TLR9 requires itscleavage in the endolysosomal compartment. Here, we show that TLR9 signals leading to the activation oftype I IFN, but not proinflammatory cytokine genes, require TLR9 trafficking from endosomes to aspecialized lysosome-related organelle. Furthermore, we identify adapter protein-3 as the proteincomplex responsible for the trafficking of TLR9 to this subcellular compartment. Our results reveal anintracellular mechanism for bifurcation of TLR9 signals by selective receptor trafficking within theendosomal system.", "metadata": {}}
+{"_id": "46153874", "title": "", "text": "Sedimentation velocity method in the analytical ultracentrifuge for the study of protein-proteininteractions.Sedimentation analysis in the analytical ultracentrifuge can be employed to detectmacromolecular interactions. Whenever two molecules interact the mass of the resulting complex isincreased and this is reflected in the sedimentation behavior. In this chapter we discuss how thisphenomenon can be utilized to determine quantitative parameters of an interaction. An example,interaction of single-stranded DNA binding protein with a subunit of DNA polymerase III holoenzyme isgiven together with a thorough treatment of the relating theory and a description of evaluationalgorithms.", "metadata": {}}
+{"_id": "46182525", "title": "", "text": "Structural trends in the aging femoral neck and proximal shaft: analysis of the Third National Health andNutrition Examination Survey dual-energy X-ray absorptiometry data.Hip scans of U.S. adults aged 20-99years acquired in the Third National Health and Nutrition Examination Survey (NHANES III) usingdual-energy X-ray absorptiometry (DXA) were analyzed with a structural analysis program. The programanalyzes narrow (3 mm wide) regions at specific locations across the proximal femur to measure bonemineral density (BMD) as well as cross-sectional areas (CSAs), cross-sectional moments of inertia(CSMI), section moduli, subperiosteal widths, and estimated mean cortical thickness. Measurements arereported here on a non-Hispanic white subgroup of 2,719 men and 2,904 women for a cortical regionacross the proximal shaft 2 cm distal to the lesser trochanter and a mixed cortical/trabecular regionacross the narrowest point of the femoral neck. Apparent age trends in BMD and section modulus werestudied for both regions by sex after correction for body weight. The BMD decline with age in the narrowneck was similar to that seen in the Hologic neck region; BMD in the shaft also declined, although at aslower rate. A different pattern was seen for section modulus; furthermore, this pattern depended on sex.Specifically, the section modulus at both the narrow neck and the shaft regions remains nearly constantuntil the fifth decade in females and then declined at a slower rate than BMD. In males, the narrow necksection modulus declined modestly until the fifth decade and then remained nearly constant whereas theshaft section modulus was static until the fifth decade and then increased steadily. The apparentmechanism for the discord between BMD and section modulus is a linear expansion in subperiostealdiameter in both sexes and in both regions, which tends to mechanically offset net loss of medullary bonemass. These results suggest that aging loss of bone mass in the hip does not necessarily mean reducedmechanical strength. Femoral neck section moduli in the elderly are on the average within 14% of youngvalues in females and within 6% in males.", "metadata": {}}
+{"_id": "46193388", "title": "", "text": "Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow.Bonemarrow stem cells give rise to a variety of hematopoietic lineages and repopulate the blood throughoutadult life. We show that, in a strain of mice incapable of developing cells of the myeloid and lymphoidlineages, transplanted adult bone marrow cells migrated into the brain and differentiated into cells thatexpressed neuron-specific antigens. These findings raise the possibility that bone marrow-derived cellsmay provide an alternative source of neurons in patients with neurodegenerative diseases or centralnervous system injury.", "metadata": {}}
+{"_id": "46193478", "title": "", "text": "A negative staining method for high resolution electron microscopy of viruses.Abstract A simple techniquehas been developed for the study of the external form and structure of virus particles. High contrast withgood preservation is obtained by mixing virus preparations with 1% phosphotungstic acid adjusted to pH7.5 and spraying directly onto electron microscope supporting films made from evaporated carbon. Theapplication of the technique to tobacco mosaic virus and turnip yellow mosaic virus is described.Structural details suggested by X-ray diffraction methods have been resolved.", "metadata": {}}
+{"_id": "46202852", "title": "", "text": "Nef induces multiple genes involved in cholesterol synthesis and uptake in human immunodeficiency virustype 1-infected T cells.Several recent reports indicate that cholesterol might play an important role inhuman immunodeficiency virus type 1 (HIV-1) replication. We investigated the effects of HIV-1 infectionon cholesterol biosynthesis and uptake using microarrays. HIV-1 increased gene expression of cholesterolgenes in both transformed T-cell lines and primary CD4(+) T cells. Consistent with our microarray data,(14)C-labeled mevalonate and acetate incorporation was increased in HIV-1-infected cells. Our data alsodemonstrate that changes in cholesterol biosynthesis and uptake are only observed in the presence offunctional Nef, suggesting that increased cholesterol synthesis may contribute to Nef-mediatedenhancement of virion infectivity and viral replication.", "metadata": {}}
+{"_id": "46248894", "title": "", "text": "Long noncoding RNA as modular scaffold of histone modification complexesLong intergenic noncodingRNAs (lincRNAs) regulate chromatin states and epigenetic inheritance. Here, we show that the lincRNAHOTAIR serves as a scaffold for at least two distinct histone modification complexes. A 5' domain ofHOTAIR binds polycomb repressive complex 2 (PRC2), whereas a 3' domain of HOTAIR binds theLSD1/CoREST/REST complex. The ability to tether two distinct complexes enables RNA-mediatedassembly of PRC2 and LSD1 and coordinates targeting of PRC2 and LSD1 to chromatin for coupledhistone H3 lysine 27 methylation and lysine 4 demethylation. Our results suggest that lincRNAs mayserve as scaffolds by providing binding surfaces to assemble select histone modification enzymes,thereby specifying the pattern of histone modifications on target genes.", "metadata": {}}
+{"_id": "46266579", "title": "", "text": "Therapeutic Clearance of Amyloid by Antibodies to Serum Amyloid P Component.BACKGROUND Theamyloid fibril deposits that cause systemic amyloidosis always contain the nonfibrillar normal plasmaprotein, serum amyloid P component (SAP). The drug(R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC) efficientlydepletes SAP from the plasma but leaves some SAP in amyloid deposits that can be specifically targetedby therapeutic IgG anti-SAP antibodies. In murine amyloid A type amyloidosis, the binding of theseantibodies to the residual SAP in amyloid deposits activates complement and triggers the rapid clearanceof amyloid by macrophage-derived multinucleated giant cells. METHODS We conducted an open-label,single-dose-escalation, phase 1 trial involving 15 patients with systemic amyloidosis. After first usingCPHPC to deplete circulating SAP, we infused a fully humanized monoclonal IgG1 anti-SAP antibody.Patients with clinical evidence of cardiac involvement were not included for safety reasons. Organfunction, inflammatory markers, and amyloid load were monitored. RESULTS There were no seriousadverse events. Infusion reactions occurred in some of the initial recipients of larger doses of antibody;reactions were reduced by slowing the infusion rate for later patients. At 6 weeks, patients who hadreceived a sufficient dose of antibody in relation to their amyloid load had decreased liver stiffness, asmeasured with the use of transient elastography. These patients also had improvements in liver functionin association with a substantial reduction in hepatic amyloid load, as shown by means of SAPscintigraphy and measurement of extracellular volume by magnetic resonance imaging. A reduction inkidney amyloid load and shrinkage of an amyloid-laden lymph node were also observed. CONCLUSIONSTreatment with CPHPC followed by an anti-SAP antibody safely triggered clearance of amyloid depositsfrom the liver and some other tissues. (Funded by GlaxoSmithKline; ClinicalTrials.gov number,NCT01777243.).", "metadata": {}}
+{"_id": "46277811", "title": "", "text": "LPA Gene, Ethnicity, and Cardiovascular EventsBackground: The relationship of LPA single nucleotidepolymorphisms (SNPs), apolipoprotein(a) isoforms, and lipoprotein(a) [Lp(a)] levels with major adversecardiovascular events (MACE) in different ethnic groups is not well known. Methods: LPA SNPs,apolipoprotein(a) isoforms, Lp(a), and oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB) levelswere measured in 1792 black, 1030 white, and 597 Hispanic subjects enrolled in the Dallas Heart Study.Their interdependent relationships and prospective association with MACE after median 9.5-yearfollow-up were determined. Results: LPA SNP rs3798220 was most prevalent in Hispanics (42.38%),rs10455872 in whites (14.27%), and rs9457951 in blacks (32.92%). The correlation of each of theseSNPs with the major apolipoprotein(a) isoform size was highly variable and in different directions amongethnic groups. In the entire cohort, Cox regression analysis with multivariable adjustment revealed thatquartiles 4 of Lp(a) and OxPL-apoB were associated with hazard ratios (95% confidence interval) for timeto MACE of 2.35 (1.50–3.69, P<0.001) and 1.89 (1.26–2.84, P=0.003), respectively, versus quartile 1.Addition of the major apolipoprotein(a) isoform and the 3 LPA SNPs to these models attenuated the risk,but significance was maintained for both Lp(a) and OxPL-apoB. Evaluating time to MACE in specific ethnicgroups, Lp(a) was a positive predictor and the size of the major apolipoprotein(a) isoform was an inversepredictor in blacks, the size of the major apolipoprotein(a) isoform was an inverse predictor in whites,and OxPL-apoB was a positive predictor in Hispanics. Conclusions: The prevalence and association of LPASNPs with size of apolipoprotein(a) isoforms, Lp(a), and OxPL-apoB levels are highly variable andethnicity-specific. The relationship to MACE is best explained by elevated plasma Lp(a) or OxPL-apoBlevels, despite significant ethnic differences in LPA genetic markers.", "metadata": {}}
+{"_id": "46305977", "title": "", "text": "Protein kinase CK2 modulates developmental functions of the abscisic acid responsive protein Rab17 frommaize.The maize abscisic acid responsive protein Rab17 is a highly phosphorylated late embryogenesisabundant protein involved in plant responses to stress. In this study, we provide evidence of theimportance of Rab17 phosphorylation by protein kinase CK2 in growth-related processes under stressconditions. We show the specific interaction of Rab17 with the CK2 regulatory subunits CK2 beta-1 andCK2 beta-3, and that these interactions do not depend on the phosphorylation state of Rab17. Live-cellfluorescence imaging of both CK2 and Rab17 indicates that the intracellular dynamics of Rab17 areregulated by CK2 phosphorylation. We found both CK2 beta subunits and Rab17 distributed over thecytoplasm and nucleus. By contrast, catalytic CK2 alpha subunits and a Rab17 mutant protein (mRab17)that is not a substrate for CK2 phosphorylation remain accumulated in the nucleoli. A dual-color imageshows that the CK2 holoenzyme accumulates mainly in the nucleus. The importance of Rab17phosphorylation in vivo was assessed in transgenic plants. The overexpression of Rab17, but notmRab17, arrests the process of seed germination under osmotic stress conditions. Thus, the role ofRab17 in growth processes is mediated through its phosphorylation by protein kinase CK2.", "metadata": {}}
+{"_id": "46328296", "title": "", "text": "Reduced plasma concentrations of nitrogen oxide in individuals with essential hypertension.Patients withessential hypertension exhibit blunted endothelium-dependent vasodilator responses, which may belargely attributable to reduced bioactivity of nitric oxide (NO). Therefore, we measured the end product ofNO, nitrate plus nitrite (nitrogen oxide), and examined the relationship between the degree ofhypertension and plasma nitrate plus nitrite levels in patients with essential hypertension. The combinedplasma concentration of nitrate plus nitrite, end products of NO metabolism, was reduced in individualswith essential hypertension relative to that in control subjects (15.7+/-1.1 versus 22.8+/-1.4 mmol xL(-1), P<.001); individuals with borderline hypertension showed values that were intermediate betweenthose of the other two groups (18.2+/-1.2 mmol x L(-1), P<.001). The plasma nitrogen oxideconcentration showed significant inverse correlations with both systolic and diastolic blood pressures. Thebasal concentration of nitrogen oxide in the plasma was reduced, at least in the peripheral circulation, inindividuals with essential hypertension.", "metadata": {}}
+{"_id": "46346525", "title": "", "text": "Isolation of superoxide dismutase mutants in Escherichia coli: is superoxide dismutase necessary foraerobic life?Mu transposons carrying the chloramphenicol resistance marker have been inserted into thecloned Escherichia coli genes sodA and sodB coding for manganese superoxide dismutase (MnSOD) andiron superoxide dismutase (FeSOD) respectively, creating mutations and gene fusions. The mutated sodAor sodB genes were introduced into the bacterial chromosome by allelic exchange. The resulting mutantswere shown to lack the corresponding SOD by activity measurements and immunoblot analysis.Aerobically, in rich medium, the absence of FeSOD or MnSOD had no major effect on growth or sensitivityto the superoxide generator, paraquat. In minimal medium aerobic growth was not affected, but thesensitivity to paraquat was increased, especially in the sodA mutant. A sodA sodB double mutantcompletely devoid of SOD was also obtained. It was able to grow aerobically in rich medium, its catalaselevel was unaffected and it was highly sensitive to paraquat and hydrogen peroxide; the double mutantwas unable to grow aerobically on minimal glucose medium. Growth could be restored by removingoxygen, by providing an SOD-overproducing plasmid or by supplementing the medium with the 20 aminoacids. It is concluded that the total absence of SOD in E. coli creates a conditional sensitivity to oxygen.", "metadata": {}}
+{"_id": "46353045", "title": "", "text": "Late presentation of HIV-infected individuals.Late presentation remains a major concern despite thedramatically improved prognosis realized by ART. We define a first presentation for HIV care during thecourse of HIV infection as 'late' if an AIDS-defining opportunistic disease is apparent, or if CD4+ T-cellsare <200/microl. In the Western world, approximately 10 and 30% of HIV-infected individuals stillpresent with CD4+ T-cells <50 and <200/microl, respectively; estimates are substantially higher fordeveloping countries. Diagnosis and treatment of opportunistic diseases and intense supportivein-hospital care take precedence over ART. Benefits of starting ART without delay, that is, whenopportunistic diseases are still active, include faster resolution of opportunistic diseases and a decreasedrisk of recurrence. The downside of starting ART without delay could include toxicity, drug interactionsand immune reconstitution inflammatory syndrome (IRIS). Among asymptomatic or oligosymptomaticindividuals presenting late, where ART and primary prophylaxis are initiated, approximately 10-20% willbecome symptomatic from drug toxicity or undiagnosed opportunistic complications, including IRIS,which require appropriate therapies. In this review we describe late presentation to HIV care, the scale ofthe problem, the evaluation of a late-presenting patient and challenges associated with initiation ofpotent antiretroviral therapy (ART) in the setting of acute opportunistic infections and othercomorbidities.", "metadata": {}}
+{"_id": "46355579", "title": "", "text": "Rapid clearance of human papillomavirus and implications for clinical focus on persistent infections.Healthprofessionals and the public need to understand the natural history of human papillomavirus (HPV)infections of the cervix to best use the information provided by new molecular screening tests. Weinvestigated outcomes of 800 carcinogenic HPV infections detected in 599 women at enrollment into apopulation-based cohort (Guanacaste, Costa Rica). For individual infections, we calculated cumulativeproportions of three outcomes (viral clearance, persistence without cervical intraepithelial neoplasiagrade 2 or worse [CIN2+], or persistence with new diagnosis of CIN2+) at successive 6-month timepoints for the first 30 months of follow-up. Cervical specimens were tested for carcinogenic HPVgenotypes using an L1 degenerate-primer polymerase chain reaction method. Infections typically clearedrapidly, with 67% (95% confidence interval [CI] = 63% to 70%) clearing by 12 months. However, amonginfections that persisted at least 12 months, the risk of CIN2+ diagnosis by 30 months was 21% (95% CI= 15% to 28%). The risk of CIN2+ diagnosis was highest among women younger than 30 years withHPV-16 infections that persisted for at least 12 months (53%; 95% CI = 29% to 76%). These findingssuggest that the medical community should emphasize persistence of cervical HPV infection, notsingle-time detection of HPV, in management strategies and health messages.", "metadata": {}}
+{"_id": "46437558", "title": "", "text": "The role of alcohol in the Russian mortality crisis.AIMS Alcohol is believed to be an important factorbehind the sharp rise in mortality during the period 1990-94 in Russia. However, the rise in the standardalcohol consumption proxy does not seem to be sufficient to explain all the increase in mortality. Thisstudy adopts a novel approach to exploring the role of the alcohol factor in the increased mortality byinvestigating whether the mismatch between trends in mortality and recorded alcohol consumption is dueto an underestimation of the consumption increase. DESIGN AND MEASUREMENTS First, the alcoholeffect on the male accident rate was estimated using data for the period 1959-89. Next, the estimatedalcohol effect and the observed accident mortality rate for the period 1990-98 were used to backcastalcohol consumption during that period. Thirdly, the backcasted alcohol series was used to predicttrajectories in alcohol poisoning mortality, the homicide rate and all-cause mortality during the period1990-98. FINDINGS There was a markedly stronger increase in the backcasted consumption proxy thanin the standard alcohol consumption proxy during the period 1990-98. There was a substantial gapbetween the observed mortality rates and the rates predicted from the standard alcohol consumptionproxy, whereas the predictions from the backcasted alcohol proxy were much closer to the target.CONCLUSIONS Much of the rise in Russian mortality in 1990-94 appears to have been due to the increasein population drinking, but this increase is grossly underestimated by the commonly used consumptionproxy combining alcohol sales, estimation of illicit alcohol production and proportion of alcohol-positiveviolent deaths.", "metadata": {}}
+{"_id": "46451940", "title": "", "text": "The lateral hypothalamus: a primary site mediating excitatory amino acid-elicited eating.Lateralhypothalamic (LH) injections of the excitatory neurotransmitter glutamate, or its excitatory amino acid(EAA) agonists, kainic acid (KA), D,L-alpha-amino-3-hydroxy-5-methyl-isoxazole propionic acid (AMPA),or N-methyl-D-aspartic acid (NMDA), can rapidly elicit an intense feeding response in satiated rats. Todetermine whether the LH is the actual locus of this effect, we compared these compounds' ability tostimulate feeding when injected into the LH, versus when injected into sites bracketing this region. Foodintake in groups of adult male rats was measured 1 h after injection of glutamate (30-900 nmol), KA(0.1-1.0 nmol), AMPA (0.33-3.3 nmol), NMDA (0.33-33.3 nmol) or vehicle, through chronically implantedguide cannulas, into one of seven brain sites. These sites were: the LH, the anterior and posterior tips ofthe LH, the thalamus immediately dorsal to the LH, the amygdala just lateral to the LH, or theparaventricular and perifornical areas medial to the LH. The results show that across doses and agoniststhe eating-stimulatory effects were largest with injections into the LH. In the LH, glutamate between 300and 900 nmol elicited a dose-dependent eating response of up to 5 g within 1 h (P < 0.01). Each of theother agonists at doses of 3.3 nmol or less elicited eating responses of at least 10 g with injections intothis site. Injections into the other brain sites produced either no eating, or occasionally smaller and lessconsistent eating responses.(ABSTRACT TRUNCATED AT 250 WORDS)", "metadata": {}}
+{"_id": "46478393", "title": "", "text": "A Gateway® compatible vector for gene silencing in bloodstream form Trypanosoma brucei.RNAinterference is the most rapid method for generation of conditional knockdown mutants in Trypanosomabrucei. The dual T7 promoter (pZJM) and the stem-loop vectors have been widely used to generate stableinducible RNAi cell lines with the latter providing tighter regulatory control. However, the steps for cloningstem-loop constructs are cumbersome requiring either multiple cloning steps or multi-fragment ligationreactions. We report the development of a vector (pTrypRNAiGate) derived from pLEW100 that utilizesthe Gateway® recombination system to facilitate easy production of hairpin RNA constructs. Thisapproach allows the final stem-loop RNAi construct to be generated from a single cloning step of thePCR-derived gene fragment followed by an in vitro recombination reaction. The new vector facilitateshigh-throughput applications for gene silencing and provides a tool for functional genomics in T. brucei.", "metadata": {}}
+{"_id": "46485368", "title": "", "text": "Prolonged effect of calcium supplementation on risk of colorectal adenomas in a randomizedtrial.BACKGROUND Calcium supplementation has been shown to decrease the risk of recurrence ofcolorectal adenomas in randomized trials. However, the duration of this protective effect after cessationof active supplementation is not known. METHODS In the Calcium Polyp Prevention Study, 930 subjectswith a previous colorectal adenoma were randomly assigned from November 1988 through April 1992 toreceive placebo or 1200 mg of elemental calcium daily for 4 years. The Calcium Follow-up Study was anobservational phase of the trial that tracked adenoma occurrence for an average of 7 years after the endof randomized treatment and gathered information regarding the use of medications, vitamins, andsupplements during that time. We obtained follow-up information for 822 subjects, 597 of whomunderwent at least one colonoscopy after the end of study treatment and are included in this analysis.Generalized linear models were used to compute relative risks (RRs) and 95% confidence intervals (CIs)for the effect of randomized calcium treatment on risk of adenoma recurrence during the first 5 yearsafter study treatment ended and during the subsequent 5 years. Statistical tests were two-sided.RESULTS During the first 5 years after randomized treatment ended, subjects in the calcium group stillhad a substantially and statistically significantly lower risk of any adenoma than those in the placebogroup (31.5% versus 43.2%; adjusted RR = 0.63, 95% CI = 0.46 to 0.87, P = .005) and a smaller andnot statistically significant reduction in risk of advanced adenomas (adjusted RR = 0.85, 95% CI = 0.43to 1.69, P = .65). However, the randomized treatment was not associated with the risk of any type ofpolyp during the next 5 years. The findings were broadly similar when the analysis was restricted tosubjects who did not report use of any calcium supplements after the treatment phase of the trial ended.CONCLUSION The protective effect of calcium supplementation on risk of colorectal adenoma recurrenceextends up to 5 years after cessation of active treatment, even in the absence of continuedsupplementation.", "metadata": {}}
+{"_id": "46517055", "title": "", "text": "Influence of DNA on the activities and inhibition of neutrophil serine proteases in cystic fibrosissputum.Uncontrolled proteolysis by neutrophil serine proteases (NSPs) in lung secretions is a hallmark ofcystic fibrosis (CF). We have shown that the active neutrophil elastase, protease 3, and cathepsin G in CFsputum resist inhibition in part by exogenous protease inhibitors. This resistance may be due to theirbinding to neutrophil extracellular traps (NETs) secreted by the activated neutrophils in CF sputum and togenomic DNA released from senescent and dead neutrophils. Treating CF sputum with DNasedramatically increases its elastase activity, which can then be stoichiometrically inhibited by exogenouselastase inhibitors. However, DNase treatment does not increase the activities of protease 3 andcathepsin G, indicating their different distribution and/or binding in CF sputum. Purified blood neutrophilssecrete NETs when stimulated by the opportunistic CF bacteria Pseudomonas aeruginosa andStaphylococcus aureus. The activities of the three proteases were unchanged in these conditions, butsubsequent DNase treatment produced a dramatic increase in all three proteolytic activities. Neutrophilsactivated with a calcium ionophore did not secrete NETs but released huge amounts of active proteaseswhose activities were not modified by DNase. We conclude that NETs are reservoirs of active proteasesthat protect them from inhibition and maintain them in a rapidly mobilizable status. Combining the effectsof protease inhibitors with that of DNA-degrading agents could counter the deleterious proteolytic effectsof NSPs in CF lung secretions.", "metadata": {}}
+{"_id": "46565020", "title": "", "text": "Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial.BACKGROUNDAN1792 (beta-amyloid [Abeta]1-42) immunization reduces Abeta plaque burden and preserves cognitivefunction in APP transgenic mice. The authors report the results of a phase IIa immunotherapy trial ofAN1792(QS-21) in patients with mild to moderate Alzheimer disease (AD) that was interrupted becauseof meningoencephalitis in 6% of immunized patients. METHODS This randomized, multicenter,placebo-controlled, double-blind trial of IM AN1792 225 microg plus the adjuvant QS-21 50 microg (300patients) and saline (72 patients) included patients aged 50 to 85 years with probable AD, Mini-MentalState Examination (MMSE) 15 to 26. Injections were planned for months 0, 1, 3, 6, 9, and 12. Safety andtolerability were evaluated, and pilot efficacy (AD Assessment Scale-Cognitive Subscale [ADAS-Cog],MRI, neuropsychological test battery [NTB], CSF tau, and Abeta42) was assessed in anti-AN1792antibody responder patients (immunoglobulin G titer > or = 1:2,200). RESULTS Following reports ofmeningoencephalitis (overall 18/300 [6%]), immunization was stopped after one (2 patients), two (274patients), or three (24 patients) injections. Of the 300 AN1792(QS-21)-treated patients, 59 (19.7%)developed the predetermined antibody response. Double-blind assessments were maintained for 12months. No significant differences were found between antibody responder and placebo groups forADAS-Cog, Disability Assessment for Dementia, Clinical Dementia Rating, MMSE, or Clinical GlobalImpression of Change, but analyses of the z-score composite across the NTB revealed differencesfavoring antibody responders (0.03 +/- 0.37 vs -0.20 +/- 0.45; p = 0.020). In the small subset ofsubjects who had CSF examinations, CSF tau was decreased in antibody responders (n = 11) vs placebosubjects (n = 10; p < 0.001). CONCLUSION Although interrupted, this trial provides an indication thatAbeta immunotherapy may be useful in Alzheimer disease.", "metadata": {}}
+{"_id": "46565968", "title": "", "text": "Quantitative characterization of metastatic disease in the spine. Part I. Semiautomated segmentationusing atlas-based deformable registration and the level set method.Quantitative assessment ofmetastatic disease in bone is often considered immeasurable and, as such, patients with skeletalmetastases are often excluded from clinical trials. In order to effectively quantify the impact of metastatictumor involvement in the spine, accurate segmentation of the vertebra is required. Manual segmentationcan be accurate but involves extensive and time-consuming user interaction. Potential solutions toautomating segmentation of metastatically involved vertebrae are demons deformable image registrationand level set methods. The purpose of this study was to develop a semiautomated method to accuratelysegment tumor-bearing vertebrae using the aforementioned techniques. By maintaining morphology ofan atlas, the demons-level set composite algorithm was able to accurately differentiate betweentrans-cortical tumors and surrounding soft tissue of identical intensity. The algorithm successfullysegmented both the vertebral body and trabecular centrum of tumor-involved and healthy vertebrae.This work validates our approach as equivalent in accuracy to an experienced user.", "metadata": {}}
+{"_id": "46594244", "title": "", "text": "Activation of lysosomal function during dendritic cell maturation.In response to a variety of stimuli,dendritic cells (DCs) transform from immature cells specialized for antigen capture into mature cellsspecialized for T cell stimulation. During maturation, the DCs acquire an enhanced capacity to form andaccumulate peptide-MHC (major histocompatibility complex) class II complexes. Here we show that a keymechanism responsible for this alteration was the generalized activation of lysosomal function. Inimmature DCs, internalized antigens were slowly degraded and inefficiently used for peptide loading.Maturation induced activation of the vacuolar proton pump that enhanced lysosomal acidification andantigen proteolysis, facilitating efficient formation of peptide-MHC class II complexes. Lysosomal functionin DCs thus appears to be specialized for the developmentally regulated processing of internalizedantigens.", "metadata": {}}
+{"_id": "46602807", "title": "", "text": "Comparison of agar dilution, microdilution, and disk elution methods for measuring the synergy ofcefotaxime and its metabolite against anaerobes.The activities of cefotaxime (CTX) and desacetylcefotaxime (des-CTX) were tested both singly and in combination against 173 anaerobic clinical isolates.The MIC of CTX for 50% of 60 Bacteroides fragilis isolates was 22.4 micrograms/ml in broth, comparedwith 47.4 micrograms/ml in agar. This reduced efficacy in agar was seen with all species tested and is inapparent conflict with reported clinical efficacy of the drug. Synergy between CTX and des-CTX wasobserved with 70 to 100% of the isolates, including 60% of all Bacteroides spp. tested. The susceptibilityresults in a synergy system correlated well with those noted in a broth-disk elution method incorporating32 micrograms of CTX and 8 micrograms of des-CTX per ml. The correlation was poorer when thebroth-disk method contained 16 micrograms of CTX and 8 micrograms of des-CTX per ml.", "metadata": {}}
+{"_id": "46617075", "title": "", "text": "Retinoblastoma regulatory pathway in lung cancer.Lung cancer is the leading cause of cancer relateddeaths accounting for more deaths than breast, colon and prostate cancers combined. The Rb-p16regulatory pathway plays an essential role in tumor suppression in the lung epithelium. This is evidencedby the nearly universal alterations in Rb-p16 pathway components in lung cancer, and the increasedincidence of pulmonary carcinomas in persons with germline Rb mutations. Interestingly, p16 loss and Rbmutations preferentially occur in phenotypically distinct lung cancer subtypes. Analysis of human tumorshas identified progressive preneoplastic lesions that accumulate molecular alterations in an orderlysequence. Epigenetic p16 gene modifications represent an early event in lung cancer progression. Thisreview summarizes the human studies that demonstrate a critical role for the Rb-p16 tumor suppressorpathway in lung carcinogenesis, and discusses how these findings in combination with geneticallyengineered mouse models have significantly contributed to our understanding of lung cancerpathogenesis.", "metadata": {}}
+{"_id": "46695481", "title": "", "text": "Human papillomavirus and Papanicolaou tests to screen for cervical cancer.BACKGROUND Screening forcervical cancer based on testing for human papillomavirus (HPV) increases the sensitivity of detection ofhigh-grade (grade 2 or 3) cervical intraepithelial neoplasia, but whether this gain representsoverdiagnosis or protection against future high-grade cervical epithelial neoplasia or cervical cancer isunknown. METHODS In a population-based screening program in Sweden, 12,527 women 32 to 38 yearsof age were randomly assigned at a 1:1 ratio to have an HPV test plus a Papanicolaou (Pap) test(intervention group) or a Pap test alone (control group). Women with a positive HPV test and a normalPap test result were offered a second HPV test at least 1 year later, and those who were found to bepersistently infected with the same high-risk type of HPV were then offered colposcopy with cervicalbiopsy. A similar number of double-blinded Pap smears and colposcopies with biopsy were performed inrandomly selected women in the control group. Comprehensive registry data were used to follow thewomen for a mean of 4.1 years. The relative rates of grade 2 or 3 cervical intraepithelial neoplasia orcancer detected at enrollment and at subsequent screening examinations were calculated. RESULTS Atenrollment, the proportion of women in the intervention group who were found to have lesions of grade 2or 3 cervical intraepithelial neoplasia or cancer was 51% greater (95% confidence interval [CI], 13 to102) than the proportion of women in the control group who were found to have such lesions. Atsubsequent screening examinations, the proportion of women in the intervention group who were foundto have grade 2 or 3 lesions or cancer was 42% less (95% CI, 4 to 64) and the proportion with grade 3lesions or cancer was 47% less (95% CI, 2 to 71) than the proportions of control women who were foundto have such lesions. Women with persistent HPV infection remained at high risk for grade 2 or 3 lesionsor cancer after referral for colposcopy. CONCLUSIONS The addition of an HPV test to the Pap test toscreen women in their mid-30s for cervical cancer reduces the incidence of grade 2 or 3 cervicalintraepithelial neoplasia or cancer detected by subsequent screening examinations. (ClinicalTrials.govnumber, NCT00479375 [ClinicalTrials.gov].).", "metadata": {}}
+{"_id": "46743299", "title": "", "text": "Chronic Exercise Increases Both Inducible and Endothelial Nitric Oxide Synthase Gene Expression inEndothelial Cells of Rat AortaChronic exercise upregulates endothelial nitric oxide synthase (eNOS) geneexpression. Whether the expression of inducible nitric oxide synthase (iNOS) is affected by exercise isunknown. We therefore investigated the effects of chronic exercise on iNOS and eNOS expression inisolated rat aortic endothelial and smooth muscle cells separately. Five-week-old male Wistar rats wererandomly divided into control and exercise groups. After 10 weeks of running training, animals weresacrificed under ether anesthesia. The standard curve quantitative competitive reversetranscriptase-polymerase chain reaction method was used to quantify NOS mRNA expression in isolatedendothelial/smooth muscle cells. To evaluate the functional role of iNOS, we examinedphenylephrine-induced vascular responses with or without pretreatment with aminoguanidine. We foundthat (1) expression of iNOS and eNOS mRNA in endothelial cells was increased by chronic exercise and(2) chronic exercise blunted phenylephrine-induced vascular responses, probably by increasing NOrelease via iNOS. Our results show that chronic exercise increases both iNOS and eNOS gene expressionin endothelium. These alterations may be partially responsible for the change in vascular response afterexercise.", "metadata": {}}
+{"_id": "46764350", "title": "", "text": "Frontal stroke syndromes.The frontal lobe is the largest lobe of the brain, and it is thus commonlyinvolved in stroke. Moreover, almost one in five strokes is limited to the prerolandic areas. This highfrequency of anatomical involvement is in sharp contrast with the apparent rarity of clinical frontaldysfunction in stroke. It is remarkable that frontal behavioral syndromes have been rather uncommonlyreported in patients with stroke as compared to patients with other diseases, such as brain tumor. Thisfact is paradoxical, because an acute process (stroke) is expected to yield more clinical dysfunction thana more chronic disease (tumor). A volume effect may be the main factor leading to this phenomenon.Another interesting aspect of frontal strokes is the contribution of so-called 'silent' strokes, the recurrenceof which may nevertheless lead to intellectual decline and compromise recovery from another stroke withmore specific neurologic dysfunction. The contribution of stroke to understanding of frontal lobedysfunction is important, because of the focal nature of this disease, and great opportunity forclinical-topographic classification correlations. One of the first modern attempts to develop aclinical-topographic classification of frontal lobe lesions came from the school of Luria, who tried todelineate three main types of frontal lobe syndromes (premotor syndrome, prefrontal syndrome,medial-frontal syndrome). Recent anatomic correlates using MRI make it possible to improve thisclassification. We suggest considering six main clinical-anatomic frontal stroke syndromes: (1) prefrontal;(2) premotor; (3) superior medial; (4) orbital-medial; (5) basal forebrain; (6) white matter. Finally,another fascinating topic relates to frontal lobe symptomatology due to stroke sparing the frontal cortexor white matter. This occurs mainly in three instances: lenticulo-capsular stroke, caudate stroke, andthalamic stroke. Studies using blood flow or metabolism measurements suggest that diaschisis (frontallobe dysfunction from a remote lesion) may play a role. We believe that this is more likely to be related todynamic interruption of complex circuitry than to static frontal lobe deactivation.", "metadata": {}}
+{"_id": "46765242", "title": "", "text": "Interaction of cytosine arabinoside and lovastatin in human leukemia cells.Cytosine arabinoside (ara-C) iswidely used for the treatment of leukemias and displays significant toxicities. Lovastatin, an HMG-CoAreductase inhibitor, is extensively used to treat hypercholesterolemia. To determine whether lovastatincould augment ara-C's activity we have examined their effects in the human erythroleukemia K562 cellline and the ara-C resistant ARAC8D cell line. A synergistic interaction between the two drugs was found.We have demonstrated that the interaction does not occur at the level of RAS but may involvelovastatin's effect of downregulating MAPK activity and preventing ara-C-induced MAPK activation. Thesestudies represent the first description of a potentially beneficial interaction between lovastatin and ara-Cthat could be applied to the treatment of human leukemia.", "metadata": {}}
+{"_id": "46816158", "title": "", "text": "The crystal structure of TAL effector PthXo1 bound to its DNA target.DNA recognition by TAL effectors ismediated by tandem repeats, each 33 to 35 residues in length, that specify nucleotides via uniquerepeat-variable diresidues (RVDs). The crystal structure of PthXo1 bound to its DNA target wasdetermined by high-throughput computational structure prediction and validated by heavy-atomderivatization. Each repeat forms a left-handed, two-helix bundle that presents an RVD-containing loop tothe DNA. The repeats self-associate to form a right-handed superhelix wrapped around the DNA majorgroove. The first RVD residue forms a stabilizing contact with the protein backbone, while the secondmakes a base-specific contact to the DNA sense strand. Two degenerate amino-terminal repeats alsointeract with the DNA. Containing several RVDs and noncanonical associations, the structure illustratesthe basis of TAL effector-DNA recognition.", "metadata": {}}
+{"_id": "46837626", "title": "", "text": "Prediction of creatinine clearance from serum creatinine.A formula has been developed to predictcreatinine clearance (Ccr) from serum creatinine (Scr) in adult males: (see article)(15% less in females).Derivation included the relationship found between age and 24-hour creatinine excretion/kg in 249patients aged 18-92. Values for Ccr were predicted by this formula and four other methods and theresults compared with the means of two 24-hour Ccr's measured in 236 patients. The above formula gavea correlation coefficient between predicted and mean measured Ccr's of 0.83; on average, the differencepredicted and mean measured values was no greater than that between paired clearances. Factors forage and body weight must be included for reasonable prediction.", "metadata": {}}
+{"_id": "46926352", "title": "", "text": "Dendritic cells, T cells and lymphatics: dialogues in migration and beyond.Immune cells continuouslyrecirculate through lymph vessels en route from peripheral tissues to the blood. Leuyte trafficking intoand within lymph vessels is mediated by an interply with lymphatic endothelial cells (LECs). However,lymphatic vessels are much more than mere conduits for fluid and immune cell transport. Dataaccumulating during past several years indicate that LECs support T cell survival, induce tolerance toself-antigens, inhibit exaggerated T cell proliferation during immune response and maintain T cellmemory. Reciprocally, leukocytes impact LEC biology: lymphatic vessel permeability depends on DCswhile lymphocytes regulate LEC proliferation during inflammation. Altogether, these novel results provideimportant insights on intimate connections between LECs and leukocytes that contribute to theunderstanding of immune responses.", "metadata": {}}
+{"_id": "47018050", "title": "", "text": "CRISPR–Cas9 genome editing induces a p53-mediated DNA damage responseHere, we report thatgenome editing by CRISPR–Cas9 induces a p53-mediated DNA damage response and cell cycle arrest inimmortalized human retinal pigment epithelial cells, leading to a selection against cells with a functionalp53 pathway. Inhibition of p53 prevents the damage response and increases the rate of homologousrecombination from a donor template. These results suggest that p53 inhibition may improve theefficiency of genome editing of untransformed cells and that p53 function should be monitored whendeveloping cell-based therapies utilizing CRISPR–Cas9. CRISPR–Cas9-induced DNA damage triggers p53to limit the efficiency of gene editing in immortalized human retinal pigment epithelial cells.", "metadata": {}}
+{"_id": "47240151", "title": "", "text": "Comparative Structural Analysis of Lipid Binding START DomainsBACKGROUND Steroidogenic acuteregulatory (StAR) protein related lipid transfer (START) domains are small globular modules that form acavity where lipids and lipid hormones bind. These domains can transport ligands to facilitate lipidexchange between biological membranes, and they have been postulated to modulate the activity ofother domains of the protein in response to ligand binding. More than a dozen human genes encodeSTART domains, and several of them are implicated in a disease. PRINCIPAL FINDINGS We report crystalstructures of the human STARD1, STARD5, STARD13 and STARD14 lipid transfer domains. Theserepresent four of the six functional classes of START domains. SIGNIFICANCE Sequence alignmentsbased on these and previously reported crystal structures define the structural determinants of humanSTART domains, both those related to structural framework and those involved in ligand specificity.ENHANCED VERSION This article can also be viewed as an enhanced version in which the text of thearticle is integrated with interactive 3D representations and animated transitions. Please note that a webplugin is required to access this enhanced functionality. Instructions for the installation and use of theweb plugin are available in Text S1.", "metadata": {}}
+{"_id": "49208216", "title": "", "text": "Staphylococcus aureus infection dynamicsStaphylococcus aureus is a human commensal that can alsocause systemic infections. This transition requires evasion of the immune response and the ability toexploit different niches within the host. However, the disease mechanisms and the dominant immunemediators against infection are poorly understood. Previously it has been shown that the infecting S.aureus population goes through a population bottleneck, from which very few bacteria escape to establishthe abscesses that are characteristic of many infections. Here we examine the host factors underlying thepopulation bottleneck and subsequent clonal expansion in S. aureus infection models, to identifyunderpinning principles of infection. The bottleneck is a common feature between models and isindependent of S. aureus strain. Interestingly, the high doses of S. aureus required for the widely used\"survival\" model results in a reduced population bottleneck, suggesting that host defences have beensimply overloaded. This brings into question the applicability of the survival model. Depletion of immunemediators revealed key breakpoints and the dynamics of systemic infection. Loss of macrophages,including the liver Kupffer cells, led to increased sensitivity to infection as expected but also loss of thepopulation bottleneck and the spread to other organs still occurred. Conversely, neutrophil depletion ledto greater susceptibility to disease but with a concomitant maintenance of the bottleneck and lack ofsystemic spread. We also used a novel microscopy approach to examine abscess architecture anddistribution within organs. From these observations we developed a conceptual model for S. aureusdisease from initial infection to mature abscess. This work highlights the need to understand thecomplexities of the infectious process to be able to assign functions for host and bacterial components,and why S. aureus disease requires a seemingly high infectious dose and how interventions such as avaccine may be more rationally developed.", "metadata": {}}
+{"_id": "49429882", "title": "", "text": "Strategies for optimizing maternal nutrition to promote infant developmentBACKGROUND The growingappreciation of the multi-faceted importance of optimal maternal nutrition to the health and developmentof the infant and young child is tempered by incompletely resolved strategies for combatting challenges.OBJECTIVE To review the importance of maternal nutrition and strategies being employed to optimizeoutcomes. METHODS Selected data from recent literature with special focus on rationale for and currentlypublished results of maternal nutrition supplements, including lipid based nutrition supplements.RESULTS 1) An impelling rationale for improving the maternal and in utero environment of low resourcepopulations has emerged to achieve improved fetal and post-natal growth and development. 2) Basedpartly on population increases in adult height over one-two generations, much can be achieved byreducing poverty. 3) Maternal, newborn and infant characteristics associated with low resourceenvironments include evidence of undernutrition, manifested by underweight and impaired linear growth.4) Apart from broad public health and educational initiatives, to date, most specific efforts to improvefetal growth and development have included maternal nutrition interventions during gestation. 5) Therelatively limited but real benefits of both iron/folic acid (IFA) and multiple micronutrient (MMN) maternalsupplements during gestation have now been reasonably defined. 6) Recent investigations of a maternallipid-based primarily micronutrient supplement (LNS) have not demonstrated a consistent benefit beyondMMN alone. 7) However, effects of both MMN and LNS appear to be enhanced by commencing early ingestation. CONCLUSIONS Poor maternal nutritional status is one of a very few specific factors in thehuman that not only contributes to impaired fetal and early post-natal growth but for which maternalinterventions have demonstrated improved in utero development, documented primarily by bothimprovements in low birth weights and by partial corrections of impaired birth length. A clearer definitionof the benefits achievable by interventions specifically focused on correcting maternal nutrition deficitsshould not be limited to improvements in the quality of maternal nutrition supplements, but on thecumulative quantity and timing of interventions (also recognizing the heterogeneity betweenpopulations). Finally, in an ideal world these steps are only a prelude to improvements in the totalenvironment in which optimal nutrition and other health determinants can be achieved.", "metadata": {}}
+{"_id": "49432306", "title": "", "text": "Key questions about the checkpoint blockade-are microRNAs an answer?The introduction ofimmune-checkpoint blockade in the cancer therapy led to a paradigm change of the management of latestage cancers. There are already multiple FDA approved checkpoint inhibitors and many other agents areundergoing phase 2 and early phase 3 clinical trials. The therapeutic indication of immune checkpointinhibitors expanded in the last years, but still remains unclear who can benefit. MicroRNAs are small RNAswith no coding potential. By complementary pairing to the 3' untranslated region of messenger RNA,microRNAs exert posttranscriptional control of protein expression. A network of microRNAs directly andindirectly controls the expression of checkpoint receptors and several microRNAs can target multiplecheckpoint molecules, mimicking the therapeutic effect of a combined immune checkpoint blockade. Inthis review, we will describe the microRNAs that control the expression of immune checkpoints and wewill present four specific issues of the immune checkpoint therapy in cancer: (1) imprecise therapeuticindication, (2) difficult response evaluation, (3) numerous immunologic adverse-events, and (4) theabsence of response to immune therapy. Finally, we propose microRNAs as possible solutions for thesepitfalls. We consider that in the near future microRNAs could become important therapeutic partners ofthe immune checkpoint therapy.", "metadata": {}}
+{"_id": "49556906", "title": "", "text": "Metformin reverses established lung fibrosis in a bleomycin modelFibrosis is a pathological result of adysfunctional repair response to tissue injury and occurs in a number of organs, including the lungs1.Cellular metabolism regulates tissue repair and remodelling responses to injury2-4. AMPK is a criticalsensor of cellular bioenergetics and controls the switch from anabolic to catabolic metabolism5. However,the role of AMPK in fibrosis is not well understood. Here, we demonstrate that in humans with idiopathicpulmonary fibrosis (IPF) and in an experimental mouse model of lung fibrosis, AMPK activity is lower infibrotic regions associated with metabolically active and apoptosis-resistant myofibroblasts.Pharmacological activation of AMPK in myofibroblasts from lungs of humans with IPF display lower fibroticactivity, along with enhanced mitochondrial biogenesis and normalization of sensitivity to apoptosis. In ableomycin model of lung fibrosis in mice, metformin therapeutically accelerates the resolution ofwell-established fibrosis in an AMPK-dependent manner. These studies implicate deficient AMPK activationin non-resolving, pathologic fibrotic processes, and support a role for metformin (or other AMPKactivators) to reverse established fibrosis by facilitating deactivation and apoptosis of myofibroblasts.", "metadata": {}}
+{"_id": "50670403", "title": "", "text": "Are expert athletes 'expert' in the cognitive laboratory? A meta-analytic review of cognition and sportexpertiseSUMMARY Recent literature has demonstrated the usefulness of fitness and computer-basedcognitive training as a means to enhance cognition and brain function. However, it is unclear whether thecombination of fitness and cognitive training that results from years of extensive sport training alsoresults in superior performance on tests of cognitive processes. In this study we examine, in aquantitative meta-analysis (k ¼20), the relationship between expertise in sports and laboratory-basedmeasures of cognition. We found that athletes performed better on measures of processing speed and acategory of varied attentionalparadigms, andathletesfrominterceptivesporttypesandmalesshowedthelargesteffects. Based on our results, more research should be done withhigher-level cognitive tasks, such as tasks of executive function and more varied sub-domains of visualattention. Furthermore, future studies should incorporate more female athletes and use a diverse rangeof sport types and levelsof expertise.", "metadata": {}}
+{"_id": "51386222", "title": "", "text": "Effects of Age, Sex, and Ethnicity on the Association Between Apolipoprotein E Genotype and AlzheimerDisease: A Meta-analysisObjective. —To examine more closely the association between apolipoprotein E(APOE) genotype and Alzheimer disease (AD) by age and sex in populations of various ethnic and racialdenominations. Data Sources. —Forty research teams contributed data onAPOEgenotype, sex, age atdisease onset, and ethnic background for 5930 patients who met criteria for probable or definite AD and8607 controls without dementia who were recruited from clinical, community, and brain bank sources.Main Outcome Measures. —Odds ratios (ORs) and 95% confidence intervals (Cls) for AD, adjusted for ageand study and stratified by major ethnic group (Caucasian, African American, Hispanic, and Japanese)and source, were computed forAPOEgenotypes \u00002/\u00002,\u00002/\u00003,\u00002/\u00004,\u00003/\u00004 and \u00004/\u00004 relative tothe \u00003/\u00003 group. The influence of age and sex on the OR for each genotype was assessed using logisticregression procedures. Results. —Among Caucasian subjects from clinic- or autopsy-based studies, therisk of AD was significantly increased for people with genotypes \u00002/\u00004 (OR=2.6, 95% Cl=1.6-4.0),\u00003/\u00004 (OR=3.2, 95% Cl=2.8-3.8), and \u00004/\u00004 (OR=14.9, 95% CI=10.8-20.6); whereas, the ORs weredecreased for people with genotypes \u00002/\u00002 (OR=0.6, 95% Cl=0.2-2.0) and \u00002/\u00003 (OR=0.6, 95%Cl=0.5-0.8). TheAPOE\u00004-AD association was weaker among African Americans and Hispanics, but therewas significant heterogeneity in ORs among studies of African Americans (P Conclusions. —TheAPOE\u00004allele represents a major risk factor for AD in all ethnic groups studied, across all ages between 40 and 90years, and in both men and women. The association betweenAPOE\u00004 and AD in African Americansrequires clarification, and the attenuated effect ofAPOE\u00004 in Hispanics should be investigated further.", "metadata": {}}
+{"_id": "51706771", "title": "", "text": "Comparison of glioblastoma (GBM) molecular classification methods.Glioblastoma (GBM) is the mostaggressive and common form of brain cancer in adults. GBM is characterized by poor survival andremarkably high tumors heterogeneity (both intertumoral and intratumoral), and lack of effectivetherapies. Recent high-throughput data revealed heterogeneous genetic/genomic/epigenetic features andled to multiple methods aiming to classify tumors according to the key molecular events that drive themost aggressive cellular components so that targeted therapies can be developed for individual subtypes.However, GBM molecular subtypes have not led to improvement of patients outcomes. Targeted ortailored therapies for specific mutations or subtypes largely failed due to the complexities arising fromintratumoral molecular heterogeneity. Most tumors develop resistance to treatment and soon recur. GBMstem cells (GSCs) have been identified. Recent single cell sequencing studies of GBM suggest thatintratumoral cellular heterogeneity can be partially explained by tumor cell hierarchy arising from GBMstem cells. Therefore, the molecular subtypes based on patient derived GSCs may potentially lead tomore effective subtype-specific treatments. In this paper, we review the molecular alterations of GBMand molecular subtyping methods as well as subtype plasticity in primary and recurrent tumorsemphasizing the clinical relevance of potential targets for further drug development.", "metadata": {}}
+{"_id": "51728753", "title": "", "text": "Mesenchymal Stromal Cells: From Discovery to Manufacturing and CommercializationOver the lastdecades, mesenchymal stromal cells (MSC) have been the focus of intense research by academia andindustry due to their unique features. MSC can be easily isolated and expanded through in vitro cultureby taking full advantage of their self-renewing capacity. In addition, MSC exert immunomodulatoryeffects and can be differentiated into various lineages, which makes them highly attractive for clinicalapplications in cell-based therapies. In this review, we attempt to provide a brief historical overview ofMSC discovery, characterization, and the first clinical studies conducted. The current MSC manufacturingplatforms are reviewed with special attention regarding the use of bioreactors for the production ofGMP-compliant clinically relevant cell numbers. The first commercial MSC-based products are alsoaddressed, as well as the remaining challenges to the widespread use of MSC-derived products.", "metadata": {}}
+{"_id": "51817902", "title": "", "text": "Delta–Notch—and then? Protein interactions and proposed modes of repression by Hes and Hey bHLHfactorsHes and Hey genes are the mammalian counterparts of the Hairy and Enhancer-of-split type ofgenes in Drosophila and they represent the primary targets of the Delta-Notch signaling pathway.Hairy-related factors control multiple steps of embryonic development and misregulation is associatedwith various defects. Hes and Hey genes (also called Hesr, Chf, Hrt, Herp or gridlock) encodetranscriptional regulators of the basic helix-loop-helix class that mainly act as repressors. The moleculardetails of how Hes and Hey proteins control transcription are still poorly understood, however. Proposedmodes of action include direct binding to N- or E-box DNA sequences of target promoters as well asindirect binding through other sequence-specific transcription factors or sequestration of transcriptionalactivators. Repression may rely on recruitment of corepressors and induction of histone modifications, oreven interference with the general transcriptional machinery. All of these models require extensiveprotein-protein interactions. Here we review data published on protein-protein and protein-DNAinteractions of Hairy-related factors and discuss their implications for transcriptional regulation. Inaddition, we summarize recent progress on the identification of potential target genes and the analysis ofmouse models.", "metadata": {}}
+{"_id": "51865482", "title": "", "text": "The Long Noncoding RNA CAREL Controls Cardiac Regeneration.BACKGROUND Adult mammalian heartloses regeneration ability following ischemic injury due to the loss of cardiomyocyte mitosis. However, themolecular mechanisms underlying the post-mitotic nature of cardiomyocytes remain largely unknown.OBJECTIVES The purpose of this study was to define the essential role of long noncoding ribonucleic acids(lncRNAs) in heart regeneration during postnatal and adult injury. METHODS Myh6-drivingcardiomyocyte-specific lncRNA-CAREL transgenic mice and adenovirus-mediated in vivo silencing ofendogenous CAREL were used in this study. The effect of CAREL on cardiomyocyte replication and heartregeneration after apical resection or myocardial infarction was assessed by detecting mitosis andcytokinesis. RESULTS An lncRNA CAREL was found significantly up-regulated in cardiomyocytes fromneonatal mice (P7) in parallel with loss of regenerative capacity. Cardiac-specific overexpression of CARELin mice reduced cardiomyocyte division and proliferation and blunted neonatal heart regeneration afterinjury. Conversely, silencing of CAREL in vivo markedly promoted cardiac regeneration and improvedheart functions after myocardial infarction in neonatal and adult mice. CAREL acted as a competingendogenous ribonucleic acid for miR-296 to derepress the expression of Trp53inp1 and Itm2a, the targetgenes of miR-296. Consistently, overexpression of miR-296 significantly increased cardiomyocytereplication and cardiac regeneration after injury. Decline of cardiac regenerative ability in CARELtransgenic mice was also rescued by miR-296. A short fragment containing the conserved sequence ofCAREL reduced the proliferation of human induced pluripotent stem cell-derived cardiomyocytes as thefull-length CAREL. CONCLUSIONS LncRNA CAREL regulates cardiomyocyte proliferation and heartregeneration in postnatal and adult heart after injury by acting as a competing endogenous ribonucleicacid on miR-296 that targets Trp53inp1 and Itm2a.", "metadata": {}}
+{"_id": "51952430", "title": "", "text": "BCAP links IL-1R to the PI3K–mTOR pathway and regulates pathogenic Th17 cell differentiationThetoll-like receptor (TLR) and interleukin (IL)-1 family of receptors share several signaling components,including the most upstream adapter, MyD88. We previously reported the discovery of B cell adapter forphosphoinositide 3-kinase (BCAP) as a novel toll-IL-1 receptor homology domain-containing adapter thatregulates inflammatory responses downstream of TLR signaling. Here we find that BCAP plays a criticalrole downstream of both IL-1 and IL-18 receptors to regulate T helper (Th) 17 and Th1 celldifferentiation, respectively. Absence of T cell intrinsic BCAP did not alter development of naturally arisingTh1 and Th17 lineages but led to defects in differentiation to pathogenic Th17 lineage cells.Consequently, mice that lack BCAP in T cells had reduced susceptibility to experimental autoimmuneencephalomyelitis. More importantly, we found that BCAP is critical for IL-1R-induced phosphoinositide3-kinase-Akt-mechanistic target of rapamycin (mTOR) activation, and minimal inhibition of mTORcompletely abrogated IL-1β-induced differentiation of pathogenic Th17 cells, mimicking BCAP deficiency.This study establishes BCAP as a critical link between IL-1R and the metabolic status of activated T cellsthat ultimately regulates the differentiation of inflammatory Th17 cells.", "metadata": {}}
+{"_id": "51972698", "title": "", "text": "Adapting the WHO package of essential noncommunicable disease interventions, SamoaProblem Samoahas been struggling to address the burden of noncommunicable diseases at the health system,community and individual levels. Approach The World Health Organization (WHO) package of essentialnoncommunicable disease interventions for primary health care in low-resource settings was adopted inseven villages throughout Samoa in 2015. The National Steering Committee Members designed andimplemented a screening process, and local facilitators and health-care workers collected health andlifestyle data. The WHO/International Society of Hypertension risk assessment was used on villagers olderthan 40 years to identify people at high risk of noncommunicable disease. Local setting Samoa is a smallisland developing state with increasing morbidity and mortality due to noncommunicable diseases. Anational representative survey indicated that 50.1% (595/1188) of the Samoan adult population is athigh risk of such diseases. High numbers of noncommunicable diseases are undiagnosed or untreated,because of shortage of health-care staff and lack of awareness of risk factors. Relevant changes Theteams collected data from 2234 adults. For people older than 40 years, 6.7% (54/804) were identified asbeing at high-risk and were encouraged to seek treatment or manage risk factors. Community membersdeveloped an awareness programme to improve understanding of lifestyle risk factors. Lessons learntEngaging community members was crucial in conducting a successful screening campaign. By identifyingthose villagers at high risk of developing noncommunicable diseases, early intervention was possible.Education improved awareness of the symptom-free nature of early-stage noncommunicable diseases.", "metadata": {}}
+{"_id": "52072815", "title": "", "text": "Alcohol use and burden for 195 countries and territories, 1990–2016: a systematic analysis for the GlobalBurden of Disease Study 2016Summary Background Alcohol use is a leading risk factor for death anddisability, but its overall association with health remains complex given the possible protective effects ofmoderate alcohol consumption on some conditions. With our comprehensive approach to healthaccounting within the Global Burden of Diseases, Injuries, and Risk Factors Study 2016, we generatedimproved estimates of alcohol use and alcohol-attributable deaths and disability-adjusted life-years(DALYs) for 195 locations from 1990 to 2016, for both sexes and for 5-year age groups between the agesof 15 years and 95 years and older. Methods Using 694 data sources of individual and population-levelalcohol consumption, along with 592 prospective and retrospective studies on the risk of alcohol use, weproduced estimates of the prevalence of current drinking, abstention, the distribution of alcoholconsumption among current drinkers in standard drinks daily (defined as 10 g of pure ethyl alcohol), andalcohol-attributable deaths and DALYs. We made several methodological improvements compared withprevious estimates: first, we adjusted alcohol sales estimates to take into account tourist and unrecordedconsumption; second, we did a new meta-analysis of relative risks for 23 health outcomes associatedwith alcohol use; and third, we developed a new method to quantify the level of alcohol consumption thatminimises the overall risk to individual health. Findings Globally, alcohol use was the seventh leading riskfactor for both deaths and DALYs in 2016, accounting for 2·2% (95% uncertainty interval [UI] 1·5–3·0) ofage-standardised female deaths and 6·8% (5·8–8·0) of age-standardised male deaths. Among thepopulation aged 15–49 years, alcohol use was the leading risk factor globally in 2016, with 3·8% (95% UI3·2–4·3) of female deaths and 12·2% (10·8–13·6) of male deaths attributable to alcohol use. For thepopulation aged 15–49 years, female attributable DALYs were 2·3% (95% UI 2·0–2·6) and maleattributable DALYs were 8·9% (7·8–9·9). The three leading causes of attributable deaths in this agegroup were tuberculosis (1·4% [95% UI 1·0–1·7] of total deaths), road injuries (1·2% [0·7–1·9]), andself-harm (1·1% [0·6–1·5]). For populations aged 50 years and older, cancers accounted for a largeproportion of total alcohol-attributable deaths in 2016, constituting 27·1% (95% UI 21·2–33·3) of totalalcohol-attributable female deaths and 18·9% (15·3–22·6) of male deaths. The level of alcoholconsumption that minimised harm across health outcomes was zero (95% UI 0·0–0·8) standard drinksper week. Interpretation Alcohol use is a leading risk factor for global disease burden and causessubstantial health loss. We found that the risk of all-cause mortality, and of cancers specifically, rises withincreasing levels of consumption, and the level of consumption that minimises health loss is zero. Theseresults suggest that alcohol control policies might need to be revised worldwide, refocusing on efforts tolower overall population-level consumption. Funding Bill & Melinda Gates Foundation.", "metadata": {}}
+{"_id": "52095986", "title": "", "text": "The Dual Immunoregulatory function of Nlrp12 in T Cell-Mediated Immune Response: Lessons fromExperimental Autoimmune EncephalomyelitisAlthough the etiology of multiple sclerosis (MS) remainsenigmatic, the role of T cells is unquestionably central in this pathology. Immune cells respond topathogens and danger signals via pattern-recognition receptors (PRR). Several reports implicate Nlrp12,an intracellular PRR, in the development of a mouse MS-like disease, called Experimental AutoimmuneEncephalomyelitis (EAE). In this study, we used induced and spontaneous models of EAE, as well as invitro T cell assays, to test the hypothesis that Nlrp12 inhibits Th1 response and prevents T-cell mediatedautoimmunity. We found that Nlrp12 plays a protective role in induced EAE by reducing IFNγ/IL-4 ratio inlymph nodes, whereas it potentiates the development of spontaneous EAE (spEAE) in 2D2 T cell receptor(TCR) transgenic mice. Looking into the mechanism of Nlrp12 activity in T cell response, we found that itinhibits T cell proliferation and suppresses Th1 response by reducing IFNγ and IL-2 production. FollowingTCR activation, Nlrp12 inhibits Akt and NF-κB phosphorylation, while it has no effect on S6phosphorylation in the mTOR pathway. In conclusion, we propose a model that can explain the dualimmunoregulatory function of Nlrp12 in EAE. We also propose a model explaining the molecularmechanism of Nlrp12-dependent regulation of T cell response.", "metadata": {}}
+{"_id": "52175065", "title": "", "text": "Acute and chronic exercise in patients with heart failure with reduced ejection fraction: evidence ofstructural and functional plasticity and intact angiogenic signalling in skeletal muscleKEY POINTS Thevascular endothelial growth factor (VEGF) responses to acute submaximal exercise and training effects inpatients with heart failure with reduced ejection fraction (HFrEF) were investigated. Six patients and sixhealthy matched controls performed knee-extensor exercise (KE) at 50% of maximum work rate beforeand after (only patients) KE training. Muscle biopsies were taken to assess skeletal muscle structure andthe angiogenic response. Before training, during this submaximal KE exercise, patients with HFrEFexhibited higher leg vascular resistance and greater noradrenaline spillover. Skeletal muscle structureand VEGF response were generally not different between groups. Following training, resistance was nolonger elevated and noradrenaline spillover was curtailed in the patients. Although, in the trained state,VEGF did not respond to acute exercise, capillarity was augmented. Muscle fibre cross-sectional area andpercentage area of type I fibres increased and mitochondrial volume density exceeded that of controls.Structural/functional plasticity and appropriate angiogenic signalling were observed in skeletal muscle ofpatients with HFrEF. ABSTRACT This study examined the response to acute submaximal exercise and theeffect of training in patients with heart failure with reduced ejection fraction (HFrEF). The acuteangiogenic response to submaximal exercise in HFrEF after small muscle mass training is debated. Thedirect Fick method, with vascular pressures, was performed across the leg during knee-extensor exercise(KE) at 50% of maximum work rate (WRmax ) in patients (n = 6) and controls (n = 6) and then after KEtraining in patients. Muscle biopsies facilitated the assessment of skeletal muscle structure and vascularendothelial growth factor (VEGF) mRNA levels. Prior to training, HFrEF exhibited significantly higher legvascular resistance (LVR) (≈15%) and significantly greater noradrenaline spillover (≈385%). Apart frommitochondrial volume density, which was significantly lower (≈22%) in HFrEF, initial skeletal musclestructure, including capillarity, was not different between groups. Resting VEGF mRNA levels, and theincrease with exercise, was not different between patients and controls. Following training, LVR was nolonger elevated and noradrenaline spillover was curtailed. Skeletal muscle capillarity increased withtraining, as assessed by capillary-to-fibre ratio (≈13%) and number of capillaries around a fibre (NCAF )(≈19%). VEGF mRNA was now not significantly increased by acute exercise. Muscle fibre cross-sectionalarea and percentage area of type I fibres both increased significantly with training (≈18% and ≈21%,respectively), while the percentage area of type II fibres fell significantly (≈11%), and mitochondrialvolume density now exceeded that of controls. These data reveal structural and functional plasticity andappropriate angiogenic signalling in skeletal muscle of HFrEF patients.", "metadata": {}}
+{"_id": "52176296", "title": "", "text": "2017 revisions of McDonald criteria shorten the time to diagnosis of multiple sclerosis in clinically isolatedsyndromesTo investigate the impact of the 2017 revisions of McDonald criteria on the diagnosis ofmultiple sclerosis (MS) in a cohort of patients with clinically isolated syndrome (CIS) and dissemination inspace (DIS) of demyelinating lesions. We retrospectively analyzed 137 patients with CIS + DIS from twoItalian MS centers. Application of the 2017 revisions of McDonald criteria in our cohort led to a diagnosisof MS in 82.5% of the patients who could have not been diagnosed with MS according to the previouscriteria at the time of the first demyelinating event. After a follow-up of 3.8 ± 2.9 years, 85.8% of thesepatients eventually satisfied also the previous (2010) criteria. Application of the 2017 revisions ofMcDonald criteria results in an earlier diagnosis of MS in a large percentage of CIS patients destined toconvert to MS.", "metadata": {}}
+{"_id": "52180874", "title": "", "text": "Efficacy of PD-1 or PD-L1 inhibitors and PD-L1 expression status in cancer: meta-analysisOBJECTIVE Toevaluate the relative efficacy of programmed cell death 1 (PD-1) or programmed cell death ligand 1(PD-L1) inhibitors versus conventional drugs in patients with cancer that were PD-L1 positive and PD-L1negative. DESIGN Meta-analysis of randomised controlled trials. DATA SOURCES PubMed, Embase,Cochrane database, and conference abstracts presented at the American Society of Clinical Oncology andEuropean Society of Medical Oncology up to March 2018. REVIEW METHODS Studies of PD-1 or PD-L1inhibitors (avelumab, atezolizumab, durvalumab, nivolumab, and pembrolizumab) that had availablehazard ratios for death based on PD-L1 positivity or negativity were included. The threshold for PD-L1positivity or negativity was that PD-L1 stained cell accounted for 1% of tumour cells, or tumour andimmune cells, assayed by immunohistochemistry staining methods. RESULTS 4174 patients withadvanced or metastatic cancers from eight randomised controlled trials were included in this study.Compared with conventional agents, PD-1 or PD-L1 inhibitors were associated with significantlyprolonged overall survival in both patients that were PD-L1 positive (n=2254, hazard ratio 0.66, 95%confidence interval 0.59 to 0.74) and PD-L1 negative (1920, 0.80, 0.71 to 0.90). However, the efficaciesof PD-1 or PD-L1 blockade treatment in patients that were PD-L1 positive and PD-L1 negative weresignificantly different (P=0.02 for interaction). Additionally, in both patients that were PD-L1 positive andPD-L1 negative, the long term clinical benefits from PD-1 or PD-L1 blockade were observed consistentlyacross interventional agent, cancer histotype, method of randomisation stratification, type ofimmunohistochemical scoring system, drug target, type of control group, and median follow-up time.CONCLUSIONS PD-1 or PD-L1 blockade therapy is a preferable treatment option over conventionaltherapy for both patients that are PD-L1 positive and PD-L1 negative. This finding suggests that PD-L1expression status alone is insufficient in determining which patients should be offered PD-1 or PD-L1blockade therapy.", "metadata": {}}
+{"_id": "52188256", "title": "", "text": "Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancersin 185 countries.This article provides a status report on the global burden of cancer worldwide using theGLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency forResearch on Cancer, with a focus on geographic variability across 20 world regions. There will be anestimated 18.1 million new cancer cases (17.0 million excluding nonmelanoma skin cancer) and 9.6million cancer deaths (9.5 million excluding nonmelanoma skin cancer) in 2018. In both sexes combined,lung cancer is the most commonly diagnosed cancer (11.6% of the total cases) and the leading cause ofcancer death (18.4% of the total cancer deaths), closely followed by female breast cancer (11.6%),prostate cancer (7.1%), and colorectal cancer (6.1%) for incidence and colorectal cancer (9.2%),stomach cancer (8.2%), and liver cancer (8.2%) for mortality. Lung cancer is the most frequent cancerand the leading cause of cancer death among males, followed by prostate and colorectal cancer (forincidence) and liver and stomach cancer (for mortality). Among females, breast cancer is the mostcommonly diagnosed cancer and the leading cause of cancer death, followed by colorectal and lungcancer (for incidence), and vice versa (for mortality); cervical cancer ranks fourth for both incidence andmortality. The most frequently diagnosed cancer and the leading cause of cancer death, however,substantially vary across countries and within each country depending on the degree of economicdevelopment and associated social and life style factors. It is noteworthy that high-quality cancer registrydata, the basis for planning and implementing evidence-based cancer control programs, are not availablein most low- and middle-income countries. The Global Initiative for Cancer Registry Development is aninternational partnership that supports better estimation, as well as the collection and use of local data,to prioritize and evaluate national cancer control efforts. CA: A Cancer Journal for Clinicians 2018;0:1-31.© 2018 American Cancer Society.", "metadata": {}}
+{"_id": "52805891", "title": "", "text": "Gut Microbiota Is a Key Modulator of Insulin Resistance in TLR 2 Knockout MiceEnvironmental factors andhost genetics interact to control the gut microbiota, which may have a role in the development of obesityand insulin resistance. TLR2-deficient mice, under germ-free conditions, are protected from diet-inducedinsulin resistance. It is possible that the presence of gut microbiota could reverse the phenotype of ananimal, inducing insulin resistance in an animal genetically determined to have increased insulinsensitivity, such as the TLR2 KO mice. In the present study, we investigated the influence of gutmicrobiota on metabolic parameters, glucose tolerance, insulin sensitivity, and signaling of TLR2-deficientmice. We investigated the gut microbiota (by metagenomics), the metabolic characteristics, and insulinsignaling in TLR2 knockout (KO) mice in a non-germ free facility. Results showed that the loss of TLR2 inconventionalized mice results in a phenotype reminiscent of metabolic syndrome, characterized bydifferences in the gut microbiota, with a 3-fold increase in Firmicutes and a slight increase inBacteroidetes compared with controls. These changes in gut microbiota were accompanied by an increasein LPS absorption, subclinical inflammation, insulin resistance, glucose intolerance, and later, obesity. Inaddition, this sequence of events was reproduced in WT mice by microbiota transplantation and was alsoreversed by antibiotics. At the molecular level the mechanism was unique, with activation of TLR4associated with ER stress and JNK activation, but no activation of the IKKβ-IκB-NFκB pathway. Our dataalso showed that in TLR2 KO mice there was a reduction in regulatory T cell in visceral fat, suggestingthat this modulation may also contribute to the insulin resistance of these animals. Our results emphasizethe role of microbiota in the complex network of molecular and cellular interactions that link genotype tophenotype and have potential implications for common human disorders involving obesity, diabetes, andeven other immunological disorders.", "metadata": {}}
+{"_id": "52824661", "title": "", "text": "TGF\u0000β\u0000mediated exosomal lnc\u0000MMP2\u00002 regulates migration and invasion of lung cancer cells to thevasculature by promoting MMP2 expressionPrevious studies indicated that transforming growth factor(TGF)-β-mediated exosomal microRNAs (miRNAs) regulate the migration and invasion of lung cancercells; however, whether and how TGF-β-mediated exosomal long noncoding (lnc) RNAs regulatemigration and invasion of lung cancer cells remains unclear. Here, coculture experiments showed thatTGF-β pretreatment increased the migration and invasion potential of lung cancer cells and TGF-βpretreated A549 cells increases vascular permeability. Furthermore, we found that TGF-β-mediatedexosomes, as carriers of intercellular communication, regulated lung cancer invasion, and vascularpermeability. Transcriptional analysis also revealed that lnc-MMP2-2 was highly enriched inTGF-β-mediated exosomes and might function by increasing the expression of matrix metalloproteinase(MMP)2 through its enhancer activity, with ectopic expression and silencing of lnc-MMP2-2 affecting lungcancer invasion and vascular permeability. Additionally, lnc-MMP2-2 and MMP2 expression was assessedsemiquantitatively, and tissue-specific correlations between lnc-MMP2-2 and MMP2 expression wereevaluated. These results suggested that exosomal lnc-MMP2-2 might regulate the migration and invasionof lung cancer cells into the vasculature by promoting MMP2 expression, suggesting this lncRNA as anovel therapeutic target and predictive marker of tumor metastasis in lung cancer.", "metadata": {}}
+{"_id": "52827184", "title": "", "text": "Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock2016Objective: To provide an update to “Surviving Sepsis Campaign Guidelines for Management ofSepsis and Septic Shock: 2012. ” Design: A consensus committee of 55 international expertsrepresenting 25 international organizations was convened. Nominal groups were assembled at keyinternational meetings (for those committee members attending the conference). A formalconflict-of-interest (COI) policy was developed at the onset of the process and enforced throughout. Astand-alone meeting was held for all panel members in December 2015. Teleconferences andelectronic-based discussion among subgroups and among the entire committee served as an integral partof the development. Methods: The panel consisted of five sections: hemodynamics, infection, adjunctivetherapies, metabolic, and ventilation. Population, intervention, comparison, and outcomes (PICO)questions were reviewed and updated as needed, and evidence profiles were generated. Each subgroupgenerated a list of questions, searched for best available evidence, and then followed the principles of theGrading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess thequality of evidence from high to very low, and to formulate recommendations as strong or weak, or bestpractice statement when applicable. Results: The Surviving Sepsis Guideline panel provided 93statements on early management and resuscitation of patients with sepsis or septic shock. Overall, 32were strong recommendations, 39 were weak recommendations, and 18 were best-practice statements.No recommendation was provided for four questions. Conclusions: Substantial agreement exists among alarge cohort of international experts regarding many strong recommendations for the best care ofpatients with sepsis. Although a significant number of aspects of care have relatively weak support,evidence-based recommendations regarding the acute management of sepsis and septic shock are thefoundation of improved outcomes for these critically ill patients with high mortality.", "metadata": {}}
+{"_id": "52850476", "title": "", "text": "Mitochondrial genome variation and the origin of modern humans.The analysis of mitochondrial DNA(mtDNA) has been a potent tool in our understanding of human evolution, owing to characteristics suchas high copy number, apparent lack of recombination, high substitution rate and maternal mode ofinheritance. However, almost all studies of human evolution based on mtDNA sequencing have beenconfined to the control region, which constitutes less than 7% of the mitochondrial genome. Thesestudies are complicated by the extreme variation in substitution rate between sites, and the consequenceof parallel mutations causing difficulties in the estimation of genetic distance and making phylogeneticinferences questionable. Most comprehensive studies of the human mitochondrial molecule have beencarried out through restriction-fragment length polymorphism analysis, providing data that are ill suitedto estimations of mutation rate and therefore the timing of evolutionary events. Here, to improve theinformation obtained from the mitochondrial molecule for studies of human evolution, we describe theglobal mtDNA diversity in humans based on analyses of the complete mtDNA sequence of 53 humans ofdiverse origins. Our mtDNA data, in comparison with those of a parallel study of the Xq13.3 region in thesame individuals, provide a concurrent view on human evolution with respect to the age of modernhumans.", "metadata": {}}
+{"_id": "52865789", "title": "", "text": "Deficiency of Interleukin-15 Confers Resistance to Obesity by Diminishing Inflammation and Enhancingthe Thermogenic Function of Adipose TissuesOBJECTIVE IL-15 is an inflammatory cytokine secreted bymany cell types. IL-15 is also produced during physical exercise by skeletal muscle and has beenreported to reduce weight gain in mice. Contrarily, our findings on IL-15 knockout (KO) mice indicate thatIL-15 promotes obesity. The aim of this study is to investigate the mechanisms underlying thepro-obesity role of IL-15 in adipose tissues. METHODS Control and IL-15 KO mice were maintained onhigh fat diet (HFD) or normal control diet. After 16 weeks, body weight, adipose tissue and skeletal mass,serum lipid levels and gene/protein expression in the adipose tissues were evaluated. The effect of IL-15on thermogenesis and oxygen consumption was also studied in primary cultures of adipocytesdifferentiated from mouse preadipocyte and human stem cells. RESULTS Our results show that IL-15deficiency prevents diet-induced weight gain and accumulation of lipids in visceral and subcutaneouswhite and brown adipose tissues. Gene expression analysis also revealed elevated expression of genesassociated with adaptive thermogenesis in the brown and subcutaneous adipose tissues of IL-15 KO mice.Accordingly, oxygen consumption was increased in the brown adipocytes from IL-15 KO mice. In addition,IL-15 KO mice showed decreased expression of pro-inflammatory mediators in their adipose tissues.CONCLUSIONS Absence of IL-15 results in decreased accumulation of fat in the white adipose tissues andincreased lipid utilization via adaptive thermogenesis. IL-15 also promotes inflammation in adiposetissues that could sustain chronic inflammation leading to obesity-associated metabolic syndrome.", "metadata": {}}
+{"_id": "52868579", "title": "", "text": "Chromatin signatures of pluripotent cell lines.Epigenetic genome modifications are thought to beimportant for specifying the lineage and developmental stage of cells within a multicellular organism.Here, we show that the epigenetic profile of pluripotent embryonic stem cells (ES) is distinct from that ofembryonic carcinoma cells, haematopoietic stem cells (HSC) and their differentiated progeny. Silent,lineage-specific genes replicated earlier in pluripotent cells than in tissue-specific stem cells ordifferentiated cells and had unexpectedly high levels of acetylated H3K9 and methylated H3K4.Unusually, in ES cells these markers of open chromatin were also combined with H3K27 trimethylation atsome non-expressed genes. Thus, pluripotency of ES cells is characterized by a specific epigenetic profilewhere lineage-specific genes may be accessible but, if so, carry repressive H3K27 trimethylationmodifications. H3K27 methylation is functionally important for preventing expression of these genes in EScells as premature expression occurs in embryonic ectoderm development (Eed)-deficient ES cells. Ourdata suggest that lineage-specific genes are primed for expression in ES cells but are held in check byopposing chromatin modifications.", "metadata": {}}
+{"_id": "52873726", "title": "", "text": "Regulation of Hippo pathway transcription factor TEAD by p38 MAPK-induced cytoplasmictranslocationThe Hippo pathway controls organ size and tissue homeostasis, with deregulation leading tocancer. The core Hippo components in mammals are composed of the upstream serine/threonine kinasesMst1/2, MAPK4Ks and Lats1/2. Inactivation of these upstream kinases leads to dephosphorylation,stabilization, nuclear translocation and thus activation of the major functional transducers of the Hippopathway, YAP and its paralogue TAZ. YAP/TAZ are transcription co-activators that regulate geneexpression primarily through interaction with the TEA domain DNA-binding family of transcription factors(TEAD). The current paradigm for regulation of this pathway centres on phosphorylation-dependentnucleocytoplasmic shuttling of YAP/TAZ through a complex network of upstream components. However,unlike other transcription factors, such as SMAD, NF-κB, NFAT and STAT, the regulation of TEADnucleocytoplasmic shuttling has been largely overlooked. In the present study, we show thatenvironmental stress promotes TEAD cytoplasmic translocation via p38 MAPK in a Hippo-independentmanner. Importantly, stress-induced TEAD inhibition predominates YAP-activating signals and selectivelysuppresses YAP-driven cancer cell growth. Our data reveal a mechanism governing TEADnucleocytoplasmic shuttling and show that TEAD localization is a critical determinant of Hippo signallingoutput.", "metadata": {}}
+{"_id": "52874170", "title": "", "text": "How do I perform a lumbar puncture and analyze the results to diagnose bacterial meningitis?CONTEXTDiagnostic lumbar punctures (LPs), commonly used to rule out meningitis, are associated with adverseevents. OBJECTIVE To systematically review the evidence about diagnostic LP techniques that maydecrease the risk of adverse events and the evidence about test accuracy of cerebrospinal fluid (CSF)analysis in adult patients with suspected bacterial meningitis. DATA SOURCES We searched the CochraneLibrary, MEDLINE (using Ovid and PubMed) from 1966 to January 2006 and EMBASE from 1980 toJanuary 2006 without language restrictions to identify relevant studies and identified others from thebibliographies of retrieved articles. STUDY SELECTION We included randomized trials of patients aged 18years or older undergoing interventions to facilitate a successful diagnostic LP or to potentially reduceadverse events. Studies assessing the accuracy of biochemical analysis of the CSF for possible bacterialmeningitis were also identified. DATA EXTRACTION Two investigators independently appraised studyquality and extracted relevant data. For studies of the LP technique, data on the intervention and theoutcome were extracted. For studies of the laboratory diagnosis of bacterial meningitis, data on thereference standard and test accuracy were extracted. DATA SYNTHESIS We found 15 randomized trials. Arandom-effects model was used for quantitative synthesis. Five studies of 587 patients comparedatraumatic needles with standard needles and found a nonsignificant decrease in the odds of headachewith an atraumatic needle (absolute risk reduction [ARR], 12.3%; 95% confidence interval [CI], -1.72%to 26.2%). Reinsertion of the stylet before needle removal decreased the risk of headache (ARR, 11.3%;95% CI, 6.50%-16.2%). The combined results from 4 studies of 717 patients showed a nonsignificantdecrease in headache in patients who were mobilized after LP (ARR, 2.9%; 95% CI, -3.4 to 9.3%). Fourstudies on the accuracy of biochemical analysis of CSF in patients with suspected meningitis met inclusioncriteria. A CSF-blood glucose ratio of 0.4 or less (likelihood ratio [LR], 18; 95% CI, 12-27]), CSF whiteblood cell count of 500/muL or higher (LR, 15; 95% CI, 10-22), and CSF lactate level of 31.53 mg/dL ormore (> or =3.5 mmol/L; LR, 21; 95% CI, 14-32) accurately diagnosed bacterial meningitis.CONCLUSIONS These data suggest that small-gauge, atraumatic needles may decrease the risk ofheadache after diagnostic LP. Reinsertion of the stylet before needle removal should occur and patientsdo not require bed rest after the procedure. Future research should focus on evaluating interventions tooptimize the success of a diagnostic LP and to enhance training in procedural skills.", "metadata": {}}
+{"_id": "52887689", "title": "", "text": "Guidelines for the use and interpretation of assays for monitoring autophagy.In 2008 we published thefirst set of guidelines for standardizing research in autophagy. Since then, research on this topic hascontinued to accelerate, and many new scientists have entered the field. Our knowledge base andrelevant new technologies have also been expanding. Accordingly, it is important to update theseguidelines for monitoring autophagy in different organisms. Various reviews have described the range ofassays that have been used for this purpose. Nevertheless, there continues to be confusion regardingacceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needsto be emphasized is that there is a difference between measurements that monitor the numbers orvolume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagicprocess vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, ablock in macroautophagy that results in autophagosome accumulation needs to be differentiated fromstimuli that result in increased autophagic activity, defined as increased autophagy induction coupled withincreased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protistssuch as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important thatinvestigators new to the field understand that the appearance of more autophagosomes does notnecessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because ofa block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereasan increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set ofguidelines for the selection and interpretation of methods for use by investigators who aim to examinemacroautophagy and related processes, as well as for reviewers who need to provide realistic andreasonable critiques of papers that are focused on these processes. These guidelines are not meant to bea formulaic set of rules, because the appropriate assays depend in part on the question being asked andthe system being used. In addition, we emphasize that no individual assay is guaranteed to be the mostappropriate one in every situation, and we strongly recommend the use of multiple assays to monitorautophagy. In these guidelines, we consider these various methods of assessing autophagy and whatinformation can, or cannot, be obtained from them. Finally, by discussing the merits and limits ofparticular autophagy assays, we hope to encourage technical innovation in the field.", "metadata": {}}
+{"_id": "52893592", "title": "", "text": "Subversion of Systemic Glucose Metabolism as a Mechanism to Support the Growth of LeukemiaCells.From an organismal perspective, cancer cell populations can be considered analogous to parasitesthat compete with the host for essential systemic resources such as glucose. Here, we employedleukemia models and human leukemia samples to document a form of adaptive homeostasis, wheremalignant cells alter systemic physiology through impairment of both host insulin sensitivity and insulinsecretion to provide tumors with increased glucose. Mechanistically, tumor cells induce high-levelproduction of IGFBP1 from adipose tissue to mediate insulin sensitivity. Further, leukemia-induced gutdysbiosis, serotonin loss, and incretin inactivation combine to suppress insulin secretion. Importantly,attenuated disease progression and prolonged survival are achieved through disruption of theleukemia-induced adaptive homeostasis. Our studies provide a paradigm for systemic management ofleukemic disease.", "metadata": {}}
+{"_id": "52925737", "title": "", "text": "Tumor-derived exosomes induce N2 polarization of neutrophils to promote gastric cancer cellmigrationBACKGROUND Exosomes are extracellular vesicles that mediate cellular communication inhealth and diseases. Neutrophils could be polarized to a pro-tumor phenotype by tumor. The function oftumor-derived exosomes in neutrophil regulation remains unclear. METHODS We investigated the effectsof gastric cancer cell-derived exosomes (GC-Ex) on the pro-tumor activation of neutrophils andelucidated the underlying mechanisms. RESULTS GC-Ex prolonged neutrophil survival and inducedexpression of inflammatory factors in neutrophils. GC-Ex-activated neutrophils, in turn, promoted gastriccancer cell migration. GC-Ex transported high mobility group box-1 (HMGB1) that activated NF-κBpathway through interaction with TLR4, resulting in an increased autophagic response in neutrophils.Blocking HMGB1/TLR4 interaction, NF-κB pathway, and autophagy reversed GC-Ex-induced neutrophilactivation. Silencing HMGB1 in gastric cancer cells confirmed HMGB1 as a key factor for GC-Ex-mediatedneutrophil activation. Furthermore, HMGB1 expression was upregulated in gastric cancer tissues.Increased HMGB1 expression was associated with poor prognosis in patients with gastric cancer. Finally,gastric cancer tissue-derived exosomes acted similarly as exosomes derived from gastric cancer cell linesin neutrophil activation. CONCLUSION We demonstrate that gastric cancer cell-derived exosomes induceautophagy and pro-tumor activation of neutrophils via HMGB1/TLR4/NF-κB signaling, which provides newinsights into mechanisms for neutrophil regulation in cancer and sheds lights on the multifaceted role ofexosomes in reshaping tumor microenvironment.", "metadata": {}}
+{"_id": "52944377", "title": "", "text": "ROS-induced R loops trigger a transcription-coupled but BRCA1/2-independent homologousrecombination pathway through CSBActively transcribed regions of the genome are protected bytranscription-coupled DNA repair mechanisms, including transcription-coupled homologous recombination(TC-HR). Here we used reactive oxygen species (ROS) to induce and characterize TC-HR at a transcribedlocus in human cells. As canonical HR, TC-HR requires RAD51. However, the localization of RAD51 todamage sites during TC-HR does not require BRCA1 and BRCA2, but relies on RAD52 and CockayneSyndrome Protein B (CSB). During TC-HR, RAD52 is recruited by CSB through an acidic domain. CSB inturn is recruited by R loops, which are strongly induced by ROS in transcribed regions. Notably, CSBdisplays a strong affinity for DNA:RNA hybrids in vitro, suggesting that it is a sensor of ROS-induced Rloops. Thus, TC-HR is triggered by R loops, initiated by CSB, and carried out by the CSB-RAD52-RAD51axis, establishing a BRCA1/2-independent alternative HR pathway protecting the transcribed genome.", "metadata": {}}
+{"_id": "53033275", "title": "", "text": "Autophagy and its potent modulators from phytochemicals in cancer treatmentAutophagy is a ubiquitouscatabolic process by which damaged or harmful intracellular components are delivered to the lysosomesfor self-digestion and recycling. It is critical in cancer treatment. Therapy-induced autophagypredominantly acts as a pro-survival mechanism, but progressive autophagy can lead to non-apoptoticcell death, also known as autophagic cell death. Plants or herbs contain various natural compounds thatare widely used in the treatment of many types of malignancies. Emerging evidence indicates thatphytochemicals targeting the autophagic pathway are promising agents for cancer treatment. However,these compounds play different roles in autophagy. In this review, we discussed the role of autophagy incancer development and therapy, and focussed on elucidating the anti-cancer activities of autophagicmodulators, especially phytochemicals. Notably, we described a novel premise that the dynamic role ofphytochemicals should be evaluated in regulation of autophagy in cancer.", "metadata": {}}
+{"_id": "53211308", "title": "", "text": "Exosomal miR-99a-5p is elevated in sera of ovarian cancer patients and promotes cancer cell invasion byincreasing fibronectin and vitronectin expression in neighboring peritoneal mesothelial cellsBACKGROUNDmicroRNAs (miRNAs) stably exist in circulating blood and are encapsulated in extracellular vesicles suchas exosomes. The aims of this study were to identify which exosomal miRNAs are highly produced fromepithelial ovarian cancer (EOC) cells, to analyze whether serum miRNA can be used to discriminatepatients with EOC from healthy volunteers, and to investigate the functional role of exosomal miRNAs inovarian cancer progression. METHODS Exosomes were collected from the culture media of serous ovariancancer cell lines, namely TYK-nu and HeyA8 cells. An exosomal miRNA microarray revealed that severalmiRNAs including miR-99a-5p were specifically elevated in EOC-derived exosomes. Expression levels ofserum miR-99a-5p in 62 patients with EOC, 26 patients with benign ovarian tumors, and 20 healthyvolunteers were determined by miRNA quantitative reverse transcription-polymerase chain reaction. Toinvestigate the role of exosomal miR-99a-5p in peritoneal dissemination, neighboring human peritonealmesothelial cells (HPMCs) were treated with EOC-derived exosomes and then expression levels ofmiR-99a-5p were examined. Furthermore, mimics of miR-99a-5p were transfected into HPMCs and theeffect of miR-99a-5p on cancer invasion was analyzed using a 3D culture model. Proteomic analysis withthe tandem mass tag method was performed on HPMCs transfected with miR-99a-5p and then potentialtarget genes of miR-99a-5p were examined. RESULTS The serum miR-99a-5p levels were significantlyincreased in patients with EOC, compared with those in benign tumor patients and healthy volunteers(1.7-fold and 2.8-fold, respectively). A receiver operating characteristic curve analysis showed with acut-off of 1.41 showed sensitivity and specificity of 0.85 and 0.75, respectively, for detecting EOC (areaunder the curve = 0.88). Serum miR-99a-5p expression levels were significantly decreased after EOCsurgeries (1.8 to 1.3, p = 0.002), indicating that miR-99a-5p reflects tumor burden. Treatment withEOC-derived exosomes significantly increased miR-99a-5p expression in HPMCs. HPMCs transfected withmiR-99a-5p promoted ovarian cancer invasion and exhibited increased expression levels of fibronectinand vitronectin. CONCLUSIONS Serum miR-99a-5p is significantly elevated in ovarian cancer patients.Exosomal miR-99a-5p from EOC cells promotes cell invasion by affecting HPMCs through fibronectin andvitronectin upregulation and may serve as a target for inhibiting ovarian cancer progression.", "metadata": {}}
+{"_id": "53302393", "title": "", "text": "The Pfam protein families database.Pfam is a widely used database of protein families, currentlycontaining more than 13,000 manually curated protein families as of release 26.0. Pfam is available viaservers in the UK (http://pfam.sanger.ac.uk/), the USA (http://pfam.janelia.org/) and Sweden(http://pfam.sbc.su.se/). Here, we report on changes that have occurred since our 2010 NAR paper(release 24.0). Over the last 2 years, we have generated 1840 new families and increased coverage ofthe UniProt Knowledgebase (UniProtKB) to nearly 80%. Notably, we have taken the step of opening upthe annotation of our families to the Wikipedia community, by linking Pfam families to relevant Wikipediapages and encouraging the Pfam and Wikipedia communities to improve and expand those pages. Wecontinue to improve the Pfam website and add new visualizations, such as the 'sunburst' representationof taxonomic distribution of families. In this work we additionally address two topics that will be ofparticular interest to the Pfam community. First, we explain the definition and use of family-specific,manually curated gathering thresholds. Second, we discuss some of the features of domains of unknownfunction (also known as DUFs), which constitute a rapidly growing class of families within Pfam.", "metadata": {}}
+{"_id": "53779698", "title": "", "text": "Exercise as a therapeutic approach to improve blood pressure in patients with peripheral arterial disease:current literature and future directions.INTRODUCTION Patients with symptomatic peripheral arterydisease (PAD) exhibit reduced functional capacity and increased mortality due to cardiovascular disease.Although exercise has been a cornerstone for clinical treatment to improve walking capacity in patientswith symptomatic PAD, its effects on cardiovascular parameters have been poorly explored. Areascovered: This review examines the role of exercise in improving blood pressure in patients withsymptomatic PAD and summarizes the current evidence on the acute (single bout of exercise) andchronic effects of walking and resistance exercise on blood pressure and its determinants. Expertcommentary: In patients with symptomatic PAD, exercise promotes acute and chronic reductions in bloodpressure. These effects were observed particularly after walking and resistance exercise. Future studiesare necessary to investigate the effects of other exercise modalities, especially non-painful exercises, oncardiovascular function in patients with symptomatic PAD.", "metadata": {}}
+{"_id": "54482327", "title": "", "text": "Morin Exhibits Anti-Inflammatory Effects on IL-1β-Stimulated Human Osteoarthritis Chondrocytes byActivating the Nrf2 Signaling PathwayBackground/Aims: Osteoarthritis (OA) is a multifactorial diseasethat is associated with inflammation in joints. The purpose of the present study was to investigate theanti-inflammatory activity and mechanism of morin on human osteoarthritis chondrocytes stimulated byIL-1β. Methods: The levels of NO and PGE2 were measured by the Griess method and ELISA. The levelsof MMP1, MMP3, and MMP13 were also measured by ELISA. Results: The results revealed that IL-1βsignificantly increased the production of NO, PGE2, MMP1, MMP3, and MMP13. Additionally, the increaseswere significantly attenuated by treatment with morin. Furthermore, IL-1β-induced NF-κB activation wassuppressed by morin. In addition, the expression of Nrf2 and HO-1 were increased by morin andknockdown of Nrf2 could prevent the anti-inflammatory effects of morin. Conclusion: In conclusion, thisstudy suggested that morin attenuated IL-1β-induced inflammation by activating the Nrf2 signalingpathway.", "metadata": {}}
+{"_id": "54490092", "title": "", "text": "Impact of blood pressure variability on cardiovascular events in elderly patients with hypertension.Bloodpressure variability is one of the characteristic features of hypertension in the elderly. However, itsclinical significance remains to be determined. We therefore examined the impact of blood pressurevariability on the development of cardiovascular events in elderly hypertensive patients. A total of 106consecutive hypertensive patients aged more than 60 years old (mean age, 73.9 +/- 8.1 years old; male,54%), all of whom underwent 24-h ambulatory blood pressure monitoring, were followed up (median, 34months; range, 3-60 months). During the follow-up period, 39 cardiovascular events were observed,including 14 cases of cerebral infarction and 7 cases of acute myocardial infarction. The coefficient ofvariation (CV) of 24-h systolic blood pressure (SBP) values was used as an index of blood pressurevariability. The patients showed a mean CV value of 10.6%, and were divided into two groups accordingto this mean value as a cut-off point: a high CV group (n = 46) and a low CV group (n = 60). Althoughbaseline clinical characteristics were similar in the two groups, Kaplan-Meier plots for event-free survivalrevealed that the rate of cardiovascular events was significantly higher in high CV group than in low CVgroup (p < 0.05). Cox's proportional hazards analysis showed that increased blood pressure variability (ahigh CV value of 24-h SBP) was an independent predictive variable for cardiovascular events. The CVvalue of daytime SBP and the SD value of both 24-h SBP and daytime SBP also had positive correlationswith the onset of cardiovascular events. These results suggest that increased blood pressure variabilitymay be an independent risk factor for cardiovascular events in elderly hypertensive patients.", "metadata": {}}
+{"_id": "54561384", "title": "", "text": "Reprogramming committed murine blood cells to induced hematopoietic stem cells with definedfactors.Hematopoietic stem cells (HSCs) sustain blood formation throughout life and are the functionalunits of bone marrow transplantation. We show that transient expression of six transcription factorsRun1t1, Hlf, Lmo2, Prdm5, Pbx1, and Zfp37 imparts multilineage transplantation potential onto otherwisecommitted lymphoid and myeloid progenitors and myeloid effector cells. Inclusion of Mycn and Meis1 anduse of polycistronic viruses increase reprogramming efficacy. The reprogrammed cells, designatedinduced-HSCs (iHSCs), possess clonal multilineage differentiation potential, reconstitute stem/progenitorcompartments, and are serially transplantable. Single-cell analysis revealed that iHSCs derived underoptimal conditions exhibit a gene expression profile that is highly similar to endogenous HSCs. Thesefindings demonstrate that expression of a set of defined factors is sufficient to activate the gene networksgoverning HSC functional identity in committed blood cells. Our results raise the prospect that blood cellreprogramming may be a strategy for derivation of transplantable stem cells for clinical application.", "metadata": {}}
+{"_id": "54561709", "title": "", "text": "Genetic variability in a frozen batch of MCF-7 cells invisible in routine authentication affecting cellfunctionCommon recommendations for cell line authentication, annotation and quality control fall shortaddressing genetic heterogeneity. Within the Human Toxome Project, we demonstrate that there can bemarked cellular and phenotypic heterogeneity in a single batch of the human breast adenocarcinoma cellline MCF-7 obtained directly from a cell bank that are invisible with the usual cell authentication by shorttandem repeat (STR) markers. STR profiling just fulfills the purpose of authentication testing, which is todetect significant cross-contamination and cell line misidentification. Heterogeneity needs to be examinedusing additional methods. This heterogeneity can have serious consequences for reproducibility ofexperiments as shown by morphology, estrogenic growth dose-response, whole genome gene expressionand untargeted mass-spectroscopy metabolomics for MCF-7 cells. Using Comparative GenomicHybridization (CGH), differences were traced back to genetic heterogeneity already in the cells from theoriginal frozen vials from the same ATCC lot, however, STR markers did not differ from ATCC referencefor any sample. These findings underscore the need for additional quality assurance in Good Cell CulturePractice and cell characterization, especially using other methods such as CGH to reveal possible genomicheterogeneity and genetic drifts within cell lines.", "metadata": {}}
+{"_id": "54562433", "title": "", "text": "The Mammalian-Specific Protein Armcx1 Regulates Mitochondrial Transport during AxonRegenerationMitochondrial transport is crucial for neuronal and axonal physiology. However, whether andhow it impacts neuronal injury responses, such as neuronal survival and axon regeneration, remainlargely unknown. In an established mouse model with robust axon regeneration, we show that Armcx1, amammalian-specific gene encoding a mitochondria-localized protein, is upregulated after axotomy in thishigh regeneration condition. Armcx1 overexpression enhances mitochondrial transport in adult retinalganglion cells (RGCs). Importantly, Armcx1 also promotes both neuronal survival and axon regenerationafter injury, and these effects depend on its mitochondrial localization. Furthermore, Armcx1 knockdownundermines both neuronal survival and axon regeneration in the high regenerative capacity model,further supporting a key role of Armcx1 in regulating neuronal injury responses in the adult centralnervous system (CNS). Our findings suggest that Armcx1 controls mitochondrial transport duringneuronal repair.", "metadata": {}}
+{"_id": "55040297", "title": "", "text": "A diversity of beta diversities: straightening up a concept gone awry. Part 1. Defining beta diversity as afunction of alpha and gamma diversityThe term beta diversity has been used to refer to a wide variety ofphenomena. Although all of these encompass some kind of compositional heterogeneity between places,many are not related to each other in any predictable way. The present two-part review aims to put thedifferent phenomena that have been called beta diversity into a common conceptual framework, and toexplain what each of them measures. In this first part, the focus is on defining a beta component ofdiversity. This involves deciding what diversity is and how the observed total or gamma diversity (g) ispartitioned into alpha (a) and beta (b) components. Several different definitions of ‘‘beta diversity’’ thatresult from these decisions have been used in the ecological literature. True beta diversity is obtainedwhen the total effective number of species in a dataset (true gamma diversity g) is multiplicativelypartitioned into the effective number of species per compositionally distinct", "metadata": {}}
+{"_id": "55128127", "title": "", "text": "A cross-cultural study of wine consumers with respect to health benefits of wineThe objective of thepresent study was to examine consumer preference and consumption behaviour with respect to thehealth benefits of wine for two contextually and culturally diverse consumer groups, namely Koreans andAustralians. Participants were required to be wine consumers over the age of 18. Responses werecollected by means of an online questionnaire. The results indicated that perceived health benefits of redwine were higher in the Australian sample than the Korean sample. Similarly, Australian consumers hadmore health related wine knowledge than Korean consumers. Red wine was the preferred wine style forboth Korean and Australian consumers; however, the proportion of preference for red wine wassignificantly higher in the Korean sample. With respect to the expenditure on wine products,AUD$11–$19 was the preferred price range for both groups. The results also indicated thathealth-oriented wine is more attractive to Korean consumers than Australian consumers. In relation togender, Korean women preferred red wine as much as men, but Australian women consumed significantlymore white wine than men. Such findings inform winemakers and wine marketers on the appropriatenessof weighting wine production and marketing to health aspects in order to maximize consumer", "metadata": {}}
+{"_id": "56391045", "title": "", "text": "DIASPORA BONDS: TAPPING THE DIASPORA DURING DIFFICULT TIMESIndia and Israel have raised overUS$35 billion by tapping into the wealth of their diaspora communities. These diaspora bonds represent astable and cheap source of external finance, often when countries lost access to international capitalmarkets. For diaspora investors, these bonds offer the opportunity to help their country of origin whilealso providing an investment opportunity. The potential for diaspora bonds is significant for manycountries with large diasporas abroad. However, diaspora bond issuance from countries with weakgovernance and high sovereign risk may require support for institutional capacity building and creditenhancement from multilateral or bilateral agencies. Haiti, for instance, could raise several hundredmillion dollars by issuing diaspora bonds provided a guarantee structure is created to build trust in thecountry's public institutions.", "metadata": {}}
+{"_id": "56486733", "title": "", "text": "Peroxisome Proliferator Activated Receptor gamma (PPARγ) Agonist Rosiglitazone Ameliorate AirwayInflammation by Inhibiting Toll-Like Receptor 2 (TLR2)/Nod-Like Receptor with Pyrin Domain Containing3 (NLRP3) Inflammatory Corpuscle Activation in Asthmatic MiceBACKGROUND The purpose of this studywas to explore the function and mechanism of peroxisome proliferator activated receptor agonist (PPARγ)in the toll-like receptor 2 (TLR2)/nod-like receptor with pyrin domain containing 3 (NLRP3) inflammatorycorpuscle pathway of asthmatic mice. MATERIAL AND METHODS Eighteen female mice (C57) wererandomly divided into 4 groups: the control group, the asthma model group challenged by ovalbumin(OVA), the rosiglitazone group, and the PPARγ agonist rosiglitazone treatment group. The infiltration ofperibronchial inflammatory cells as well as the proliferation and mucus secretion of bronchial epithelialgoblet cells were observed by hematoxylin and eosin and periodic acid-Schiff staining. Western blots wereemployed to detect the expression levels of TLR2, PPARγ, nuclear factor-kappa B (NF-kappaB), NLRP3,and ASC [apoptosis-associated speck-like protein containing C-terminal caspase recruitment domain[CARD]). RESULTS The number of inflammatory cells and eosinophils, and the levels of OVAs IgE,interleukin-4 (IL-4), and IL-13 were significantly higher in the C57 asthma group compared to the C57control group and the treatment group (P<0.05). The infiltration of peribronchiolar inflammatory cells,wall thickening, goblet cell hyperplasia, and mucus secretion in the treatment group were all significantlydecreased compared to those in the asthma group. PPARg expression in the treatment group wassignificantly higher compared to the asthma group and the control group (P<0.05). The proteinexpression levels of TLR2, NF-kappaB, NLRP3, and ASC were significantly lower compared to the asthmagroup but were higher compared to the control group (P<0.05). CONCLUSIONS PPARγ rosiglitazoneameliorates airway inflammation by inhibiting NF-kappaB expression in asthmatic mice, and furtherinhibits the activation of TLR2/NLRP3 inflammatory corpuscles.", "metadata": {}}
+{"_id": "56528795", "title": "", "text": "Omi/HtrA2 Participates in Age-Related Autophagic Deficiency in Rat LiverLiver is a vital organ with manyimportant functions, and the maintenance of normal hepatic function is necessary for health. As anessential mechanism for maintaining cellular homeostasis, autophagy plays an important role in ensuringnormal organ function. Studies have indicated that the degeneration of hepatic function is associated withautophagic deficiency in aging liver. However, the underlying mechanisms still remain unclear. The serineprotease Omi/HtrA2 belongs to the HtrA family and promotes apoptosis through either thecaspase-dependent or caspase-independent pathway. Mice lacking Omi/HtrA2 exhibited progeriasymptoms (premature aging), which were similar to the characteristics of autophagic insufficiency. In thisstudy, we demonstrated that both the protein level of Omi/HtrA2 in liver and hepatic function werereduced as rats aged, and there was a positive correlation between them. Furthermore, severalautophagy-related proteins (LC3II/I, Beclin-1 and LAMP2) in rat liver were decreased significantly withthe increasing of age. Finally, inhibition of Omi/HtrA2 resulted in reduced autophagy and hepaticdysfunction. In conclusion, these results suggest that Omi/HtrA2 participates in age-related autophagicdeficiency in rat liver. This study may offer a novel insight into the mechanism involved in liver aging.", "metadata": {}}
+{"_id": "56893404", "title": "", "text": "Macrosomia and Hyperinsulinaemic Hypoglycaemia in Patients with Heterozygous Mutations in the HNF4AGeneBackground  Macrosomia is associated with considerable neonatal and maternal morbidity. Factorsthat predict macrosomia are poorly understood. The increased rate of macrosomia in the offspring ofpregnant women with diabetes and in congenital hyperinsulinaemia is mediated by increased foetalinsulin secretion. We assessed the in utero and neonatal role of two key regulators of pancreatic insulinsecretion by studying birthweight and the incidence of neonatal hypoglycaemia in patients withheterozygous mutations in the maturity-onset diabetes of the young (MODY) genes HNF4A (encodingHNF-4α) and HNF1A/TCF1 (encoding HNF-1α), and the effect of pancreatic deletion of Hnf4a on foetal andneonatal insulin secretion in mice.", "metadata": {}}
+{"_id": "57121667", "title": "", "text": "ART adherence clubs: A long-term retention strategy for clinically stable patients receiving antiretroviraltherapyThe ART-adherence club model described here provides patient-friendly access to antiretroviraltherapy (ART) for clinically stable patients. It reduces the burden that stable patients place on healthcarefacilities, increasing clinical human resources for new patients, and those clinically unstable and at risk offailing treatment. In the model, 30 patients are allocated to an ART club. The group meets either at afacility or community venue for less than an hour every 2 months. Group meetings are facilitated by a layclub facilitator who provides a quick clinical assessment, referral where necessary, and dispensespre-packed ART. From January 2011 to December 2012, after adoption for phased rollout by the WesternCape Government, more than 600 ART clubs were established in Cape Town, providing ART care to over16 000 patients. This extensive, rapid rollout demonstrates active buy-in from patients and facility staff.South Africa should consider a similar model for national rollout.", "metadata": {}}
+{"_id": "57574395", "title": "", "text": "Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer’smodelsDefective brain hormonal signaling has been associated with Alzheimer's disease (AD), a disordercharacterized by synapse and memory failure. Irisin is an exercise-induced myokine released on cleavageof the membrane-bound precursor protein fibronectin type III domain-containing protein 5 (FNDC5), alsoexpressed in the hippocampus. Here we show that FNDC5/irisin levels are reduced in AD hippocampi andcerebrospinal fluid, and in experimental AD models. Knockdown of brain FNDC5/irisin impairs long-termpotentiation and novel object recognition memory in mice. Conversely, boosting brain levels ofFNDC5/irisin rescues synaptic plasticity and memory in AD mouse models. Peripheral overexpression ofFNDC5/irisin rescues memory impairment, whereas blockade of either peripheral or brain FNDC5/irisinattenuates the neuroprotective actions of physical exercise on synaptic plasticity and memory in AD mice.By showing that FNDC5/irisin is an important mediator of the beneficial effects of exercise in AD models,our findings place FNDC5/irisin as a novel agent capable of opposing synapse failure and memoryimpairment in AD.", "metadata": {}}
+{"_id": "57762078", "title": "", "text": "Influence of antidepressant therapy on sick leave in primary care: ADAS, a comparative observationalstudyBackground Compared to other European countries, Sweden's yearly sick leave expenditures aremoderate. Common mental disorders (CMD) are important causes of sick leave, affecting 10-15% of theadult population. A Swedish register based study indicates that antidepressant therapy for patients onlong-term sick leave for CMD leads to longer sick leave and higher frequency of non-time-limited sicknesscompensation as compared to psychotherapy, work oriented rehabilitation, and other therapies. Aim Toverify if patients on antidepressant therapy and on long-term sick leave for depression, anxiety andstress-related mental disorders have a longer sick leave than patients treated with other therapies.Method Prospective, observational study at 28 primary health care centers in the Region Västra Götaland,Sweden, including 192 patients on sick leave for CMD. Outcome measures were gross and net sick leavedays. Interpretation There were no significant differences in sick leave days (gross or net) due to CMDwhen comparing the patients treated and not treated with antidepressants during the 12 monthobservation period. The groups differed at baseline only concerning frequency of exhaustion disorder,with a higher frequency of exhaustion disorder in the group without antidepressants. Analysis of otherpossible factors associated with shorter or longer sick leave only showed associations with the patient'sown perception of possibility of returning to work in near and distant future. An important factorassociated with longer sick leave was the patient's own perception of possibility of return to presentworkplace. As CMD are important causes of sick leave and sick leave costs, this factor should behighlighted in future research on the rehabilitation process.", "metadata": {}}
+{"_id": "57783564", "title": "", "text": "CDX2 inhibits the proliferation and tumor formation of colon cancer cells by suppressing Wnt/β-cateninsignaling via transactivation of GSK-3β and Axin2 expressionCaudal-related homeobox transcriptionfactor 2 (CDX2), an intestine-specific nuclear transcription factor, has been strongly implicated in thetumourigenesis of various human cancers. However, the functional role of CDX2 in the development andprogression of colorectal cancer (CRC) is not well known. In this study, CDX2 knockdown in colon cancercells promoted cell proliferation in vitro, accelerated tumor formation in vivo, and induced a cell cycletransition from G0/G1 to S phase, whereas CDX2 overexpression inhibited cell proliferation.TOP/FOP-Flash reporter assay showed that CDX2 knockdown or CDX2 overexpression significantlyincreased or decreased Wnt signaling activity. Western blot assay showed that downstream targets ofWnt signaling, including β-catenin, cyclin D1 and c-myc, were up-regulated or down-regulated inCDX2-knockdown or CDX2-overexpressing colon cancer cells. In addition, suppression of Wnt signalingby XAV-939 led to a marked suppression of the cell proliferation enhanced by CDX2 knockdown, whereasactivation of this signaling by CHIR-99021 significantly enhanced the cell proliferation inhibited by CDX2overexpression. Dual-luciferase reporter and quantitative chromatin immunoprecipitation (qChIP) assaysfurther confirmed that CDX2 transcriptionally activates glycogen synthase kinase-3β (GSK-3β) and axisinhibition protein 2 (Axin2) expression by directly binding to the promoter of GSK-3β and the upstreamenhancer of Axin2. In conclusion, these results indicated that CDX2 inhibits the proliferation and tumorformation of colon cancer cells by suppressing Wnt/β-catenin signaling.", "metadata": {}}
+{"_id": "58006489", "title": "", "text": "Prostaglandin E2 mediates sensory nerve regulation of bone homeostasisWhether sensory nerve cansense bone density or metabolic activity to control bone homeostasis is unknown. Here we foundprostaglandin E2 (PGE2) secreted by osteoblastic cells activates PGE2 receptor 4 (EP4) in sensory nervesto regulate bone formation by inhibiting sympathetic activity through the central nervous system. PGE2secreted by osteoblasts increases when bone density decreases as demonstrated in osteoporotic animalmodels. Ablation of sensory nerves erodes the skeletal integrity. Specifically, knockout of the EP4 gene inthe sensory nerves or cyclooxygenase-2 (COX2) in the osteoblastic cells significantly reduces bonevolume in adult mice. Sympathetic tone is increased in sensory denervation models, and propranolol, aβ2-adrenergic antagonist, rescues bone loss. Furthermore, injection of SW033291, a small molecule toincrease PGE2 level locally, significantly boostes bone formation, whereas the effect is obstructed in EP4knockout mice. Thus, we show that PGE2 mediates sensory nerve to control bone homeostasis andpromote regeneration.", "metadata": {}}
+{"_id": "58050905", "title": "", "text": "The Bone and Joint Decade 2000-2010.The World Health Organisation has declared the period 2000 to2010 the Bone and Joint Decade. This is indeed timely and appropriate. Hundreds of millions of people inthe world today are beset with a host of disabilities caused by trauma, ageing and degeneration and otheraffections of the musculo-skeletal system. With the state of art of orthopaedic surgery and rheumatology,sufferers of bone and joint disabilities have benefited a great deal from advances in pharmacology, newertechniques of imaging, surgery and man-made materials to replace diseased or damaged bone andcartilage. However, man-made materials, being non-living, are subject to wear and tear and loosening inthe host bone. As we advance into the Bone and Joint Decade, further improvement in the treatment ofbone and joint diseases lies in more basic cartilage and bone research. The Human Genome Project hasprovided us with a better understanding of disease genes and the possibility of gene manipulation toprevent and treat specific diseases. Cartilage cells culture and transplant are already a reality. Tissueengineering, i.e. growing cells in three-dimensional substrates of collagen or synthetic biodegradablepolymers, started in the 1980s, will in future be used to replace damaged bone and cartilage parts withliving and bone and cartilaginous tissues, respectively. The first steps have been taken; more researchneeds to be done. And it is not unreasonable to expect a significant breakthrough in the treatment ofbone and joint diseases at the end of this decade. Ann Acad Med Singapore 2002; 31:621-2", "metadata": {}}
+{"_id": "58564850", "title": "", "text": "Prevalence of late-life depression and gap in mental health service use across Europeanregions.Background We aimed to determine the prevalence and gap in use of mental health services forlate-life depression in four European regions (Western Europe, Scandinavia, Southern Europe and Centraland Eastern Europe) and explore socio-demographic, social and health-related factors associated with it.Methods We conducted a cross-sectional study based on data from the Survey on Health, Ageing andRetirement in Europe. Participants were a population-based sample of 28 796 persons (53% women,mean age 74 years old) residing in Europe. Mental health service use was estimated using informationabout the diagnosis or treatment for depression. Results The prevalence of late-life depression was 29%in the whole sample and was highest in Southern Europe (35%), followed by Central and Eastern Europe(32%), Western Europe (26%) and lowest in Scandinavia (17%). Factors that had the strongestassociation with depression were total number of chronic diseases, pain, limitations in instrumentalactivities of daily living, grip strength and cognitive impairment. The gap in mental health service use was79%. Conclusions We suggest that interventions to decrease the burden of late-life depression should betargeted at individuals that are affected by chronic somatic comorbidities and are limited in mental andphysical functioning. Promotion of help-seeking of older adults, de-stigmatization of mental illness andeducation of general practitioners could help decrease the gap in mental health service utilization.", "metadata": {}}
+{"_id": "59453688", "title": "", "text": "Impedance and Interface Properties of Al/Methyl-Red/p-InP Solar CellAn Al/methyl-red/p-InP solar cellwas fabricated via solution-processing method and was characterized by using current-voltage (I-V) andcapacitance-voltage-frequency (C-V-f) measurements at room temperature. From dark I-Vcharacteristics, the values of ideality factor and barrier height of the device were calculated as 1.11 eVand 2.02, respectively. It has been seen that the device exhibited a good photovoltaic behavior with amaximum open circuit voltage of 0.38 V and short-circuit current of 2.8 nA under only 200 lx lightintensity. The barrier height and acceptor carrier concentration values for the Al/methyl-red/p-InPdevices were extracted as 1.27 eV and from linear region of its characteristics, respectively. Thedifference between (I-V) and (C-V) for Al/methyl-red/p-InP device was attributed the different nature ofthe I-V and C-V measurements. Also, the energy distribution curves of the interface states and their timeconstants were obtained from the experimental conductance properties of the Al/methyl-red/p-InPstructure at room temperature. The interface state densities and their relaxation times of the device haveranged from and s at (1.11-) eV to and s at (0.79-) eV, respectively. It was seen that both the interfacestate density and the relaxation time of the interface states have decreased with bias voltage fromexperimental results.", "metadata": {}}
+{"_id": "60206680", "title": "", "text": "R: A Language for Data Analysis and GraphicsAbstract In this article we discuss our experience designingand implementing a statistical computing language. In developing this new language, we sought tocombine what we felt were useful features from two existing computer languages. We feel that the newlanguage provides advantages in the areas of portability, computational efficiency, memorymanagement, and scoping.", "metadata": {}}
+{"_id": "60515890", "title": "", "text": "The Mouse Brain in Stereotaxic Coordinates\" The Mouse Brain in Stereotaxic Coordinates\" is the mostwidely used and cited atlas of the mouse brain in print. It provides researchers and students with bothaccurate stereotaxic coordinates for laboratory use, and detailed delineations and indexing of structuresfor reference. The accompanying DVD provides drawings of brains structures that can be used astemplates for making figures for publication. The 3rd edition is both a major revision and an expansion ofprevious editions. Delineations and photographs in the horizontal plane of section now complement thecoronal and sagittal series, and all the tissue sections are now shown in high resolution digital colorphotography. The photographs of the sections and the intermediate sections are also provided on theaccompanying DVD in high-resolution JP 2000 format. The delineations of structures have been revised,and naming conventions made consistent with Paxinos and Watson's \"Rat Brain in StereotaxicCoordinates, 6th Edition\". The 3rd edition of this atlas is now in more practical 14\"x11\" format forconvenient lab use. This edition is in full color throughout. It includes a CD of all plates and diagrams, aswell as Adobe Illustrator files of the diagrams, and a variety of additional useful material. Coronal andsagittal diagrams are completely reworked and updated. Rhombomeric borders are included in sagittalfigures, for the first time in mammals. Microscopic plates are scanned with a new method in much higherquality.", "metadata": {}}
+{"_id": "61050894", "title": "", "text": "ggplot2: Elegant Graphics for Data Analysisggplot2: Elegant Graphics for Data Analysis is a new additionto the UseR! series by Springer, probably the fastest expanding source of resources for computationalstatistics at the current moment. The books in this series are all linked with R, either presenting a newpackage developed by the own authors of the book or describing how to applying statistical techniqueswith the different packages available in R. ggplot2 is an implementation in R of The Grammar of Graphics(Wilkinson 2005) a systematic approach to the specification of statistical graphics that was introduced ina book previously reviewed in the Journal of Statistical Software by Cox (2007). This implementation hasbeen developed by Hadley Wickham, who is also the author of the book reviewed here.", "metadata": {}}
+{"_id": "63858430", "title": "", "text": "Multiple Imputation For Nonresponse In Surveysmultiple imputation for nonresponse in surveys isavailable in our book collection an online access to it is set as public so you can download it instantly. Ourbook servers hosts in multiple locations, allowing you to get the most less latency time to download anyof our books like this one. Merely said, the multiple imputation for nonresponse in surveys is universallycompatible with any devices to read.", "metadata": {}}
+{"_id": "67045088", "title": "", "text": "Inhibition of the dipeptidyl peptidase DPP4 (CD26) reveals IL-33-dependent eosinophil-mediated controlof tumor growthPost-translational modification of chemokines mediated by the dipeptidyl peptidase DPP4(CD26) has been shown to negatively regulate lymphocyte trafficking, and its inhibition enhances T cellmigration and tumor immunity by preserving functional chemokine CXCL10. By extending those initialfindings to pre-clinical models of hepatocellular carcinoma and breast cancer, we discovered a distinctmechanism by which inhibition of DPP4 improves anti-tumor responses. Administration of the DPP4inhibitor sitagliptin resulted in higher concentrations of the chemokine CCL11 and increased migration ofeosinophils into solid tumors. Enhanced tumor control was preserved in mice lacking lymphocytes andwas ablated after depletion of eosinophils or treatment with degranulation inhibitors. We furtherdemonstrated that tumor-cell expression of the alarmin IL-33 was necessary and sufficient foreosinophil-mediated anti-tumor responses and that this mechanism contributed to the efficacy ofcheckpoint-inhibitor therapy. These findings provide insight into IL-33- and eosinophil-mediated tumorcontrol, revealed when endogenous mechanisms of DPP4 immunoregulation are inhibited. Eosinophilshave been described mainly in allergy settings but are increasingly appreciated as being involved in otheraspects of immunity. Albert and colleagues use a clinically approved inhibitor of the dipeptidyl peptidaseDPP4 to facilitate the recruitment of eosinophils to mouse tumors, where they are essential in tumordestruction.", "metadata": {}}
+{"_id": "67787658", "title": "", "text": "Cycling Quiescence in Temozolomide Resistant Glioblastoma Cells Is Partly Explained by microRNA-93and -193-Mediated Decrease of Cyclin DGlioblastoma multiforme (GBM) is a fatal malignancy of thecentral nervous system, commonly associated with chemoresistance. The alkylating agent Temozolomide(TMZ) is the front-line chemotherapeutic agent and has undergone intense studies on resistance. Thesestudies reported on mismatch repair gene upregulation, ABC-targeted drug efflux, and cell cyclealterations. The mechanism by which TMZ induces cell cycle arrest has not been well-established.TMZ-resistant GBM cells have been linked to microRNA (miRNA) and exosomes. A cell cycle miRNA arrayidentified distinct miRNAs only in exosomes from TMZ-resistant GBM cell lines and primary spheres. Wenarrowed the miRs to miR-93 and -193 and showed in computational analyses that they could targetCyclin D1. Since Cyclin D1 is a major regulator of cell cycle progression, we performed cause-effectstudies and showed a blunting effects of miR-93 and -193 in Cyclin D1 expression. These two miRs alsodecreased cell cycling quiescence and induced resistance to TMZ. Taken together, our data provide amechanism by which GBM cells can exhibit TMZ-induced resistance through miRNA targeting of Cyclin D1.The data provide a number of therapeutic approaches to reverse chemoresistance at the miRNA,exosomal and cell cycle points.", "metadata": {}}
+{"_id": "68317730", "title": "", "text": "Longitudinal changes in maternal corin and mid-regional proatrial natriuretic peptide in women at risk ofpre-eclampsiaObjectives Corin, an atrial natriuretic peptide-converting enzyme, has been found topromote trophoblast invasion and spiral artery remodeling. Reduced maternal plasma atrial natriureticpeptide (ANP) levels and elevated corin levels have been reported in pregnancies complicated by PE. Theaim of this study was to investigate longitudinal changes in maternal plasma levels of corin andmidregional proatrial natriuretic peptide (MR-PANP) in pregnancies that develop preeclampsia (PE) andgestational hypertension (GH). Methods Nested case control study drawn from a larger prospectivelongitudinal study in singleton pregnancies identified by screening at 11 + 0 − 13 + 6 weeks’ gestation asbeing at high risk for PE. Blood samples were taken every four weeks until delivery. Values werecompared in pregnancies that developed preterm-PE (requiring delivery before 37 weeks), term-PE, GH,and those that remained normotensive. The distribution of maternal plasma corin and PANP were madeGaussian after log 10 transformation. Analysis of repeated measures with multilevel mixed-effects linearmodel (fixed effects and random effects) was performed. The multilevel model was compared to one-levelmodel by the likelihood radio (LR) test. Results A total of 471 samples were analyzed from 122 women,including 85 that remained normotensive, 12 that developed GH, 13 term-PE and 12 preterm-PE. In thenormotensive group, log10corin levels were associated with gestational age ( p p  = 0.001). In the GHand term-PE groups, corin did not differ significantly from the normotensive group ( p  = 0.64 and p  =0.16, respectively). Compared to the normotensive group, MR-PANP levels were significantly higher in thepregnancies that developed preterm-PE and GH ( p  = 0.046 and p  = 0.019, respectively), but notterm-PE ( p  = 0.47). Conclusions Maternal plasma corin and MR-PANP could potentially be usefulbiomarkers for the prediction of preterm-PE. Disclosures A. Khalil: Research Support Recipient;Commercial Interests: USCOM, Roche, Alere, NICOM, Q-fFN; Speaker: Roche.", "metadata": {}}
+{"_id": "69045262", "title": "", "text": "Children's Exercise PhysiologyThe reorganized and newly revised \"Children's Exercise Physiology, SecondEdition, \" presents the most up-to-date research, methodology, and approaches related to children'sphysiologic responses to exercise. The book examines not only the current major issues that separatechildren from adults, but also the underlying mechanisms of these differences. Readers will learn whatmakes children different from adults physiologically--such as size, biochemical differences,neuromuscular differences, and lack of sexual and hormonal maturation--and the reasons for thesedifferences. Those involved with young athletes, disease management, and health promotion will gainvaluable insight into the physiologic determinants of exercise performance. Children's exercise physiologyis a fast-moving field. In the eight years since the first edition of this book was published, much newinformation has surfaced. This streamlined new edition contains 13 instead of 15 chapters, anintroduction, and updated features: -Chapter objectives, discussion questions and research directions,and a glossary of terms promote learning.-A reorganized table of contents improves the flow fromchapter to chapter.-A new final chapter covers the role of the central nervous system. Also included isin-depth discussion of the determinants of aerobic fitness and VO2 kinetics and the significance ofmaximal aerobic power in children. With improved chapters on thermoregulation and metabolic andendocrinologic responses to exercise, you can be confident you're getting the latest information with\"Children's Exercise Physiology, Second Edition. \"", "metadata": {}}
+{"_id": "70439309", "title": "", "text": "Cost-effectiveness in health and medicine1. Cost-Effectiveness Analysis as a Guide to Resource Allocationin Health: Roles and Limitations 2. Theoretical Foundations of Cost-Effectiveness Analysis 3. Framing andDesigning the Cost-Effectiveness Analysis 4. Identifying and Valuing Outcomes 5. Assessing theEffectiveness of Health Interventions 6. Estimating Costs in Cost-Effectiveness Analysis 7. TimePreference 8. Reflecting Uncertainty in Cost-Effectiveness Analysis 9. Reporting Cost-EffectivenessStudies and Results Appendix A: Summary of Recommendations for the Reference Case Appendix B:Cost-Effectiveness of Strategies to Prevent Neural Tube Defects Appendix C: The Cost-Effectiveness ofDietary and Pharmacologic Therapy for Cholesterol Reduction in Adults", "metadata": {}}
+{"_id": "70455704", "title": "", "text": "Weight gain during pregnancy: reexamining the guidelines.As women of childbearing age have becomeheavier, the trade-off between maternal and child health created by variation in gestational weight gainhas become more difficult to reconcile. Weight Gain During Pregnancy responds to the need for areexamination of the 1990 Institute of Medicine guidelines for weight gain during pregnancy. It builds onthe conceptual framework that underscored the 1990 weight gain guidelines and addresses the need toupdate them through a comprehensive review of the literature and independent analyses of existingdatabases. The book explores relationships between weight gain during pregnancy and a variety offactors (e.g., the mother's weight and height before pregnancy) and places this in the context of thehealth of the infant and the mother, presenting specific, updated target ranges for weight gain duringpregnancy and guidelines for proper measurement. New features of this book include a specific range ofrecommended gain for obese women. Weight Gain During Pregnancy is intended to assist practitionerswho care for women of childbearing age, policy makers, educators, researchers, and the pregnant womenthemselves to understand the role of gestational weight gain and to provide them with the tools neededto promote optimal pregnancy outcomes.", "metadata": {}}
+{"_id": "70516463", "title": "", "text": "To err is human. Building a safer health systemHuman beings, make errors Healthcare Services is acomplex industry prone to accidents. The IOM Report [1] points out that some systems are more prone toaccidents than others. When a system fails there are often multiple faults. In healthcare,human errorsare the greatest contributors to accidents,however when human error is to blame it often depends uponfailures within the system. These failures exists in the system before the error occurs, the same as withlatent errors which are difficult to identify since they may be hidden in computers or within the variousmanagerial layers. Most of the errors can be prevented by designing systems that make it hard for peopleto do the wrong thing and easy for people to do the right thing. In healthcare, this means designingprocesses that are able to ensure that patients are safe from accidental injury. As healthcare and thesystem that delivers it become more complex, the opportunities for errors abound. The IOM report “ToErr is Human” proposes an approach for reducing medical errors and improving patient safety. Theenvironment within which this occurs has a critical influence on quality. This influence may contain twodimensions; the first consists of the domain of quality which includes the practice that is consistent withcurrent medical knowledge. The second dimension consists of forces in the external environment that candrive quality improvement in the delivery system. Although the risk of dying as a result of a medicalerror, far surpasses the risk of dying in an airline accident, public attention has been more focused onimproving safety in the airline industry than in healthcare systems. Because of the absence ofstandardized nomenclature, it is important to define what an error is and what is an adverse event, theIOM Report defines them in the following way: “An error is the failure of a planned action to be completedas intended or the use of a wrong plan to achieve an aim. ” An adverse event is an injury caused bymedical management rather than the underlying condition of the patient. An adverse event attributableto error is a “preventable adverse event”.", "metadata": {}}
+{"_id": "70633421", "title": "", "text": "Excess risk of lymphomas, leukemia and myeloma in patients with rheumatoid arthritisThe incidence ofmalignant neoplasms among 11 483 male and 34 618 female individuals with rheumatoid arthritis wasstudied using two separate nationwide data registers covering the whole Finnish population: the SocialInsurance Institution9s Population Data Register, which includes information on medication for certainchronic diseases, and the Finnish Cancer Registry, with data on all cancer patients diagnosed in Finland.The follow-up comprised a total of 213 911 person years. The total incidence of all malignant neoplasmswas higher in males and on the level expected in females. The expected number of cases of leukemia,lymphomas, Hodgkin9s disease and myeloma in both sexes was 59·6 as compared with the 130 casesobserved. This difference is statistically highly significant (p", "metadata": {}}
+{"_id": "70704988", "title": "", "text": "Advanced Human NutritionAdvanced Human Nutrition, Second Edition provides an in-depth overview ofthe human body and details why nutrients are important from a biochemical, physiological, and molecularperspective. Figures help illustrate the content and bring the meaning to life to enhance the reader'sunderstanding. Complex pathways, for example, are presented in a student-friendly fashion, as arediagrams that illustrate metabolism and the molecular functions of nutrients. Multiple elements within thetext, such as \"Here's Where You Have Been\" and \"Here's Where You Are Going,\" help drive home keypoints from the chapter and provide real-world examples to bring the content to life. Topics coveredinclude: * cell aging, damage and repair systems * human nutrition, digestion, and absorption withrelation to organs, exocrine and endocrine functions, histology, and absorptive activities * microflora andsatiety/hunger mechanisms * macronutrients during exercise and the role of liquids and sports drinks *prevalent diseases in western cultures such as coronary heart disease, cancer, and osteoporosis AnInstructor's Manual, PowerPoint Presentations, and a TestBank are available are free downloads.", "metadata": {}}
+{"_id": "70895396", "title": "", "text": "The Endothelium: Modulator of Cardiovascular FunctionIntroduction. Methods To StudyEndothelium-Dependent Responses. Endothelium-Derived Relaxing Factor. Physiological Actions. OtherRelaxing Substances Released By the Endothelium. Production of Contracting Agents. Local Regulation ofEndothelium-Dependent Responses. Neurohumoral Regulation. Heterogeneity and Chronic Modulation.Disease. Therapeutic Implications. References. Subject Index.", "metadata": {}}
+{"_id": "71341302", "title": "", "text": "Vegetarian vs. conventional diabetic diet – A 1-year follow-upAbstract Objective Our previous 6-month,randomized study demonstrated the beneficial effect of a vegetarian (V) compared to a conventional diet(C) with similar caloric restriction on cardiovascular risk factors for patients with type 2 diabetes (T2D),namely increased insulin sensitivity, reduced body weight, reduced volume of visceral and subcutaneousfat, decreased LDL-cholesterol and improved oxidative stress markers and chosen adipokines. Weconducted post-trial monitoring to determine whether the improved outcomes persisted 1 year after theend of the study. Methods 62 subjects with T2D who completed the study were asked to come for a1-year follow-up to measure weight, waist circumference, HbA1c and blood lipids. No attempts weremade to maintain their previously assigned diets. Results 44 patients (71%) attended the post-trialmonitoring. Hypoglycemic agents were increased by 14% in V and by 26% in C; insulin therapy wasintroduced in 5% in V and in 13% in C one year after the end of the intervention. Neither weight norwaist circumference changed significantly in either group. HbA1c increased ( p  ≤ 0.05) similarly in bothgroups (+0.49 ± 1.04% in V vs. +0.42 ± 0.8% in C). Blood lipids did not change in either group.Conclusion One year after the end of the intervention, the positive effects of a vegetarian diet oncardiovascular risk factors compared to a conventional diet were partially maintained.", "metadata": {}}
+{"_id": "71625969", "title": "", "text": "Alcohol, wine, and healthAbstract Background: For the past 20 years numerous epidemiological studieshave correlated the consumption of alcohol and a variety of disease states: overall mortality,arteriosclerotic vascular diseases, hypertension, cancers, peptic ulcer, respiratory infections, gall stones,kidney stones, age-related macular degeneration, bone density, and cognitive function. Methods: Areview of these articles reveals that each of these studies has compared the outcome of individuals atvarious levels of alcohol consumption with that of abstainers. Results: Each analysis has identified aU-shaped or J-shaped curve of reduced relative risk for a given disease state compared with abstainers. Aclear definition of consumption in moderation becomes evident: for men it should not exceed 2 to 4drinks per day, and for women it should not exceed 1 to 2 drinks per day. Conclusions: Alcohol by itselfhas favorable effects on the level of high-density lipoprotein cholesterol, and inhibition of plateletaggregation. Wine, particularly red wine, has high levels of phenolic compounds that favorably influencemultiple biochemical systems, such as increased high-density lipoprotein cholesterol, antioxidant activity,decreased platelet aggregation and endothelial adhesion, suppression of cancer cell growth, andpromotion of nitric oxide production.", "metadata": {}}
+{"_id": "71628189", "title": "", "text": "Contraceptive practices of women requesting termination of pregnancy : A study from ChinaAbstract Inorder to develop a program for prevention of unwanted pregnancies, we conducted a survey ofcontraceptive practices and reasons for contraceptive failures of 1520 women seeking abortion at eightlarge hospitals in Zheng Zhou City, Henan Province, P.R. China, during the period from March 1996 toMay 1996. The most frequent cause of the unplanned pregnancy was contraceptive failure (71.9%);61.7% (938) of these current pregnancies were potentially predictable by virtue of nonuse ofcontraception (427) or by recognition of contraceptive failures (511). Among the contraceptive failures,the proportion of condom mishaps was the highest (29.7%), next was IUD failures (23.5%), then rhythmmiscalculation (15.9%). Most of abortion seekers (77.1%) used some contraceptive methods previously.But, only 19.7% of them used a contraceptive method at the first sexual intercourse. Among 1520abortion seekers, 57.6% had used condoms previously; 50.9% of the condom users had at least oneinstance of condom mishap. The rhythm method had been used by 31.7% of abortion seekers previously;59.1% of the rhythm users had at least one instance of rhythm failure. Of the 16.8% of abortion seekerswho had used pills, 58.0% of them had pill failures. Among condom and pill failures, most of them(46.4% condom users and 56.0% pill users) belonged to the user failure category (poor complicance). Ofthose seeking abortion, 56.4% had experienced at least one instance of previous abortion; 5.3% hadexperienced previous abortions at least two times. Emergency contraception had been utilized by only 10subjects prior to this current pregnancy.", "metadata": {}}
+{"_id": "72180760", "title": "", "text": "Oncologists' perceptions of the effects of cancer patients' companions on physician-patient interactionsTodetermine physicians' perceptions of the effects that the companions of cancer patients have onphysician-patient communication, semistructured interviews were conducted with 12 oncologists (6medical, 4 surgical, and 2 radiation) from a total population of 21 oncologists. The physicians estimatedthat threefourths of their patients brought companions with them to consultations and said that theseconsultations were more complex for the physician. The behaviors of the companions varied fromdomination to passive note taking, and the companions who were young professional men or olderwomen who accompanied their husbands were the most assertive and asked the most questions. Allpossible coalitions were observed during medical visits. The physicians perceived that companions andpatients often had different agendas and noted differences in the companions' behaviors according totheir gender and whether they lived in rural or urban areas.", "metadata": {}}
+{"_id": "72372925", "title": "", "text": "Wolff's Headache and Other Head Pain.There has never been a book on headache that came close to thatof the late Harold Wolff. The second edition was published 10 years ago; it was and is a masterpiece ofwriting, an exhaustive yet engrossing delineation of Wolff's long study and understanding of headache.The new edition, revised by Dalessio, serves to bring certain aspects of headache up to date, most ofthem having to do with drug therapy. The emphasis on total therapy rather than simply drug therapy hasbeen preserved, however. Dalessio has altered slightly the form of the book, although the \"new chapters\"on cluster headache and trigeminal neuralgia are merely transplants from other sections of the original.Migraine, the main part of the book, has been reshaped, with some anecdotal portions removed, but littlehas been added. It is of interest that nothing in the section on observations of methysergide (UML-491 inWolff's", "metadata": {}}
+{"_id": "72580164", "title": "", "text": "Ansichten von Hausärzten zur Versorgung von unheilbar kranken Patienten am Lebensende - Ergebnisseeiner Befragung in NiedersachsenBackground: Family doctors play an important role in the health care forterminal ill and patients. The current level of palliative care in Germany is strongly criticised, however,empirical data is scare, particularly with respect to family doctors. Methods: Therefore, the attitudes offamily doctors (sample: n= 257) in four representative regions in Lower Saxony were studied by usingsemi-structured telephone interviews. This was part of a health system researchers’ expert report.Results: 71doctors could be interviewed (28%). On the average, they cared for four palliative patientswith cancer diseases and eight palliative patients with other diseases than cancer at that time. Many ofthe doctors were available for their patients around the clock, particularly in the final phase. The mainarea for improvement was considered to be the psychosocial support – rather than pain therapy, which isusually focussed. Furthermore, a considerable openness for the establishment of new palliative carestructures was shown. Conclusion: Family doctors are highly motivated for palliative care and open forimprovements. In the process, the diversity of opinion among professions and disciplines about thecurrent situation and the further development of palliative care should be respected and considered.", "metadata": {}}
+{"_id": "72933407", "title": "", "text": "Novel Risk Factors for Systemic Atherosclerosis: A Comparison of C-Reactive Protein, Fibrinogen,Homocysteine, Lipoprotein(a), and Standard Cholesterol Screening as Predictors of Peripheral ArterialDiseaseContextSeveral novel risk factors for atherosclerosis have recently been proposed, but fewcomparative data exist to guide clinical use of these emerging biomarkers. ObjectiveTo compare thepredictive value of 11 lipid and nonlipid biomarkers as risk factors for development of symptomaticperipheral arterial disease (PAD).Design, Setting, and ParticipantsNested case-control study using plasmasamples collected at baseline from a prospective cohort of 14 916 initially healthy US male physiciansaged 40 to 84 years, of whom 140 subsequently developed symptomatic PAD (cases); 140 age- andsmoking status–matched men who remained free of vascular disease during an average 9-year follow-upperiod were randomly selected as controls. Main Outcome MeasureIncident PAD, as determined bybaseline total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol(LDL-C), total cholesterol–HDL-C ratio, triglycerides, homocysteine, C-reactive protein (CRP),lipoprotein(a), fibrinogen, and apolipoproteins (apo) A-I and B-100.ResultsIn univariate analyses, plasmalevels of total cholesterol (P<.001), LDL-C (P = .001), triglycerides (P = .001), apo B-100 (P = .001),fibrinogen (P = .02), CRP (P = .006), and the total cholesterol–HDL-C ratio (P<.001) were all significantlyhigher at baseline among men who subsequently developed PAD compared with those who did not, whilelevels of HDL-C (P = .009) and apo A-I (P = .05) were lower. Nonsignificant baseline elevations oflipoprotein(a) (P = .40) and homocysteine (P = .90) were observed. In multivariable analyses, the totalcholesterol–HDL-C ratio was the strongest lipid predictor of risk (relative risk [RR] for those in the highestvs lowest quartile, 3.9; 95% confidence interval [CI], 1.7-8.6), while CRP was the strongest nonlipidpredictor (RR for the highest vs lowest quartile, 2.8; 95% CI, 1.3-5.9). In assessing joint effects, additionof CRP to standard lipid screening significantly improved risk prediction models based on lipid screeningalone (P<.001).ConclusionsOf 11 atherothrombotic biomarkers assessed at baseline, the totalcholesterol–HDL-C ratio and CRP were the strongest independent predictors of development of peripheralarterial disease. C-reactive protein provided additive prognostic information over standard lipidmeasures.", "metadata": {}}
+{"_id": "73136607", "title": "", "text": "Assessment of older people: Self-maintaining and instrumental activities of daily living.THE use of formaldevices for assessing function is becoming standard in agencies serving the elderly. In the GerontologicalSociety's recent contract study on functional assessment (Howell, 1968), a large assortment of ratingscales, checklists, and other techniques in use in applied settings was easily assembled. The present stateof the trade seems to be one in which each investigator or practitioner feels an inner compusion to makehis own scale and to cry that other existent scales cannot possibly fit his own setting. The authors jointhis company in presenting two scales first standardized on their own population (Lawton, 1969). Theytake some comfort, however, in the fact that one scale, the Physical Self-Maintenance Scale (PSMS), islargely a scale developed and used by other investigators (Lowenthal, 1964), which was adapted for usein our own institution. The second of the scales, the Instrumental Activities of Daily Living Scale (IADL),taps a level of functioning heretofore inadequately represented in attempts to assess everyday functionalcompetence. Both of the scales have been tested further for their usefulness in a variety of types ofinstitutions and other facilities serving community-resident older people. Before describing in detail thebehavior measured by these two scales, we shall briefly describe the schema of competence into whichthese behaviors fit (Lawton, 1969). Human behavior is viewed as varying in the degree of complexityrequired for functioning in a variety of tasks. The lowest level is called life maintenance, followed by thesuccessively more complex levels of func-", "metadata": {}}
+{"_id": "73323408", "title": "", "text": "Diabetes in pregnancy: management of diabetes and its complications from preconception to thepostnatal period (NG3)In February 2015 the National Institute for Health and Care Excellence (NICE)published new guidance (NG3) on the management of diabetes in pregnancy. Care teams need to beaware of this guidance and implement its recommendations. These include preconception care with targetHbA1c 48 mmol/mol. Women at risk of gestational diabetes mellitus (GDM) should have a 75 g oralglucose tolerance test (OGTT). Diagnostic criteria for GDM have changed to fasting glucose of 5.6 mmol/Lor above or 2 hour glucose of 7.8 mmol/L or above. Glycaemic targets in all diabetic pregnancies havechanged to fasting glucose below 5.3 mmol/L (4–5.2 mmol/L if on insulin) and 1 hour postprandialglucose below 7.8 mmol/L if these can be achieved safely. Continuous glucose monitoring and insulinpump therapy should not be used routinely but can be used if glycaemic control is problematic. Capillaryketone testing should be routine for women with type 1 diabetes when hyperglycaemic and for all womenwith diabetes including, GDM when acutely unwell. More flexibility is offered around recommendeddelivery timing: 37+0 weeks to 38+6 weeks for women with types 1 and 2 diabetes; prior to 40+6 inGDM (and earlier if complications arise). Postnatal testing following GSM should be by fasting glucose(not OGTT) at 6–13 weeks post partum. Testing later than this can use HbA1c. Introducing these changeswill have resource implications, including a likely increase in the number of women diagnosed with GDM.", "metadata": {}}
+{"_id": "73473433", "title": "", "text": "Mental health difficulties across childhood and mental health service use: findings from a longitudinalpopulation-based study.BACKGROUND Over the past 20 years the prevalence of child and adolescentmental disorders in high-income countries has not changed despite increased investment in mental healthservices. Insufficient contact with mental health services may be a contributing factor; however, it is notknown what proportion of children have sufficient contact with health professionals to allow delivery oftreatment meeting minimal clinical practice guidelines, or how long children experience symptoms priorto receiving treatment. AimsTo investigate the level of mental healthcare received by Australian childrenfrom age 4 years to 14 years. METHOD Trajectories of mental health symptoms were mapped using theStrengths and Difficulties Questionnaire. Health professional attendances and psychotropic medicationsdispensed were identified from linked national Medicare Benefits Schedule (MBS) and PharmaceuticalBenefits Scheme records. RESULTS Four trajectories of mental health symptoms were identified (low,high-decreasing, moderate-increasing and high-increasing). Most children with mental health symptomshad few MBS mental health attendances, and only a minority received care meeting study criteria forminimally adequate treatment. Children in the high-increasing and moderate-increasing trajectories weremore likely to access care, yet there was no evidence of improvement in symptoms. CONCLUSIONS It isimportant that children and adolescents with mental health problems receive treatment that meetsminimal practice guidelines. Further research is needed to identify the quality of care currently providedto children with mental health difficulties and how clinicians can be best funded and supported to providecare meeting minimal practice guidelines. Declaration of interestsNone.", "metadata": {}}
+{"_id": "74137632", "title": "", "text": "Rembrandt ScholzThis paper examines the potential impact of changes in medical care on changingpopulation health in Lithuania, Hungary and Romania, with west Germany included for comparison. Weused the concept of deaths from certain causes that should not occur in the presence of timely andeffective health care (amenable mortality) and calculated the contribution of changes in mortality fromthese conditions to changes in life expectancy between birth and age 75 [e (0-75)] for the periods1980/81 to 1988 and 1992 to 1997. Temporary life expectancy improved consistently in west Germany(men: 2.7 years, women: 1.6 years). In contrast, gains were relatively small in the other countries,except among Hungarian women, who gained 1.3 years. Romanian men lost 1.3 years. In the 1980s,falling infant mortality made a substantial contribution to improvements in temporary life expectancy inall countries, of about a quarter to half a year. Of this, more than half can be attributed to amenableconditions. At older ages, falling amenable mortality contributed about 40% among those aged over 40 inGermany and, to a lesser extent, Hungary, while causing a loss of life expectancy in Romania. In the1990s, improvements in infant mortality continued to make substantial contributions to life expectancy inLithuania and Hungary but had little impact in either Germany or Romania. Among adults, improvementsin amenable mortality continued to benefit Hungarians and west Germans. In Lithuania, up to two-thirdsof the gain in temporary life expectancy were attributable to falling mortality from ischaemic heartdisease whereas medical care otherwise seems to have had a negative impact. Romanian men andwomen experienced increases in amenable mortality that contributed up to a half of the overall loss of lifeexpectancy. Our findings suggest that during the last 20 years changes in medical care had considerableimpact, positively as well as negatively, on changing mortality in selected central and eastern Europeancountries.", "metadata": {}}
+{"_id": "74701974", "title": "", "text": "The Women's Interagency HIV StudyThe Women's Interagency HIV Study comprises the largest U.S.cohort to date of human immunodeficiency virus (HIV)-seropositive women (N = 2,058) with acomparison cohort of seronegative women (N = 568). The methodology, training, and quality assuranceactivities employed are described. The study pop", "metadata": {}}
+{"_id": "75636923", "title": "", "text": "Prevalence of the Metabolic Syndrome Among Us Adults: Findings From the Third National Health andNutrition Examination SurveyMetabolic syndrome is diagnosed when three or more of the followingcriteria are met: abdominal obesity (waist circumference more than 102 cm in men and 88 cm inwomen); hypertriglyceridemia of 150 mg/dl or above; a high-density lipoprotein (HDL) cholesterol levelless than 40 mg/dl in men or 50 mg/dl in women; blood pressure of 130/85 mm Hg or higher; or fastingglucose of at least 110 mg/dl. Individuals with metabolic syndrome are likelier than others to developdiabetes and cardiovascular disease and have increased mortality from all causes (and fromcardiovascular disease in particular). The investigators attempted to determine the prevalence of thesyndrome in the United States by analyzing data on 8814 men and women 20 years of age or older whotook part in the Third National Health and Nutrition Examination Survey in the years 1988 to 1994. This isa cross-sectional health survey of a sample of the noninstitutionalized civilian American population. Theoverall age-adjusted prevalence of metabolic syndrome was 23.7%. The prevalence rose from 6.7% inpersons 20 to 29 years of age to 42% in those aged 70 years and more. There was virtually nogender-related difference in prevalence rates for the combined racial groups. Metabolic syndrome wasmost prevalent in Mexican Americans and least prevalent in whites, African Americans, and \"others. \"Among both African Americans and Mexican Americans, women had higher prevalence rates than men.Extrapolating from age-specific prevalence rates and US census counts from the year 2000, 47 million USresidents have metabolic syndrome. Considering its prevalence, it seems important to estimate the directmedical costs of metabolic syndrome. In the great majority of cases the critical causes are impropernutrition and insufficient physical activity, emphasizing the importance of controlling obesity andencouraging physical activity in the United States.", "metadata": {}}
+{"_id": "76415938", "title": "", "text": "Baseline cytology, human papillomavirus testing, and risk for cervical neoplasia: A 10-year cohortanalysisAs more is learned about the development of cervical cancer, the value of annual Pap smearscreening for all women is being questioned. This study was conducted to investigate whether women athigher risk for the development of cervical cancer could be identified by testing for the presence ofhuman papillomavirus (HPV) in the cervical smear. These women could be followed annually, and theinterval between screening Pap smears for women at lower risk could be increased. Study participantswere women enrolled in the Kaiser Permanente healthcare plan in Portland, Oregon, who underwentannual Pap smear screening between April 1989, and November 1990. More than 20,000 women (20,810of 23,702) had satisfactory cervical smears with sufficient samples for HPV testing, which was conductedusing a polymerase chain reaction-based method with MYO9/11 primers. Most women (83.6%) had atleast one follow-up smear during the study period; however, women with atypical squamous cells (ASC)or worse had more smears than women with normal results (mean, 4.4 vs. 3.3). Follow-up wasconducted more or less annually for a total period of 122 months. HPV results were not used in decidingpatient management. Ninety-six percent of the 20,810 baseline Pap smears were diagnosed as negative(N = 20,156). Thirteen percent of these patients tested positive for HPV. The baseline smears of 654 ofthe 20,810 women (3.1%) were classified as ASC or worse. Of these 654 smears, 417 (63.8%) werepositive for HPV. One hundred seventy-eight women had a cytologic diagnosis of a low-grade squamousintraepithelial lesion or worse; of these, 143 (80.3%) tested positive for HPV. During the 10 years offollow-up, 171 patients developed cervical intraepithelial neoplasia (CIN) 3 or cervical cancer. Thebaseline smear was normal in 112 of these women and ASC or worse in 59 (34.5%). Only half (49.2%) ofthe 58 patients diagnosed within the first 45 months of follow-up had an abnormal baseline smear.During this first 45 months, 7.85% of the women whose initial Pap test was at least ASC were diagnosedwith CIN 3 or cancer. The cumulative incidence at 10 years of follow-up was 10.2%. Sixty of the 171women with CIN 3 or cervical cancer had a negative baseline HPV test. Of the 118 women who werediagnosed during the first 45 months of follow-up, 89 (79.4%) were HPV positive initially. The cumulativeincidence of CIN 3 or cancer among the group with a positive baseline HPV test was 6.92% over 10 yearsbut only 1.73% at 45 months. The risk of developing CIN 3 or cancer remained elevated throughout thestudy in those women with a positive baseline HPV test. The predictive ability of the baseline Pap smeardiminished as the follow-up interval increased. Fifteen percent of the patients (N = 3216) had a positivePap smear, a positive HPV test, or both at the initial examination. One hundred twenty-three (71.9%)were among the 171 women who developed CIN 3 or cancer. Eighty-six percent (102 of 123) of thepatients who were diagnosed within the first 45 months were positive with at least one of the screeningstudies. The cumulative incidence over 45 months for women who had positive HPV testing and/orabnormal Pap smear results was 4.54%. Women with negative results in both screening tests had acumulative risk of 0.16% for the same period. At 10 years the cumulative risk incidence for these twogroups was 6.83% and 0.79%, respectively, yielding a negative predictive value of 99.1% for combinedtesting.", "metadata": {}}
+{"_id": "76463821", "title": "", "text": "Preconception Care and the Risk of Congenital Anomalies in the Offspring of Women With DiabetesMellitus: A Meta-AnalysisPreconception care (PCC) and strict periconceptional glycemic control are bothused to minimize the risk of congenital birth defects in offspring of women with type 1 or type 2 diabetesmellitus (DM). These malformations are ascribed in large measure to poor periconceptional control. Thisstudy evaluated PCC by a meta-analysis of published studies of PCC in women with DM, published from1970 to 2000. Two reviewers independently abstracted the data, and the rate and relative risk (RR) ofmajor and minor malformations were pooled from eligible studies using a random effects model. Earlyfirst-trimester values of glycosylated hemoglobin were recorded. Eight retrospective and eightprospective cohort studies were included; they were carried out in Europe, the United Kingdom, theUnited States, and Israel. Most participants had type 1 DM, but three studies included women with type 2DM. Women given PCC tended to be about 2 years older on average than the others. Methods of PCCwere quite variable, although most centers provided some maternal education about the pregnancy risksassociated with poor glycemic control. In seven studies reporting early gestational glycosylatedhemoglobin values, mean levels were consistently lower in PCC patients. Among 2104 offspring, thepooled rate for major and minor anomalies was 2.4% in the PCC group and 7.7% in non-PCC recipients,for a pooled RR of 0.32. Among 2651 offspring, major malformations were less prevalent in the PCCgroup (2.1 vs. 6.5%; pooled RR = 0.36). Comparable results were obtained when only prospectivestudies were analyzed and in studies where the infant examiners were unaware of the mothers' PCCstatus. The lowest risk of major anomalies was in a study that administered folic acid periconceptionallyto its PCC recipients; the RR was 0.11. This meta-analysis, which included both retrospective andprospective studies, demonstrates an association of PCC with a significantly lower risk of congenitalanomalies in the offspring of women with established DM. The lowered risk was accompanied bysignificantly lower glycosylated hemoglobin values in the first trimester in recipients of PCC.", "metadata": {}}
+{"_id": "76776022", "title": "", "text": "Behçet's disease associated with a lymphoproliferative disorder, mixed cryoglobulinemia, and an immunecomplex mediated vasculitis.Abstract A woman, now 59 has been followed for 13 years with severalmanifestations of Behcet's disease. These were aphthous stomatitis, genital ulcers, uveitis causingblindness, recurrent erythema nodosum, and synovitis. In 1970 a poorly differentiated diffuselymphocytic lymphoma appeared and was treated with radiotherapy. In 1976 she developed a mixedcryoglobulinemia and an immune complex mediated vasculitis manifested by purpura and neuropathywhich improved on prednisone and chlorambucil therapy. The subsequent course of herlymphoproliferative disorder suggest that it was in fact benign.", "metadata": {}}
+{"_id": "77971703", "title": "", "text": "Older People at the End of Life: Delivery of Care and Needs for Improvement from the Perspective ofBereaved RelativesBACKGROUND Due to demographic changes with an increasing number of older peoplewith chronic illness and multimorbidity palliative care for geriatric patients has become increasinglyimportant. The aim of this study was to explore the perspective of bereaved relatives with regard to theirexperiences and expectations concerning the delivery of care for older people in the last phase of life.METHODS Qualitative interviews with 12 relatives of deceased older patients (aged 60 years or older).The interviews were recorded, transcribed, coded and analysed using the approach of qualitative contentanalysis according to Mayring. RESULTS The bereaved relatives perceived that the care for geriatricpatients in the last phase of life was inappropriate in various respects. They criticised overtreatment (e.g.skin cancer diagnostic) as well as unmet needs (e.g. treatment of pain, patient centred care,communication). Family doctors were seen as the primary contact persons in the professional healthsystem. CONCLUSIONS From the perspective of bereaved relatives care for older people in the last phaseof life has serious deficits. They criticise an inappropriate priority setting and the disregard of palliativecare. There is a need for better communication and information exchange regarding the needs andexpectations of patients and relatives, and regarding the targets of treatment. Therefore it may be helpfulto use advance directives more intensively. Furthermore, it seems to be necessary to strengthengeneralist palliative care particularly delivered by family doctors and community nurses.", "metadata": {}}
+{"_id": "79231308", "title": "", "text": "Role of Computerized Physician Order Entry Systems in Facilitating Medication Errorsas compared with103 (8.2 percent) in the control group; the Kaplan-Meier estimates of the likelihood of freedom fromdeep-vein thrombosis or pulmonary embolism at 90 days were 94.1 percent (95 percent confidenceinterval, 92.5 to 95.4 percent) and 90.6 percent (95 percent confidence interval, 88.7 to 92.2 percent),respectively (P 0.001). The computer alert reduced the risk of deep-vein thrombosis or pulmonaryembolism at 90 days by 41 percent (hazard ratio, 0.59; 95 percent confidence interval, 0.43 to 0.81; P0.001). CONCLUSIONS The institution of a computer-alert program increased physicians’ use ofprophylaxis and markedly reduced the rates of deep-vein thrombosis and pulmonary embolism amonghospitalized patients at risk. Editorial Comment: Most hospitals have adopted electronic systems to alertphysicians of drug interactions or possible substitutions, as well as other measures designed to improvethe quality of care and decrease expenses. This approach was taken one step further by these authors,who evaluated whether notifying physicians that their patients were at increased risk for venousthromboembolism would decrease the incidence of deep vein thrombosis or pulmonary embolism. Thepremise was that simply notifying the physician would increase the use of appropriate prophylacticmeasures. Major surgery (defined as anything requiring general anesthesia), cancer and age greater than75 years were included among the risk factors, each of which frequently applies to a urology population.In fact, more than 13% of the patients in the intervention group had a known diagnosis of a genitourinarycancer. The computer alert decreased the risk of deep vein thrombosis or pulmonary embolism by 41%.There are 2 lessons urologists can learn from this study. First, many urology patients are at increased riskfor venous thromboembolism and appropriate prophylaxis should be used. In addition, althoughcomputer alert systems may seem intrusive at times, clinicians can expect to see more and more of themif there is further documentation that they improve the quality of care.", "metadata": {}}
+{"_id": "79336156", "title": "", "text": "Beta-band oscillations--signalling the status quo?In this review, we consider the potential functional roleof beta-band oscillations, which at present is not yet well understood. We discuss evidence from recentstudies on top-down mechanisms involved in cognitive processing, on the motor system and on thepathophysiology of movement disorders that suggest a unifying hypothesis: beta-band activity seemsrelated to the maintenance of the current sensorimotor or cognitive state. We hypothesize that betaoscillations and/or coupling in the beta-band are expressed more strongly if the maintenance of thestatus quo is intended or predicted, than if a change is expected. Moreover, we suggest that pathologicalenhancement of beta-band activity is likely to result in an abnormal persistence of the status quo and adeterioration of flexible behavioural and cognitive control.", "metadata": {}}
+{"_id": "79696454", "title": "", "text": "Safety, pharmacokinetics and efficacy of IMCgp100, a first-in-class soluble TCR-antiCD3 bispecific t cellredirector with solid tumour activity: Results from the FIH study in melanoma.3016Background: Tcell-based bispecific agents have shown activity in hematologic cancers, but solid tumor efficacy remainselusive. IMCgp100 is a bispecific biologic comprising an affinityenhanced TCR specific for gp100 and ananti-CD3 scFV. In vitro, IMCgp100 binds gp100+ melanoma cells causing redirection of cytotoxicity andinduction of potent immune effects. Methods: The Phase I was conducted in HLA-A2+ pts with advancedmelanoma, using a 3+3 design to define the MTD. Pts were treated with IMCgp100 (iv) weekly (QW, Arm1) or daily (4QD3W, Arm 2) to evaluate safety, PK and efficacy. The recommended phase 2 regimen(RP2D-QW) was defined. Results: In the Ph I dose escalation,31 pts received doses from 5ng/kg to900ng/kg. In arm 1 dose-limiting toxicity of gr 3 or 4 hypotension was seen and associated with rapidtrafficking of peripheral lymphocytes to skin and tumor. The MTD was determined to be 600ng/kg QW.IMCgp100 has an approximately dose-proportional profile with a plasma T1/2 of 5-6 hrs at the RP2...", "metadata": {}}
+{"_id": "80109277", "title": "", "text": "The Bitterest Pills: The Troubling Story of Antipsychotic Drugs© Joanna Moncrieff 2013. All rightsreserved. A challenging reappraisal of the history of antipsychotics, revealing how they were transformedfrom neurological poisons into magical cures, their benefits exaggerated and their toxic effects minimizedor ignored.", "metadata": {}}
+{"_id": "80522346", "title": "", "text": "Variables Affecting Kinetics of Minimal Residual Disease Clearance in Children with LymphoblasticLeukaemia; Results of the United Kingdom Medical Research Council (UK MRC) Protocols ALL97,ALL97/99 and ALL2003.We studied the influence of patient, leukaemia and treatment characteristics onthe kinetics of Minimal Residual Disease (MRD) clearance in children with lymphoblastic leukaemiatreated using an intensive risk stratified approach. UK MRC protocol ALL97 (1997–1999), and itsamended version ALL 97/99 (1999–2002), compared the efficacy and toxicity of dexamethasone (DEX)with prednisolone (PRED), and 6-thioguanine (TG) with 6-Mercaptopurine (MP) in a randomised fashion.The trial produced a 5 year event-free survival (EFS) of 80%, with better systemic and Central NervousSystem outcomes in DEX compared with PRED recipients but no difference between TG and MP recipients.Several changes to the risk stratification and treatment regimens during the period of the trial providedan opportunity to determine their impact on MRD clearance. We compared this with clearance in thosetreated on the successor trial ALL 2003 (more intensive induction containing DEX and PegylatedAsparaginase). The variables investigated for their potential influence on MRD status at the end ofinduction (EOI) were: NCI Risk; Asparaginase intensity (Erwinia Asparaginase [ERW] in ALL 97 and earlypart of ALL97/99 vs native or Pegylated E. Coli Asparaginase [E. Coli] in later part of ALL 97/99 andALL2003); DEX vs PRED; and marrow response at day 8/15 of induction (Slow Early Response [SER]>25% blasts vs Rapid Early Response [RER] \u0000 25% blasts). MRD was assessed using either asemi-quantitative sequence-specific PCR (ALL97) or Real-Time Quantitative PCR (ALL99 and ALL 2003) ofantigen receptor gene re-arrangements at EOI. MRD status was defined as NEG if no MRD was detectedby two markers sensitive to 10 −4 ; POS if > 10 −4 , and Positive Outside Quantitative Range (POQR) ifpositive −4 . Results were available from retrospective testing in 66 ALL97 and 76 ALL97/99 patients,and 204 ALL2003 patients monitored prospectively. There was no significant difference in the proportionsof patients MRD NEG, POS or POQR in steroid or NCI sub-groups. Significantly more ERW Asparaginaserecipients were MRD POS compared with E.Coli (p −4 at EOI have the same low risk of relapse as thosewho have undetectable MRD.", "metadata": {}}
+{"_id": "81498132", "title": "", "text": "Chromosome numbers in certain Indian species ofUtricularia L. (Lentibulariaceae)Chromosome numbersfrom meiotic studies have been reported for the following species ofUtricularia: U. aurea Lour. (n=21);U.baouleënsis A. Chev. (n=10);U. caerulea L. (n=20);U. inflexa var.stellaris (Linn.f.) P. Taylor (n=21);U.minutissima Vahl (n=8);U. scandens Benj. (n=6, 7); andU. stricticaulis Stapf (n=7). There are twocyto-races inU. scandens.", "metadata": {}}
+{"_id": "82665667", "title": "", "text": "Detection of [Ca2+]I Changes In Sub-Plasma Membrane Micro Domains in A Single Living Cell By anOptical Fiber-Based NanobiosensorAn optical fiber-based nanobiosensor, for advanced detection of [Ca2+ ]i (i.e. intracellular Ca 2+ concentration) changes in sub-plasma membrane microdomains in a singleliving smooth muscle cell and a single living cardiomyocyte, was successfully prepared by coating silverand then immobilizing Calcium Green-1 Dextran, a calcium ion sensitive dye, on the distal end of thenanoprobe. The constructed nanobiosensor was capable of detecting ultra-low and local intracellularcalcium ion concentration within the nanomolar range, which is around the physiological level of freecytosolic calcium ion in a single living cell. The response time was less than milliseconds enabling thedetection of transient elementary calcium ion signaling events associated with calcium ion microdomains.The effects of stimulants such as high potassium buffer solution and norepinephrine solution were alsoinvestigated. The resulting system could thus greatly facilitate the development of an advancednano-diagnostic platform for in vivo and real-time sensing/diagnosing of [Ca 2+ ]i at the single cell level.", "metadata": {}}
+{"_id": "82971616", "title": "", "text": "Construction of plant bacterial artificial chromosome (BAC) libraries: an illustrated guide.J. Agric.Genomics, 5 ABSTRACT Bacterial artificial chromosome (BAC) libraries have become invaluable tools inplant genetic research. However, it is difficult for new practitioners to create plant BAC libraries de novobecause published protocols are not particularly detailed, and plant cells possess features that makeisolation of clean, high molecular weight DNA troublesome. In this document we present an illustrated,step-by-step protocol for constructing plant BAC libraries. This protocol is sufficiently detailed to be of useto both new and experienced investigators. We hope that by reducing the obstacles to BAC cloning inplants, we will foster new and accelerated progress in plant genomics.", "metadata": {}}
+{"_id": "83308790", "title": "", "text": "Activation by IKKα of a second, evolutionary conserved, NF-κB signaling pathwayIn mammals, thecanonical nuclear factor κB (NF-κB) signaling pathway activated in response to infections is based ondegradation of IκB inhibitors. This pathway depends on the IκB kinase (IKK), which contains two catalyticsubunits, IKKα and IKKβ. IKKβ is essential for inducible IκB phosphorylation and degradation, whereasIKKα is not. Here we show that IKKα is required for B cell maturation, formation of secondary lymphoidorgans, increased expression of certain NF-κB target genes, and processing of the NF-κB2 (p100)precursor. IKKα preferentially phosphorylates NF-κB2, and this activity requires its phosphorylation byupstream kinases, one of which may be NF-κB–inducing kinase (NIK). IKKα is therefore a pivotalcomponent of a second NF-κB activation pathway based on regulated NF-κB2 processing rather than IκBdegradation.", "metadata": {}}
+{"_id": "83667891", "title": "", "text": "Identification and transmission of Piper yellow mottle virus and Cucumber mosaic virus infecting blackpepper (Piper nigrum) in Sri LankaSri Lankan black pepper with symptoms of yellow mottle diseasecontained a mixture of viruses: Piper yellow mottle virus (PYMV) particles (30 × 130 nm), Cucumbermosaic virus (CMV, 30 nm diameter isometric particles), and unidentified, isometric virus-like particles(30 nm diameter). An effective purification procedure is described for PYMV. Immunosorbent andconventional electron microscopy successfully detected badnavirus particles only when at least partiallypurified extracts were used. PYMV was confirmed as the cause of the disease, with the other two virusesapparently playing no part in producing symptoms. PYMV was transmitted by grafting, by the insectvectors citrus mealy bug (Planococcus citri) and black pepper lace bug (Diconocoris distanti), but not bymechanical inoculation or through seeds. The CMV isolate was transmitted to indicator plants bymechanical inoculation and by the vector Aphis gossypii, but not by Myzus persicae; but neithermechanical nor insect transmission of CMV to black pepper was successful. A sensitive polymerase chainreaction assay was developed to detect PYMV in black pepper.", "metadata": {}}
+{"_id": "83707680", "title": "", "text": "A forkhead-domain gene is mutated in a severe speech and language disorderIndividuals affected withdevelopmental disorders of speech and language have substantial difficulty acquiring expressive and/orreceptive language in the absence of any profound sensory or neurological impairment and despiteadequate intelligence and opportunity1. Although studies of twins consistently indicate that a significantgenetic component is involved1,2,3, most families segregating speech and language deficits showcomplex patterns of inheritance, and a gene that predisposes individuals to such disorders has not beenidentified. We have studied a unique three-generation pedigree, KE, in which a severe speech andlanguage disorder is transmitted as an autosomal-dominant monogenic trait4. Our previous work mappedthe locus responsible, SPCH1, to a 5.6-cM interval of region 7q31 on chromosome 7 (ref. 5). We alsoidentified an unrelated individual, CS, in whom speech and language impairment is associated with achromosomal translocation involving the SPCH1 interval6. Here we show that the gene FOXP2, whichencodes a putative transcription factor containing a polyglutamine tract and a forkhead DNA-bindingdomain, is directly disrupted by the translocation breakpoint in CS. In addition, we identify a pointmutation in affected members of the KE family that alters an invariant amino-acid residue in the forkheaddomain. Our findings suggest that FOXP2 is involved in the developmental process that culminates inspeech and language.", "metadata": {}}
+{"_id": "84085333", "title": "", "text": "The Growth and Sporulation of the Benign and Malignant Tertian Malarial Parasites in the Culture Tubeand in the Human HostResearches on the cultivation of the parasites of malaria in Liverpool werecommenced some time ago at my suggestion by Dr. Sinton, and then, with better success, by Drs. J. G.Thomson and McLellan, and by Dr. D. Thomson. We are greatly obliged to Sir Edwin Durning-Lawrence,Bart., for giving us the services of Dr. J. G. Thomson for this important enquiry.— Ronald Ross, 21st May,1913.", "metadata": {}}
+{"_id": "84244109", "title": "", "text": "Innate immunity to a facultative intracellular bacterial pathogen.The murine response to Listeriamonocytogenes has long been considered a paradigm of T-cell-mediated immunity. There is, however,substantial evidence that T-cell-deficient mice are capable of surviving a L. monocytogenes challenge.Recently, advances have been made in our understanding of the cell biology and pathogenesis ofinfection.", "metadata": {}}
+{"_id": "84379954", "title": "", "text": "Diversity and Evenness: A Unifying Notation and Its ConsequencesThree commonly used measures ofdiversity, Simpson's index, Shannon's entropy, and the total number of species, are related to Renyi'sdefinition of a generalized entropy. A unified concept of diversity is presented, according to which there isa continuum of possible diversity measures. In a sense which becomes apparent, these measures provideestimates of the effective number of species present, and differ only in their tendency to include or toignore the relatively rarer species. The notion of the diversity of a community as opposed to that of asample is examined, and is related to the asymptotic form of the species—abundance curve. A new andplausible definition of evenness is derived.", "metadata": {}}
+{"_id": "84580585", "title": "", "text": "Guide to yeast genetics and molecular biologyThis volume and its companion, Volume 350, arespecifically designed to meet the needs of graduate students and postdoctoral students as well asresearchers, by providing all the up-to-date methods necessary to study genes in yeast. Procedures areincluded that enable newcomers to set up a yeast laboratory and to master basic manipulations. Relevantbackground and reference information given for procedures can be used as a guide to developingprotocols in a number of disciplines. Specific topics addressed in this book include cytology, biochemistry,cell fractionation, and cell biology.", "metadata": {}}
+{"_id": "84784389", "title": "", "text": "Cutadapt removes adapter sequences from high-throughput sequencing readsWhen small RNA issequenced on current sequencing machines, the resulting reads are usually longer than the RNA andtherefore contain parts of the 3' adapter. That adapter must be found and removed error-tolerantly fromeach read before read mapping. Previous solutions are either hard to use or do not offer requiredfeatures, in particular support for color space data. As an easy to use alternative, we developed thecommand-line tool cutadapt, which supports 454, Illumina and SOLiD (color space) data, offers twoadapter trimming algorithms, and has other useful features. Cutadapt, including its MIT-licensed sourcecode, is available for download at http://code.google.com/p/cutadapt/", "metadata": {}}
+{"_id": "84884645", "title": "", "text": "Reproductive physiology of marsupialsPreface 1. Historical introduction 2. Breeding biology of marsupialsby family 3. Sexual differentiation and development 4. Male anatomy and spermatogenesis 5. The femaleurogenital tract and oogenesis 6. Ovarian function and control 7. Pregnancy and parturition 8. Lactation9. Neuroendocrine control of seasonal breeding 10. Marsupials and the evolution of mammalianreproduction References Index.", "metadata": {}}
+{"_id": "85326624", "title": "", "text": "Stage-Specific and Differential Notch Dependency at the αβ and γδ T Lineage BifurcationSummary Signalstransduced by Notch receptors are indispensable for T cell specification and differentiation of αβ T lineagecells. However, the role of Notch signals during αβ versus γδ T lineage decision remains controversial.Here, we addressed this question by employing a clonal analysis of CD4 − CD8 − (DN) progenitorpotential to position the divergence of αβ and γδ T cell lineages to the late DN2 to DN3 developmentalstages. Accordingly, αβ and γδ precursor frequencies within these T cell progenitor subsets weredetermined, both in the presence and absence of Notch signaling through Delta-like 1. Notch signals werefound to be critical for the DN to CD4 + CD8 + (DP) transition, irrespective of the identity (pTαβ or γδ) ofthe inducing T cell receptor complex, whereas γδ T cells developed from γδTCR-expressing T cellprogenitors in the absence of further Notch ligand interaction. Collectively, our findings demonstrate adifferential, stage-specific requirement for Notch receptor-ligand interactions in the differentiation of αβand γδ T cells from T cell progenitors.", "metadata": {}}
+{"_id": "85394684", "title": "", "text": "Investigating the Intron Recognition Mechanism in EukaryotesRecent studies indicate that many introns,as well as the complex spliceosomal mechanism to remove them, were present early in eukaryoticevolution. This study examines intron and exon characteristics from annotations of whole genomes toinvestigate the intron recognition mechanism. Exon definition uses the exon as the unit of recognition,placing length constraints on the exon but not on the intron (allowing it a greater range of lengths). Incontrast, intron definition uses the intron itself as the unit of recognition and thus removes constraints oninternal exon length forced by the use of an exon definition mechanism. Thus, intron and exon lengthswithin a genome can reflect the constraints imposed by its splicing. This study shows that it is possiblefirstly to recover valid intron and exon information from genome annotation. We then compare internalintron and exon information from a range of eukaryotic genomes and investigate possible evolutionarylength constraints on introns and exons and how they can impact on the intron recognition mechanism.Results indicate that exon definition-based mechanisms may predominate in vertebrates although theexact system in fish is expected to show some differences with the better characterized system frommammals. We also raise the possibility that the last common ancestor of plants and animals containedsome type of exon definition and that this mechanism was replaced in some genes and lineages by introndefinition, possibly as a result of intron loss and/or intron shortening.", "metadata": {}}
+{"_id": "85665741", "title": "", "text": "BRAF mutation predicts for MEK-dependence in non-small cell lung cancer (NSCLC).5247 ConstitutiveERK signaling is common in human cancer and is often the result of activating mutations of BRAF, RASand upstream receptor tyrosine kinases. Missense BRAF kinase domain mutations are frequentlyobserved in melanoma, colon and thyroid cancers and less frequently in lung and other cancer types. Thevast majority (>90%) involve a glutamic acid for valine substitution at codon 600 (V600E), which resultsin elevated BRAF kinase activity. BRAF kinase domain mutations with intermediate and impaired kinaseactivity have also been identified, most frequently in NSCLC. We have previously reported that tumorswith V600E BRAF mutation are selectively sensitive to MEK inhibition. Using the potent and selectiveMEK1/2 inhibitor PD0325901 (Pfizer), we examined a panel of NSCLC cell lines with mutant EGFR, KRAS,and/or low, intermediate and high-activity BRAF kinase domain mutations for MEK dependence. In all butone case, EGFR, KRAS and BRAF mutations were mutually exclusive with the exception being a cell linewith concurrent NRAS and intermediate activity BRAF mutations. Consistent with our prior results, NSCLCcells with V600E BRAF mutation were exquisitely sensitive to MEK inhibition (PD0325901 IC50 of 2nM).The proliferation of cells with non-V600E mutations, including those with high (G469A), intermediate(L597V) and impaired (G466V) kinase activities, was also MEK dependent with IC50’s ranging between2.7 and 80 nM. Inhibition of MEK in these cells resulted in downregulation of cyclin D1 and G1 growtharrest, with variable induction of apoptosis. Despite high basal ERK activity, NSCLC tumor cells with EGFRmutation were uniformly resistant to MEK inhibition (at doses of up to 500nM), despite effective andprolonged inhibition of ERK phosphorylation. Tumor cells with RAS mutation had a more variableresponse, with some cell lines demonstrating sensitivity, while others were completely resistant. Therewas no correlation between basal ERK activity and sensitivity to MEK inhibition. A strong inversecorrelation between Akt activity and PD0325901 sensitivity was observed. These results suggest that MEKinhibition may be useful therapeutically in tumors with V600E and non-V600E BRAF kinase domainmutations. The results also suggest that inhibition of both MEK and Akt signaling may be required inNSCLC tumors with high basal AKT activity.", "metadata": {}}
+{"_id": "85693958", "title": "", "text": "THE REGULATION OF NUMBERS OF TROPICAL OCEANIC BIRDSSUMMARY    The ways in which thenumbers of tropical sea-birds might be limited are considered; it is argued that food is the only factorlikely to be generally effective in limiting numbers, but it seems improbable that food shortage couldexert a density-dependent control of the mortality of the birds outside the breeding season.Wynne-Edwards' hypothesis that colonies of sea-birds are able to keep their own numbers below the levelat which food shortage would become acute, primarily by exerting control on the output of young, isrejected as unproven and improbable. It is suggested that colonies of tropical oceanic birds deplete thefood in the waters round them, and that as the populations increase competition for food becomes moreintense, and relatively fewer adults succeed in raising chicks. This would provide a density-dependentcontrol of the output of young and could regulate the numbers of the birds. The peculiarities of long-livedsea-birds (e.g. clutches of one, long fledging periods, deferred maturity) which Wynne-Edwards suggestsare adaptations evolved in order to lower the reproductive rate until it balances the mortality, apparentlycould not be evolved as such; they are more probably adaptations enabling the birds sometimes to raisesingle chicks in spite of competition for food that makes it impossible to raise more than one. It isconsidered that variation in the age of first breeding provides an important supplement to variation inreproductive success in regulating the numbers of long-lived tropical sea-birds. The possible applicationsof this hypothesis to sea-birds breeding in higher latitudes are briefly considered, as are its implications inrelation to conservation and exploitation of populations of sea-birds.", "metadata": {}}
+{"_id": "86129154", "title": "", "text": "Induced pluripotent stem cell lines derived from human somatic cells.Somatic cell nuclear transfer allowstrans-acting factors present in the mammalian oocyte to reprogram somatic cell nuclei to anundifferentiated state. We show that four factors (OCT4, SOX2, NANOG, and LIN28) are sufficient toreprogram human somatic cells to pluripotent stem cells that exhibit the essential characteristics ofembryonic stem (ES) cells. These induced pluripotent human stem cells have normal karyotypes, expresstelomerase activity, express cell surface markers and genes that characterize human ES cells, andmaintain the developmental potential to differentiate into advanced derivatives of all three primary germlayers. Such induced pluripotent human cell lines should be useful in the production of new diseasemodels and in drug development, as well as for applications in transplantation medicine, once technicallimitations (for example, mutation through viral integration) are eliminated.", "metadata": {}}
+{"_id": "86160128", "title": "", "text": "Fenugreek (Trigonella foenum-graecum): A Review of Health Beneficial Physiological EffectsAmong thespices that are esoteric food adjuncts being used to enhance flavoring and color, fenugreek (Trigonellafoenum-graecum) also modifies the texture of food. This seed spice is also employed for medicinalpurpose in many traditional systems as antibacterial, gastric stimulant, against anorexia, antidiabeticagent and as a galactogogue. In recent decades, several health beneficial physiological attributes offenugreek seeds have been seen in animal studies as well as human trials. These include antidiabeticeffect, hypocholesterolemic influence, antioxidant potency, digestive stimulant action, andhepatoprotective effect. Among these beneficial physiological effects, the antidiabetic andhypocholesterolemic property of fenugreek, both of which are mainly attributable to the intrinsic dietaryfiber constituent, have promising nutraceutical value. This article presents an overview of experimentalevidence for the nutraceutical potential of fenugreek seeds.", "metadata": {}}
+{"_id": "86211914", "title": "", "text": "The Rat Brain in Stereotaxic CoordinatesThe preceding editions made \"The Rat Brain in StereotaxicCoordinates\" the second most cited book in science. This Fifth Edition is the result of years of researchproviding the user with the drawings of the completely new set of coronal sections, now from one rat, andwith significantly improved resolution by adding a third additional section level as compared to earliereditions. Numerous new nuclei and structures also have been identified. The drawings are presented intwo color, providing a much better contrast for use, and the accompanying CD-ROM contains all of thedrawings from the atlas as well as the corresponding color micrographs (which are not included in thebook). Affordable, comprehensive, compact, and convenient, the Fifth Edition continues the legacy of thismajor neuroscience publication and is a guide to all students and scientists who study the rat brain. Itcontains 161 coronal diagrams based on a single brain and includes a CD-ROM featuring all of thedrawings from the book, plus the accompanying color micrographs that are not in the printed atlas. Thedelineations are drawn entirely new from a new set of sections. The diagrams are spaced at constant 120m intervals resulting in the high resolution and convenience of use. The drawings use blue color lines andblack labels to facilitate extraction of information. The stereotaxic grid was derived using the sametechniques that produced the widely praised stereotaxic grid of the previous editions. Over 1000structures are identified, a number for the first time in this edition.", "metadata": {}}
+{"_id": "86217760", "title": "", "text": "The Self-Incompatibility Genes of Brassica: Expression and Use in Genetic Ablation of FloralTissuesINTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . 394 POLLINATION AND POLLEN TUBE GROWTH . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . 395 Interaction s between the M ale G ameto phyte and Pistil . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395 SelfIncom patibili ty Systems: Gameto phytic and S porophyti c Determin ation of Pollen Phenoty pe . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . 397 DEVELOPMENTAL S TUDIES OF REPRODUCTIVE STRUCTURES . . . . . . . . ... . ... . . . . 398 Tissues of the Pistil with Special Reference to Pollination Functions 398 The MaleGametophyte . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . 399 MOLECULAR ANALYSIS OF SELF-INCOMPATIBILITY . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . 40 1 The S-M ultigene F amily o j Brassica. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . .. . . . . . . . . . 402 Allelism at the S-Lo cus and the SLG Gene\"\"\"\"\"\"\"\"\"\"\"\"\"\"\"\"\"\"\"\"\"\"\"\"\" 402 TheS-Locus Related (SLR) Genes 405 Molecular Complexity oj the S-Locus . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . 407 EXPRESSION OF THE SLG GENE IN PIS TILS AND ANTHERS . . . . . . . . . . . .. . . . . . . . . . . 409 Expression in Cruc ifers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . .. . . . . . . . . . 409 Express ion in Tr ansgen ic Tob acco and the Rel at ionship ofG ameto phytic and S poro phyt ic Incompatibilities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . 4 10 GENETIC INTERACTIONS IN SELF-INCOMPATIBILITY RESPONSES . . . . . . . . . . . . . . 41 2 The Analysis o j Se lf-Com patible Lines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . 4 1 2 The An alysis o j Transgenic Pl ants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . 4 1 3 GENETIC ABLATION O F FLORAL TISSUES . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 415 As a Tool Jor the Study o j Pl ant Develo pmen t . . . . . . . . .. . . . . . . . . . . . . . . . . .. . . . . . . .. . . . . . . . . . 415 As a Tool Jar Cro p Im pro vement . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . \"\"\" 416", "metadata": {}}
+{"_id": "86231298", "title": "", "text": "The Ulp1 SUMO isopeptidase distinct domains required for viability, nuclear envelope localization, andsubstrate specificityProtein modification by the ubiquitin-like SUMO protein contributes to many cellularregulatory mechanisms. In Saccharomyces cerevisiae, both sumoylating and desumoylating activities areessential for viability. Of its two known desumoylating enzymes, Ubl-specific protease (Ulp)1 andUlp2/Smt4, Ulp1 is specifically required for cell cycle progression. A \u0000200-residue segment, the Ulpdomain (UD), is conserved among Ulps and includes a core cysteine protease domain that is even morewidespread. Here we demonstrate that the Ulp1 UD by itself can support wild-type growth rates and invitro can cleave SUMO from substrates. However, in cells expressing only the UD of Ulp1, many SUMOconjugates accumulate to high levels, indicating that the nonessential Ulp1 NH2-terminal domain isimportant for activity against a substantial fraction of sumoylated targets. The NH2-terminal domain alsoincludes sequences necessary and sufficient to concentrate Ulp1 at nuclear envelope sites. Remarkably,NH2-terminally deleted Ulp1 variants are able, unlike full-length Ulp1, to suppress defects of cells lackingthe divergent Ulp2 isopeptidase. Thus, the NH2-terminal regulatory domain of Ulp1 restricts Ulp1 activitytoward certain sumoylated proteins while enabling the cleavage of others. These data define keyfunctional elements of Ulp1 and strongly suggest that subcellular localization is a physiologicallysignificant constraint on SUMO isopeptidase specificity.", "metadata": {}}
+{"_id": "86326468", "title": "", "text": "Gastropathies in the LundehundThe mucin profiles of the gastric mucosa in Lundehunds suffering fromintestinal lymphangiectasia were examined and compared to the mucin profiles in control dogs from otherbreeds. A previous study performed on this material had shown that all examined Lundehunds hadgastritis and about 30% had gastric carcinoma. Neutral and acid mucins were identified using the periodicacid-Schiff (PAS) and Alcian blue (pH 2.5) periodic acid-Schiff (AB-PAS) methods. The acid mucins weredivided into sialomucins and sulfomucins based on their reaction with high-iron diamine Alcian blue, pH2.5 (HID-AB). In Lundehunds with chronic atrophic gastritis in the fundic and body regions the surfaceand foveolar epithelium showed a predominantly normal mucin profile although some Lundehunds had areduced mucin content. The mucous neck cells extended from below the gastric foveolae towards themuscularis mucosae. Morphometric examination showed that the abnormal presence of mucous neckcells occupied 41% of the height of the gastric mucosa in Lundehunds compared to only 19% in thecontrol dogs (p<0.05). Of the four Lundehunds with gastric carcinoma, two possessed neoplastic cellsthat contained minimal or no mucins. The amount and type of mucin in the neoplastic cells of theremaining two Lundehunds varied both between individuals and within a neoplasm. This study shows thatthe abnormal presence of mucous neck cells and the associated pseudopyloric metaplasia comprised thepredominant changes in the gastric mucin profiles of Lundehunds.", "metadata": {}}
+{"_id": "86602746", "title": "", "text": "MicroRNAs: small RNAs with a big role in gene regulationKey PointsMicroRNAs (miRNAs) are a family of\u000021–25-nucleotide small RNAs that negatively regulate gene expression at the post-transcriptional level.The founding members of the miRNA family, lin-4 and let-7, were identified through genetic screens fordefects in the temporal regulation of Caenorhabditis elegans larval development. Owing to genome-widecloning efforts, hundreds of miRNAs have now been identified in almost all metazoans, including flies,plants and mammals. MiRNAs exhibit temporally and spatially regulated expression patterns duringdiverse developmental and physiological processes. Most of the miRNAs that have been characterized sofar seem to regulate aspects of development, including larval developmental transitions and neuronaldevelopment in C. elegans, growth control and apoptosis in Drosophila melanogaster, haematopoieticdifferentiation in mammals, and leaf development, flower development and embryogenesis in Arabidopsisthaliana. The majority of the animal miRNAs that have been characterized so far affect protein synthesisfrom their target mRNAs. On the other hand, most of the plant miRNAs studied so far direct the cleavageof their targets. The degree of complementarity between a miRNA and its target, at least in part,determines the regulatory mechanism. In animals, primary transcripts of miRNAs are processedsequentially by two RNase-III enzymes, Drosha and Dicer, into a small, imperfect dsRNA duplex(miRNA:miRNA*) that contains both the mature miRNA strand and its complementary strand (miRNA*).Relative instability at the 5′ end of the mature miRNA leads to the asymmetric assembly of the maturemiRNA into the effector complex, the RNA-induced silencing complex (RISC).Ago proteins are a keycomponent of the RISC. Multiple Ago homologues in various metazoan genomes indicate the existence ofmultiple RISCs that carry out related but specific biological functions. Bioinformatic prediction of miRNAtargets has provided an important tool to explore the functions of miRNAs. However, the overall successrate of such predictions remains to be determined by experimental validation. AbstractMicroRNAs are afamily of small, non-coding RNAs that regulate gene expression in a sequence-specific manner. The twofounding members of the microRNA family were originally identified in Caenorhabditis elegans as genesthat were required for the timed regulation of developmental events. Since then, hundreds of microRNAshave been identified in almost all metazoan genomes, including worms, flies, plants and mammals.MicroRNAs have diverse expression patterns and might regulate various developmental and physiologicalprocesses. Their discovery adds a new dimension to our understanding of complex gene regulatorynetworks.", "metadata": {}}
+{"_id": "86694016", "title": "", "text": "Molecular mechanisms of invadopodium formation: the role of the N-WASP–Arp2/3 complex pathway andcofilinInvadopodia are actin-rich membrane protrusions with a matrix degradation activity formed byinvasive cancer cells. We have studied the molecular mechanisms of invadopodium formation inmetastatic carcinoma cells. Epidermal growth factor (EGF) receptor kinase inhibitors blockedinvadopodium formation in the presence of serum, and EGF stimulation of serum-starved cells inducedinvadopodium formation. RNA interference and dominant-negative mutant expression analyses revealedthat neural WASP (N-WASP), Arp2/3 complex, and their upstream regulators, Nck1, Cdc42, and WIP, arenecessary for invadopodium formation. Time-lapse analysis revealed that invadopodia are formed denovo at the cell periphery and their lifetime varies from minutes to several hours. Invadopodia with shortlifetimes are motile, whereas long-lived invadopodia tend to be stationary. Interestingly, suppression ofcofilin expression by RNA interference inhibited the formation of long-lived invadopodia, resulting information of only short-lived invadopodia with less matrix degradation activity. These results indicate thatEGF receptor signaling regulates invadopodium formation through the N-WASP–Arp2/3 pathway andcofilin is necessary for the stabilization and maturation of invadopodia.", "metadata": {}}
+{"_id": "86704258", "title": "", "text": "Genome downsizing in polyploid plantsAll else being equal, polyploids are expected to have largerC-values (amount of DNA in the unreplicated gametic nucleus) than their diploid progenitors, increasingin direct proportion with ploidy. This expectation is observed in some polyploid series, especially thosenewly formed, but there are examples suggesting that C-values in particular polyploids are less thanexpected. The availability of the Angiosperm DNA C-values database (http://www.rbgkew.org.uk/cvavhomepage.html) has allowed this question to be addressed across a broadrange of angiosperms and has revealed striking results deviating from expectation: (i) mean 1C DNAamount did not increase in direct proportion with ploidy, and (ii) mean DNA amount per basic genome(calculated by dividing the 2C value by ploidy) tended to decrease with increasing ploidy. These resultssuggest that loss of DNA following polyploid formation, or genome downsizing, may be a widespreadphenomenon of considerable biological significance. Recent advances in our understanding of themolecular events that take place following polyploid formation together with new data on how DNAamounts can both increase and decrease provide some insights into how genome downsizing may takeplace. The nature of the evolutionary forces that may be driving DNA loss are also discussed.", "metadata": {}}
+{"_id": "87337034", "title": "", "text": "Construction of an antisense CYP86MF gene plasmid vector and production of a male-sterile Chinesecabbage transformant by the pollen-tube methodSummaryA plant expression vector pBIA9-AMFcontaining an antisense fragment of the CYP86MF gene and the tapetum-specific A9 promoter wasconstructed. Plasmid vectors were introduced by floral-dipping and pollen-tube transformation methodsto Chinese cabbage pak-choi (Brassica campestris ssp. chinensis (L.) Makino var. communis Tsen et Lee,syn. B. rapa ssp. chinensis (L.) Makino var. communis Tsen et Lee) and flowering Chinese cabbage (B.campestris ssp. chinensis (L.) Makino var. parachinensis (Bailey) Tsen et Lee). Results showed that KanRseedlings could be obtained by the pollen-tube method through germination tests of T1 progeny seeds,but not by the floral-dipping method. One of the two KanR seedlings proved that the antisense fragmentof the CYP86MF gene was integrated into the Chinese cabbage genome by PCR amplification andSouthern blotting. Northern hybridization indicated that the CYP86MF gene, under the A9 promoter, wasinhibited in the transformant, and self-infertility was found in the trans...", "metadata": {}}
+{"_id": "87430549", "title": "", "text": "Stem Cells,Cancer and Cancer Stem CellsStem cells are defined as cells able to both extensivelyself-renew and differentiate into progenitors. Research data show that more resistant stem cells thancommon cancer cells exist in cancer patients. To identify unrecognized differences between cancer stemcells and cancer cells might be able to develope effective classification,diagnose and treat ment forcancer.", "metadata": {}}
+{"_id": "87610599", "title": "", "text": "Characterization and culture of human embryonic stem cellsObjective To explore the in vitro maintenanceand characterization of human embryonic stem cells(hESCs).Methods hESCs were cultured on feederlayer with ES culture medium,which consists of 20% Knockout Serum Replacement,Knockout DMEM and10 ng/mL bFGF.Undifferentiated status of hESCs was identified by cell morphology,and the expressions ofcell surface marker SSEA-1,SSEA-3 and TRA-1-60.G banding technique was employed for cell karyotypeanalysis. Pluropotency of cells were analyzed via in vitro embyoid body(EB) formation and in vivoterotoma formation. Results Most of cells showed undifferentiated properties in cell morphology andnormal karyotype throughout extended culture periods. They maintained undifferentiated status withpositive immunoreactivity to SSEA-3,SSEA-4 and TRA-1-60.in vitro EB formation and in vivo teratomaformation demonstrated the pluripotency of human ES cells. Conclusion The fundamental requirement tohESCs for research and clinical application were their undifferentiated status and pluropotency in culture.Our result demonstrated their potential for these purposes.", "metadata": {}}
+{"_id": "87986426", "title": "", "text": "Detection of Sugarcane bacilliform virus isolate and its influence on yield and quality of cane inYunnanSugarcane bacilliform virus(SCBV) was detected by PCR from sugarcane showing chlorosis andmottle symptom from Kaiyuan,Yunnan Province. Part sequence of replicase gene of the isolateSCBV-Kaiyuan was determined. Sequence analysis indicated that the 589 bp of SCBV-Kaiyuan sharedidentities of 73.2%-74.0% and 83.1%-84.1% at nucleotide and amino acid levels with SCBV-Australiarespectively,66.7%-68.4% and 65.6%-67.7% with SCBV-Morocco. The quality and yield of the sugarcaneinfected with SCBV-Kaiyuan was also investigated. The juice extraction,sucrose content,gravity purity andaverage stalk weight were decreased 1.55%,1.24%,2.22% and 0.26 kg in plants infected withSCBV-Kaiyuan,but reducing sugar was increased by 0.21% in infected plants.", "metadata": {}}
+{"_id": "90064424", "title": "", "text": "Mitotic chromosomes fold by condensin-dependent helical winding of chromatin loop arraysDuringmitosis, chromosomes fold into compacted rod shaped structures. We combined imaging and Hi-C ofsynchronous DT40 cell cultures with polymer simulations to determine how interphase chromosomes areconverted into compressed arrays of loops characteristic of mitotic chromosomes. We found that theinterphase organization is disassembled within minutes of prophase entry and by late prophasechromosomes are already folded as arrays of consecutive loops. During prometaphase, this arrayreorganizes to form a helical arrangement of nested loops. Polymer simulations reveal that Hi-C data areinconsistent with solenoidal coiling of the entire chromatid, but instead suggest a centrally locatedhelically twisted axis from which consecutive loops emanate as in a spiral staircase. Chromosomessubsequently shorten through progressive helical winding, with the numbers of loops per turn increasingso that the size of a helical turn grows from around 3 Mb (~40 loops) to ~12 Mb (~150 loops) in fullycondensed metaphase chromosomes. Condensin is essential to disassemble the interphase chromatinconformation. Analysis of mutants revealed differing roles for condensin I and II during these processes.Either condensin can mediate formation of loop arrays. However, condensin II was required for helicalwinding during prometaphase, whereas condensin I modulated the size and arrangement of loops insidethe helical turns. These observations identify a mitotic chromosome morphogenesis pathway in whichfolding of linear loop arrays produces long thin chromosomes during prophase that then shorten byprogressive growth of loops and helical winding during prometaphase.", "metadata": {}}
+{"_id": "90756514", "title": "", "text": "REVIEW ON CLINICALLY DEVELOPING ANTIBIOTICSThe world is running out of antibiotics. Between 1940and 1962, more than 20 new classes of antibiotics were marketed. Since then, only two new classes ofantibiotics were marketed. Now, not enough analogues are reaching the market to stem the tide ofantibiotic resistance, particularly among gram-negative bacteria which indicates the need of novelantibiotics for their effective action. This review describes those antibiotics in late-stage clinicaldevelopment. Most of them belong to existing antibiotic classes and a few with a narrow spectrum ofactivity are novel compounds directed against novel targets. The reasons for some of the past failures tofind new molecules and a path forward to help attract investments to fund the discovery of newantibiotics are described.", "metadata": {}}
+{"_id": "94109411", "title": "", "text": "Improved Au/Zn/Au ohmic contacts for p-type InPIn this work, an innovated Si3N4 as an out-diffusionbarrier layer to Au/Zn/Au contact system for p-type InP has been proposed. Before the contacts wereannealed, Si3N4 layer was deposited on the Au(200Å)/Zn(700Å)/Au(200Å), then the Si3N4 was removedby HF and a 2000A layer of pure gold was deposited to facilitate wire bonding. The specific contactresistance dropped to a minimum value of 6×10-7 Ω • cm2 (for an acceptor concentration of about3×1018 cm-3) and the contact became perfectly Ohmic. Besides, Si3N4 layer is an excellent passivationlayer and antireflection coating in InP/InGaAs/InP (p-i-n) photodiodes.", "metadata": {}}
+{"_id": "94365950", "title": "", "text": "The reclamation of brine generated from desalination process by bipolar membraneelectrodialysisAbstract Some techno-economical analyses and environmental impact evaluation haveproved that bipolar membrane electrodialysis (BMED) is feasible for the reclamation of industrial salinewater. However, to date, the technology cannot be put into practice due to some unsolvedapplication-oriented problems, such as the requirements of BMED for feed solution, the availability of theproduced acid and base, relatively high salt concentration of the effluent, and relatively low desalinatingefficiency and capacity. In this work, a novel hybrid process, which coupled conventional electrodialysisinstalled with monovalent selective cation-exchange membranes with BMED running in a constant-voltagemode, was designed to reclaim brine generated from surface water desalination by the ion-exchangeprocess. Subsequently, the response surface methodology was employed to establish the empiricalmodels for understanding the influences of some initial operating conditions on BMED performance.Finally, the BMED-based reclamation scheme was confirmed again by a continuous BMED experiment onreal solution. Specially, the effects of product concentration on current efficiency and energy consumptionwere investigated. In this case, an acceptable current efficiency and energy consumption were obtainedon the basis of the conventional membranes and spacers when the product concentration was set as 0.9M, which is adequate for the regeneration of ion-exchange resins.", "metadata": {}}
+{"_id": "95102458", "title": "", "text": "Process analysis and economic evaluation for Poly(3-hydroxybutyrate) production byfermentationAbstract Several processes for the production and recovery of poly(3-hydroxybutyrate)(PHB) by Alcaligenes eutrophus, Alcaligenes latus, Methylobacterium organophilum, and recombinantEscherichia coli were designed based on the previously reported data and analyzed by computer-aidedbioprocess design. PHB productivity, content, and yield significantly affected the final price of PHB. Forthe annual production of 2,850 tonnes of purified PHB, the process employing A. eutrophus with therecovery method of surfactant-hypochlorite digestion resulted in lowest price of PHB, $ 5.58/kg. As theproduction scale increased to one million tonnes per year, the price of PHB dropped to $ 4.75/kg. Thecost of carbon substrate significantly affected the overall economics in large production scale. Therefore,the production cost can be considerably lowered when agricultural wastes, such as whey and molasses,are used.", "metadata": {}}
+{"_id": "95764370", "title": "", "text": "Modification in the chemical bath deposition apparatus, growth and characterization of CdSsemiconducting thin films for photovoltaic applicationsAbstract In this paper, growth and characterizationof CdS thin films by Chemical Bath Deposition (CBD) technique using the reaction between CdCl 2 , (NH 2) 2 CS and NH 3 in an aqueous solution has been reported. The parameters actively involved in theprocess of deposition have been identified. A commonly available CBD system has been sucessfullymodified to obtain the precious control over the pH of the solution at 90°C during the deposition andstudies have been made to understand the fundamental parameters like concentrations of the solution,pH and temperature of the solution involved in the chemical bath deposition of CdS. It is confirmed thatthe pH of the solution plays a vital role in the quality of the CBD–CdS films. Structural, optical andelectrical properties have been analysed for the as-deposited and annealed films. XRD studies on theCBD–CdS films reveal that the change in Cadmium ion concentration in the bath results in the change incrystallization from cubic phase with (1 1 1) predominant orientation to a hexagonal phase with (0 0 2)predominant orientation. The structural changes due to varying cadmium ion concentration in the bathaffects the optical and electrical properties. Optimum electrical resistivity, band gap and refractive indexvalue are observed for the annealed films deposited from 0.8 M cadmium ion concentration. The films aresuitable for solar cell fabrication. Further on, annealing the samples at 350°C in H 2 for 30 min resulted inan increased diffraction intensity as well as shifts in the peak towards lower scattering angles due toenlarged CdS unit cell. This in turn brought about an increase in the lattice parameters and narrowing inthe band-gap values. The results are compared with the analysis of previous work.", "metadata": {}}
+{"_id": "96222213", "title": "", "text": "Combined sampler robot and high-performance liquid chromatography: a fully automated system forbiological small-angle X-ray scattering experiments at the Synchrotron SOLEIL SWINGbeamlineSmall-angle X-ray scattering for macromolecules in solution is now widely used in structuralbiology to complement high-resolution structure determination obtained by X-ray crystallography or NMR.In the context of third-generation synchrotron sources, this increasing interest leads to developments insample environments and automation. The presence of an online purification system is justified by theneed for sample monodispersity. A combined system including an auto-sampler robot and onlinehigh-performance liquid chromatography (HPLC) has been developed and optimized at the SWINGbeamline of Synchrotron SOLEIL (Gif-sur-Yvette, France). In the sample changer mode, a few microlitresof sample can be injected between two air bubbles and circulated at a controlled speed of typically 40 µlmin−1. A maximum of 14 samples per hour could be measured in this mode by remote controlling thesample injections. In the HPLC mode, an initially polydisperse sample can be separated into each of itscomponents before immediate data acquisition. The sample cell is thermostated, and offers avisualization control and online UV–Vis absorption monitoring.", "metadata": {}}
+{"_id": "97566194", "title": "", "text": "Feasibility assessment of desalination application in Australian traditional agricultureAbstract Within somedata limitations, the paper provides a first assessment of areas in Australia with potential forimplementing desalination technologies to supply agricultural water. At the national scale, these areaswere identified based on a set of selected criteria: distance from land currently used for irrigatedagriculture and feedlots; distance from town sites; exclusion of areas of environmental protection;exclusion of areas with surface elevation greater than 600 m AHD; and exclusion of regions with limitedgroundwater resources. Industries involved in the production of high-value crops are most likely tobenefit from desalinated water as they use more-efficient irrigation practices and have the highest grossvalue of irrigated agricultural production. Groundwater was identified as the most likely feedwater sourcefor cost-effective desalination, which is also the case worldwide. Brine disposal is a major factor in overallcost effectiveness of desalination. When feedwater salinity is relatively low, mixing permeate withfeedwater leads to an increase in water production and a reduction in water cost. It was estimated thatAustralian farmers are unlikely to pay more than AU$1.2/kL for agricultural water. Generally foragriculture, desalinated water is still more expensive than water from other sources; however, there arelikely to be circumstances when the costs could be comparable.", "metadata": {}}
+{"_id": "99829811", "title": "", "text": "Development of a specific monoclonal antibody assay and a rapid testing strip for the detection ofapramycin residues in food samplesABSTRACTA specific monoclonal antibody (MAb) against apramycin(AP) was produced and used to develop an indirect competitive enzyme-linked immunosorbent assay(idcELISA) and a rapid testing strip for the detection of AP residues in foods. MAb exhibited negligiblecross-reactivity with other aminoglycosides. Under optimized conditions in 0.01 M PBS, the half maximuminhibitory concentration (IC50) of MAb was 0.41 ng/ml with a limit of detection (LOD) of 0.15 ng/ml. TheELISA results were obtained within 90 min. The mean recoveries from all the spiked food samples werewithin the range of 79.02–105.49%, with coefficients of variation in the range of 2.21–11.4%. The striptest results obtained within 5 min had visual LODs in the range 2.5–5 µg/kg (ng/ml) for all food samplestested. Therefore, the developed strip test represents a fast and convenient detection method of APresidues in foods.", "metadata": {}}
+{"_id": "104143831", "title": "", "text": "Utilization of Desalination Brine for Sodium Hydroxide Production: Technologies, Engineering Principles,Recovery Limits, and Future DirectionsAs global desalination capacity continues its rapid growth, theimpetus for reducing the adverse environmental impacts of brine discharge grows concurrently. Althoughmodern brine outfall designs have significantly limited such impacts, they are costly. Recovering valuablecomponents and chemical derivatives from brine has potential to resolve both environmental andeconomic concerns. In this article, methods for producing sodium hydroxide (“caustic”) from seawaterreverse osmosis (SWRO) brine for internal reuse, which typically involve brine purification, brineconcentration, and sodium chloride electrolysis, are reviewed. Because process energy consumptiondrives process cost and caustic purity determines product usability in drinking water systems, reviewedtechnologies are benchmarked against thermodynamic minimum energy consumption and maximum(stoichiometric) NaOH production rates. After individual reviews of brine purification, concentration, andelectrolysis technologies, five existing facilities ...", "metadata": {}}
+{"_id": "108886332", "title": "", "text": "Training toddlers seated on mobile robots to drive indoors amidst obstaclesThe goal of this research is totrain children seated on mobile robots to purposefully and safely drive indoors. Our previous studies showthat in about six weeks of training, infants can learn to drive directly to a goal using conventionaljoysticks. However, they are unable to acquire the advanced skill to avoid obstacles while driving. Thislimits mobility impaired children from exploring their home environment safely, which in turn impactstheir cognitive and social developments in the important early years. In this paper, we describe resultswhere toddlers are trained to drive a robot within an obstacle course. Using algorithms based on artificialpotential fields to avoid obstacles, we create force field on the joystick that trains them to navigate whileavoiding obstacles. In this ‘assist-as-needed’ approach, if the child steers the mobile robot outside a forcetunnel centered around the desired direction, the driver experiences a bias force on the hand. The resultssuggest that force-feedback joystick results in faster learning than with a conventional joystick.", "metadata": {}}
+{"_id": "109795294", "title": "", "text": "Coming soon to a Wal-Mart near youAccording to the Web site of the Association for AutomaticIdentification and Data Capture Technologies [http://www.aimglobal.org/technologies/rfid], \"radiofrequency identification (RFID) technology is an automatic way to collect product, place, and time ortransaction data quickly and easily without human intervention or error. \" With the ability to trackeverything from crates of disposable razors to individual peanut-butter jars on the store shelves, RFIDtechnology offers the potential of \"real-time supply chain visibility. \" Promoters of RFID technology feel[C. Humer, 2003] that \"RF tags are to this decade what the Internet was to the 1990's-a promise ofradical change in the way business is done. \" However, before the full potential of RFID technology can berealized, several hurdles need to be overcome: reliability, cost, lack of standards, and security. As thesehurdles gradually diminish, Wal-Mart publicly embraces the technology.", "metadata": {}}
+{"_id": "109946221", "title": "", "text": "Innovative beneficial reuse of reverse osmosis concentrate using bipolar membrane electrodialysis andelectrochlorination processesReverse osmosis (RO) is a widely used and rapidly growing desalinationtechnology. A major disadvantage of this process is that the concentrate from the RO process, whichcould be as much as 25% of the feed stream, represents a polluting stream. This waste stream couldpose a significant challenge to the implementation of this process, particularly for inland communitieswhich do not have the option of ocean disposal. An excellent environmentally benign approach to disposalcould be beneficial reuse of the waste stream. This study presents two innovative beneficial reusestrategies for RO concentrate produced by an integrated membrane system (IMS) from a wastewaterreclamation facility. The technologies evaluated in this study included bipolar membrane electrodialysis(BMED) for conversion of RO concentrate into mixed acid and mixed base streams, andelectrochlorination (EC) for onsite chlorine generation. Bench-scale studies conducted with BMEDdemonstrated that RO concentrate could be desalted while producing mixed acids and mixed bases withconcentrations as high as 0.2N. Similarly, the EC process was capable of producing a 0.6% hypochloritesolution from RO concentrate. The acids and bases as well as the hypochlorite produced could be directlyapplied to the RO process as well as upstream pre-treatment processes. A preliminary economicevaluation of the viability of these two approaches was conducted by conducting rough order ofmagnitude cost estimates based on the bench-scale performance of these processes on RO concentrate.A comparison of the overall costs of an Integrated Membrane System utilizing these innovative reusestrategies with conventional disposal options and thermal zero liquid discharge treatment is presented.This comparison indicates that a reuse approach might be economically viable for inland wastewaterreuse facilities that utilize RO membranes and have limited options for concentrate disposal.", "metadata": {}}
+{"_id": "116075383", "title": "", "text": "Amplification of siRNA in Caenorhabditis elegans generates a transgenerational sequence-targetedhistone H3 lysine 9 methylation footprintExogenous double-stranded RNA (dsRNA) has been shown toexert homology-dependent effects at the level of both target mRNA stability and chromatin structure.Using C. elegans undergoing RNAi as an animal model, we have investigated the generality, scope andlongevity of dsRNA-targeted chromatin effects and their dependence on components of the RNAimachinery. Using high-resolution genome-wide chromatin profiling, we found that a diverse set of genescan be induced to acquire locus-specific enrichment of histone H3 lysine 9 trimethylation (H3K9me3),with modification footprints extending several kilobases from the site of dsRNA homology and with locusspecificity sufficient to distinguish the targeted locus from the other 20,000 genes in the C. elegansgenome. Genetic analysis of the response indicated that factors responsible for secondary siRNAproduction during RNAi were required for effective targeting of chromatin. Temporal analysis revealedthat H3K9me3, once triggered by dsRNA, can be maintained in the absence of dsRNA for at least twogenerations before being lost. These results implicate dsRNA-triggered chromatin modification in C.elegans as a programmable and locus-specific response defining a metastable state that can persistthrough generational boundaries.", "metadata": {}}
+{"_id": "116556376", "title": "", "text": "Physicians' initial management of acute low back pain versus evidence-based guidelines. Influence ofsciatica.BACKGROUND Little information is available on physician characteristics and patientpresentations that may influence compliance with evidence-based guidelines for acute low back pain.OBJECTIVE To assess whether physicians' management decisions are consistent with the Agency forHealth Research Quality's guideline and whether responses varied with the presentation of sciatica or byphysician characteristics. DESIGN Cross-sectional study using a mailed survey. PARTICIPANTSParticipants were randomly selected from internal medicine, family practice, general practice, emergencymedicine, and occupational medicine specialties. MEASUREMENTS A questionnaire asked forrecommendations for 2 case scenarios, representing patients without and with sciatica, respectively.RESULTS Seven hundred and twenty surveys were completed (response rate=25%). In cases 1 (withoutsciatica) and 2 (with sciatica), 26.9% and 4.3% of physicians fully complied with the guideline,respectively. For each year in practice, the odds of guideline noncompliance increased 1.03 times (95%confidence interval [CI]=1.01 to 1.05) for case 1. With occupational medicine as the referent specialty,general practice had the greatest odds of noncompliance (3.60, 95% CI=1.75 to 7.40) in case 1, followedby internal medicine and emergency medicine. Results for case 2 reflected the influence of sciatica withinternal medicine having substantially higher odds (vs case 1) and the greatest odds of noncompliance ofany specialty (6.93, 95% CI=1.47 to 32.78), followed by family practice and emergency medicine.CONCLUSIONS A majority of primary care physicians continue to be noncompliant with evidence-basedback pain guidelines. Sciatica dramatically influenced clinical decision-making, increasing the extent ofnoncompliance, particularly for internal medicine and family practice. Physicians' misunderstanding ofsciatica's natural history and belief that more intensive initial management is indicated may be factorsunderlying the observed influence of sciatica.", "metadata": {}}
+{"_id": "117907685", "title": "", "text": "Appropriate Critical Values When Testing for a Single Multivariate Outlier by Using the MahalanobisDistanceThe Mahalanobis distance is a well-known criterion which may be used for detecting outliers inmultivariate data. However, there are some discrepancies about which critical values are suitable for thispurpose. Following a comparison with Wilks's method, this paper shows that the previously recommended{p(n-1)/(n-p)}F p,n−p are unsuitable, and p(n-1) 2 F p,n−p−1 /n(n−p−1+pF p,n−p−1 ) are the correctcritical values when searching for a single outlier The importance of which critical values should be used isillustrated when searching for a single outlier in a clinical laboratory data set containing 10 patients andfive variables. The jackknifed Mahalanobis distance is also discussed and the relevant critical values aregiven. Finally, upper bounds for the usual Mahalanobis distance and the jackknifed version are discussed.", "metadata": {}}
+{"_id": "118215171", "title": "", "text": "How to calculate sample size in animal studiesResearcher must calculate the sample size before startingof any animal study. It should be adequate enough to detect a small significant difference between thegroups. Small sample size is not only responsible for the insignificant result but also for the less power ofthe study. Calculation of sample size involves complex statistics but it can be simplified to help theresearchers who are not from statistical background.", "metadata": {}}
+{"_id": "120385993", "title": "", "text": "On the Theory and Computation of Evolutionary DistancesThis paper gives a formal definition of thebiological concept of evolutionary distance and an algorithm to compute it. For any set S of finitesequences of varying lengths this distance is a real-valued function on $S \\times S$, and it is shown to bea metric under conditions which are wide enough to include the biological application. The algorithm,introduced here, lends itself to computer programming and provides a method to compute evolutionarydistance which is shorter than the other methods currently in use.", "metadata": {}}
+{"_id": "121001457", "title": "", "text": "Over 30% efficient InGaP/GaAs tandem solar cellsA two-terminal monolithic InGaP/GaAs tandem solarcell with a new efficiency record of 30.28% is realized with a practical large area of 4 cm2 under one-sunair-mass 1.5 global illumination. We report improvements of the tandem cell performance by introducinga double-hetero (hereafter DH) structure InGaP tunnel junction, in which the InGaP layers are surroundedby high band gap AlInP barriers. The DH structure by AlInP barriers increase the peak current of InGaPtunnel junction. The AlInP barrier directly below the InGaP top cell, which takes the part of a back surfacefield (hereafter BSF) layer, is found to be considerably effective in reflecting minority carriers in the topcell. The AlInP BSF layer does not only form a high potential barrier but also prevents the diffusion of zincfrom a high doped tunnel junction toward the top cell during epitaxial growth. Furthermore, an InGaPtunnel junction reduces the absorption loss, which exists in a GaAs tunnel junction, and increases thephotogenerated curr...", "metadata": {}}
+{"_id": "121581019", "title": "", "text": "Electrical, optical, and structural properties of indium-tin-oxide thin films for organic light-emittingdevicesHigh-quality indium–tin–oxide (ITO) thin films (200–850 nm) have been grown by pulsed laserdeposition (PLD) on glass substrates without a postdeposition annealing treatment. The structural,electrical, and optical properties of these films have been investigated as a function of target composition,substrate deposition temperature, background gas pressure, and film thickness. Films were depositedfrom various target compositions ranging from 0 to 15 wt % of SnO2 content. The optimum targetcomposition for high conductivity was 5 wt % SnO2+95 wt % In2O3. Films were deposited at substratetemperatures ranging from room temperature to 300 °C in O2 partial pressures ranging from 1 to 100mTorr. Films were deposited using a KrF excimer laser (248 nm, 30 ns full width at half maximum) at afluence of 2 J/cm2. For a 150-nm-thick ITO film grown at room temperature in an oxygen pressure of 10mTorr, the resistivity was 4×10−4 Ω cm and the average transmission in the visible range (400–700 nm)was 85%. For a 170-n...", "metadata": {}}
+{"_id": "126549848", "title": "", "text": "Disaster Management and Community Planning, and Public Participation: How to Achieve SustainableHazard MitigationThe paper offers first a brief historical overview of disaster management planning.Second, it reviews Australian and American research findings and show that they urge the field of disastermanagement to shift its focus from response and recovery to sustainable hazard mitigation. It is arguedthat in order for this shift to occur, it is necessary to integrate disaster management and communityplanning. Current practice seldom reflects such a synthesis, and this is one of the reasons why hazardawareness is absent from local decision-making processes. Third, it is asserted that if mitigativestrategies are to be successfully implemented, then the disaster management process must incorporatepublic participation at the local decision-making level. The paper concludes with a case study ofCalifornia's Portola Valley, which demonstrates that when public participation is integrated into disastermanagement planning and community planning, the result is sustainable hazard mitigation.", "metadata": {}}
+{"_id": "129199129", "title": "", "text": "A second generation of homogenized Canadian monthly surface air temperature for climate trendanalysis[1] This study presents a second generation of homogenized monthly mean surface airtemperature data set for Canadian climate trend analysis. Monthly means of daily maximum and of dailyminimum temperatures were examined at 338 Canadian locations. Data from co-located observing siteswere sometimes combined to create longer time series for use in trend analysis. Time series ofobservations were then adjusted to account for nation-wide change in observing time in July 1961,affecting daily minimum temperatures recorded at 120 synoptic stations; these were adjusted usinghourly temperatures at the same sites. Next, homogeneity testing was performed to detect and adjust forother discontinuities. Two techniques were used to detect non-climatic shifts in de-seasonalized monthlymean temperatures: a multiple linear regression based test and a penalized maximal t test. Thesediscontinuities were adjusted using a recently developed quantile-matching algorithm: the adjustmentswere estimated with the use of a reference series. Based on this new homogenized temperature data set,annual and seasonal temperature trends were estimated for Canada for 1950–2010 and Southern Canadafor 1900–2010. Overall, temperature has increased at most locations. For 1950–2010, the annual meantemperature averaged over the country shows a positive trend of 1.5°C for the past 61 years. Thiswarming is slightly more pronounced in the minimum temperature than in the maximum temperature;seasonally, the greatest warming occurs in winter and spring. The results are similar for Southern Canadaalthough the warming is considerably greater in the minimum temperature compared to the maximumtemperature over the period 1900–2010.", "metadata": {}}
+{"_id": "140098548", "title": "", "text": "Prevention of radiographic-contrast-agent-induced reductions in renal function byacetylcysteine.BACKGROUND Radiographic contrast agents can cause a reduction in renal function thatmay be due to reactive oxygen species. Whether the reduction can be prevented by the administration ofantioxidants is unknown. METHODS We prospectively studied 83 patients with chronic renal insufficiency(mean [+/-SD] serum creatinine concentration, 2.4+/-1.3 mg per deciliter [216+/-116 micromol perliter]) who were undergoing computed tomography with a nonionic, low-osmolality contrast agent.Patients were randomly assigned either to receive the antioxidant acetylcysteine (600 mg orally twicedaily) and 0.45 percent saline intravenously, before and after administration of the contrast agent, or toreceive placebo and saline. RESULTS Ten of the 83 patients (12 percent) had an increase of at least 0.5mg per deciliter (44 micromol per liter) in the serum creatinine concentration 48 hours afteradministration of the contrast agent: 1 of the 41 patients in the acetylcysteine group (2 percent) and 9 ofthe 42 patients in the control group (21 percent; P=0.01; relative risk, 0.1; 95 percent confidenceinterval, 0.02 to 0.9). In the acetylcysteine group, the mean serum creatinine concentration decreasedsignificantly (P<0.001), from 2.5+/-1.3 to 2.1+/-1.3 mg per deciliter (220+/-118 to 186+/-112micromol per liter) 48 hours after the administration of the contrast medium, whereas in the controlgroup, the mean serum creatinine concentration increased nonsignificantly (P=0.18), from 2.4+/-1.3 to2.6+/-1.5 mg per deciliter (212+/-114 to 226+/-133 micromol per liter) (P<0.001 for the comparisonbetween groups). CONCLUSIONS Prophylactic oral administration of the antioxidant acetylcysteine, alongwith hydration, prevents the reduction in renal function induced by contrast agents in patients withchronic renal insufficiency.", "metadata": {}}
+{"_id": "140907540", "title": "", "text": "Sample size calculation in epidemiological studiesSummary Sample-size determination is often animportant step in planning an epidemiological study. There are several approaches to determining samplesize. It depends on the type of the study. Descriptive, observational and randomized controlled studieshave different formulas to calculate sample size. In this article, we discuss the formulas that can help toestimate sample size in an epidemiological trial. We present a few examples from clinical practice, whichmay contribute to the understanding of this problem. Keywords: sample size determination Determiningan appropriate sample size for a clinical trial is an essential step in the statistical design of the pro-ject.An adequate sample size helps ensure that the stu-dy will yield reliable information, regardless ofwhether the ultimate data suggest a clinically important difference between the treatments being studied,or the study is in-tended to measure the accuracy of a diagnostic test or the incidence of a disease.Unfortunately, many studies pub-lished in medical literature are conducted with inadequate sample sizes,making the interpretation of negative results difficult. Conductingastudywithaninadequatesamplesize isnot only futile, it is also unethical. Exposing pa-tients to the risks inherent in a research is justifiableon-lyif there is a realistic possibility that the results willbe-nefitthosesubjects,futuresubjects,orleadtosubstantialscientificprogress. How many individuals will Ineed to study? This ques-tion iscommonly asked by a clinical investigator and ex-poses oneof manyissues that are best to be settled before actually carryingout a study. Consultation with a statisti-cian isworthwhilein addressing many issues of study de-sign, but a statisticianis not always readily available.Sample Size (n) is the number of individuals in a group under study. The larger the sample size, thegrea-ter the precision and, thus, power for a given study de-sign to detect an effect of a given size. Forstatisticians, an n > 30 is usually sufficientfortheCentralLimitTheo-rem to hold so that normal theoryapproximations can be used for measures such as the standard error of the mean. However, this samplesize (n = 30) is unrelated to the cli-nicians’ objective of detecting biologically significantef-fects, whichdetermines the specificsamplesizeneededfor a specificstudy[1].", "metadata": {}}
+{"_id": "142559798", "title": "", "text": "Tammarniit (Mistakes): Inuit Relocation in the Eastern Arctic, 1939-63Preface Introduction 1. Are InuitIndians?: Relief, Jurisdiction, and Government Responsibility 2. Social Welfare and Social Crisis in theEastern Arctic 3. Planning for Relocation in the Eastern Arctic 4. Recolonizing the Arctic Islands: The 1953Relocations to Resolute Bay and Craig Harbour 5. The Ennadai Lake Relocations, 1950-60 6. The GarryLake Famine 7. The Whale Cove Relocation 8. Relocation and Responsibility, 1955-63 Notes BibliographyIndex", "metadata": {}}
+{"_id": "142562844", "title": "", "text": "Levels of selection in evolutionEver since the groundbreaking work of George Williams, W. D. Hamilton,and Richard Dawkins, evolutionary biologists have recognized that natural selection generally does notoperate for the good of the group, but rather for the good of lower-level units such as the individual, thecell, even the gene. One of the fundamental problems of biology is: what keeps competition betweenthese various levels of natural selection from destroying the common interests to be gained fromcooperation? In this volume twelve prominent scientists explore this question, presenting acomprehensive survey of the current theoretical and empirical research in evolutionary biology. Recentstudies show that at many levels of biological organization, mechanisms have evolved to preventpotential conflict in natural selection. Editor Laurent Keller's aim in this book is to bring together leadingresearchers from all biological disciplines to outline these potential conflicts and discuss how they areresolved. A multi-level approach of this kind allows important insights into the evolution of life, as well asbridging the long-standing conceptual chasm between molecular and organismal biologists. The chaptershere follow a rigorous theoretical framework, giving the book an overall synergy that is unique tomulti-authored books. The contributors, in addition to the editor, are H. Charles J. Godfray, Edward AllenHerre, Dawn M. Kitchen, Egbert Giles Leigh, Jr., Catherine M. Lessells, Richard E. Michod, LeonardNunney, Craig Packer, Andrew Pomiankowski, H. Kern Reeve, John Maynard Smith, and Eors Szathmary.\"", "metadata": {}}
+{"_id": "143381103", "title": "", "text": "A psychometric evaluation of the Beck Depression Inventory–II.This article provides psychometricinformation on the second edition of the Beck Depression Inventory (BDI-II; A. T. Beck, R. A. Steer, & G.K. Brown, 1996), with respect to internal consistency, factorial validity, and gender differences. Bothmeasures demonstrated high internal reliability in the full student sample. Significant differences betweenthe mean BDI and BDI-II scores necessitated the development of new cutoffs for analogue research onthe BDI-II. Results from exploratory and confirmatory factor analyses indicated that a 2-factor solutionoptimally summarized the data for both versions of the inventory and accounted for a cumulative 41%and 46% of the common variance in BDI and BDI-II responses, respectively. These factor solutions werereliably cross-validated, although the importance of each factor varied by gender. The authors concludethat the BDI-II is a stronger instrument than the BDI in terms of its factor structure.", "metadata": {}}
+{"_id": "143796742", "title": "", "text": "Why people feel crowded: An examination of objective and subjective crowdingPrior studies have foundonly a modest relationship between objective and subjective crowding, defying logic and commonsensicalnotions of why people feel crowded. Using data from a representative sample of Bangkok, Thailand,where the level of household crowding is four times that in western societies, we explore severalpossibilities of why this is the case. Examining seven different indicators of objective crowding, ouranalyses suggest that the modest relationship is not an artifact of measurement. Contrary to theassumption of prior investigations, the findings indicate that the objective-subjective crowdingrelationship is nonlinear and that there is a ceiling effect muting the impact of increased objectivecrowding. The analyses further suggest that the strength of the relationship is mitigated somewhat, withpart of the feeling of being crowded accounted for by household circumstances, such as the degree ofcontrol an individual has over the use of household space.", "metadata": {}}
+{"_id": "143868995", "title": "", "text": "Self-Report and Tests of Memory AgingMemory complaints have not correlated well with tests of memory.However, given self-report questions, which tap processes of everyday remembering. sixty volunteersaged 21-84 years adequately rated their memory competence. Categorized into four memory processes,self-report and six tests of verbal, faces, story and nonverbal auditory, visual, and tactual memory ,werecanonically correlated (r = 0.67) and both sets of measures declined with age in parallel. Thc old weremore accurate than the young in their ratings but by no means on all tests and expectation to performpoorly seemed to have influenced some performances.", "metadata": {}}
+{"_id": "144555102", "title": "", "text": "Code of the Street: Decency, Violence, and the Moral Life of the Inner CityInner-city black America isoften defined by random, senseless street violence. In fact, although violence is a salient feature, its useis far from random; it is regulated through an informal but well-known code of the street. How you dress,how you talk, whether you make eye-contact, your understanding of the pecking order - such crucialdetails can have life-or-death consequences and young people are particularly at risk. In this anatomy ofthe inner-city psyche, the author shows how the code is a response to the lack of well-paid jobs; to thestigma of race; to rampant drug use; to alienation and to lack of hope. The police exercise no control,and the individual's safety and sense of worth are defined by how much respect he can command inpublic; this deference is based physical and psycholgical control and on an implied threat of violence. Themost powerful force counteracting the code is the strong, loving decent family. Unfortunately, the cultureof the street thrives and often defeats decency because it controls public space so that individuals withbetter aspirations are often entangled in the code.", "metadata": {}}
+{"_id": "144801076", "title": "", "text": "A generic measure of relationship satisfaction.The variety of interpersonal relationships in contemporarysociety necessitates the development of brief, reliable measures of satisfaction that are applicable tomany types of close relationships. This article describes the development of such a measure. In Study I,the 7-item Relationship Assessment Scale (RAS) was administered to 125 subjects who reportedthemselves to be \"in love. \" Analyses revealed a unifactorial scale structure, substantial factor loadings,and moderate intercorrelations among the items. The scale correlated significantly with measures of love,sexual attitudes, self-disclosure, commitment, and investment in a relationship. In Study II, the scalewas administered to 57 couples in ongoing relationships. Analyses supported a single factor, alphareliability of .86, and correlations with relevant relationship measures. The scale correlated .80 with alonger criterion measure, the Dyadic Adjustment Scale (Spanier, 1976), and both scales were effective(with a subsample) in discriminating couples who stayed together from couples who broke up. The RAS isa brief, psychometrically sound, generic measure of relationship satisfaction.", "metadata": {}}
+{"_id": "145335387", "title": "", "text": "ECONOMIC RESTRUCTURING AND SUBURBANIZATION IN CHINAAs in other countries, suburbanization inChina occurred after the cities had experienced a period of sustained industrial and population growth.This study examines suburbanization in Beijing, Shanghai, Shenyang, and Dalian. As a result of economicrestructuring, the urban core registered net population loss from 1982 to 1990 because ofdecentralization while the inner suburbs gained population. Among the forces driving suburbanizationwere marketization of urban land, the shift of industrial land to tertiary use, transportation improvement,the availability of foreign and domestic capital, housing rehabilitation in the city, and new housingconstruction in the suburbs. There were certain similarities but major differences between American andChinese suburbanization. Unlike the current metropolitan landscape in the United States where suburbangrowth has given rise to a polycentric spatial structure, suburbanization in China is still at the incipientstage of development with suburbs dominated by centra...", "metadata": {}}
+{"_id": "145383432", "title": "", "text": "The Assumption of Caregiving: Grandmothers Raising the Children of the Crack Cocaine Epidemic:In thisarticle, selected findings are presented from a study of the experiences of 71 African American womenwho have become the sole caregivers for at least one grandchild or great-grandchild as a result of theinvolvement of the parent in use of crack cocaine. Despite the unique circumstances of each situation,three patterns of the assumption of caregiving emerged from analysis of the intensive interviews andparticipant observation: sudden assumption, negotiated assumption, and inevitable assumption of thepermanent caregiver role. Each pattern is described along six dimensions: forewarning, initiation, thetrigger event, the caregiver's goal, her assumed trajectory of the caregiving period, and her perceivedinfluence on her own destiny. These accounts provide important information for those who work withwomen, children, and families, as well as unique insight into the consequences of the crack cocaineepidemic.", "metadata": {}}
+{"_id": "145416918", "title": "", "text": "The effect of information related to fat content and taste on consumer responses to a reduced-fatfrankfurter and a reduced-fat chocolate barThe effects of product information on responses to frankfurtersausages and chocolate bars were studied by comparing sensory and hedonic ratings in two conditions:blind tasting and tasting with information present. Furthermore, the effect of information alone wasinvestigated by having the subjects rate the expected sensory and hedonic intensities of the products onthe basis of packages with different claims. Three groups of subjects were tested by giving them differentinformation: The basic group (no added claims, n = 31), the reduced-fat group (products claimed to havereduced-fat, n=29) and the flavorful group (products claimed to have full meat/chocolate flavor, n = 31).Product information increased the rated pleasantness of the frankfurter in all three information groupscompared to the blind ratings. The information did not affect the pleasantness of the chocolate bars. Theexpected attribute intensities of the frankfurters and chocolates were rated lower by the reduced-fatgroup than by the other groups. Overall, the effect of product information was more clearly seen inratings of sensory attributes than in pleasantness ratings.", "metadata": {}}
+{"_id": "145716849", "title": "", "text": "Transnationalism and identityTransnationalism and identity are concepts that inherently call forjuxtaposition. This is so because many peoples' transnational networks of exchange and participation aregrounded upon some perception of common identity; conversely, the identities of numerous individualsand groups of people are negotiated within social worlds that span more than one place. In thisintroductory article, the transnational perspective on migration studies is first discussed, followed bysome critiques and outstanding questions. The final section summarises points raised by the contributingauthors of the main articles in this themed issue of JEMS, especially with regard to various waystransnational settings and dynamics affect the construction, negotiation and reproduction of identities.", "metadata": {}}
+{"_id": "146653163", "title": "", "text": "Social Isolation and Social Support: An Applied PerspectiveConsiderable empirical evidence substantiatesthe importance of social networks and support to health and well-being among the elderly. Butconsiderably more research is necessary before successful interventions can be more generallyimplemented to positively alter an elder's network. In this article, the authors discuss social supportandisolationfrom an appliedperspective. They have combined presentations originally made at a NationalInstitute on Aging-sponsored symposium on applied gerontology held in August 1992. They make somegeneral observations concerning the field of applied social relations in later life, describe the mentalhealth aspects of these relations, list some fundamental principles and existing technology for this field,describe the use of a brief screening instrument for social isolation developed by one of the authors(Lubben), and explore varying domains of knowledge concerning elder soical relations. They conclude byoutlining some areas that they see as requiring the attention o...", "metadata": {}}
+{"_id": "147107523", "title": "", "text": "Wine and health: faraway concepts?Purpose – The purpose of this paper is to explore consumers’perceptions and beliefs in the health benefits of wine and the relationship with wine consumptionpatterns. Design/methodology/approach – In store face-to-face survey results from 402 wine consumerswere elaborated with two-step cluster analysis. ANOVA confirmed differences among groups. Groupswere profiled by a χ2 significance analysis when adequate. A multivariate binary logistic regressionestimated wine consumption influence on healthiness perceptions. Findings – Consumers converge intofour groups: two health-oriented – optimistic and medical; two non-health-oriented – unintentionaldrinker and unconvinced. Groups are not significantly differentiated in socio-economic terms. Wineconsumption behaviour influences health orientation, specifically for monthly and wine drinkers, vsweekly and other alcohol drinkers. Health-oriented consumers favourably welcome and are willing to paymore for health-enhancing wine. Consumers believe that wine c...", "metadata": {}}
+{"_id": "153755807", "title": "", "text": "The Changing Problem of Overcrowded HousingAbstract Overcrowding has increased in the U.S. afterdecades of decline—dramatically so in some locales and for some ethnic groups. The nature of theproblem and its very definition for policy purposes are also changing. We examine the specialcharacteristics of the overcrowded, where they are located, why the incidence of crowding has resurged,and why it is confined to specific locales. Ethnicity, age, immigration, and poverty play important roles,but housing market conditions appear much less important. We also show that the planning standardused to judge overcrowding is a relative one that has varied over time, and that the social norms varyamong ethnic groups. The issue of overcrowding may exemplify the current perplexities about imposinguniform standards in an evolving multiethnic society. Worst-case housing needs would be better targetedin highly impacted locales by allowing more “place diversity” in the setting of standards.", "metadata": {}}
+{"_id": "154050141", "title": "", "text": "Best response dynamics and socially stable strategiesAbstract An evolutionarily stable strategy (MaynardSmith and Price, Nature (London) 246 (1973), 15–18) is a strategy which is robust against a tiny invasionof mutants. Best response dynamics is a dynamic process in which the frequency of a strategy increasesonly if it is a best response to the present strategy distribution. Gilboa and Matsui ( Econometrica 59(1991), 859–867) proposed a stability concept directly derived from this dynamic process. Modifying theabove two stability concepts, this paper shows the equivalence between the static concept and thedynamic one. Their set-valued versions always exist. Examples are given to see their usefulness inanalyzing forward induction and preplay communication.", "metadata": {}}
+{"_id": "154243324", "title": "", "text": "From youth to adult homelessnessGovernments have shown an interest in early intervention strategies toreduce youth homelessness, but critics say that early intervention programs lack clear outcomes. Thispaper investigates what happens when early intervention programs are not in place and young peopleprogress to adult homelessness. The paper assesses the 'social adaptation' hypothesis that the longeryoung people are homeless the more they adapt to homelessness as a way of life. The paper usesinformation on 1,677 individuals who first became homeless when they were 18 or younger.Three-quarters of the sample had progressed to adult homelessness (defined as 25 or older) andone-quarter were now young adults aged 19 to 24. The findings confirm that the longer people arehomeless, the more difficult it becomes to get out of homelessness. However, the social adaptationaccount overstates the extent to which people accept homelessness as a 'way of life'. People can returnto conventional accommodation if they are given long-term support. The paper concludes with threepolicy recommendations.", "metadata": {}}
+{"_id": "154549459", "title": "", "text": "Urban spatial development in the land policy reform era: evidence from BeijingThis paper examines thecharacteristics of urban spatial development in Beijing and identifies the extent to which thesecharacteristics can be attributed to the emerging land market in Beijing as well as the impact of landpolicy reform. Based on the observations of land use rights granted from 1993 to the first half of 2000 inthe built-up area of Beijing, empirical analyses illustrate that both land prices and land developmentdensity decrease with distance to the city core. It further provides evidence that the slope of the land rentcurve also depends on land use types. This leads to the conclusion that the land market influences landdevelopment decisions and urban form. Finally, it shows that the slope of the land rent curve and theelasticity of land-capital substitution change over time. The former declines, as expected. This is becauseBeijing's massive investments in transport have reduced transport costs, which in turn has shifted theland rent curve. The latter rises, implying the price effect on land development density. Bothchanges—in land rent function and the elasticity of land-capital substitution-point to the maturing of theBeijing land market. It should be mentioned that there are enormous land developments outside the landmarket (land development on administratively allocated land). These developments can significantlydistort urban land use patterns portrayed through this study.", "metadata": {}}
+{"_id": "154763124", "title": "", "text": "The Mismatch Argument: The Construction of a Housing Orthodoxy in AustraliaAustralia's housing policydiscourse contains many orthodoxies. While orthodoxies are never totally accepted within a discourse,they are the dominant notions within them and as such carry significant symbolic authority. Oneorthodoxy that has particular authority in Australia is the notion that there is a 'mismatch' in the housingsystem between the available stock and the size of households to the extent that there is significantunderutilisation and underoccupancy of housing. The mismatch argument's power as orthodoxy is suchthat the idea is assumed in much housing policy discussion. Criticism of the mismatch orthodoxy can takemany approaches, such as empirical, conceptual and discursive. The discursive critique focuses not onthe empirical relationship between households and dwellings, but on the statements about thatrelationship. The resulting analysis shows how the mismatch orthodoxy arose in Australia and its effectson housing discourse. This paper examines the construction of the mismatch orthodoxy, from its firstuses in the early 1970s to its entrenchment in national and state housing policy research in the early1990s. It shows how the structures of the discourse construct the orthodoxy, despite empirical andconceptual criticisms of it. Of particular importance is the effect the orthodoxy has on people deemed tobe underutilising their dwellings, and on how the orthodoxy affects policy interpretations, such asoccupancy standards.", "metadata": {}}
+{"_id": "154796494", "title": "", "text": "Citizen Participation and Citizen Evaluation in Disaster RecoveryIn April 1997, Grand Forks, North Dakota,and East Grand Forks, Minnesota, experienced a disastrous flood. Both cities have been textbookexamples of success according to the Federal Emergency Management Agency. They have an updatedinfrastructure, paid for largely by the federal government. Their downtowns are on the road to recoverywith new construction and businesses. The paths of the two cities have diverged in the social and politicalaftermath of the flood. East Grand Forks, following consultant suggestions, instituted extensive citizenparticipation initiatives. East Grand Forks has experienced political stability and citizen satisfaction. GrandForks relied primarily on bureaucratic guidance to react to the disaster. Grand Forks has experiencedchanges in government structure, turnover of elected and appointed officials, and much less positivecitizen evaluation. This study examines the effect of perceptions of citizen participation on the citizens’evaluation of the success of the recovery.", "metadata": {}}
+{"_id": "155200372", "title": "", "text": "Population growth, urban sprawl and landscape integrity of Beijing CityThe detailed landscape pattern ofthe urban area within the 6th ring road in Beijing City was identified using airborne remote sensing dataacquired between 1997 and 2002. The landscape indices at landscape level were computed usingFragstats 3.3, and changes in land use/cover types in Beijing from 1997 to 2002 were examined. Theresults show that urban built area (UBA) and farmland changed greatly within the 6th ring road, and thatfarmland had been replaced by UBA. The number of patches increased by 106.6%, mean patch areadecreased by 51.6%, the splitting index increased by 94.3%, and the landscape diversity index increasedby 17.8%. The landscape pattern had become more fragmented and diversified in these 5 years. Themain driving forces for landscape change were the increasing demand for land for construction due to thegrowing population, unreasonable urban growth, and improvements in housing standards. The landscapepattern change in Beijing led by rapid urbanisation has negatively influenced urban...", "metadata": {}}
+{"_id": "167469018", "title": "", "text": "Drink Choice: Factors Influencing the Intention to Drink WineThis paper explores the reasons whyconsumers choose wine over other alcoholic beverages, with a focus upon the beliefs held by consumerstowards the behaviour of wine drinking. The research findings show that attitudes are somewhat morepredictive of the intention to drink wine than perceived social pressure. Nevertheless, both attitudinal andnormative elements are required to adequately explain wine consumption. Despite the fact that the issueof health figured prominently amongst the salient beliefs identified in the qualitative phase of theresearch, the subsequent quantitative research found that drinking wine because of its purported healthbenefits was not a significant attitudinal or behavioural factor. Drinking wine because it provides ‘avariety of tastes and flavours’ and because it ‘goes well with food’ was found to be significantly moreimportant. The results suggest that efforts to actively promote awareness of the health benefits of winedrinking may have limited value.", "metadata": {}}
+{"_id": "167944455", "title": "", "text": "Application of growth technologies in enhancing food security and sustainabilityAnabolic steroids havebeen widely used in the beef cattle industry for over 50 years as safe and effective growth-promotingagents, and today, more than 90% of all feedlot cattle in the US receive some type of steroidal implantduring their lifetime (NAHMS, USDA 2000). A list of approval of growth promotants by the FDA is shownin Table 1. Generally, implants have been shown to increase growth rate 8 to 28%, improve feedefficiency 5 to 20%, and enhance lean tissue mass of the carcass 3 to 10% (Duckett and Owens, 1997).This improvement in production efficiency has multiple benefits: 1) it clearly and dramatically reducesproduction costs by reducing the amount of feed required per unit of gain (Avery and Avery, 2007); 2) itreduces the amount of land necessary to produce equivalent amounts of food for consumers; 3) it limitsthe production of greenhouse gases by reducing the number of animals required to produce equivalentamounts of beef (Avery and Avery, 2007); and 4) it extends cost savings to consumers by providing ayear-round, affordable supply of beef at reduced prices (Lawrence and Ibarburu, 2006). Since animalproducts contribute significantly to the total caloric and nutrient intake in the human population, alteringthe composition of growth toward more lean tissue and less adipose tissue results in a healthier productwith fewer calories that still is rich in beneficial nutrients. In addition to steroidal implants, a newer classof orally active growth promotants, known as b-adrenergic agonists (BAA; Ractopamine-HCl; 2003 andZilpaterol-HCl; 2006), have been approved for use in finishing beef cattle in the last decade. Theseproducts provide similar production benefits as steroidal implants, but differ in application and mode ofaction. Beta-adrenergic agonists are fed during the last 20 to 42 days of the cattle finishing period,depending on the specific product. The purpose of this paper is to explain how anabolic implants and BAAwork and their benefits to beef cattle production.", "metadata": {}}
+{"_id": "168265642", "title": "", "text": "Metabolic modifiers as performance-enhancing technologies for livestock productionWith the current andpredicted increase in world population, growing global demand and consumption of food will result inincreasing competition for land, water, and energy. In turn, this will severely affect our ability to producefood as will the urgent requirement to reduce the impact of food systems on the environment (Godfray etal., 2010). Globalization has boosted trade in livestock inputs and products and resulted in industrygrowth, and concurrently livestock production has undergone a complex process of technical andgeographical change (Gerber et al., 2007). This has resulted in a challenge to livestock producers;growing demand for their produce with a dwindling supply of resources, with the only solution being asignificant increase in efficiency. Also, as incomes increase in the burgeoning economies, so does thedemand for high-quality animal proteins such as meat, milk, and eggs; thus the Food and AgricultureOrganization of the United Nations suggests that food requirements will increase by 70% by 2050(Anonymous, 2009). The recent success in developed and emerging technologies suggests that theanimal industries are well placed to prosper through these new challenges. To ensure thesetechnologies—such as metabolic modifiers including somatotropin, immunization againstgonadotropin-releasing factor, and orally active dietary additives like ractopamine, zilpaterol, cysteamine,chromium, betaine, and dietary neuroleptics—can be effectively utilized throughout the animal industries,further emphasis is required on their acceptance and development. As a result of these technologicaladvancements, producers have benefited because of improved production efficiencies while meat packershave improved processing efficiencies because of increased lean meat yield. Ostensibly, the consumerhas also benefited because meat is leaner and less expensive to purchase. However, there have beensome concerns that the focus on increasing production efficiency and lean meat yield has been to thedetriment of meat quality (Dunshea et al., 2005). It is also interesting that at a time of apparentlygreater need for these technologies, there are external influences such as market differentiation andtrade barriers as well as consumer resistance that challenge the use of technologies. A tenet of this articleis that if we are to meet the increased global demand for animal protein, then we must continue todevelop and adopt technologies to improve livestock efficiency, but we must be cognizant of the potentialbarriers affecting acceptance.", "metadata": {}}
+{"_id": "195317463", "title": "", "text": "Assessment of hemodynamic efficacy and safety of 6% hydroxyethylstarch 130/0.4 vs. 0.9% NaCl fluidreplacement in patients with severe sepsis: The CRYSTMAS studyInadequate initial treatment anddelayed hemodynamic stabilization (HDS) may be associated with increased risk of death in severe sepsispatients. In order to compare the hemodynamic efficacy and safety of 6% HES 130/0.4 and NaCl 0.9%for HDS in patients with severe sepsis, we designed a prospective, multicenter, active-controlled,double-blind, randomized study in intensive care units. 174 out of 196 patients reached HDS (88 and 86patients for HES and NaCl, respectively). Significantly less HES was used to reach HDS vs. NaCl (1,379±886 ml in the HES group and 1,709 ±1,164 ml in the NaCl group (mean difference = -331± 1,033, 95%CI -640 to -21, P = 0.0185). Time to reach HDS was 11.8 10.1 hours vs. 14.3 ±11.1 hours for HES andNaCl, respectively. Total quantity of study drug infused over four consecutive days, ICU and hospital LOS,and area under the curve of SOFA score were comparable. Acute renal failure occurred in 24 (24.5%) and19 (20%) patients for HES and NaCl, respectively (P = 0.454). There was no difference between AKINand RIFLE criteria among groups and no difference in mortality, coagulation, or pruritus up to 90 daysafter treatment initiation. Significantly less volume was required to achieve HDS for HES vs. NaCl in theinitial phase of fluid resuscitation in severe sepsis patients without any difference for adverse events inboth groups. NCT00464204", "metadata": {}}
+{"_id": "195680777", "title": "", "text": "Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses oflong-term outcome among 100,000 women in 123 randomised trials.BACKGROUND Moderate differencesin efficacy between adjuvant chemotherapy regimens for breast cancer are plausible, and could affecttreatment choices. We sought any such differences. METHODS We undertook individual-patient-datameta-analyses of the randomised trials comparing: any taxane-plus-anthracycline-based regimen versusthe same, or more, non-taxane chemotherapy (n=44,000); one anthracycline-based regimen versusanother (n=7000) or versus cyclophosphamide, methotrexate, and fluorouracil (CMF; n=18,000); andpolychemotherapy versus no chemotherapy (n=32,000). The scheduled dosages of these three drugs andof the anthracyclines doxorubicin (A) and epirubicin (E) were used to define standard CMF, standard 4AC,and CAF and CEF. Log-rank breast cancer mortality rate ratios (RRs) are reported. FINDINGS In trialsadding four separate cycles of a taxane to a fixed anthracycline-based control regimen, extendingtreatment duration, breast cancer mortality was reduced (RR 0·86, SE 0·04, two-sided significance[2p]=0·0005). In trials with four such extra cycles of a taxane counterbalanced in controls by extra cyclesof other cytotoxic drugs, roughly doubling non-taxane dosage, there was no significant difference (RR0·94, SE 0·06, 2p=0·33). Trials with CMF-treated controls showed that standard 4AC and standard CMFwere equivalent (RR 0·98, SE 0·05, 2p=0·67), but that anthracycline-based regimens with substantiallyhigher cumulative dosage than standard 4AC (eg, CAF or CEF) were superior to standard CMF (RR 0·78,SE 0·06, 2p=0·0004). Trials versus no chemotherapy also suggested greater mortality reductions withCAF (RR 0·64, SE 0·09, 2p<0·0001) than with standard 4AC (RR 0·78, SE 0·09, 2p=0·01) or standardCMF (RR 0·76, SE 0·05, 2p<0·0001). In all meta-analyses involving taxane-based or anthracycline-basedregimens, proportional risk reductions were little affected by age, nodal status, tumour diameter ordifferentiation (moderate or poor; few were well differentiated), oestrogen receptor status, or tamoxifenuse. Hence, largely independently of age (up to at least 70 years) or the tumour characteristics currentlyavailable to us for the patients selected to be in these trials, some taxane-plus-anthracycline-based orhigher-cumulative-dosage anthracycline-based regimens (not requiring stem cells) reduced breast cancermortality by, on average, about one-third. 10-year overall mortality differences paralleled breast cancermortality differences, despite taxane, anthracycline, and other toxicities. INTERPRETATION 10-year gainsfrom a one-third breast cancer mortality reduction depend on absolute risks without chemotherapy(which, for oestrogen-receptor-positive disease, are the risks remaining with appropriate endocrinetherapy). Low absolute risk implies low absolute benefit, but information was lacking about tumour geneexpression markers or quantitative immunohistochemistry that might help to predict risk,chemosensitivity, or both. FUNDING Cancer Research UK; British Heart Foundation; UK Medical ResearchCouncil.", "metadata": {}}
+{"_id": "195683603", "title": "", "text": "Invariant NKT cells modulate the suppressive activity of IL-10-secreting neutrophils differentiated withserum amyloid A.Neutrophils are the main effector cells during inflammation, but they can also controlexcessive inflammatory responses by secreting anti-inflammatory cytokines. However, the mechanismsthat modulate their plasticity remain unclear. We now show that systemic serum amyloid A 1 (SAA-1)controls the plasticity of neutrophil differentiation. SAA-1 not only induced anti-inflammatory interleukin10 (IL-10)-secreting neutrophils but also promoted the interaction of invariant natural killer T cells (iNKTcells) with those neutrophils, a process that limited their suppressive activity by diminishing theproduction of IL-10 and enhancing the production of IL-12. Because SAA-1-producing melanomaspromoted differentiation of IL-10-secreting neutrophils, harnessing iNKT cells could be usefultherapeutically by decreasing the frequency of immunosuppressive neutrophils and restoringtumor-specific immune responses.", "metadata": {}}
+{"_id": "195689316", "title": "", "text": "Body-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospectivestudies.BACKGROUND The main associations of body-mass index (BMI) with overall and cause-specificmortality can best be assessed by long-term prospective follow-up of large numbers of people. TheProspective Studies Collaboration aimed to investigate these associations by sharing data from manystudies. METHODS Collaborative analyses were undertaken of baseline BMI versus mortality in 57prospective studies with 894 576 participants, mostly in western Europe and North America (61% [n=541452] male, mean recruitment age 46 [SD 11] years, median recruitment year 1979 [IQR 1975-85], meanBMI 25 [SD 4] kg/m(2)). The analyses were adjusted for age, sex, smoking status, and study. To limitreverse causality, the first 5 years of follow-up were excluded, leaving 66 552 deaths of known causeduring a mean of 8 (SD 6) further years of follow-up (mean age at death 67 [SD 10] years): 30 416vascular; 2070 diabetic, renal or hepatic; 22 592 neoplastic; 3770 respiratory; 7704 other. FINDINGS Inboth sexes, mortality was lowest at about 22.5-25 kg/m(2). Above this range, positive associations wererecorded for several specific causes and inverse associations for none, the absolute excess risks forhigher BMI and smoking were roughly additive, and each 5 kg/m(2) higher BMI was on averageassociated with about 30% higher overall mortality (hazard ratio per 5 kg/m(2) [HR] 1.29 [95% CI1.27-1.32]): 40% for vascular mortality (HR 1.41 [1.37-1.45]); 60-120% for diabetic, renal, and hepaticmortality (HRs 2.16 [1.89-2.46], 1.59 [1.27-1.99], and 1.82 [1.59-2.09], respectively); 10% forneoplastic mortality (HR 1.10 [1.06-1.15]); and 20% for respiratory and for all other mortality (HRs 1.20[1.07-1.34] and 1.20 [1.16-1.25], respectively). Below the range 22.5-25 kg/m(2), BMI was associatedinversely with overall mortality, mainly because of strong inverse associations with respiratory diseaseand lung cancer. These inverse associations were much stronger for smokers than for non-smokers,despite cigarette consumption per smoker varying little with BMI. INTERPRETATION Although otheranthropometric measures (eg, waist circumference, waist-to-hip ratio) could well add extra information toBMI, and BMI to them, BMI is in itself a strong predictor of overall mortality both above and below theapparent optimum of about 22.5-25 kg/m(2). The progressive excess mortality above this range is duemainly to vascular disease and is probably largely causal. At 30-35 kg/m(2), median survival is reducedby 2-4 years; at 40-45 kg/m(2), it is reduced by 8-10 years (which is comparable with the effects ofsmoking). The definite excess mortality below 22.5 kg/m(2) is due mainly to smoking-related diseases,and is not fully explained.", "metadata": {}}
+{"_id": "195689757", "title": "", "text": "Targeting metabolic remodeling in glioblastoma multiforme.A key aberrant biological difference betweentumor cells and normal differentiated cells is altered metabolism, whereby cancer cells acquire a numberof stable genetic and epigenetic alterations to retain proliferation, survive under unfavorablemicroenvironments and invade into surrounding tissues. A classic biochemical adaptation is the metabolicshift to aerobic glycolysis rather than mitochondrial oxidative phosphorylation, regardless of oxygenavailability, a phenomenon termed the \"Warburg Effect\". Aerobic glycolysis, characterized by highglucose uptake, low oxygen consumption and elevated production of lactate, is associated with a survivaladvantage as well as the generation of substrates such as fatty acids, amino acids and nucleotidesnecessary in rapidly proliferating cells. This review discusses the role of key metabolic enzymes and theirassociation with aerobic glycolysis in Glioblastoma Multiforme (GBM), an aggressive, highly glycolytic anddeadly brain tumor. Targeting key metabolic enzymes involved in modulating the \"Warburg Effect\" mayprovide a novel therapeutic approach either singularly or in combination with existing therapies in GBMs.", "metadata": {}}
+{"_id": "196664003", "title": "", "text": "Signaling architectures that transmit unidirectional information despite retroactivityA signaling pathwaytransmits information from an upstream system to downstream systems, ideally in a unidirectionalfashion. A key obstacle to unidirectional transmission is retroactivity, the additional reaction flux thataffects a system once its species interact with those of downstream systems. This raises the fundamentalquestion of whether signaling pathways have developed specialized architectures that overcomeretroactivity and transmit unidirectional signals. Here, we propose a general procedure based onmathematical analysis that provides an answer to this question. Using this procedure, we analyze theability of a variety of signaling architectures to transmit one-way (from upstream to downstream) signals,as key biological parameters are tuned. We find that single stage phosphorylation and phosphotransfersystems that transmit signals from a kinase show a stringent design trade-off that hampers their abilityto overcome retroactivity. Interestingly, cascades of these architectures, which are highly represented innature, can overcome this trade-off and thus enable unidirectional transmission. By contrast,phosphotransfer systems, and single and double phosphorylation cycles that transmit signals from asubstrate are unable to mitigate retroactivity effects, even when cascaded, and hence are not well suitedfor unidirectional information transmission. Our results identify signaling architectures that, allowingunidirectional transmission of signals, embody modular processes that conserve their input/outputbehavior across multiple contexts. These findings can be used to decompose natural signal transductionnetworks into modules, and, at the same time, they establish a library of devices that can be used insynthetic biology to facilitate modular circuit design.", "metadata": {}}
+{"_id": "198133135", "title": "", "text": "Association between pre-diabetes, type 2 diabetes and trabecular bone score: The Vietnam OsteoporosisStudy.AIMS Trabecular bone score (TBS) is a surrogate indicator of bone microarchitecture. Thepresenent study sought to examine the association between type 2 diabetes (T2D) and trabecular bonescore (TBS) in adult Vietnamese men and women. METHODS The study was part of the VietnamOsteoporosis Study, in which 2702 women and 1398 men aged ≥30 yrs were recruited from the generalcommunity in Ho Chi Minh City. HbA1c levels were measured by the ADAMS™ A1c HA-8160 (Arkray,Kyoto, Japan), and classified into 3 groups: normal if HbA1c <5.7%; pre-diabetes (5.7 to 6.4%); anddiabetes (>6.4%). TBS was evaluated by iNsight Software, version 2.1 (Medimaps, Merignac, France) onlumbar spine BMD scan (Hologic Horizon). Differences in TBS between diabetic status were analyzed bythe multivariable regression model with adjustment for age and body mass index. RESULTS Theprevalence of pre-diabetes and diabetes in men and women was 30.2% and 8.3%, respectively. Inwomen, TBS was lower in pre-diabetes (-0.02; P<0.001) and diabetes (-0.02; P<0.001) compared withnormal individuals. In men, there was no statistically significant difference in TBS between diabeticstatus. Moreover, TBS was significantly inversely correlated with HbA1c levels in women (P = 0.01), butnot in men (P = 0.89). CONCLUSION Women, but not men, with type 2 diabetes and pre-diabetes havelower TBS than individuals without diabetes. These data suggest that diabetes and prediabetes areassociated with deterioration of bone microarchitecture.", "metadata": {}}
+{"_id": "198309074", "title": "", "text": "Adhesion molecules and chemokines: relation to anthropometric, body composition, biochemical anddietary variablesIntroduction: Among the inflammatory mediators involved in the pathogenesis ofobesity, the cell adhesion molecules Pselectin, E-selectin, VCAM-1, ICAM-1 and the chemokine MCP-1stand out. They play a crucial role in adherence of cells to endothelial surfaces, in the integrity of thevascular wall and can be modulated by body composition and dietary pattern. Objectives: To describeand discuss the relation of these cell adhesion molecules and chemokines to anthropometric, bodycomposition, dietary and biochemical markers. Methods: Papers were located using scientific databasesby topic searches with no restriction on year of publication. Results: All molecules were associatedpositively with anthropometric markers, but controversial results were found for ICAM-1 and VCAM-1. Notonly obesity, but visceral fat is more strongly correlated with E-selectin and MCP-1 levels. Weight lossinfluences the reduction in the levels of these molecules, except VCAM-1. The distribution ofmacronutrients, excessive consumption of saturated and trans fat and a Western dietary pattern areassociated with increased levels. The opposite could be observed with supplementation of w-3 fatty acid,healthy dietary pattern, high calcium diet and high dairy intake. Regarding the biochemical parameters,they have inverse relation to HDLC and positive relation to total cholesterol, triglycerides, blood glucose,fasting insulin and insulin resistance. Conclusion: Normal anthropometric indicators, body composition,biochemical parameters and eating pattern positively modulate the subclinical inflammation that resultsfrom obesity by reducing the cell adhesion molecules and chemokines.", "metadata": {}}